CN1731996A - Methods and dosage forms for reducing heart attacks in a hypertensive individual with a diuretic or a diuretic and an ace inhibitor combination - Google Patents

Abstract

The present invention relates to methods and dosage forms for reducing and/or preventing the incidence of cardiovascular disease, including heart attacks, in individuals who are at risk, such as those individuals suffering from hypertension. The treatments and dosage forms of the present invention concern the administration of a diuretic, such as a thiazide diuretic like Thalitone(R), either alone or in combination with an ACE-inhibitor, such as ramipril or ramiprilat like Altace(R), to reduce and/or prevent the incidence of cardiovascular disease, namely, heart attacks or failure, in individuals who suffer from hypertension or are at risk.

Description

Alleviate the method and the dosage form of hypertension individual heart disease with the compositions of diuretic or diuretic and ACE inhibitor

The application requires the rights and interests of the U.S. Provisional Patent Application serial number 60/433,845 of December in 2002 submission on the 16th.

Invention field

The present invention relates to be used for alleviate and/or the prevention dangerous individual, as suffer from the method and the dosage form of cardiovascular disease such as the heart disease outbreak of hypertensive individuality.Treatment of the present invention and dosage form relate to uses a kind of diuretic, as thiazide diuretics such as Thalitone , described diuretic can use separately or with ramipril (ramipril) or ramiprilat ((ramiprilat, as Altace ) etc. ACE inhibitor co-administered, with the cardiovascular diseases of alleviation and/or prophylaxis of hypertension individuality or dangerous individual, i.e. heart disease or depleted outbreak.

Summary of the invention

Have been found that now, by giving individuality, especially the diuretic (such as thiazide diuretics such as chlortalidone) that has the individual effective dose of hypertension risk can reduce even eliminate its cardiovascular disease sickness rate of (comprising heart failure), described diuretic give separately or with angiotensin-convertion enzyme inhibitor (" ACE inhibitor "), thunderous rice Puli, ramiprilat are united and are given.When diuretic and ACE inhibitor were co-administered, single dosage form such as they can tablet, liquid, capsule sheet or capsule was used, or uses with isolating dosage form.Diuretic preferred for the present invention is thiophene ketone (thalidone), as Thalitone , its can with 15mg, 30mg, 45mg, 50mg, 60mg or the more single daily dose of volume use.ACE inhibitor preferred for the present invention is a ramipril, as Altace , its can with 1.25mg, 2.5mg, 5mg, 10mg or the more single daily dose of volume use.

Unexpectedly, have been found that now that diuretic is alleviated in dangerous individual or the therapeutic effect of eliminating the cardiovascular disease that comprises heart failure far above with beta-adrenergic blocking agent (as propranolol and atenolol), calcium channel blocker, ACE inhibitor (as lisinopril), vasodilation (as hydralazine), nervus centralis agonist (as oral clonidine or methyldopa), reserpine or α ₁This type of individuality of-blocker (as prazosin and doxazosin) treatment.More unexpectedly, the therapeutic effect of the combination of diuretic (as thiazide diuretics such as chlortalidone) and ACE inhibitor (as Altace ) is far above ought be only with diuretic or beta-adrenergic blocking agent (as propranolol and atenolol), calcium channel blocker, ACE inhibitor (as lisinopril), vasodilation (as hydralazine), nervus centralis agonist (as clonidine or methyldopa), reserpine or α ₁-blocker (as prazosin and doxazosin) obtains the individual treatment effect in this type of individuality.

Although the present invention has described embodiment preferred and embodiment in context, those technical staff that are proficient in this field obviously should be understood that can make it under the situation that does not deviate from spirit and scope of the invention and revise or variation.Therefore, the invention is not restricted to above-mentioned special description, and should limit scope of the present invention by additional claim to preferred embodiment and embodiment.

I. summarize

This method has been described a kind of based on randomized clinical trial practice, the antihypertensive pharmacological treatment, and a particular aspects, cholesterol reduces in 40,000 hypertension high-risk patients that comprise 55% non-descendants American (Black people) at least.The purpose of antihypertensive test is that whether variant between diuretic (chlortalidone) treatment and three kinds of antihypertensive-calcium antagonistss (amlodipine), ACE inhibitor (lisinopril) and adrenergic blocking drug-pharmacological treatment (NHLBI has tested the suggestion of doxazosin in acceptance termination on January 24th, 2000 antihypertensive, please refer to JAMA.2000 for the associating sickness rate that will determine mortality coronary heart disease (CHD) and non-lethal myocardial infarction; 283:1967-1975).Treat wind, the total incidence that reduces cardiovascular disease and the effect in mortality rate and the general mortality rate on the decrease in view of known antihypertensive, the antihypertensive test will not comprise placebo or untreated matched group.The purpose of cholesterol reducing test is will determine to compare with the matched group of accepting " effectively nursing ", accept the blood cholesterol levels moderate of 3-hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin too much, the age is the mortality rate whether the serum cholesterol level reduction of 55 years old or above masculinity and femininity will reduce all causes of the death.

Second purpose of these two kinds of tests is to compare the effect of their therapeutic schemes separately to cardiovascular disease mortality rate, main sickness rate, healthy cost and quality of life relevant with health.Second purpose of antihypertensive test be will more various treatments to the relevant main sickness rate of general mortality rate with hypertension (as the sickness rate of left ventricular hypertrophy and carrying out property renal insufficiency with disappear) effect.Also to organize in (age surpasses 65 years old, women, non-descendants American, type ii diabetes) and study of the effect of resisting hypertension scheme above-mentioned first and second results in key.Second purpose that body fat reduces test is that will to study HMG CoA reductase inhibitor be the long-term safety (especially when mentioning the mortality rate that non-cardiovascular disease causes) of 55 years old or above masculinity and femininity to the age, body fat reduces the effect to cancer morbidity and mortality rate, and body fat reduces combination sickness rate to mortality CHD and non-lethal myocardial infarction (especially surpass 65 at the age, the key group of women, non-descendants American, type ii diabetes in).Simultaneously, because this test is not a blindness, the generation of myocardial infarction (based on the variation of the concentrated coding of finding in the ECG research in 2 years) will be regarded as terminal point.Average experimental period, be expected to be 6.0 years, its scope from 4.2 years (for the whipper-in patient who enters) to 8 years (for the first place patient who enters).

For the statistics that makes the main hypothesis of antihypertensive test (promptly relatively each pharmaceutical admixtures of diuretic) is renderd a service (statistical power) maximum, patient's number of its diuretic arm will be 1.7 times (Table I .1) of its other three arm numbers.Estimating will have half to be randomized to either this two tests among the ALLHAT participant, and second half will only be randomized to either the antihypertensive test.

The design of Table I .1:ALLHAT

Cholesterol reduces test (2 arms)	Antihypertensive test (4 arms) *				Add up to
						Chlortalidone	Amlodipine	Lisinopril	Doxazosin *
	Pravastatin	3,655	2,115	2,115	2,115						10,000
Effectively nursing						3,655	2,115	2,115	2,115	10,000
	Ineligible	7,310	4,230	4,230	4,230						20,000
Add up to						14,620	8,460	8,460	8,460	40,000

^*NHLBI has accepted to stop the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975

Is unallowed owing to adding so many patients in the pattern of carrying out clinical trial in traditional clinic of employing independent management in cost, therefore this test will be adopted organized pattern, the patient is distributed in about 600 tame nursing main and hypertension medical institutions, clinic and health center, and wherein each place on average provides 67 patients.The clinical mechanism of Veterans Affairs (VA) hypertension comprises about 70 tame clinics, and they provide about 20% research patient.Form with minimum degree be retained, and need to use some not to be used to the clinical procedure of daily patient care.

II. background and principle

A. antihypertensive test

1) hypertension and coronary heart disease (CHD)

Estimate the U.S. have 5,000 ten thousand people suffer from hypertension (systolic pressure, SBP, 〉=140mmHg and/or diastolic pressure, DBP, 〉=90mmHg) or accept the antihypertensive Drug therapy.There are 2,000 3 million peoples to take antihypertensive [1] in nineteen eighty-three.In the U.S., be used for the treatment of hypertensive AC cost and estimate to reach 7,500,000,000 dollars [2] in 1986.Major part is used to buy medicine in these expenses, and in view of the patient's of needs treatments number, this will bring sizable economic problems.Suppose that all other factorses all remain unchanged, every cost on medicine in patient's every year is brought up to 500 dollars from 100 dollars, then treats the required expense of 2,000 5 hundred ten thousand patients and will rise to 10,000,000,000 dollars.

Although the etiology of known hypertension and CHD relation, being used to of in numerous middle aged patients, carrying out a large amount of randomized clinical trials of alleviating hypertension (DBP 90-114mmHg) can't prove that antihypertensive drug treats the generation that can reduce CHD death or non-lethal myocardial infarction.Mainly adopt thiazide diuretics and comprise that effective percentage is 9% in the overall result of the test that surpasses 43,000 experimenters at such 9, its confidence limit is 95%, this and 19% useful performance or 1% unfavorable performance consistent [3].Compare with the maximum predicted effect,, be about 23% from the viewed therapeutic effect of epidemic data to CHD to identical BP difference.On the contrary, the viewed in these trials beneficial effect to apoplexy is 36%, this and the prediction that is obtained by epidemic data almost consistent [4].Recently to the general introduction [5] of 14 tests comprising all hypertension levels estimate to have big effect (effective percentage 14%, confidence interval 95%, 4-22%).Because these general introductions are not included in the strong positive findings of the test of carrying out among the older experimenter, especially the systolic hypertension (SHEP) in the above the average age for marriage program, wherein making the apoplexy sickness rate reduce by 36% based on the treatment of diuretic makes the sickness rate of main CHD incident reduce by 27% (confidence interval 95% simultaneously, 4-43%), over-evaluated effective percentage [6] so have reason to suspect this.

An explanation that is used for proving the former test failure that the CHD of expected degree alleviates is that the medicine of being studied the especially ill effect of diuretic may be offset the potential effect that brings high blood pressure down.These ill effects comprise that hypokalemia, hypomagnesemia, hyperuricemia, hyperlipemia, hyperglycemia, insulin sensitivity that diuretic causes are impaired and ventricular ectopy is active may increase [6,7].Estimating that T-CHOL that diuretic causes raises is about 4%, and in the LDL cholesterol up to 10%[7], although long-term treatment can weaken this effect [5].This class blood fat rising will be enough to (if not persistence) counteracting blood pressure and be reduced to the benefit that CHD brings.

2) antihypertensive of new kind

Developed new antihypertensive-calcium antagonists and angiotensin converting enzyme (ACE) inhibitor of two classes in early days in the eighties, and they are approved for chronic antihypertensive treatment.These medicaments are much more expensive than conventional medicament such as diuretic and beta blocker, but except expense increases, their effect also limited (as bigger effect or less side effect) [2].The 4th national hypertension detects, evaluates and the treatment (JNC of joint committee, Joint National Committee on Detection, Evaluation, andTreatment of High Blood Pressure) recommend beta blocker, calcium antagonists, ACE inhibitor and diuretic as equal acceptable first-selected treatment [9].50% or more mild hypertension patients in find that all use all may command diastolic pressures of this four classes medicine separately.The 5th JNC report [10] has been rethought the selection of first-selected medicine and has been recommended diuretic and beta blocker as preferred agents.In addition, JNC-V added the alpha-1 adrenergic blocker and have α simultaneously and the medicine of β blocking effect as first-selected medicine.

In these medicament categories, on a large scale long-term hypertension clinical trial, only beta blocker and diuretic have been carried out direct comparison.It is roughly the same to the influence of M ﹠ M in three this tests that 1985-86 finishes in Europe are presented at based on the therapeutic scheme of diuretic and beta blocker.These test analysis-by-synthesiies are shown that the CHD mortality rate of beta blocker is lower, are 6% (confidence interval 95% ,-10%--+22%) [11].These data and the nearest (MRC of medical research committee, Medical ResearchCouncil) test of carrying out in older patient is opposite, wherein, compare (all being about 45%) with patient, lead obviously lower with the patient's of thiazide diuretic treatment CHD with beta blocker (atenolol) or placebo treatment.

Other data show, calcium blockers can suppress the development of the atherosis damage of rabbit model medium-sized artery, but the test data of M ﹠ M is inconsistent.A diltiazem that carries out in the MI patient of back is tested and has not been shown in having the patient who hangs down ejection fraction to have effect, but the conclusion that all back MI that comprehensively carry out with calcium blockers test is found mortality rate rising 6% (4%--+18%) [12].The new conclusion that is included in other three tests of carrying out among angina pectoris or the myocardial infarction patient has shown the better result of these medicaments, promptly compares it with the dihydropyridine calcium blockers and can reduce heart rate [13].Other test of carrying out in the hyperpietic shows with calcium blockers treatment back left ventricular mass minimizing [14].

In ACE inhibitor, have at least three kinds to it is reported and to alleviate left ventricular hypertrophy [15] in 7 kinds of licensed-in medicines.ACE inhibitor has reduced the mortality rate [16] of serious and slight heart failure simultaneously, has reduced the sickness rate of asymptomatic left ventricular dysfunction simultaneously, comprising CHD[17].Mention that to atherosclerotic effect Chobanian and colleague thereof have reported and prevent coronary heart disease damage [18] that in the Watanabe rabbit model this may be owing to the cel l proliferation to blood vessel wall causes.

More known alpha block agent are to fat, and especially the LDL cholesterol has good effect [19,20].Some researchs have found that also insulin resistance improves [21,22], and this discovery is especially relevant with the type ii diabetes patient.Show on evidence that also these medicaments can alleviate left ventricular hypertrophy and hematoblastic ability of aggregation, and stimulate tissue plasminogen activator [23-27].

Have only two long-term random experiments to compare the representative medicine of all these drug types: the research (TOMHS) [19] of the test of antihypertensive being carried out by VA joint study group in 1 year by a definite date [28] and the slight hypertension therapeutic in 4.4 years by a definite date.Although some differences of the variation of BP control, side effect, quality of life, biochemical action and target organ have been reported in these tests, these differences are not enough to become the good and bad evidence of other medicines of some medicines.

By the data show that the big quantity research that carries out in human and animal's model obtains, new medicine is better than, equals or be worse than standard drug when treatment hypertension.A report of Britain hypertension association (BritishHypertension Society) claims: " therefore we can reach a conclusion; beta blocker or diuretic all are acceptable first-selected medicines ... unfortunately ... new antihypertensive is not also adopted in test on a large scale, as calcium antagonists and angiotensin-convertion enzyme inhibitor.Therefore the comparing data that does not have these widely used medicines, and we press for large-scale comparative test and know the effect of these medicaments [29]." the American Studies person has also drawn similar conclusion [30-32].

3) importance of comparison antihypertensive in non-descendants American

Than white people, hypertension is more common in non-descendants American, and its sequela is frequent more and serious.In the National Health and Nutrition Examination Surveys second time (NHANES II), hypertensive prevalence is 51% in the 25-74 non-descendants American in year, and white people only are 40%[33].The sickness rate of the latter stage nephropathy that takes place after non-descendants American's relaying hypertension is almost than suffering from hypertensive white people high 8 times [34].It is reported to suffer from hypertensive non-descendants American's left ventricular hypertrophy, apoplexy and apoplexy and dead risk is also bigger.Explanation for these differences has, and the prevalence of coexistence disease such as diabetes in non-descendants American is higher, and the medical treatment and nursing that they accept is less.

Suppose that treatment can effectively reduce the M ﹠ M of hypertension related cardiovascular disease, the risk that the colony that then accepts less nursing suffers from these complication will disproportionately raise.In these people, the lower people of those socioeconomic statuss (SES) especially, the expense of Drug therapy has become them to select and keep the Consideration of treatment most critical.Therefore, the trend of the medicine that present this use is expensive more more may become the obstacle of low SES mass treatment, and they artificially represent with the non-descendants U.S., but not that descendants American suffers from the probability of hypertension relevant disease is bigger.If the effect of medicine aspect the prophylaxis of hypertension complication that diuretic etc. are more cheap is identical with other existing medicine, then the non-descendants American of low SES then more may benefit from it.If more cheap efficacy of drugs a little less than, the non-descendants American of then low SES more this result may occur, because they trend towards accepting more cheap medicine or not use medicine.In either case, suppose that non-descendants American lacks clinical treatment information relatively, they should account in test larger proportion, and result of the test just can be directly used in them like this.For those reasons, at least 55% non-descendants American is arranged among this test crowd.

B. cholesterol reduces test

1) cholesterol and coronary heart disease

In human and selected animal model, set up cholesterol by observation epidemiological study, metabolism, pathology and genetics research and by randomized clinical trial, the cyclical level of especially relevant with low density lipoprotein, LDL (LDL) component cholesterol, this level are that coronary heart disease (CHD) is that main diseases is because of [35].Mainly prove that the LDL-cholesterol levels reduces will make the CHD sickness rate reduce [36-41] suffering from hypercholesterolemia or set up the clinical trial of carrying out in the middle-aged male of CHD.The experimental evidence that cholesterol is reduced in the effect in the elderly men only limits to analyze less clinical experiment group, lacks the women's at any age experimental evidence simultaneously.Because clinical data is few, the early stage policy that NCEP (NCEP, National CholesterolEducation Program) makes expert group propose in 1987 according to them at " aspect detection, evaluation and treatment adult blood hypercholesterolemia " is judged provides greater room [42].

The uncertainty that the policy of NCEP is used for elderly men and women is the considerable result of public health.Myocardial infarction can cause the tragedy influence to the life of middle age and the productivity, but all are died among the people of CHD and are arranged above 65 years old [43] 80% above age in the U.S..The women surpasses 60% in all over-65s populations, and CHD mainly occurs on one's body the women in this age group.In 1989, CHD caused almost 400,000 people's death, and annual direct health care cost is 14,400,000,000 dollars in this age group.Along with the growth at people's age " birth peak " this generation and life-span increase the age distribution that has changed U.S. population, estimate that in following 40 years these data also will rise.

Although cholesterol levels raise with CHD between the evidence that concerns be strong and consistent, clinical trial [44,45] does not prove also that cholesterol reduces and can reduce general mortality rate.In addition, observational study [46] has shown the U-shaped relation between cholesterol and the mortality rate, and promptly the cholesterol levels mortality rate that is lower than 160mg/dl and is higher than the people of 240mg/dl is higher than the people of cholesterol levels between 160-240mg/dl.In the minimum people of cholesterol levels, hemorrhagic apoplexy, some cancer and breathing and digestive disease are murderous other reasons [46].In addition, in the PPT at random that carries out in hypercholesterolemiapatients patients, because the wound related mortality raises, medium (drug-induced) cholesterol levels reduces the CHD mortality rate reduction that causes and is cancelled [44].Although observe some gratifying test back trend, do not render a service and design the general mortality rate [45,47] of these tests to draw the treatment phase with suitable statistics.Also need how more effective clinical trial to prove this result.

2) old people and the American cholesterol of non-descendants

Although the observable clinical test results that studies show that is applicable to the lower male of cholesterol levels, and be applicable to the women, the predictive ability of cholesterol levels increases with the age and reduces [48-51] in these researchs.Analysis-by-synthesis to 21 male and 13 women shows, when the age during at over-65s the CHD risk reduce relevant with lower blood cholesterol levels, although consider the parameter in the research, the significance,statistical below 65 years old among the male may be 60%[50 at least].Yet obviously reducing of this relative risk relevant with aging may be than simultaneously because the compensation height [51] that CHD absolute sickness rate increase dead and myocardial infarction brings.Therefore in the old people, can not ignore the publilc health value that potential cholesterol levels reduces.This unanswered problem is, when what degree is reality when the relatively large age begins the treatment of cholesterol reducing can stop with these " contributive " CHD incident.

Although compare with the non-population of ethnic minorities, the American LDL-cholesterol levels of non-descendants is lower and the HDL-cholesterol levels is higher, and hypercholesterolemia is the American subject matter of right and wrong descendants still, especially in the women who suffers from obesity and diabetes.At 1976-80, the serum cholesterol level of the non-descendants U.S. masculinity and femininity in nearly 23% 25-74 year is for high-risk status [33], and the cholesterol reducing level estimates to reduce mortality rate and the sickness rate of CHD in these people.Above-mentioned cholesterol reduces test and only comprises the non-descendants American experimenter of minority.So the hypothesis that reduction will make non-descendants American and white man's CHD produce similar reduction about cholesterol levels is also not to be confirmed.

3) in elderly men and women, use HMG CoA reductase inhibitor

Because the effect of used medicine and acceptable limited, many previous cogencys of the clinical trial of cholesterol reducing in middle-aged male are weakened.Yet, since in JIUYUE, 1987 lovastatin (first kind of HMG CoA reductase inhibitor) by after the FDA approval, it is used more and more widely, and it all is effectively in the patient of institute's has age and can obtains good tolerance [52-55].Two little angiography tests confirm that lovastatin has good result [56,57] to coronary atherosclerosis.Other two kinds of HMG CoA reductase inhibitor pravastatins and simvastatin are also ratified by FDA late period in 1991; They also all are used the several years in other country.FDA is considering to ratify the 4th kind of HMG CoA reductase inhibitor now: fluvastatin.

Seldom observe these medicines up to now and have side effect.Bad crystalline lens do not occur in the research report of nineteen ninety EXCEL to lovastatin and change [55], this impels FDA to remove from Product labelling and carries out the requirement that slit lamp (slit lamp) is checked every year.In the patient who accepts these medicines of 1-2%, observe the remarkable but reversible asymptomatic rising of serum transaminase level.It is reported, the serious adverse of HMG CoA reductase inhibitor is a myositis, under rare occasion, also can develop into rhabdomyolysis and renal failure, and use other potential cytotoxicity (myotoxic) medicine (immunosuppressant, fibrate etc.) and impaired renal function will strengthen this result simultaneously.Yet the sickness rate of myositis is very not low when having these factors, and can be apparently higher than the sickness rate of placebo when low dosage.Although HMG CoA reductase inhibitor can be strengthened the effect of anticoagulant, also be not reported in and use antihypertensive can produce tangible clinical response among the ALLHAT.

In a word because their effect, be easy to use, toxicity is low and all have the compatibility with most of other medicines, as if HMG CoA reductase inhibitor is fit to elderly men and women very much to be used.They also expand us to the existing resulting cholesterol levels of large-scale clinical trial and reduction degree about the benefit of cholesterol reducing and the understanding of safety.

(old people's cholesterol reduces plan (CRISP to a two-year preliminary study about cholesterol reducing of carrying out in the old people, Cholesterol Reduction in Seniors Program)) start from July nineteen ninety, carry out 5 clinical center.Although it has adopted traditional test model, promptly based on the medical institutions that subsidized rather than the pattern of raising based on the clinic of this test, this preliminary study has confirmed to reduce the feasibility [58] of replenishing the old people in the test at cholesterol.In this preliminary study, raise 431 masculinity and femininities of 65 years old altogether, surpassed the target of in 10 months, raising 400 experimenters.The cohort of this preliminary study (women accounts for 72%, and wherein ethnic groups accounts for 25%) is since in June, 1992, compares compliance, safety and the effect of placebo with two kinds of discrete dosages schemes of lovastatin relatively (every day 20mg with 40mg).These two kinds of dosage all can be tolerated well, are 85-90% at the compliance of treatment after 1 year.Reduce the result who slightly exceeds 20mg dosage (24%) of (28%) with the average LDL of 40mg dosage acquisition.To 20mg and 40mg dosage also (difference) observe a small amount of increase (7% and 9%) of HDL cholesterol and the reduction (4% and 10%) of triglyceride.

III. suppose and the research ability

A. antihypertensive test portion

First hypothesis of this test is: accepting (1) calcium antagonists (amlodipine), (2) ACE inhibitor (lisinopril), or (3) alpha-1 adrenergic blocker ((NHLBI accept to have stopped the suggestion of antihypertensive test doxazosin arm to doxazosin on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975) among the hyperpietic as first-selected treatment, the associating sickness rate of mortality CHD and non-lethal myocardial infarction will be lower than the contrast of the similar blood pressure degree that adopts the first-selected treatment of thiazide diuretic (chlortalidone) conduct.Will be in age these hypothesis of checking in 55 years old or above masculinity and femininity crowd, except that hypertension, these people have at least a CHD risks and assumptions, and wherein have 55% at least with right and wrong descendants American.Based on following assumed conditions, verify that the statistics effectiveness of these hypothesis is about 82.5%:

1) sample size is 40,000 (about 22,000 male and 18,000 women), is distributed in four treatment groups, shown in Table I .1.

2) sickness rate in 6 years of CHD incident is 7.8% in the diuretic group.This ratio (annual 1.35%) is based on the test of Framingham and HDFP (reduce 33-50% with time trend and with healthy volunteer's effect downward modulation 25%), and with recently in SHEP observed ratio similar.

3) compare with the diuretic arm, the CHD incident rate of each all reduces by 20% (before proofreading and correct non-compliance and following up a case by regular visits to loss, these two factors make effective percentage reduce by 16.3% together) in three non-diuretic therapy arms.

4) adopt time-dependent Markov model, estimates that every kind of other intersection ratio of studying between medicine and chlortalidone and/or the non-research medicine is that be 2.75% 3 year every year, and be 6% (based on TOMHS) at back 3 years that follow up a case by regular visits to.The probability of intersecting in the research is at least once estimated to be about 24%.(conservative) estimates that CHD risk and the chlortalidone relevant with non-research medicine are the same.

5) when research finishes, because competitive risk (non-CHD death) or follow up a case by regular visits to loss, there is patient's (8.6% people is arranged every year) of 16.8% CHD state can't determine that this is based on the data of Framingham and HDFP (seeing appendix I).

6) randomly draw at 10,000 and carry out cholesterol and reduce that the CHD incident rate has lowered 25% (before proofreading and correct non-compliance and following up a case by regular visits to loss) among the patient of active treatment arm of test.

7) I type error=0.05 (two aspects).This is 2.37 consistent with multiple comparisons being proofreaied and correct the critical Z value in back.

The intersection (#4) and (#5) rate of loss are carried out more pessimistic or optimistic estimation expectation statistics effectiveness between 77--86%.In appendix I relevant for other details of these calculating.

To estimate that also (NHLBI has accepted to stop the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000 about accepting amlodipine, lisinopril or doxazosin at random; Second of the effect hypothesis behind patient's 283:1967-1975) (accepting the patient of chlortalidone) the terminal point: (1) general mortality rate with respect to those, (2) combination coronary heart disease (angina pectoris of CHD+ revascularization procedure+hospitalization), (3) apoplexy, (4) combination cardiovascular disease (CHD+ apoplexy+revascularization procedure+angina pectoris [be in hospital or treatment]+CHF[is in hospital or treatment]+peripheral arterial disease [being in hospital or the outpatient service revascularization procedure]), (5) left ventricular hypertrophy that causes of ECG, (6) nephropathy (comprising that serum creatinine tilts alternately) and latter stage nephropathy (dialysis or transplanting), (7) health-related quality of life, (8) fatal and nonfatal cancer, and (9) gastrointestinal hemorrhage.

B. cholesterol reduces test portion: (square method appendix 1)

First hypothesis of this test is: the above-mentioned LDL cholesterol levels of accepting pravastatin and cholesterol reducing diet in random assortment is in the hyperpietic of (patient who has suffered from CHD is between 100-129mg/dl) between the 120-189mg/dl, and the mortality rate of all causes of the death will be lower than the patient that routine care is accepted in those random assortment.Based on following assumed conditions, verify that the statistics effectiveness of these hypothesis is about 80%:

1) sample size is 20,000 (about 11,000 male and 9,000 women), mean allocation between pravastatin and routine care group.

2) 6 of the conventional therapy group years total incidences are that 13.2% (annual 2.35%) is (based on the data (seeing appendix I) of Framingham, HDFP and SHEP.Based on the mortality rate data of electing to high-risk group of the SHEP participant that compares with ALLHAT patient, estimation will have 40% to die from CHD, and 16% dies from other cardiovascular reason, and has 44% to die from the non-cardiovascular reason.

3) mortality rate of pravastatin treatment arm reduces by 12.5%.This prediction reduces by 25% and the mortality rate of other cardiovascular disease reduces by 15% based on the CHD mortality rate, and the hypothesis that do not exert an influence of murderous other reason.To make the LDL cholesterol levels reduce by 30% if suppose pharmaceutical admixtures cooperated fully, and the average LDL cholesterol levels during beginning is 155mg/dl (scope is 120-189mg/dl), then CHD reduces by 25%, is 0.0062 with respect to the logistic regression coefficient.For comparing, in 356,222 MRFIT (male), T-CHOL is 0.0118 to the logistic regression coefficient of CHD mortality rate in the group (35-57 year) of all the ranges of age, and in 36,704 male in oldest group (55-57 year), be 0.0086.From MRFIT data extrapolation prompting, the coefficient of T-CHOL CHD and CHD may be between 0.005 and 0.006 among the ALLHAT.

4) " withdrawing from " rate (from pravastatin to not receiving treatment) was 5% in 1 year, and all times all are 2.5% subsequently, and " adding " rate (never receive treatment to and accept pravastatin or similar medicine) every year is 2%.Estimate that these ratios will cause having 15.3% patient who accepts pravastatin to withdraw from treatment in the 6th year and having 10.6% the patient who accepts routine care to add treatment.Notice that cholesterol reduces that effectiveness-this test of test (unlike the antihypertensive test) pays close attention to be cholesterol reduce this effect-not because of weakening for other scheme that produces same lipid variation of effect rather than certain drug or drug categories from pravastatin " conversion ".

5) there is not the loss of tracking.

6) mortality rate of each arm has reduced by 10% in three non-diuretic therapy arms of antihypertensive test.

7) I type error=0.05 (two aspects), this is 1.96 consistent with critical Z value.

Also calculated to the effect (2.2-2.5%) of annual death rate scope with to the effect of worse group of compliance (when finishing in the 6th year withdraw from and the adding rate is respectively 17.8% and 12.9%).Estimate that these hypothesis statistics effectiveness down (sees appendix I) between 75-82%.

Second hypothesis relates to the reduction of patient's (accepting the patient of routine care with respect to those) behind terminal point of determining to accept at random pravastatin: the associating sickness rate of (1) CHD death and non-lethal myocardial infarction, especially in some subgroup, surpass 65 (original CRISP hypothesis), type ii diabetes and women etc. as non-descendants American, age, (2) in the variation of two-year ECG research center muscle infarction sickness rate, (3) mortality rate that causes of specific reasons, the sickness rate of cancer morbidity that (4) are total and site specific cancer; And (5) health-related quality of life.

The research effectiveness of the effect of the associating sickness rate of research pravastatin and non-lethal myocardial infarction dead to CHD is estimated as 97%, in any subgroup that comprises 10,000 patients near 80% (seeing appendix 1).Yet the treatment doctor does not also know that their patient has accepted pravastatin or routine care, and this will influence the objectivity of the clinical diagnosis of non-lethal myocardial infarction.For preventing this deviation, also will assess the sickness rate of non-lethal myocardial infarction according to the variation of two-year ECG research, will be to its evaluation by not knowing that the personnel that patient treatment distributes carry out.Similar qualitatively difference confirms just can confirm the difference between pravastatin-routine care in the clinical events when only obtaining the ECG terminal point.

IV. qualified and get rid of

A. antihypertensive test

1. age/gender: 55 years old or above masculinity and femininity.

2. medical history: the history of hypertension that the case record is arranged.

3. seat blood pressure:

The seat blood pressure that records based on the present therapeutic state of patient with when twice visit is selected (Table IV .1):

(a) it is qualified using the bimestrial at least patient of one or both antihypertensives, and this patient's blood pressure is gathered (most of blood pressure measurement≤160/100mmHg).Accept inferior therapeutic dose and be or three kinds of invalid combination or the patient of multiple antihypertensive and the patient that sensation might be controlled in the ALLHAT scheme agree to enter test through main researcher or his/her designee.

(b), must at first set up hypertensive diagnosis for the patient who does not receive treatment.(comprising JNC V standard in the workbook) about hypertension diagnosis.Treatment or treatment must not run into minimum and the maximal blood pressure standard less than bimestrial patient, shown in Table IV .1.For having the qualification of the test of entering, the lower limit of SBP or DBP and the two the upper limit must take place in two occasions that separate a day at least.For in visit 1 or visit the patient who did not reach the standard of entering at 2 o'clock and can reappraise its blood pressure later.

Table IV .1. blood pressure choice criteria

The state of visit 1 and visit 2		Lower limit 1(mmHg)		The upper limit 2(mmHg)
								?SBP	?DBP	?SBP	?DBP
Based on the hypertension agents that uses 〉=2 months	Visit 1 visit 2	?--- ?---	?--- ?---	?160 ?180	?100 ?110
						Based on using＜2 months medicine or not treatment at present	Visit	1 and visit 2	?140	?90	?180	?110
1SBP or DBP lower limit must run in visit 1 and visit in 2 o'clock 2The SBP or the DBP upper limit must run in visit 1 and visit in 2 o'clock

4. be one of following at least:

A. one or more in the following atherosclerosis cardiovascular disease performance:

(i) old people or the myocardial infarction or the apoplexy (＞6 months) at unknown age,

The (ii) history of revascularization procedure (medical history),

The (iii) atherosclerotic cardiovascular disease of case record.This includes but not limited to: can be by coronary vasodilator, peripheral blood vessel, aorta or the carotid artery stenosis of angiography proof, and Doppler's research or the arm index that reduces; Can be by the ischemic heart desease (for example variation of ST-T-ripple) of electrocardiogram proof, ultrasonicly electronicly retouch the meter art, or the reflexive radio nuclide imaging; The intermittent claudication history; Or transient ischemic attack history.(provided the more complete tabulation of the performance of atherosclerotic cardiovascular disease in the workbook.)

B.II type diabetes [plasma glucose＞140m/dl is not (fasting) or 200mg/dl (not fasting) and/or accepts insulin or oral hypoglycemic] (in the past in 2 years),

C.HDL-cholesterol＜35mg/dl (any twice measurement in 5 years in the past)

D. left ventricular hypertrophy among any ECG in 2 years one of (following) in the past:

V 5Or V 6R amplitude＞26mm V 5Or V 6R amplitude+V 1The R amplitude that the R amplitude＞12mm I leads＞15mm II of S amplitude＞35mm VL or R amplitude+V that the S amplitude＞25mm VL leads of leading of R amplitude+III that the R amplitude＞20mm I leads of leading of III or VF3S amplitude male＞28mm, the LVH of the computerized ECG instrument of women＞22mm record
	For making the LVH reading as seen, measure lead in the QRS amplitude of complete normal heart beating once to the end for the second time.

E. left ventricular hypertrophy (2 years in the past) on any ultrasoundcardiogram is based on 25mm or thicker combination wall (the ventricle barrier film adds rear wall) thickness.

F. smoke now (smoking in 30 days in the past).

5. get rid of:

A. pass by to suffer from symptomatic MI or apoplexy in 6 months.

B. be in hospital or symptomatic congestive heart failure and/or ejection fraction＜35%, if know through treating.

C. pass by angina pectoris in 6 months.(this is meant actual chest pain.If the patient has the angina history and do not have the chest pain history,, he prevents that the history of angina drug from also needn't foreclose even if having to use.See and get rid of 5e.)

D. known have a renal insufficiency (serum creatinine 〉=2mg/dl).

E. the patient is owing to the reason beyond the hypertension need be used diuretic, calcium antagonists, ACE inhibitor or alpha-1 adrenergic blocker.(if the patient uses calcium channel blocker because of angina, if safety he can use beta blocker instead and treat this disease.So just will not its eliminating.)

F. the two or more antihypertensive drug of needs of patients comes stabilizing blood pressure (SBP≤160mmHg, DBP≤100mmHg).Use three kinds or multiple inferior therapeutic dose or invalid patient, and the patient that sensation might be controlled agrees to enter test through main researcher or his/her designee in the ALLHAT scheme from the antihypertensive drug that makes up.See IV A 3 (a).

G. to any main research medicaments insensitive or contraindication is arranged.

H. the low factor of probability of therapeutic scheme is complied with in explanation; Such as dull-witted, ethanol or drug dependence history arranged in 6 months in the past, plan removal of home or tourism on a large scale or the history of not abideing by indication or accepting the regulation medicine is arranged.

The disease that i. may cause non-cardiovascular disease death during studying is as the malignant tumor that can not cure.

J. the systolic pressure of twice independent measurement surpasses 180mmHg during treating with antihypertensive, or diastolic pressure surpasses 110mmHg.

K. participate in other clinical trial at present

B. cholesterol reduces test

1. eligible and participation antihypertensive is tested.

2. fasting LDL cholesterol: 120-189mg/dl (the known patient who suffers from CHD is 100-129mg/dl).These separations, be equivalent to male and 25-85% ALLHAT the range of age in the women of about 30-90% in ALLHAT the range of age, probably account for ALLHAT participant's 60% (24,000), through staying wherein 20,000 after refusal and other eliminating.

3. the fasting triglyceride levels is lower than 350mg/dl.

4. other eliminating:

A. use lipid lowerers or heavy dose (500mg/ days) OTC (over-the-counter) nicotinic acid at present.Must stop using lipid lowerers two months of qualified patient, and when back-call, stop with probucol more than 1 year.

B. to the contraindication of HMG CoA reductase inhibitor (for example significantly hepatopathy, accept immune known treatment, known research medicine had allergy or do not tolerate).

C. known have untreated other reason (for example hypothyroidism, nephrotic syndrome) that causes hyperlipemia.

D.ALT exceeds 2 times than upper limits of normal.

V. raise

The main dependence case history of raising of ALLHAT is followed the trail of (Chart Review) to determine whether the patient meets the condition of antihypertensive test or these two tests.To before a series of, obtain to make the required data of final decision that whether meet the antihypertensive test in (pre-randomization) visit at random, be no more than two months usually during this period of time.The number of these visits and frequency depend on that the patient studies complexity, the reducible blood pressure of this scheme and the patient of preceding scheme adaptability and the interest to cholesterol reduction test.Whether cholesterol is carried out in random assortment is reduced test owing to have only the patient who is carried out antihypertensive test by random assortment just to be considered, thus up to the antihypertensive test for the first time behind the random access (4 week) consider that just random assortment carries out a back test.The step of definite ALLHAT candidate's various groupings and random assortment in one or two research is described below.

Case history is followed the trail of:

In each clinic, the patient may be fit to the antihypertensive part of ALLHAT, and these patients' subgroup may also meet the requirement that the ALLHAT cholesterol reduces test portion, and this can follow the trail of to determine by case history.Should follow the trail of the diet of the treatment of blood pressure and antihypertensive, LDL cholesterol levels (if perhaps can't obtain LDL then can with reference to total cholesterol levels) and cholesterol reducing and/or medicine, other relevant medical history and patient's reliability and they to former predetermined treatment and compliance, to determine whether to meet study condition (IV chapter) before studying him beginning visit.

A. antihypertensive test portion

Visit 1: determine adaptability and interest earlier

Visit 1 purpose be to obtain to the adaptability of ALLHAT and to it interest and begin to make the patient to stop using any existing antihypertensive drug.Can estimate to follow the trail of by case history and differentiate most of hyperpietic, and will understand patient's most information (quantity of age, risk factor state, antihypertensive drug etc.) through treatment.The researcher finishes one page questionnaire to write down preliminary the comprising and exclusion standard (IV chapter) that all have run into needs.Case history follow the trail of can not obtain or any file in 2 years unavailable past (expression exist ECG, the diabetes of left ventricular hypertrophy fasting blood glucose level, show T-CHOL (TC) level of lipid standard), or diagnosed out the patient of HDL in the past in 5 years for twice, a part and this research that will be considered to the conventional medical supervision of patient can not repay especially.

Visit 1 will mainly comprise and obtain the first registration blood pressure, answers the patient about the problem of research and if necessary obtain the permission that the patient begins to study by the pre-research of antihypertensive.To comprise the suggestion of reclaiming antihypertensive below.If can change patient's antihypertensive safely then the participant can directly enter visit 2.Visit 1 and 2 can be separated 1 day at least, but needn't carry out continuously.

For the patient who does not receive treatment, must set up according to JNC V standard hypertensive diagnosis.In case finish this step, the patient of those SBP 〉=140mmHg and/or DBP 〉=90mmHg and those SBP and DBP be no more than respectively 180 and patient's (seeing Table IV.1) of 110mmHg also can enter ALLHAT.For going to the clinic just to be found the new patient of hypertension for the first time, can be used as the visit 1 of ALLHAT in this initial visit, determine to carry out any other evaluation (not using any research cost) that institute needs as long as carried out.From pre-research pharmaceutical admixtures, get rid of the blood pressure lowering process and can simplify this patient process subsequently.

The blood pressure lowering visit:

The not all patient who accepts the antihypertensive treatment needs the blood pressure lowering visit.Usually, directly drug withdrawal of the antihypertensive of following type:

1. diuretic: then he need get in touch with the doctor if the patient significant edema occurs and/or obviously feels dyspnea (rapid breathing, at night or when motion).

2. reserpine.

3. angiotensin converting enzyme (ACE) inhibitor.

4. calcium channel blocker.

5. vasodilator (for example hydralazine).

6. α ₁-blocker (for example prazosin).

If the medicine of the dose that the patient takes following kind during greater than conventional initial dose needs drug withdrawal gradually:

1. nervus centralis agonist (for example, oral clonidine or methyldopa)-withdrawal time is 1-2 week

2. beta-adrenergic blocking agent (for example, Propranolol or atenolol)-withdrawal time is more than 2 weeks

The back myocardial infarction patient who accepts beta blocker for prevention needn't stop treatment.This situation is also arranged once in a while, promptly, preferably closely monitor or long-term drug withdrawal according to doctor's judgement.Need special nursing when in other suffers from the patient of cardiovascular disease, stopping using antihypertensive.

Systolic pressure surpasses patient that 180mmHg or diastolic pressure the surpass 110mmHg blood pressure of should resurveying in several days.If blood pressure still is higher than 180/110, then this patient can not carry out the antihypertensive test.

Visit 2: randomisation process:

Satisfy all standards of ALLHAT and through the patient of researcher authorization can stop using safely before all antihypertensive drug and be randomized to either in one of four ALLHAT treatment arms, obtain just can entering after their agreement and visit 2 research.Current visit is carried out in 1 back 1 day-12 week of visit usually, and this depends on the bring high blood pressure down length of required time of pre-research treatment.Initial refuse to obey with medicine or with a kind of medicine just well the patient of controlling blood pressure in visit 1 back by random assortment, and other patient needed the blood pressure lowering process (being less than 3 months usually) than length before finishing visit 2.Longer blood pressure lowering process is prevented from (although not forbidding), and this is because many also more difficult simple proposal that keep in test of patient that can not stop their pre-research process immediately.

Researcher will with the clinic test center telephone contact to understand situation that each satisfies the patient of visit 2 all adaptability requirements, comprise the letter of commitment (consent form) of signing.Clinic test center will check adaptability and number for this patient distributes a research numbering and a medicine bottle, this medicine bottle numbering and (1) chlortalidone, (2) amlodipine, (3) lisinopril, or (4) doxazosin (NHLBI accept to have stopped the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975) correspondence.Researcher and patient do not know the distribution condition for the treatment of.In current visit, will obtain the patient's of every random assortment tranquillization ECG, serum glucose, serum potassium and creatinine, fasting lipid profile and ALT.The patient of each random assortment will provide him the initial dose to appointment research medicine, and will return first dosage level (visit 3) (referring to the VI part) after 4 weeks.

The patient of all random assortment will obtain suitable health suggestion (if restriction sodium and ethanol, stop smoking, the overweight limit caloric of exercise), and this is needed in the process of the test.

B. cholesterol reduces test portion

Visit 1: to the initial mensuration of adaptability and interest

Satisfying visit 1 requires (seeing above) about all adaptabilities of antihypertensive test portion and/or agrees that the patient who begins to bring high blood pressure down from pre-research antihypertensive also should be apprised of the cholesterol reducing test portion that carries out ALLHAT.Those have interest and will be as the potential candidate of this test in visit 1 the first two months lipid lowerers (comprise and take in be above standard 500mg or more nicotinic acid every day) to this test portion.The patient who took probucol before visit 1 in 1 year does not meet the requirement of ALLHAT to this part.

Visit 2: measure fasting LDL (being assigned randomly to the antihypertensive test portion)

To obtain following patient's FastingLipid content (T-CHOL, triglyceride, HDL-cholesterol, the LDL-cholesterol that calculates) and Serum ALT: conformance with standard also is randomized to either the patient of ALLHAT antihypertensive test portion.The patient of fasting at least 9 hours (best 12 hours) will not remeasure in 2 one weeks of back of visit.Remeasure the fasting lipid if desired, then this will be considered to visit a part of 2.

Visit 3 or 4: randomization

2 o'clock fasting LDL-C of visit the patient of (for the patient of the known CHD of suffering from between the 100-129mg/dl) TG≤350mg/dl of fasting simultaneously between the 120-189mg/dl will be by Advise By Wire they can carry out cholesterol and reduce test portion and notifiedly carry out fasting to conduct interviews 3.If they signed the letter of commitment of participating in this ALLHAT part at 3 o'clock in visit, then the researcher follows the trail of lipid with Advise By Wire clinic test center and reduces comprising with exclusion standard and will receive the patient being assigned randomly to the instruction of carrying out pravastatin treatment or routine care of part.Each is randomized to either the patient who accepts pravastatin treatment and will obtains the tablet of 20mg and be apprised of and take two every night.The patient who is assigned to routine care will can not obtain any lipid lowerers that ALLHAT provides.The patient who accepts the patient of routine care and accept pravastatin will be apprised of the diet that will observe NCEP step 1 (calorie that calorie that fat provides＜30%, saturated fat provide＜10%, the cholesterol of absorption every day＜300mg).In current visit, will obtain fasting lipoprotein curve and randomly assign the participant's of this test portion baseline as each.

The ethnic composition that keeps ALLHAT:

Select in clinical clinic before their the ALLHAT practice, part Study investigator will understand the non-descendants American patient ratio roughly of wishing to participate in this research.To select clinical clinic so that have 55% right and wrong descendants American among total study population at least, clinic test center will conform to their expection to the performance that clinical clinic is monitored to guarantee them in research process simultaneously.If the American toatl proportion of non-descendants is starkly lower than 55%, then steering committee will adopt remedial, such as stop to collect non-descendants American patient or increase new clinical clinic to improve this deficiency in some or all existing clinical clinics temporarily.

Table V .I: the patient's summary that enters two ALLHAT parts

		Purpose
				Visit #	Moon number after the visit 2	The antihypertensive test	Cholesterol reduces test
-	6.0 to-0.2	Case history is followed the trail of
				1 *	-2.0 to-0.2	Assessment adaptability and interest
1a，b，c *	-1.5 ,-1.0 ,-0.5 (as required)	Begin to bring high blood pressure down from the pre-research of antihypertensive
				2	0	Random assortment, consulting diet/life style	Fasting LP curve **， ALT
3 *	1	Collect a day regular data and carry out dose titration if desired	Random assortment, fasting LP ProBle **The diet of NCBP step 1
				4	3	Collect a day regular data and carry out dose titration if desired	Carry out dose titration ALT, TC if desired

5.6，7	6,9,12 (time can be longer if desired *)	Collect a day regular data and carry out dose titration if desired	Collect a day regular data and carry out dose titration if desired
				8，9，10，..	Per 4 months	Collect a day regular data	Collect a day regular data

^*Do not provide separate compensation to these visits.When visit 3 (1 months), if the patient is randomized to either lipid reduction part then affords redress.After visit 1 month except that at 3,6,9 and the December in the 1st year and per 4 months later on, does not afford redress to the visitor.

^*T-CHOL, triglyceride and HDL cholesterol levels.Calculate the LDL level with the Friedewald formula.

Visit shadow representation after the random assortment.

VI. antihypertensive is interfered

(NHLBI has accepted to stop the suggestion of antihypertensive test doxazosin arm to all four arms on January 24th, 2000, please refer to JAMA.2000; Blood pressure target 283:1967-1975) is that (these targets are [10] that the suggestion with reference to the 5th National Committee (Fifth JointNational Committee) proposes for diastolic pressure＜90mmHg and systolic pressure＜140mmHg.Because the strong epidemiology relation [59] between known systolic pressure and the CVD mortality rate, the systolic pressure target that JNC sets is lower than the target that SHEP adopts, promptly 140 and 159mmHg between and meansigma methods be 142mmHg).The influence that will be subjected to patient tolerability and clinical judgment for the quantity that realizes the research medicine that these targets adopt and dosage is especially when adopting two or more pharmaceutical admixtures.Except only a few exception, be that the patient of systolic pressure＞160mmHg and/or diastolic pressure 〉=100mmHg will strengthen treatment for blood pressure level, even if must adding the medicine of low dosage and medicine same type blindness step 1.

Therapeutic purposes are to realize controlling of blood pressure on the lowest possible dosage of choice drug.Adopt the invalid patient of choice drug of maximal dose level can add two wires (open label) medicine to those.

Four kinds (NHLBI has accepted to stop the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975) each in the choice drug all gives in the morning, once a day.Below be the dosage level of every kind of medicine:

Table VI .1 first-selection (blindly) antihypertensive drug

The medicament that step 1 adopts	Initial dosage	Dosage	1	Dosage 2	Dosage 3
						Chlortalidone	12.5	12.5	12.5	25
Amlodipine	2.5	2.5	5	10
					Lisinopril	10	10	20	40
Doxazosin *	1	2	4	8

The source of the medicament of four kinds of steps 1: chlortalidone: Ogden Bioservices, Inc., Rockville, iYiaryland; Amlodipine: Pfizer, Inc., New York, New York; Lisinopril: Zeneca Pharmaceuticals Group, Wilmington, Delaware; And doxazosin (NHLBI accept to have stopped the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975): Pfizer, Inc., New York, NewYork.

With the title of the medicine of hidden every kind of dosage level, itself is not hidden but dosage water is flat.Initial dosage level only adopts in first week after random assortment so that husky azoles piperazine (NHLBI accepts to stop the suggestion that antihypertensive has been tested the doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975) potential side effect minimum (for other three kinds of medicines, the initial dosage and the dosage of step 1 are the same).The dosage level of step 1 should be since weekend.Do not need clinical interview.

To all patients, reappraised dosage titre (visit 3) if necessary at least at 1st month, and reappraised once (visit 4) at 3rd month.Drug research will be from initial dosage, and the patient pays a return visit once whether be necessary to increase dosage to understand usually every other month.

IX. result evaluation

Will be by the appearance of finishing when following up a case by regular visits to by the research doctor and increase has the check table proof research terminal point of interim report if necessary at every turn.These diagnosis will be confirmed by following death certificate, discharge summary and title page.Following result is that the also quilt that can obtain is made form according to development test:

A. dead (having death certificate to confirm)

Doctor-the researcher of clinical clinic will be to the following cause of death (1) coronary heart disease of classifying, (2) other cardiovascular disease, (3) tumor disease, (4) other medical reasons, or (5) non-medical reasons.To near the research terminal point time, carry out national index of mortality (NDI, National Death Index) research to identify and to write down and follow up a case by regular visits to the death that may occur among the loss patient.Owing to NDI inherent time lag, also will carry out secret tracking to selected participant.The doctor will be required to report the cause of death of research terminal point.

B. cardiovascular terminal point

1) myocardial infarction (being studies confirm that by discharge summary or title page or biennial ECG) comprises the myocardial infarction suspected patient of accepting the thrombolytic treatment.

2) apoplexy (confirming) by discharge summary or title page.

3) congestive heart failure

A) be in hospital or outpatient service (confirming) by discharge summary or title page

B) be not in hospital but through treatment (check box by the terminal point questionnaire confirms)

4) angina pectoris

A) be in hospital or revascularization procedure (being confirmed by discharge summary or title page) is carried out or (ii) do not carried out in outpatient service (i)

B) be not in hospital but through treatment (check box by the terminal point questionnaire confirms)

5) peripheral arterial disease

A) be in hospital or revascularization procedure (being confirmed by discharge summary or title page) or outpatient service revascularization procedure (being confirmed by the outpatient service record) are carried out or (ii) do not carried out in outpatient service (i)

B) be not in hospital but through treatment (check box by the terminal point questionnaire confirms)

6) left ventricular hypertrophy (studies confirm that) by biennial ECG

The LVH standard also will be made explanations in clinical clinic based on the special standard of the ECG that lists among the IV.A.4.d.To read ECG at the center again to specify Minnesota code (Minnesota Codes).The result standard of LVH is based on Minnesota code.The Minnesota code center will adopt coding 3-1 or 3-3 to identify universality LVH.These amplitude standard settings are considered to " ECG-LVH probability " usually, but when and any 4-3 or stricter 4-code, or when 5-3 or stricter 5-code combination, then will be considered to " being diagnosed as ECG-LVH ".

Minnesota code 3-1:V ₅Or V ₆R amplitude＞26, or arbitrary R amplitude＞20 in the leads I, II, III, aVF, or R amplitude＞12mm of the aVL that leads.

Minnesota code 3-3:V ₅Or V ₆R amplitude+V ₁S amplitude＞35mm, or the R amplitude＞15mm of leads I but≤20mmin.

The coding center also will relatively be write down development/degeneration of subsidiary ECG-LVH and ECG-LVH with continuous ECG.

C. other terminal point

1) renal function that weakens (confirming) by the mutual slope of serum creatinine level to the time continuous measurement

2) the ending phase nephropathy is (by chronic dialysis; Renal transplantation causes)

A) be in hospital or outpatient service (confirming) by discharge summary or title page

B) sight is examined the patient and is handled (check box by the terminal point questionnaire confirms)

3) cancer-position and type

A) be in hospital or outpatient service (confirming) by discharge summary or title page

B) sight is examined the patient and is handled (check box by the terminal point questionnaire confirms)

4) nonfatal accident and suicide attempts

A) be in hospital or outpatient service (confirming) by discharge summary or title page

B) sight is examined the patient and is handled (check box by the terminal point questionnaire confirms)

5) gastrointestinal hemorrhage

A) data assessment by the health care Bureau of Finance (Health Care Finance Administration) and Department of Veterans Affairs (Department of Veterans Affairs)

6) quality of life-will assess and quality of life associated health situation with the categorical rating of health status.

7) utilization of medical treatment and nursing-will collect by visit and utilize data.To provide the expense that each utilizes unit (office visit, outpatient service etc.) in hospital based on its DRG.In addition, with ask a problem with quality of life of determining successive range to determine life years according to mass calibration.Age for 10% surpasses patient's sample of 65 years old, will write down these visit datas of cross-check according to medical care insurance.

When the researcher who requires this research is visited routine or the appearance of each research terminal point of identifying between the visit finish a short-term terminal point questionnaire and submit to clinic test center.With regard to each terminal point that relates to death or be in hospital, the researcher also will obtain and submit to a death certificate or discharge summary or title page as diagnosis basis.For the myocardial infarction and the apoplexy subgroup of (10%) hospitalization (fatal or non-lethal) at random, clinic test center will need the described more detailed information as appendix I, research ECG and the enzyme level (with regard to myocardial infarction with regard to) of terminal point committee with regard to estimating impatient phase, and neurosurgeon's report like this and CT and/or MRI report (with regard to apoplexy) also can be estimated the accuracy (definition of relative appendix I) of discharge diagnosis.

X. research institution

Summary:

ALLHAT will adopt the organizational structure that obviously is different from conventional support NHLBI clinical trial.This test will be undertaken by a large amount of (600) medical practitioner-researchers, and they will give each patient some compensation according to working out good expenses statement.About 20% research patient is wished to replenish in the hypertension clinic of veteran (VA) affairs portion.Except that routine data handle and monitor task, clinic test center also will be responsible for selecting these doctor-researchers and payt, employ the Regional Co-ordinator raises with compliance with monitoring and is that central laboratory and ECG coding center provide and manage secondary contract.Administration committee (SteeringCommittee) will select the expert of Related Research Domain.To provide below about the character of this test portion and the detailed description of effect.

Project office (Program Office)

Project office is positioned at NHLBI, (the Division ofEpidemiology and Clinical Applications of epidemiology and clinical practice branch, DECA) and (the Division ofHeart and Vascular Diseases of cardiovascular disease branch, DHVD), to provide and monitor the contract that fund is provided for research, fund is provided and guarantees that IND studies with meaning the clinical clinic of VA.Authorities, NHLBI, will appoint data and security monitoring committee (Data and Safety Monitoring Boardand, DSMB) and the chairman of administration committee and vice-president.Work as authorities, NHLBI, after the generation, project office will appoint administration committee and other to be considered to be necessary that the process that should study or result are to committee that NHLBI advises.

Clinic test center

Clinic test center will mainly be responsible for identify participating in the suitable medical practice of ALLHAT, pays to each random assortment and the patient that finishes research according to the expenses statement of formulating, and the data that draw of editor, keeping and analysis and research.Its researcher and staff's mission critical is design data acquisition system and monitor data quality.The special duty of clinic test center comprises:

1) formulates, prepares and distribute research approach, tables of data and operation and step handbook.

2) appoint execution doctor and defrayment so that the clinical clinic of carrying out this research to be provided.

3) appoint Regional Co-ordinator and defrayment (seeing below).

4) (Obtaining Institutional Review Board is OPRR) to the permission of uncovered practice to obtain public board of review.

5) keep the member's of administration committee the open state of year fund to determine the potential conflict of interest.

6) with central laboratory and ECG coding center sign subcontract with provide that institute needs in time and the measurement (seeing the VIII chapter) of standard

7) sign subcontract to obtain the research medicine, medicine is bottled, labelled and to be distributed to clinical clinic with drug flow center (drug flow center).

8) performance of monitoring study portion and give project office and administration committee in time provides comprehensive report.

9) in the process of raising, monitor the American ratio of the non-descendants in each clinical clinic, and when the toatl proportion of studying is starkly lower than 55% target, recommend suitable corrective action.

10) data and security monitoring committee (DSMB) half a year can the time statistical report (seeing below) of detailed and up-to-date research process is provided.

11) keep the treatment network so that they can visit their initial research doctor for the research participant who moves new area to and can't continue to study.

12) provide logic support (if necessary) and record research meeting.

13) adjust and manage the terminal point verification.

14) interval in DSMB and administration committee's recommendation starts the loss patient is followed up a case by regular visits in the research of national index of mortality with foundation animation (seeing below).

15) prepare the to cooperate research manuscript of usefulness with administration committee.

Clinical clinic:

To there be 600 families to participate in this research by specified independent medical institutions of clinic test center.Estimate that some medical institutions (especially VA clinic, HMO and large-scale hospital) will provide a large amount of patients, and the patient that some medical institutions provide will be less than 100 people.Estimate in these medical institutions that the American ratio of non-descendants is also different, but will be 55% target proportion (seeing the V chapter) to guarantee to reach aggregate level its close supervision.

Each clinical clinic will be by formulating doctor's supervision of being responsible for carrying out ALLHAT.Yet the research table can be finished by doctor's assistant or nurse or other specified titular people, and is consistent with the interior tissue of medical practice.In each clinic, must there be a key staff to be designated as the chief leading cadre of implementing plan; This people will participate in main training and annual meeting.Clinic test center will that be subjected to having finished, correct and through the correlational study table of signature after for each is assigned randomly to the patient of ALLHAT various piece and defrayment is visited in research that each is finished.

The Regional Co-ordinator:

The Regional Co-ordinator is the experienced doctor who reduces aspect hypertension and the hypertension therapeutic, and they will handle the conventional scheme problem of about 50 clinical clinics in each.Under the guidance of clinic test center, they with help solve with quality control, scheme adhere to situation, for raising and keep relevant problem in the clinic of distributing to them.The doctor expeditor will obtain nurse expeditor's support and can select participant and clinical clinic.All are participated in the VA hypertension clinic of research and will be supervised by an expeditor.

The drug flow center

The drug flow center will be set up with (1) by clinic test center and obtain, packs and distribute two whole medicines that the ALLHAT part is required, (2) carry out concealment system so that each researcher or their patient can't distinguish four kinds of first-selected antihypertensives (the two wires antihypertensive drug need not be hidden) and (3) study the suitable support of medicines for clinical clinic in time provides all.

Administration committee:

Administration committee will be specified by NHLBI, to provide with regard to research approach and later decision-making about the design of the research that do not need to visit the blindness data and the ultimate analysis and the disclosed expert opinion of execution and result of study.The official that its ballot member will be NHLBI plan, main researcher, Regional Co-ordinator and the 7-9 name of clinic test center treatment hypertension and/or hypercholesterolemia and crucial clinical trial problem as raise and adhere on speciality and empirical expert are arranged.Each member of administration committee needs to submit a annual report that discloses financial condition to clinic test center, and themselves is got rid of can be outside the shareholder or long-term consultant of drugmaker that the research directly is benefited or other company.Administration committee can (more frequent in the planned development stage) with holding every year once.

To set up executive committee to monitor test operation in administration committee's session.The composition of executive committee will comprise the chairman of administration committee and the representative of vice-president and project office, clinic test center and Department of Veterans Affairs.To comprise following content for the report of executive committee: adaptability and medical treatment and nursing, processing, open and support study dies, science and educational plan and terminal point.Each content all is responsible for to scan the various aspects of test by project office, clinic test center and administration committee, comprise that frequency is kept and/or processing especially, as raise, adhere to, quality control, blood pressure and lipid interference, laboratory method, terminal point affirmation, support study dies, open, and the annual plan of convening the researcher meeting.

Scheme is followed the trail of committee (Protocol Review Committee):

Scheme is followed the trail of committee and will be responsible for notifying NHLBI to agree to start research approach.Its member and chairman will be by authorities, and NHLBI appoints also to be made of 7 experts that have nothing to do with this research at least.It will be had a meeting at Bethesda after research approach is finished.Meeting will be participated in by the main researcher (and designated person) of clinic test center and the personnel of project office, and the chairman of administration committee and vice-president will attend the meeting and answer the problem about scheme simultaneously.

Data and security monitoring committee (DSMB):

DSMB will be responsible for monitoring the various aspects of research, comprise that those need visit the research of blindness data.DSMB and chairman thereof will be by authorities, and NHLBI appoints and is made of at least 7 experts that have nothing to do with this research.Possible DSMB member's list also will enlarge even follow the trail of committee's differentiation by scheme fully, and it will finish its mission after DSMB sets up.

DSMB holds at least half a year once can.The main researcher of clinic test center and the personnel of specified clinic test center will participate in these meetings (but can not vote), and be responsible for preparing and submitting to about the recent statistics of research process and report.These reports will comprise about raise, random assortment, adhere to, the data of blood pressure level, plasma lipoprotein, drug side effect and research terminal point, and statistical test and the desired special analysis of DSMB.The chairman and the vice-president of project leader (he will as the executive secretary of DSMB), project officer and specified NHLBI personnel and administration committee will participate in these meetings in its limits of functions and powers.

Effectively raising the stage, process (especially right and wrong descendants American patient) is raised in monitoring to DSMB and the participant treats the random assortment of arm at each, and, can not revise (or stopping one or two study portion) in one or two study portion suggestion if reach the research design target.When to finish research when effectively raising the stage DSMB will provide suggestion.Any significant change of the scheme that administration committee is recommended during the research all needs to obtain the permission of DSMB.All ballots are passed through with simple majority.

In any moment of research, DSMB can in officely how descend any treatment arm of the arbitrary study portion of suggestion termination on the basis of evidence:

1) the strong evidence that obtains by this research or other research about this research treatment side effect, this side effect is enough to above stopping to continue on for the target group to any potential benefit of CHD and with it;

2) the strong evidence that obtains by this research or other research about the obvious beneficial effect of this research treatment, so just can not continue with it negates other seminar;

3) reason such as, compliance insufficient owing to raising, drug reaction, incident rate realizes successfully that in the feasibility time frame probability of research hypothesis is very little.

DSMB can convene conclave at any time.The member of DSMB, project leader and project officer will participate in these meetings.

Authorities, NHLBI will make final decision about the suggestion that stops any test portion to whether accepting DSMB.

XI. data management

Report distributes

Report with at least 5 types of generations:

1) raise report: reduce test for antihypertensive test and lipid, clinic and zone will produce once these reports at least weekly.These reports will be distributed to project office, administration committee and Regional Co-ordinator.

2) other conventional monitoring report comprises about visit and adheres to the data that Drug therapy, quality control and research terminal point write down.Clinic and zone will produce once these reports at least weekly, and these reports simultaneously will be distributed to project office, administration committee and Regional Co-ordinator.

3) about the report of clinical use, confirm report, access plan harmony in the exterior memorandum, terminal point record report and limited cross editor comprising random assortment.These reports needn't produce in every month.The access plan table will produce when participant's random assortment, and comprise all research during access window and the singular process of expection.Report and suitable tabulation will be sent to the clinic, and final report will be sent to project office, administration committee and Regional Co-ordinator simultaneously.

4) administration committee's report will be produced by annual meeting, and it and routine are raised with monitoring report similar.

5) data and security monitoring committee report will comprise that antihypertensive test and lipid reduce raising and monitor data of test of cure group.They also will comprise the data and the biennial ECG event data of central laboratory, and the final report of treatment group research terminal point.

Quality control

All clinical clinics will require to participate in one of three sub-region training conferences.These training conferences will comprise research approach location, blood pressure measurement training and conclusive evidence, ECG standard the location and finish training with the transfer study table.

Periodic refresher training is held according to the meeting schedule of executive committee.These education meetings can comprise follows the trail of correct blood pressure measurement process or contingent any problem in daily monitor activities.

Clinic test center will evaluate the integrity and the accuracy of all data before data enter.Any found problem will solve by phone or the fax with clinical clinic.The research table then will be with the typing of double data.To carry out the limited cross editor to differentiate the form and the process of whether omitting.

Non-blindness

Some in particular cases (for example medical treatment unexpected), must inform the appointed treatment group of patient.At first whether the interrogation expeditor stops the blindness test with decision.If the Regional Co-ordinator can't determine that then the researcher will attempt to get in touch any other Regional Co-ordinator, or doctor Davis of clinic test center or doctor Goff, or doctor Payne of NHLBI or doctor Cutler, and the relevant medical problem is discussed.If medically be suitable, then patient and clinical center researcher's blindness will be made great efforts to keep.If the Regional Co-ordinator agrees that if perhaps the researcher adheres to, the researcher should get in touch clinic test center can carry out non-blindness treatment with decision.If unexpected can't get in touch clinic test center simultaneously, but the non-blindness mechanism of researcher association centre carries out non-blindness treatment.

When thinking that being necessary to stop blindness testing, must write down current incident with 1 page table by the Clinical Researcher.This form will be transferred to clinic test center and data typing patient research report will forever be preserved.

Stop the research treatment

If the researcher thinks owing to side effect, other symptom, patient require to be necessary to make the patient to stop the research treatment, then need not to stop the patient being maintained secrecy.At first whether the interrogation expeditor allows the patient stop the research treatment with decision.If the Regional Co-ordinator agrees that if perhaps the researcher adheres to, the researcher should get in touch clinic test center to inform their occurent thing and reason thereof.

Reimbursemen

Clinical clinic will be carried out the research terminal point of finishing with each of following up a case by regular visits to that lipid reduces test, each scheme requirement and compensate by person-time antihypertensive test, random assortment being carried out in each random assortment.These expenses by clinic test center's payment in every month once.For compensation is given the ratification, the research table must be received by clinic test center, and all problems relevant with this table all must be answered, and this table must be by the typing research data base.Under research terminal point situation, compensation will be divided into the several separate part: be research table itself, death certificate or discharge summary, and be other documentary evidence (for 10% sample that needs verification).

Data analysis

The main terminal point of the antihypertensive part of ALLHAT is mortality and non-lethal CHD.The dominant response variable is the time of developing into this incident after the random assortment.X 2 test [60] will be used for comparison each non-diuretic therapy group and diuretic group.X 2 test also can be used for the secondary endpoints of general mortality rate, i.e. the combined result and the end-stage renal disease of apoplexy, coronary heart disease (angina of CHD+ revascularization procedure+hospitalization) and cardiovascular disease (CHD+ apoplexy+revascularization procedure+angina [be in hospital or outpatient service]+CHF[is in hospital or outpatient service]+peripheral arterial disease [being in hospital or outpatient's revascularization procedure]).Whether X 2 test also can be used to detect following group and there are differences between mortality and non-lethal CHD therapeutic outcome--and-1) masculinity and femininity, 2) 〉=65 years old and＜65 years old, 3) non-descendants American and 4) diabetes and non-diabetic.For the LVH result of ECG, and health-related quality of life, adopt ratio to check between the treatment group and whether there are differences.For the nephropathy result, the inverse of each participant's creatinine slope will be calculated.To calculate the weight average average of each treatment group participant inverse, and will adopt vertical model of Laird and Ware between group, to compare these averages [61].

The main terminal point that the ALLHAT lipid reduces part is a general mortality rate.The dominant response variable is to be assigned randomly to the dead time.X 2 test will be used for relatively being assigned to the group that lipid reduces the group of treatment and is assigned to non-treatment.X 2 test also can be used for the secondary endpoints of the death that fatal and non-lethal CHD, fatal and non-lethal cancer and specific reasons cause.Whether X 2 test also can be used to detect following group and there are differences between mortality and non-lethal CHD therapeutic outcome--and 1) masculinity and femininity, 2) 〉=65 years old and＜65 years old, 3) non-descendants American and 4) diabetes and non-diabetic.For the MI result of ECG, and health-related quality of life, adopt ratio to check between the treatment group and whether there are differences.

Monitoring in mid-term and analysis(square method appendix 2)

Mid-term monitoring is paid close attention to is patient's absorption-all take in and the absorption in clinical center, to the comparable baseline of adhering to situation, treatment group of scheme, according to incident rate estimation sample size, crossing-over rate, competitive risk with follow up a case by regular visits to losss, untoward reaction data and treat effect to main and less important result of study.Interim analysis will be carried out simultaneously with the meeting of data and security monitoring committee (DSMB).

We advise that DSMB uses reduction at random to monitor hypertension and lipid reduces the treatment difference of studying [62,63].By this method, suppose current data and to null hypothesis (H ₀) hypothesis be true, if when project finishes, refuse H ₀Condition hypothesis more than or equal to some value γ given in advance ₀, then can consider to stop alternative hypothesis (H _a).Perhaps, under special design alternative hypothesis, if refusal H ₀Condition hypothesis less than some value γ given in advance _a, then can consider to stop null hypothesis.In this way, I class error (depends on the number of times of checking data, the incident of checking and γ apparently higher than α ₀Value), simultaneously II class error (depends on the number of times of checking data, the incident of checking and γ equally apparently higher than β _aValue).Selection to γ will be determined by DSMB.

These monitor procedures are should will be used as complicated and be responsible for the guidance of decision, and each meeting DSMB considers to continue or stops that randomization distributes and/or must do like this when following up a case by regular visits to.

The hypertension test

In this test, we have three, and (NHLBI has accepted to stop the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975) the comparison of interested comparison-diuretic and angiotensin-convertion enzyme inhibitor, the comparison of diuretic and calcium channel blocker, and the comparison of diuretic and alpha blocker (NHLBI accept to have stopped the suggestion of antihypertensive test doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975).In the Dunnett of α=0.019 process, each more all has its monitoring policy.Fig. 1 has shown each relatively border of reduction at random of 80%.Check and depend on that the notice time (number of the CHD incident that is recorded is divided by the number of expection CHD incident) accounts for data and the ratio of security monitoring executive session total time.

Fig. 1. the monitoring border-ACE of hypertension test (or the contrast of CCB or alpha block agent and diuretic (NHLBI accepts to stop the suggestion that antihypertensive has been tested the doxazosin arm on January 24th, 2000, please refer to JAMA.2000; 283:1967-1975).

We also wish to use one to render a service the rule that stops to test to show effect owing to lacking.Here we also plan to use reduction at random or condition to render a service.If under alternative hypothesis condition render a service less than 10% we will consider termination test.Fig. 1 has also shown the border that this condition is renderd a service.

In the hypertension test, will monitor total mortality rate.

Lipid reduces test

Test hereto, we will adopt with hypertension and test similar method, when having only a comparison (general mortality rate), α=0.05.Fig. 2 has shown the monitoring border.

Fig. 2. lipid reduces the monitoring border of test

XII. pioneer's stage (Vanguard Phase)

Pioneer's stage that will comprise the gamut test in initial 6 months of research.For 600 of random assortment (always having 40,000) patient's purpose 20 tests are carried out in selection and carried out this pioneer's stage.The purpose in pioneer's stage comprises:

1. determine in clinical, to raise feasibility with the Follow-Up Clinic hyperpietic based on the practice of office and hypertension;

2. determine the experimenter of qualified antihypertensive test and be ready to participate in the ratio that cholesterol reduces the experimenter of test;

3. optimize the strategy of raising at least 55% non-descendants American participant;

4. improve and make outpatient service hyperpietic experimenter maximum possible observe the method for antihypertensive and cholesterol reduction therapeutic scheme;

5. in based on the practice of outpatient service, optimize the strategy that keeps outpatient service hyperpietic experimenter;

6. in clinical, improve the method for standardization terminal point conclusive evidence based on the practice of outpatient service and hypertension; And

7. obtain and optimize the effectiveness of various operational approach, such as approval, training and the activity relevant of medicine circulation, public board of review with the Regional Co-ordinator.

If the forerunner has set up the basic probability of this method the stage, then will make any necessary modifications and recover other practice, to realize the purpose of raising of this research.

XIII. reference material

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Appendix I: sample size is calculated

The ALLHAT that carries out the component of antihypertensive (AH) and reduction body fat (LL) separately renders a service and calculates.For the AH component, effectiveness is based on two tail comparisons of diuretic arm and other each arm of the comprehensive I type error rate of use 0.05.The Dunnett type that this use is used for multiple comparisons is calibrated and is finished.Component for reducing body fat only has a comparison, does not therefore need to calibrate.

In order to estimate the effectiveness of ALLHAT, we have to specify event rate, therapeutic effect and the crossing-over rate of expection, and loss is from the tracking results of competitive risk or other reason.

The antihypertensive component

1 year CHD ratio that we conservatively estimate in the diuretic arm was about for 1.35% (ratio was about 7.8% in 6 years).This is used for the data from Framingham 12, Framingham 16 and HDFP based on the exponential decay model.We count all hyperpietics (age is 45-75) from the Framingham data, get rid of up-to-date MI (in 2 years).Whether variable has age, sex and the patient who comprises in the described model is in high-risk status (be defined as and satisfy the ALLHAT directory standard).Grade is adjusted into 67 years old mean age, male's 55% sickness rate.The HDFP data are similarly analyzed, comprised 50 years old or those above people.Carry out the classification of HDFP and the analysis of relevant nursing group separately.Below carry out following reduction at long-term trend and healthy volunteer's influence.

Table 1: adjustment factor

Test	The long-term trend reduction	Volunteer's reduction
			Framingham?12	1/2	1/4
Framingham?16	1/3	1/4
			HDFP	1/2	1/4

For example, the estimated annual morbidity from Framingham 12 exponential dampinies multiply by (1-1/2) (1-1/4)=3/8.The estimated influence that is based upon long-term trend and healthy volunteer and the sickness rate of the exponential damping adjusted is as described below:

Table 2: the estimation year CHD from Framingham and HDFP leads

Test	The annual morbidity of estimating

Framingham?12	1.32％
		Framingham?16	1.42％
The relevant nursing of HDFP	1.76％
		The HDFP classfied system of nursing	0.92％

We think that to lead be rational for a year CHD of 1.35%.SHEP leads somewhat higher.Healthy volunteer's influence that SHEP has led automatic Synthesis, and because it is recently test, its sickness rate seldom need carry out the long-term trend adjustment.We think that the scope of annual morbidity is between 1.05% to 1.65%.

Estimate crossing-over rate by TOMHS.The Markov model that we will depend on the time is fitted to described data.Suppose that at first 3 years processes probability that another Drug therapy intersects that neutralizes be 2.75%, and in the end 3 years be that 6% model representation goes out match and gets fine (see figure 1) in the process.Under this model, about 24% patient exchanged to another kind of Drug therapy once at least in 6 years, and about 21% patient exchanged to another Drug therapy 6 year latter stage.The patient who supposes to exchange to the trouble diuretic arm of another active antihypertensive drug treatment has reduced sickness rate, even some in other antihypertensive are without any benefit.The patient who supposes to exchange to the active resisting hypertension arm of trouble of another antihypertensive drug treatment has together increased sickness rate with the diuretic arm, even described patient has exchanged to another to his favourable antihypertensive drug treatment.The patient can exchange, and then exchange is returned.We suppose because there is deviation in the selection of pharmacists in various second antihypertensive drug treatments, but therefore exist the patient of negligible number not receive treatment.Some is not conservative for this hypothesis, but we think that this can offset by the above conservative hypothesis of mentioning indirectly.We think that also two other ratios of 22% and 26% probability exchanged once respectively at least.These corresponded respectively to 6 year latter stage has 20% and 22.5% patient to accept another Drug therapy (seeing Fig. 2 and 3) approximately.Back one ratio seems too cautious.At least after this exchange three ratios (22%, 24% and 26%) once are called exchange rate 1,2 and 3.

In 6 years, be about 8% from the estimated amount of damage of competitive risk.This comprises other cardiovascular mortality rate (in 6 years 2.6%) and non-cardiovascular mortality rate (in 6 years 5.4%).These ratios calculate in the mode that is similar to us and calculates the sickness rate of main terminal point.Use identical healthy volunteer and long-term trend adjustment.We are added to the loss in every year about 1.5% in the follow-up investigation, and the total losses ratio is about 16.8% in 6 years.We think that other two loss ratios are 16.8 ± 5%.Described three loss ratios (11.8%, 16.8% and 21.8%) after this are called loss ratio 1,2 and 3.

In order to calculate the effectiveness of AH component, we also have to consider described LL component.Apparent by HDFP and Framingham, patient and those incongruent patients of meeting the requirement of LL component are under the roughly the same risk.Therefore, we draw this hypothesis.Before the effect of considering the antihypertensive drug treatment, we reduce by 25% with the sickness rate in the active arm of LL, to calculate the beneficial effect that cholesterol reduces.Notice that suppose that the active patient of all LL adheres to taking described medicine and accepts useful completely treatment, this point is guarded.We suppose that 20,000 patients will take the LL component among 40,000 ALLHAT patients.

The sickness rate of our hypothesis in active resisting hypertension arm reduces by 20%.Then, we calculate according to the following stated and render a service:

1) optimal allocation of carrying out diuretic and treating the patient of arm, the patient's number that promptly is in the diuretic arm should be with the ratio that is in the patient's number in other each AH arm:

(seeing Table 3).

2) proofread and correct the fiducial value (marginal value after the correction is about c=2.37) of respectively treating with diuretic.

Table 3: patient's roughly distribution

The cholesterol passage reduces test	The resisting hypertension test
					Diuretic	Calcium channel blocker	ACE inhibitor	The alpha block agent *
	The LL placebo	3.7k	?2.1k	?2.1k					?2.1k
The LL activating agent					3.7k	?2.1k	?2.1k	?2.1k
	In the LL component, do not have	7.3k	?4.2k	?4.2k					?4.2k

^*On January 24th, 2000, NHLBI has accepted to stop the suggestion of the resisting hypertension test of doxazosin arm.Please refer to JAMA.2000,283:1967-1975.

We utilize computer program estimate based on the morbidity, the exchange and the loss the year ratio the test sickness rate.We are to this program of patient's isolated operation in LL activating agent and the LL placebo arm.Based on these values described in the table 3 and patient's distribution, we obtain the test sickness rate of diuretic arm and other AH arm.For example, use about 0.0135 annual morbidity, exchange ratio 2 and loss ratio 2, we estimate that described test sickness rate should be as described below:

Table 4: 6 years estimated CHD lead

The LL kind	The diuretic arm	Other AH arm
			The LL placebo	0.0710	?0.0595
The LL activating agent	0.0537	?0.0449
			No LL	0.0710	?0.0595

We estimate that the total incidence in diuretic arm and another AH arm is:

p ₀＝(0.0710)(0.75)+(0.0537)(0.25)＝0.0667，

p ₁＝(0.0595)(0.75)+(0.0449)(0.25)＝0.0559。

Use arcsine transformation to carry out test statistics.

$Z=\frac{\arcsin \left(\sqrt{{\hat{p}}_0}\right)\arcsin \left(\sqrt{{\hat{p}}_1}\right)}{\sqrt{(1/4)(1/{\mathrm{<figure-callout\; id="0"\; label="n"\; filenames="A20038010797601501.png,A20038010797601502.png"\; state="\{\{state\}\}">n</figure-callout>}}_0+1/n_1)}}.---\left(1\right)$

In formula (1), n _oWith n1 be respectively sample size in diuretic and another AH arm, p ₀And p ₁It is morbidity ratio observed in those arms.For the optimal allocation patient and $n_o=40000[\sqrt{3}/(3+\sqrt{3})=14641$ With ${\mathrm{<figure-callout\; id="1"\; label="n"\; filenames="A20038010797601502.png,A20038010797601511.png"\; state="\{\{state\}\}">n</figure-callout>}}_1=40000[1/(3+\sqrt{3})]=8453$ 。If described Z statistical value surpasses described gauged marginal value c=2.37, we will give up it.If we accumulate the normal distribution function with Ф (x) expression, the effectiveness value can be expressed as:

$\mathrm{\&Phi;}\left(\frac{\arcsin \left(\sqrt{p_0}\right)\arcsin \left(\sqrt{p_1}\right)}{\sqrt{(1/4)(1/{\mathrm{<figure-callout\; id="0"\; label="n"\; filenames="A20038010797601501.png,A20038010797601502.png"\; state="\{\{state\}\}">n</figure-callout>}}_0+1/n_1)}}c\right).---\left(2\right)$

Return the example that uses 0.0135 annual morbidity, exchange ratio 2 and loss ratio 2, we find p _o=0.0667, p ₁=0.0559.With these values and n _o=14,641 and n ₁=8,453 substitution formula (2), we obtain effectiveness value=0.824.

Body fat reduces part

The main terminal point that body fat reduces part is a general mortality rate.We suppose that all participants' life state can solve by national death certificate, therefore, do not have any loss in follow-up investigation.

The most of people of early stage appearance in test do not follow the doctor's advice, and based on the experiment of HMG CoA reductase inhibitor before, we think and have deferred to doctor's advice well.We also estimate under the condition of the cost of given LL agent and patient's relative medium body lipid level do not have many LL comfort patients to carry out active LL Drug therapy.We suppose that annual about 2% LL comfort patient has carried out active LL Drug therapy, and its benefit is similar to pravastatin (sneaking into 2% every year).This means that about 11.4% LL placebo patients carried out an active medicine treatment at least in 6 years.We suppose that also 5% LL activating agent patient stops to carry out Drug therapy in the time of some of 1 year, and the active patient of about 2.5% LL stops to carry out Drug therapy (1 year sneak into than being 5%, each year is 2.5% afterwards) in each remaining year.The active patient of this correspondence LL of about 16.3% in 6 years has stopped Drug therapy.Under above assumed condition, about 10.6% LL placebo patients had been carried out the active medicine treatment when finishing in 6 years, and about 15.3% LL activating agent patient had carried out the active medicine treatment when finishing in 6 years.We have also considered one group of more pessimistic hypothesis, and promptly a year incorporation rate is 2.5%, and the loss rate in 1 year is 6%, afterwards every year 3%.Described first group of hypothesis is called sneaks into/loss rate 1, and one group of more pessimistic hypothesis is called sneaks into/loss rate 2.

Our estimated death rate is about annual 2.35%.This hypothesis is based on CHD mortality rate (in 6 years for 4.5%-5%), the independent sickness rate of other cardiovascular mortality (in 6 years about 2.6%) and non-cardiovascular mortality rate (in 6 years about 5.4%).The parameter damped system that these independent ratios use us to be used for main terminal point is estimated.As be used for the AH part, adjust as identical long-term trend and healthy volunteer.This mortality rate that draws estimation is annual 2.25-2.30%.According to high slightly mortality rate observed among the SHEP, we increase to for 2.35%/year with it.We think that the scope of annual death rate is 2.20-2.50%.

The reasonable reduction of the mortality rate percent that very difficult estimation is caused by the LL Drug therapy.If the dead reduction by 30% of CHD, other cardiovascular death reduction by 15% and non-cardiovascular death do not reduce, then can reduce by 14%.As if this look less optimistic.We think that reducing by 12.5% is reasonably, so we think that three kinds of different percents are reduced to 11%, 12.5% and 14%.

We are with the mortality rate reduction by 10% of the mortality rate in three AH arms than diuretic arm.

Calculate 6 annual death rate of LL placebo and LL activating agent arm to be similar to AH part calculation mode.Calculate the independent ratio of diuretic arm and other AH arm, and the distribution condition shown in the use table 3 obtains composite ratio.6 years ratios that shown the LL part of ALLHAT in the following table 5.

Table 5: 6 annual death rate of estimation

The LL catalogue	The diuretic arm	Other each AH arm
			The LL placebo	0.13253	?0.11998
The LL activating agent	0.11903	?0.10769

Therefore, 6 years ratios in LL placebo and activating agent arm are as follows:

Reuse arcsine transformation and calculate effectiveness.Unique difference was exactly the sample size n in LL placebo and the activating agent arm between this calculating and AH calculated _oAnd n ₁Equate, and repeatedly relatively need not to adjust.Therefore we can use n _o=n ₁=10000 and the formula 2 of c=1.96.

Conclusion

The effectiveness of AH part is shown in Fig. 4-6 under different assumed conditions.Under different assumed conditions, render a service and do not have what big-difference.Consider exchange ratio 2 and loss ratio 2, we find estimate the diuretic ratio be 1.35%/year condition under effectiveness be 82.4%, as calculating more than us.

The effectiveness of LL general mortality rate part as shown in Figure 7.We find to sneak into/and loss rate is 1 and is reduced to from the mortality rate of LL treatment under 12.5% the condition that rendeing a service almost is 80% exactly.If it only is 11% (other hypothesis before) that mortality rate reduces, then renders a service and be reduced to 68.8%.On the other hand, if be reduced to 14% (other hypothesis before) from the mortality rate of LL treatment, then rendeing a service is 88.1%.Under the condition of more pessimistic sneaking into/loss rate 2, be reduced at 2.35%/annual death rate and from the mortality rate of LL treatment under 12.5% the condition, effectiveness is 76.9% (not shown).

Appendix II: the specific definition of coronary heart disease death, non-dead acute myocardial infarction and apoplexy

Coronary heart disease death:

Follow coronary heart disease (CHD) as underlying cause of death, and add following arbitrary death:

1) the dead myocardial infarction hospitalization that carried out before;

2) just suffer from angor or myocardial infarction and the unknown non-coronary heart disease process of potential mortality previously;

3) dead in symptom 24 hours appears in CHD, or do not having symptom but exist in 24 hours of the unknown non-coronary heart disease process of potential mortality (comprising death dead at once and that do not witness) dead;

4) program relevant such as coronary bypass grafting (CABG) or the death that caused through percutaneous transluminal coronary reconstructive vascular operation (PTCA) with coronary artery disease.

Attention: the terminal point incident that causes by non-coronary artery main cause be MI death its cause death in response to being described as-non-CHD.

Coronary artery death will be further divided into:

1) clear and definite mortality MI: unknown non-Atheromatosis because of and dead 4 weeks in tangible MI,

2) clear and definite mortality CHD: unknown non-Atheromatosis because of and following one or both: the historical or non-ischemic myocardial disease of chest pain in dead 72 hours or the chronic ischemic heart disease when not having valve heart disease, or

3) possible fatal CHD: unknown non-Atheromatosis because of, and and main diseases because of consistent death evaluation.

In the patient who does not have the non-coronary heart disease process of known potential mortality, whether dead coronary heart disease death also can be divided into quick or non-quick two classes according in 24 hours after the morbidity (perhaps patient continue time) when not observing symptom.

The non-lethal acute myocardial infarction

The evaluation of clear and definite clinical acute myocardial infarction (MI) and coding should be based at least two that satisfy in following three working standards, and with the conformance to standard of World Health Organization (WHO):

1. the symptom (as chest pain) consistent with acute MI continues at least 20 minutes.

2. the ECG consistent with acute MI changes, as new lasting ST fragment risings＞0.1mV or new pathology Q ripple (QRS＞0.04 second) occurs, in two adjacent guiding of each leisure.

3. serum biochemical markers compatible with acute MI, as:

Total CK is the twice of upper limits of normal at least, 5% of MB part＞total CK, perhaps

2 times of troponin＞upper limits of normal, perhaps

LDH1/LDH2 ratio＞1.

Apoplexy

The rapid outbreak that continues the nerve defective is attributable to the obstruction of Arterial system or breaks, and comprises the apoplexy that occurs in the surgical operation, also do not know its be cerebroma, tumor, infection or other non-ischemic secondary disease because of.Described defective must continue more than 24 hours, unless and then just dead, perhaps, exist and the corresponding to verifiable infringement of acute apoplexy through CT or MRI scanning.

A. non-lethal apoplexy (following any one):

1) clear and definite objective discovery: local nerve defective (being with or without obstinate headache outbreak or loss of consciousness recently), with the persistent period greater than 24 hours, there is not other disease that causes the nerve defective, as tumor, subdural hemorrhage, cerebral blood vessel visualization or metabolic disease, and/or

2) diagnostic result that confirms unusual apoplexy by CT or MBI is with present nerve symptom or signal or just lumbar puncture (for subarachnoid hemorrhage) is consistent.

B. mortality apoplexy: the death of apoplexy being classified as the cause of death, underlying cause of death or the instant cause of the death identifies, add following any one or a plurality of:

Hospitalization takes place before dead when 1) suffering stroke, as mentioned above,

2) early stage apoplexy and the unknown ill process of the non-cerebrovascular of potential mortality, and/or

Be diagnosed as the apoplexy of the cause of the death when 3) after death checking.

Appendix III: the electrocardio scintigram standard of noiseless myocardial infarction, ischemia, left atrium hypertrophy and bundle branch retardance

Described ALLHAT research has been write down from benchmark visit and biennial clinical interview and has been appointed as the electrocardiogram report that quality contrasts the acute hospitalization sample of incident.Estimate the clinical ECG of general and intermittent event (comprising noiseless myocardial infarction).

General and the interim ECG that finds during clinical interview

Can use the Minnesota coding standard to determine that ALLHAT participant suffers from general MI, ischemia, left atrium hypertrophy and bundle branch retardance.Intermittently MI, ischemia, left atrium hypertrophy and bundle branch retardance can be used and be used for simultaneously relatively the standard of RCG and determine.

The general baseline ECG that finds

1. general MI

The baseline ECG of coding:

A) any 1-1-x sign indicating number, or

B) 1-2-x adds 4-1-x arbitrarily, or 4-2, or 5-1, or 5-2

2. general ischemia

The baseline ECG of coding:

A) any 4-2 is to 4-1-x

B) any 5-2 is to 5-1

3. general LVH

The baseline ECG of coding:

A) 3-1 or 3-3 (soft LVH)

B) 3-1 or 3-3 add any 4-3 to 4-1-x, or 5-3 is to 5-1 (hard LVH)

4. general bundle branch retardance

The baseline ECG of coding:

a)7-1-1

b)7-2-1

c)7-4

ECG incident intermittently

By the relevant document that ECG compares simultaneously, the ECG pattern that forms between the ECG of baseline visit and back one visit has confirmed described intermittent event.

A. Jian Xie M1

ED1 is to ED7 arbitrarily

B. Jian Xie ischemia incident

Any EV1-EV9 pattern

C. Jian Xie LVH or LVH's is progressive/decline

E-LVH1 is to E-LVH4

D. bundle branch retardance intermittently

EBBB1 is to EBBB3

Compare in the time of adnexa 1:ECG

The explanation that ECG compares simultaneously:

In order to compare continuously, think that coding 1-2-6 does not have the Q-coding.

Uncertain Q-coding is 1-2-8 or any 1-3-x coding.

Diagnostic Q-coding is any 1-1-x or any 1-2-x, except 1-2-6 or 1-2-8.

The appointment of " ED " is meant formed diagnostic Q-coding mode.

By continuous comparison, confirm that all ED patterns are for enlarging markedly.

If have the 7-1-1 coding, then can not specify ED1 to ED7.

If have 7-2-1 or 7-4 coding, then can not specify ED2 to ED7.

" EV " specifies and is meant formed ST-T wave mode.

By continuous comparison, confirm that all ED patterns are for enlarging markedly or reducing.

If have 7-1-1,7-2-1 or 7-4 coding, then can not specify Ev1 to EV9.

Significant changing pattern continuously

Clear and definite Q-ripple MI (diagnostic mode of formation)

ED1. no Q-coding (or 1-2-6) in baseline ECG has the record (Minnesota coding 1-1-1 is to 1-2-5 or 1-2-7) that diagnostic Q-encodes afterwards, confirms to enlarge markedly.

Or

1-2-8 in baseline ECG or any 1-3-X coding have the record that any 1-1-X encodes afterwards, confirm to enlarge markedly.

ED2a. uncertain Q-coding (1-2-8 or any 1-3-x coding), in baseline ECG, there is not main St to sink, have the record (1-1-1 is to 1-2-5 or 1-2-7) of diagnostic Q-coding afterwards, add that main ST sink (4-1-X or 4-2), confirms to enlarge markedly.

ED2b. uncertain Q-coding (1-2-8 or any 1-3-x coding), in baseline ECG, has Hom under the main ST that pre-exists (4-1-X or 4-2), the record (1-1-1 is to 1-2-5 or 1-2-7) that has diagnostic Q-coding afterwards adds Hom under the more serious ST (4-1-X), confirms to enlarge markedly.

ED3a. uncertain Q-coding (1-2-8 or any 1-3-x coding), in baseline ECG, there is not main T-ripple to be inverted, the record (1-1-1 is to 1-2-5 or 1-2-7) that has diagnostic Q-coding afterwards adds that more serious ST is inverted (5-1 or 5-2), confirms to enlarge markedly.

ED3b. uncertain Q-coding (1-2-8 or any 1-3-x coding), in baseline ECG, have the T-ripple that pre-exists and be inverted (5-1 or 5-2), the record (1-1-1 is to 1-2-5 or 1-2-7) that has diagnostic Q-coding afterwards adds that more serious ST is inverted (5-1 or 5-2), confirms to enlarge markedly.

ED4a. uncertain Q-coding (1-2-8 or any 1-3-x coding) does not have ST to rise in baseline ECG, and the record (1-1-1 is to 1-2-5 or 1-2-7) that has diagnostic Q-coding afterwards adds that the ST fragment rises (9-2), confirms to enlarge markedly.

ED4b. uncertain Q-coding (1-2-8 or any 1-3-x coding), in baseline ECG, has the ST rising (9-2) that pre-exists, the record (1-1-1 is to 1-2-5 or 1-2-7) that has diagnostic Q-coding afterwards adds that more serious ST rises (9-2), confirms to enlarge markedly.

ED5. do not have Q-coding (or 1-2-6) in baseline ECG, also do not have 4-1-S and 4-2, uncertain afterwards Q-encoded recording (1-2-8 or any 1-3-x coding) adds 4-1-X or 4-2 record, confirms to enlarge markedly.

ED5b. the Q-coding (or 1-2-6) that in baseline ECG, does not have Hom under the main ST that pre-exists (4-1-x to 4-2), be that uncertain Q-encoded recording (1-2-8 or any 1-3-x coding) adds Hom under the more serious ST (4-1-X) record afterwards, confirm to enlarge markedly.

ED6a. not having Q-coding (or 1-2-6) in baseline ECG, also do not have 5-1 or 5-2, is the record that uncertain Q-coding (1-2-8 or any I-3-x coding) adds 5-1 or 5-2 afterwards, confirms to enlarge markedly.

ED6b. in baseline ECG, do not have the main T-ripple that pre-exists and be inverted the Q-coding (or 1-2-6) of (5-1 or 5-2), be the record that uncertain Q-coding (1-2-8 or any 1-3-x coding) adds more serious T-ripple inversion (5-1 or 5-2) afterwards, confirm to enlarge markedly.

ED7a. not having Q-coding (or 1-2-6) and 9-2 in baseline ECG, is the record that uncertain Q-coding (1-2-8 or any 1-3-x coding) adds 9-2 afterwards, confirms to enlarge markedly.

ED7b. the Q-coding (or 1-2-6) that does not have the ST rising (9-2) that pre-exists in baseline ECG is that uncertain Q-coding (1-2-8 or any 1-3-x coding) adds more serious ST rising (9-2) record afterwards, confirms to enlarge markedly.

Diagnosis ECG:

D1. the ECG record that has diagnostic Q-coding (1-1-1 is to 1-2-5 or 1-2-7).

D2. have the ST fragment rise (9-2) add that the T ripple is inverted the ECG record of (5-1 or 5-2).

The ST-T pattern that forms:

If have 7-1-1,7-2-1 or 7-4, then can not use this diagnosis.For the participant of hospitalization, described EV pattern can occur raising or reduction aspect the coding seriousness.

EV1.

Be 4-0 (no 4-coding) among the baseline ECG, 4-4 or 4-3 are to have 4-1-1 afterwards, and the record of 4-1-2 or 4-2 confirms to enlarge markedly.Or only for the ECG of hospital, in the ECG of hospital the earliest, be 4-1-1,4-1-2, or 4-2 are to have 4-0 afterwards, the record of 4-4 or 4-3 confirms to enlarge markedly.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in the Q-coding of being found, do not enlarge markedly.

EV2.

4-2 or 4-1-2 are arranged in baseline ECG, are the record with 4-1-1 afterwards, confirm to enlarge markedly; Or 4-2 is arranged in baseline, and be record afterwards with 4-1-2, confirm to enlarge markedly; Or only for the ECG of hospital, in the ECG of hospital the earliest, be 4-1-1, be logout afterwards with 4-1-2 or 4-2, confirm significantly to reduce; Or in baseline ECG, 4-1-2 is arranged, and in following the tracks of RCG, 4-2 is arranged afterwards, confirm significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in the Q-coding of being found, do not enlarge markedly.

EV3.

Be 5-0 among the baseline ECG, 5-4 or 5-3 are the record with 5-2 or 5-1 afterwards, confirm to enlarge markedly.Or only for the ECG of hospital, in the ECG of hospital the earliest, be 5-1 or 5-2, be to have 5-0 afterwards, the logout of 5-4 or 5-3 confirms significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in discovery Q-coding, do not enlarge markedly.

EV4.

Being coding 5-2 among the baseline ECG, is the record with 5-1 afterwards, confirms to enlarge markedly; Or only for the ECG of hospital, in the ECG of hospital the earliest, be 5-1, be logout afterwards with 5-2, confirm significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in the Q-coding of being found, do not enlarge markedly.

EV5.

Being coding 9-0 among the baseline ECG, is the record with 9-2 afterwards, confirms to enlarge markedly; Or only for the ECG of hospital, in the ECG of hospital the earliest, be 9-2, be logout afterwards with 9-0, confirm significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in the Q-coding of being found, do not enlarge markedly.

EV6.

Being coding 4-1-1 among the baseline ECG, is the record with 4-1-1 afterwards, confirms to enlarge markedly; Or only for the ECG of hospital, in the ECG of hospital the earliest, be 4-1-1, be logout afterwards with 4-1-1, confirm significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in the Q-coding of being found, do not enlarge markedly.

EV7.

Being coding 5-1 among the baseline ECG, is the record with 5-1 afterwards, confirms to enlarge markedly; Or only for the ECG of hospital, in the ECG of hospital the earliest, be 5-1, be logout afterwards with 5-1, confirm significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in the Q-coding of being found, do not enlarge markedly.

EV8.

Being coding 5-2 among the baseline ECG, is the record with 5-2 afterwards, confirms to enlarge markedly; Or only for the ECG of hospital, in the ECG of hospital the earliest, be 5-2, be logout afterwards with 5-2, confirm significantly to reduce.

Add

In baseline ECG and tracking ECG, all there is not the Q-coding; Or in baseline ECG or tracking ECG, have the Q coding, but in discovery Q-coding, do not enlarge markedly.

EV9a.

Hom, T ripple are inverted or ST rising (4-2/4-1-x under the main ST that does not have Q-coding (or 1-2-6) among the baseline ECG and be pre-existing in, 5-2/5-1 or 9-2), be uncertain Q-coding (1-2-8 or 1-3-x coding) arbitrarily and so not serious or do not have Hom under the ST, T ripple to be inverted or ST rising (4-0/4-4/4-3/4-2/4-1-x afterwards, 5-0/5-3/5-2/5-1 or 9-0/9-2), confirm that the Q-coding enlarges markedly, ST or T ripple change confirmation and significantly reduce.

EV9b.

Hom, the inversion of T ripple or ST rising (4-2/4-1-x under the main ST that has uncertain Q-coding (1-2-8 or any 1-3-x coding) among the baseline ECG and be pre-existing in, 5-2/5-1 or 9-2), be diagnosis Q-coding (1-1-1 to 1-2-5 or 1-2-7) and so not serious or do not have Hom under the ST, T ripple to be inverted or ST rising (4-0/4-4/4-3/4-2/4-1-x afterwards, 5-0/5-3/5-2/5-1 or 9-0/9-2), confirm that the Q-coding enlarges markedly, ST or T ripple change confirmation and significantly reduce.

The bundle branch retardance that forms

E-BBB1. not having 7-1-1 (reference), is the ECG with 7-1-1 afterwards, and the QRS duration increased 〉=0.02 second, confirmed to enlarge markedly.

E-BBB2. not having 7-2-1 (reference), is the ECG with 7-2-1 afterwards, and the QRS duration increased 〉=0.02 second, confirmed to enlarge markedly.

E-BBB3. not having 7-4 (reference), is the ECG with 7-4 afterwards, and the QRS duration increased 〉=0.02 second, confirmed to enlarge markedly.

The LVH that forms

E-LVH1. not having 3-1 (reference), is the ECG with 3-1 afterwards, confirms to enlarge markedly.

E-LVH2. not having 3-3 (reference), is the ECG with 3-3 afterwards, confirms to enlarge markedly.

E-LVH3. not having 3-1 (reference), is to have the ECG of 3-1 or do not have 3 codings afterwards, confirms significantly to reduce.

E-LVH4. not having 3-3 (reference), is to have the ECG of 3-3 or do not have 3 codings afterwards, confirms significantly to reduce.

Uncertain ECG pattern:

EI. the ECG record that has 1-2-8; It under the condition that does not have 7-2-1 or 7-4 ECG record with 1-3-x.

E2. the ECG record (4-1-x, 4-2 or 4-3) that has Hom under the ST-fragment.

E3. has the inverted ECG record of T-ripple (5-1,5-2 or 5-3).

E4. the ECG record that has ST-fragment rising coding 9-2.

Other ECG pattern:

All other ECG that find comprise normal.

The ECG pattern of codified not:

UI. compile by the Minnesota coding and be the technical error of 9-8-1.

A. three or above misguidance.

B. produce the muscle jitter illusion of possible wrong Initial R.

C. other makes Q-wave measurement impossible technical error that becomes, as obvious off-center or tangible slicing.

D. be defined as other condition of " not codified " by the Minnesota coding.

The ECG that lacks:

A. there is not ECG to encode.

Appendix IV: the quality contrast of the myocardial infarction of hospitalization (MI) is estimated

Below be used for acute hospitalization MI definition and be not inclined to base area point investigation AL04 classified, but make quality to comment by estimate by terminal point grouping committee.

Existing standard is based on CCSP experimental research, Minnesota heart survey and other supervision research and studies in conjunction with ARIC.Below make peace greatly described in the above-mentioned document those of the combination of required pain, ECG and the enzyme classification of each diagnostic procedure identical.

The MI of clear and definite hospitalize

Must satisfy following one or more standard:

1. form diagnostic ECG pattern (ED1-ED7) (appendix III, adnexa 1), or

2. diagnostic ECG pattern (D1 or D2) and unusual enzyme (appendix III, adnexa 1), or

3. pained (as described below) and unusual enzyme; With

A. form ST-T pattern EV1-EV9 (appendix III, adnexa 1), or

B. uncertain ECG pattern E1-E4 (appendix III, adnexa 1)

The MI of possible hospitalization

Must not satisfy the following stated one or more standard there being enough evidences to prove under the condition of MI of clear and definite hospitalization:

1. pained and unusual enzyme, or

2. pained and uncertain enzyme and

A. form the ST-T pattern, or

B. diagnostic ECG pattern, or

3.a. unusual enzyme and

B. form the ST-T pattern

The MI of suspicious hospitalization

Must not satisfy the following stated one or more standard there being enough evidences to prove under the condition of MI of clear and definite or possible hospitalization:

1. unusual enzyme, or

2. pained and incomplete enzyme and

A. diagnostic ECG pattern, or

B. form the ST-T pattern, or

3. pained and uncertain enzyme, or

4. uncertain enzyme and

A. diagnostic ECG pattern or

B. form the ST-T pattern or

C. uncertain ST-T pattern

The definition of the concrete key element of chest pain, enzyme and ECG below is provided, and they are used for clear and definite, possible, the suspicious MI of last diagnostic or do not have MI.

Pained definition

Pain has following two features:

In the shirtfront, left arm or jaw have pain Anywhere

2. do not have the clear and definite non-heart disease that causes pain because of.

Unusual cardiac enzymes

If the enzyme value that is write down satisfies following arbitrary standards, then enzyme can be decided to be unusually:

" 1.a.CK-MB existence ": (not being to use the standard of " existence " or " not existing ") if laboratory have record to be worth more specifically, or CK-MB more than or equal to total CK value 10% and

B. there is not known non local ischemic reason (operation on heart, serious muscle injury, rhabdomyolysis) to cause the enzyme value to improve, or

2.a.LDH ₁: LDH ₂〉=1 He

B. there is not evidence to show the trouble hemolytic disease, or

3.a. total CK and LDH all be upper limits of normal twice at least (these increase situations can not occur on the same day) and

B. do not have known non local ischemic reason (operation on heart, serious muscle injury, rhabdomyolysis) to cause the enzyme value to improve, and do not have evidence to show the trouble hemolytic disease.

The uncertain enzyme of heart

If do not satisfy the standard of unusual enzyme, then enzyme is classified as " uncertain ", and, if:

1. any is the twice at least of upper limits of normal for total CK or total LDH, or

2. total CK and total LDH all between upper limits of normal and upper limits of normal twice (these increase situations can not occur on the same day) or

3.CK-MB account for the 5-9% of total CK, or be " faint existence ".

Provided the general introduction of enzymatic diagnosis standard in the following rule (table 1), it is relevant with LDH with total CK.

The rule of total CK of table 1. and LDH enzymatic diagnosis standard

		Total CK
						Upper limits of normal		The twice of upper limits of normal
		Total LDH	The twice upper limits of normal of upper limits of normal	Uncertain	Uncertain					Unusually
Normally	Uncertain						Uncertain
				Normally	Normally			Uncertain

Table 2

Pained	ECG finds	Enzyme	Diagnosis
				Exist	Progressive diagnostic mode (EDI-ED7)	Unusually	Definite MI
Uncertain	Definite MI
		Do not finish	Definite MI
Normally	Definite MI
		Diagnosis ECG pattern	Unusually			Definite MI
Uncertain	Possible MI
			Do not finish		Suspicious MI
Normally	No MI
			Progressive ST-T pattern (EVI-EV9)		Unusually	Definite MI
Uncertain	Possible MI
		Do not finish			Suspicious MI
Normally	No MI
		Uncertain ECG pattern			Unusually	Definite MI
Uncertain	Possible MI
			Do not finish		No MI
Normally	No MI
			No, not codified or other		Unusually	Possible MI
Uncertain	Suspicious MI
		Do not finish			No MI

		Normally	No MI
				Do not exist, unknown or damaged	Progressive diagnostic mode (EDI-ED7)	Unusually	Definite MI
Uncertain	Definite MI
		Do not finish	Definite MI
Normally	Definite MI
		Diagnosis ECG pattern	Unusually			Definite MI
Uncertain	Suspicious MI
			Do not finish		No MI
Normally	No MI
			Progressive ST-T pattern (EVI-EV9)		Unusually	Possible MI
Uncertain	Suspicious MI
		Do not finish			No MI
Normally	No MI
		Uncertain ECG pattern			Unusually	Suspicious MI
Uncertain	Suspicious MI
			Do not finish		No MI
Normally	No MI
			No, not codified or other		Unusually	Suspicious MI
Uncertain	No MI
		Do not finish			No MI
Normally	No MI

Method appendix 1

The body fat of ALLHAT reduces the calibrated effectiveness of part

The body fat of ALLHAT reduces the effect basis gross sample size 10,000 and the son group size 4,000 of part and proofreaies and correct.As two kinds of more pessimistic rules, loss rate is 1 year 6%, afterwards every year 3%.As two kinds of more pessimistic rules, described incorporation rate is annual 2.5%.The loss of general mortality rate is decided to be 0, and for CHD, specifically specifies in the rules of resisting hypertension component (a little higher than annual 3%).Shown in sickness rate be used to calculate the effect of antihypertensive therapy.Described efficacy results is shown in table 1 and 2.Also consider more pessimistic loss rate, be annual 5%.This will render a service and reduce about 2 percentage points.

Table 1: the effectiveness of general mortality rate

Suppose that loss is 0, the first year loss rate=6%, annual afterwards 3%, annual incorporation rate=2.5%.

Treatment reduces	Contrast rate/year	N＝4,000	N＝10,000
					0.01
	0.015
				10% reduces	0.020
	0.025
					0.030	19％	41％
	0.01	13％	25％
					0.015	17％	35％
12.5% reduces	0.2	21％	44％
					0.025	24％	52％
	0.030	28％	59％
					0.01	16％	34％
	0.015	22％	47％
				15% reduces	0.02	28％	58％
	0.025	33％	68％
					0.030	39％	75％
	0.01	26％	55％
					0.015	37％	72％
20% reduces	0.02	46％	84％

	0.025	54％	91％
					0.030	62％	95％
	0.01	39％	76％
					0.015	54％	90％
25% reduces	0.02	65％	96％
					0.025	75％	99％
	0.030	82％	99％+
					0.01	53％	90％
	0.015	70％	98％
				30% reduces	0.02	82％	99％
	0.025	89％	99％+
					0.030	94％	99％+

The effectiveness of table 2:CHD

Identical as mentioned above loss rate and incorporation rate.Draw the effectiveness of the loss rate of in rules, inferring.

Treatment reduces	Contrast rate/year	?N＝4,000	N＝10,000
					0.008	?21％	44％
	0.010	?25％	52％
				20% reduces	0.012	?29％	60％
	0.014	?33％	66％
					0.016	?36％	72％
	0.008	?31％	63％
					0.010	?37％	73％
25% reduces	0.012	?43％	80％
					0.014	?48％	86％
	0.016	?53％	90％
					0.008	?42％	80％
	0.010	?50％	88％
				30% reduces	0.012	?58％	93％
	0.014	?64％	96％

	0.016	?70％	98％
					0.008	?55％	91％
	0.010	?65％	96％
				35% reduces	0.012	?72％	98％
	0.014	?79％	99％
					0.016	?84％	99％+

Method appendix 2. monitoring borders

When the data in the rechecking test, if do not consider these multiple " observation " (Armitage, Mc.Pherson and Rowe, 1969; Proschan, Follmann and 1992), described I type error rate enlarges markedly.In two arm trial, make up the border, eliminated or improved greatly the expansion of this I type error rate.These are called group continuously, rather than continuum boundary, and this is because intermediate analysis is to carry out after multi-group data produces naturally, rather than carry out after each new observation.Most popular these require very strong evidence to prove the importance of test in early days, and the evidence that roughly proves in the same degree in test latter stage, and these evidences require not carry out intermediate analysis.These are not the situations (Pocock, 1977) of described first group of consecutive steps.For this reason, Pocock oneself does not recommend to use its step (individual reports).

Described O ' Brien-Fleming (1979) border has above character.Described defective is the number of times that need carry out aforesaid observation, and these observations must be carried out after equating the report increase.In this test, the ratio of the number of times of estimating during by observed event number and off-test after this comes appraisal report time t.Therefore, t=0 is initial, and t=1 is the end of research.Suppose that we are equating that report increment (event times) carries out 8 times to data afterwards and observes.Fig. 1 has provided the border that is used for relatively specifying arm and diuretic arm.Multiple comparisons correction and diuretic have been made relatively three times.

Method that Lan and DeMets (1983) have proposed a kind of " consumption function (spending function) ", it checks described data after not commensurability report, and the number of times that does not need to carry out aforementioned observation.Described consumption function α ^*(t) cumulant of the expression 1 type probability of error, t consumes by the time, simultaneously α ^*(1)=α.The amount and the report time of the consumption of the 1 type probability of error link together.This is compared with Slud and the described method of Wei (1982), and said method is consumed the 1 type probability of error of fixed amount when each time observed data, and is irrelevant with report time.Amplify and the serious 1 type probability of error can occur with Slud and Wei step, but then can (Proschan, Follmann, andWaclawiw, 1992) to the Lan-DeMets step.If described observation just in time occurs in (see figure 1) after the equal increase of report, a kind of consumption function that Lan and DeMets proposed (seeing the equation in the appendix) has the border that is similar to O ' Brien-Fleming border.Even the advantage of Lan-DeMets method is also can use when described observation and unequal-interval.In this case, there is variation a little on described border.

Another kind of monitoring tools of great use is that condition is renderd a service (Lan, Simon, and Halperin, 1982 or Lan and Wittes, 1988).The described result's that statistical significance is arranged who obtains when off-test conditional probability calculates under different hypertension therapeutic effects.Unlike O ' Brien-Fleming or Lan-DeMets border, condition is renderd a service and is generally used for judging whether test finishes, and it can not draw the result's of statistical significance realization probability.If condition is renderd a service very low (the treatment works well for the test of instant hypothesis residue), described test just stops.Reduction is meant and stops test at random, and this is because condition is renderd a service and preassigned threshold values intersects.For example, be less than or equal to 0.10, just can agree to stop described test if condition is renderd a service (being assumed to be preassigned alternative hypothesis).If use this rule, then the probability of 2 type errors (when being fictitious time, being accepted as null hypothesis) is greater than the situation of not reducing at random.This is that the amplification degree of 2 type error rates is very little because can accept described null hypothesis in the research end or at the intermediate point place.Lan, Simon and Halperin (1982) are even show the described test of continuous monitoring, it is still quite little.Davis and Hardy (1990) are presented in the more real situation and (monitor described test 5-10 time), and described amplification is much smaller.

The major issue that runs in the group continuous monitoring is exactly a report time.Mention the number of times that the morbidity number of times of observation is estimated divided by off-test after using before us and estimate report time.Is what arm but described number of times? in both arms monitoring, can use total morbidity number in two arms or the morbidity number of times in the control arm.That uses two arms determines to be exactly the morbidity number of times of being estimated when estimating off-test, not only will reflect the sickness rate of matched group, also will reflect the effect of treatment.In ALLHAT, we have four resisting hypertension arms, therefore, have three less important specified therapeutic effect.Recommend to use the diuretic arm to fall ill to determine report time.

List of references

Armitage，P.，Mc.Pherson，C.K.，and?Rowe，B.C.(1969).Repeated?significance?tests?onaccumulating?data.Joural?of?the?Royal?Statistical?Society?A.132，235-244.

Lan，K.K.G.and?DeMets，D.L.(1983).Discrete?sequential?boundaries?for?clinical?trials.Biometrika?70，659-663.

Lan，K.K.G.，Simon，R.，and?Halperin，M.(1982).Stochastically?curtailed?tests?in?long?termclinical?trials.Communications?in?Statistics-Sequential?Analysis?1(3)，207-219.

Lan，K.K.G.and?Wittes，J.(1988).The?B-value：a?tool?for?monitoring?data.Biometrics44，579-585.

O′Brien，P.C.and?Fleming，T.R.(1979).A?multiple?testing?procedure?for?clinical?trials.Biometrics?35，549-556.

Pocock，S.J.(1977).Group?sequential?methods?in?the?design?and?analysis?of?clinical?trials.bBiometrika?64，191-199.

Proschan，M.A.，Follmann，D.A.，and?Waclawiw，M.A.(1992).Effects?of?assumptionviolations?on?type?1?error?rate?in?group?sequential?monitoring.Biometrics?48，1131-1143.

Slud，E.and?Wei，L.J.(1982).Two?sample?repeated?significance?tests?based?on?the?modifiedWilcoxon?statistic.Journal?of?the?American?Statistical?Association?77，862-868.

Adnexa

The consumption function of recommending

${\mathrm{\&alpha;}}^{*}\left(t\right)=2\left[1\mathrm{\&Phi;}(Z_{\mathrm{\&alpha;}/4}/\sqrt{t})\right],$

The Lan-DeMets consumption function that we recommend is: α wherein is the 1 type error rate on both sides, is used for specifying comparison with diuretic; (be Standard Normal Distribution, Z _αThe/4th, its 100 (1-(/ 4) percentage point.When we judge with diuretic, when proofreading and correct repeatedly relatively, Z _α/ 4 values are about 2.64.

The termination rules of suggestion

1) the Lan-DeMets version of use O ' Brien-Fleming is to determine harm/benefit.

2) described border is symmetric.

3) report time will calculate as the ratio of estimating morbidity in the diuretic arm.

4) be taken at first of about 10% report time and observe, annual when the DSMB meeting then.

5) result that special concern intersects Haybittle-Peto border (Z=4.0 is to the antihypertensive part) and Z=3.0 (body fat reduces component) when beginning.

6) use the condition under the specified alternative null hypothesis bar of rules to render a service.

Be used to prevent that the resisting hypertension and the body fat of having a heart attack from reducing treatment (1994-2002)

University of Texas's publilc health clinical trial coordination center

Describedly prevent that the antihypertensive of having a heart attack and body fat from reducing treatment (ALLHAT) is a kind of clinical trial based on practice, (and Blood Institute NHLBI) subsidizes for National Heart, Lung by national heart, lung and Blood Research Institute.Described test is carried out in the whole U.S., Puerto Rico, archipelago, dimension capital and Canadian about 600 department's interns and general doctor and special clinic.

On February 14th, 1994 to having selected 42,418 patients altogether between 31 days January in 1998.Wherein most of right and wrong descendants American.Carried out commitment the first half of the year in 1994, the test of beginning full-scale in the whole year in 1994, and continued 8 years, up on March 31st, 2002.

Described research comprises two parts:

The antihypertensive part is used for comparing to determine new antihypertensive with diuretic, whether reduces high-risk coronary artery disease in hypertension patients (CHD) outbreak as ACE inhibitor, calcium blockers and alpha block agent.

Body fat reduces part, is used for determining whether can reduce serum cholesterol with pravastatin, HMG-CoA reductase inhibitor, reduces the general mortality rate of the hypertension aged patient of moderate hypercholesterolemia.

Because the effectiveness that body fat reduces can be tested in the patient's subgroup that is used for studying ALLHAT resisting hypertension component,, cost is made peace carry out separately any one suitable greatly so described two test combinations together.

Because non-descendants American disproportionately suffers from hypertension and sequela thereof, so most participant's right and wrong descendants American.

Background

The antihypertensive component

This century the eighties early stage, developed three kinds of new antihypertensives (calcium antagonists, angiotensin-invertase (ACE) inhibitor and α-adrenergic blocker), and approval is used for the treatment of chronic antihypertensive.The cost of some in these medicaments is therapeutic agent before such as diuretic and beta blocker 30 times.Think that simultaneously their side effect is less, and have many adeditive attributes (except the effect that they bring high blood pressure down), can reduce the M ﹠ M of coronary heart disease (CHD).

But, with these medicaments as TOMHS (Arch Intern Med 1991; 151:1413-1423) with VA sulfide test (N Engl J Med 1993; 328 914-921) compare in the research, do not demonstrate the main difference in the reduction of side effect or blood pressure.The effectiveness of new medicament prevention CHD can not be estimated in extensive interim trial.Although the medicament before comparing, their cost increases and absence of proof proves its superiority, in the past in the period of 5 to 10, and its application (especially using calcium antagonist and CAE inhibitor) showed increased.

Body fat reduces component

Known hypercholesterolemia is main CHD risks and assumptions, but proves that cholesterol reduces the test that CHD is reduced and do not prove complete in the clean reduction on (all-cause) mortality rate.Because these tests are mainly carried out in middle-aged male, and the extrapolation effect of old male and women's conclusion also is discussed.In the late nineteen eighties, the HMG-CoA reductase inhibitor of introducing provides new effective body fat to reduce therapy, and it has good toleration, and has adverse effect seldom.Nearest NHLBI research has confirmed the probability and effectiveness (the Arch Int Med 1994 of lovastatin cholesterol reducing in old adult at last; 154:529-539).

The design of ALLHAT research

Open (the Am J Hypertension 1996 of the ultimate principle of ALLHAT and design; 9:342-360).In ALLHAT, the hyperpietic accepts a kind of in four kinds of medicines at random in double-blind trial.Do not have the patient to accept placebo, and provide the second limited step medicament to select to the last unsteered patient of choice drug treatment.Follow the tracks of the patient in per 3 months in 1 year, in 6 years follow-up investigation phases subsequently, on average carried out a secondary tracking in per 4 months.

Select about 10,000 patients to go on a diet in nonocclusive mode in the hypotensive agent part at random and add upper body fat reduction, perhaps going on a diet adds general duty nursing.After the randomization, the frequency of the follow-up investigation of two test portions and content are all similar.

ALLHAT studies the candidate

The antihypertensive part

55 years old age or more than

Known hyperpietic, BP is less than or equal to 160/100mmHg when treatment; Or when not treating BP more than or equal to 140/90mmHg and be less than or equal to 180/110

At least suffer from next disease:

1. on ECG and Echocardiogram left ventricular hypertrophy appears

2. known atherosclerosis CVD

3.II type diabetes

4.HDL cholesterol＜35mg/dl

5. current is the smoker

Main eliminating project

Suffer from MI or apoplexy recently

Known congestive heart disease or angina pectoris

Need the medication of research other reason except that hypertension

Need two or more antihypertensives to control BP

Serious general disease

High serum creatinine (2mg/dl or more than)

Body fat reduces part

Qualified in and at random the antihypertensive part

LDL cholesterol 120-189mg/dl (patient who is used to suffer from CHD is 100-129)

Main eliminating project:

Current use body fat reduces Drug therapy

The contraindication of HMG-CoA reductase inhibitor

The secondary disease of known untreated hyperlipoidemia because of

2 times of ALT＞upper limits of normal

The state university of Texas-health science center, Houston

Morning Monday

On April 17th, 2000 Monday

Studies show that the blood pressure medicine reduces cardiopathic risk

Jackie Preston work, public affairs office

Chlortalidone (Chlorthalidone), a kind of diuretic commonly used of suffering from the hyperpietic that is used for the treatment of is compared doxazosin and alpha block agent, and it has significantly reduced cardiopathic onset risk, as described in the researcher of UT-Houston.

Described discovery is recorded as the resisting hypertension of prevention of cardiac and the part that body fat reduces therapeutic test (ALLHAT) by the publilc health institute, the eight term multicenter study that this is subsidized by national cardiopulmonary and Blood Research Institute (National Heart, Lung and Blood Institute (NHLBI)).Described result of study is announced in being published in " the Journal of the American Medical Association " on April 10,9.

" we compare the people who takes doxazosin at demonstration; the research participant who takes doxazosin (doxazosin) has reduced half with the risk that it suffers from a heart complaint ", Barry R.Davis.M.D., Ph.D say that he is the professor of publilc health school and the director of clinical trial coordination center

ALLHAT researcher wants to know whether whether more cheap medicine such as diuretic can be better aspect antagonism reduction hypertension and adverse side effect (comprising heart disease and stroke) thereof.

24,335 patients have been followed the tracks of in described research, and the age is more than 55 years old, suffer from least a in hypertension and several cardiovascular disease risks and assumptions, as heart disease and stroke.The patient specifies at random and takes a kind of in four kinds of hypertension agents, comprises chlortalidone and doxazosin.

" compare the chlortalidone group, the risk of cardiovascular diseases of described doxazosin group increases 25%, and cardiopathic risk is then double " Davis mentions.

Based on described discovery, NHLBI has stopped the research of doxazosin part.

Davis says that described research provides better treatment for suffering from hypertensive patient.

" our result of study has confirmed that at present chlortalidone is the first-selected measure that treatment has the hypertensive old people of trouble of heart disease risk " Davis says.

In 1993, publilc health school obtained 103,20 from NHLBI, and 000 dollar subsidy is used to carry out ALLHAT, was the maximum since the dawn of human civilization contract in UT-Houston.

American more than 4,600,000 has a heart disease, be the U.S. cause disabled and dead main diseases because of, be the disease of the modal hospital of the philtrum obligation diagnosis of age over-65s.

American more than 5,000 ten thousand suffers from hypertension, perhaps hypertension.The popularity degree of described disease in white people is than high by 50% in non-descendants American.

Antihypertensive therapy scheme and change blood pressure to the relation between the hyperpietic's that takes doxazosin or chlortalidone at random the risk of heart failure: further analyze resisting hypertension and body fat and reduce treatment with prevention of cardiac

Barry R.Davis, MD, PhD; Jeffrey A.Cutler, MD; Curt D.Furberg, MD, PhD; Jackson T.Wright Jr., MD, PhD; Michael A.Farber, MD; James V.Felicetta, MD; With John D.Stokes, MD, be ALLHAT joint study group

Background:

The resisting hypertension of described prevention of cardiac and body fat reduce therapeutic test and mention, compare situation with the chlortalidone begin treatment, the cardiopathic initiation potential of high-risk hyperpietic is the former twice (relative risk, 2.04[95%CI, 1.79-2.32]) in the treatment that begins with doxazosin.Patient's average heart contraction/diastolic blood pressure in test of carrying out the doxazosin treatment is 3/0mmHg, is higher than the patient's who takes chlortalidone blood pressure.There are 68% (6167 people in 9061) and a part of patient in back to have 59% (9081 people in 15256) to carry out extra Drug therapy among the patient of a preceding part, make the target blood pressure less than 140/90mmHg.

Purpose:

For the influence of the blood pressure of the antihypertensive drug of determining open labelling and generation to the relative risk of heart failure.

Design:

Double blinding at random,, activity-contrast clinical trial.

Set:

In the U.S. and Canadian 623 places.

The patient: the hyperpietic, 55 years old or more than, have at least one in other heart disease risks and assumptions.

Disturb:

Chlortalidone (12.5-25mg/d) or doxazosin (2-8mg/d) are followed the tracks of 4-8 according to plan.

Measure:

Blood pressure, medicine and accidental heart failure data (treatment outside hospital, hospitalization or death) are from February, 1994 to 1999 year December.

The result:

After treatment, be unexposed open labeled drug treatment (sulfide) or the open treatment that exposes with each component, doxazosin and chlortalidone at cardiopathic relative risk be 3.10 respectively (Cl, 2.51-3.82) and 1.42 (Cl, 1.20-1.69).To following the tracks of after heart contraction/diastolic blood pressure proofreaies and correct, described comprehensive relative risk be 2.00 (Cl, 1.72-2.32).

Conclusion:

In suffering from hypertensive high-risk patient, height when the heart failure onset risk ratio when taking doxazosin is taken chlortalidone, this can weaken by adding other antihypertensive, but can not eliminate.Observed little difference can not be explained the increase of this risk in the described heart contraction blood pressure.

Ann?intem?Med.2002-137：313-320

As for author's situation, see the article end

JAMA.2000:283:1973-5 is seen in the tabulation fully of ALLHAT coordination research group.

It is a kind of double blinding multichannel clinical trial at random that described antihypertensive and body fat reduction treatment prevention of cardiac are sent out test (ALLHAT), comprise 42 in 623 clinical clinics, 418 patients, and design is determined with calcium channel blocker (amoldipine), whether the treatment (comparing the treatment with diuretic (chlortalidone)) of angiotensin converting enzyme inhibitor (lisonopril) and α-adrenergic blocker (doxazosin) beginning has reduced the probability (1) of mortality coronary heart attack among the high-risk hyperpietic or non-fatal myocardial infarction. and secondary endpoints is the mortality rate that a variety of causes causes, apoplexy and other heart disease are sent out incident.In 10356 participants' subgroup, body fat reduces the mortality rate that EXPERIMENTAL DESIGN determines to compare with general duty nursing with methylol glutamy CoA-reductase inhibitors (pravastatin) cholesterol reducing content the various causes of disease that whether can reduce old medium hypercholesterolemia patient.

In January, 2000, the doxazosin arm of described test stops, this be because compare the main cardiovascular disease of arm with chlortalidone (relative risk, 1.25[95%CI, 1.17-1.33]; P＜0.001), especially heart failure (relative risk, 2.04%[95%CI, 1.79-2.32]; P＜0.001) enlarges markedly.It is also important that, have this low probability, if promptly planning studies last do not have difference (relative risk, 1.02[95%, CI0.90-1.17]; P＜0.001), doxazosin demonstrates at this moment the contribution of main terminal point is surpassed chlortalidone so.These Treatment Analysis have compared patient who takes chlortalidone and the patient who takes doxazosin.

In this article, we have analyzed treatment and have changed how to influence doxazosin and the comparison of chlortalidone aspect heart failure.Our main purpose is the degree that the relative risk of determining doxazosin and chlortalidone depends on condition as described below: 1) described medicine whether be as single therapeutic agent or and other medicament combination of components, and 2) reduce and shrink and the difference of diastolic blood pressure aspect.

Method

Research design

The ultimate principle of described ALLHAT and design have detailed description (1) elsewhere.In brief, qualified participant is the masculinity and femininity of age more than 55 years old, and they suffer from heart contraction or diastole hypertension (more than or equal to 140/90mmHg, or with the hypertension of medicine control) and add at least one other risks and assumptions in the coronary event.(more than 6 months) myocardial infarction or apoplexy before described risks and assumptions comprises, the left ventricular hypertrophy, type ii diabetes history, the current smoker of being and the HDL-C content that show on electrocardiogram or heart echo scintigram are low.Get rid of the people of those heart disease syndrome histories that hospitalization or treatment are arranged or the known mark of leaving hospital less than 0.35 people.

Take in unless reduce medicine for the sake of security gradually, the participant who has taken antihypertensive drug requires to carry out continuously, and up to any natural law, this moment, they cut out all medicines in the past.After any natural law, begin to carry out the treatment of drug research.

Register from year January in February, 1994 to 1998.The quantity of described protocol is 42448 participants, has changed 625 places, and this is because will get rid of relatively poor 30 patients (2) of content of announcement record.The participant takes chlortalidone and doxazosin by the scheme that computer random is arranged with 1.7: 1 ratio.Randomization carries out classification by the center, and stops within a certain period of time, keeps described ratio thus.All participants provide written content of announcement, and all centers all obtain the approval of examination administration committee of association.

Content
	This at random, the early stage openly result of double-blind trial shows that the hyperpietic with the doxazosin treatment heart failure occurs than the patient Geng Chang with the chlortalidone treatment, can explain that with the difference of other medicines treatment or controlling blood pressure these find?
Contribution
	These analyze the poor slightly control control to blood pressure that shows with the doxazosin acquisition can not explain why higher the heart disease onset risk is.In the patient who accepts treatment separately, compare the situation of chlortalidone, with the risk the highest (relative risk 3.10) of doxazosin.In the patient who carries out the substep nursing with other medicines then minimum (relative risk, 1.42).
Enlightenment
	When using other antihypertensive drug, the heart failure risk that causes with doxazosin (comparing with chlortalidone) increases and can reduce, but can not eliminate.

Result acceptance

In each clinical interview, the appearance of research terminal point is determined by clinical investigator.The achievement in research of respectively the being in hospital summary of need leaving hospital, each death need be provided death certificate.ALLHAT is defined as symptomatic heart failure has a left side or the right ventricle dysfunction sign or the symptom that significantly can not be included into other cause of disease.The patient has at least a symptom (dyspnea when sudden nocturnal dyspnea, sleep, New YorkHeart Association are decided to be III class dyspnea or other symptom [being in the state less than normal outbreak] or orthopnea) and a kind of sign (the characteristic pulmonary pattern in sound, ankle joint edema, tachycardia, cardiomegaly or the thoracic cavity X-ray radiography, S ₃Gallop rhythm or jugular phlebectasia) (3).Symptom and sign are followed the trail of by patient's medical history, case history by clinical investigator or treatment doctor's diagnosis is determined, but this data and concentrated the collection.

Check 24 hospitalization or fatal cardiopathic disposable sample in invisible mode by ALLHAT terminal point sub-committee, have 20 (83%) to be considered to have the partial data of clarifying a diagnosis in 24.In these 20 cases, unanimous ratio is 90% (in 20 18) between sub-committee and the clinical investigator.This is similar in two treatment groups.After report in provide the details of closing heart disease diagnosis effectiveness.

The measurement of blood pressure and treatment

Described ALLHAT rules are clear and definite is used for the substep nursing for treating program of vascular hypertension.The observer of training uses standard technique to measure blood pressure in test (1,2).All blood pressures are calculated as the meansigma methods of twice measurement that was obtained at interval in 30 seconds between them.The pressure value of all four researchs in the arm be all less than 140/90mmHg, and minimum the unknown first medicine that may dosage obtains this level, and adds the therapeutic agent of the second and the 3rd open labelling after the maximal dose that reaches first medicine.

Chlortalidone and doxazosin are taken once in the morning every day.By design, make described dosage in the treatment group, reach controlling of blood pressure of equal value.First, second and the 3rd dosage level are respectively chlortalidone 12.5mg/d, 12.5mg/d (pseudotitration) and 25mg/d; Doxazosin 2mg/d, 4mg/d (pseudotitration) and 8mg/d.Use the 1mg doxazosin of double blinding and the chlortalidone of 12.5mg in first week, make the postural hypotension frequency minimum relevant with doxazosin.Medicine identity when sheltering each dosage level, but drug dose is not hidden.

After randomization, required as the January and the March of each rules, the patient is carried out dose titration, but they can carry out more frequently, up to reaching the target blood pressure.Afterwards, in 1 year, carried out required observation in per 3 months, carried out in per afterwards 4 months.The second step medicine that adds open labelling on demand with allowance.These medicines are reserpine (0.05-0.2mg/d), clonidine (0.1-0.3mg, twice of every day) and atenolol (25-100mg/d).Clinical investigator is depended in the selection of the second step medicine.The 3rd step medicine is hydralazine (25-100mg, twice of every day).The details of these medicines has explanation (1) in other place.

Figure: carry out randomization and carry out the participant that list is treated and open treatment is analyzed afterwards by seminar

The investigator selects the antihypertensive of the open labelling of writing out a prescription, rather than the medicine that provides of this research.But, do not encourage to use under study for action very much following medicine--thiazine diuretic, calcium antagonist, angiotensin converting enzyme inhibitor and α-adrenergic blocker, to avoid diluting therapeutic combination.When clinical symptoms (not being not controlled hypertension) occurring (for example, angor or heart disease), can use medicine from any research classification.If controlling of blood pressure specifically needs to go on foot 1 medicine, continue the treatment of unknown medicine simultaneously, to go on foot the therapeutic agent that 1 medicine can be used as open labelling so, but dosage can not surpass maximal dose that theFifth Joint National Committee (4) recommends half.In most of the cases, allowing patient or investigator know to distribute not for the treatment task must (in a word, participant or investigator only knows＜1% medicine identity).Drug type (diuretic, calcium channel blocker, angiotensin converting enzyme inhibitor, α-adrenergic blocker, atenolol, reserpine, clonidine, hydralazine and other antihypertensive of 9 kinds of open labellings of possibility of record when each time observed, they comprise the beta blocker of non-atenolol, though medicine name does not mark) in any one.Because diuretic, angiotensin converting enzyme inhibitor and beta blocker have similar function in prevention and treatment heart failure, we claim that these are resisting hypertension heart failure medicine.The data of the antihypertensive that uses were collected before the research registration, rather than collected by drug categories.

Table 1. participant's baseline characteristic

Feature	Do not contact (single treatment) with open labeled drug		Contact with open labeled drug
						The chlortalidone group	The doxazosin group	The chlortalidone group	The doxazosin group
The participant, n	6175	?2894	?8969	?5967
					Age, year	66.8±7.9	?66.8±8.0	?67.0±7.5	?66.8±7.6
The race divides
					The non-Hispanic of white race	37.5	?37.8	?53.8	?50.5
The non-Hispanic of black race	33.4	?28.3	?30.9	?35.1
					The white race Hispanic	18.8	?22.5	?8.3	?7.9
Black race's Hispanic	5.1	?6.0	?2.0	?2.2

Other	3.9	?5.5	?4.9	?4.3
					The women, %	51.3	?50.7	?44.1	?44.4
Education degree, year	10.50±4.1	?10.4±4.5	?11.3±4.0	?11.3±3.7
					Smoking at present, %	24.5	?23.4	?20.2	?20.9
Before research, accept antihypertensive therapy, %	85.5	?84.9	?93.3	?92.8
					Atheroma forms heart disease, %	39.9	?42.1	?48.8	?47.3
The ST-T ripple, %	9.9	?8.5	?10.2	?10.5
					Type 2 diabetes mellitus, %	35.4	?35.0	?36.2	?35.1
HDL-C content is low, %	11.9	?11.5	?12.7	?12.2
					Left ventricular hypertrophy, %
In electrocardiogram	15.0	?14.3	?16.4	?16.7
					On the heart echo scintigram	3.5	?3.2	?4.6	?4.6
Blood pressure, mmHg
					Shrink	143.9(15.3	?144.4(15.4	?147.8(15.7	?147.2(15.8
Diastole	83.8(9.8	?83.9(9.9	?84.1(10.3	?83.9(10.1
					Serum potassium content, mmol/l	4.4(0.7	?4.4(0.8	?4.3(0.7	?4.3(0.6
The serum glucose level of fasting, mmol/l (mg/dl	6.9(3.4 (124(61)	?6.8(3.3 ?(126(59)	?6.9(3.1 ?(124(56)	?6.8(3.0 ?(126(56)
					Serum creatinine concentration (mol/l, mg/dl	77.8(23.3 (0.8(0.3)	?77.8(23.3 ?(0.8±0.3)	?77.8±23.3 ?(0.8±0.3)	?77.8±22.9 ?(0.8±0.3)
Serum cholesterol content, mmol/l (mg/dl)
					The cholesterol total amount	5.6±1.1 (216±42)	?5.6±1.1 ?(216±42)	?5.6±1.1 ?(216±42)	?5.6±1.1 ?(216±42)
The low density lipoprotein, LDL gallbladder	3.5±1.0	?3.5±1.0	?3.5±1.0	?3.5±1.0

Sterin	(135±37)	(135±37)	(135±37)	(135±37)
					HDL-C	1.2±0.4 (46(15)	1.2(0.4 (46(15)	1.2(0.4 (46(15)	1.2(0.4 (46(15)
The fasting triglyceride	2.0(1.5 (177(133)	2.0(1.9 (168±168)	2.0±1.5 (177±133)	1.9±1.3 (168±115)

^*Have to add/value of minus sign is meansigma methods (SD

Statistical analysis

Distribute according to participant's treatment at random, and do not consider the seriality of blind research treatment, analyze the data of using extra drug.Treatment group by whole group is checked described result " all heart failures " (treatment outside hospital, hospitalization or fatal) and " hospitalization or fatal heart failure ".Described before " as randomized " disease time of analyzing is the interval of heart failure that has result's patient from randomization to diagnosis for the first time, perhaps from randomization to having research to finish or the interval of those barren follow-up investigations losses.In this research, do not contact the participant's of open labeled drug the incidence rate as a result of treatment group, with the result of this comparison with contact situation under ratio in each treatment group compare.Those are contacted with the resisting hypertension heart failure drugs or discontiguous patient also similarly compares.Carry out the medicament contact analysis, relatively the doxazosin of the chlortalidone of two kinds of dosage and three kinds of dosage is to the influence (6 kinds of possible comparisons) of the relative risk observed.

Use Kaplan-Meier program (5) to calculate cumulative incidence rate.Use proportional limit risk (5) to calculate relative risk (risk) with 95%CIs and bilateral P value.The analysis of described drug exposure and non-drug exposure is also used the Cox of the reaction condition of the co-variation of the dependence time that expression exposes and this condition of expression and medicament distribution product to return to carry out.Also carried out the Cox regression analysis, it is limited to the durability degree of doxazosin and the various dosage of chlortalidone.Because these analyses that rely on the time are based on statistics and epidemiology basis, therefore, careful explanation (6) should be done in P value, relative risk and confidence interval.

Systolic blood pressure before considering between the described treatment group at random is poor, carry out two types analysis, first, be divided at random the heart contraction blood pressure ((140mmHg or＜140mmHg), diastolic blood pressure ((90mmHg or＜90mmHg) and these blood pressures combinations (eight groups) afterwards, 9-12 month according to its blood pressure with participant's classification.Systolic blood pressure and diastolic blood pressure is poor between the calculating treatment this moment group, and sickness rate, relative risk and the 95%CI more than 1 year.The second, carry out the Cox regression analysis of whole group, it comprises that baseline shrinks and the co-variation amount of the dependence time of the fixed co-variation amount of diastolic blood pressure and tracking contraction and diastolic blood pressure.

When clinic observation, obtain to follow the tracks of blood pressure.Miss the blood pressure that visit draws disappearance.Record misses the reason of visit, comprises not tracing into, refuse feedback and concurrent disease.Use all information that can obtain (owing to lack numerical value, reduce the sample scale), and specify the tracking blood pressure (not capturing measured value at back 6 months) that misses visit, use multiple attribution method to organize and analyze (7,8) according to time and treatment.

The importance in fund source

National Heart, Lung, and Blood Institute has subsidized this research, and relates to except that excentral all aspects of direct management research.This comprises collection, analysis and decryption, and whether decision submits the communique manuscript to.

Conclusion

Described valid conclusion is limited to the identical data of setting in the above communique analysis (1).The treatment persistence of all participant's follow-up investigations is 3.3 years.338 patients (3.7%) lose tracking in 500 patients (3.3%) and the doxazosin group in the chlortalidone group.At duration of test, about 68% patient progressively takes extra medicine in about 59% patient and the doxazosin group in the chlortalidone group.

Described figure shows patient's quantity of random assortment, and the time during it analyzes with each becomes.Participant's number of the maximal dose level that being also shown in has a heart attack reaches blind step 1 medicine before and those are progressively taken participant's number of any open labeled drug or any open labeled drug of resisting hypertension heart disease.The relative risk (doxazosin is to chlortalidone) of the extra drug treatment of accepting before the record heart attack is 1.31 (95%CI, 1.27-1.35) (p＜0.001).Those never begin to carry out among the patient of resisting hypertension heart failure drugs treatment, and about 1/4 patient uses the calcium antagonist begin treatment, and heart failure outbreak (being respectively 7 and 2 in chlortalidone group and doxazosin group) can appear in these patients hardly.

Table 1 shows the basic feature of chlortalidone group and doxazosin group, is divided into open labeled drug treatment and the situation that contacts these medicines of not contacting.In each stratum, the distribution characteristics of treatment group is very similar, and special case is few.Treat in the stratum single, compare chlortalidone group arm, the black race patient in the described doxazosin arm is more than white people patient, yet, treating in the stratum at open labelling, the black race patient in the described chlortalidone arm is more than white people patient.In addition, in single treatment stratum, described doxazosin arm comprises more Hispanic patient and the people who more suffers from the atherosclerosis cardiovascular disease, but the unusual people of ST-T ripple is less.Before studying, accepted to have an appointment among the participant of antihypertensive therapy 30% blood pressure less than 140/90mmHg.On the whole, accept before treatment (90.2%) and accept before the people's that treats mean blood pressure be respectively 145/83mmHg and 156/89mmHg.

All heart failure of table 2. and hospitalization or cardiopathic sickness rate of mortality and relative risk

Heart failure and treatment kind	Per 100 people's sickness rate in the time of 4 years		The patient that conclusion is arranged		Relative risk (95%CI)	The P value
								The chlortalidone group	The doxazosin group	The chlortalidone group	The doxazosin group
All heart failure	←---------------------n--------------→
							Random assortment	4.46± 0.26	?8.14±0.43	?420	?491	2.04 (1.79-2.32)	＜0.001
Do not contact open therapeutic agent	2.64± 0.31	?6.63±0.79	?144	?227	3.10 (2.51-3.82)	＜0.001
							Contact open therapeutic agent	6.93± 0.59	?8.75±0.79	?276	?264	1.42 (1.20-1.69)	＜0.001
The open therapeutic agent of contact resisting hypertension heart failure	6.90± 0.69	?9.81±0.95	?207	?214	1.45 (1.20-1.76)	＜0.001
							Do not contact the open therapeutic agent of resisting hypertension heart failure	6.10± 1.22	?7.43±1.62	?69	?50	1.25 (0.87-1.80)	＞0.2
Hospitalization or fatal heart failure
							Random assortment	3.53± 0.23	?5.77±0.37	?327	?346	1.83 (1.58-2.13)	＜0.001
Do not contact open therapeutic agent	2.03± 0.28	?3.69±0.57	?109	?139	2.52 (1.96-3.24)	＜0.001
							Contact open therapeutic agent	5.64± 0.54	?6.77±0.62	?218	?207	1.39(1.15-1.68)	＜0.001
The open therapeutic agent of contact resisting hypertension heart failure	5.86± 0.64	?7.83±0.87	?172	?172	1.38 (1.12-1.71)	＜0.001
							Do not contact the open therapeutic agent of resisting hypertension heart failure	4.01± 0.90	?4.61±1.22	?46	?35	1.31 (0.85±2.04)	＞0.2

^*Data are expressed as meansigma methods ± SE.

Table 2 has shown at all patients' of random assortment heart failure conclusion relatively to be treated group, not to contact those and those the Cox regression analysis that contacts this Drug therapy of the treatment of open labeled drug.The 4-annual morbidity that contacts the participant of open labeled drug treatment is higher than the participant that those do not contact described Drug therapy.For two groups of conclusions, compare risk with chlortalidone treatment, do not contact with the patient who contacts open labeled drug treatment in risk with the doxazosin treatment remarkable.Risk-ratio in described single treatment group (when various heart failure situation is 3.1, is 2.5 when hospitalization or fatal heart failure situation) is greater than the risk-ratio in the random group.Contact the participant's of open labeled drug treatment risk-ratio less (about 1.4), but still very remarkable statistically (p＜0.001).

The time dependence co-variation amount of the open labelling treatment of expression contact (or the open labelling treatment of resisting hypertension heart failure) obtains essentially identical result with the Cox recurrence that exposes the interaction condition of distributing with treatment.When race, the ethnic division of Hispanic, have atherosclerotic cardiovascular disease and exist the ST-T ripple to add as the co-variation amount unusually fashionable, described discovery just can not change basically.

Table 3: the relative risk of heart failure, the dosage of comparison doxazosin and chlortalidone, the participant does not contact open treatment

The dosage of doxazosin and the dosage of chlortalidone	All heart failure		Hospitalization or mortality heart failure
						Relative risk (95%CI)	The p value	Relative risk (95%CI)	The p value
2mg/d is to 12.5mg/d	?2.81(2.24-3.53)	＜0.001	?2.27(1.73-2.98)	＜0.001
					4mg/d is to 12.5mg/d	?3.51(2.78-4.43)	＜0.001	?2.84(2.15-3.76)	＜0.001
8mg/d is to 12.5mg/d	?3.25(2.28-4.64)	＜0.001	?2.81(1.84-4.30)	＜0.001
					2mg/d is to 25mg/d	?2.43(1.73-3.42)	＜0.001	?1.84(1.22-2.77)	0.004
4mg/d is to 25mg/d	?3.04(2.10-1.39)	＜0.001	?2.30(1.48-2.58)	＜0.001
					8mg/d is to 25mg/d	?2.81(2.24-3.53)	＜0.001	?2.27(1.73-2.98)	0.043

Table 3 has shown the relative risk of all heart failure and hospitalization or fatal heart failure in according to the treatment group of the dosage level of doxazosin and chlortalidone.This analysis is limited to contacting the tracking persistent period of open labelling treatment.Under the doxazosin of all dosage levels, it is conspicuous that described risk increases.For the chlortalidone of fixed dosage, when doxazosin dosage increases to 4mg (but whether increase to from 4mg 8mg situation) from 2mg, find that relative risk increases.For the doxazosin of fixed dosage, when chlortalidone dosage when 12.5 increase to 25mg, relative risk reduces.But all relative risks are significant and whole conclusion is consistent.

For following the tracks of blood pressure, two conclusions of whole cohort shown in the table 2 relatively be not controlled.In whole test, systolic blood pressure in the doxazosin group is than the high 2-3mmHg in the chlortalidone group, but between described group, and diastolic blood pressure can there were significant differences.The ratio of missing blood pressure measurement is 7% when January, is 16% when June, is 16% in the time of 1 year, is 20% in the time of 3 years, is 16 in the time of 5 years.

Table 4: with heart failure sickness rate and relative risk after doxazosin or the chlortalidone treatment 1 year, and after randomization individual month blood pressure difference of 9-12

Blood pressure	The heart failure sickness rate		Use the relative risk of doxazosin or chlortalidone	The difference of the contraction/relaxation blood pressure between doxazosin group and the chlortalidone group
					The chlortalidone group	The doxazosin group
	MmHg ←--------------/100 man-years that fall ill----------→ mmHg
Shrink
	≥140	?1.48	?1.93	?1.30(1.05-1.60)	1.6/0.0
＜140						?0.96	?1.51	?1.58(1.18-2.13)	0.4-1.2
	Diastole
≥90						?1.54	?1.79	?1.17(0.88-1.53)	4.3/0.3
	＜90	?1.09	?1.76	?1.61(1.29-2.00)	2.4-0.6
Contraction/relaxation
	≥140/≥90	?1.53		?1.17(0.88-1.55)	2.3/0.0
≥140/＜90						?1.41		?1.49(1.08-2.05)	1.2/-0.3
	＜140/≥90	?1.61		?1.11(0.25-3.98)	0.2/-0.1
＜140/＜90						?0.92		?1.63(1.20-2.05)	0.5/-1.1

Table 4 has shown the sickness rate and the relative risk of heart failure therapy group when surpassing 1 year, becomes the blood pressure matched group at 1 year time stage.The relative risk of the stratum that described contraction or diastolic blood pressure are lower is higher, and the difference between the average shrinkage blood pressure in doxazosin and chlortalidone is less.In combined group, (blood pressure＜140/90mmHg) has maximum relative risk, and has only the difference between the average shrinkage blood pressure little in optimally-controlled stratum.After adjusting baseline and following blood pressure, and described all heart failure (relative risk, 2.04{CI, 1.79-2.32} be to 2.00{CI, 1.76-2.28}; P＜0.001) and hospitalization or fatal heart failure (relative risk, 1.83{CI, 1.58-2.13} be to 1.80{CI, 1.54-2.09}; P＜0.001) conclusion can not change basically

Discuss

We find that in the main cardiovascular disease of prevention especially in the heart failure outbreak, the effect of doxazosin is not as chlortalidone.Because this is the active control test, so we can not determine whether chlortalidone is useful, whether doxazosin is harmful to or both.Chlortalidone demonstrates and can prevent and treat heart failure (9), and doxazosin does not show above-mentioned arbitrary effect.In the contraction hypertension in the Elderly program and placebo compare, the risk of heart failure when using chlortalidone reduces by 50% (9).

In ALLHAT, not all participant continues their specified treatment, and the reason of progressively carrying out open labeled drug treatment is different in each random group.These reasons have different influences to the concurrent risk of heart failure.The main discovery of research is to compare chlortalidone at present, and higher with the risk of heart failure of doxazosin treatment, this can alleviate by the antihypertensive drug that adds other, but can not eliminate.

Present analysis exists indication deviation and diagnosis deviation (10).When the investigator provides the extra drug treatment according to sign and symptom, when for example being used for controlling blood pressure or reducing perceptible side effect, there is the indication deviation.When being subjected to influencing of relevant aceognosia, investigator or patient just have the diagnosis deviation.Participant in the doxazosin group accepts participant's obviously more reliable (relative risk 1.31) of other medicines than in the chlortalidone group, often more early take other medicine in the doxazosin group.Because the weak point in the time ratio chlortalidone group of doxazosin group switching centre force failure outbreak, therefore in the doxazosin group, use the ratio (46%) of all heart failure outbreaks that occur before the open labelling treatment higher, thereby cause relative risk to enlarge than chlortalidone group (34%).Owing to open labelling treatment is not provided, should have the diagnosis deviation.Therefore deviation may appear indicating in then not carrying out of other because why blood pressure and side effect influenced that some participant will progressively carry out the extra drug treatment.

Based on this reason, the participant who contacts open labeled drug treatment should have the relative risk of weakening.This influence can be observed in heart failure all heart failure and hospitalization or fatefulue.In addition, the other medicines of existence are the described difference of influence further, and this is because there is relevant with blood pressure and incoherent effect.Diagnosis and indication deviation play some effects, and this is because participant and investigator know to have taken any open labeled drug and why take.This exposure back result shows open labelling treatment (comprising the resisting hypertension heart failure therapy) but reduces not eliminate the relative risk of two conclusions in described two treatment groups.In each treatment group, the influence of these conclusions is bigger before the ratio contact other medicines after the contact other medicines.Suffer from hypertensive participant more rambunctious and have bigger risk of heart failure.

There is above-mentioned potential deviation equally in the dosage analysis that is limited to the participant who carries out single treatment.For the chlortalidone of fixed dosage, described relative risk increases with the increase of doxazosin dosage; And for the doxazosin of fixed dosage, described relative risk increases with the dosage of chlortalidone and reduces.Increase with respect to chlortalidone dosage, the increase of doxazosin dosage is short relevant with the persistent period that heals with medicine.If doxazosin can not prophylaxis of heart failure, will take the patient of chlortalidone of fixed dosage and the patient who takes the doxazosin of fixed dosage so and compare, find that the bigger patient's ratio of risk of heart failure increases, this is because more difficult controlling blood pressure.This influence has often increased relative risk.

In whole test, the average shrinkage blood pressure in the chlortalidone group is than the low 2-3mmHg in the doxazosin group at last.But after the blood pressure difference of adjusting whole test, described relative risk has changed some.Based on the conclusion in the Framingham cardiac studies (11), the difference in this systolic blood pressure causes reducing at the most 2% relative risk, described discovery and our discovery consistent (relative risk is after adjusting 2.00, from 2.04 minimizings).In addition, in the time of 1 year, the participant is classified according to blood pressure, show that the relative increase of lower blood pressure and risk is relevant.Clearly, in ALLHAT, the difference degree in blood pressure can not explain that the risk of heart failure in the doxazosin group increases (comparing the chlortalidone group).What we analyzed may limit the measurement error that comprises blood pressure, and the equilibrated possible loss of known and unknown characteristics is a variable behind the randomization because we use.

In the very low patient of risk of heart failure, as have simple hypertensive youngster or do not have the philtrum of other risk of cardiovascular diseases factor, if controlling blood pressure well, the discovery of ALLHAT just can not support to refute the initial stage treatment of carrying out with α-adrenergic blocker, and this treatment allows to add or replace with other antihypertensive drug class.Suffering from the elderly men of benign prostatauxe (in them, α-adrenergic blocker looks like the optimal treatment mode of urinary disease), existing loose disease is used another kind of antihypertensive treatment.But our analysis does not provide the guidance of selecting second Chinese medicine.

In brief, the doxazosin receiver more may take extra medicine than chlortalidone receiver, before contact extra drug treatment, and the ratio that in the doxazosin group, suffers from heart failure obviously higher in the chlortalidone group.The clear chlortalidone, the dosage-response relation of doxazosin compared of described tables of data.Progressively take any medicine, even the heart failure prophylactic agent, the relative risk that still can not eliminate the heart failure outbreak reduced.The obvious difference of blood pressure has been considered observed result seldom in accepting research process.Described basic discovery insists and compares treatment with chlortalidone, no matter used dosage or add other medicines is that high-risk patient brings over-drastic heart disease risk with the treatment of doxazosin.

From University of Texas School of Public Health, Houston, Texas; The National Heart, Lung.and BloodInstirure, Bethesda, Maryland; Wake Forest University School of Medicine, Winston-Salem, North Carolina; Case Western Reserve University School of Medicine, Kieseland, Ohio; Pitman Internal Medicine Associates, Pirman, New Jersey; With Carl T.HaydenVeterans Affairs Medical Center, Phoenix, Arizona.

The support that obtains: by National Heart, Lung, the contract NO-HC-35130 of and Blood Institute.Research medicine by Pfizer, Inc. (A Muluohe and doxazosin), AstraZeneca (atenolol and lisinopril) and Bristol-Myers Squibb (pravastatin) provide; Pfizer, Inc., by National Heart, Lung, and Blood Institute provides with funds.

Potential economic interests conflict: B.R.Davis, J.T.Wright Jr., J.V.Felicetra; Honoraria:C.D.Furberg, J.T.Wright Jr., J.V.Felicerta; Stock Ownership:M.A.Farber; Grans Received:C.D.Furberg, J.T.WrighrJr., J.V.Felicerta.

The requirement of indivedual second editions: Batry R.Davis, MD, PhD, the University of Texas School of PublicHeath, 1200 Herman Presser Street, HoustonTX77030; E-mail, bdavis@sph.uth.rmc.edu.

Current author address and author's submission can be with reference to www.annals.org.

Current author's address:

Dr.Davis：The?University?of?Texas?School?of?Public?Health，1200?Herman?Presser?Street，Houston.TX?77030。

Dr.Cutler:The National, Heart.Lung and Blood Institute, 6701 Rock-ledge Dirve, Beihesda, MD 20892.

Dr.Furberg：Wake?Forest?University?School?of?Medicine，Medical?Center?Boulevard，Winston-Saiem，NC?27157.

Dr.Wright：Case?Western?Reserve?University?School?of?Medicine。10900?Euclid?Avenue，Cleveland，OH44106。

Dr.Farber：Pitman?Internal?Medicine?Associates，410?North?Broadway，Pitman.NJ。

Dr.Felicetra：Carl?T.Hayden?Veterans?Affairs?Medical?Center，650?Easr?Indian?SchoolRoad，Phoenix，AZ?85012。

Dr.Stokes：2323?Curlew?Road，Palm?Harbor，FL?34683。

Author's submission: Conception and design:B.R.Davis, J.A.Cutler, C.D.Furberg, 3.T.Wright.

The analysis of data and explanation: B.R.Davis, J.A.Cutler, C.D.Furberg, J.T.Wright.

Document rough draft: B.R.Davis, J.A.Cutler, J.T.Wright, M.A.Far-ber.

The key revision C:B.R.Davis of the document of important intellectual achievement, J.A.Cutler, C.D.Furberg, J.T.Wright, M.A.Farber, J.V.Felicerta, J.D.Stokes

The final certification of document: B.R.Davis, JA.Cutler, C.D.Furberg, J.T.Wright, J.V.Felicerta.

Research material or patient provide: B.RDavis, M.A.Farber, J.D.Stokes.

Statistics suggestion: B.R.Davis.

Acquisition fund: B.R Davis, J.A.Cutler.

Management, technology or law support: B.R.Davis, J.A.Cultler, C-D.Furberg.

Data collection and arrangement: B.R.Davis, J.V.Felicetta, J.D.Stokes.

List of references

1.Davis?BR.Cutler?JA，Gordon?Dj，Fuberg?CD，Wright?JT?Jr，Cushman?WC，et，al.Rarionale?and?design?for?the?Antihypertensive?and?Lipid?Lowering?Treatment?to?Prevent?HeartAttack?Trial(ALLHAT).ALLHAT?Research?Group.Am?J?Hypertens.1996；9：342-60.[PMD：8722437]

2.Major?cardiovascular?events?in?hypertensive?patients?randomized?to?doxazosin?vschlor(@alidone：the?antihypertensive?and?lipid-lowering?treatment?to?prevent?heart?attack?trial(ALLHAT).ALLHAT?Collaborative?Research?Group.JAMA.2000；283：16967-75.[PMID：10789664]

3.Piller?LP，Davis?BR，Cutler?JA，er?al.Validarion?of?heart?f@ilure?events?in?ALLHATpartidpanc?assigned?to?doxazosin?f，Abstracr].Am?J?Hypertens.2001；14：181A.

4.The?fifth?report?of?the?Joint?National?Committee?on?Detection，Evaluation，andTreatment?of?High?Blood?Pressure(JNC?V).Arch?Intern?Med.1993；153：154-83.(PMID：8422206]

5.Klein?JP，Moeschberger?ML.Survial?Analysis：Techniques?for?Censored?and?TruncatedData.New?York：Springer-Verlag；1997.

6.Jennison?C，Tumbull?BW.Group?Sequential?Methods?with?Applications?to?ClinicalTrials.Boca?Raton，FL：Chapman?&?Hall/CRC?Pr；2000.

7.Rubin?DB，Schenker?N.Multiple?imputation?for?interval?estimation?from?simple?randomsamples?with?ignorable?nonresponse.Journal?of?the?American?Statistical?Association.1986；81：366-74.

8.Schafer?JL.Multiple?imputation：a?primer.Stat.Methods?Med?Res.1999；8：3-15.IMID：10347857]

9.Kostris?JE，Davis?BR，Cuder?J，Grimm?RH?Jr，Berge?KG?Cohen?JD，et?al.Prevention?ofheart?Mure?by?antihypertensive?drug?treatment?in?older?persons?with?isolated?systolichypertension.SHEP?Cooperative?Research?Group.JAMA.1997；278：212-6.[PMID：9218667]

10.Peduzzi?P，Wittes?J，Detre?K，Holford?T.Analysis?as-randomized?and?the?problem?ofnon-adherence：an?sample?from?the?Veterans?Affairs?Randomized?Trial?of?Coronart?ArteryBypass?Surgery.Star?Ivled.1993；12：1185-95.[PMID：8210821]

11.Kannel?WB，D′Agostino?RB，Silbersharz?H，Belanger?AJ，Wilson?PW，Levy?D.Profilefor?estimating?risk?of?heart?failure.Arch?Internt?Med.1999；159：1197-204.[PMID：10371227]

Resisting hypertension and body fat at prevention of cardiac reduce in the therapeutic test (ALLHAT)

Participant's baseline characteristic

Richard H.Grimm, Jr, Karen L.Margolis, Vasilios Papademetriou, William C.Cushman, Charles E.Ford, JudyBettencourt, Michael H.Alderman, Jan N.Basile, Henry R.Black, VincentDeQuattro, JohnEckfeldt, C.Morton Hawkins, H.Mitchell Perry, Jr, MichaelProschan----ALLHAT cooperating research group

Summary----diuretic and beta blocker have demonstrated the cardiovascular morbidity that can reduce the hyperpietic and the risk of mortality rate in long-term interim trial.Research does not compare new more expensive antihypertensive (calcium antagonist, ACE inhibitor and α-adrenergic blocker) and the not agnate group of diuretic that reduces the cardiovascular disease incidence rate that is used for middle age and senile hypertension patient.Described research is clinical trial at random, double blinding, active control, and whether the outbreak that is used for determining Main Conclusions (fatal coronary heart disease or non-fatal myocardial infarction) is different between with diuretic begin treatment and each personal other 3 kinds of antihypertensive drug begin treatment.At least a other risk of cardiovascular diseases factor, age suffers from random assortment more than or equal to 55 years old masculinity and femininity and gives chlortalidone (12.5-25mg/d), A Muluohe (2.5-10mg/d), lisinopril (10-40mg/d) or doxazosin (2-8mg/d), follows the tracks of 4-8.This record declaration reduce the baseline characteristic of participant in the therapeutic test (ALLHAT) at the resisting hypertension of prevention of cardiac and body fat.625 positions are selected 42,448 participants altogether at random from the U.S., Canada, Puerto Rico and US Virgin Islands.The described mean age is 67 years old, and 35% age was greater than 70 years old.In those randomizations, the 36%th, black race, the 19%th, Hispanic, the 47%th, woman.Described sample comprises a high proportion of diabetics (36%), patient's (47%) and smoker's (22%) of cardiovascular disease is arranged.Between treatment group at random on the baseline, there is not any significant differences.By answering following problem, ALLHAT will increase our understanding to the hypertension management greatly: new antihypertensive whether and the conventional therapy that carries out with diuretic similar, more superior or poorer than it than it? (Hypertension 2001; 37:19-27).

Keyword: hypertension, key element-antihypertensive-diuretic-clinical trial-body fat

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Received on May 2nd, 2000, ground floor decision on May 18th, 2000, revised edition was accepted on June 30th, 2000.

From Berman Center for Outcomes and Clinical Research and Hennepin County MedicalCenter (R.H.G., K.L.M.), Minneapolis, Minn; Veterans Affairs Medical Center (V.P.), Washington, DC; Memphis Veterans Affairs Medical Center (W.C.C.), Memphis, Term; University of Texas-Houston (C.E.F., J.B., C.M.H.), School of Public Health, Houston; AlbertEinstein College of Medicine (M.H.A.), Bronx, NY:Veterans Affairs MedicalCenter (J.N.B.), Charleston, SC; Rush-Presbyterian-St.Luke ' s Medical Center (H.R.B.), Chicago, Ill:Los AngelesCount, / Universiy of Southern California Medical Center and WhiteMemorial Medical Center (V.D.), Los Angeles; University of Minnesota Hospital andClinic (J.E.), Minneapolis:Veterans AfFairs Medical Center (H.M.P), St.Louis, Mo; With theNational Heart.Lung, and Blood Institute (M.P), Division ofEpidemiology and ClinicalApplications, Bethesda, Md.

With Richard H.Grimm, Jr, MD, PhD, Director, Bets an Center for Outcomes and ClinicalResearch, Hennepin County Medical Center-865B, 701 Park Ave South, Minneapolis.MN55415 contact.

2001?American?Heart?Association，Inc。

Hypertension can be from Http: //www.hypertensionaha.org. obtains.

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In the U.S., surpass people's hypertension height (BP) of 4,000 ten thousand, promptly shrink BP (SBP) 〉=140mmHg and/or diastole BP (DBP) 〉=90mmHg, or they are accepting the antihypertensive treatment. ¹Hypertension has influenced the white American's masculinity and femininity (age 60-74 year) of half; With the negro male and the women that surpass in age group hoc anno of 2/3.Arrive the eighties 70, suffer among the hypertensive middle aged experimenter of 1 and 2 stages at majority and carried out large-scale randomized clinical trial, prove that the antihypertensive drug treatment has reduced by 40% with the ratio of apoplexy.But, compare the discovery of apoplexy, to the 10-15% that is reduced to of coronary heart disease (CHD) sickness rate.This is lower than, and epidemiologic data estimates. ²

Subsequently, in the contraction hypertension of Elderly program (SHEP) experiment, the treatment of the thiazide diuretic of low dosage demonstrates CHD death and non-lethal myocardial infarction (MI) has been reduced by 27% (95%CI6%-43%). ³In the diastole and the similar result that shunk other test data sheet among the hypertensive gerontal patient. ^4,5Proof estimates that a possible explanation of the test failure of CHD reduction degree is exactly adverse effect, the especially influence of high dose thiazide diuretic of research medicine before, and they can offset the potential benefit that BP reduces.These adverse effects comprise that the insulin sensitivity of the inductive hypokalemia of diuretic, low magnesium disease, hyperuricemia, hyperlipoidemia, hyperglycemia, breakage and possible ventricular ectopy activity increase.But these side effect are minimum when current recommended dose (12.5-25mg chlortalidone), and nearest intermediate analysis has been emphasized the concrete CHD benefit based on absorption under the low dosage diuretic.

70 to the late nineteen eighties, introduced and upgraded more expensive antihypertensive, as calcium antagonist, ACE inhibitor and α-adrenergic blocker as antihypertensive.But, judge its purposes be better than before the evidence of medicine limited, and conflicting.Only there are some researchs in parallel group of test, to check different antihypertensives.Described ACE inhibitor (the how general riel of Kapp) is in 2 big tests (the how general riel prevention of Kapp project (CAPPP) ¹⁰With UK protectiveness diabetes study (UKDPS) ¹¹) in and diuretic and/or beta blocker compare.Neither one studies show that the global advantage of the how general riel of Kapp (captopril) at the main cardiovascular terminal point of prevention.The result of some observational studies and clinical trial has suspected calcium antagonist gradually, and especially fugitive dihydro piperidines is for the effect of the hyperpietic's of prevention of cardiac or diabetes cardiovascular disease outbreak ^12-15But other data show that the calcium antagonist of leaving usually is safely and effectively to preventing these groups patient central vessel disease incidence. ^16-19

Four random experiments have compared the representative example of the above medicines of 3 classes.Described by Department ofVeterans ' s Affairs Cooperative Study Group on Antihypertensive Agent ' ²⁰The test of carrying out in 1 year, 4-HANE research ²¹With slight hypertension therapeutic research (TOMHS) in 4.4 years ²²Some differences that change at BP control, side effect, quality of life, biological chemistry action and target organ have been write down.But there be not the pattern (compare other medicines) favourable always to a class medicine in these differences.These tests do not have the cardiovascular terminal point incident as drug categories Main Conclusions relatively.Finish recently to suffering from the Swedish test (STOP-2) that hypertensive aged patient carries out ²³In 6614 hypertensive patients of trouble, ACE inhibitor, calcium antagonist and diuretic and/or beta blocker have been compared.In this research, BP reduction and fatal and nonfatal cardiovascular disease incidence are similar in 3 groups.But STOP-2 does not comprise Black people, hypertensive people of 1 stage or old people less than 70 years old.And the result of this test needs more massive test to confirm that described large-scale experiment has more extensive crowd's hyperpietic.

Whether therefore, need more data to estimate described new drug more superior than the diuretic of the ratio that is used to reduce the hypertension and cardiovascular syndrome, quite or relatively poor.Particularly, the resisting hypertension of described prevention of cardiac and body fat are reduced compositions sickness rate that treatment treatment (ALLHAT) research design determines mortality CHD and non-lethal MI difference whether between diuretic therapy and 3 kinds of different resisting hypertension physiology treatments.In order to obtain to suffer from the ALLHAT result of Hypertensive Population on a large scale, described research design becomes to replenish a high proportion of group with the relevant sickness rate of hypertension: old, women, non-descendants American and suffer from the people of type 2 diabetes mellitus.Except the resisting hypertension test, described test also makes participant's subgroup carry out body fat at random to reduce test, is used for relatively suffering from the general mortality rate among patient's (taking pravastatin and general duty nursing at random relatively) of light to moderate hypercholesterolemia.The baseline characteristic of this group illustrates in independent report.This report describes the baseline characteristic of participant in ALLHAT resisting hypertension part in detail.

Method

Describe the ALLHAT of described double blinding, randomization, active control as mentioned above in detail. ²⁴Participant in ALLHAT is 625 high-risk hyperpietics that clinical clinic replenishes in the U.S., Canada, Puerto Rico and US Virgin Islands.Described additional process was carried out between 31 days January in 1998 on February 14th, 1994.Described test finishes in March, 2000 after 6 years at average tracking.But in February, 2000, the doxazosin arm of described test stops, and this is that the 4-of doxazosin accumulates congested heart disease rate height (being respectively 8.1% pair of chlortalidone 4.5% of doxazosin) because compare chlortalidone.In addition, the conclusion (relative risk 1.25,95%CI 1.17-1.33) that in the doxazosin group, has 25% high-risk comprehensive cardiovascular disease. ²⁵

The qualified standard of BP 2 meansigma methodss that sealing BP measures during based on the current antihypertensive therapy state of patient and 2 visits.For untreated patient (or those treatment times less than 2 months), it is that SBP is at least 140mmHg or DBP is at least 90mmHg that the BP during twice visit comprises standard.In twice visit, require SBP≤180mmHg and DBP≤110mmHg.With 1 to 2 kind of Drug therapy patient more than 2 months, is SBP≤160mmHg in 1 o'clock standard of visit for those, DBP≤100mmHg; In 2 o'clock standard of visit is SBP≤180mmHg, DBP≤110mmHg.The reading of visit 2 is high more just can partly recall antihypertensive therapy.Those patients that take the antihypertensive of two or more therapeutic doses are underproof.Except satisfying the BP criterion of acceptability, the patient must at least 55 years old, and have at least one extra cardiovascular morbidity risks and assumptions.The standard that comprises that these are extra is listed in the table 1, and has the exclusion standard of test.Described initial designs comprises the Black people participant who replenishes 45% women and 55%.

Provide notice promise after, the participant accepts double blinding step 1 treatment among the 1-4 at random, take once following medicine every day: chlortalidone (for the first time and the 12.5mg that instils for the second time, instiling for the third time is 25mg), A Muluohe (2.5,5 or 10g), lisinopril (10,20 or 40mg) or doxazosin (2,4 or 8mg).Under all dosage, the medicine of each research is identical in appearance.Interrupt randomization by clinical center, and classification.The ratio that the participant is assigned in each arm is 1.7: 1: 1: 1, maximum quantity distribute to chlortalidone, render a service with the maximum statistics that obtains to be used for comparison diuretic arm and 3 non-diuretic arms.

Described initial doxazosin dosage is 1mg in 1 week, and 2mg in 1 month afterwards instiled in every month afterwards, makes BP finally be SBP＜140, DBP＜90mmHg.Instil in a similar fashion chlortalidone, A Muluohe and lisinopril from lowest dose level, but do not change at 1 all post doses.In addition, provide open labeled drug to treat the patient that under the situation of blind step 1 Drug therapy of maximum tolerated dose, can not obtain satisfied BP control.In step 2, obtain three open labeled drug treatments, in step 3, obtain one.The Drug therapy of described step 2 comprises reserpine (0.05-0.2mg/ every day), clonidine (0.1-0.3mg/ every day twice) and atenolol (25-100mg/ once a day).The medicine of step 3 is hydralazine (25-100mg/ every day twice).Under the influence of lifestyle factors (sodium, alcohol, motion and heat are taken in), standard set-up is provided for all participants, in research process, strengthens on demand.

Other standard that comprises and get rid of of table 1.

Other standard that comprises (listed those any one)

Old (＞June) that hospital diagnosis is put down in writing or medium MI or apoplexy of age

The Q ripple is arranged on the ECG

Akinesis on heart echo scintigram or the ventriculogram or dyskinesis

Cerebral infarction on CT or the MRI

The history that forms step again of blood vessel comprises

Reconstructive vascular operation (coronary artery or edge nervous system tremulous pulse)

By-pass operation (coronary artery, edge nervous system tremulous pulse, carotid artery, vertebrobasilar)

Large aneurysm is repaired

The formation again of other blood vessel (atherectomy, expansion location)

Atherosclerotic's cardiovascular disease of other record comprises

The angina pectoris history

Intermittently lame, gangrene or ischemic ulcer history

Instantaneous ischemic history of attack

Coronary artery, edge nervous system tremulous pulse or carotid artery stenosis 〉=50% are by angiography or Doppler research record

Ischemic heart disease is put down in writing by the following stated

Stress thallium (reversible or fixed ischemia)

Di Pulaidamo thallium (reversible or fixed ischemia)

Exercise test (Hom 〉=1mm under the ST, 〉=1 minute)

Stress echocardiogram (reversible wall motion abnormalities)

Hall moral monitoring (Hom under the ST: (1mm, (1 minute)

Ankle-arm index＜0.9

The abdominal aorta aneurysm that ultrasonography, CT or X ray are surveyed

Carotid artery or femoral artery noise

Hom or the inversion of T-ripple under the main ST on the ECG in 2 years in the past

Hom under the J-at 0.5mm place point, and at any leads I, II, aVL or V ₁-V ₆In ST

Following Hom platform and descending

At any leads I, II, aVL or V ₂-V ₆In at least the T-ripple of 1mm be inverted

Type 2 diabetes mellitus

Serum glucose (the 7.8mmol/l of fasting in 2 years in the past

Serum glucose (the 11.1mmol/l of non-fasting in 2 years in the past

Take insulin or oral hypoglycemia medicine

Current is the smoker

In the past in 5 years when 2 occasions HDL cholesterol＜0.90mmol/l

Left ventricular hypertrophy on ECG and heart echo scintigram in 2 years in the past

V ₅Or V ₆In R amplitude＞26mm

V ₅Or V ₆In the R amplitude add V ₁In S amplitude＞35mm

R amplitude＞12mm in aVL

R amplitude＞15mm in leads I

R amplitude＞20mm in leads I I or III or aVF; R amplitude in leads I adds

S amplitude＞25mm among the leads I II

R amplitude in aVL add among the V3 S amplitude＞28mm (to the male) or＞22mm is (to the woman

The property)

The left ventricular hypertrophy of computerization ECG machine record

Comprehensive wall thickness 〉=25mm on heart echo scintigram

Exclusion standard

Symptomatic MI or apoplexy in 6 months in the past

Symptomatic congested heart disease

If left ventricle discharge section＜35% is known words

Symptomatic angina pectoris in 6 months in the past

Known renal function deficiency (serum creatinine 〉=180 μ mol/L)

Need thiazide diuretic, ACE inhibitor, calcium antagonist or α-adrenergic blocker, be used for

Reason except that high BP

Allergy or contraindication to any step 1 medicine

Need＞2 kinds antihypertensive, obtain gratifying BP 〉=160/100mmHg or BP＞180/110mmHg

The probability of abideing by doctor's advice low (for example dull-witted, abuse medicine)

The disease that in research process, might cause non-cardiovascular disease death

Participant in another clinical trial

Table 2.ALLHAT participant's race, ethnic division, sex, the age when the test registration, the diabetic history when the test registration and the frequency distribution of preexist ASCVD

			Sex		Age
											The race	Total amount	Hispanic	The male *	The women *	?55-59	?60-69	?70-79	?80+	Diabetes	?ASCVD
White race, n	25292 (59.2)	5314	?14698	?10592	?4321	?11445	?7790	?1736	?8476	?13278
											Black race, n	15094 (35.6)	1406	?6852	?8241	?3298	?7008	?3817	?971	?6023	?5790
Asia/island, Pacific Ocean resident, n	481 (1.1)	11	?275	?206	?97	?242	?130	?12	?173	?243
											American Indian/Arras original inhabitants, n	78 (0.2)	5	?57	?21	?21	?37	?20	?0	?32	?39
Other, n	1503 (3.5)	1364	?698	?805	?352	?723	?376	?52	?593	?555
											Sum, n	42448	8100	?22580	?19865	?8089	?19455	?12133	?2771	?15297	?19905
Sum, %	100.0	19.1	?53.2	?46.8	?19.1	?45.8	?28.6	?6.5	?36.0	?46.9

Value in the bracket is a percent.

^*Owing to omit 2 white people participants and 1 black race participant's gender data, so cell is not counted in sum

At the baseline place,, the participant is carried out the blood profile curve tracing in order to measure potassium in the serum, fasting glucose, creatinine, cholesterol total amount, HDL cholesterol, triglyceride and aramine aminotransferase.The LDL cholesterol is estimated by the Friedewald formula.When may the time, require in the past to carry out metal blood again after the relatively poor participant of 8 hours internal consumption food or beverage and draw.If there was not ECG last year, require to carry out ECG.Then, use the Minnesota coding standard to concentrate and read all ECGs.At the baseline place, described clinical center research coordination person finishes through guidance and lists the questionnaire (table 1) that comprises standard.Check all known and diseases that put down in writing of participant.In addition, described questionnaire comprise relevant race, ethnic division, sex, year of school, at present use estrogen, regularly use aspirin, smoking (past or present) and have the project of CHD at present.To exist CHD to be defined as MI history (comprising unrecorded MI), main cardiac arrest, the formation again of coronary artery, angina pectoris, reversible coronary perfusion defective when angiography forms coronary stricture＞50% or noninvasive cardiac work up.Measure height and body weight at the baseline place.

For the base-line data in the present research, if check type 2 diabetes mellitus based on the standard list (table 1) that comprises, then the participant is considered to suffer from diabetes.The standard that is used for diagnosing diabetes is the standard of the american diabetes association when the research beginning, when ADA did not change when reducing the fasting glucose standard in 1997 yet.26 according to concluding that to give a definition the participant suffers from atherosclerotic cardiovascular disease (ASCVD): if CHD is listed in the baseline questionnaire as mentioned above, perhaps as if the formation history again or other ASCVD (seeing Table 1 definition) that comprise the dated existence of standard check table old age or middle aged MI or apoplexy, blood vessel.

The evaluation criteria of tracking step, research terminal point and morbidity has been described before. ^24-25Described main research terminal point is the comprehensive outbreak of mortality CHD and non-lethal MI.Consider treatment intersect, follow the tracks of omit and multiple comparisons after, the size of calculating described study sample makes to render a service and reaches 80%, to detect 16% difference of between diuretic and other 3 medicine groups main terminal point.

Conclusion

Table 2 provides the randomized participant of ALLHAT frequency distribution according to race, ethnic division, sex, registration age, diabetic history and the ASVCD that exists before.Among randomized 42448 participants, 25292 (59.6%) is that white people, 15094 (35.6%) are black race in ALLHAT.Aisan and American Indian account for 1.1% and 0.2% respectively.With the group that themselves participant who classifies as " other " is the 3rd class maximum, add up to 1503 (or 3.5%), carry out randomization, great majority also are described as Hispanic with themselves among them.In these, 8100 (19.1%) Hispanic participant is arranged, 65.6% is designated as " white race Hispanic ", 17.4% with themselves is designated as " asian ancestry's Hispanic " or " the Indian Hispanic of the U.S. " for " black race's Hispanic ", 0.2%, and 16.8% is " other Hispanic ".The male has accounted for ALLHAT participant's 52.3%.Maximum class the range of age is 60-69 year (45.8%) among the participant.Second largest age subgroup is 70-79 year (28.6%).Have 19.1% at 55-59 between year, have 6.5% with above 80.At the baseline place, the ALLHAT participant of vast scale has diabetes (36.0%) and/or ASCVD sign (46.9%).

Table 3 has shown the baseline characteristic of randomization treatment group.By design, described chlortalidone group maximum has 15268 participants (36.0%).Other 3 medicine groups are just above 9000 participants (21.3%).In all tables, described non-Hispanic white people have got rid of 5314 (12.5%) participants after this harmony in the exterior, and they think it is " white race Hispanic " themselves.Described participant makes up with described " other " class.The described mankind of black race comprise Hispanic and non-Hispanic black race.Hispanic ALLHAT participant's feature will be described in more details in independent announcement.Notice and in randomization treatment group, have three obvious still little differences (p＜0.05).There is little difference in serum potassium between lisinopril and chlortalidone group, may be because drawing causes to fasting glucose after the randomization in some participants.Compare the chlortalidone group, A Muluohe is carried out randomized participant unlikely have the CHD history, and have low slightly creatinine content.

Sex and race's baseline characteristic is provided in table 4.Described participant's mean age is 67 years old, and masculinity and femininity white people participant is older than black race participant.Black race's (comparing white people) that this species diversity mainly comes from vast scale is 55-59 year class (29.1% pair 15.8%).The white people of vast scale (comparing black race) are 70-79 year class (being respectively 32.0% pair 25.9%).With male participant relatively, the women participant of small scale is white people's (being respectively 38.5% pair 54.6%), vast scale be black race's (being respectively 41.5% pair 30.4%).

The baseline characteristic of table 3. antihypertensive treatment group

	Antihypertensive
						Baseline characteristic	Chlortalidone	A Muluohe	Lisinopril	Doxazosin	All
Sample size	15268	?9053	?9060	?9067	?42448
						The women, %	47.0	?47.3	?46.3	?46.4
The race, %
						White race, non-Hispanic	47.2	?47.6	?47.0	?46.4	?47.1
Black race	35.2	?35.5	?35.5	?36.3	?35.6
						Other *	17.6	?16.9	?17.5	?17.2	?17.4
The BP treatment, %	90.2	?90.3	?90.2	?90.2	?90.2
						Smoking state, %
Current	21.9	?21.9	?21.9	?21.7	?21.8
						Past	40.5	?40.0	?40.3	?40.1	?40.3

Diabetic history	?36.3	?36.8	?35.5	?35.5	?36.0
						The CHD history	?26.0	?24.5	?25.2	?26.2	?25.7
Use aspirin, %	?36.0	?36.5	?36.4	?36.5	?36.3
						The last LVH of ECG, %	?5.2	?5.2	?5.4	?5.0	?5.2
Age, y	?66.9±7.7	?66.9±7.7	?145.0±14.1	?66.8±7.7	?66.9±7.7
						Education, y	?11.0±4.0	?11.0±3.9	?83.4±9.9	?11.0±4.0	?11.0±4.0
Visit 1BP
						SBP，mmHg	?144.8±13.8	?144.8±14.0	?145.0±14.1	?144.8±13.9	?144.8±14.0
DBP，mmHg	?83.3±9.9	?83.2±10.0	?83.4±9.9	?83.5±9.7	?83.4±9.9
						Pulse, bpm	?73.7±10.7	?73.6±10.7	?73.5±10.8	?73.5±10.7	?73.6±10.7
BMI，kg/m2	?29.7±6.1	?29.8±6.1	?29.8±6.1	?29.7±5.9	?29.8±6.1
						Potassium, mmol/l	?4.34±0.69	?4.35±0.70	?4.37±0.72	?4.36±0.70	?4.35±0.70
Fasting glucose, mmol/l	?6.85±3.24	?6.83±3.16	?6.82±3.11	?6.80±3.12	?6.83±3.17
						Creatinine, (mol/l	?77.83±23.65	?77.06±22.13	?77.83±22.89	?77.83±21.36	?77.83±22.89
The cholesterol total amount, mmol/l	?5.60±1.13	?5.61±1.14	?5.58±1.10	?5.57±1.10	?5.59±1.12
						The cLDL cholesterol, mmol/l	?3.52±0.97	?3.51±0.97	?3.52±0.95	?3.51±0.94	?3.52±0.96
The HDL cholesterol, mmol/l	?1.21±0.38	?1.22±0.38	?1.21±0.38	?1.21±0.37	?1.21±0.38
						The fasting triglyceride, mmol/l	?1.95±1.48	?1.95±1.53	?1.95±1.58	?1.92±1.53	?1.95±1.52

Unless have describedly in addition, value is meansigma methods ± SD.LVH is meant left ventricular hypertrophy; BMI is meant Body Mass Index, and cLDL is meant the LDL of calculating

^*Other race comprises 5314 non-black race Hispanics, 78 American Indian/alaskan natives and 481 Asia/Pacific Ocean islanders.Black race's Hispanic is included in black race's apoplexy due to endogenous wind.

ECG only obtains from 38955 participants, and 39538 participants provide education degree, and 40126 participants can obtain serum potassium, creatinine and cholesterol level.31255 participants can obtain fasting glucose; 37498 participants can obtain the cLDL cholesterol; In 40099 participants, measure the HDL cholesterol; In 31304 participants, measure triglyceride.

P＜0.01; P＜0.05 (for each feature, carry out the test of 2-ratio or 2-sample average difference, compare 3 non-diuretic groups and chlortalidone)

At the baseline place, most participant (90.2%) accepts antihypertensive therapy.Compare other group, the Black people that accept antihypertensive therapy 〉=2 month compare white man's (being respectively 26.9% couple 29.8%) and have high slightly baseline DBP, and also have lower BP control ratio at the baseline place (SBP＜140 and DBP＜90mmHg).In white man male's (30.9%), observe best BP control.BP control level is 28.1% in white man women, and the negro male is 27.6%, and black women is 26.3%.The negro male more may be present smoker, and Black people more may have diabetic history usually, have higher static pulse, and glucose content are higher.Black women has higher Body Mass Index, and in general, compares white man, and Black people more may have central laboratory's reading (being respectively 8.6% and 3.3%) of left ventricular hypertrophy on ECG.The probability that white man has the CHD history almost is Black people's a twice (being respectively 33% and 17%).Baseline lipoprotein content is different because of the other subgroup of race and sex.Black people's cholesterol total amount (LDL cholesterol, HDL cholesterol) is than white man Geng Gao, and content of triglyceride is obviously lower than white man.Women's cholesterol total amount (LDL cholesterol, HDL cholesterol) is higher, and male's content of triglyceride is higher.

Table 4. do as one likes is not and the ALLHAT participant's of race's classification baseline characteristic

	All			The male			The women
										Feature	All	White race (NH)	Black race	All	White race (NH) *	Black race *	All	White race (NH) *	Black race *
Sample size, n (%)	?42448±100.0	?19978±47.1	?15094±35.6	22580±53.2	?12337±54.6	?6852±30.3	19865±46.8	?7639±38.5	8.241±41.5
										Age, year	?66.9±7.7	?67.5±7.5	?66.3±7.8	66.7±7.3	?67.1±7.0	?66.1±7.4	67.1±8.2	?680±8.1	66.4±8.2
55-59，％	?19.1	?15.8	?21.8	18.0	?15.3	?20.8	20.3	?16.7	22.8
										60-69，％	?45.8	?45.9	?46.4	47.9	?48.3	?48.3	43.5	?42.2	44.9
70-79，％	?28.6	?31.9	?25.3	29.2	?32.0	?25.9	27.9	?31.7	24.8
										≥80，％	?6.5	?6.3	?6.4	4.9	?4.4	?5.1	8.4	?9.5	7.6
Education, year	?11.0±4.0	?12.3±3.2	?10.1±3.8	11.5±4.0	?12.6±3.4	?10.1±4.0	10.4±3.9	?11.9±2.8	10.1±3.6
										The registration therapeutic state	?86.8	?87.2	?86.9	86.0	?86.9	?85.4	87.8	?87.6	88.1
Drug therapy 〉=February, %	?143±13	?143±13	?143±13	142±13	?142±13	?142±13	143±13	?143±13	143±13
										SBP，mmHg	?82±10	?81±9	?83±10	82±9	?81±9	?84±9	82±10	?80±10	83±10
DBP，mmHg	?3.4	?2.8	?4.0	3.5	?2.8	?4.4	32	?.2.7	3.7
										Drug therapy＜February, %
SBP，mmHg	?158±13	?158±13	?160±13	158±13	?159±13	?160±13	158±14	?158±13	160±13
										DBP，mmHg	?89±10	?88±9	?91±10	90±10	?88±9	?93±10	89±10	?87±10	90±10
Not treatment, %	?9.8	?10.0	?9.1	10.4	?10.2	?10.2	9.1	?9.7	8.2
										SBP，mmHg	?159±12	?158±11	?159±13	158±12	?158±11	?158±13	160±12	?159±12	160±13
DBP，mmHg	?91±9	?89±9	?92±9	91±9	?89±9	?93±9	90±9	?89±9	92±9
										SBP/DBP＜ 140/90，％	?27.4	?29.8	?26.9	28.6	?30.9	?27.6	26.1	?28.1	26.3
The smoker, %	?21.8	?21.0	?25.1	24.0	?20.8	?31.7	19.3	?21.5	19.7
										Past is the smoker, %	?40.3	?47.4	?34.5	52.5	?58.0	?44.7	26.4	?30.2	26.0

Never smoking, %	37.9	?31.6	?40.4	?23.5	?21.3	?23.6	?54.3	?48.3	?54.3
										Diabetic history, %	36.0	?31.5	?39.9	?34.0	?31.2	?36.1	?38.4	?32.1	?43.1
The CHD history, %	25.6	?33.1	?17.4	?31.1	?38.7	?20.7	?19.3	?24.3	?14.7
										Use aspirin for treatment, %	36.3	?48.0	?25.3	?43.5	?54.1	?30.2	?28.2	?38.2	?21.3
Use estrin treatment, %							?18.0	?28.4	?11.4
										ECG?LVH，％	5.2		?3.3?8.6	?5.0	?3.1	?9.0	?5.4	?3.6	?8.2
Pulse, bpm	73.6±10.7	?72.9±11.0	?74.7±10.5	?72.5±11.1	?71.8±11.2	?73.8±10.9	?74.8±10.1	?74.5±10.4	?75.4±10.1
										Body weight, kg	83.1±18.1	?85.2±18.1	?84.4±18.2	?87.8±16.7	?90.2±16.4	?87?6±17.3	?77.7±18.0	?77.2±17.9	?81.8±18.6
BMI，kg/m2	29.8±6.1	?29.6±5.8	?30.5±6.7	?29.1±5.2	?29.3±5.0	?28.9±5.4	?30.4±6.9	?30.0±6.8	?31.6±7.1
										Serum analysis
Potassium, mmol/l	4.4±0.7	?4.4±0.6	?4.3±0.8	?4.4±0.7	?4.4±0.6	?4.3±0.7	?4.3±0.7	?4.3±0.6	?4.2±0.8
										Fasting glucose, mmol/l	6.83±3.17	?6.58±2.77	?7.04±3.53	?6.82±3.11	?6.60±2.72	?6.78±3.31	?6.95±3.36	?6.56±2.85	?7.29±3.71
Creatinine, μ mol/l	77.83± 22.89	?77.06± ?19.84	?82.40± ?25.94	?82.40± ?22.89	?83.17± ?19.08	?91.56± ?26.71	?69.43± ?19.84	?67.91± ?17.55	?73.25± ?21.36
										The cholesterol total amount, mmol/l	5.59±1.12	?5.58±1.10	?5.63±1.16	?5.40±1.05	?5.35±1.01	?5.37+1.08	?5.86±1.15	?5.94±1.14	?5.85±1.18
The cLDL cholesterol, mmol/l	3.52±0.96	?3.48±0.91	?3.60±1.03	?3.41±0.90	?3.38±0.87	?3.45±0.96	?3.65±1.00	?3.64±0.96	?3.71±1.07
										The HDL cholesterol, mmol/l	1.21±0.38	?1.13±0.35	?1.35±0.41	?1.12±0.33	?1.03±0.29	?1.23±0.37	?1.34±0.39	?1.29±0.39	?1.43±0.41
The fasting triglyceride, mmol/l	1.95±1.52	?2.20±1.70	?1.46±1.02	?1.98±1.53	?2.16±1.66	?1.49±1.07	?1.94±1.52	?2.28±1.76	?1.50±1.03

Unless have describedly in addition, value is meansigma methods ± SD.NH is meant non-Hispanic, and black race's Hispanic is included in the black race.Owing to miss gender data by 2 white race participants and 1 participant of black race, so this unit is not counted in sum.

Table 5. sex and race's login standard

	All			The male			The women
										Feature	All	White race (NH)	Black race	All	White race (NH) *	Black race *	All	White race (NH) *	Black race *
Sample size, n (%)	42448	?19978	?15094	?22580	?12337	?6852	?19865	?7639	?8241
										MI/ apoplexy history, %	23.1	?27.8	?19.6	?27.8	?31.7	?23.9	?17.9	?21.5	?16.2
The formation again of blood vessel, %	12.9	?20.8	?5.4	?17.8	?25.9	?7.2	?7.4	?12.6	?4.0
										Other ASCVD, %	24.0	?27.5	?19.7	?23.2	?26.7	?18.3	?24.9	?28.7	?21.0
The ischemic ST-T ripple changes, %	10.4	?9.2	?13.1	?9.8	?8.7	?12.9	?11.1	?10.1	?13.2
										Type 2 diabetes mellitus, %	36.0	?31.5	?39.9	?34.0	?31.2	?361	?38.4	?32.1	?43.1
Smoking at present, %	19.9	?19.1	?22.3	?21.4	?18.3	?27.5	?18.2	?20.2	?18.0
										HDL cholesterol＜35mg/dL, %	11.7	?16.4	?6.6	?15.2	?20.1	?8.5	?7.7	?10.5	?4.9
LVH on the heart echo scintigram	4.1	?4.1	?4.1	?3.8	?3.5	?3.7	?4.5	?5.2	?4.4
										LVH on the ECG	16.5	?9.8	?24.2	?16.8	?9.8	?27.6	?16.2	?9.8	?21.3

Black race's Hispanic is included in the black race.

Owing to miss gender data by 2 white race participants and 1 participant of black race, so this unit is not counted in sum.

Table 5 has been listed the participant's ratio with each risks and assumptions standard, and described standard meets the participant and participates in described test.Based on MI and/or apoplexy history, blood vessel forms again or other ASVCD, compares Black people participant, white man participant more may participate in this research.Black people more can meet the research that ischemic ECG variation, diabetes, smoking and ECG go up left ventricular hypertrophy.Because MI, apoplexy or the blood vessel that takes place forms again in advance, thereby the male more may enter this research; And the women more may enter and is based on diabetic history.Be defined as＜the low HDL cholesterol of 35mg/dl be white man male use always comprise standard (20.2%), but littler in Black people and white man women.

Provided the baseline characteristic of high-risk subgroup in the table 6.The people who suffers from diabetes accounts for ALLHAT participant 15294 (36.0%).As expected, the people of other group of weight ratio of diabetes participant is bigger, and the average weight index is 31.1kg/m2.Diabetes patient's fasting glucose higher (9.51mmol/l), triglyceride higher (191.1mg/dl) and lower HDL cholesterol (44.9mg/dl) and other subgroup compare.In the participant who suffers from the baseline cardiovascular disease, the ratio of diabetics is lower, and vice versa.In some cases, reach qualified after, the record that additionally enters standard may be not exclusively.Age relatively has high slightly baseline systolic pressure and lower diastolic pressure greater than 70 years old group and other high-risk group, and this group more may have left ventricular hypertrophy disease.In both cases, in the described diabetic groups more than 70 years old, the women has accounted for half.About 60% of the subgroup of ASCVD and smoking at present is the male.

Discuss

ALLHAT is the randomization double-blind trial of the maximum of carrying out in the hyperpietic.In the time in 4 years, 42448 high-risk patients have been registered at 625 centers of the U.S., Canada, Puerto Rico and US Virgin Islands.High-risk being based on exists hypertension, age 〉=55 year old and at least a other cardiovascular risk factor to determine.

Patient among the ALLHAT is assigned randomly to 1-4 treatment group: chlortalidone, A Muluohe, lisinopril or doxazosin.Described treatment group is in the baseline balance, in the variable of any record without any clinical significant differences.The research of design comprises the non-descendants American (35.6%) of high percentage ratio, and sex is near equal proportion (46.8% women).It also comprises large quantities of Hispanic participants (19.1%).In when registration, 35.1% patient age is greater than 70 years old, 36% suffer from diabetes, 46.9% have an ASCVD history (surpass half and have CHD), 22% be the smoker at present.Owing in ALLLHAT, registered a large amount of patients, therefore can in these subgroups, check the effect of ALLHAT treatment.

Not fully representative in the test before great majority of Black people and Hispanic.In the hypertension test of measuring cardiovascular morbidity, Black people only represent based on tangible subgroup in the active treatment arm test of diuretic.Known Black people have more frequent and more serious hypertension, and this is just forming in one's early years. ¹This discovery is reflected in the ALLHAT group at baseline place: Black people participant is younger, and DBP is higher.Black people also suffer more cardiovascular syndrome, and the risk of end-stage renal disease is higher. ^6.27。At the baseline place of this research, form again or ASCVD based on early stage MI history or apoplexy, blood vessel, unlikely register Black people's (comparing white man); Based on diabetes, smoking or left ventricular hypertrophy (on ECG), Black people more may be logged.ALLHAT provides good chance to study and estimate the treatment type of Black people's central vessel sickness rate and the effect of BP control.

ALLHAT also can solve the problem that produces in some other tests.In CAPPP, the hyperpietic is assigned randomly in conventional therapy (diuretic or beta blocker) or the how general riel treatment of Kapp with the pattern of open labelling.Though it is what difference the mortality rate of 10 cardiovascular disease or fatal or non-lethal MI do not have between 2 groups, fatal and the non-lethal apoplexy is more frequent in the group that how general riel is treated with Kapp.This discovery is partly owing to the following fact: in whole research, how general the baseline SBP and the baseline DBP of Kapp riel group be higher, higher slightly than the value in the conventional therapy group.In ALLHAT, there is not this baseline BP difference.

The feature of table 6. cardiovascular risk factor subgroup

	The risks and assumptions subgroup
						Baseline characteristic	Diabetes	?ASCVD	Smoking	〉=70 years	All
Sample size, n (%)	15297±36.0	?19905±46.9	?9272±21.8	?14904±35.1	?42448
						The women, %	49.9	?42.4	?41.5	?49.1	?46.8
The race, %
						White race, non-Hispanic	41.2	?55.5	?45.3	?51.3	?47.1
Black race	39.4	?29.1	?10.9	?32.1	?35.6
						Other *	19.4	?15.4	?13.8	?16.6	?17.4
Diabetic history, %	100.0	?24.5	?20.0	?34.1	?36.0
						The CHD history, %	18.8	?54.4	?17.4	?30.1	?25.6
ASCVD，％	31.9±0.4	?100.0	?33.4±0.5	?56.7±0.4	?6.9±0.2
						Smoking at present, %	12.1	?15.6	?100.0	?13.2	?21.8
LVH on the ECG	8.9	?11.4	?13.0	?17.9	?16.5
						Age, year	66.5±7.4	?68.2±7.8	?64.1±6.8	?75.5±4.7	?66.9±7.7
Visit 1BP
						SBP，mmHg	144.7±13.5	?144.4±14.0	?145.2±14.6	?145.9±13.7	?144.8±14.0
DBP，mmHg	82.1±9.9	?82.5±10.0	?84.7±10.0	?80.9±10.0	?83.4±9.9
						BMI，kg/m2	31.1±6.2	?29.2±5.8	?28.3±5.9	?28.3±5.4	?29.8±6.1
Potassium, mmol/l	4.4±0.7	?4.4±0.7	?4.4±0.7	?4.4±0.7	?4.4±0.7
						Fasting glucose, mmol/l	9.39±3.87	?6.33±2.73	?6.12±2.68	?6.53±2.81	?6.83±3.17
Creatinine, μ	76.3±24.42	?80.12±22.13	?77.83±22.89	?81.64±23.54	?77.83±22.89

mol/l
						The cholesterol total amount, mmol/l	?5.57±1.18	?5.59±1.12	?5.56±1.12	?5.53±1.09	?5.59±1.12
The cLDL cholesterol, mmol/l	?3.47±0.98	?3.52±0.95	?3.49±0.96	?3.48±0.94	?3.52±0.96
						The HDL cholesterol, mmol/l	?1.16±0.35	?1.2±0.37	?1.23±0.40	?1.24±0.39	?1.21±0.38
The fasting triglyceride, mmol/l	?2.16±1.85	?1.94±1.44	?1.90±1.58	?1.79±1.22	?1.95±1.52

Unless have describedly in addition, value is meansigma methods ± SD.

^*Other race comprises 5314 non-black race Hispanics, 78 American Indian/alaskan natives and 481 Asia/Pacific Ocean islanders.Black race's Hispanic is included in black race's apoplexy due to endogenous wind.

ECG only obtains from 38955 participants, and 39538 participants provide education degree, and 40126 participants can obtain serum potassium, creatinine and cholesterol level.31255 participants can obtain fasting glucose; 37498 participants can obtain the cLDL cholesterol; In 40099 participants, measure the HDL cholesterol; In 31304 participants, measure triglyceride.

The heart achievement prevention of finishing is recently estimated (HOPE) research and has been compared ACE inhibitor ramipril and the effect of placebo in having the old high-risk patient of intact left ventricular function. ²⁸Described having studies confirm that compared placebo, and ramipril has obviously reduced the ratio of the formation again of death, MI, apoplexy, blood vessel, heart disease and other cardiovascular syndrome.Patient in HOPE below half suffers from hypertension.In the hypertension participant, in existing hypertension therapeutic, add the research Drug therapy, SBP and DBP are lower among the patient of use ramipril treatment.Though this a spot of BP reduces half that (2-3mmHg) estimates to have accounted for the ramipril beneficial effect, described HOPE research design has still stayed many unanswered problems.Therefore, ALLHAT still is positioned at the answer that subject matter is provided: whether new antihypertensive is more superior, similar or relatively poor than the conventional therapy that carries out with diuretic.

ALLHAT is ongoing research, needs most the hypertension therapeutic problem of solution when having examined the turn of the century closely.The result of ALLHAT has obviously increased the understanding that we control hypertension, and the clearly statement of following administration guide is contributed.

Thank

This research is by National Heart, and Lung and Blood Institute subsidize.

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3.SHEP?Cooperative?Research?Group.Prevention?of?stroke?by?antihyper-tensivc?drugtreatment?in?older?persons?with?isolated?systolic?hyper-tension.IAMA.1991；265：3255-3264.

4.Dahlof?B.Lindhoim?LH，Hansson?L，Schersten?B，Ekbom?T，Westcr?P.Morbidity?andmortality?in?the?Swedish?Trial?in?Old?Patients?with?Hyper-tension(STOP-Hypertension).Lancet.1991；338：1281-1285.

5.MRC?Working?Party.Medical?Research?Council?trial?of?treatment?of?hypertension?inolder?adults：principal?results.BMJ.1992：304：405-412.

6.Joint?National?Committee?on?Prevention.Detection.Evaluation，and?Treatment?of?HighBlood?Pressure.The?sixih?report?of?the?Joint?National?Committee?on?Prevention，Detection，Evaluation，and?Treatment?of?High?Blood?Pressure.Arch?Intern?Med.1997；157：2413-2446.

7.Coheh?L.Kitzes?R.Clinical?chies?to?magnesium?deficiency.IsrJ?Med?Sci.1987；23：1238-1240.

8.Fermai?P，Rosman?J，Weidmann?P.Aniihypenensive?agents，serum?lipoproteins?andglucose?metabolism.Am?J?Cardiol.1991；67：26B-35B.

9.Psaty?BM，Smith?NL，Siscovick?DS，Koepseil?TD，Weiss?NS，Heckbert?SR.LemaitreRN，Wagner?EH，Furberg?CD.Health?outcomes?associated?with?antihypertensive?therapiesused?as?first-line?agents：a?systematic?review?and?meta-analysis.JAMA.1997；277：739-745.

10.Hansson?L，Lindholm?LH，Niskanen?L，Lanke?J，Hedner?T，Niklason?A，LuomanmakiK，Dahlof?B，de?Faire?Us?Morlin?C，Karlberg?BE，Wester?PO，Bjorck?JE.Effect?ofangiotensin-converting-enzyme?inhibition?compared?with?conventional?therapy?oncardiovascular?morbidity?and?morality?in?hypertension：the?Captopril?Prevention?Project(CAPPP)ran-domised?trial.Lancet.1999；353：611-616.

11.UK?Prospective?Diabetes?Study?Group.Efficacy?of?atenolol?and?captopril?in?reducingrisk?of?macrovascular?and?microvascular?compJications?in?type?2?diabetes：UKPDS?39.BK.1998；317：713-720.

12.Yusuf?S，Held?P.Furberg?C.Update?of?effects?of?calcium?antagonists?in?myocardialinfarction?or?angina?in?light?of?the?second?Danish?Verapamil?Infarction?Trial(DAVIT-II)andother?recent?studies，Am?J?Cardiac.1991；67：1295-1297.

13.Furberg?CD，Psaty?Blvl.Should?calcium?antagonists?be?first?line?drugs?inhypertension？Fer--.1995；20：365-369.

14.Estacio?RO.Jeffers?BW，Hiatt?wR，Biggerstaff?SL，Gifford?N，Schrier?RW.The?effectof?nisoldipine?as?compared?with?enaiapril?on?cardiovas-cular?outcomes?in?patients?withnon-insulin-dependent?diabetes?and?hypertension.N?Engl?J?Med.1998；338：645-62.

15.Tatti?P.Pahor?M，Byington?RP，Di?Mauro?P，Guarisco?R，Strollo?G?Strollo?F.Outcomeresults?of?the?Fosinopril?versus?Amlodipine?Cardio-vascular?events?randomized?Trial(FACET)m?patients?with?hypertension?and?NIDDM.Diabetes?Care.1998；21：597-657.

16.Packer?M，O′Connor?C，Ghali?je，Pressler?M.Carson?P，Belkin?R.Miller?A，NeubergG，Frid?D，Wertheimer?F，Cropp?A，DeMets?D.Effect?of?amlodipine?on?morbidity?andmortaliry?in?servere?chronic?heart?failure.-Vied-1996：335：1107-1114.

17.Alderman?MH，Cohen?H，Roque?R，Madhaven?S.Effect?oftong-actms?andshort-acting?calcium?antagonists?on?cardiovascular?outcomes?in?hypertensive?patients.Lancet.1997；349：594-598.

18.Staessen?J.Fagard?R，Lutgarde?T，Celis?H，Arabidze?G，Birkenhager?W，Bulpitt?C.Randomised?double-blind?comparison?of?placebo?and?active?treatment?for?older?patients?withisolated?systolic?hypetension.Lancet.1997；350：757-764.

19.Tuomilehto?J，Rastenyte?D.Birkenhager?WH，Thijs?L，Antikainen?R.Buipitt?CJ，Fletcher?AE，Forene?F，Goldhaber?As?Palatin?P，Sarti?C，Fagard?R.Effects?of?calcium-channelblockade?in?older?patients?with?diabetes?and?systolic?hypertension.N?Engl?J?Med，1999；340：677-684.

20.Materson?B，Reda?D.Cushman?W，Massie?B，Freis?E.Kochar?M，Hamburger?R，FyeC，Lakshman?R，Gottdiener?J，Ramirez?E，Henderson?W.Single-drug?therapy?for?hypertensionin?men.N?Engl?J?Med.1993；328：914-921.

21.Philipp?T.Anlauf?M，Distler?A，Holzgreve?H.Michaelis?J，Wellek?S.Randomised；double?blind，multicentre?comparison?of?hydrochlorothia-zide，atenolol，nitrendipine，andenalapril?in?antihypetensive?treatment：results?of?the?HANE?study.BMJ.1997；315：154-159.

22.Neaton?1.Grimm?R，Prineas?R，Stamler?J，Grandits?G，Eimer?P，Cutier?J，Flack?J，Schoenberger?J，54cDonald?R，Lewis?C，Liebson?P，Treatment?of?Mild?Hypertension?Studyfinal?results.JMAM.1993；270：713-724.

23.Hansson?L，Lindholm?LH，Ekbom?T，Dahlof?B，@anke?J，Schersten?B，Wester?PO，Hedner?T，de?Faire?U.Randomised?trial?of?old?and?new?hypertensive?drugs?in?elderly?patients：cardiovascular?mortality?and?mor-bidity?in?the?Swedish?Trial?in?Old?Patients?withhypertension-2?study.Lancet.1999；354：1751-1756.

24.Davis?BR，Cutter?JA.Gordon?DJ，Furberg?CD，Wright?JT，Cushman?WC.Grimm?RH，LaRosa?J，Whelton?PK，Perry?HM，Alderman?MH，Ford?CE.Oparil?S，Francis?C，Proschan?M，Pressel?S，Black?HR.Hawkins?CM.Rationale?and?design?for?the?Antihypertensive?and?LipidLowering?Treatment?to?prevent?Heart?Attack?Trial，(ALLHAT).Am?J?Hypertens.1996；9：342-360.

25.ALLHAT?Collaborative?Research?Group.Major?cardiovascular?events?in?hypertensivepatients?randomized?to?doxazosin?vs.chlorthalidone.JAMA.2000；283：1967-1975.

26..American?Diabetes?Association.Report?of?the?Expert?Committee?on?the?Diagnosisand?Classification?of?Diabetes?Mellitus.Diabetes?Care.1998；21：B1-B167.

27.Klag?MJ，Whelton?PK，Randall?BL，Neaton?JD，Brancati?FL，Stamler?J.End-stagerenal?disease?in?African-American?and?white?men：16-year?MRFJT?findings.JMAM.1997；277：1293-1298.

28.Heart?Outcomes?Prevention?Evaluation?study?Investigators.Effects?of?anangiotensin-converting-enzyme?inhibitor，ramipril?on?death?from?cardio-vascular?events?inhigh-risk?patients.n?Engl?J?Med.2000；342：145-153.

The antihypertensive and the body fat of prevention of cardiac outbreak reduce treatment

(ALLHAT) ultimate principle and scheme

Barry R.Davis, Jeffrey A.Cutler, David J.Gordon, Curt D.Furberg, Jackson T.Wright, Jr., William C.Cushman, Richard H.Grimm, John LaRosa, aul K.Whelton, H.MitcheIt Perny, Michael H.Alderman, Charles E.Ford, Suzanrre Oparil, Charles Francis, Michael Prosckan, Sara PresseZ, Henry R.Black and C.Morton Hawkins-----ALLHAT seminar

Is novel antihypertensive medicine (more expensive on average) the same with diuretic good or better in reducing coronary heart attack and developing? can the LDL cholesterol that reduces medium hypercholesterolemia older individuals reduce cardiovascular disease and the outbreak of mortality rate total amount?

Medical practice that these are important and public health problem can be by prevention of cardiac outbreak resisting hypertension and body fat reduce therapeutic test (ALLHAT, a kind of in 40,000 high-risk hyperpietics, carry out the randomization double-blind trial) and solve.Whether ALLHAT designs the comprehensive outbreak of measuring mortality coronary heart disease (CHD) and non-lethal myocardial infarction and there are differences between the randomized patients of diuretic (chlortalidone) treatment and three kinds of alternative treatment schemes (calcium antagonist (A Muluohe), angiotensin converting enzyme inhibitor (lisinopril) and α-adrenergic blocker (doxazosin)).ALLHAT comprises that also the body fat of randomized open labelling reduces test; this experimental design is determined 20; among 000 medium hypercholesterolemia patient (subgroups in 40000), whether the LDL cholesterol that reduces with 3-hydroxymethyl glutaryl Kiev enzyme A (HMG CoA) reductase inhibitor, pravastatin has reduced the mortality rate (comparing the matched group of acceptance " general duty nursing ") of the various causes of disease.

The main criterion of acceptability of ALLHAT is 1) age 55 or more than; 2) contraction or diastole hypertension; With 3) heart attack one or more other risks and assumptions (for example, the evidence of atheromatosis or type ii diabetes).Reduce test for body fat, participant's LDL cholesterol is necessary for 120-189mg/dl (those patients for known CHD are 100-129mg/dL), and content of triglyceride is lower than 350mg/dl.Treatment and the average duration plan of following the tracks of are 6 years, and, ultimate principle, scheme, purpose, treatment procedure and the research organization of ALLHAT have been described in this article.Am?JHypertens?1996；9：342-360

Keyword: hypertension, hypercholesterolemia, pharmacological treatment, clinical trial, ALLHAT test, chlortalidone, A Muluohe, doxazosin, lisinopril, economics.

Receive January 9 nineteen ninety-five, in the acceptance on the 28th of nineteen ninety-five JIUYUE.

From the coordination center of clinical trial, University of Texas School of Public Health, Houston, Texas (BRD, CEF, SP, CMH); Division ofEpidemiology and Clinical Applications, NationalHeart, Lung and Blood Institute, Bethesda, Maryland (JAC, DJG, MP); Department-of.PublicHealthSciences, Bowman Gray School of Medicine, Winston-Salem, North Carolina (CDF); Division of Hypertension, Case Western University School of Medicine, Cleveland, Ohio (JTW); Memphis Veterans ' Administration Medical Center, Memphis, Tennessee (WCC); Department ofInternal Medicine, University of Minnesota Medical School, Minneapolis, Minnesota (RHG); Tulane Medical Center, New Orleans, Louisiana (JL); Welch Center for Prevention, Epidemiology and Glinical Research, Johns Hopkins Medical Institutions, Baltimore, Maryland (PKW); St.Louis Veterans ' Administration Medical Center, St.Louis, Missouri (HMP); Department ofEpidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, New York (MHA); Division of Medicine, University of Alabama at Bir-mingham, Birrningham, Alabama (SO); Columbia University, New York, New York (CF); And Rush-Presbyterian-St.Luke ' sMedical Center, Chicago, Illinois (HRB).

Participation center and investigator have been listed at the end of this article.

This research is by the National Heart, Lung, and Blood Institute, National Institutes ofHealth, US Department of Health and Human Services, Bethesda, the Health andHuman Services contract number (NO1-HC-35130) of Maryland provides subsidy.See the extra statement of thanking in the chapters and sections.

Mailing address and second edition can be to BarrvZ Davis, MD, and PhD (Houston@TX 77830 for University of Texas School ofPublic Health, 1200 Herman Pressler Street) asks for.

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Estimation has 5,000 ten thousand people's hypertension (systolic blood pressure [SBP] 〉=140mmHg or diastolic blood pressure [DBP] 〉=90mmHg) or carrying out antihypertensive drug treatment in the U.S.. ^1,2Compare white man, hypertension is obviously more common in Black people, and its sequela is more common and serious in Black people.The constructive explanation that the syndrome ratio increases among these Black people comprises that coexistence disease such as diabetes are more popular, and part is owing to obtain the approach of medical treatment and nursing and reduce, thereby treatment and control there are not effect.Treat hypertensive cost parameter and depend on the cost of used hypotensive agent to a great extent. ³The given patient's number that will treat (between the 1988-91 2,000 3 hundred ten thousand), medicament selection has the remarkable economical implication. ^2,3Under the condition that all other factorses remain unchanged, compare every patient

500 situation is with every patient

The annual increment of 2,000 5 hundred ten thousand required costs of patient of Drug therapy of 100 is 10,000,000,000 dollars.

Although the etiology between described known hypertension and the coronary heart disease (CHD) relation can not prove usually that to the result of the extensive randomized clinical trial of light to moderate hypertension (DBP90-114mmHg) described antihypertensive drug treats the sickness rate that has reduced CHD mortality rate or non-fatal myocardial infarction in a large amount of middle aged experimenters. ⁴Make a general survey of the sickness rate that all hypertension tests have shown antihypertensive drug treatment can reduction CHD. ⁵But the effect of described reduction all is not so good as the conclusion that the expectation extrapolation draws. ⁶And described making a general survey of do not considered in the Elderly program (SHEP) the hypertensive obvious good effect of heart contraction recently, therein, based on the treatment of diuretic the sickness rate of main CHD has been reduced by 27% (95% confidence interval, 4-43%). ⁷Other test data sheet of in suffering from the hypertensive gerontal patient of diastole/contraction, carrying out similar result. ^8.9The possible explanation that above-mentioned test can not draw the CHD reduction degree of expectation is the medicine of being studied, and especially diuretic has detrimental effect, and it can offset the potential benefit that blood pressure reduces.These detrimental effects comprise the inductive hypokalemia of diuretic, low magnesium disease, antihyperuricemic, hyperlipemia, hyperglycemia, damaged insulin allergy and possible active the increasing of ventricular ectopy. ^1.10.11. still, these detrimental effects are very little under the dosage of recommending at present.

In the seventies later stage and the eighties, developed novel antihypertensive medicine-calcium antagonist, angiotensin invertase (ACE) inhibitor and α-adrenergic blocker, and confirmed can be used for chronic antihypertensive therapy.At present, these medicines are expensive more on average.But it is limited to evidence suggests that its purposes is better than the effect of old medicine.Only have two long-term large-scale random experiments to compare all these medicines: carried out the 1-term by Department of Veterans ' Affairs Cooperative Study Group at antihypertensive and tested, ¹²And 4.4 terms of moderate hypertension research (TOMHS) treatment. ¹³Though these test data sheets some differences in controlling of blood pressure, side effect, quality of life, biochemistry effect and target organ change, these differences do not show that a class medicine compares other medicines and remain favourable.And these tests do not have clinical endpoint, are used as the strong Main Conclusions of comparative drug.

Other relevant data are all from zooscopy and the clinical trial carried out on the patient who suffers from a heart complaint.In the rabbit model, calcium channel blocker has suppressed the development of atherosclerotic lesions, but the clinical testing data on M ﹠ M is contradictory.In diltiazem (diltiazem) test of back myocardial infarction (MI), back-hoc analyzes and shows that the low patient of ejection fraction is had adverse effect, still the patient of non-low ejection fraction is not had benefit.All back-MI tests that summary is carried out with calcium channel blocker, discovery increase by 6% aspect mortality rate (95% confidence interval ,-4%-+18%). ¹⁴The more new data packets of this summary is drawn together three extra tests of carrying out in suffering from angina pectoris or myocardial infarction patient, shown disadvantageous result, especially uses the situation of dihydro piperidines calcium channel blocker. ¹⁵Describedly cause mortality rate to increase with nifedipine and the fugitive preparation of nicardipine mainly appearing among the patient of nearest trouble MI.These results are different with long-acting dihydro piperidines such as A Muluohe.

Angiotensin invertase (ACE) inhibitor has reduced serious and so not serious cardiopathic mortality rate, and has reduced the sickness rate that asymptomatic left ventricular dysfunction comprises CHD. ¹⁹Write down with ACE inhibitor and improved the insulin resistance performance, observed result is especially relevant with the patient of type ii diabetes. ^20.21And Chobanian and its colleague have reported the coronary heart disease infringement that can prevent the rabbit model with the how general riel treatment of Kapp, ²²Perhaps, this is because influential to the cell proliferation in the blood vessel wall.Do not confirm also that in the mankind ACE inhibitor has the resisting hypertension effect.

Described alpha block agent shows that body fat curve is had medium useful effect, especially to HDL cholesterol, LDL cholesterol and LDL/HDL ratio. ^13.23Existing report can improve insulin resistance with the alpha block agent. ²⁴Exist some evidences to show that these medicaments can reduce platelet aggregation, and stimulation organize plasminogen to activate son. ^25-27

Whether these are more superior than old medicine, equal or relatively poor in treatment hypertension and its cardiovascular syndrome of prevention from can not judge newtype drug at the data of human and animal's Study of model.Suppose that this point is very important to clinical and publilc health, estimate new antihypertensive with regard to the result who is sought after extensive contrast test so and compare importance in angiocardiopathy preventing with old medicine.

The experimental evidence of the effect of cholesterol reducing in reducing the CHD morbidity wherein lacks the research to women, ethnic groups and old people to the almost complete research of white race, middle-aged male.The epidemiology evidence of observed result is further illustrated among the old people, the relation between cholesterol level and the CHD so strong (still though very high in the old people with cholesterol-associated risk, this is because its absolute sickness rate height), ²⁸And mandatory to women and ethnic groups also not as the male. ²⁹Although CHD reduces in the intermediate analysis of these experiments, the reduction of CHD mortality rate by other deadly because of increase offset. ^30-40Though the net change on the general mortality rate is often favourable to the high-risk group, ^34.40As before suffering from the male of myocardial infarction, ^30.32But it does not have effect in most of primary prevention experiments. ³¹Yet the cholesterol of public data reduces experiment (individual special case is arranged) can not have enough statistics effectiveness, solves the influence to general mortality rate, ⁴¹Although reduced the CHD morbidity.And the possible toxicity of the medicine of limited treatment persistent period or the degree of cholesterol reducing and the cholesterol reducing that some are old makes the explanation overshadowed 3 of these analyses in great majority experiments ^0,35-403-hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor (the LDL cholesterol levels can be reduced by 25% or more than, and almost do not have significant side effects) have and be beneficial to development and more effectively test, thereby address these problems.Recently the 1-term in the middle of research (cholesterol in advanced procedures (CRISP) reduces) confirmed in the placebo experiment of reductase inhibitor, to replenish and keep old people's probability. ⁴²

An above-mentioned special case is Scaninavian Simvastatin survival study Study (4S) .41.This research will be carried out random assortment from 4444 masculinity and femininities of six Scandinavian countries, and they suffer from the CHD and the cholesterol levels (between 212-309mg/dl) of record, treat with Simvastatin and placebo.Described main terminal point is a general mortality rate, and tracking time meansigma methods value is 5.4 years.Described result of experiment shows below: 1) average LDL cholesterol reduces by 35% in the Simvastatin group; 2) compare placebo group, the mortality rate low 30% of described Simvastatin group; 3) do not have in other cause of the death that the CHD mortality rate reduces by 42% under the condition of movement tendency; 4) non-fatal CHD terminal point class Sihe significantly reduces; 5) mortality rate of the various causes of disease reduces in old people (60-70 year) and younger patient; 6) for the men and women, the CHD sickness rate reduces.

When this research of design, described 4S experimental result is not reported.When the result announced, described Steering committee had considered the problem whether the cholesterol experiment should continue.Decision continues to be based on two reasons.The first, the resisting hypertension of described 4S experiment and prevention of cardiac outbreak reduces treatment (ALLHAT) with body fat and handles very different study populations.In fact, only 3% the patient who has carried out ALLHAT cholesterol experiment (in November, 1994) at random satisfies 4S experiment login standard: existing CHD, the age, total cholesterol level was greater than 212mg/dl less than 70 years old.The second, because the ALLHAT matched group carries out " general duty nursing ", rather than placebo, therefore do not stop the research doctor to think that to any the patient of needs leaves the prescription that cholesterol reduces medicine.Only variation is to have got rid of to suffer from the patient that CHD and LDL are higher than 129mg/dl, and described patient advises having taken cholesterol probably and reduces medicine.Before, this upper limit is 159mg/dl.Though some doctors also leave these medicines for the patient of other ALLHAT " general duty nursing ", the benefit that but Steering committee thinks that in main prevention cholesterol reduces and LDL content is lower than second prevention of 130mg/dl still be can not determine, even after carrying out the 4S experiment, and the patient of most of general duty nursings in these classifications can not take this medicine.

Purpose and scheme

ALLHAT is (by National, Heart, Lung, and Blood Institute (NHLBI) and Department of Veterans ' Affairs subsidize) be a kind of randomization clinical experiment based on practice, in 40,000 high-risk hyperpietics, carry out, 55 years old age or more than, wherein about 45% is the women, the 55%th, and Black people.ALLHAT has two parts.Described resisting hypertension partly is double blind experiment at random, is used for determining whether the combination outbreak of mortality coronary heart disease (CHD) and non-lethal myocardial infarction is different between diuretic (chlortalidone) treatment and three alternative resisting hypertension pharmacology treatments (calcium antagonist (A Muluohe) and ACE inhibitor (lisinopril) and α-adrenergic blocker (doxazosin)).Described body fat reduction part is an open labelling experiment at random, be designed for and determine 20,000 moderate hypercholesterolemia masculinity and femininity (55 years old age and above (40, the subgroup of 000 resisting hypertension experiment)) in, reduced the mortality rate (and the matched group of accepting " general duty nursing " compares) of the various causes of disease with the serum cholesterol of HMG CoA reductase inhibitor (pravastatin) reduction.

Suppose and study effectiveness

The main hypothesis of described resisting hypertension experimental section is that the combination outbreak (for the first time or recurrence) of mortality CHD and non-lethal myocardial infarction is being assigned randomly to 1) calcium antagonist (A Muluohe), 2) ACE inhibitor (lisinopril) and 3) α-adrenergic blocker (doxazosin) is as lower among the hyperpietic in the first-selected treatment (with comparing being assigned randomly to the hyperpietic of thiazide diuretic (chlortalidone) as first-selected treatment).Therefore, described statistical project must be leaned on three main comparisons.

Render a service maximum for the statistics that makes the resisting hypertension experiment, the patient who is assigned to the diuretic arm is 1.7 times (table 1) that is assigned to the patient of other three arms separately. ⁴³The ultimate principle of sample size is listed in appendix.Hypothesis is exactly that half ALLHAT participant is assigned randomly to two experimental sections, and second half only is assigned randomly to the resisting hypertension experimental section.Second hypothesis of this part is listed in the table 2.

The main hypothesis that described cholesterol reduces experimental section be exactly the LDL cholesterol level be 120-189mg/dl (to those known CHD, hyperpietic 100-129mg/dl) (take at random general he cut down spit of fland and cholesterol reduce food (National Cholesterol Education Program[NCEP] Step I recipe ⁴⁴) the mortality rate of the various causes of disease in the subgroup is than low in accepting those patients that diet adds general duty nursing.The ultimate principle of described sample size is listed in the appendix.The less important hypothesis of this part is listed in the table 2.

The sample size in advance of table 1:ALLHAT treatment group

Cholesterol reduces test (2 arms)	Resisting hypertension test (4 arms)				Altogether
						Chlortalidone	A Muluohe	Lisinopril	Doxazosin
	Pravastatin	3,655	?2,115	?2,115						?2,115	?10,000
General duty nursing					3,655	?2,115	?2,115	?2,115	?10,000
	Edible not	7,310	?4,230	?4,230						?4,230	?20,000
Altogether					14,620	?8,460	?8,460	?8,460	?40,000

Second supposition of table 2.ALLHAT test portion

Antihypertensive test-, in the patient who accepts A Muluohe, lisinopril or doxazosin at random, reduce following terminal point (or other outbreak) with respect to accepting those of chlortalidone:

1. general mortality rate

2. make up coronary heart disease (formation again of CHD or blood vessel or the angina pectoris of hospitalization)

3. apoplexy

The combination cardiovascular disease (CHD or apoplexy or coronarius form again or angina pectoris [hospitalization or Drug therapy] or CHF[hospitalization or Drug therapy] or edge nervous system disease [formation again of outpatient's blood vessel hospitalization or Drug therapy])

5. the left ventricular hypertrophy of checking out by ECG

6. nephropathy

A. the slope of serum creatinine and inverse

B. end-stage renal disease (chronic renal dialysis or liver transplantation begin)

7. the quality of life relevant with health

8. the prime cost of medical treatment and nursing

Body fat reduces test-with respect to accepting those of general duty nursing, reduce following terminal point (or other outbreak) in the patient who accepts pravastatin at random:

1.CHD dead and non-lethal myocardial infarction combination outbreak, especially in some subgroup, black race for example, the original cholesterol reduction among the patient of over-65s (at Seniors Program[CRISP] hypothesis38), type ii diabetes and women

2. myocardial infarction studies variation among the ECG biyearly

3. specify the mortality rate (for example, cancer, tumor) of the cause of disease

4. the cancer of all and locality outbreak

5. the quality of life relevant with health

6. the prime cost of medical treatment and nursing

CHD, coronary heart disease, CHF, congested heart disease, ECG, electrocardiogram

Selecting general mortality rate is that this experiment is non-blindness as a main cause of main terminal point.And the evaluation of this a part of center flesh infarction depends on conventional centre code electrocardiogram (ECG), rather than research doctor's subconsciousness evaluation.Though can check other secondary endpoints, can think that it is " soft data ", can be that the best of main terminal point authenticates and replenishes.

Though carry out blindness research in many modes is preferred natch, and other factors is also infeasible in the whole research of ALLHAT.When carrying out, test can monitor syndrome and crossing-over rate, not enough if the real data indication is renderd a service, then stop this research.

Login and tracking step

Recruit and baseline visit

The recruitment of ALLHAT depends on the whole bag of tricks, especially is used for distinguishing in participating in clinical clinic following the trail of as described test member's patient's case history.Access plan and step to ALLHAT participant are listed in table 3.Judge that clearly the desired data meet the resisting hypertension test portion can obtain in two at random visits in advance, this visit at interval 1 day to 2 months usually.The target of visit 1 is qualification and the importance of estimating among the ALLHAT, if need, and begins to stop to allow the patient take beta blocker and central nervous system's alpha antagonist.The hyperpietic that can estimate many treatments can follow the trail of by case history and distinguish, and most relevant information (for example, the quantity of age, risks and assumptions state and antihypertensive) is known.The temporary visit that the needs of patients of beta blocker and central nervous system's alpha antagonist is extra is progressively to carry out Drug therapy.Have only the patient who is assigned randomly to the resisting hypertension test portion can think to reduce part at random, at the back randomization (normally after 4 weeks) of first time resisting hypertension test before, can not carry out randomization the latter for cholesterol.

Table 3:ALLHAT patient visits arrangement

Visit #	From visiting the moon number of 2 beginnings	Purpose
				The resisting hypertension test	Cholesterol reduces test
		-	-6.0 to 1 days			Discern potential participant
1	-2.0 to 1 days			Assessment qualification and importance
		1a，b，c	On demand			If when taking alpha block agent or central nervous system's alpha antagonist from the antihypertensive of research in advance progressively down
2	?0			Randomization, laboratory diet/life style sincere advice	Fasting ALT
		3	?1			Routine data is collected, and dose titration is if need	Randomization, fasting LP curve *NCEP goes on foot 1 diet

4	3	Routine data is collected, and dose titration is if need	Dose titration, as needs, ALTTC+
				5，6，7	6,9,12 (if needing then more frequent)	Routine data is collected, and dose titration is if need	Routine data is collected, and dose titration is if need
8，9，10…	Per 4 months	Routine data is collected	Routine data is collected

^*Cholesterol total amount, triglyceride, HDL and LDL cholesterol levels.LDL calculates back randomization visit by the Friedewald formula

ALT, alanine aminotransferase ' NCEP, national cholesterol education program ⁴⁴TC, the cholesterol total amount

The blood pressure criterion of acceptability that is used for resisting hypertension test is listed in table 4, and it is based on the meansigma methods that takes a seat blood pressure measurement in patient's present therapeutic state and twice visit for twice.For untreated patient, used standard is diastole and shrinks hypertensive present JNC V definition (Phase I-II).For the treatment the patient, described standard is rational controlling of blood pressure degree, promptly the visit 1 in ,≤160mmHg (contraction) and≤100mmHg (diastole); In visit 2 ,≤180mmHg (contractions) and≤110mmHg (diastole) (when Drug therapy has partly been withdrawn).Other that is used for that resisting hypertension and body fat reduces test comprises with exclusion standard lists in table 5.

Table 4.ALLHAT blood pressure criterion of acceptability

The state of visit 1 and 2	Lower limit *(mmHg)		The upper limit (mmHg) +
					SBP	?DBP	SBP	DBP
	Take 1-2 kind medicine, treatment hypertension at least 2 months	-	?-	160 					100 
						180 §	110 §
		Take the medicine time less than 2 months, or not treatment at present	140	?90				180	110

^*In visit 1 and visit 2, must satisfy the lower limit of SBP or DBP

+ must satisfy the upper limit of SBP or DBP in 2 in visit 1 and visit

 only visits 1

§ only visits 2

The main ALLHAT of table 5. comprises and exclusion standard

The antihypertensive test

1. comprise

A) behavior of one or more performances of atherosclerosis cardiovascular disease: 1) old (＞June) or middle aged myocardial infarction or apoplexy; 2) the formation history again of blood vessel; Or 3) Ji Zai atherosclerosis cardiovascular disease

B) type ii diabetes [plasma glucose＞140mg/dL (fasting) or 200mg/dL (non-fasting) or insulin or oral hypoglycemia medicine]

C) HDL cholesterol＜35mg/dL (in the past in 5 years 〉=situation of 2 decisions under)

D) left ventricular hypertrophy on electrocardiogram or heart echo scintigram

E) the ST-T ripple electrocardiogram of local defect changes indication

F) smoking at present

2. get rid of

A) Symptomatic MI or apoplexy in 6 months in the past

B) if Symptomatic congested heart disease, or left ventricle discharge section＜35% is known words

C) Symptomatic angina pectoris in 6 months in the past

D) serum creatinine 〉=2mg/dL

E) need thiazide diuretic, ACE inhibitor, calcium antagonist or α-adrenergic blocker, be used for the reason except that high BP

F) need＞2 kinds antihypertensive, obtain gratifying BP control

G) to the allergy or the contraindication of any step 1 medicine

H) in accordance with the low factor of probability of doctor's advice, for example plan is excessively moved or travelling

I) in research process, might cause the disease of non-cardiovascular disease death

J) blood pressure: systolic blood pressure＞180mmHg, diastolic blood pressure＞110mmHg is based on two independent readings in screening or the progressively reduction process

Body fat reduces test

1. comprise

A) registration in the resisting hypertension test

B) the LDL cholesterol is 120-189mg/dl (100-129mg/dl is for known congestive heart disease patient), content of triglyceride≤350mg/dl

2. get rid of

A) used the body fat left to reduce the nicotinic acid that to have bought without doctor formula of medicament or heavy dose (〉=500mg/ days) at present

B) to the contraindication of liver hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor (for example, significantly hepatopathy, carry out the intolerance of immunosuppressant therapy, known Sensitive disease or research medicine)

C) known untreated second cause of disease of hyperlipidemia (for example, hypothyroidism, nephropathy syndrome)

D) alanine aminotransferase (ALT)＞2.0 * upper limits of normal

-----------------------------------------------------------------

Randomization

The patient who satisfies the ALLHAT criterion of acceptability can cut out former antihypertensive safely, and is assigned randomly among of four ALLHAT treatment arms, and the notice letters of commitment of 2 researchs that can conduct interviews are provided.This visit is carried out between visit 1 day to 8 weeks after 1 usually, and this depends on from the Drug therapy of studying in advance and gradually reduces required time length; Or the hypertension state of determining.Soon just can not take medicine after 1 or on a kind of medicine, can carry out random assortment in visit, and other patient needed than the process of growing that gradually reduces (usually less than 2 months) before finishing visit 2 as the patient of fine contrast with beginning.Keep single absorption method in the process of the test because many patients that can not stop the absorption method to study in advance soon also are difficult in, therefore do not encourage the longer time that gradually reduces.In process of the test, can provide suitable hygiology suggestion (minimizing sodium is with pure, motion, if the overweight heat that carries out limits) for all randomized patients, the while is strengthened as required.

Satisfied the resisting hypertension test portion all-access 1 qualified requirement or agreed to begin to gradually reduce in advance that the cholesterol of the also notified ALLHAT of carrying out of patient of the antihypertensive drug of research reduces test portion.Those patients that interesting and body fat of no use reduces Drug therapy in the expression in 12 months of conducting interviews are considered to the potential candidate of this test.

In visit 2, will obtain fasting body fat group (the LDL cholesterol 44 of cholesterol total amount, triglyceride, HDL cholesterol, calculating) and serum alanine transaminase (ALT is SGPT before).In this visit, those show interest and the LDL cholesterol is that 120-189mg/dl is (for known HCD's by Advise By Wire, be 100-129mg/dl), the patient of metal triglyceride≤350mg/dl meets cholesterol and reduces test portion, and informs 3 the fasting of conducting interviews.Participate in 3 o'clock ALLHAT part of visit if they meet, the described clinic test center of described investigator's Advise By Wire, and receive the patient carry out general he cut down the appointment at random (patient also can enter test at 4 o'clock at random in visit) of spit of fland or general duty nursing.Each is taken the general patient that he cuts down the spit of fland at random and requires to take the 20mg tablet of appropriate amount, and is taking every night twice.Specify the patient of general duty nursing and specify general patient's suggestion that he cuts down the spit of fland to abide by NCEP step I diet (from heat＜30% of fat; Heat＜10% from saturated fat; Cholesterol/sky＜300mg).The research doctor keeps reduction, and those can not tolerate the viewpoint of the patient dose of described full dosage.All ALLHAT patients are carried out body fat curve determination at 2 o'clock in visit, all patients in the cholesterol test are carried out body fat curve determination visit 3 o'clock.General he cut down in the group of spit of fland, when visit 4 and all annual visits, also measure cholesterol levels; Carry out all fat curve determinations in the mode of selecting 10% crowd at random.In the general duty nursing group, when the visit in the second, the 4th and the 6th year, measure cholesterol levels, carry out all fat curve determinations in the mode of selecting 5% crowd at random.

Treatment procedure

Resisting hypertension is got involved

The blood pressure target is＜90mmHg (diastole) in all four arms,＜140mmHg (contraction).Described therapeutic purposes are may obtain controlling of blood pressure under the choice drug of dosage minimum.The quantity of the research medicine of leaving when pursuing these purposes and the influence that dosage is subjected to patient tolerability and clinical judgment are especially under the situation of using 2 two or more medicines.The acceptable dosage level of various medicines is listed in the table 6.

Table 6.ALLHAT first (blind), second and three-way (open labelling) antihypertensive

	Initial dose +	Dosage 1 +	Dosage 2 +	Dosage 3 +
					Step 1 medicine
Chlortalidone	12.5	?12.5	?12.5	?25
					A Muluohe	2.5	?2.5	?5	?10
Lisinopril	10	?10	?20	?40
					Doxazosin	1	?2	?4	?8
Step 2 and 3 medicament
					Reserpine		Every day 0.05 or per two days 0.1	Every day 0.1	Every day 0.2
Clonidine (oral)		Twice 0.1 of every days	Twice 0.2 of every days	Twice 0.3 of every days
					Atenolol		Every day 25	Every day 50	Every day 100
Hydralazine (is three-way)		Twice 25 of every days	Twice 50 of every days	Twice 100 of every days

^*The source of four kinds of first-selected medicaments: chlortalidone: Ogden Biosu-ices, Inc., Rock-oille, Maryland; A Muluohe: Pfizer, Inc., New York, Ne-w York; Lisinopril: Zenecn Phamracmticnls Group, YViImirrgton, Delawure; And doxazosin: Pfizer, Inc., New York, new York

⁺All dosage are in milligram.

Medicine identity under each dosage level is concealed.Only first week was used the initial dose level after randomization, made the potential first dosage hypopiesia minimum of doxazosin.For other three kinds of medicines, the dosage of described initial dose and step 1 is identical.And for the other medicines that make three kinds of dosage keep blindness, dosage 1 and 2 chlortalidone are 12.5mg.The patient returns to increase dosage common every 1-month, shrinks and diastolic pressure up to reaching target.If can not tolerate the blindness medicine of initial dose, then cut out.Attempt using once more this Drug therapy afterwards, but because enough controlling of blood pressure need be provided, the patient to treat with the medicine of open labelling, and continue under study for action.

For any one still can not reach the patient of satisfied controlling of blood pressure in four treatment arms under the choice drug of maximal allowance dose, select second and three medicine (table 6) of use except that (not replacing) described choice drug with open mark pattern, unless do not tolerate choice drug.The selection of two wires medicine is to be judged by treatment research investigator.Because described research investigator does not know the identity of the choice drug taken to the patient, so use the frequencies of each two wires medicine similar probably in four treatment arms.Though under concrete condition, the investigator can select with study in those different prescription two wires antihypertensives of providing, but avoid using thiazide diuretic, calcium antagonist, ACE inhibitor and α-adrenergic blocker, unless tried the maximal allowance dose of three kinds of medicines, and can not successful controlling blood pressure.

Cholesterol reduces to be got involved

The cholesterol of described ALLHAT reduces part can add that with HMG CoA reductase inhibitor (general he cuts down the spit of fland) diet and general duty nursing add that diet compares at random in patient's subgroup of the resisting hypertension part that participates in research.The general dosage that he cuts down the spit of fland can be 40mg, takes at night.Suggestion in the step I diet that all participants in the ALLHAT part will accept to be recommended by National CholesterolEducation Program43 when entering research at random.It is can be after entering ALLHAT resisting hypertension part at random at least 4 all to carrying out in 90 days at the most to enter this test portion at random.

The judgement of conclusion

Terminal point is confirmed

The appearance of research terminal point can be put down in writing by the inventory that each tracking visit is finished, and is replenished by intermediate record when needed.These diagnosis can be supported by the copy and the discharge summary of death certificate.In table 7, listed the conclusion that in conceptual phase, obtains and tabulate.The described cause of death can be classified by doctor-investigator in clinical clinic.Country's index of mortality (NDI) investigation will be carried out when research closes to an end, and distinguish and be documented in the death condition that occurs among the patient who loses tracking.Because the intrinsic time lags behind among the NDI, private follow-up service also can be used to select the participant.

Table 7.ALLHAT achievement

1. dead

The myocardial infarction that a is clear and definite

B. clear and definite coronary heart disease

C. possible coronary heart disease

D. apoplexy

E. congestive heart disease

F. other cardiovascular disease

G. cancer

H. thunder bolt, commit suiside or kill a person

I. other non-cardiovascular cause of disease

J. unknown etiology

2. myocardial infarction

3. apoplexy

4. angor (hospitalization or treatment)

5. congestive heart disease (hospitalization or treatment)

6. edge nervous system disease (hospitalization or treatment)

7. new cancer diagnosis (hospitalization or treatment)

8. thunder bolt or attempt to commit suiside (hospitalization or treatment)

9. left ventricular hypertrophy (once every two years research, electrocardiogram)

10. renal function

A. serum creatinine content is to the slope of the inverse of time

B. end-stage renal disease (from chronic renal dialysis or liver transplantation)

11. quality of life

12. medical treatment and nursing

Described research investigator require to finish to when routine visit or between the short terminal point questionnaire survey of the research terminal point appearance distinguished, and submit to clinic test center.For each terminal point that relates to death or be in hospital, described investigator also obtain and submitted to death certificate and diagnosis based on the copy of discharge summary.For the subgroup of (10%) hospitalization (fatal and nonfatal) myocardial infarction and apoplexy at random, more detailed information will be inquired by clinic test center.For this subgroup, ECG and enzyme level (forming for myocardial infarction) and neurologist's report and Computerized tomography art (CT) or NMR (Nuclear Magnetic Resonance)-imaging (MRI) report (to apoplexy) in hospital will be estimated by research terminal point committee, and estimate the accuracy of discharge diagnosis.

Data analysis

The main terminal point of the resisting hypertension part of ALLHAT is comprehensive mortality CHD and non-lethal MI.Described main response variable is the time from randomization to morbidity.Described Log level test ⁴⁶To be used for more non-diuretic therapy group and diuretic group.For the secondary endpoints of the mortality rate of the various causes of disease, apoplexy, comprehensive coronary heart disease and cardiovascular conclusion and end-stage renal disease, also can use the test of Log level.For left ventricular hypertrophy that draws by ECG (LVH) and the quality of life relevant, can whether there are differences in the relatively treatment group of usage ratio with health.For the conclusion of nephropathy, obtain the inverse of participant's creatinine value when baseline, 3 months and the 2nd, 4 and 6 year.Use the treatment group as fixed influence, Laird and Ware are used in time conduct influence at random ⁴⁷Vertical model evaluation interact in time the influence the treatment situation.

The important terminal point that the body fat of ALLHAT reduces part is the mortality rate of the various causes of disease.Described main response variable is the time from randomization to morbidity.Described Log level test ⁴⁶To be used for more general he cut down the spit of fland and add the group of diet and the group that general duty nursing adds diet.For the secondary endpoints of the mortality rate that makes up fatal CHD and non-fatal MI, fatal and non-fatal cancer and the concrete cause of disease, also can use the test of Log level.In addition, the test of described Log level can be used for the treatment that comparison is carried out in each subgroup of fatal CHD of following combination and non-fatal MI: male, women, 〉=65 years old,＜65 years old, Black people, non-Black people, diabetes and non-diabetic.For the ECG conclusion of the quality of life relevant, can whether there are differences in the relatively treatment group of usage ratio with health.

Interim monitoring concentrates on that the patient takes total amount and abides by baseline comparability, sample size hypothesis (with regard to sickness rate), crossing-over rate, the competitive risk of rules, treatment group at each clinical center, center and miss tracking, adverse effect data and the therapeutic effect on main and less important research conclusion.The meeting of interim analysis and data and security monitoring committee (DSMB) is consistent.Can use at random shortening to monitor resisting hypertension and body fat and reduce treatment difference in the research. ^48.49

Organizational structure

ALLHAT has the visibly different organizational structure of supporting with common NHLBI of clinical trial.When applying following condition, this what is called " big simple experiment " pattern (is carried out in International Studyof Infarct Survival (ISIS) test, by the investigator of Oxford university before ⁵⁰Put in order, and use for the first time by the NHLBI in the test of numerical survey group ⁵¹) be suitable: 1) need very big sample size, 2) may be fairshaped rules, 3) in clinical practice, often run into target disease, and 4) problem studied among the clinicist is very interested.

Described test is put into practice doctor-investigator by a large amount of (400-500) and is carried out, and distributes based on patient's number according to fixed payment scheme to compensate them.The clinical outpatient service of the hypertension of Department of Veterans ' Affairs (DVA) estimates to recruit the research patient of about 15-20%.Described clinic test center (except its routine data is handled and the monitoring responsibility) will be responsible for distinguishing these doctor-investigators and pay their expense, be used to raise regional doctor and nurse research coordination person, monitor and recruit and follow the doctor's advice, and provide and monitor the subcontract at medicine Distribution Center, central laboratory and ECG coding center.The expert of administration committee is also appointed by NHLBI in the relevant item.

According to the patient who is assigned randomly to each test portion and finish the compensation that each follow-up study visit gives practitioner's fixed charge.This expense is estimated to fill and lead up the expense that above-mentioned data collection (observation that gradually reduces and instil, questionnaire survey, blood drawing, ECG record) is produced.Described expense does not comprise the cost of required experiment work and ECG coding, and these are undertaken by central authority, and directly by clinic test center's direct payment, perhaps the cost separate payment of terminal point is studied in record.

Described clinic test center bears whole responsibility to training and quality control.All clinical clinics all require to participate in the training chapters and sections.Described training chapters and sections comprise the orientation of studying rules, training and the orientation of proof, ECG and test procedure and participant's the training that replenishes and keep of blood pressure determination, and study finishing and shifting of form.Periodic refresher training can arrange research person's meeting in conjunction with carrying out with routine.These education chapters and sections comprise to the tracking of correct blood pressure measurement step or by following the trail of conventional monitor activities discerns any problem.

The obligation of the relevant quality control of described clinic test center comprises: 1) in order to guarantee that complete sum is accurate, followed the trail of all forms, 2 before data entry) by take on the telephone or fax connection solves problem 3 with clinical clinic) the Double Data login of form is provided; 4) distinguish the intersection form of losing form and step, 5) the carrying out of monitoring study portion and in time provide Top Line Report to program office and administration committee, 6) in meeting, provide the details of flow of research and the statistical report of renewal everyday to DSMB.

All aspects of the obligated monitoring research of described DSMB comprise those that obtain the blindness data.Described DSMB and chairman thereof are appointed by the leader of NHLBI, and they are and the described research personnel that it doesn't matter.In the active recruitment stage, described DSMB will monitor the process (especially Black people participant) of superorder, at random the participant is arranged into respectively and treats in the arm, and when not reaching the purpose of research approach, in one or two study portion, recommend to revise (or termination).The approval that any other remarkable change also needs to obtain DSMB appears in the rules that administration committee is recommended in research process.

In research process, suggestion stops any treatment arm of each study portion under the condition on DSMB arbitrary basis below finding:

1) show research treatment significant adverse from the mandatory evidence of this test or another test, be enough to overthrow any potential benefit of relevant CHD, and get rid of in the target group, further use may;

2) the mandatory evidence from this test or another test shows research treatment significant adverse, and being enough to the continuation of other seminar negates to be untenable in ethics;

3) successfully the probability of the hypothesis of solution research is very low in feasible time range, and this is because replenish degree, drug reaction, sickness rate or other key performance standards not enough, that follow the doctor's advice.

The leader of NHLBI will make final decision to whether accepting the suggestion that DSMB stops to study any part.

Sum up

Hypertension is the American, especially common health problem among older individuals and the Black people.It relates to enlarging markedly of M ﹠ M risk.In the hypertension individuality, carry out only having diuretic and beta blocker to demonstrate and to reduce this risk in the long-term clinical trial.Still do not know that whether more expensive novel antihypertensive medicine provides the benefit that increases, and does not know whether to reduce the morbidity of cardiovascular disease yet.

Do not know with regard to coronary heart attack reduction and mortality rate yet, treat medium hypercholesterolemia elderly men and women's potential benefit with HMG CoA-reductase inhibitor.The conclusion of ALLHAT just can obtain up to 2002, should help to solve these problems of medical practice and the main importance of publilc health.

Thank

This research is by National, Heart, and Lung, and Blood Institute subsidizes.The direct study source of supply of medicine of described ALLHAT investigator: Panzer, Inc. (A Muluohe and doxazosin); Zeneca (atenolol and lisinopril) and Bristol-Myers Squibb (pravastatin), and by Pfizer to the NHLBI support of providing with funds.The author thanks Teri doctor Manolio (NHLBI designer in the past) in the plan of ALLHAT and the concrete contribution of pioneer's conceptual phase very much.

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Adnexa

The consideration of relevant sample size

The statistics of the main hypothesis of test resisting hypertension test is renderd a service and is about 82.5%, based on following hypothesis: 1) sample size is 40,000 (about 22,000 male and 18,000 women), 2) the CHD6-annual morbidity is 7.8% (to study from Framingham in the diuretic group, hypertension is surveyed and tracing program [HDFP] and the middle hypertension of shrinking of Elderly program [SHEP] [personal communication]), 3) and the diuretic arm relatively, the CHD sickness rate of adjusting uncomplaisance and missing in three non-diuretic therapy arms after following the tracks of reduces by 16.3%, 4) other research medicine and chlortalidone separately and the crossing-over rate between the non-research medicine be 2.75% (in first 3 years), what be 6% (ratio is from the TOMHS[personal communication]) in back 3 years of following the tracks of-produce accumulation 24% carried out the ratio that Drug therapy is intersected at least with another in 6 years, 5) because competitive risk (non-CHD death) or miss tracking, when finishing, research can not determine that the patient of CHD state is 16.8%, 6) at 10 of the activity therapy arm that is assigned randomly to cholesterol reduction test portion, among 000 patient CHD sickness rate reduce by 25% (adjust non-follow the doctor's advice and before tracking misses), 7) I type error is 0.05 (both sides), is 2.37 corresponding to using the Dunnett step to carry out repeatedly comparing critical-Z-value afterwards. ⁴³

The age criterion that initial ALLHAT rules are used be 60 or more than, not with present smoking as risks and assumptions.Reduce the login age and also reduced the CHD sickness rate, then cause the CHD sickness rate to remain on for 1.35%/year but add the smoking risk.Also can consider more pessimistic or optimistic hypothesis.These comprise that sickness rate increased to 1.65% year from 1.05/, crossing-over rate from 22% to 26%, loss rate from 11.8% to 21.8%.Under these hypothesis, render a service and estimate from 77% to 86%.

Based on National Health and Nutrition Examination Survey (NHANES) Il ⁵²About the 65-74 data in year, (wherein, ALLHAT patient's the LDL cholesterol cutpoint of not suffering from CHD is corresponding to 25 and 86 percentage points (male) and 14 and 76 percentage points (women), has that to surpass ALLHAT research patient its LDL concerning cholesterol reduces test of 60% qualified.Suppose that will participate in cholesterol the qualified patient of 80%LDL (or all ALLHAT patients 50%) reduces test.Afterwards at the NHANES of nearlyer (1988-91) III data (National Center for Health Statistics, personal communication) obtain low slightly estimated value (low) at 60% end, reacted the LDL cholesterol levels and from Black people and age 75-84 the year people more multidata in downward interim trend usually.

The statistics that described test cholesterol reduces the main hypothesis of test is renderd a service and be about 85.5%:1 under following hypothesis) sample size is 20,000 (about 11,000 male and 9,000 women), divide equally general he cut down in spit of fland and the general duty nursing group, 2) 6 annual death rate are that 12.2% (2.15% year) is (from Framingham in the general duty nursing group, HDFP and SHEP[personal communication]), 3) adjust to reject and add before general he cut down that mortality rate reduces by 14% in the spit of fland treatment group, 4) in 1 year " rejecting " rate be 5% (from general he cut down the spit of fland and do not treat treatment), each year is 2.5% afterwards, annual " addings " rate be 2.5% (from general he cut down the spit of fland and do not treat treatment)-when finishing in 6 years general he to cut down the accumulation ratio for the treatment of in the spit of fland be 15.3%, general duty nursing be 10.6%, 5) there is not mortality rate to follow the tracks of loss, 6) mortality rate reduces by 10% in three non-diuretic therapy arms of resisting hypertension test portion, 7) I type error is 0.05 (both sides), is 1.96 corresponding to critical-Z-value.

The ratio of described adding and rejecting is from several hypothesis.1) based on the practice before with HMG CoA reductase inhibitor, it is fine to follow the doctor's advice, and the situation of uncomplaisance only occurs in early days in test.2) in most of the cases, described research doctor is patient's a main care physician, and therefore the test of comparing in the conventional university needs less to be concerned about that other doctor can change patient's medicine.3) low among the patient that the patient's of cholesterol reduction test LDL cholesterol content ratio is treated in common practice in.In the U.S., although the LDL higher level, the patient that many significant need cholesterol reduce medicine does not receive treatment.Suppose that body fat reduces the relative medium body lipid level with the patient of cost of medicament, specify the many patients that do not carry out Drug therapy not carry out active body fat and reduce Drug therapy.4) suggestion ALLHAT doctor does not want the patient that random arrangement has been taken cholesterol reduction medicine or should take these medicines (as the part of general duty nursing) with regard to its viewpoint.Therefore in first place, the potential active treatment that is crossed to of randomization not in most of parts.5) announce the result according to the 4S test, described rules are made amendment, and get rid of the patient that CHD and LDL cholesterol are higher than 130mg/dl (reducing test from cholesterol).And the adding rate of described 4S research in 5.4 years is 13%, and elimination factor is 10%.

Age criterion be 60 years old or more than, and do not comprise present smoker in the original ALLHAT rules of risks and assumptions, our estimated death rate is 2.35%, unadjusted treatment difference is 12.5%.Revise and 4S experimental study result (adjusting 305 treatment differences) in rules, feel that new hypothesis is rational.

Also can consider more pessimistic or optimistic hypothesis.These comprise 1) mortality rate is 2.15%/year to 2.50%/year; 2) elimination factor is 17.8%, and the adding rate is 12.9%, 3) 12.5% mortality rate reduces by 14%.Under these assumed conditions, render a service valuation between 76-90%.

ALLHAT studies the investigator

In the ALLHAT study group and coordinating clinical centers and service center researcher are listed below: Clinical Center: VAMC Allen Park, Alien Park, Ml: James R.Sowers, MD (PI); Martin Berman, DO; Carol E.Bodrie, RN; Elizabeth Jones; Kathy M.Rice.Wade Park VAMC, Cleveland, OH: Eleni 1.Pelecanos, MD, MPH (PI); Dorothy Herd, CNP.Memphis VAMC, Memphis, TN: Gale H.Rutan, MD, MPH (PI); Roger G.Smith, MD; Anita W.McKnight, BSN, RN. Miami VAMC, Miami, FL: Barry J.Materson, MD, MBA (PI); Gustavo Godoy, MD; Richard Preston, MD; Mary Healy Smith, ARNP-CS, BSN, MS.Manhattan VAMC, New York, NY: Lois Anne Katz, MD (PI); Mary Keary, RN.Dallas County Health Department, Selma, AL: Sherri Nichols, RN (PI); Joan Stewart, RN.The Wellness Plan, Detroit, MI: Marc Keshishian, MD <Pl); Ri chard Miller, MD; Marlene Vaughn, RN.RUSH Prudential HMO, Van Buren Office, Chicago, IL: Vance LauderdaIe, MD (PI); Terese Berrucci, RN, MS.RUSH Prudential HMO, Coleman Office, Chicago, IL: Howard Martin, MD (PI); Sandy Gibson, MD; Marie Bosley, RN; Donna Lee Patterson, RN.University of South'Carolina, Columbia, SO G.Paul Eleazer, MD (PI); Carlton A.Hornung, PhD (PI); Davinder Lally, MD (PI); Mya D.Kline. University of South Carolina Medical School, Columbia, SC: lisa Befhea, MD; Sharrn Sfeadman, PAarmD; Mya D.Kline.People 's Health Centers, St.Louis, MO: Kelly D. ~ Gage, MD (PI); Betty Keny MA, PNP; Elaine Feehan, RN; CJara Scott.UT-HHSC/MS, Houston, TX: Carlos Henera, MD (PI); Tina Coriiiier, Research Assistant.West Alabama Health Services, Inc., Euiau), Ah: Sandra] Hullett, MD (PJ); Glenn Hughes, PhD; Voncelia Hall, LPN.West Alabama Health Services-Greensboro Center # 2, Greensboro, AL: Sandral Hullett, MD (PI); Glenn Hughes, PhD; Voncelia Hal], LPN.WAHS-Livingston Health Center, Livingston, AL Sandral Hullett, MD (PI); Glenn Hughes, PhD; Voncelia Hall, LPN.Worksite Treatment, New York, NY: Karen M.Johnston, MD (PI); Karen Fuller, BSN. Sloreworkers'Local # 3, New York, NY: KaTen M.Johnston, MD (PI); Karen Fuller, BSN. University ofNV School of Medicine, Las Vegas, NV: Stephen Newmark, MD (PJ); Gail Vranesh, RN.West Gastroenterology Group, Ingltnoood, CA: Timothy C.Simmons, MD (PI); Fred Glet-ten, MD; Donald Henderson, MD; Adebambo Ojuri, MD; Bisrat Yirgou.Newark Community Health Center, Newark, 'N]: Jonathan N.Tobin, PhD (PI); Anita Vaughn, MD (PI); Praba] Ray, MD; Judith Quiles, RN.Bedford-Stuyvesant Family Health Center, Brooklyn, NY: M.Monica Sweeney, MD (PI); Jonathan N.Tobin, PhD (PI); Maria Jaime, RPA.Lyndon B.Johnson Health Complex, Inc., Brooklyn, NY: Jonathan N.Tobin, PhD (PI); Marie Therese DeCastro, MD; Sheila Hood, RN.Osteapathic Health Care Center.Philadel- phia, PA: George D.Vermeire, DO (PI); Shirley Combs.PCOM Cambria Street Healthcare Center, Philadelphia, PA: Patrice Taylor, DO (PI). Jackson-Hinds Camp Hlth Care Center, Jackson, MS: Evelyn R.Walker, MD (PJ); Adonna James, RN.UCLA-King/Drew Medical Center, Los Angeles, CA: Harry J.Ward, MD (PI); Benjamin Scott; Sed-onia V.Prets.Mobile Medical and Diagnostic Center, Mobile, AL: Raymond L.Bell, MD (PI); Beverly K.Johnson, KN.Oakhurst Community Health Center, Decalur, GA: Robert Kimbrough, MD (PI); Robert J.Anderson, PharMD; Betsy Redmond, RD-Kaiser Psrmanente of Georgia, Tucker, GA: Joshua Barzilay, MD (PI); JeanneJordan, RN, BSN.Candler Medical Group, Savannah, GA: Paul S.Bradley, MD (PI); Ray R.Maddox, PharmD.Forest Hill Family Practice, Richmond, VA: Benjamin F.Zambrana, PhD, "MD (PI); Kay Zambrana. AHEC Family Practice Center, Pine Bluff, AR: Herbert F.Fendley, MD (PI); Julian Eddie Maples, Jr., RN, RR.T.Cardiovascular Physicians, Ltd., Milwaukee, WI: Bin-ton J.Friedman, MD (PI); Barbara Ullsperger.Albert Einstein Hospital, Bronx, NY: William H.Frishman, MD (PI); Suzanne E.Furia, RN, BSN.The Medical Research Center, Inc., Washington, DC; Bruce N.Garrett, MD (PI); Patricia Sullivan, RN, BS.Outreach Health Services, Shubuta, MS: James C Graham, MD (PI); Cathy Duvall, LPN.University Health Associates, Charleston, WV: Stephen R.Grubb, MD, FACT (PI); Vickie Cruz.Oschner Clinic-Perkins, Baton Rouge, LA: Alok K.Gupta, MD (PI); Helen Penfield, RN.Mid Delta Family Practice Clinic, Cleveland, MS: Nate Brown, MD (PI); Evelyn Peggy, FNP-C; Sarah Cooks.Westm 'ew Clinic, West St.Paul, MN: Marvin A-Heuer, MD (PI); Susan Hassing; Julie Unlenkott.Cook County Hospital, Chicago, 1L: Arthur Hoiiman, MD, MPH (PI); Judy Statsinger.Ridgeview Research Center, Chanhassen, MN: James E.Carra-"bre, MPE, MD, CCFP (PI); Karen M.Long, RN, MSN, CFNP; Yancy Schafer, LPN.LJCL4 School of Medicine, Los Angeles.CA: Ka Kit P. Hui, MD, FACP (PI); Jagoda Pask, MD, PhD; Elaine Pang.University of Mississippi Medical Center, Jackson, MS: Daniel W.Jones, MD (PI); Catherine Adair, RN.Augusta Hyper tension, PC, Augusta, GA: Wayne-H.Kaesemeyer, MD (PI); Pamela M.Boiter, RN.Hamilton Health Center, "Harrisburg, PA: David K.Kelley, MD (PI); Kim Myers, PA.Lehigh Valley Hospital, Alkniown, PA: Nel-■ son Kopyt, DO (PI); Yehia Y Mishriki, MD; Mary Anne Gergits, RN. MS, CCRC.Palomar Medical Group, Escondido, CA: Emmet W.Lee, MD (PI); Elaine A. Murphy, CRC.North Hills Family Practice, North Richland Hills, TX: Leo L.Altenberg, MD (PI); Carol Dvorak, RN, BSN.Primary Care Internal Medicine, Detroit, M.Anita Moncrease, MD (PI); Ann Edwards.The Jamaica Hospital, Jamaica, NY: Robert I.Mendelson, MD (PI); Kenneth Nordlicht, MD; Robert I.Mendelson, MD.Bowdoin Street Heslth Center, Boston, MA: Joseph A.Ingelfinger, MD (PI); Alice Chan.Ohio State University General Internal Medicine, Columbus, OH: Robert A.Murden, MD, FACP (PI); Lori McCollough, BA.Aft. Sinai Outpatient Clinic, Hartford, CT: Ellen Olarsh Nestler MD (PI); Nellie Medina, RN. Wake Forest University Family Physicians, Winston-Salem, NC: Kevin A.Pearce, MD, MPH (PI); John Summerson, MS.John Peter Smith Hospital, 'Fort Worth, TX: Stephen E.Piwinski, MD (PI); Julia Meaders, RN.Harlem Hospital Center New Yorfc, NY: Velvie Anne Pogue, MD (PI); Donna Dowie, MD.Trinity Diagnostic Associates.Carrollton, TX: Henry A.Funzi, MD, FACIP (PI); Lola Hussey, RN, CCRN.John D.Stokes, MD, PA, Palm Harbor, FL:; John D.Stokes, MD (PI); Catherine Rousseau, Medical Assistant.Medical Parameters, Martinez, GA: Robert B.Rhoades, MD (PI); Shirley K.Wiley, MA.Gould Medical Group, Modesto, CA George Chao, MD (PJ); Carl K-.Sufit, MD; Ruth Bright, RN, CCRC; Dora DarJeen Johnson, RN, CRC.North Pacific Internal Medicine Group, Portland, OR: Frank D. McBarron, MD (PI); Kathy L Root.Richard Fowler, MD, PC, Mesa, AZ: Richard F.Fowler, MD (PI); Dianne Woods, RN.University of Illinois College of Medicine, Peorin, IL: James F. Graumlich, MD (PI); Steven Belknap, MD; Susan Cole, MD; Nancy L.Smith, RN, MS. Carver Family Health Center, Peoria, IL: James F.Graumlich, MD (PI); James Barnett, MD; Nancy L.Smith, RN, MS.The Cleveland Clinic Foundation, Cleveland, OH: Donald G.Vidt, MD (PI); David Litaker, MD; FTan Yanik, Nurse Coordinator.Sinai Hospital of Baltimore; Baltimore, MD: Michael D.Freedman, MD (PI); Ralph Weber, MD; Karyn Heagy, RN.Clinic for Digestive and Nutritional Disorders, Tallabassee, FL: Joseph Lee Webster, Sr., MD (PI); Thelma J.Caldwell, RN.AHEC of South Arkansas Family Practice Clinic, El Dorado, AR: Mark K.Buck, MD (PI); Renee McCafferry, MS.ALL-HAT Clinical Center 067A, Danville, IL: Bisrat Haileineskel, PharmD (PI); T.Halloran, MD; R.Sadiq, MD; Lee Ding, RPH. Danville Carle Clinic, Danville, IL: Bisrat Hailerneskel,. PharmD (PI); T.Halloran, MD; Lee Ding, RPH.Community Healthcare Clinic, Houston, TX: Admerle Hall-Hoskins, DO (PI). Mercy Diagnostic and Treatment Center, Chicago, IL: Charles G.Terzian, MD, MPH (PI); Char Piotrowski, RN.ALLHA7 'Clinical Center 071A, Hinesville, GA: R.Glenn Carter, MD (PI); LariAnn S.Thomas, MSN, RNCS.University of Oklahoma College of Medicive-Tulsa, Tulsa, OK: Martina J.Jdley, MD, MSPH (PI); Tracy Lawson, RN.Bronx Nephrol-ogy Hypertension PC, Bronx, NY:. Mario A.. Henriquez, MD, FACP (PI); Ana Silvia Henriquez, MPH.Wilson Health Center, Rochester, NY: Frederick J.Zugibe, MD (Fl); Robert L. VonBuskirk, BSN.East Albany Medical Center, Albany, GA: Phillip R.Poulos, MD (PI); Ron Malcolm, PA; Madeline (Madge) Holm, BSN.Brookdale Hospital Medical Center, Brooklyn, NY: Samuel Spitalewitz, MD (PI); Alba Corrsa, RN.Clearwater Cardiovascular Consultants, Largo, FL: Jorge P.Navas, MD (PI); Kay Livingston, RN.Baylor College-of Medicine, Houston, TX: Carlos Vallbona, MD (PI); Glori Chauca, MD; Valory Pavlik, PhD.Loma Linda Faculty Medi-oil Offices, Loma Linda, CA: Gregory Wise, MD (PI); Denise Jackson, MD; Leslie Albert, RN. 'United Hospital, Grand Forks, ND: Richard]. Gray, MD (PI); Kelly Hagen, RN.ALLHAT Clinical Center 084A; Pine Bluff, AR: Martha Ann Flowers, MD (PI); Stacye D.McLemore.UT Southwestern Medical Center, Hypertension Division, Dallas, TX: Norman KapJan, MD (PI); Patsy Hargrave.ALLHAT Clinical Center 086A, Gahanna, OH: Albert M-Salomon, DO (PI); Marjorie ...

A.Considine.Pulsifer?Medical?Associates?PC，Rochester，NY；David?Dobrzynski，MD(PI)；Joyce?Hackemer，RPA-C.The?Med?I?Peds?Managed?Care?Clink，WBAMC，El?Paso，TX；；An-drew?C.Quint，MD(PI)；Elisabeth?Marcus.Valley?Medical?Group，Bakersfield，CA：Carlos?A.Alvarez，MD(PI)；Laurie?Mitchell，RN.South?Carolina?Henri?Center，Columbia，SC：William?Lawrence?Schoolmeester，MD(PI)；Jacqueline?Sheriod，BSN.Tlie?Mt，Sinai?MedicalCenter，Cleveland，OH：Joseph?P.Frolkis，MD，PhD(Pl)；Robert?L.Haynie，MD，PhD；PamelaSuhan，RN.Beaverton?Medical?Clinic，Bever-ton，OR：Scott?W.FaJley，MD(PI).Mayo?Clinic，Division?of?Hypertension，Rochester，MN：Daniel?J.Wilson，MD(PI)；Vincent?J.Canzanello，MD；Lois?Klein.Cardiology?Foundation?of?Lankenau，Wyrmewood，PA：James?F.Burke，MD(PI)；Heather?L.Horton，MD；Bettye?Briggs，BSN.Dekalb?Medical?Specialty?Center，Decatur，GA：Charles?A.Gilbert，MD(PI)；Elaine?Fuika，RN，CCRN.VAMC?Augusta，Augusta，GA：Thomas?J.Hartney，MD(PI)；Nanci?McPhaiI，.MD；Thomas?J.Hartney，MD.VAMCBaltimore，Baltimore，MD：Bruce?P.Hamilton，MD(PI)；Mary?Dangleis，RN，CRNP.VAMCKansas?City，Kansas?City，MO：Thomas?B.Wiegmann，MD(PI).VAMC?Bronx，Bronx，NY：Clive?Rosendorff，MD，PhD(PI)；Steven?A.Atlas，MD，PhD；Clive?Rosendorff，MD，PhD.VAMC?Brooklyn#3，Brooklyn，NY：Donald?F.Kreuz，MD(PI)；Stacy?Robinson，RN.VAMCBuffalo，Buffalo，NY：James?Lohr，MD(PI)；Peggy?Gugliuzza，RN.VAMC?East?Orange，EastOrange，Nj：Sithiporn?Sastrasinh，MD(PI)；Vicky?Johnson.VAMC?Houston，Houston，TX：Gabriel?B，Ha?bib，MD(PI)；Florence?Chodkiewicz.VAMC?Indianapolis，Indianapolis，IN：J.Howard?Pratt，MD(PI)；Jerrlyn?Jones，MSN.VAMC?Louisville，Louisville，XT：″VastiL.Broadstone，.MD(PI)；Eloise?Campbell，RN.V-AMC?Milwaukee，Milwaukee，WLMahendr?S.Kochar，MD(PI)；Glor?ria?Koteeki，LPN.VAMC?New?Orleans，New?Orleans，LA：Vecihi?Batuman，MD(PI)＞Patricia?Willhoit，RN，NP.VAMC?Kansas?City，MO，KansasCity，MO：Santosh?Sharma，MD(PI)；Cheryl?Holt，RN.VAMC?St.Louis，St.Louis，MO：David?W.Moskowitz，MD(PI)；Sharon?Carmody.VAMC?Washington，DC，Washington，DC：Vasflios?Papademetriou，MD(PI)；Barbara?Gregory，RN.VAMC?Alexandria，Alexandria，LA：Jerome?M.Sampson，MD(PI)；Everet?W.WirzeJ，MD；Janet?Schmitt，PharmD.VAMC?BattleCreek，Battle?Creek，MI；David?Hallegua，MD(PI)；Michael?J.Underwood，MA.VAMC?Bay?Pines，Bay?Pines，FL：Ramon?Lopes，MD(PI)；Debbie?Williams，RN.VAMCBrooklyn#2，Brooklyn，NY：William?L.Green，MD(PI)；Amal?Fara-g，MD；Estelita?Anteola，RN.VAMC?Charleston，Charleston，SC：Jan?N.Basile，MD(PI).VAMC?Dayton，Dayton，OH：Mohammed?Saldayen，MD(PI)；Anil?Kumar?Mandal，MD；Helen?J.Neff，RN.′VAMC?Dublin，Dublin，GA：Avinash?C.Pradhan，MD(PI)；Dianne?K.Harrison，RN.VAMC?Lake?City，LakeCity，FL：Girish?Bhaskar，MD(PI)；Ut?Van?Tran，MD；Gloria?Duren.VAMC?Jackson，Jackson，MS：C.Andrew?Brown，MD(PI)；ArdelTHinton，MS.VAMC?North′Little?Rock，North?LittleRock，AR：William?J.Carter，MD(PI)；Miriam?Rose?Oakum，MD；Kathrine?Holland，RNP.VAMC?Loma?Linda，Loma′Linda，CA：Paul?G.St.John?Hammond，MD(PI)；Jan?Scott，RN.VAMC?Long?Beach，Long?Beach，CA：Michael?A.Weber，MD(PI)；Deanna?G.Cheung，MD；Gaurang?Shah，MD；Eric?Bowes.VAMC?Minneapolis，Minneapolis，MN：Jordan?Holtzman，MD(PI)；Denise?Finley，RN.VAMC?Murfreesboro，Murfreesboro，TN：Rimda?Gupta，MD(PI)；Regina?Cassidy，PharmD.VAMC?Nashville，Nashville，TN：Ghodrat?A.Sia′mi，MD，PhD(PI)；Walter?Wilkins，RN.VAMC?Northport?Medical?Services，North-port，NY：JoanneHolland，MD(PI)；Christine?Spiller，RN.VAMC?Phoenix，Phoenix，AZ：James?V.Felicefta，MD(PI)；Karen?Bowen，RN.VAMC?Richmond，Richmond，VA：Pramod?Mo-hanty，MD(PI)；Edie?Earley，RN.VAMC?Salisbury，Salisbury，NO?Ronald?D.Smith，′MD(PI)；Valeria?Shipp，RN，VAMC-1?San?Francisco，San?Francisco，CA：Barry?Massie，MD(PI)；Elaine?Der，RNP.VAMC-2?Son?Franciscor?San?Francisco，CA：Marvin?Siperstein，MD(PI)；Edward?Jai，PharmD.VAMC?San}iian，San?Juan，PR：Jose?Luis?Cian-chini，MD(PI)；Jean?DaMore，RN.VAMC?Columbia，SC，Columbia，SC：Alberto?Saenz，MD(PI)；Delia?C.Hart，RN，BSN；Wendy?Nicholson，RN，BSN.VAMC?North?Chicago，North?Chicago，IL：Sant?P.Singh，MD(PI)；Jen-Chieh?Cheng，MD；Laura?Kirkham，RN.VAMC?Lenvenwarih，Leav-enworth，KS：Donald?L.Courtney，MD(PI)；Marie?Cook.VAMC?Shreveport，Shrevepori，LA：ArthurGhausmer，MD，PhD(PI)；Arm?Leitz，RN，MSN.VAMC?Pittsburgh，Pittsburgh，PA：MelissaMcNeil，MD(PI)；Catherine?Kelley，PharmD.VAMC?Tampa，Tampa，FL：Raquel?Rosen，MD(PI)；Nancy?Rolbiecki，LPN.Camdev?Internal?Medicine?Associates，PA，Camden，SC：John?B.DuBose，III，MD(PI)；Dale?S.Banvick，MSN，RN，CS.Raleigh?Internal?Medicine?Associates，PA，Raleigh，NC：Christopher?M.Perkins，MD(PI)；James?O′Rourke，MD；Lynda?E.Seal，RN.Morehovse?School?of?Medicine，Atlanta，GA：Edward?F.Parrish，III，MD(PI)；Tim?Briscoe，PharmD.Morehouse?Medical?Associates，Atlanta，GA：Elizabeth?Ofiii，MD(PI)；Victoria?M.Calhoun，BSN；Marion?Chancellor?RN.￡.O.Family?Health?Center，Inc.，Miami，FL：FatimaA.Zafar，MD(PI)；Patricia?A.Sea-brooks，ARNPC，DNSc.Family?Practice?Group，Pocatello，ID：Michael?S.Baker，MD(PI)；Trish?Berghmd..PA-C.New?Britain?General?Hospital，NewBritain，CT：Sandra?Raff，MD(PI)；James-Bernene，MD；Lawrence?Koch，MD；AnthonyLachman，MD；Elizabeth?Solano，MD；Diane?Bemene，RN；Linda?Ciartia，RN.ALLHAT?Clinical?Center?U7B，Unionville，CT：Sandra?Raff，MD(PI)；JamesBernene，MD；John?Lawson，MD；Diane?Bernene，RN；Linda?Garcia，RN.ALLHAT?ClinicalCenter?148A，Shreveport，LA：Byron?Andra?M.Jackson，MD(PI)；Van?Cleary，MD；ByronAndra?M.Jackson，MD.Marshfkld?Clinic，Marshfield，WI：Richard?Dart，MD(PI)；DawnDavid.Lakeland?Center-Marshfield?Clinic，Minocqua，WI：Richard?Dart，MD(PI)；LindaPowers，MD；Jane?Carl.MediQuesl?Research?Group，Ocala，FL：Robert?L.Feldman，MD(PI)；Lynn?Craggs，BS；Veta?Page，RN；Mary?Standley，RN，BS；Sh′ari?Strickland，LPN.Black-stone?Cardiology?Associates，Pawhickei，RI；Kenneth?A.La-Bresh，MD(PI)；ElizabethBums.Chinatown?Service?Center，Los?Angeles，CA：Diana?J.Lee，MD(PI)；Jin?Sin?Khoo，MD；Praphaphone?Insbdengmay，MPH.Koryo?Health?Foundation，Los?Angeles，CA：Diana?J.Lee，MD(PI)；Sang?Lee，MD；Praphaphone?Insbdengmay，MPH.T.H.E.Clinic，Inc.，LosAngeles，CA：；Diana?J.Lee，MD(PI)；Marilyn?Z：Norwood，RNP；PraphaphoneInsixiengmay，MPH.Asian?Pacific?Health?Care?Venture，Inc.，Los?Angeles；CA：Diana?j.Lee，MD(PI)；Praphaphone?Insixiengmay，MPH.Th′e?Mary?Imogene?Bassett?Hospital，Cooperstown，NY：Anne?N.Nafziger，MD，MHS(PI)；Roberta?L.Steere，RN.2199?WorksiteHypertension?Program，New?York，NY：Geoffrey?Gibson，PhD(PI)；Celiz?Shmukler，MD；Norma?Martinez，RN.University?of?South?Dakota，Sioux?Falls，SD：Angelina?Trujillo，MD(PI)；Rapid?City，SD：Angelina?Trujillo，MD(PI)；Cindy?Need-ham.Ogdcn?ResearchFoundaiiori，Ogden，UT：C.Basil?Williams，MD(Tl)；Cynthia?L-Slot，CRC.Southern?DrugResearch，Inc.，Birmingham，AL：Barry?K.McLean，MD(PI)；Melinda?L?Waiuwright；GailWingo.Northwestern?Medical?Faculty?Foundation，Chicago，1L：Martiii?J.Arron，MD(PI).Erizkson?Medical?Clinic，Park?Rapids，MN：Vern?E.Erickson，MD(PI)；Karen?Bensen.Centro?Cardiovascular?de?Caguas，Caguas，PR：Pedro}.Colon，MD，FACC(Pl)；Nivea?1.Vaz-quez，BBA.\Nood\and?Avevue?Health?Center，Philadelphia，PA：Paul?D.Donnan，MD(PI)；Michelle?Fiolkowski，PA-QT?Columbia?Medical?Plan，Columbia，MD：George?Groman，MD(PI)；Michael?Kelemen，MD；Eileen?Brighrwell，BS.University?of?Arkansas?Medical?Center，Little?Rock，AR：Stephanie?L.La?whom，MD(PI)；Carol?Davison，RN.Southwest?MedicalAssociates，Las?Vegas，NV；James?W.Snyder，MD(PI)；Barbara?Adelman，RN；JaniceChristopher，LPN?II，CCRC.Cardiovascular?Institute?of?the?South，Lake?Charles，LA：Jose?A.Silva，MD(PI)；Nairn?Mahmoud?Adli，MD；Luis?Felipe?Tami，MD，FACC，FCCP，JFACA；Catherine?Mary?Tami，RN，BSN.Cardiology?Clinic?of?Muskogee，Inc.，Muskogee，OK：YeeSe?C.Ong，MD(PI)；Viola?Christy，RN.East?Side?Internists，Inc.，Providence，Rl：Richard].Ruggieri，MD(PI)；Susan?Ruggieri.Sigurds?fanners，MD，PC，Hancock，Ml：Sigurds]anners，MD(P5)；Candace?E.Koski?Jan-ners，RN，BSN.University?of?Kansas?Medical?Center，Kansas?City，KS：Brian?Friedman，MD(PI)；Linda?Gerrond，MD；David?B.Wilson，MD；Leigh?Ann?Price，BS.Cardiology?Associates，For！Charlotte，FL：Louis?D.RosenSeld，MD(PI)；Terra?McDonald.Christ?Hospital?Cardiovascular?Research?Center，Cincinnati，OH：Robert?Toltzis，MD{Tl)；Linda?Martin，RN，BSN，MBA.Truman?Medical?Center?UMKCSchool?of?Medicine，Kansas?City，MO：Nathaniel?Winer，MD(Pi)；Carol?J.Tudor.AtlanticCardiology?Associates，Exeter，NH：Marl：I.Jacobs，MD(PI)；Jennifer?M.Doane，RN.UABIMontgomery?Internal?Medicine?Residency?Program，Montgomery，AL?Stephen?S.Brady，DO(PI)；Theresa?L?Doj-miney.Howard?S.Ellison，MD，PC，Conyers，GA：Howard?S.Ellison，MD(PI)；Jamie?D.Ellison.Maimonides?Primary?Care，Brooklyn，NY：Andrew?Conti，MD(PI).Tatum?Family.Health?Clinic，Gary，IN：David?E.Ross，MD(PI)；Henedina?W.Macabaliraw，MD；Barbara?Johnson；RN，NNP-Medical?Diagnostics?Center，Indianapolis，IN：John?Howard?Pratt，MD(PI)；Jerrlyn?Jones，MSN.The?Health?Associates，Baltimore，MD：Boris?Kerzner，MP(PI)；Susan?E.Childs，BS，BSN，MS.Winona?Memorial?Hospital，India-napolis，IN：Jack?H.Hall，MD(PI)；Dortie?Fausset，MBA，RN；Pam?Linden，RN.Faculty-Resident?Group?Practice，Michael?Reese?Hospital，Chicago，TL：Kevin?E.Hunt，MD(PI)；Rosemary?Dawkins，RN.Maricova?Medical?Center，Phoenix，AZ：William?Dachnian，MP(PI)；Maria?Dachman，RN.University?of?California?Davis?Medical?Center(UCDMC)，Sacramento，CA：Charles?Whitcomb，MD，FACC(PI)；Jean-nie?Robertson.Colorado?FamilyMedicine，PC，Denver?CO：ConstanrineJ.Tsamasfyros，MD(PI)；Laura?Clayton.Mon-iefioreMedical?Center，Bronx，NY：Janet?U.Goricin，MD(PI)；Mark?Menegus，MD；Laurie?Posner，MD；Linda?Solomon.Cardiovascular?Medical?Specialists，PA，Hollywood.FL-Jonathan?R.Jaffe，MD(PI)；Lisa?Nitzberg，MD.lnter？nedic?Health?Cener，Port?Charlotte，FL：Terence?P.Connelly，MD.(PI)；Denise?Eckstein，BSN.Domi-Med，Inc.，Chamblee，GA：Donald?J.Weidler，MD，PhD(PI)；Mayra?Baez.Morehouse?Family?Practice?Center，Atlanta，GA：Donald?J.Weidler，MD，PhD(PI).Lutheran?Geriatric?Care?Services，Fort?Wayne，IN：Jerald?L.Andrew，MD(PI)；Christy?Cobbum，MA；Beth?Molnar，RN，NP?University?of?LouisvilleHypertension?Section，Louisville，KY：Gurdarshan?S.Thindj?MD，MS，-FACT，FACC；CathyFaughn，CMA.Trover?Clinic-Madisonville，Madisonville，KY：Abi?V.Rayner，MD(PI？；Connie?R.Tyler，KN.Trover?Clinic-Earlington，Earlingion.KY：Abi?V.Rayner，MD(PI)；Connie?R.Tyler，RN.Wyman?Park?Medical?Associates，Baltimore，MD：Naomi?R.Feldman，MD(PI)；Loretta?Vogtman，LPN.Good?Samaritan?Hospital，Inc.，Balti-more，MD：Duncan?Salmon，MD，FACC(PI).HealthSpan?Health?Systems?Corporation-United?Family?Health?Center，Minneapolis，MN：Katherine?F.Guthrie，MD(PI)-ALLHATClinical?Center?203A，Silver?Spring，MD：Ravi?Passi，MD(PI)；Anita?Passi.Kenneth?H.Williams?and?Associates，Baltimore，MD：Kenneth?H.Williams，MD(PI)；Barbara?Socha，MD；Kenneth?H.Williams，MD.Deaconess?Central?Hospital，St.Louis，MO：Madan?Chilappa，MD(PI)；DannieDe?Cor-boy，PhannD；Cheryl?Miller，PharmD.Bellevue?HospitalCenter-Ambulatory?Care?Practice，New?York，NY：Richard?I.Levin，MD，FACP，FACC(PI).New?York?Downtown?Hospital，New?York，NY：Ira?C.Schulman，MD(PI)；William?J，Cole，MD；KellyAnn?Mele，RN.Bellevue?Hospital?Center-Met?Plan，New?York，NY：Stuart?A.Didcermar，MD(PI)；Andre?Neusy，MD；KellyAnn?Mele，RN.Valley?Medical?Center，Ketiering，OH：Meenakshi?Patel，.MD(PI)；.7113?Blum，RN.Ringrose?Clinic，Inc.，Guthrie，OK：Robert?E.Ringrose，MD(PI)；Laura?Parham.Altvs?Medical?and?Surgical?Clinic，Altus，OK：Joe?Leverett，MD(PI)；Sharon?Van?Pelt，LPN.Cardiology?Associates?of?Johnstown，Johnstown，PA：Charles?J.Oschwald，MD，FACC(PI)；Amanda?Boring，EMT.LancasterHeart?Foundation，Lancaster，PA：Seth?J.Worley，MD，FACC(PI)；Linda?Burkhardt，RN.Family?Medicine，Brent?Clark，MD，Pittsburgh，PA：Brent?Clark，MD(PI).Sanf?Ram?MedicalAssociates，West?Grove，PA：DeepaJc?Sant?Ram，MD(PI).Family?Medical?Center，Johnstown，PA：Michael?Ta-tarko，St.，MD(PI)；Jeanne?Spencer，MD；Loretta?Nagy，LPN.VincoMedical?Center，Conemaugh，PA：Michael?Te-tarko，St.，MD(PI)；Patty?Allbaugh，RN.Ebandfieff?Medical?Center，Nanty?Glo，PA：Michael?Tatarko，Sr.，MD(FT)；Jean?Marie?Koh，MD.Associates?in?Diagnostic?Internal?Medicine，Pittsburgh，PA：Peter?P.Tanzer，MD(PI)；Roberta?A.Mueller，RN.Cardiology?Outpatient?Clinic-University?of?Pittsburgh，Pittsburgh，PA；Galal?M.Ziady，MD(PI)；Deborah?Dongilli，BSN.Excelsior?Medical?Clinic，Sumter，SC：Joseph?C.Williams，MD(PI)；Beverly?Hill，Medical?Assistant.Memphis?Medical?Specialists，Inc.，Memphis，TN：Howard?W.Marker，MD(PI).University?of?Texas?Health?Center?at?Tyler，Tyler，TX：David?R.Shafer，MD(PI)；Barbara?HUtscher，RN.Consultants?in?Medicine，Inc.，PS，Bdlingham，WA：Grant?E.Deger，MD(PI).University?of?Arkansas?for?Medical?SciencesDiabetes?Clinic，Little?Rock，AR：Vivian?A.Fonseca，MD，MRCP(PI)；Janet?Hinson，RN.Howard?University?Hypertension?and?Lipid?Clinic，Washington，DC：Tarn-rat?M.Ketta，MD，PhD(PI)；OteJioS.Randall，MD；Shichen?Xu，MD；Tamrat?M.Retta，MD，PhD.InternalMedicine?Associates，Washington，DC：Jerry?M.Earll，MD(PI).Hypertension?Center，Medical?Center?of?Delaware，Wilmington，DE：William-E.Miller，MD?CPI)；Matthew?Burday，DO-Palm?Beach?Center?for?Clinical?Investigation，West?Palm?Beach，FL：Lee?A.Fischer，MD(PI)；Holly?Hadley，MD；Pearlie?Singleton.Uchenna?A.Okoronkwa，II，MD，PC，Oakland，CA：Uchenna?A.Okoronkwo，II，MD(PI)；Jerryann?Dunmore.LSU?Clinics，New?Orleans，LA-Henry?Rothschild，MD，PhD(PI).LSU?Hypertension?Research?Clinic，New?Orleans，LA：M.Eileen?Cook，MD(PT)；Nancy?Bark，BS.Acadian?Cardiology，Lafayette，LA：Vernon?A.Valentino，MD(PI)；Traci?Quails，RN，BSN.Androscoggin?Cardiology?Associates，Auburn，ME：Robert?J.Weiss，MD，FACC，FACP(PI)；Carol?Ridley，RN.Hahnemann?UniversityHospital，Philadelphia，PA：Steven?P.KutaJeic，MD，FACC(Pi)；Christina?Ann?Baess-ler，RN.

Chapel?Hill?Infernal?Medicine，Chapel?Hill?NC：Paula?F.Miller，MD(PI).UnitedHospitals?Medical?Center.Newark，N]：Aloysius?B.Cuyjet，MD，FACC(PI)；Thelma?AllenStich，MS，RNC，CS，CDE.Family?Practice?Center，Columbus，GA：Michael?F.Walsh，MD(PI)；S.Troy?Smith，PharmD.MSU-KCM.S?Internal?Medicine，Kalamazoo，Ml：AnneCava-r.agh，MD(PI)；Kathy?S.Church，BSN，CEN.；Danny?M.Anderson，MD，Inc.，Sonora，CA：Danny?M.Anderson，MD(PI)；Judith?Joy?Boggess，MD；Linda?B.Johnson，LVN.St.Thomas?Medical?Croup，Nashville，TN：Mark?C.Houston，.MD(PI)；Laurie?Kays，RN.HeartCenter?of?Salt?Late，Salt?Lake?City，UT：J.Joseph?Perry，MD(PI)；Wendy?Schvanev-eldt，RN.Central?North?Alabama?Health?Services，Inc.，Hunts-ville，AL：Ronald?M.Wyatt，MD(Pi′)；Deborah?Degree，RN，BS.Bernard?M.Sklar?MD，Inc.，Alameda，CA：Bernard?M.Sklar，MD(PI)；Maile?C.Matier，IAS，FNP.Knoxville?Cardi-ofogy?Associates，Alcoa，TN：Alan?LeeSmuckler，MD(PI)；Jamie?E.Etherton，RN.Knoxville?Medical?Group-Knoxville，Knoxville，TN：Lee?R.Dilworth，MD(PI)；Jamie?E.Etherton，RN.Talladega?Internal?Medicine，PC，Tallodega，AL：Simon?Gebara，MD(PI)；Gitia?Bliss，RN.Clinical?Hypertension?Center，LosAngeles，CA：Vincent?DeQuattro，MD(PI)；L.Julian?Hayward，MD；DePing?Lee，MD.Brevard?Cardiology?Grovp，MerriH?Island，FL：Khalid?H.Sheikh，MD，FACC(PI)；EugeneKilleavy，MD，FACC；Terri?Henegen，RN.Washington?County?Internal?Medicine，PC，Sandersville，GA：William?Rawlings，MD(PI)；Wentzelle?Kim?Kitchens，MD；Jean?RawlingsSumner，MD；Jessica?Heldreth，LPN.Family?Practice?Center?Comprehensive?MedicalCorporaiion，Indianapolis，IN：David?L.Fryman，MD(PI)；Neeta?O′Mara，PharmD.Goel?Medical?Corporation，Merrillville，IN：Harish?A.Shah，M～D(PI)；Arun?Goel，MD；T.Nguyen，MD；Kari?Smith，RMA.The?Heart?Clinic?PA，Kansas?City，KS：Nalini?G.Premsingh，MD(PI)；Kirit?Masrani，MD；Rita?Brown，PA.Kaiser?Landover?Center，Landover，MD：John?S.Golden，MD(PI)；Valerie?Walls.ALLHAT?Clinical?Center?256A，Bridgeioaler，NJ：Alexander?B.Kudryk，MD(PI)；Fred?M.Tepper，MD.ALLHAT?Clinical?Center?257A，Mount?Holly，N)：R.Bruce?Denniston，MD，FACP(PI)；Annette?Fagano，RN.University?ofWashington，Seattle，WA：Allan?J.Ellsworth，PharmD(PI).Denmark?Medical?Center，Denmark，SC：Monnieque?Singleton，MD(PI)；Barbara?Boineau，MOT.Family?MedicalCenter，Charleston，SC：C.Wayne?Weart，PharmD，FASP，BCPS(PI)；Teresa?Price.The?FristClinic，Nnshville，TN：Byron?Haitas，MD(PI)；Cynthia?A.Borum，BSN.Illinois?Center?forClinical?Trials，Chicago，1L：Glen?A.Sussman，PhD(PI)；Seth?Tarmenbautn，MD；Leslie?Zun，MD，MBA，FACEP；Kathleen?Colombo，BSN.North?General?Hospital，New?York，Nit′：MyoMaw，MD(PI)；Karen?Adam-son，MD.Charles?F.Scott，MDPC，East?Point，GA：Charles?F.Scott，MD(PI)；Cymanthia?Crowley，MA.Memorial?Medical?Center，Savannah，GA：Lloyd?S.Goodman，MD(PI)；Theodora?L.Gongaware，MD；Nasser?Mikhail，MD；Donna?Tuten，RN.Simon-Williamson?Clinic，PC，Birmingham，AL：Richard?Fuller，MD(PI)；Maria?Harper，RN；James?Richard?Kilgore，PA.Indianapolis?Cardiovascular?Research?Office，Indianapolis，IN：&radley?A.VVeinberg，MD(PI)；David?Quinn，CCRN.East?Carolma?University?School?ofMedicine，Greenville，NC：Mark?D.Danrow，MD(PI)；Elizabeth?A.Mahoney，PA.SelmaMedical?Associates，Winchester，VA：Randolph?H.Renzi，MD(PI)；Linda?Stoilings，RN.Naval?Medical?Center?San?Diego，San?Diego.CA：HoIIace?D.Chas-tain，II，MD(PI)；KerBoyce，MD.Thomas?A?McKnight，MD，PC，Fremont，NE：Thomas?A.McKnight，MD(PI)；Jean?K.Schafersman，CMA.ALLHAT?Clinical?Center?275A，Philadelphia，FA：′Pasquale?F.Nestico，MD(PI)；Amy?Signell.Mobile?Diagnostic?Center，Mobile，AL?Thomas?A.Kesslcr，MD(PI)；Nancy?P.Wettermark.Truman?Medical?Center-East，Kansas?City，MO：Diane?M.Harper，MD(PI)；Roberta?h.O′Kelly，BA.Gng?Medical?Center，Oxon?Hill，MD：Stephen?T.Ong，MD，MPH(PI)；Debbie?Clements，Clinical?Supervisor.St.]ohn?Family?Practice，St.Petersburg，FL：Hugo?A.St.John，MD(PI)；Teresa?St.John，BSN.Internal?Medicine?Centerof?Akron，Akron，OH：Joseph?A.Finocchio，MD(PI)；Irene?Chenowith，MD；Norma?Durbin，RN，BSN.UMDNJ-Nno?Jersey?Medical?School，Newark，NJ：Maya?P.Raghuwan-shi，MD(PI)；Lester?Muhammad.Beaumont?Internal?Medicine?Associates?PA，Beaumont，TX：CarlosArroyo，MD(PI)Judy?Freeman.VAMC?East?Orange，East?Orange，NJ：Suat?Akgun，MD(PI)；Eileen?Moser，MD；Linda?Condit，RN.VAMC?Danville，Daiiville，IV.William?Marshall，MD(PI)；Richard?Jones，PA.VAMC?Las?Vegas，Las?Vegas，NV：Gopal?Das，MD(PI)；Carol?A.King，DrPH.VAMC?Albany，NY，Albany，NY：James?T.Higgins，MD(PI)；Robert?Garris，PharmD；J.B.Goss，RPh；Kerry?Johnston，.RPh；Michael?Levin，MD；Marc?Stem，MD；JulieHassenfeld，BA.VAMC?Providence，Providence，RI：Satish?Sharma，MD(PI)；ElizabethCoccio；RN.VAMC?Batavia，Rochester，NY：Thomas?Pingree，MD(PI)；Rebekah?Loy，PhD.VAMC?Marion，Marion，IL：Mohammed?Mansuri，MD(PI)；Shaheda?Mansuri，MD；MelissaGuess，RN.VAMC?Des?Moines，Des?Moines，IA：RusseU?Glynn，MD(PI)；Beth?Hargens，RN.VAMC?Salt?Lake?City，Salt?Lake?City，UT：Rajat?Kaul，MD(PI)；Jeanie?O′Donnell，MSN.VAMC?Fargo，Fargo，ND；Kushal?Handa，MD，BSc(PI)；Twila?Xeim，BS.VAMC?Decatur，Decatnr，GA：W.?Virgil?Brown，MD(PI)；Anh?Le，MD；M.Martinez-Maldonado，MD；LuisPimentel，MD；Mary?Ellen?Sweeney，MD.Cleveland?Clinic?Florida，Ft.Lauderdale，FL：Jerry?6.Ciocon，MD，FACP，FACA，AGSF(PI)；Gregory?Cohn，MD；Lori?Blanco，RN.SinaiHospital，Center?for?Cardiovascular?Research，Detroit，Ml：Nicholas?Z.Kerin，MD(PI)；Kathy?Faitel/RN，BSN.Diabetes?and?Metabolism?Associates，APMC，New?Orleans，LA：Jonathan?K.Wise，MD，FACP(PI)；Skye?N.Noble，LPN.IB.Price，MD，PA，Qvincy，FL：IraB.Price，MD(PI)；Patricia?Walden.Family?Practice?Center，Ottiimwa，IA：Robert?H.Schneider，MD(PI)；Veronica?Butler，MD；Linda?Hoffman；Joyce?Horan，LPN.FamilyPractice?Residency?Florida?Hospital，Orlando，FL：David?G?Pocock，MD(PI)；-Karen?L.Kundinger，RN，BSN.Marc?S.Posner，MD，PA，Baltimore，MD：MarcS.Posner，MD(PI)；Cyndy?Comp-ton.ALLHAT?Clinical?Carter?302A，Portsmouth，VA：Doris?M.Rice，MD(PI)；Bonnie?Stadtler?Deaconess?Research?Institute，Billings，MT：Stuart?J.Ruben，MD(PI)；Connie?D.Hamilton，RN.Medicine?H?Clinic?E.A.Conway?Hospital，Monroe，LA：BarbaraBeard，DO(PI)；Tammy?V.Jones，DO；Regena?Trichell.Springfield?Medical?Center，PanamaCity，FL：Misal?Khan，MD(PI)；Sandra?Fenandez.CardiologyConsultants，Pensacola，FL-Brent?D.Videau，MD(PI)；Elizabeth?Stock；Terri?Wilcox，RN.TheBowling?Green?Study?Center，Bowling?Green，QH：William?E.Feeman，Jr.，MD(PI)；Gvvenda?Sue?Schroeder.Comprehensive?Adult?Risk?Evaluation(CARE)，Oakland，CA：General?K.HOliard，MD(PI)；Barbara?Holmes，MA.David?A-Jolivet，MD，PA，Houston，TX：David?A.Jolivet，MD(PI)；Monica?Brizuela.Temple?University?School?of?Medicine，Philadelphia，.PA：David?S.Kountz，MD，FACP(PI)；Margot?Boigon，MD；Michael?Jacobs，PharmD；Nancy?Moffatt，MSN，CRNP.Health?Care?Plan?Inc.，West?Seneca，NY：Brian?D-Snyder，MD(PI)；Kelly_Thomas，RN.Eastwick?Medical?Associates，Philadelphia，PA：Donald?Fox，MD(PI)；Robert?A.Centrone，DO；Steven?A.′Feinstein，MD；Harvey?A.Soifer，DO；Marie?T.Cipollone，MT.Andre?K.Artis，PC，Gary，IN：James?E.Carter，Jr.，MD(PI)；Mary?Hutchinson.Warrior?Family?Practice，Tuscaloosa，AL：H.Joseph?Fritz，MD(PI)；Carolyn?S.Buford，LPN.ALLHAT?Clinical?Center?318A，New?York，NY：Mahshid?Ar-faniaAssadi，MD，FACP(PI)；Cyrus?Assadi，MD.Union?Diagnostic?Clinic，St.Louis，MO：Francois?R.Charles，MD(PI)；Mary?L.Gregory，DA.University?of?Arizona，Tucson，AT：Charles?Y.Lui，MSc，MD，FACC′FACA(PI)；.Sharon?Snvder，RN，MS.Family?MedicineClink，PC，Onawa，IA：Curtis?A.Mock，MD(PI)；Rhonda?R.Gibson，RN，BS；Mac-Nea！Center?for?Clinical?Research，Berwyn，JL：Charles?j.Bar-eis，MD(PI)；Robert?J.McNally，jr.，RN，BSN；Teresa?Flegel，RN，BSN.Gunnar?Medical?Group，Chicago，TL：Charles?J.Bareis，MD(PI)；Peter?P.Mayock，MD；Robert?J.McNally，Jr.，RN，BSN.Tri-Couniy?Emergency?Medical?Services?Inc，Hartville，OH：Jean?A.Lang，DO(PI)；ThomasA.Gibbs，DO；Pamela?Blankenship，MA，CPT.Herman?Rose，MD，PA，Fort?Worth，TX：Herman?Rose，MD，FACP(PI)；Maxine?Pickard.Drs.Samuels?and?Huddlesion?APMC，Chal-mette，LA：Bruce?S.Samuels，MD(PI)；Andre?G.Smith，LPN.Athens?Internal?Medicine，Athens，AL：Nauman?Qure-shi，MD(PI)；Theresa?Tucker，RN.Doctors?Diagnostic?Center，Minneapolis，MN：David?A.Berman，MD(PI)；Diane?Crimmins，RN，CCRN.ALLHATClinical?Center?328A，Buffalo，NY：Joseph?L.Maddi，MD(PI)；Johanna?Canney，RN.SummitCardiology?Associates，Inc.，Cuyahoga?Falls，OH：Alfred?I.Narraway，DO，FACC(PI)；Stephen?L.DiBlasi，DO；Karen?S.Kurojoski，DO；Mary?L.′Hughes，RN，PA-C.BethesdaFamily?Practice，Cincinnati，OH：John?G.O′Hand-Jey，MD(PI)；Beth?Akridge，RT.Lawrence].Misko，MD，Inc.，Glendom，CA：Neil?E.Doherty，III，MD(PI)；Vivian?Doherty，RN，MSN.East?Bay?Cardiology?Medical?Group，San?Pablo，CA：Gary?B-Marcus，MD，FACC，FACP(PI)；Brenda?Perry，RN，MS，NP.Falmouth?Cardiology?Associates，PC，Falmovth，MA：Thomas?Sbarra，MD(PI)；Catherine?M.Geary，MSN，RN，CS.UCI?HeariDisease?Prevention?Progam，Irvine′，CA：Nathan?D.Wong，PhD(PI)；David?Abrahamson，MB，BCh，FACC；Julius?M.Gardin，MD，FACC；Jonathan?M.Tobis，MD；Richard?Will-ner，MD；Sheila?Deakin，RN.Napa?Valley?Cardiology，Napa，CA：Dale?R.Stemple，MD，FACC(PI)；Dan?Lyle，RN.Easihnd.Medical?Primary?Care，Bloomington，JL：Galen?F.Weaver，MD，FACP(PI)；Karen?Nenne，RN.Ben?Taub?General?Hospital，Houston，TX：Horado?J.Adrogue，MD(PI)；Debby?S.Verrett.Cardiovascular?Laboratory，Ryder?Memorial?Hospital，Hwnacao，PR：Maria?L.Rios，MD(PI)；Marisol?Rios.Primary?Health?Care?Practices?PC，Maam.GA：William?E.May，MD，FACP(PI)；Caroline?D.Martin，BA，MBA.Michigan?MedicalSpecialists?PC，Grand?Rapids，Ml：Marian?E.Oleszkowicz，MD(PI)；Kyle?A.Rasikas，MD；Barb?Fritsma，LPN.Lionel?B.Katchem，DO，PC，Ontario，CA：Lionel?B.Katchem，DO(PI)；Arlene?J.(Penny)Katchem.ALLHAT?Clinical?Center?346A，New?York，NY：Edu-ardo?L.Pignanelli，MD(PI)；Minucha?Ferxeira-Montesino.Center?for?Family?Medicine，Greenville，SC：Palmira?S.Snape，MD(PI)；Eva?G.Darr，PharmD，BCPS-Richmond?Area?High?BloodPressure?Center，Richmond，VA：Dean?C.Williams，MD(PI)；Brian?Rojas，NREMT-P；LindaCampiong，BA，MPH.Hoioard?S.Yager，MDPC，Atlanta，GA：Howard?S.Yager，MD(PI)；Faye?Yager.Stevens?Cardiology?Group，Edmonds，WA：Stephen?R.Yamall，MD，FACC(PI)；Angelika?Micketti，CMA.Goshen?Medical?Center-Plainview?Site，Rose?Hill，NC：FranciscoBecerra，MD(PI).SUNY-HSC?at?Syracuse，Syracuse，NY：Gunnar?H.Anderson，Jr.，MD(PI)；Nancy?D.Blakeman，BSN.New?York?Methodist?Hospital，Brooklyn，NY：C.V..RamanaReddy，MB，BS(PI)；ThayyuJlathil?Bhararhan，MD；Muthus-wamy?Krishnamurthy，MD，FACP；Manohar?R，Angirekula，MD.UHSCOM，Kansas?City；MO：Anthony?Dekker，DO(PI)；J.Lewis?Alderman，PhD；Matt?Furman，BA.UHSCOM-Excelsior?Springs，MO，Excelsior?Springs，MO：Anthony?Dekker，DO(PI)；James?LaSalle，DO.Pitman?InternalMedicine?Associates，Pitman，NJ：Michael?A.Farber，MD(PI)；Lewis?John?DeEugenio，MD；Bruce?J.McGann..MD；Sandra?Drebes，LPN.Pitman?Internal?MedicineAssociates-Swedesboro，Swedesboro，N]：Michael?A.Farber，MD(PI)；Lewis?JohnDeEugenio)MD；Bruce?J.McGann，MD；Brenda?Locantora，LPN.University?of?Iowa?Hos-pitals，Iowa?City，IA：William?Lawton，MD(PI)；Delores?Kuebrich，RN.Mercer?University，Macon，GA：Paul?H.VA-mato，MD(PI)；David?C.Parish，MD，MPH，FACP；Bobbye?M.Wieman，RN.Pavillion?Medical?Associates，Baltimore，MD：James?Mersey，MD(PI)；NancyWaligorski，RN，CDE.Elliott?N.Schxaariz，MD，PC，Oakland′，CA：Elliott?N.Schwartz，MD(PI)；Patricia?Ellen?Schwartz，RN，CoMedPro，North?Andover，MA：Albert?Sobrado，MD(PI)；Janet?Pellegrino，FNP.VAMC?Hampton，Hampton，VA：Donald?Richardson，MD(PI)；DonaldRichardson，MD.ALLHAT?Clinical?Center?367A，New?Roads，LA：Donald?W.Doucet，MD(PI)；Madeline?L.Doucet.Russell?W.Simpson，MD?and?Associates，PC，Denver，CO：Ralph?P.Ec-cles，DO(PI)；Russell?W.Simpson，MD；Marilyn?M.Wilson.Medical?Arts?Clink，Corsicana，7X；Kent?E.Rogers，MD(FI)；PriscUla?A.Hutchins，Medical?Assistant.NavarroPrimary?Health?Care?Clinic，Corsicana，TX：Kent?E.Rogers，MD(PI)；Billie?J.Conger，RN.San]oaauin?General?Hospital，French?Camp，CA：Ramesh?Dharawar，MD，FACC(PI)；AliUsman，MD；Ramesh?Dharawar，MD，FACC.The?Brooklyn?Hospital?Center，Brooklyn，NY：Kenneth?Ong，MD(PI)；Samuel?Chan，MD；Walter?J.Pierce，MD；Joann.Varvatsas.KaiserPermanente，Harbor?City，CA：Suzanne?Barrett，-PAC(PI).Suffolk?Community?Health?Center，Suffiok，VA：Vanessa?A.Blowe，MD(PI)；Cathy?R.Gordon，RN，BSN.Wayne?SlateUniversity，Sou′thfield，Ml：Gary?W.Edelson，MD(PI)；Mohamed?S.Siddique，MD；AnnPawluszka，RN.Patuxeni?Medical?Group，Inc，Annapolis，MD：Louis?Kofi?Essandoh，MD(PI)；Kim?Burroughs.Central?Plaius?Clinic，Sioux?Falls，SD：Barry?J.Lankhorst，MD，FACP(PI)；Pamela?Jo?Rogers，LPN.Donald?R.StemmuUer，MD，SC，Lake?Forest，1L：DonaldR.Steinmuller，MD(PI)；Mary?W.SteinmuUer?BSN.Community?ServiceClinic，LaGrange，GA：Joseph?Minore，MD(PI)；William?M.McQellan，Jr.，MD；Judy?W.McCuUough，RN.Lipid?Clinic/New?England?Medical?Center，Boston，MA：Ernst].Schaefer，MD(PI)；Leo?Sernan，MD，PhD；Patricia?M.Wedge.University?of?South?Florida，Division?ofCardiology，Tarn-pa，FL：Lofty?L.Basta，MD(PI)；Ruth?Kallai，AKNP；Elizabeth?A.Ford，RN，BSN.Ferndale?Clinic，Ferndale，Ml：Michael?S.Doyle，MD(PI)；Joan?Segler，KN，BSN.￡./.Clinical?Research，Inc./Grand?Valley?Cardiology?Specialists，Grand?Rapids，MI：].RobertGrove，MD(PI)；Elaine?L.Johnson，RN，CCRC.Milwaukee?Cardiology?Associates，S.C.，Milwaukee.，WI：Anita?M.Arnold，DO(PI)；Timothy?Sommers，RN.Suburban?HeightsMedical?Center，S.C.，Chicago?Heights，IL：Jairo?B.Cruz，MD(PI)；Theresa?Garzelloni，RN；Susan?Mouritzen，RN.AHEC′Family?Medical?Center，Fort?Smith，AR：Jimmv?D.Acklin，MD(PI)；Charles?C.Marsh，PharmD.

NHLBI project office, Bethesda, MD:Jeffrey Cutler, MD, project manager; Gerald H.Payne, MD, project officer; David Gordon, MD, PhD, project adjutant person; Debra Egan, MPH, MSc, project adjutant person; ChukeNwachuku, MA, Project Administrator official; Michael Proschan, PhD, Biostatistician; Kristee M.CamiUetti, the contract official.

ALLHAT clinic test center, Houston, TX:C MortonHawkins, Sc.D, chief researcher; BarryR.Davis, MD, PhD, associating chief researcher; Charles E.Ford, PhD, joint study person; David Goff, MD, PhD, joint study person; Robert J.Hardy, PhD, joint study person; Darwin R.Labarthe, MD, PhD, joint study person; Sara Pressel, MS, project manager; Christine Mirvillo, the Project Administrator manager; Beverly Learner, the Project Administrator manager.ALLHAT drug flow center, Rockville, MD:Mary Mease, RPh, chairman; Greg Berezuk, RPh, co-chairman.

ALLHAT central laboratory, Minneapolis, MN:John Eckfeldt, MD, PhD, chairman; MarenNowicki, BS, medical skill expert; Jean Bucksa, the laboratory manager.

ALLHAT ECG reading center, Minneapolis, MN:Richard S.Crow, MD, chairman; MarshaMcDonald, MA, co-chairman.

Pfizer, Inc., New YorkNY:Margaret M.Cobb, MD, PhD, associate administrator's medical science chairman; PatriciaWalmsley, MD, associate administrator's medical science chairman; Tony Whitehead, MD, assistant's medical science chairman.

Zeneca, Wilmington, DE:OrysiaTresznewsky, MD, chairman, the research of heart kidney; Michael D.Dugan, MD, chairman assistant, clinical and medical service matters.

Bristol-Myers Squibb, Princeton, NJ:Mark E.McGovern, MD, clinical research chairman; MargotMellies, MD, chairman, clinical metabolism research.

ALLHAT administration committee: Michael H.Alderman, MD; Henry R.Black, MD; WilliamC.Cushman, MD; CharesK.Francis, MD; Curt D.Furberg, MD, PhD (Chair); RichardH.Grimm, MD, PhD; C.Morton Hawkins, ScD; John LaRosa, MD; Suzanne Oparil, MD; Geraid H.Payne, MD; H.Mitchell Perry, Jr., MD; Jeffrey L.ProbstSeld, MD; PaulK.Whelton, MD, MSc; Jackson T.Wright, Jr., MD, PhD (Vice-Chair).

ALLHAT zone doctor and research coordination person: Michael H.Alderman; MD; Lillian Carroll, RN; Henry R Black, MD; Tracy Lucente, MPH; Julie Hynes, MS, RD; William C.Cushman, MD; Sandra M.Walsh, MA; Richard H.Grimm，MD，PhD；Carla?Yunis，MD；LeslieHolland；Suzanne?Oparil，MD；Angela?J.Williard，RN，BSN；PamelaRugasa，RN；JeffreyL.Probstfield，MD；Kim?Dammann，RN；Rebecca?Letterer，RN；Susan?Ross，RN；PaulK-Whelton，MD，MSc；JeffWilliamson，MD，MHS；Gail?Louis，RN；Jackson?T.Wright，Jr.，MD，PhD；RobertA.Pospisil，RN。

ALLHAT data and security monitoring committee: William B.Applegate, MD; Julie S.Buring, ScD; Richard Carleton, MD (Chair); Edward Cooper, MD; Keith C.Ferdinand, MD, FACC; Marian Fisher, PhD; Raymond W.Gifford, Jr., MD; Sheldon Sheps, MD.

Claims (14)

1. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic of described individual effective dose every day, wherein said diuretic is alleviated cardiovascular disease in this individuality therapeutic effect is better than the effect of only treating with beta-adrenergic blocking agent.

2. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic of described individual effective dose every day, wherein said diuretic is alleviated cardiovascular disease in this individuality therapeutic effect only is better than the effect with the calcium channel blocker treatment.

3. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic of described individual effective dose every day, wherein said diuretic is alleviated cardiovascular disease in this individuality therapeutic effect only is better than the effect with the vasodilation treatment.

4. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic of described individual effective dose every day, wherein said diuretic is alleviated cardiovascular disease in this individuality therapeutic effect is better than the effect of only using the nervus centralis agonist treatment.

5. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic of described individual effective dose every day, wherein said diuretic is alleviated cardiovascular disease in this individuality therapeutic effect is better than only uses reserpinized effect.

6. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic and the ACE inhibitor of described individual effective dose every day, wherein said diuretic and ACE inhibitor are alleviated cardiovascular disease in this individuality therapeutic effect is better than the effect of only using this diuretic therapy.

7. method of alleviating the dangerous individual cardiovascular disease, this method comprises: give the diuretic and the ACE inhibitor of described individual effective dose every day, wherein said diuretic and ACE inhibitor are alleviated cardiovascular disease in this individuality therapeutic effect is better than only uses vasodilation, nervus centralis agonist, calcium channel blocker, α ₁-blocker, beta-adrenergic blocking agent, reserpinized effect.

8. as claim 1,2,3,4,5,6 or 7 described methods, wherein said diuretic is chlortalidone (chlortahlidone).

9. as claim 6 or 7 described methods, wherein said diuretic is a chlortalidone.

10. as claim 6 or 7 described methods, wherein said ACE inhibitor is a ramipril.

11. as claim 6 or 7 described methods, wherein said ACE inhibitor is a ramiprilat.

12. as claim 6 or 7 described methods, wherein said diuretic is a chlortalidone, described ACE inhibitor is a ramipril.

13. as claim 1,2,3,4,5,6,7,8,9,10,11,12 or 13 described methods, wherein said cardiovascular disease is a heart failure.

14. as claim 1,2,3,4,5,6,7,8,9,10,11,12 or 13 described methods, wherein said individuality is the hypertension individuality.

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