JP2006511567A - Methods and dosage forms for reducing heart attacks in hypertensive individuals using diuretics or using a combination of diuretics and ACE inhibitors - Google Patents

Abstract

The present invention relates to methods and dosage forms for reducing and / or preventing the occurrence of cardiovascular diseases such as heart attacks in individuals at risk, eg, individuals suffering from hypertension. The treatments and dosage forms of the present invention may be used to reduce and / or prevent the occurrence of cardiovascular diseases, i.e. heart attacks or heart failure, in individuals suffering from or at risk for hypertension. It relates to the administration of a thiazide diuretic such as (Thalitone®) alone or in combination with an ACE inhibitor such as ramipril or ramiprilat such as Altus®.

Description

This application claims the benefit of US Provisional Patent Application No. 60 / 433,845, filed Dec. 16, 2002.
The present invention relates to methods and dosage forms for reducing and / or preventing the occurrence of cardiovascular diseases such as heart attacks in individuals at risk, eg, individuals suffering from hypertension. The treatments and dosage forms of the present invention may be used to reduce and / or prevent the occurrence of cardiovascular disease, i.e., heart attack or heart failure, in an individual suffering from or at risk for hypertension. It relates to the administration of a thiazide diuretic such as (Thalitone®) alone or in combination with an ACE inhibitor such as ramipril or ramiprilat such as Altus®.

  Administering an effective amount of a diuretic, such as a thiazide diuretic such as chlorsalidon, alone or in combination with an angiotensin converting enzyme inhibitor ("ACE inhibitor"), such as ramipril or ramiprilat, particularly those at risk for hypertension By doing so, it has been found in the present invention that the occurrence of cardiovascular diseases such as heart attacks in such individuals can be reduced if not eliminated. When diuretics are administered with an ACE inhibitor, they can be administered in a single dosage form such as a tablet, solution, caplet or capsule, or in separate dosage forms. A preferred diuretic for use in the present invention is a thalidon, such as thaliton (Thalitone®), administered in a single daily dose of 15 mg, 30 mg, 45 mg, 50 mg, 60 mg or more. A preferred ACE inhibitor for use in the present invention is ramipril, eg Altus (Altace®), administered in a single daily dose of 1.25 mg, 2.5 mg, 5 mg, 10 mg or more.

Quite surprisingly, the therapeutic effects of diuretics in reducing or eliminating cardiovascular diseases such as heart attacks in individuals at risk are adrenergic beta blockers such as propanolol and atenolol, calcium channel blockers, ACE inhibitors such as lisinopril It is much larger compared to such individuals treated with vasodilators such as hydralazine, central agonists such as oral clonidine or methyldopa, reserpine, or alpha ₁ blockers such as prazosin and doxazosin. Found in the invention. Even more surprisingly, the therapeutic effect of a combination of a diuretic such as a thiazide such as thaliton (Thalitone®) and an ACE inhibitor such as Altus (Altace®) is a diuretic, or propanolol and Adrenergic beta blockers such as atenolol, calcium channel blockers, ACE inhibitors such as lisinopril, vasodilators such as hydralazine, central agonists such as oral clonidine or methyldopa, reserpine, or alpha ₁ blockers such as prazosin and doxazosin It is significantly superior to the individual therapeutic effects achieved in such individuals when treated with alone.

  Although the invention has been described with reference to preferred embodiments and specific examples, those skilled in the art will readily appreciate that other modifications and changes may be made thereto without departing from the spirit or scope of the invention. Will. Accordingly, the invention is not limited to the details of the description of the preferred embodiments and specific examples, but only by the scope of the invention as defined in the claims appended hereto.

I. Overview This protocol is a practice for antihypertensive medications in 40,000 high-risk hypertensive patients, including at least 55% of American blacks (self-named “blacks”), and cholesterol-lowering medications in certain subpopulations thereof. Describes a randomized clinical trial based. The purpose of the anti-hypertensive trial category is to have a combination of fatal coronary heart disease (CHD) and non-fatal myocardial infarction, diuretic (chlorsalidon) treatment and three alternative antihypertensive drug treatments [ie calcium Antagonist (amlodipine), ACE inhibitor (ricinopril), and adrenergic alpha blocker (doxazosin) (Recommended by NHLBI to discontinue the doxazosin division of the antihypertensive trial on January 24, 2000. JAMA. 2000; 283: 1967-1975)]]. The antihypertensive trial category does not include a placebo or untreated control group because the benefits of antihypertensive treatment in reducing the overall morbidity and mortality from stroke, cardiovascular disease, and mortality from all causes are already established. The purpose of the cholesterol lowering test category was to determine serum cholesterol levels in men and women over 55 years of age with moderate hypercholesterolemia by using pravastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor. The decline is to see if the mortality from all causes is reduced compared to the control group receiving “normal care”.

  A secondary objective of both study categories is to compare the effects of their respective treatment plans on cardiovascular mortality, major morbidity, medical costs, and health-related quality of life. A further secondary objective of the antihypertensive trial is to compare the effects of alternative treatments on mortality from all causes and on major hypertension-related morbidity (eg, the occurrence and reduction of left ventricular hypertrophy and progressive renal failure) That is. The effects of antihypertensive treatment regimes on the outcomes of the primary and secondary objectives will also be evaluated in a central subgroup [over 65 years old, female, American black, type 2 diabetes]. Additional secondary objectives of lipid-lowering studies include long-term safety of HMG CoA reductase inhibitors (especially related to mortality from non-cardiovascular disease), cancer development and The effects of lipid lowering on mortality, and the effects of lipid lowering on the concurrent occurrence of fatal CHD and non-fatal myocardial infarction, particularly in the central subgroup [female over 65, American black, type 2 diabetes ] To evaluate. Also, because this segment of the study is not blinded, the occurrence of myocardial infarction based on central decoding changes in biennial electrocardiograms is considered an endpoint. The duration of the study ranges from 4.2 years (for the last patient) to 8 years (for the first patient), with an average duration expected to be 6.0 years.

In order to maximize statistical power regarding the first hypothesis of this antihypertensive trial (ie, the comparison of each alternative drug treatment plan with diuretic treatment), its diuretic department has three other departments 1.7 times more patients are assigned in each case (Table I.1). Half of ALLHAT participants are expected to be randomized into both study categories, and half are expected to be randomized only into the antihypertensive study category.

  The trial involves approximately 600 primary care and hypertension specialists because it is prohibitively expensive to involve so many participants in traditional clinical trial organizations that use independently funded clinics. We will use an organized model that involves patients collected through clinics, clinics, and medical centers, each serving an average of 67 patients. The Department of Veterans Affairs (VA) hypertension clinic is expected to supply approximately 20% of the study patients, including approximately 70 of these clinical laboratories. Formalities are kept to a minimum, and few clinical procedures that are not performed in normal patient care are required.

II. Background and principle
A. Antihypertensive test
1) Hypertension and coronary heart disease (CHD)
An estimated 50 million people in the United States suffer from hypertension (systolic blood pressure SBP > 140 mmHg and / or diastolic blood pressure DBP > 90 mmHg) or are taking antihypertensive drugs. In 1983, 23 million people were taking antihypertensive drugs [1]. The cost of outpatient hypertension treatment in the US in 1986 was estimated at $ 7.5 billion [2]. Most of these costs are due to the cost of the drug used, which has a considerable economic impact when considering the number of patients treated. Assuming all other factors remain constant, treating 25 million patients with a drug that costs $ 100 per patient per year of treatment compared to using a drug that costs $ 500 per patient per year The cost savings will be $ 10 billion.

  Despite the known etiological relationship between CHD and hypertension, large randomized clinical trials in mild to moderate hypertension (DBP 90-114 mmHg), mostly in middle-aged subjects, There is no definitive indication that antihypertensive treatment reduces the incidence of CHD death or nonfatal myocardial infarction. The cumulative results of nine such trials involving more than 43,000 subjects primarily using thiazide-like diuretics yielded a 9% benefit with a 95% confidence limit consistent with a 19% benefit or 1% adverse effect Suggest [3]. This observed therapeutic effect is comparable to the maximum expected effect on CHD of approximately 23% for comparable blood pressure differences, as derived from epidemiological data. In contrast, the observed beneficial effect on stroke in these trials (36%) almost exactly matches that expected from epidemiological data [4]. A more recent review of 14 trials in participants with all hypertension levels [5] estimates a slightly larger effect (14% benefit, 95% confidence interval, 4-22%). Although there is grounds for suspicion that this may be an overestimation of benefits, these reviews are based on recent trials in older adults, especially diuretics, which reduced stroke incidence by 36% and major CHD events by 27% Reduced (95% confidence interval, 4 to 43%) does not include strongly positive results of the Systolic Hypertension in the Elderly Program (SHEP) [6].

  One explanation that previous studies have failed to show the expected degree of CHD mitigation is that the side effects of the drugs used in the study, particularly diuretics, may have offset the potential benefits of blood pressure reduction. There is. These side effects include diuretic-induced hypokalemia, hypomagnesemia, hyperuricemia, hyperlipidemia, hyperglycemia, impaired insulin sensitivity and possibly enhanced ventricular ectopic activity [6,7]. Although the diuretic-induced increase in total cholesterol is approximately 4% and the diuretic-induced increase in LDL cholesterol is estimated to be 10% [7], these effects can be mitigated by long-term treatment [7] Five]. Such an increase in blood lipids, if maintained, will be sufficient to offset a substantial portion of the benefits of CHD from lowering blood pressure.

2) A new class of antihypertensive drugs
In the early 1980s, two new classes of antihypertensive drugs, calcium antagonists and angiotensin converting enzyme (ACE) inhibitors, were developed and licensed for the treatment of chronic hypertension. These drugs tend to be more expensive than older drugs such as diuretics and beta-blockers, and evidence that can justify their use despite such increased costs (eg greater potency or more The few side effects are limited [2]. The 4th Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) recommends beta-blockers, calcium antagonists, ACE inhibitors and diuretics as equally acceptable first-line treatments [ 9]. A total of four classes of drugs have been found to suppress diastolic blood pressure in more than 50% of patients with mild hypertension as a single drug. The 5th JNC report [10] reviewed the choice of initial treatment and recommended diuretics and beta-blockers as preferred drugs. JNC-V is also adding an adrenaline alpha blocker and drugs that have both alpha and beta blockers as alternative first-line therapeutics.

  Of these drug classes, only β-blockers are directly compared to diuretics in large-scale long-term clinical trials in hypertension. Three such trials completed in Europe from 1985 to 1986 showed similar effects on morbidity and mortality in diuretic and beta-blocker-based programs. Accumulated analysis of these trials showed a 6% lower CHD mortality (95% confidence interval, -10% to + 22%) from beta-blockers [11]. These data are in contrast to the recent Medical Research Council (MRC) study in the elderly, where patients treated with thiazide diuretics were treated with beta-blocker (atenolol) or placebo or both It showed a more significant (about 45%) lower CHD rate.

  Other data indicate that calcium blockers can suppress the development of atherosclerotic lesions in a rabbit model, but test data on morbidity and mortality are inconsistent. One of the diltiazem trials in patients after myocardial infarction was interpreted as showing benefit in patients without a low ejection fraction, but a comprehensive review of all post-myocardial infarction trials with calcium blockers is available Reports a 6% (-4% to + 18%) increase in mortality [12]. A revised version of this manual, including three additional trials in patients with angina or myocardial infarction, suggests better results with drugs that lower heart rate compared to dihydropyridine calcium blockers [13]. Other trials in hypertension have shown a decrease in left ventricular mass following treatment with calcium blockers [14].

  Among ACE inhibitors, at least three of the seven permitted drugs in this class have been reported to reduce left ventricular hypertrophy [15]. ACE inhibitors reduce mortality in both severe and moderate heart failure [16] and reduce morbidity such as CHD in asymptomatic left ventricular dysfunction [17]. Regarding the effects on atherosclerosis, Chobanian et al. Reported prevention of coronary artery lesions in the Watanabe rabbit model [18], presumably due to effects on cell proliferation in the vessel wall.

  Some alpha blockers have been shown to have moderately favorable effects on lipid profiles, particularly LDL cholesterol [19,20]. A few studies have also found improvements in insulin resistance, an observation that may be particularly relevant for patients with type 2 diabetes [21,22]. There is also some evidence that these drugs can reduce left ventricular hypertrophy and platelet aggregation and stimulate tissue plasminogen activator [23-27].

  The following two long-term randomized trials are only compared with all representatives of these drug classes: a one-year trial [28] conducted by the VA Cooperative Study Group on AntiLypertensive Agents and 4.4 years Treatment of Mild Hypertension Study (TOMES) [19]. These studies report some differences in blood pressure suppression, side effects, quality of life, biochemical effects and target organ changes, but these differences are consistent with only some drugs. It does not show the pattern to be highly evaluated.

  Therefore, data from a wide variety of studies in human and animal models suggest that newer drugs may be superior, comparable or inferior to standard drugs in the treatment of hypertension. ing. A report from the British Hypertension Society, “We therefore conclude that β-blockers or diuretics are equally acceptable first-line treatments .... Unfortunately, large-scale trials are Newer antihypertensive drugs such as antagonists and angiotensin converting enzyme inhibitors are not used, so there is no comparable data on these widely used drugs to evaluate the role of these drugs Large-scale comparative studies are urgently needed [29]. US researchers have reached similar conclusions [30-32].

3) Importance of comparison of antihypertensive drugs in American blacks Hypertension is much more common in American blacks than in whites, and its sequelae are more frequent and severe. The prevalence of hypertension in the 2nd National Health and Nutrition Examination Survey (NHANES II) was 51% for American blacks aged 25 to 74 years, compared with 40% for whites [33] . The incidence of end-stage renal disease secondary to hypertension is about 8 times higher in American black hypertensives than in white hypertensives [34]. The risk of left ventricular hypertrophy, stroke, and death from death is all reported to be higher in American black hypertensives. Suggested explanations for these differences include the higher prevalence of co-morbidities such as diabetes and poor medical use in American blacks.

  Assuming that treatment effectively reduces morbidity and mortality, a population with low medical use could be expected to suffer from an unbalanced high rate of these complications. In such groups, particularly those with low socioeconomic status (SES), the cost of drug therapy can be a top priority consideration in the selection and maintenance of treatment. Thus, the current trend of using more expensive drugs is likely to be a barrier to treatment in low-SES individuals, who are represented by an imbalance in American black and carry the great burden of hypertension-related diseases. Low-SES American blacks are most likely to benefit from this information if cheaper drugs, such as diuretics, are as effective in preventing hypertension complications as other available drugs It is a person. When cheaper drugs are less effective, low SES American blacks are the most likely to suffer. Because they tend to take cheaper drugs or not at all. In any case, given the relative lack of clinical trial information in black Americans, they should be the primary representative subject in the current trial so that the results obtained will be directly applicable to them . For these reasons, at least 55% of the population for this trial is American black.

B. Cholesterol reduction test
1) Cholesterol and coronary heart disease Cholesterol, especially cholesterol levels bound to the low-density lipoprotein (LDL) fraction, have been determined by metabolic and disease in humans and selected animal models through observational epidemiological studies. Physiological and genetic studies, as well as randomized clinical trials, have been identified as a major etiological factor in coronary heart disease (CHD) [35]. Clinical trials showing reduced incidence of CHD from reduced LDL cholesterol levels are conducted primarily in middle-aged men with hypercholesterolemia or established CHD [36-41]. Experimental evidence for the effect of cholesterol lowering in older men is limited to analysis of a small subgroup of clinical trials and is lacking for any age in women. Because of this lack of clinical trial data, the National Cholesterol Education Programs (NCEP) expert panel on the detection, evaluation, and treatment of high blood cholesterol in adults is in its 1987 guidelines and there is considerable room for judgment for the elderly. Is tolerated by physicians [42].

  Uncertainties when applying NCEP guidelines to older men or women have a significant impact on public health. Middle-aged myocardial infarction results in a catastrophic loss of life and productivity, but more than 80% of all CHD deaths in the United States occur after age 65 [43]. Over 60% of the population over the age of 65 is women, and the majority of CHD events in this age group are in women. In 1989, CHD incurred $ 14.4 billion in direct annual health care costs and approximately 400,000 deaths in this age group. This total number can be expected to increase over the next 40 years as the “baby boom” generation's aging and longer lifespan shift the age distribution of the US population to the elderly.

  Although the evidence that links high cholesterol levels to CHD is strong and consistent, clinical trials [44,45] have not shown that lowering cholesterol reduces total mortality. Furthermore, an observational study [46] shows a U-shaped relationship between cholesterol and mortality, with those with cholesterol levels below 160 mg / dl and above 240 mg / dl than those in the range of 160-240 mg / dl High mortality rate. Hemorrhagic stroke, some cancers and deaths from respiratory and gastrointestinal disorders contribute to excessive mortality at the lowest cholesterol level [46]. In addition, the reduction in CHD mortality due to moderate (drug-induced) cholesterol reduction in randomized primary prevention trials in patients with hypercholesterolemia is offset by an increase in trauma-related mortality [44]. These trials, including those observing favorable post-test trends [45, 47], were not designed with reasonable statistical power to examine total mortality within the planned treatment period. Absent. Larger and more effective clinical trials are needed to examine this issue.

2) Cholesterol in the elderly and black Americans Observational studies suggest that clinical trial results may be applicable to men and women with lower cholesterol levels, but the level of cholesterol in these studies Prognostic efficacy decreases with increasing age [48-51]. An aggregate analysis of a cohort of 21 males and 13 females shows that the risk of CHD associated with low blood cholesterol levels in those older than 65 years is less than 65 years with considerable variation between studies Suggesting that it is probably 60% (at least statistically significant in men) [50]. However, this apparent decrease in relative risk associated with aging can be overwhelmed by a concomitant increase in the absolute incidence of CHD death and myocardial infarction [51]. Therefore, the potential public health value of cholesterol reduction in the elderly cannot be ignored. A problem that has not been clarified is how well these “contributory” CHD events are actually preventable when cholesterol lowering therapy is initiated at a relatively old age.

  In American blacks, LDL cholesterol levels are slightly lower and HDL cholesterol levels are slightly higher than in non-minority populations, but hypercholesterolemia remains a serious problem in American blacks, especially in obese and diabetic women. Approximately 23% of American black men and women aged 25-74 had high-risk serum cholesterol levels in 1976-80 [33]. The reduction in cholesterol levels in them would be expected to reduce CHD mortality and morbidity. Traditional cholesterol-lowering tests include only a few American black subjects. The assumption that lowering cholesterol results in similar reductions in CHD in American blacks and whites has not been proven.

3) Use of HMG CoA reductase inhibitors in elderly men and women Many conventional cholesterol-lowering clinical trials in middle-aged men have been neutralized due to the limited efficacy and tolerability of the drugs used. However, lovastatin, the first HMG CoA reductase inhibitor, has become more and more widely used since its approval by the FDA in September 1987, is effective and well tolerated by patients of all ages [52-55]. Two small angiographic studies have shown the beneficial effect of lovastatin on coronary atherosclerosis [56,57]. Two additional HMG CoA reductase inhibitors, pravastatin and simvastatin, were approved by the FDA in late 1991 and both have already been used in foreign countries for several years. The FDA is currently reviewing the approval of fluvastatin, the fourth HMG CoA reductase inhibitor.

  At present, few serious side effects of these drugs have been observed. FDA has removed its requirement for annual slit lamp microscopy from the product label because no adverse lens changes occurred in the 1990 report of the lovastatin EXCEL study [55]. Significant but reversible asymptomatic increases in serum transaminase levels have been observed in 1-2% of patients receiving these drugs. Myositis, which rarely progresses to striated muscle and renal failure, is the most serious side effect reported for HMG CoA reductase inhibitors, and other potentially myotoxic drugs (immunosuppressants, It is aggravated by the combined use of fibrates, etc., and renal dysfunction. However, the frequency of myositis is very low in the absence of these factors and does not significantly exceed the placebo rate at low doses. Although HMG CoA reductase inhibitors can enhance the action of anticoagulants, no clinically significant interactions with antihypertensives used in ALLHAT have been reported.

  Taken together, HMG CoA reductase inhibitors are considered suitable for use in elderly men and women due to their potency, ease of administration, low toxicity and compatibility with most other drugs. They also provide an opportunity to extend our knowledge of the benefits and safety of cholesterol lowering at cholesterol levels and degrees of reduction not previously examined in large clinical trials.

  A two-year pilot trial (Cholesterol Reduction in Seniors Program, CRISP) was started in July 1990 at five clinical centers for the study of cholesterol reduction in the elderly. It used the usual clinical trial model in a funded clinical laboratory, rather than the clinic-based registration model planned for clinical trials, but the pilot trial was The feasibility of collecting older people was demonstrated [58]. A total of 431 men and women over the age of 65 were enrolled in the pilot trial and exceeded the target of 400 subjects within 10 months. The pilot study cohort was designed to compare compliance, safety and efficacy of two alternative dosing regimens (20 mg and 40 mg daily) with 72% women and 25% ethnic minorities Tracked until June 1992. Both doses were well tolerated with 85-90% compliance after 1 year of treatment. The average LDL reduction (28%) obtained with the 40 mg dose was only slightly above that obtained with the 20 mg dose (24%). Slight decreases in HDL cholesterol (7% and 9%) and triglycerides (4% and 10%) were also observed at doses of 20 mg and 40 mg (respectively).

III. Hypotheses and test power
A. Antihypertensive study category The first hypothesis of this study category is (1) calcium antagonist (amlodipine), (2) ACE inhibitor (ricinopril) or (3) adrenergic alpha blocker (doxazosin) (January 2000) The recommendation that the doxazosin department of the antihypertensive trial should be discontinued on the 24th was accepted by NHLBI (see JAMA. 2000; 283: 1967-1975). As a result, lethal CHD and non-fatal myocardial infarction will be less likely to occur simultaneously than patients who have achieved similar blood pressure suppression using thiazide-like diuretics (chlorsalidon). These hypotheses are tested in a population of men and women over the age of 55. All members of this population have at least one additional CHD risk factor in addition to hypertension, and at least 55% of this population are American black. The statistical power to test these hypotheses is approximately 82.5% based on the following assumptions:
1) 40,000 sample sizes (approximately 22,000 men and 18,000 women) assigned to the four treatment groups, as shown in Table I.1.
2) In the diuretic group, the 6-year CHD event frequency is 7.8%. This ratio (1.35% / year) is based on the Framingham and HDFP experiments (33-50% downward revision for transient trends and 25% downward revision for healthy volunteer effects) and later observed in SHEP Is similar to the ratio.
3) 20% reduction in CHD event rate in each of the three non-diuretic treatment trials compared to the diuretic trial (combined to give an effective reduction of 16.3%, before adjustment for non-compliance and unfollow-up) .
4) Using a time-dependent Markov model, the ratio of crossovers between each of the other test drugs and chlorsalidon and / or non-test drug is based on each of the first three years of follow-up (based on TOMHS) Is estimated at 2.75% and 6% over the last 3 years of follow-up. The probability of at least one crossover during this test is estimated to be approximately 24%. It is estimated (conservatively) that the CHD risk associated with non-tested drugs is the same as for chlorsalidon.
5) Based on Framingham and HDFP data (see Appendix I), 16.8% of patients (8.6% of patients-years) at the end of the study due to competitive risk (non-CHD death) or unfollow-up CHD status will not be determined.
6) 25% reduction in CHD event rate in 10,000 patients randomized to active treatment trials in the cholesterol lowering trial category (before adjustment for non-compliance and unfollow-up).

  7) Type 1 error α = 0.05 (both sides). This corresponds to an adjusted critical Z score of 2.37 for multiple comparisons.

  The power estimates ranged from 77-86% for more pessimistic or optimistic hypotheses of crossover (# 4) and loss (# 5) rates. Further details regarding these calculations are provided in Appendix I.

  Amlodipine, lisinopril, or doxazosin (on January 24, 2000, a recommendation to discontinue the doxazosin division of the antihypertensive trial was accepted by NHLBI; see JAMA. 2000; 283: 1967-1975) We also evaluate the second hypothesis regarding the effects of the following endpoints in patients randomized to (compared to those receiving chlorsalidon): (1) all-cause mortality, (2) coronary Complication of arterial heart disease (CHD + revascularization treatment + hospitalized angina), (3) Stroke, (4) Complication of cardiovascular disease (CHD + stroke + revascularization treatment + angina [inpatient or treatment] + CHF [hospitalization or treatment] + peripheral arterial disease [hospitalization or outpatient revascularization]], (5) left ventricular hypertrophy by electrocardiogram, (6) reverse gradient serum creatinine and end-stage renal disease (dialysis or transplantation) , (7) Health related Oriti of life, (8) fatal and non-fatal cancer, and (9) gastrointestinal bleeding caused by type.

B. Cholesterol lowering test category (see Protocol Appendix 1)
The first hypothesis for this study category is that pravastatin and a cholesterol-lowering diet are used in the above-mentioned hypertensive subpopulation with LDL cholesterol levels of 120-189 mg / dl (100-129 mg / dl in patients with known CHD). Patients who are randomized to take will have a lower all-cause mortality rate than patients randomized to receive normal care. Based on the following assumptions, the statistical power to test this hypothesis is about 80%:
1) 20,000 specimen sizes (approximately 11,000 men and 9,000 women) assigned to the pravastatin group and the regular care group.
2) Six-year total mortality (2.35% / year) of 13.2% in the normal care group (based on Framingham, HDFP and SHEP data (see Appendix I)). Based on mortality data in high-risk subgroups of SHEP participants selected for comparability with ALLHAT patients, 40% of deaths are due to CHD and 16% are due to other cardiovascular causes 44% are estimated to be due to non-cardiovascular causes.
3) A 12.5% reduction in mortality in the pravastatin treatment trial. This estimate is based on the assumption that CHD mortality is reduced by 25%, mortality from other cardiovascular diseases is reduced by 15%, and mortality from other causes is unaffected. Assuming that full compliance with the drug regimen reduces LDL cholesterol levels by 30% and average LDL cholesterol levels are 155 mg / dl (range: 120-189 mg / dl) at enrollment, a 25% reduction in CHD is Corresponds to a logistic regression coefficient of 0.0062. For comparison, the logistic coefficient relating total cholesterol to CHD mortality in 356,222 MRFIT (male) selected subjects was 0.0118 for the entire age range (35-57 years) and the oldest group (55-57 years) ) For the 36,704 men in the group. Extrapolation from MRFIT data suggests that the coefficient relating total cholesterol in ALLHAT to CHD may be in the range of 0.005 to 0.006.
4) 5% in the first year and 2.5% “drop off” rate in all subsequent years (no treatment from pravastatin) and 2% / year “drop in” rate (no treatment to pravastatin or similar) Drugs). These rates are estimated at the end of 6 years, with 15.3% of pravastatin patients discontinuing treatment and 10.6% of regular care patients starting treatment. The power of cholesterol-lowering tests focuses on the general effects of cholesterol lowering (as opposed to antihypertensive testing) rather than the effects of specific drugs or drug classes, and other effects that produce equivalent lipid changes from pravastatin It is not reduced by a “crossover” to the plan.
5) There are no untrackable persons.
6) A 10% reduction in mortality in each of the three non-diuretic treatment trials in the anti-hypertensive trial category.
7) Type 1 error α = 0.05 (both sides). This corresponds to a critical Z score of 1.96.

  Power ranges from annual mortality (2.2-2.5%) and a series of some more pessimistic assumptions about compliance (affected 17.8% and 12.9% of dropouts and drop-ins at the end of 6 years, respectively) Rate). Statistical power estimates ranged from 75 to 82% under these assumptions (see Appendix I).

  We also evaluate the second hypothesis regarding the reduction in the following endpoints (compared to those receiving regular care) in patients randomized to receive pravastatin: (1) In particular, the United States Black, patients older than 65 years (original CRISP hypothesis), type 2 diabetes and a combination of non-fatal myocardial infarction in a subgroup such as women, (2) Biennial ECG showing myocardial infarction (3) Cause-specific mortality, (4) Total and site-specific cancer development, and (5) Health-related quality of life.

  The power of this study to examine the effects of concurrent pravastatin on CHD death and non-fatal myocardial infarction was 97% overall, with 10,000 patients with risk characteristics similar to the whole cohort It is estimated that it is close to 80% in any subgroup that it contains (see Appendix 1). However, the objectivity of clinical diagnosis of non-fatal myocardial infarction is potentially compromised because the treating physician is not blinded as to whether his patient received pravastatin or received normal care. To address the bias, the occurrence of non-fatal myocardial infarction is also assessed by changes in the biennial ECG. The assessment is made by a decipherer who is not informed about the patient's treatment assignment. Differences between pravastatin and normal care in clinical events are only trusted if confirmed by qualitatively similar differences in ECG endpoints.

IV. Eligibility and exclusion
A. Antihypertensive test
1． Age / Gender: Males and females 55 years and older.

2． History: proven history of hypertension
3． Sitting blood pressure eligibility is based on the patient's current treatment status and the average of two sitting blood pressure measurements at each of the two visits (Table IV.1):
(A) Patients whose blood pressure has been suppressed for at least 2 months with one or two antihypertensive drugs (mostly blood pressure measurements below 160/100 mmHg) are eligible. Patients taking 3 or 4 antihypertensive drugs in sub-therapeutic or ineffective combinations, and patients who appear to be able to be suppressed with the ALLLHAT protocol, are the study director or his / her designee It is possible to participate in the test according to the judgment.

(B) For untreated patients, a diagnosis of hypertension must first be established (JNC V criteria for diagnosis of hypertension are included in the Manual of Operations). Untreated patients or patients treated for less than 2 months must meet the minimum and maximum blood pressure criteria shown in Table IV.1. In order for registration to be accepted, the lower limit SBP or DBP and both upper limits must be met at least two days apart. Patients who do not meet blood pressure registration criteria at the first or second visit can be reassessed for blood pressure eligibility at a later time.

Four. At least one of the following:
a. One or more of the following symptoms of atherosclerotic cardiovascular disease:
(I) old or unknown myocardial infarction or stroke (> 6 months),
(Ii) History of revascularization treatment (past),
(Iii) Proven atherosclerotic cardiovascular disease. This includes coronary, peripheral, aortic or carotid artery stenosis demonstrated by angiography, Doppler examination or ankle-arm index; by electrocardiography (eg ST-T wave changes), echocardiography or radionuclide imaging Proven ischemic heart disease; intermittent is history of line; or history of transient cerebral ischemic attack, including but not limited to symptoms of atherosclerotic cardiovascular disease A more complete list can be found in the Manual of Operations).

b. Type 2 diabetes [plasma glucose> 140 mg / dl (fasting) or 200 mg / dl (non-fasting) and / or insulin or oral hypoglycemic drug] (within the past 2 years),
c. HDL cholesterol <35 mg / dl (on any of two measurements within the last 5 years),
d. Left ventricular hypertrophy (one of the following) on any ECG within the past two years:

e. Left ventricular hypertrophy on any echocardiogram (within the past 2 years), based on the thickness of the combined walls (ventricular septum + posterior wall) greater than 25 mm.
f. Current smoking (any cigarette that has been smoked within the last 30 days).

Five. Exclude:
a. Symptomatic MI or stroke within the last 6 months.
b. Hospitalized or treated symptomatic congestive heart failure and / or ejection fraction <35% (if known).
c. Angina pectoris within the past 6 months (this means actual chest pain. If a patient has a history of angina and no history of chest pain, he / she may take anti-anginal medications. This exemption does not apply even if taken, see Exclusion 5e).
d. Known renal failure (serum creatinine > 2 mg / dl).
e. Patients who need diuretics, calcium antagonists, ACE inhibitors or adrenergic alpha blockers for reasons other than high blood pressure (if the patient is taking calcium channel blockers for angina, he / she If considered, it can be changed to a beta blocker for this indication, in which case this exclusion criterion would not apply).
f. Patients who require 3 or more antihypertensive drugs to achieve satisfactory blood pressure suppression (SBP < 160 mmHg and DBP < 100 mmHg). Patients taking three or more antihypertensive drugs in sub-therapeutic or ineffective combinations, and patients who appear to be able to be suppressed with the ALLLHAT protocol, are at the discretion of the study director or his / her designee. It is possible to participate in the trial. See IV A3 (a).
g. Sensitivity or contraindications to any of the first-line test drugs.
h. Factors that suggest a low likelihood of complying with the protocol, such as dementia, a history of alcohol or drug abuse within the past 6 months, a long-distance move or long-term trip, or a promise Unreliable history of taking prescription drugs.
i. Diseases such as incurable malignancies that can die from non-cardiovascular disease during the trial.
j. Blood pressure greater than 180 mmHg systolic or greater than 110 mmHg diastolic during two separate measurements during the step-down of antihypertensive medication.
k. I am currently participating in another clinical trial.

B. Cholesterol reduction test
1． Eligible and registered in anti-hypertension trials.
2． Fasting LDL cholesterol: 120-189 mg / dl (100-120 mg / dl in patients with known CHD). These cutpoints roughly correspond to the 30th and 90th percentiles in men and the 25th and 85th percentiles in women in the ALLHAT age range, approximately 60% (24,000) of ALLHAT participants (20,000 of them) Will remain after refusal or other exclusions).
3. Fasting triglyceride levels below 350 mg / dl.

Four. Additional exclusion
a. Current use of prescription lipid-lowering drugs or higher doses ( > 500 mg / day) of non-prescription niacin. Eligible patients should have taken lipid-lowering drugs for at least 2 months and probucol for a year or more on the second visit.
b. Contraindications to HMG CoA reductase inhibitors (eg significant liver disease, under treatment with immunosuppressive therapy, known allergies or non-tolerability to study drug).
c. Known untreated secondary causes of hyperlipidemia (eg hypothyroidism, nephrotic syndrome).
d. ALT> 2.0 x normal upper limit.

V. Registration
Enrollment for ALLHAT is primarily based on medical history review to identify patients with potential eligibility for the anti-hypertensive study category or both study categories. The data needed to make a definitive determination of eligibility for the antihypertensive trial category is generally obtained in a series of preliminary random visits conducted over a period of 2 months or less. The number and frequency of those visits will depend on the complexity of the patient's preliminary study plan, the blood pressure response to step-down from that plan, and the patient's suitability and interest in the cholesterol lowering test category. Since only patients randomized to the anti-hypertensive trial category are eligible for randomization to the cholesterol-lowering study category, randomization to the latter will be performed after the first randomization for the anti-hypertensive study ( 4 weeks) will not be held until the visit. The process from identification of these various categories of potential ALLHAT candidates to randomization in one or both trial segments is described below.

Medical history review:
At each clinical laboratory, a history review will identify patients who may have potential fitness for the antihypertensive category of ALLHAT and a subpopulation of such patients who may also be eligible for the cholesterol lowering category of ALLHAT . Treatment of blood pressure and hypertension, LDL cholesterol (or total cholesterol if LDL is unknown) and cholesterol-lowering diet and / or drugs, or other related medical history, and patient confidence in previously prescribed treatment and The impression of compliance should be reviewed in accordance with the test conformance requirements (Chapter IV) prior to his / her first test visit.

A. Antihypertensive Trial Category Visit 1: Preliminary Determination of Eligibility and Interest The purpose of Visit 1 (First Visit) is to assess eligibility and interest in ALLHAT and to administer any existing antihypertensive drug to the patient Is to start interrupting. The majority of treated hypertensive patients are expected to have been identified by medical review, and most of the relevant information (age, risk factor status, number of antihypertensive drugs, etc.) is expected to be already known. Researchers are required to complete a one-page questionnaire to demonstrate that all preliminary inclusion and exclusion criteria (Chapter IV) are met. Not obtained by medical history review or within the past 2 years (ECG to assess the presence of left ventricular hypertrophy, fasting blood glucose level for diabetes, total cholesterol (TC) level to assess lipid eligibility) or past 5 Any evidence not available within a year (2 measurements of HDL) is considered part of the patient's normal medical care and is not specifically compensated for by this trial.

  Visit 1 will mainly obtain first blood pressure measurements for enrollment, answers to patient questions regarding this study, and patient informed consent to begin reducing pre-test antihypertensive drugs as needed It becomes more. Recommendations for discontinuing antihypertensive medication are included below. If the patient's change in antihypertensive medication can be safely done without tapering, the participant can proceed directly to Visit 2. Visits 1 and 2 should occur at least one day apart but need not be consecutive visits.

For untreated patients, a diagnosis of hypertension according to the JNC V criteria must be established. Once this is done, patients with SBP > 140 mmHg and / or DBP > 90 mmHg and patients with SBP and DBP of 180 mmHg or less and 110 mmHg or less (see Table IV.1) may also be eligible for ALLHAT enrollment. For new patients found to have increased blood pressure at the first visit to the clinical laboratory, this first visit may be ALLHAT visit 1. However, all additional evaluations necessary to determine test eligibility must be performed (without hindering the test). The subsequent course of such patients is simplified because there is no need for reduction from the preliminary study drug regimen.

Reduced visits:
Not all patients taking antihypertensive drugs require a step-down visit. In general, the following categories of antihypertensive drugs can usually be interrupted without tapering:
1． Diuretic: The patient should be informed to contact a physician if significant enhancement of significant edema and / or dyspnea (shortness of breath during night or intense activity) occurs to him / her.
2． Reserpine.
3． Angiotensin converting enzyme (ACE) inhibitor.
Four. Calcium channel blocker.
Five. Vasodilators (eg, hydralazine).
6． α ₁ blocker (eg, prazosin).

If the patient is taking more than the usual starting dose, the following categories of drugs need to be gradually reduced:
1． Central antagonists (eg oral clonidine or methyldopa)-tapering over 1-2 weeks.
2． Adrenergic beta blockers (eg, propranolol or atenolol)-gradual decrease over 2 weeks.

  Patients after myocardial infarction receiving beta-blockers for prophylaxis do not need to discontinue treatment. In physician judgment, closer monitoring or longer interruptions may be preferable. Further care should be taken in the gradual reduction of antihypertensive drugs in patients with cardiovascular disease.

  Patients with blood pressure above systolic 180 mmHg or diastolic 110 mmHg should revisit within a few days for repeated blood pressure measurements. If blood pressure is still above 180/110, the patient should not be randomized to an anti-hypertensive trial.

Visit 2: Randomization:
Meets all ALLHAT eligibility criteria, and can safely discontinue all previous antihypertensive drugs at the discretion of the investigator and can be randomized to one of four ALLHAT treatment groups Patients will proceed to Visit 2 trials after obtaining their informed consent. This visit will generally take place from 1 day to 12 weeks after Visit 1, depending on the length of time that needs to be reduced from the pre-test medication. Patients who are not initially taking drugs or are well controlled with one drug can be randomized immediately after visit 1, but other patients are longer before they can complete visit 2. A reduction process (typically less than 3 months) may be required. Longer reductions are not allowed (unless prohibited). This is because a large number of patients who cannot be interrupted quickly from a preliminary study plan can be more difficult to maintain in a simple plan during the study.

  The researcher calls the Clinical Trials Center for each patient who meets all eligibility requirements on Visit 2, including a signed consent form. The clinical trial center reviews eligibility and exclusion criteria and assigns the patient a study patient identification number, (1) chlorsalidon, (2) amlodipine, (3) lisinopril, or (4) doxazosin (24 January 2000) On the day, a recommendation was received by NHLBI to discontinue the doxazosin department of the antihypertensive trial. See JAMA. 2000; 283: 1967-1975). The treatment assignment is not known to either the practitioner or the patient. Resting electrocardiogram, serum glucose, serum potassium and creatinine, fasting lipid profile and ALT should be obtained for all randomized patients at this visit. Each randomized patient is instructed to provide an appropriate supply of his / her starting dose of the assigned study drug and to be revisited for the first dose titration (Visit 3) after 4 weeks (See Section VI).

  All randomized patients receive appropriate hygiene advice (sodium and alcohol restrictions, smoking cessation, exercise, caloric restriction in case of overweight) and are strengthened as needed during the study.

B. Cholesterol-Lowering Test Category Visit 1: Preliminary Eligibility and Interest Assessment Meets all Visit 1 eligibility requirements (see above) for the anti-hypertensive test category and / or begins to reduce from pre-test antihypertensive drugs Patients who agree should also be informed about the ALLHAT cholesterol lowering test category. Those who have shown possible interest in this study category and have not been treated with lipid-lowering drugs (including over 500 mg / day of the OTC drug niacin) in the 2 months prior to Visit 1 It shall be considered a potential candidate. Patients taking probucol within 1 year prior to Visit 1 are ineligible for this study category of ALLHAT.

Visit 2: Fasting LDL measurement (randomized to anti-hypertensive test category)
For eligible patients who are randomized to the ALLHAT anti-hypertensive trial category, obtain a fasting lipid series (total cholesterol, triglycerides, HDL cholesterol, calculated LDL cholesterol) and serum ALT. Patients who have not fasted for at least 9 hours (optimally 12 hours) should be rescheduled for blood collection within the week of Visit 2. This is considered part of Visit 2 if resetting is required due to fasting lipids.

Visit 3 or 4: Randomized Patients with a fasting LDL-C of 120-189 mg / dl (100-129 mg / dl in patients with known CHD) and a fasting TG of 350 mg / dl or less in Visit 2 Call to inform them that you are eligible for the cholesterol-lowering test category and visit 3 to be hungry. If they signed an informed consent to participate in this ALLHAT category at Visit 3, the researcher would call a clinical trial center to review eligibility and exclusion criteria for the lipid lowering category and to pravastatin or regular care Receive a random assignment of patients. Each patient randomized to receive pravastatin is instructed to provide an appropriate supply of 20 mg tablets and to take two every night. Patients who are usually assigned to care are not prescribed any lipid-lowering drugs by ALLHAT. Patients assigned to regular care and patients assigned to pravastatin are instructed to follow the NCEP Stage 1 diet (less than 30% fat-derived calories, less than 10% saturated fat-derived calories, less than 300 mg / day cholesterol). At this visit, a fasting lipoprotein profile is obtained as a baseline for each randomized participant in this study segment.

Maintaining the racial composition of ALLHAT
Before these clinics are selected as clinical laboratories for ALLHAT, potential study researchers are asked to show the approximate proportion of American black patients they expect to enroll in the study. Clinical laboratories will be selected to provide an overall study population that includes at least 55% of American blacks and will be monitored by clinical trial centers throughout the study to ensure that implementation is in line with expectations. If the overall proportion of American blacks appears to be significantly less than 55%, the Steering Committee will temporarily freeze the registration of non-American black patients in some or all existing clinical laboratories. Improvement measures such as the addition of new clinical laboratories to correct deficiencies may be implemented.

VI. Antihypertensive Intervention All four trials (NHLBI accepted a recommendation to discontinue the doxazosin division of the antihypertensive trial on January 24, 2000. See JAMA. 2000; 283: 1967-1975) Blood pressure target values in diastolic are less than 90 mmHg and systolic less than 140 mmHg (these values are in accordance with Fifth Joint National Committee recommendations [10]. Strong epidemiology between systolic blood pressure and CVD mortality [59] JNC has set a lower systolic target value than that used in SHEP, which is 140-159 mmHg (average achieved value is 142 mmHg) is there). The number and dose of test drugs prescribed to achieve these goals is influenced by patient acceptance and clinical judgment, especially when using a regimen of three or more drugs. With rare exceptions, patients with blood pressure values of systolic 160 mmHg or higher and / or diastolic 100 mmHg or higher must be added with a low-dose drug in the same class as the blinded stage 1 drug Even so, treatment should be strengthened.

  The therapeutic goal is to achieve blood pressure suppression at the lowest possible dose of a first-line drug. Second-line (unblinded label) drugs should be left for patients who have insufficient maximum dose levels of first-line drugs.

Each of the four first-line drugs (NHLBI accepted a recommendation to discontinue the doxazosin department of the anti-hypertensive trial on January 24, 2000; see JAMA. 2000; 283: 1967-1975) Dosage once daily in the morning. The following dosage levels are available for each drug.

  The drug type is blinded at each dose level, but the dose level itself is not blinded. Minimizing the potential side effects of doxazosin (January 24, 2000, the recommendation that the doxazosin division of the antihypertensive trial should be discontinued is accepted by NHLBI; see JAMA. 2000; 283: 1967-1975) To limit, the initial dose level is used only in the first week after randomization. Visit is not necessary.

  Reassess all patients for dose titration as needed at least at 1 month (visit 3) and at 3 months (visit 4). Test dosing begins with the initial dose. Patients should typically visit at monthly intervals for dose increases that may be necessary.

IX. Measurement of results The occurrence of test endpoints is demonstrated by a checklist completed by the test physician at each follow-up visit, supplemented by interim reports as necessary. As described below, these diagnoses are supported by a discharge summary and a copy of the face sheet and death certificate. The following outcome measures are taken and summarized throughout the course of the test.

A. Death (proven by death certificate)
The underlying causes of death are categorized by clinical laboratory physicians and researchers as follows: (1) coronary heart disease, (2) other cardiovascular diseases, (3) proliferative diseases, (4) Other medical causes, or (5) non-medical causes. Near the end of the study, a National Death Index (NDT) Search is performed to identify and substantiate deaths that may have occurred in unfollowable patients. Due to the time lag inherent in NDI, private search agencies are also used for selected participants. Physicians are also required to report the cause of death on the study endpoint document.

B. Cardiovascular endpoint
1) Myocardial infarction (provided by discharge summary or face sheet or bi-day electrocardiogram) (including suspected myocardial infarction with thrombolytic therapy)
2) Stroke (proven by discharge summary or face sheet)
3) Congestive heart failure
a) Hospitalization or treatment (proven by discharge summary or face sheet)
b) Not hospitalized but treated (provided by endpoint questionnaire check box)
4) Angina pectoris
a) Hospitalization or treatment with (i) or without (ii) revascularization treatment (proven by discharge summary or face sheet)
b) Not hospitalized but treated (provided by endpoint questionnaire check box)
5) Peripheral artery disease
a) Hospitalization or treatment with or without (ii) revascularization treatment (provided by discharge summary or face sheet) or outpatient revascularization treatment (provided by treatment sheet)
b) Outpatient medical treatment (proven by check box on endpoint questionnaire)
6) Left ventricular hypertrophy (proven by bi-day electrocardiogram)
LVH inclusion criteria are based on specific ECG criteria listed in IV.A.4.d and are interpreted in clinical laboratories. Reread the ECG in the middle to assign Minnesota Codes. Results criteria for LVH are based on Minnesota Codes. To identify the dominant LVH, the Minnesota Coding Center uses Code 3-1 or 3-3. These series of amplitude criteria are generally considered "probable ECG-LVH", but any 4 to 3 or more severe 4-code or 5 to 3 or more severe 5-code When combined with it, it is considered “definite ECG-LVH”.
Minnesota Code 3 to 1: V ₅ or R amplitude in V _6> 26 mm or inductive I, II, III, R amplitude in R amplitude> 20 or inductive aVL, either in aVF> 12 mm,.
Minnesota Codes 3–3 : R amplitude at V ₅ or V ₆ + S amplitude at V ₁ > 35 mm, or R amplitude> 15 mm but < 20 mm (in lead I).
The Coding Center also demonstrates incident ECG-LVH and ECG-LVH progression / regression through continuous FCG comparisons.

C. Other endpoint
1) Decreased renal function (as demonstrated by the reciprocal of the slope of serum creatinine level versus time in successive measurements)
2) End stage renal disease (start of chronic dialysis, kidney transplantation)
a) Hospitalization or treatment (proven by discharge summary or face sheet)
b) Outpatient treatment (proven by check box on endpoint questionnaire)
3) Cancer: site and type
a) Hospitalization or treatment (proven by discharge summary or face sheet)
b) Outpatient treatment (proven by check box on endpoint questionnaire)
4) Non-lethal accidents and attempted suicide
a) Hospitalization or treatment (proven by discharge summary or face sheet)
b) Outpatient treatment (proven by check box on endpoint questionnaire)
5) Gastrointestinal bleeding
a) Evaluation with data from Health Care Finance Administration and Department of Veterans Affairs
6) Quality of life: Use a general category scale of health status to assess health-related quality of life.
7) Medical use: Collect usage data through interviews. Costs are allocated to each usage unit (hospital, visit, treatment, etc.) based on its DRG. It also asks one question to determine the quality of life on a continuous scale to determine quality adjusted life years. These interview data will be checked against medical records for 10% specimens of patients over 65 years of age.
The study investigator is required to complete and submit to the clinical trial center a short endpoint questionnaire for each occurrence of the study endpoint identified during or during the regular visit. For each endpoint, including death or hospitalization, the researcher will obtain and submit a discharge summary or face sheet or copy of the death certificate from which the diagnosis was made. For randomized (10%) subpopulations of hospitalized (lethal and non-fatal) myocardial infarction and stroke, hospitalized ECG and enzyme levels (for myocardial infarction) and neurologist and CT and / or MRI reports To ensure that (in the case of a stroke) can be assessed by the Trial Endpoint Committee and the accuracy of discharge diagnosis (as defined in Appendix I) can be assessed, Request more detailed information.

X. Test organization
Overview:
ALLHAT utilizes a tissue structure that differs significantly from clinical trials supported by regular NHLBI. The trial will be conducted by a large number (600) of practitioners-researchers who will be compensated based on the percentage of each patient found on the fixed payment schedule. Approximately 20% of study patients are expected to be enrolled by the Department of Veterans Affairs (VA) hypertension clinic. In addition to its normal data processing and monitoring responsibilities, the clinical trial center will make these doctor-researcher decisions and payments, hire a regional liaison coordinator to monitor registration and compliance, and the central laboratory and Responsible for providing and subcontracting the ECG decoding center. The Steering Committee is appointed according to the expertise in the relevant subject areas. A detailed explanation of the nature and role of the test categories is given below.

Program Office
The program office is located in NHLBI, Division of Epidemiology and Clinical Applications (DECA) and Division of Heart and Vascular Diseases (DHVD), which provides contracts to monitor and fund VA clinics Prepare an agreement to provide and secure an IND for this trial. The NHLBI Director appoints the Data and Safety Monitoring Board (DSMB) and the Steering Committee chair and vice chair. With the consent of the NHLBI Director, the Program Office will appoint a Steering Committee and any other committees that may be needed to advise NHLBI on issues related to the progress or results of this study.

Clinical Trials Center :
The clinical trial center will determine the appropriate clinics to participate in ALLHAT, pay them according to the flat fee system for each randomized patient, complete the trial form, and use the data from this trial. Responsible for editing, storing and analyzing. Its researchers and staff play a central role in designing data collection systems and monitoring data quality. Specific clinical trial center responsibilities include:

1) Development, preparation and distribution of test protocols, data formats and manuals of operations and procedures.
2) Appointment and remuneration of a practitioner providing a clinical laboratory for the conduct of this study.

3) Appointment of regional liaison coordinator and payment of remuneration (see below).
4) Approval of the Obtaining Institutional Review Board (OPEN) for undisclosed practices.
5) Storage of annual accounting disclosure statement files to the Steering Committee members to identify potential conflicts of interest.
6) Subcontracting contracts with the central laboratory and ECG decoding center to obtain the timely and standardized measurements necessary for this test.
7) Subcontracting to a drug delivery center to deliver bottles and labels and deliver test drugs to clinical laboratories.
8) Monitor the implementation of test categories and submit timely summary reports to the program office and steering committee.
9) Monitor the proportion of American blacks in each clinical laboratory during enrollment and if the overall rate for the study appears to be significantly below the target of 55% Recommended corrective measures.
10) A detailed and up-to-date statistical report of the progress of the study should be submitted to the Data and Safety Monitoring Board (DSMB) at its semiannual meeting.
11) Maintain a referral network of study participants who have moved to a new area and are unable to continue with the original investigator.
12) Providing minutes for test meetings and logistical support (if necessary).
13) Coordination and supervision of endpoint confirmation work.
14) Initiation of the National Death Index survey to determine the life status of unfollowable patients at intervals recommended by the DSMB and the steering committee (see below).
15) Preparation of test manuscripts in collaboration with the steering committee.

Clinical Site :
These consist of 600 separate clinics appointed by the clinical trial center to conduct this trial. It is anticipated that some clinics will provide a large number of patients (especially VA clinics, HMOs and large group clinics), while other clinics may provide fewer than 100 patients. In addition, the proportion of American blacks is expected to vary from clinic to clinic, but is closely monitored to ensure that the overall 55% target is met (see Chapter V).

  Each clinical laboratory is expected to be under the supervision of a physician certified to be responsible for the implementation of ALLHAT. However, depending on the internal organization of the clinic, a doctor's assistant or nurse or other appointed person may complete the test document. At each laboratory, one support staff member must be appointed as the primary responsibility for the implementation of the protocol. This person attends central training and annual meetings. Payment for each patient randomized to each ALLHAT segment and for completed study visits will be made by the Clinical Trial Center upon receipt of the relevant completed and properly signed study documents.

Regional Coordinator :
Regional Liaison Coordinators are physicians with expertise in the treatment of hypertension and cholesterol lowering, and they handle routine protocol questions individually for about 50 clinical laboratories. Under the supervision of a clinical trial center, they help solve problems related to quality control, protocol adherence, registration, and maintenance of the clinics assigned to them. The doctor coordinator is assisted by the nursing coordinator and can choose to participate as a clinical laboratory. All participating VA hypertension clinics are supervised by a single coordinator.

Drug Distribution Center
The drug delivery center will (1) receive, package and deliver all the medicines required for the two ALLHAT categories, and (2) the four first-line antihypertensive drugs will be distinguished from each other by the study investigator or their patients. A clinical trial to ensure that no blinded antihypertensive drugs are blinded (2) and that appropriate and timely supply of all study drugs to clinical laboratories Ordered by the center.

Steering Committee :
The Steering Committee will provide expert advice on the study protocol and on all decisions related to subsequent study planning and implementation that do not require access to blinded data, and the final analysis and publication of study results As appointed by NHLBI. Its voting members include NHLBI planning officers, clinical research center director researchers, community liaison coordinators, and expertise and experience in the treatment of hypertension and / or hyperlipidemia and in critical clinical trial issues (eg registration and adherence) 7 to 9 professionals who have been bought and appointed. Each Steering Committee member should submit an annual accounting disclosure statement to the clinical trial center and all stock or holding advisors in pharmaceuticals and other companies that have a direct economic interest in the results of this trial. You are asked to let go of your position. The Steering Committee meets once a year (more often during protocol development).

  An executive committee is established to oversee the conduct of the study during the steering committee meeting. Executive committee members include the chairman and vice chairman of the steering committee and representatives of the program office, clinical trial center and Department of Veterans Affairs. The following subcommittees report to the executive committee: Eligibility and Medical Care, Operations, Publications and Ancillary Studies, Scientific and Educational Program , As well as the Endpoint. These subcommittees are responsible for testing aspects that require frequent attention and / or special expertise (eg, registration, adherence, quality control, blood pressure and lipid interventions, testing methods, endpoint validation, ancillary testing, publication and research) Has delegated delegates from program offices, clinical trial centers and steering committees to oversee the annual program).

Protocol Review Committee:
The Protocol Inspection Committee is responsible for advising NHLBI on the initial approval of the study protocol. Its members and chairman are appointed by the NHLBI director and consist of at least seven other experts not otherwise involved in the study. Once the test protocol is complete, it will meet in Bethesda. This meeting will be attended by the director of the clinical trial center (and the appointed staff), as well as the Steering Committee chair and vice-chairman who will make presentations and answer questions about the protocol, as well as program office staff.

Data and Safety Monitoring Board (DSMB) :
The DSMB is responsible for monitoring all aspects of this study, including those requiring access to blinded data. The DSMB and its chairman are appointed by the NHLBI Director and consist of at least seven other experts not otherwise associated with the study. Most or even all members of the DSMB member are dispatched from the Protocol Inspection Committee, which completes its dispatch when the DSMB is configured.

  DSMB meets at least every six months. Researchers at the clinical trial center and appointed clinical trial center staff attend these meetings (but do not have voting rights) and produce and publish the latest statistical reports on the progress of the trial. These reports include data on enrollment, randomization, adherence, blood pressure levels, plasma lipoproteins, adverse drug response and study endpoints, as well as statistical tests and special analyzes required by DSMB. The Project Director (who is the DSMB Secretary General), the Project Officer and the appointed NHLBI staff, as well as the Steering Committee Chair and Vice-Chairman, are also authorized by these functions. Join the meeting.

  In the ongoing enrollment phase, the DSMB monitors the progression of enrollment (especially American black patients) and randomization of participants in various treatment trials, and either or if the study plan goals are not met Changes in both test categories (or their termination) may be recommended. The DSMB will indicate when the ongoing study enrollment phase should be terminated. Any significant changes in the protocol presented by the steering committee during the course of the study will also require DSMB approval. All votes are determined by a simple majority.

  At any time during this study, DSMB may recommend discontinuing any treatment study in any study category for any of the following reasons:

1) immovable evidence from this or another study of adverse effects of study treatment sufficient to negate any potential benefit to CHD and exclude further use of study treatment in the target population;
2) There is immovable evidence from this or another study of the significant beneficial effects of the study, and its continued denial against other study groups cannot be ethically supported;
3) Due to improper registration, compliance, drug response, event rate, etc., the probability of successfully examining the test hypothesis within a feasible time frame is very low.

The DSMB can convene an Executive Session at any time. DSMB members, Project Directors and Project Officers attend these meetings.
The NHLBI Director will make a final decision on whether to accept the DSMB recommendation to discontinue any segment of this study.

XI. Data management
Report distribution Create at least five types of reports.
1) Registration reports: These are expected to be prepared at least weekly by clinic and region and for anti-hypertension and lipid lowering studies. These will be distributed to the Project Office, Steering Committee and Regional Liaison Coordinator.
2) Other regular monitoring reports include data on visits and medication adherence, quality control and trial endpoint validation. These are created at least monthly by the clinic and the region and distributed to the Project Office, Steering Committee and Regional Coordinator.
3) Randomized proof reports, visit plans and reminder endpoint proof reports and limited cross-forms edits for clinic use reports. These are created at most once a month. Visit plans are created when participants are randomized and include special procedures that are anticipated for all visit times and the duration of the study. Reports and appropriate listings are sent to the clinic, and summary reports are sent to the Project Office, Steering Committee, and Regional Coordinator.
4) Steering Committee reports are prepared for annual meetings and are similar to regular registration and monitoring reports.
5) Data and Safety Monitoring Board reports include registration and monitoring data by treatment group for both antihypertensive and lipid lowering studies. They include data from central laboratories as well as summary reports of bi-day and event ECG data, and study endpoints by treatment group.

Quality Control All clinical laboratories are required to participate in one of three regional training sessions. These training sessions include study protocol orientation, blood pressure measurement training and certification, electrocardiographic orientation, and study writing and sending training.

  Regular re-learning training will be conducted along with regularly planned steering committee meetings. These re-learning sessions may include a review of correct blood pressure measurement methods and a review of any issues found during normal monitoring activities.

  All documents are examined for completeness and accuracy at a clinical trial center prior to data entry. Any problems found are resolved by telephone or facsimile transmission with a clinical laboratory. Next, input the test document twice. Perform limited cross-forms edits to identify missing documents and procedures.

Deblinding In some special cases (eg, medical emergencies), the patient's assigned treatment group may be revealed. The regional liaison coordinator will be at the forefront and advise on deciding whether to eliminate blinding. If the liaison coordinator cannot arrive, the investigator should contact someone at the other liaison coordinator, or Dr. Davis or Goff at the Clinical Trial Center, or Dr. Payne or Cutler at NHLBI for appropriate medicine. Should be consulted. Efforts will be made to maintain blinding of patients and clinical center researchers if medically appropriate. If the regional liaison coordinator agrees or if the investigator persists, the investigator should contact the clinical trial center to determine the deblinded treatment assignment. If an emergency occurs and the clinical trial center cannot be reached, the investigator will assign a deblinded treatment by contacting the deblinded facility.

  If it is determined that blinding needs to be resolved, the clinical researcher records the situation on a one-page document. This document is sent to a clinical trial center and entered into the master file as a permanent record part of the patient's test record.

Discontinuation of study medication If the investigator believes that the study treatment needs to be discontinued due to side effects or other symptoms at the discretion of the physician, it may not be necessary to eliminate the blinding of the patient. unknown. The regional liaison coordinator is at the forefront and advises in deciding whether to discontinue the study treatment for the patient. If the regional liaison coordinator agrees or if the researcher persists, the researcher will contact the clinical trial center to inform them that this action is being taken and why.

Reimbursement clinical laboratories will be reimbursed on a per capita basis for each randomization to antihypertensive trials, randomization to lipid lowering trials, each follow-up visit required by the protocol, and each completed study endpoint . These payments are made monthly from the clinical trial center. In order for a reimbursement to be formally recognized, a test document must be received at a clinical trial center, all questions relating to that document must be resolved, and that document must be entered into the study database. . In the case of study endpoints, there are separate reimbursements in several parts for the study document itself, for death certificates or discharge summaries, and for additional proofs for 10% specimens for proof.

Data analysis
The primary endpoint of the ALLHAT antihypertensive category is lethal + non-fatal CHD. The main response variable is the time from randomization to the occurrence of this event. Each non-diuretic treatment group is compared to the diuretic treatment group using a log rank test [60]. Mortality from all causes, stroke, concurrent coronary (CHD + revascularization + hospitalized angina) and cardiovascular disease (CHD + stroke + revascularization + angina [hospital or treatment] + CHF Log rank test is also used for outcomes of [hospitalization or treatment] + peripheral arterial disease [hospitalization or outpatient revascularization]] and secondary endpoints of end-stage renal disease. The log rank test is also used to test whether there is a therapeutic difference in the following subgroups for fatal and non-fatal CHD: 1) males and females, 2) 65 years and older and under 65 years, 3) American blacks, and 4) Diabetes and non-diabetes. For ECV LVH results and health-related quality of life, we use ratio comparisons to see if there are differences in treatment groups. For kidney disease outcomes, the reciprocal of the slope of each participant's creatinine is calculated. The weighted average of the reciprocal number of participants in each treatment group is calculated and these averages are compared between groups using the longitudinal model of Laird and Ware [61].

  The primary endpoint of the ALLHAT lipid-lowering category is mortality from all causes. The main response variable is the time from randomization to death. A log rank test is used to compare the group assigned to lipid lowering treatment with the group assigned to non-treatment. Log rank tests are also used for fatal and non-fatal CHD, fatal and non-fatal cancers and secondary endpoints for cause-specific mortality. The log rank test is also used to test whether there is a therapeutic difference in the following subgroups for fatal and non-fatal CHD: 1) males and females, 2) 65 years and older and under 65 years, 3) American blacks, and 4) Diabetes and non-diabetes. For electrocardiogram MI results and health-related quality of life, we use ratio comparisons to see if there are differences in treatment groups.

Interim monitoring and analysis (see protocol appendix 2)
Interim monitors include patient ingestion (overall and within the clinical center), adherence to protocols, baseline comparability of treatment groups, event rates, sample size assumptions for crossover risk and unfollow-up, side effect data, and primary and secondary Focus on the effect of treatment on the outcome of the next trial. Interim analysis will be conducted in conjunction with the Data and Safety Monitoring Board (DSMB) meeting.

We recommend that DSMB use stochastic curtailment to monitor therapeutic differences in both hypertension and lipid lowering studies [62,63]. Assuming that the current data and assumptions are true, if the conditional probability of rejecting the null hypothesis (H ₀ ) at the end of the planned test is greater than or equal to some predetermined value γ ₀ Depending on the method, _a favorable termination for the alternative hypothesis (H _a ) can be considered. Alternatively, if the conditional probability of rejecting H ₀ under an alternative hypothesis established by the plan is less than a certain predetermined value γ ₀ , an advantageous termination to the null hypothesis will be considered. With this approach, type 1 errors increase slightly beyond α (depending on the number of data surveys, timing of the survey, and the value of γ ₀ ), and type 2 errors increase slightly beyond β. (This again depends on the number of data surveys, the timing of the surveys, and the value of γ ₀ ). The selection of γ ′ is determined by DSMB.

  These monitoring methods are presented as guidelines for the complex and subjective decisions that DSMB must make when considering whether to continue or end randomization and / or follow-up at each DSMB meeting. Yes.

Hypertension test In this study, we compared three comparisons of interest: diuretic and angiotensin converting enzyme inhibitor, diuretic and calcium channel blocker, and diuretic and alpha blocker. Comparison with drugs (NHLBI accepted a recommendation to discontinue the doxazosin section of the anti-hypertensive trial on January 24, 2000; see JAMA. 2000; 283: 1967-1975). Each comparison has its own monitoring guidelines by the Dunnett method with α = 0.019. Figure 1 shows the 80% stochastic curtailment boundaries for each of these comparisons. This investigation depends on the information time (number of recorded CHD events divided by the number of expected CHD events) in the calendar time of the Data and Safety Monitoring Board meeting. .

  Due to the lack of power to show the effect, it would be desirable to use the rules for cancellation. Here we also present the use of probabilistic simplification or conditional power. If the conditional power under the proposed alternative hypothesis is less than 10%, discontinuation may be considered. Figure 1 also shows this conditional power boundary.

  In the hypertension test, total mortality is also monitored.

Lipid reduction test For this test, we also present a method similar to that for the hypertension test. In this case, however, only one comparison (mortality due to all causes) is performed at α = 0.05. Figure 2 shows the monitor boundary.

XII. Initial Phase The first six months of this study include an initial phase for full scale testing. Twenty clinics are selected to perform this initial phase aimed at randomizing 600 patients (out of a total of 40,000). Early stage objectives include:

  1． To determine the feasibility of enrolling and tracking outpatient hypertensive subjects in practicing clinics and hypertension clinics.

  2． Determine the percentage of subjects with anti-hypertensive testing who are eligible and willing to participate in the cholesterol lowering study.

  3． Optimize methods for enrolling black American participants at a rate of at least 55%.

  Four. Develop methods to maximize adherence to antihypertensive and cholesterol-lowering drug regimens in outpatient hypertensive subjects.

  Five. Optimize the method for maintenance of outpatient hypertensive subjects in the practicing clinic.

  6． Develop methods for standardized endpoint confirmation in practicing clinics and hypertension clinics.

  7． Evaluate and optimize the effectiveness of various practices such as drug delivery, Institutional Review Board approval, training, and activities involving community liaison coordinators.

  Once the initial phase confirms the basic feasibility of this protocol, any necessary modifications are made and additional clinics are registered as needed to meet the enrollment goals of this study.

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Appendix I: Sample size calculation
Power calculations for ALLHAT were performed separately for the anti-hypertensive (AH) and lipid-lowering (LL) categories. In the case of the AH category, power was based on a two-sided comparison between diuretics and each of the other drugs, using an overall first-class error rate of .05. This was achieved using Dunnett type adjustment for multiple comparisons. In the case of the LL category, no adjustment was necessary because only one comparison was made.

  In order to estimate power for ALLHAT, we had to identify the expected event rate, treatment effect, and the rate of untrackable and crossover due to competitive risk or other reasons.

Antihypertensive category The CHD rate for diuretics was estimated to be about 1.35% / year (six-year rate was about 7.8%) using the traditional method. This was based on an exponential regression model applied to the data from Framingham 12, Framingham 16, and HDFP. From the data of Framingham, all hypertensives aged 45 to 75 years were added except those with a recent (within 2 years) MI. Variables included in this model were age, gender, and whether the patient was at high risk (defined as meeting ALLHAT inclusion criteria). The ratio was adjusted to an average age of 67 years and a male prevalence of 55%. A similar analysis was performed on HDFP data. This data included those over 50 years of age. The HDFP stepped and referred care cohorts were analyzed separately. The following discounts were applied on long-term trends and healthy volunteer effects:

For example, the estimated annual event rate from the exponential regression of Framingham 12 was multiplied by (1-1 / 2) 1-1 / 4) = 3/8. Estimated event rates based on exponential regression adjusted for long-term trends and healthy volunteer effects were as follows:

  We thought that an annual CHD rate of 1.35% was reasonable. The SHEP rate was slightly higher. Since the SHEP rate automatically includes the effect of healthy volunteers, which was a recent trial, the rate will not require much long-term trend adjustment. We decided to consider the event rate range of 1.05% / year to 1.65% / year.

  The crossover rate was estimated from TOMHS. A time-dependent Markov model was fitted to the data. A model that assumes a probability of 2.75% in each year for the first 3 years and 6% for the last 3 years of the crossover for another drug appears to fit well (see FIG. 1). In this model, about 24% of all patients crossover to another drug at least once in 6 years, and about 21% of all patients to another drug at the end of 6 years. Will cross over. Patients in a diuretic trial crossing over for another active antihypertensive drug are hypothesized to show a reduced event rate even if some of the other antihypertensive drugs cannot benefit . A patient in an active antihypertensive trial that crosses over to another antihypertensive drug may have the patient crossed over to another antihypertensive drug that is as beneficial as he / she has been assigned Even if sex is present, it is assumed to show an increased event rate consistent with diuretic testing. The patient can cross over and then cross back. Since physicians can afford to choose from a wide variety of second-line antihypertensive drugs, it is assumed that the percentage of patients not taking any drugs is negligible. Although this assumption is somewhat anti-conservative, it is believed that it is offset by the conservative assumption suggested above. We also considered two other ratios, the probability of 22% and 26% respectively crossing over at least once. These correspond to approximately 20% and 22.5% of patients with another drug at the end of 6 years, respectively (see FIGS. 2 and 3). The latter ratio seems very conservative. The three ratios of 22%, 24% and 26% for at least one crossover will hereinafter be referred to as crossovers 1, 2 and 3, respectively.

  The loss from competing risk was estimated at about 8% over 6 years. This consisted of other cardiovascular mortality (2.6% over 6 years) and non-cardiovascular mortality (5.4% over 6 years). These ratios were calculated in the same way as the event rate for the primary endpoint was determined. The same healthy volunteers and long-term trend adjustment were applied. Adding about 1.5% / year for follow-up, resulting in a total loss rate of about 16.8% over 6 years. Two other loss rates of 16.8% ± 5% were considered. The three loss rates of 11.8%, 16.8%, and 21.8% are hereinafter referred to as loss rates 1, 2, and 3, respectively.

  To calculate the power for the AH category, the LL category had to be considered as well. Based on HDFP and Framingham, patients who fit the LL category appear to have approximately the same risk as those who do not. Therefore, this assumption was made. Before considering the benefits of antihypertensive drugs, the event rate in the LL activity test was discounted by 25% to represent the beneficial effects of cholesterol lowering. It should be noted that this is conservative in that it assumes that all LL active patients are taking the drug and benefiting sufficiently. Suppose that 20,000 out of 40,000 ALLHAT patients are in the LL category.

A 20% discount on the event rate in the active antihypertensive trial was assumed. The power was then calculated based on the following.
1) Optimal allocation of patients to diuretics and treatment trials, ie the ratio of the number of patients in the diuretic trial to the number in each other AH trial is
(Total number of tests -1) ^1/2 = 3 ^1/2 (See Table 3)
Should be.
2) Adjustment for comparison between each treatment and diuretic (adjustment critical value of about c = 2.37)

A computer program was used to estimate the test event rate based on the annual rate of events, crossovers and losses. The program was run separately for patients with LL activity and LL placebo trials. Based on these values and the patient assignments shown in Table 3, we obtained test event rates for diuretic and other AH trials. For example, using an annual event rate of approximately .0135, crossover 2 and loss 2, we estimate that the test event rate is:

  The total event rates in the diuretic study and in another AH study are estimated as follows:

p ₀ = (.0710) (.75) + (.0537) (.25) = .0667,
P ₁ = (. 0595) (. 75) + (. 0449) (. 25) =. 0559.
The test statistic used inverse sine transformation.

In equation (1), n ₀ and n ₁ are the sample size in the diuretic and another AH test, respectively, and p ₀ and p ₁ are the observed event rates in those tests. For optimal patient assignment,

and

It is. If the Z statistic exceeds the adjusted critical value c = 2.37, it is rejected. When the cumulative normal distribution is represented by Φ (x), the power is

Can be shown. Recall that for our example using an annual event rate of .0135, a crossover rate of 2 and a loss of 2, p ₀ = .0667 and p ₁ = .0559. Substituting these values and n ₀ = 14,641 and n ₁ = 8,453 into Equation 2 yields right output = .824.

Lipid-lowering category The primary endpoint of the lipid-lowering category is total mortality. If the life status of all participants can be confirmed from the National Death Index, there will be no untraceable person.

  Based on previous experiments with HMG CoA reductase inhibitors, compliance appears to be very good and the majority of non-compliance occurs early in the study. Also, given the cost of LL drugs and the relatively moderate patient lipid levels, few LL placebo patients will take active LL drugs. Each year, it is estimated that approximately 2% of all LL placebo patients take active LL drugs with benefits similar to pravastatin (2% dropin annually). This means that approximately 11.4% of all LL placebo patients will take the active drug at least once in 6 years. In addition, it is estimated that 5% of LL active patients discontinue their medication at some point in the first year, and in each of the remaining years approximately 2.5% of LL active patients discontinue their medication (initially Dropout rate of 5% in the year and 2.5% in each subsequent year). This means that about 16.3% of patients with LL activity will stop taking medication at least once in 6 years. Under the above assumptions, approximately 10.6% of all LL placebo patients take active drugs at the end of 6 years, and approximately 15.3% of LL active patients stop taking their drugs at the end of 6 years. I will. We also looked at a more pessimistic set of assumptions: an annual drop-in rate of 2.5% and a dropout rate of 6% in the first year and 3% / year thereafter. The first assumption will be referred to as drop-in / drop 1 and the more pessimistic set of assumptions will be referred to as drop-in / drop 2.

  The mortality rate was estimated to be about 2.35% / year. This estimate is independent of CHD mortality (4.5% to 5% over 6 years), other cardiovascular mortality (about 2.6% over 6 years) and non-cardiovascular mortality (about 5.4% over 6 years) It was based on the incidence. These independent ratios were estimated using the parametric regression method used for the primary endpoint. The same long-term trend and healthy volunteer adjustment as in the AH category were performed. This gave an estimated mortality rate of 2.25% to 2.30% / year. Based on the slightly higher mortality observed in SHEP, this was increased to 2.35% / year. An annual mortality range of 2.20% to 2.50% was examined.

It is difficult to estimate a reasonable reduction in mortality from LL medication. A 30% reduction in CHD mortality, a 15% reduction in other cardiovascular mortality, and a 0% reduction in non-cardiovascular mortality would result in a 14% reduction. This seems a bit optimistic. Since the 12.5% reduction seemed reasonable, three different reduction rates were considered: 11%, 12.5%, and 14%.
A 10% discount on mortality in the three AH trials other than the diuretic trial.
As with the AH category, 6-year mortality was calculated for the LL placebo and LL activity tests. Separate rates were calculated for the diuretic test and other AH tests, and the allocation shown in Table 3 was used to obtain the combined rate. Table 6 below shows the 6-year rates in the ALLHAT LL category.

Therefore, the 6-year rates in the LL placebo and activity studies are as follows:

Again, the power was calculated using the inverse sine transform. The only difference between this calculation and the AH calculation is that n ₀ and n ₁ in the sample size LL placebo and activity tests are equal and no adjustment is made for multiple comparisons. Therefore, it is possible to use Equation 2 with n ₀ = n ₁ = 10,000 and c = 1.96.

Results The power for AH classification under different assumptions is shown in Figs. There is no significant difference in power under these different assumptions. Focusing on crossover rate 2 and loss 2, we can see that the power under the expected diuretic rate of 1.35% / year is 82.4%, as calculated above.

  The power of the LL total mortality category is shown in FIG. It can be seen that the power is almost exactly 80% under a drop-in / drop rate of 1 and a 12.5% reduction in mortality from LL treatment. If there is only a 11% decrease in mortality (other assumptions similar to the above), it drops to 68.6%. On the other hand, if there is a 14% decrease in mortality from LL treatment (other assumptions similar to the above), the power is 88.1%. Under the more pessimistic drop-in / drop-out 2, the power is 76.9% under a 2.35% / year mortality rate and 12.5% reduction in mortality from LL treatment (the graph shows Not shown).

Appendix II: Detailed definition of coronary artery disease death, non-fatal acute myocardial infarction and stroke
Coronary artery disease death :
In addition to death associated with coronary heart disease (CHD) as the underlying cause of death certificates, one of the following:
1) Early hospitalization due to myocardial infarction,
2) With previous angina or myocardial infarction and no known potentially fatal non-coronary disease process,
3) Death within 24 hours of CHD symptoms or death within 24 hours without symptoms but with known potentially fatal non-coronary disease processes (immediate and unidentified deaths) including),
4) Deaths caused by procedures related to coronary artery disease, such as coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA).
Note) Death due to non-coronary basic cause whose end event was MI is attributed to the basic cause, not CHD.

Coronary artery disease death is subdivided as follows:
1) Clear lethal MI: MI apparent within 4 weeks of death, with no known non-atherogenic causes,
2) Obvious fatal CHD: With no known non-atherosclerotic cause, with one or both of the following: No chest pain within 72 hours of death, or valvular disease or non-congestive cardiomyopathy A history of chronic congestive heart disease, or
3) Possible fatal CHD: death certificate consistent with the underlying cause, without any known non-atherosclerotic cause.
In patients without a known potentially fatal non-coronary disease process, coronary artery disease death also occurred or did not occur within 24 hours after the onset of symptoms (or without symptoms) Rapid or non-rapid classification based on when the patient was last seen.

Non-fatal acute myocardial infarction The identification and interpretation of a clear clinical acute myocardial infarction (MI) should be based on meeting at least two of the three commonly accepted criteria that meet the World Health Organization criteria: is there:
1． Symptoms compatible with an acute MI with a duration of at least 20 minutes (eg chest pain),
2． ECG changes adapted to acute MI, for example > 0.1 mV new persistent ST segment rise or new pathological Q wave (QRS> 0.04 sec) (each in two consecutive leads),
3． Serum biochemical markers compatible with acute MI, for example
Total CK at least twice the upper limit of normal with an MB fraction> 5% of total CK, or troponin> 2 times the upper limit of normal, or
LDH1 / LDH2 ratio > 1.

Rapid onset of persistent neurological deficits resulting from occlusion or rupture of the arterial system that is not known to be secondary to stroke brain trauma, tumor, infection or other non-ischemic causes, eg during surgery Stroke. As long as it does not result in death, the defect should last more than 24 hours, or a lesion suitable for acute stroke can be demonstrated on a CT or MRI scan.

A. Non-lethal stroke (one of the following):
1) Clear objective findings of local neurological deficits (with or without recent onset of severe headache or loss of consciousness) and durations longer than 24 hours and tumors, subdural hematomas, brain Absence of other disease processes that cause neurological deficits, such as angiography or metabolic disorders, and / or
2) Diagnosis of stroke based on abnormalities shown by CT or MRI consistent with current neurological symptoms or signs, or positive lumbar puncture (in case of subarachnoid hemorrhage).

B. Fatal stroke: In addition to the fact that the death certificate listed the stroke as consistent with the underlying cause or direct cause, one or more of the following:
1) End-stage hospitalization due to stroke as defined above,
2) no previous stroke and potentially fatal non-cerebrovascular disease processes, and / or
3) Stroke diagnosed as the cause of death during postmortem examination.

Appendix III: ECG criteria for asymptomatic myocardial infarction, ischemia, left ventricular hypertrophy and leg block
The ALLHAT study records electrocardiographic information from baseline and alternate visits and from acute hospitalization specimens referred to as quality control events. Clinical ECG is assessed as a general and interim event (including “asymptomatic” myocardial infarction).

General and provisional ECG findings at the visit
The determination that an ALLHAT participant has general MI, ischemia, LVH or leg block can be made using the Minnesota Code criteria. Provisional MI, ischemia, LVH or leg block can be determined using the criteria indicated for simultaneous comparison of ECG.

General baseline ECG findings
1． General MI
Baseline ECG interpretation:
a) any 1-1-x code or
b) Any 1-2-x and 4-l-x or 4-2, or 5-1, or 5-2
2． General ischemia Baseline ECG interpretation:
a) Any 4-2 to 4-l-x
b) Any 5-2 to 5-1
3． General LVH
Baseline ECG interpretation:
a) 3-1 or 3-3 (soft LVH)
b) 3-1 or 3-3 and any 4-3 to 4-l-x, or 5-3 to 5-1 (rigid LVH)
Four. General leg block Baseline ECG interpretation:
a) 7-1-1
b) 7-2-1
c) 7-4

Interim ECG Events Emerging ECG patterns between baseline visits and ECGs from subsequent visits, as evidenced by simultaneous ECG comparisons, demonstrate interim events.
a. Provisional MI
Any ED1 to ED7
b. Interim ischemic event Any EV1-EV9 pattern
c. Provisional LVH or LVH progression / regression
E-LVH1 to E-LVH4
d. Provisional leg block
EBBB1 to EBBB3
Attachment 1
Simultaneous ECG comparison
Explanation of simultaneous ECG comparison:
• Code 1-2-6 is considered a no-Q code for purposes of continuous comparison.
• The ambiguous Q code is 1-2-8 or any 1-3x code.
The diagnostic Q-code is any 1-1-x or any 1-2-x (excluding 1-2-6 or 1-2-8).
• “ED” signifies a diagnostic Q-code pattern that is occurring.
• All ED patterns are confirmed as significant increases by continuous comparison.
• When the 7-1-1 code is present, ED1 to ED7 cannot be assigned.
• ED2 to ED7 cannot be assigned if the 7-2-1 or 7-4 code is present.
• “EV” indicates the ST-T wave pattern that is occurring.
• All EV patterns are confirmed as significant increases or decreases by continuous comparison.

-EV1-EV9 cannot be assigned if the 7-1-1, 7-2-1 or 7-4 code is present.

Significant continuous change pattern
Clear Q wave MI (diagnostic pattern during development)
ED1. No Q-code (or 1-2-6) in baseline ECG, followed by diagnostic Q-code (Minnesota code 1-1-1 to 1-2-5 or 1-2-7) (significant increase) As confirmed).
Or record with 1-2-8 or any 1-3X code in the baseline ECG, followed by any 1-1-X code (confirmed as a significant increase).
ED2a. Ambiguous Q code in baseline ECG (1-2-8 or any 1-3x code), and no primary ST drop, followed by diagnostic Q code (1-1-1 to 1-2-5 or 1-2-7), in addition, records with a main ST decline (4-1-X or 4-2) (confirmed as a significant increase).
ED2b. Ambiguous Q code (1-2-8 or any 1-3x code) with existing primary ST decline (4-1-X or 4-2) in baseline ECG, followed by diagnostic Q code (1 -1-1 to 1-2-5 or 1-2-7), plus a record with a more pronounced ST decline (4-1-X) (confirmed as a significant increase).
ED3a. Ambiguous Q code in baseline ECG (1-2-8 or any 1-3x code), and main T-wave inversion followed by diagnostic Q code (1-1-1 to 1-2-5 or 1-2-7), in addition, recording with main T-wave reversal (5-1 or 5-2) (confirmed as a significant increase).
ED3b. Ambiguous Q-code (1-2-8 or any 1-3x code) with existing major T-wave reversal (5-1 or 5-2) in baseline ECG, followed by diagnostic Q-code (1 -1-1 to 1-2-5 or 1-2-7) plus a record with a more pronounced T-wave reversal (5-1 or 5-2) (confirmed as a significant increase).
ED4a. Ambiguous Q code in baseline ECG (1-2-8 or any 1-3x code), and main T-wave inversion followed by diagnostic Q code (1-1-1 to 1-2-5 or 1-2-7) In addition, ST segment rise (9-2) recording (confirmed as a significant increase).
ED4b. Ambiguous Q-code (1-2-8 or any 1-3x code) with an existing ST elevation (9-2) in the baseline ECG, followed by a diagnostic Q code (1-1-1 to 1) -2-5 or 1-2-7) In addition, a record with a more pronounced ST elevation (9-2) (confirmed as a significant increase).
ED5. No Q code (or 1-2-6) and no 4-1-1X or 4-2 in the baseline ECG, followed by an ambiguous Q code (1-2-8 or any 1-3x code) , In addition, records at 4-1-1X or 4-2 (confirmed as significant increase).
ED5b. Baseline ECG no existing Q code (or 1-2-6) with a drop in main ST (4-1-x to 4-2) followed by an ambiguous Q code (1-2-8 or any 1- 3-x code) plus a record with a more pronounced ST decline (4-1-X) (confirmed as a significant increase).
ED6a. No Q code (or 1-2-6) and no 5-1 or 5-2 in the baseline ECG, followed by an ambiguous Q code (1-2-8 or any 1-3x code), In addition, recording at 5-1 or 5-2 (confirmed as a significant increase).
ED6b. No Q code (or 1-2-6) with existing main T-wave inversion (5-1 or 5-2) in baseline ECG, followed by ambiguous Q code (1-2-8 or any 1-3) -x code) plus a record with a more pronounced T-wave reversal (5-1 or 5-2) (confirmed as a significant increase).
ED7a. No Q code (or 1-2-6) and 9-2 in the baseline ECG, followed by an ambiguous Q code (1-2-8 or any 1-3x code), plus 9- Record at 2 (confirmed as a significant increase).
ED7b. No Q code (or 1-2-6) with an existing ST rise (9-2) in the baseline ECG, followed by an ambiguous Q code (1-2-8 or any 1-3x code), In addition, a record with a more pronounced ST elevation (9-2) (confirmed as a significant increase).

Diagnostic ECG:
D1. ECG recording with diagnostic Q code (1-1-1 to 1-2-5 or 1-2-7).
D2. ECG recording with ST segment elevation (9-2) plus T-wave reversal (5-1 or 5-2).

Current ST-T pattern:
This diagnosis cannot be attributed when 7-1-1, 7-2-1 or 7-4 is present. In hospitalized patients, EV patterns can result from an increase or decrease in code strength.

EV1. Baseline ECG records at 4-0 (4-no code), 4-4 or 4-3, followed by 4-1-1, 4-1-2 or 4-2 (as significant increase) Or for hospitalized ECGs only, 4-1-1, 4-1-2 or 4-2 and subsequent 4-0, 4-4 or 4-3 in the initial hospitalized ECG Accompanying event record (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV2. 4-2 or 4-1-2 in the baseline ECG, and subsequent recording at 4-1-1 (confirmed as a significant increase), or 4-2 in the baseline, and subsequent, Record at 4-1-2 (confirmed as a significant increase); or, for hospitalized ECG only, 4-1-1 in the initial hospitalized ECG, followed by 4-1-2 or 4-2 Event record with (confirmed as significant decrease), or 4-1-2 in baseline ECG, followed by 4-2 in follow-up ECG (confirmed as significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV3. 5-0, 5-4 or 5-3 in the baseline ECG, followed by a record at 5-2 or 5-1 (confirmed as a significant increase); Record of events with 5-1 or 5-2 in the initial hospitalized ECG, followed by 5-0, 5-4 or 5-3 (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV4. Code 5-2 in the baseline ECG, followed by a record at 5-1 (confirmed as a significant increase); , Event record with 5-2 (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV5. Code 9-0 in the baseline ECG, followed by a record at 9-2 (confirmed as a significant increase); or for admission ECG only, 9-2 in the initial admission ECG, and subsequent , Event log with 9-0 (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV6. Code 4-1-1 in the baseline ECG, and subsequent recording at 4-1-1 (confirmed as a significant increase); or for hospitalized ECG only, 4-1 in the initial hospitalized ECG -1, and subsequent event records with 4-1-1 (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV7. Code 5-1 in the baseline ECG, followed by a record at 5-1 (confirmed as a significant increase); or for hospitalized ECG only, 5-1 in the initial hospitalized ECG, and subsequent , Event log with 5-1 (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

EV8. Code 5-2 in the baseline ECG, and subsequent recording at 5-2 (confirmed as a significant increase); or for hospitalized ECG only, 5-2 in the initial hospitalized ECG, and subsequent , Event record with 5-2 (confirmed as a significant decrease).
In addition to it,
No Q code in both baseline and follow-up ECG, or Q code present in baseline or follow-up ECG (but no significant increase in Q code found).

  EV9a. Baseline ECG no Q code (or 1-2-6) and existing main ST decline, T-wave reversal or ST rise (4-2 / 4-1-x, 5-2 / 5-1, or 9- 2), followed by an ambiguous Q code (1-2-8 or any 1-3x code) and less pronounced or nonexistent ST decrease, T wave reversal or ST increase (4-0 / 4- 4 / 4-3 / 4-2 / 4-1-x, 5-0 / 5-3 / 5-2 / 5-1, or 9-0 / 9-2); Q code as a significant increase Confirmed, ST or T wave changes are confirmed as a significant decrease.

  EV9b. Ambiguous Q code in baseline ECG (1-2-8 or any 1-3x code) and existing main ST decrease, T wave reversal or ST increase (4-2 / 4-1-x, 5-2 / 5-1, or 9-2), followed by diagnostic Q code (1-1-1 to 1-2-5 or 1-2-7) and less pronounced or absent ST reduction, T Wave reversal or ST rise (4-0 / 4-4 / 4-3 / 4-2 / 4-1-x, 5-0 / 5-3 / 5-2 / 5-1, or 9-0 / 9 -2); Q code is confirmed as a significant increase, ST or T wave changes are confirmed as a significant decrease.

Leg block in action
E-BBB1. ECG with 7-1-1 increased in QRS duration > 0.02 seconds, confirmed as no significant increase in reference body, followed by 7-1-1.
E-BBB2. ECG with 7-2-1 without a 7-2-1 in the reference, followed by a 7-2-1 increase in QRS duration > 0.02 seconds, confirmed as a significant increase.
E-BBB3. ECG with no 7-4 in the reference, followed by 7-4 with a QRS duration > 0.02 seconds, confirmed as a significant increase.

LVH occurring
E-LVH1. ECG with no 3-1 in the reference ECG, followed by 3-1 identified as a significant increase.
E-LVH2. ECG with 3-3 absent in the reference ECG, followed by a significant increase in 3-3.
E-LVH3. ECG with 3-1 in the reference ECG, followed by 3-1 or no 3 code identified as a significant decrease.
E-LVH4. ECG with 3-3 in the reference ECG, followed by a 3-3 or no 3 code identified as a significant decrease.

Ambiguous ECG pattern:
EI. ECG record with 1-2-8; or ECG record with 1-3x in the absence of 7-2-1 or 7-4.
E2. ECG recording with ST segment depression (4-1x, 4-2 or 4-3).
E3. ECG recording with T-wave reversal (5-1, 5-2 or 5-3).
E4. ECG record with ST segment elevation code 9-2.
Other ECG patterns:
All other ECG findings, including normal ones.

Unreadable ECG pattern:
UI. Technical error coded 9-8-1 by Minnesota code.
a. 3 or more defect inductions.
b. Muscle tremor artifact that gives possible false initial R.
c. Other technical errors that make the Q-wave unmeasurable, such as extreme clipping or extreme lack of centering.
d. Other states defined as “indistinguishable” by the Minnesota code.

Non-existing ECG:
A. No ECG available for reading.

Appendix IV: Quality Control Assessment of Inpatient Myocardial Infarction (MI) The following definition of acute inpatient MI is not intended for classification by clinic researchers on AL04, but quality control by the Endpoints Subcommittee It is for evaluation monitoring.
The criteria described are based on the CCSP Pilot Study, Minnesota Heart Survey, and other research studies included in the ARIC trial. The combination of pain, ECG and enzyme category required for each diagnosis described below is almost the same as that described in the above document.

Clear hospitalization MI
Must meet one or more of the following criteria:
1． Diagnostic ECG pattern during development (ED1-ED7) (Appendix III, Attachment 1),
Or
2． Diagnostic ECG patterns (D1 or D2) and abnormal enzymes (Appendix III, Attachment 1),
Or
3． Heart pain (defined below) and abnormal enzymes.

And
a. ST-T pattern EV1-EV9 (Appendix III, Attachment 1)
Or
b. Ambiguous ECG patterns E1 to E4 (Appendix III, Attachment 1).

Possible hospitalization MI
In the absence of sufficient evidence for a clear hospitalized MI, one or more of the following criteria must be met:
1． Heart pain and abnormal enzymes,
Or
2． Heartache and ambiguous enzymes and
a. The ST-T pattern that is occurring or
b. Diagnostic ECG patterns,
Or
3． Abnormal enzymes and
b. The ST-T pattern that is occurring.

Suspected hospitalized MI
One or more of the following criteria must be met in the absence of sufficient evidence for a clear or possible inpatient MI:
1． Unusual enzyme or
2． Heartache and incomplete enzymes and
a. Diagnostic ECG pattern or
b. The ST-T pattern that is occurring or
3． Heartache and ambiguous enzymes or
Four. Ambiguous enzymes and
a. Diagnostic ECG pattern or
b. The ST-T pattern that is occurring or
c. Ambiguous ST-T pattern.

  Listed below are definitions of specific elements of chest pain, enzymes and ECG that contribute to a clear, possible, suspected or non-MI final diagnosis.

Definition of chest pain Pain with both of the following characteristics:
1． It occurs somewhere in the front chest, left arm or chin.
and
2． There is no obvious cause of pain other than the heart.

An enzyme is classified as abnormal if any enzyme value recorded for an abnormal heart enzyme meets any of the following criteria:
1.a. CK-MB is “present”: (if the laboratory uses the “present” or “non-existing” criteria without reporting a more specific value) or CK-MB is 10% of the total CK value That's it.

and
b. There are no known non-ischemic causes (heart surgery, severe muscle trauma, striated muscle degeneration) in relation to elevated enzyme levels.

Or
2.a. Ratio LDH ₁ : LDH ₂ > 1.

and
b. There is no evidence of hemolytic disease.
Or
3.a. Both total CK and LDH are at least twice the upper limit of normal (these increases need not occur on the same day).
and
b. There are no known non-ischemic causes (heart surgery, severe muscle trauma, striated muscle degeneration) and no evidence of hemolytic disease with respect to elevated enzyme levels.

Not satisfied criteria for ambiguous cardiac enzymes abnormal enzyme, and, in the following cases, the enzyme is classified as being "ambiguous":
1． Either total CK or total LDH is at least twice the normal upper limit.
Or
2． Both total CK and total LDH are between the upper limit of normal and twice the upper limit of normal (these increases need not occur on the same day).
Or
3． CK-MB is 5-9% of total CK or “present a little”.

A summary of enzyme diagnostic criteria for total CK and LDH is shown in the following algorithm (Table 1).

Protocol Addendum 1
Modified power for lipid-lowering classification of ALLHAT
The power for ALLHAT's lipid-lowering category was corrected based on a total sample size of 10,000 and a subpopulation of size 4,000. The drop-off rate used was the pessimistic of the two predictions in the protocol (ie 6% in the first year and 3% / year thereafter). As the drop-in rate, the pessimistic one (ie 2.5% / year) of the two protocol expectations was used. The loss in total mortality was considered to be zero, while for CHD it was as specified in the anti-hypertensive category protocol (slightly above 3% / year). The event rate shown is after expressing the benefit of antihypertensive treatment. The power results are shown in Tables 1 and 2. A more pessimistic loss of 5% / year was also considered. This reduced the power by about 2%.

Protocol Addendum 2
When repeatedly examining data in a monitor boundary test, ignoring these multiple “looks” can dramatically increase the type 1 error rate (Armitage, Mc. Pherson and Rowe, 1969, Proschan, Follmann And Waclawiw, 1992). A boundary has been established in two-armed trials that eliminates or significantly exacerbates this type 1 error rate increase. These are referred to as group-sequential rather than continuous boundaries. This is because the intermediate analysis is performed after the data group is generated, not after each new observation. The most common of these requires very strong evidence to show significance at the very beginning of the study and at the end of the study is almost the same as that required in the absence of an interim study. Requires some degree of proof. This was not the case for the first group sequential method presented (Pocock, 1977). For this reason, Pocock himself recommends using this method (personal communication).

  The O'Brien-Fleming (1979) boundary has the properties described above. The disadvantage is that it requires that the number of looks be specified in advance, and these searches need to be done after an equal increase in information. In the case of this test, the information time t is estimated by the ratio of the number of events observed so far to the number expected by the end of the test. Therefore, t = 0 is the start of the test and t = 1 is the end of the test. Suppose you planned eight surveys on the data after an equal increase in information (number of events). Figure 1 shows the boundaries for the comparison of a given drug with a diuretic. In the case of three comparisons with diuretics, multiple comparison adjustments have been made.

Lan and DeMets (1983) presented a “spending function” approach that allows data to be examined after various amounts of information and does not require identification of the number of previous studies. The consumption function α ^* (t) is α ^* (1) = α, and represents the cumulative amount of the first type error probability consumed by the information time t. The amount of error probability of type 1 consumed is inextricably related to information time. This is in contrast to the method of Slud and Wei (1982), which consumes a certain amount of first-class error probabilities in each survey on the data, regardless of information time. A significant increase in the first type of error rate can occur with the Slud and Wei methods, but not with the Lan-DeMets method (Proschan, Follmann and Waclawiw, 1992). One of the consumption functions suggested by Lan and DeMets (see the formula in the appendix) is very similar to the O'Brien-Fleming boundary if the investigation happens by chance after an equal increase in information Has a boundary (see Figure 1). The advantage of the Lan-DeMets approach is that it can be used even if the surveys are not equally spaced. In this case, the boundary will change somewhat.

  Another very useful monitoring tool is conditional power (Lan, Simon and Halperin, 1982 or Lan and Wittes, 1988). A conditional probability of obtaining a statistically significant result at the end of the study is calculated under various hypothetical treatment effects. Unlike O'Brien-Fleming or Lan-DeMets boundaries, conditional power is usually used to justify the conclusion of a test that has no real possibility to give statistically significant results. If the conditional power is very low, assuming a large therapeutic benefit for the remainder of the study, the study will be discontinued. Stochastic curtailment means that the test is stopped when the conditional power crosses a predetermined threshold. For example, if the conditional power assuming a given alternative hypothesis is 10 or less, it could be agreed to stop the test. With such a rule, the probability of the second kind of error (accepting the null hypothesis if it is false) is greater than if it is not accompanied by a stochastic simplification. This is because the null hypothesis can be accepted at the end of the test or at an intermediate time point. The degree of the second type error rate increase is very small. Lan, Simon and Halperin (1982) showed that even when the test was continuously monitored, it was very small. Davis and Hardy (1990) have shown that the increase is much smaller in the more realistic situation where the test is monitored 5-10 times.

  An important issue that arises in group continuous monitoring is the issue of information time. It was described above that the information time is estimated using the number obtained by dividing the number of events observed so far by the number expected at the end of the test. But in which department? In a two department monitor, the total number of events in both departments or the number of events in the control department could be used. The advantage of using both departments is that it provides a larger sample size for estimating information time. The disadvantage is that in order to estimate the number of events expected by the end of the study, not only the control group event rate but also the therapeutic effect must be predicted. In ALLHAT, four antihypertensive departments (and thus three therapeutic effects) must be identified. It is recommended to use a diuretic department event to determine information time.

References
Armitage, P., Mc. Pherson, CK and Rowe, BC (1969) .Repeated significance tests on accumulating data.Journal of the Royal Statistical Society A. 132, 235-244.
Lan, KKG and DeMets, DL (1983). Discrete sequential boundaries for clinical trials. Biometrilca 70, 659-663.
Lan, KKG, Simon, R. and Halperin, M. (1982). Stochastically curtailed tests in long term clinical trials. Communications in Statistics-Sequential Analysis 1 (3), 207-219.
Lan, KKG and Wittes, J. (1988) .The B-value: a tool for monitoring data.Biometrics 44, 579-585.
O'Brien, PC and Fleming, TR (1979) .A multiple testing procedure for clinical trials. Biometrics 35, 549-556.
Pocock, SJ (1977) .Group sequential methods in the design and analysis of clinical trials.Biometrika 64, 191-199.
Proschan, MA, Follmann, DA and Waclawiw, MA (1992) .Effects of assumption violations on type 1 error rate in group sequential monitoring.Biometrics 48, 1131-1143.
Slud, E. and Wei, LJ (1982). Two sample repeated significance tests based on the modified Wilcoxon statistic. Journal of the American Statistical Association 77, 862-868.
Appendix Recommended Spending Function

The recommended Lan-DeMets consumption function is that α is the bilateral type I error rate for a given comparison with a diuretic, Φ is a standard normal distribution function, and Z _{α / 4} is its 100 (1- α / 4) The percentile. When adjusted for multiple comparisons with diuretics, the value of Zα _{/ 4} is about 2.64.

Cancellation rules presented
1) Use O'Brien-Fleming's modified Lan-DeMets method for harm / benefits.
2) The boundary is symmetric.
3) Information time is calculated as the expected event rate in the diuretic department.
4) Survey about 10% of the information time first, and then annually at the DSMB meeting.
5) At the beginning, pay particular attention to the results of crossing the Haybittle-Peto boundary with Z = 4.0 in the anti-hypertensive category and Z = 3.0 in the lipid-lowering category.
6) Use conditional power under the protocol specific alternative hypothesis on uselessness.

FIG. 1 is a graph showing the crossover rate from TOMHS. FIG. 2 is a graph showing the crossover rate from TOMHS. FIG. 3 is a graph showing the crossover rate from TOMHS. FIG. 4 is a graph showing hypertension detection power (component-crossover rate 1). FIG. 5 is a graph showing the hypertension detection power (component-crossover rate 2). FIG. 6 is a graph showing the hypertension detection power (component-crossover rate 3). FIG. 7 is a graph showing the power (component-total mortality) of lipid-lowering.

Claims (14)

  A method for alleviating cardiovascular disease in an individual at risk comprising the daily administration of an effective amount of a diuretic to said individual, said diuretic alleviating cardiovascular disease in such an individual Wherein the therapeutic effect of is greater than such therapeutic effect in such individuals treated with only adrenergic beta blocker.   A method for alleviating cardiovascular disease in an individual at risk comprising the daily administration of an effective amount of a diuretic to said individual, said diuretic alleviating cardiovascular disease in such an individual Wherein the therapeutic effect of is greater than such therapeutic effect in such individuals treated with only calcium channel blockers.   A method for alleviating cardiovascular disease in an individual at risk comprising the daily administration of an effective amount of a diuretic to said individual, said diuretic alleviating cardiovascular disease in such an individual Wherein the therapeutic effect of is greater than such therapeutic effect in such individuals treated with only vasodilators.   A method for alleviating cardiovascular disease in an individual at risk comprising the daily administration of an effective amount of a diuretic to said individual, said diuretic alleviating cardiovascular disease in such an individual Wherein the therapeutic effect of is greater than such therapeutic effect in such individuals treated only with central agonists.   A method for alleviating cardiovascular disease in an individual at risk comprising the daily administration of an effective amount of a diuretic to said individual, said diuretic alleviating cardiovascular disease in such an individual The therapeutic effect of is greater than such therapeutic effect in such individuals treated with reserpine alone.   A method for reducing cardiovascular disease in an at-risk individual comprising administering to said individual daily an effective amount of a diuretic and an ACE inhibitor, said cardiovascular disease being reduced in such an individual A method wherein the therapeutic effect of the diuretic and ACE inhibitor is greater than such therapeutic effect in such individuals treated with such diuretic alone. A method for reducing cardiovascular disease in an at-risk individual comprising administering to said individual an effective amount of a diuretic and an ACE inhibitor daily, said cardiovascular disease being reduced in such an individual The therapeutic effect of the diuretic and ACE inhibitor is such a therapeutic effect in such individuals treated only with vasodilators, central agonists, calcium channel blockers, alpha ₁ blockers, adrenergic beta blockers, reserpine A method characterized by being larger.   8. A method according to claim 1, 2, 3, 4, 5, 6 or 7 wherein the diuretic is chlorsalidon.   The method according to claim 6 or 7, wherein the diuretic is chlorsalidon.   8. The method according to claim 6 or 7, wherein the ACE inhibitor is ramipril.   8. The method of claim 6 or 7, wherein the ACE inhibitor is ramiprilat.   8. The method of claim 6 or 7, wherein the diuretic is chlorsalidon and the ACE inhibitor is ramipril.   14. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 wherein the cardiovascular disease is heart failure.   14. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 wherein the individual is a hypertensive individual.

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