EP1589965A1 - Verfahren und dosierformen zur verringerung von herzanfällen bei einem hypertoniker mit einem diuretikum oder kombination aus einem diuretikum und einem ace-hemmer - Google Patents

Verfahren und dosierformen zur verringerung von herzanfällen bei einem hypertoniker mit einem diuretikum oder kombination aus einem diuretikum und einem ace-hemmer

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Publication number
EP1589965A1
EP1589965A1 EP03813841A EP03813841A EP1589965A1 EP 1589965 A1 EP1589965 A1 EP 1589965A1 EP 03813841 A EP03813841 A EP 03813841A EP 03813841 A EP03813841 A EP 03813841A EP 1589965 A1 EP1589965 A1 EP 1589965A1
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EP
European Patent Office
Prior art keywords
patients
study
trial
diuretic
antihypertensive
Prior art date
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Application number
EP03813841A
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English (en)
French (fr)
Inventor
Jefferson J. Gregory
Victoria Christian
Robert M. Califf
Raymond J. Lipicky
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King Pharmaceuticals Inc
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King Pharmaceuticals Inc
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Publication date
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Publication of EP1589965A1 publication Critical patent/EP1589965A1/de
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to methods and dosage forms for reducing and/ or preventing the incidence of cardiovascular disease, including heart attacks, in individuals who are at risk, such as those individuals suffering from hypertension.
  • the treatments and dosage forms of the present invention concern the administration of a diuretic, such as a thiazide diuretic like Thalitone®, either alone or in combination with an ACE-inhibitor, such as ramipril or ramiprilat like Altace®, to reduce and/or prevent the incidence of cardiovascular disease, namely, heart attacks or failure, in individuals who suffer from hypertension or are at risk.
  • a diuretic such as a thiazide diuretic like Thalitone®
  • an ACE-inhibitor such as ramipril or ramiprilat like Altace®
  • a diuretic such as a thiazide diuretic like chlorthalidone
  • an angiotensin-converting enzyme inhibitor such as ramipril or ramiprilat.
  • ACE-Inhibitor angiotensin-converting enzyme inhibitor
  • the diuretic may be administered in a single dosage form, such as a tablet, liquid, caplet or capsule, or in separate individual dosage forms.
  • a preferred diuretic for use in accordance with the present invention is thalidone, such as Thalitone®, administered as a single daily dose in an amount of 15mg, 30mg, 45mg, 50mg, 60mg or more.
  • a preferred ACE- inhibitor for use in accordance with the present invention is ramipril, such as Altace®, administered as a single daily dose in an amount of 1.25mg, 2.5mg, 5mg, lOmg or more.
  • a diuretic in reducing or eliminating cardiovascular disease including heart failure
  • a beta-adrenergic blocker like propanolol and atenolol
  • a calcium- channel blocker such as Lisinopril
  • an ACE-inhibitor such as Lisinopril
  • a vasodialator such as hydralazine
  • a central agonists such as oral clonidine or methyldopa, reserpine or an alphai-blocker, like prazosin and doxazosin.
  • the therapeutic effect of the combination of a diuretic, such as a thizaide, like Thalitone®, and an ACE-inhibitor, such as Altace® is far superior to the individual therapeutic effect achieved in such individuals when treated with only a diuretic or a beta-adrenergic blocker, like propanolol and atenolol, a calcium-channel blocker, an ACE-inhibitor, such as Lisinopril, a vasodialator, such as hydralazine, a central agonists, such as oral clonidine or methyldopa, reserpine or an alphai-blocker, like prazosin and doxazosin.
  • a diuretic such as a thizaide, like Thalitone®
  • an ACE-inhibitor such as Altace®
  • This protocol describes a practice-based, randomized, clinical trial of antihypertensive pharmacologic treatment and, in a specific subset, cholesterol-lowering, in 40,000 high-risk hypertensive patients, including at least 55% African- Americans (self-described "black”).
  • the purpose of the antihypertensive trial component is to determine whether the combined incidence of fatal coronary heart disease (CHD) and non-fatal myocardial infarction differs between diuretic (chlorthalidone) treatment and three alternative antihypertensive pharmacologic treatments — a calcium antagonist (amlodipine). an ACE inhibitor (lisinopril), and an alpha adrenergic blocker - (doxazosin)*.
  • the antihypertensive trial component will not include a placebo or no-treatment control group.
  • the purpose of the cholesterol-lowering trial component is to determine whether lowering serum cholesterol in moderately hypercholesterolemic men and women aged 55 years and older with the 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor pravastatin will reduce aD-cause mortality as compared to a control group receiving "usual care".
  • HMG CoA 3-hydroxymethylglutaryl coenzyme A reductase inhibitor pravastatin
  • Secondary objectives of both trial components are to compare the effects of their respective treatment regimens on cardiovascular mortality, major morbidity, health costs, and health-related quality of life. Additional secondary objectives of the antihypertensive trial are to compare the effects of alternative treatments on all-cause mortality and on major hypertension- related morbidity such as incidence and regression of left ventricular hypertrophy and progressive renal dysfunction. Also the effect of the antihypertensive regimens on the aforementioned primary and secondary outcomes will be assess in key subgroups [over age 65, women, African-Americans, type LC diabetics].
  • Additional secondary objectives of the lipid- lowering trial are to assess the long-term safety of HMG CoA reductase inhibitors in men and women aged 55 years and above (particularly with regard to mortality from non-cardiovascular causes), the effect of lipid-lowering on cancer incidence and mortality, and the effect of lipid lowering on the combined incidence of fatal CHD and non-fatal myocardial infarction, especially in key subgroups [over age 65, women, African- Americans, type II diabetics]. Also, because this component of tire trial will not be blinded, the incidence of myocardial infarction based on centrally coded changes in the biennial study ECG will be looked at as an end point. The mean duration of the trial is expected to be 6.0 years, ranging from 4.2 years (for the last patient entered) to 8 years (for the first patient entered).
  • VA hypertension clinics are expected to comprise approximately 70 of these clinical sites and to contribute about 20% of the study patients. Forms will be kept to a minimum, and few clinical procedures not performed for routine patient care will be required.
  • JNC-V added the alpha adrenergic blockers, as well as drugs with combined alpha and beta blocking actions, as alternative first-line treatments.
  • beta-blockers have been compared directly to diuretics in large-scale, long-term clinical trials in hypertension.
  • MRC Medical Research Council
  • ACE-inhibitors At least three of the seven licensed drugs in this class have been reported to reduce left ventricular hypertrophy [15]. ACE inhibitors reduce mortality in both severe and less severe heart failure [16], and reduce morbidity, including CHD, in asymptomatic left ventricular dysfunction [17]. With regard to effects on atherosclerosis, Chobanian and colleagues have reported prevention of coronary lesions in the Watanabe rabbit model [18], perhaps due to effects on cellular proliferation in the vessel wall.
  • alpha-blockers have been shown to have moderate favorable effects on the lipid profile, particularly on LDL cholesterol [19,20].
  • a few studies have also found improvements in insulin resistance, an observation that may be especially relevant to patients with type JJ diabetes mellitus [21,22].
  • these agents may reduce left ventricular hypertrophy and platelet aggregability and stimulate tissue plasminogen activator [23-27].
  • Hypertension is considerably more common among African-Americans than Caucasians, and its sequelae are more frequent and severe.
  • Prevalence of hypertension in the second National Health and Nutrition Examination Survey (NHANES II) was 51% in African-Americans aged 25-74 years compared to 40% in Caucasians [33].
  • Incidence of end-stage renal disease secondary to hypertension is nearly eight-fold higher in African- American than Caucasian hypertensives [34].
  • Risks of left ventricular hypertrophy, stroke and stroke death have all been reported to be greater among African- American hypertensives. Suggested explanations for these differences have included higher prevalence of co-existing illnesses such as diabetes among African- Americans, and decreased access to medical care.
  • CHD coronary heart disease
  • Experimental evidence for the efficacy of cholesterol lowering in older men is confined to the analysis of small subgroups of clinical trials, and is lacking for women of any age. This paucity of clinical trial data led the National Cholesterol Education Program's (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults to allow considerable room for physician judgment regarding: the elderly in their 1987 guidelines [42].
  • NCEP National Cholesterol Education Program's
  • LDL-cholesterol levels are slightly lower and HDL-cholesterol levels . are slightly higher in African-Americans than non-minority populations, hypercholesterbêtia is still a substantial problem among African- Americans, particularly in women with obesity and diabetes.
  • Prior cholesterol-lowering trials have included only a handful of African- American subjects. The assumption that cholesterol lowering will produce similar reductions in CHD in African-Americans and Caucasians is unproven.
  • lovastatin the first of the HMG CoA reductase inhibitors, has been used increasingly widely since its approval by the FDA in September, 1987, and has been efficacious and well-tolerated by patients of all ages [52-55].
  • Two small angiographic trials have demonstrated a 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 ; both have been used for several years in other countries.
  • the FDA is currently considering approval of a fourth HMG CoA reductase inhibitor, fluvastatin.
  • HMG CoA reductase inhibitors may potentiate the effects of anticoagulants, clinically significant interactions with the antihypertensive agents to be used in ALLHAT have not been reported.
  • HMG CoA reductase inhibitors appear to be well-suited for use in older men and women. They also offer the opportunity to extend our knowledge of the benefits and safety of cholesterol lowering to cholesterol levels and degrees of reduction not previously addressed by large clinical trials.
  • the primary hypotheses of this trial component are that the combined incidence of fatal CHD and nonfatal myocardial infarction will be lower in hypertensive patients receiving (1) a calcium antagonist (amlodipine), (2) an ACE inhibitor (lisinopril), or (3) an alpha adrenergic ⁇ ⁇ blocker (doxazosin)* as first-line therapy than in those in whom a similar degree of blood pressure control is achieved using a thiazide-like diuretic (chlorthalidone) as first-line therapy.
  • a calcium antagonist amlodipine
  • ACE inhibitor lactyl
  • doxazosin alpha adrenergic ⁇ ⁇ blocker
  • chlorthalidone thiazide-like diuretic
  • CHD status will be undeterminable at the end of the study for 16.8% of patients (8.6% of person-years) due to competing risks (non-CHD death) or loss to follow-up, based on data from Framingham and HDFP (see Appendix I).
  • a type I error 0.05 (two-sided). This corresponds to a critical Z-score of 2.37 after adjustment for multiple comparisons.
  • Age/sex Men and women aged 55 years and older.
  • Eligibility is based on the patient's current treatment status and on the average of two seated blood pressure measurements at each of two visits (Table IV.1):
  • Atherosclerotic cardiovascular disease (i) Old or age-indeterminate myocardial infarction or stroke (>6 months),
  • Atherosclerotic cardiovascular disease This includes, but is not limited to: coronary, penpheral vascular, aortic, or carotid stenosis as documented by angiography, Doppler studies, or diminished ankle-arm index; ischernic heart disease as documented by electrocardiography (e.g., ST-T wave changes), echocardiography, or radionuclide imaging; history of intermittent claudication; or history of transient ischernic attack. (A more complete list of manifestations of atherosclerotic cardiovascular disease is provided in the Manual of Operations.) b.
  • Type II diabetes mellitus [plasma glucose >140 mg/dl (fasting) or 200 mg/dl (non- fasting) and/or on insulin or oral hypoglycemic agent] (in the past 2 years), c. HDL-cholesterol ⁇ 35 mg/dl (on any 2 determinations within past 5 years) ⁇ . Left ventricular hypertrophy (one of the following) on any ECG within the past 2 years:
  • QRS amplitudes are measured in the second to last complete normal beat of the lead.
  • Known renal insufficiency serum creatinine > 2 mg/dl.
  • e Patients requiring diuretics, calcium antagonists, ACE inhibitors, or alpha adrenergic blockers for reasons other than hypertension. (If a patient is on a calcium-channel blocker for angina, he/she may be switched to a beta-b locker for this indication if it is deemed safe to do so. This exclusion criterion would not then be applicable.
  • Visit 1 The objective of Visit 1 is to assess eligibility for and interest in ALLHAT and to begin withdrawing the patient from any existing antihypertensive medications. It is anticipated that . the majority of treated hypertensives will have been identified by chart review, and that much of the pertinent information (age, risk factor status, number of antihypertensive drugs, etc.) will already be known. The investigator will be required to complete a one-page questionnaire to document that all the preliminary inclusion and exclusion criteria (Chapter TV) have been met.
  • Visit 1 will consist primarily of obtaining the first entry blood pressure, answering the patient's questions about the study, and obtaining the patient's informed consent to begin the step-down if necessary from pre-study antihypertensive drugs. Recommendations for antihypertensive drag withdrawal are included below. If a patient's antihypertensive medications can be safely switched without tapering, the participant may move directly to Visit 2. Visits 1 and 2 should be separated by at least one day, but need not be consecutive visits.
  • ALLHAT Visit 1 For new patients found to have elevated blood pressure at their initial visit to the clinical site, this initial visit may serve as ALLHAT Visit 1 provided that any additional evaluations needed to determine study eligibility are performed (at no cost to the study). The subsequent course of such patients is simplified by elimination of the need for a step-down from a pre-study drug regimen.
  • Diuretics The patient should be informed to contact the physician if he/she develops marked edema and/or significant increase in dyspnea (shortness of breath, either at night or on exertion).
  • Angiotensin converting enzyme (ACE) inhibitors 3.
  • Vasodilators e.g., hydralazine
  • Alphaj -blockers e.g., prazosin
  • Central agonists e.g., oral clonidine or methyldopa
  • Beta-adrenergic blockers e.g., propranolol or atenolol
  • Post-myocardial infarction patients receiving beta-blockers for prophylaxis need not discontinue therapy. There may be occasional circumstances where, in the physician's judgment, closer monitoring or a longer period of withdrawal is preferred. Extra care should be taken in tapering antihypertensive drugs in those patients with cardiovascular disease.
  • Patients who have met all ALLHAT eligibility criteria and in the judgment of the investigator can safely discontinue all prior antihypertensive drugs and be randomized to one of the four ALLHAT treatment arms shall, after giving their informed consent, be entered into the study at Visit 2. This visit will generally take place between 1 day and 12 weeks after Visit 1, depending on the length of time required to step down from pre-study medications. Patients initially taking no drugs or well-controlled on one drug may be randomized soon after Visit 1, while other patients may require a longer step-down process (generally less than three months) before they can complete Visit 2. More prolonged step-downs are discouraged (though not prohibited), since many patients who cannot quickly be withdrawn from their pre-study regimens may. also be more difficult to maintain on a simple regimen during the trial.
  • the investigator will telephone the Clinical Trials Center regarding each patient who meets all eligibility requirements at Visit 2, including a signed consent form.
  • the Clinical Trials Center will review the eligibility and exclusion criteria and will assign that patient a study identification number and a bottle number corresponding to (1) chlorthalidone, (2) amlodipine, (3) lisinopril, or (4) doxazosin*.
  • the treatment assignment will be masked from both the practitioner and patient.
  • a resting ECG, serum glucose, serum potassium and creatinine, fasting lipid profile and ALT should be obtained at this visit for all patients who are randomized.
  • Each randomized patient will be issued an appropriate supply of his/her starting dose of the assigned study drug and will be instructed to return for the first dosage titration (Visit 3) four weeks later (see Section VI).
  • a fasting lipid battery total cholesterol, triglycerides, HDL-cholesterol, calculated LDL- cholesterol
  • serum ALT serum ALT
  • Clinical sites will be selected to produce an overall study population of at least 55% African- Americans and will be monitored by the Clinical Trials Center throughout the study to assure that their performance matches their expectations. If the overall proportion of African- Americans appears to be falling significantly short of 55 >, the Steering Committee may implement remedial measures such as temporarily freezing recruitment of non- African- American patients at some or ail existing clinical sites or adding new clinical sites to correct the shortfall.
  • the blood pressure goal in all four arms* will be ⁇ 90 mrnHg diastolic and ⁇ 140 mmHg systolic. 1
  • the number and dose of study drugs prescribed in pursuit of these goals will be influenced by patient tolerance and clinical judgment, particularly in use of greater than two- drug regimens. With rare exceptions, treatment should be intensified for patients with BP levels > 160 mm Hg systolic and/or > 100 mm Hg diastolic, even if low doses of drugs from the same classes as the blinded Step 1 drugs must be added.
  • the therapeutic goal is to achieve blood pressure control on the lowest possible dosage of the first-line drug.
  • the addition of second- line (open label) drugs should be reserved for those in whom the maximal dosage level of the first-line drug is insufficient.
  • Each of the four* first-line drugs will be administered once daily in the morning. The following dosage levels will be available for each drug:
  • Sources of the four Step 1 agents are: chlorthalidone: Ogden Bioservices, Inc., R c vi ⁇ le, Maryland; amlodipine: Pfizer, Inc., New York, New York; and lisinopril: Zeneca Pharmaceuticals Group, Wilmington, Delaware; and doxazosin*: Pfizer, Inc., New York, New York.
  • the identity of the drug will be masked at each dosage level , but the identity of the dosage level will not be masked.
  • the initial dosage level will be used only during the first week after randomization to rninimize the potential side effects of doxazosin*. (For the other three drugs, the initial dose and Step 1 dosages are identical.)
  • the Step 1 dosage level should be initiated at the end of the week. A clinic visit is not required.
  • Occurrences of study endpoints will be documented by a checklist completed by the study physician at each follow-up visit and supplemented by interim reporting as needed. These diagnoses will be supported by copies of death certificates, discharge summaries and face sheets as described below. The following outcome measures will be obtained and tabulated over the course of the stud ⁇ ':
  • the underlying cause of death will be classified by the physician-investigator at the clinical site as due to (1) Coronary Heart Disease, (2) Other Cardiovascular Disease, (3) Neoplastic Disease, (4) Other Medical Causes, or (5) Non-Medical Causes.
  • a National ' Death Index (NDI) Search will be performed near the end of the study to identify and document deaths that may have occurred among patients who are lost to follow-up. Because of the time lag inherent in the NDI, a private tracing service will also be utilized for selected participants. Physicians will also be asked to report cause of death on the study endpoint form.
  • Angina pectoris a) Hospitalized or procedure (i) with or (ii) without a revascularization procedure (documented by hospital discharge summary or face sheet) b) Not hospitalized but treated (documented by check box on end point questionnaire) 5) Peripheral arterial disease a) Hospitalized or procedure (i) with or (ii) without a revascularization procedure (documented by hospital discharge summary or face sheet) or outpatient revascularization procedure (documented by procedure sheet) b) Treated medically as outpatient (documented by check box on end point questionnaire)
  • the LVH inclusion criteria are based on specific ECG criteria as listed in IV.A.4.d and will be interpreted at the clinical site. ECGs will be re-read centrally to assign Minnesota Codes. The outcome criteria for LVH are based on the Minnesota Code. The Minnesota Coding Center will use Codes 3-1 or 3-3 to identify prevalent LVH. These amplitude criteria sets are generally considered “probable ECG-LVH", but when combined with any 4-3 or more severe 4-code, or 5-3 or more severe 5-code, it is considered "definite ECG- LVH".
  • Minnesota Code 3-1 R amplitude > 26 mm in either V 5 or V 6 or R amplitude > 20 in any of leads I, II, III, aVF, or R amplitude > 12 mm in lead aVL.
  • the Coding Center will also document incident ECG-LVH and progression/regression of ECG-LVH using serial ECG comparison.
  • Quality of life A generic categorical measure of health status will be used to assess health related quality of life.
  • the study investigators will be required to complete and submit to the Clinical Trials Center a short end points questionnaire for each occurrence of a study endpoint identified at or between regular visits. For each end point involving a death or hospitalization, the investigator will also obtain and submit a copy of the deatli certificate or hospital discharge summary or face sheet upon which the diagnosis is based.
  • the Clinical Trials Center will request the more detailed information as described in Appendix I so that the in-hospital ECGs and enzyme levels (for myocardial infarctions), and neurologists' reports and CT and/or M I reports (for strokes) can be evaluated by the study end points committee and the accuracy of the discharge diagnoses (versus the definitions in Appendix I) can be assessed.
  • ALLHAT will employ an organizational structure that differs markedly from the usual NHLBI-supported clinical trial.
  • the trial will be performed by a large number (600) of practicing physician-investigators who will be compensated on a per capita basis for each, patient seen according to a fixed payment schedule.
  • Approximately 20% of study patients are expected to be recraited by Department of Veterans Affairs (VA) hypertension clinics.
  • VA Department of Veterans Affairs
  • the Clinical Trials Center in addition to its conventional data handling and monitoring responsibilities, will be responsible for identifying and paying these physician-investigators, hiring regional coordinators to monitor recruitment and compliance, and for awarding and supervising subcontracts for a central laboratory and an ECG coding center.
  • a Steering Committee will be selected for their expertise in the relevant subject areas. A detailed description of the nature and role of the study components is given below.
  • the Program Office located in the NHLBI, Division of Epidemiology and Clinical Applications (DECA) and Division of Heart and Vascular Diseases (DHVD), will award and monitor the contract that provides funding for the study, set up the agreements to fund the VA clinics, and hold the IND for the study.
  • the Director, NHLBI will appoint the Data and Safety Monitoring Board (DSMB) and the Chair and Vice-chair of the Steering Committee.
  • DSMB Data and Safety Monitoring Board
  • the Program Office will appoint the Steering Committee and any other committees deemed necessary to advise the NHLBI on issues pertaining to the progress or results of the study.
  • the Clinical Trials Center will have primary responsibility for identifying suitable medical practices to participate in ALLHAT, paying them according to a fixed fee schedule for each patient randomized and study form completed, and for editing, storing, and analyzing data generated by the study. Its investigators and staff will have a central role in designing the data collection system and in monitoring data quality. Specific Clinical Trials Center responsibilities include:
  • Each clinical site is expected to be under the supervision of a physician identified as responsible for the conduct of ALLHAT.
  • study forms may be completed by a physician's assistant or nurse practitioner or other designated qualified personnel, consistent with the internal organization of that medical practice.
  • one support staff member must he designated as chiefly responsible for protocol implementation; this person will participate in central training and annual meetings.
  • Payment for each patient randomized to each ALLHAT component and for each study visit completed will be made by the Clinical Trials Center upon receipt of the relevant completed, correct and signed study form.
  • Regional Coordinators :
  • Regional coordinators will be physicians with expertise in hypertension and cholesterol lowering treatment, who will handle routine protocol questions for approximately 50 clinical sites apiece. Under direction of the Clinical Trials Center, they will assist in solving problems related to quality control, protocol adherence, recruitment and retention for the sites assigned to them. Physician coordinators will be supported by a nursing coordinator and may opt to participate as clinical sites as well. All participating VA hypertension clinics will be supervised by a single coordinator.
  • a Drug Distribution Center will be established by the Clinical Trials Center to (1) receive, package and distribute all pharmaceuticals required for the two ALLHAT components, (2) implement a system of masking so that the four first-line antihypertensive agents cannot be distringuished from each other by the study investigators or their patients (the second-line antihypertensive drugs will not be masked), and (3) provide appropriate supplies of all study medications to the clinical sites on a timely basis.
  • the Steering Committee will be appointed by the NHLBI to provide expert advice on the study protocol and on all subsequent decisions pertaining to the design and conduct of the study that do not require access to blinded data, and the eventual analysis and publication of the study results. Its voting members will be the NHLBI Project Officer, the principal investigator of the Clinical Trials Center, the Regional Coordinators, and 7-9 experts selected for their expertise and experience in the treatment of hypertension and/or hypercholesterolemia and in key clinical trials issues such as recruitment and adherence. Each Steering Committee member will be required to submit an annual financial disclosure statement to the Chnical Trials Center and to divest themselves of any stock holdings or retainer-type consultant positions in pharmaceutical and other companies that have a direct financial interest in the outcome of the study. The Steering Committee will meet once per year (more frequently during protocol development).
  • An Executive Committee will be instituted to oversee trial operations between Steering Committee meetings. Composition of the Executive Committee will include the Chair and Vice- Chair of the Steering Committee and representatives of the Program Office, the Clinical Trials Center, and the Department of Veterans Affairs. Reporting to the Executive Committee will be the following subcommittees: Eligibility and Medical Care, Operations, Publications and Ancillary Studies, Scientific and Educational Program, and Endpoints. Each of the subcommittees will have representation from the Program Office, Clinical Trials Center, and Steering Committee to oversee aspects of the trial that require frequent attention and/or special expertise, such as recruitment, adherence, quality control, blood pressure and lipid intervention, laboratory methods, endpoint verification, ancillary studies, publications, and the annual program for the investigators' meetings.
  • Protocol Review Committee The Protocol Review Committee will be responsible for advising the NHLBI regarding the initial approval of the study protocol. Its members and chair will be appointed by the Director, NHLBI, and will consist of at least seven experts who are not otherwise affiliated with the study. It will meet in Bethesda when the study protocol has been completed. The meeting will be attended by the principal investigator (and designated staff) of the Clinical Trials Center and the Chair and Vice-Chair of the Steering Committee who will make presentations and answer questions regarding the protocol, and by Program Office staff.
  • DSMB Data and Safety Monitoring Board
  • the DSMB will be responsible for monitoring all aspects of the study, including those that require access to blinded data.
  • the DSMB and its chair will be appointed by the Director, NHLBI, and will consist of at least seven experts who are not otherwise affiliated with the study. It is likely that the roster of the DSMB members may be largely or even entirely derived from the Protocol Review Committee, which will complete its mission as the DSMB is formed.
  • the DSMB will meet at least semi-annually.
  • the principal investigator of the Clinical Trials Center and designated Clinical Trials Center staff will attend these meetings (but will not have a vote) and will be responsible for preparing and presenting up-to-date statistical reports on the progress of the study. These reports will include data on recruitment, randomization, adherence, blood pressure levels, plasma lipoproteins, adverse drug responses, and study end points, as well as statistical tests and special analyses requested by the DSMB.
  • the Project Director who will serve as the DSMB's Executive Secretary
  • Project Officer and designated NHLBI staff and the Chair and Vice-chair of the Steering Committee will also participate in these meetings m ex officio capacities.
  • the DSMB will monitor the progress of recruitment (particularly of African-American patients) and the random allocation of participants to the various treatment arms and may recommend modifications in (or termination of) one or both study components if the study design goals are not being met.
  • the DSMB will recommend when to end the active recruitment phase of the study.
  • the approval of the DSMB will also be required for any significant changes in the protocol recommended by the Steering Committee during the course of the study. All votes will be decided by a simple majority.
  • the DSMB may recommend discontinuation of any of the treatment arms of either study component on any of the following grounds:
  • the DSMB may convene an Executive Session at any time. DSMB members, the Project Director and the Project Officer will attend these sessions.
  • the Director, NHLBI will make the final decision on whether or not to accept the DSMB's recommendation to discontinue any component of the study.
  • Reports for clinic use include randomization verification reports, visit schedules and reminders, endpoint documentation reports, and limited cross-forms edits. These will be generated no more often than monthly. Visit schedules are generated as participants are randomized and include all visit windows and expected special procedures for the duration of the study. Reports and appropriate listings will be sent to the clinics, and summary reports will be sent to the Project Office, Steering Committee and Regional Coordinators.
  • Steering Committee reports will be generated for annual meetings and will be similar to routine recruitment and monitoring reports.
  • Data and Safety Monitoring Board reports will include recruitment and monitoring data by treatment group for both the antihypertensive trial and the lipid-lowering trial. They will also include summary reports of data from the central laboratory and biennial and event ECG data, as well as study endpoints by treatment group.
  • All clinical sites will be required to attend one of three regional training sessions. These training sessions will include orientation to the study protocol, blood pressure measurement training and certification, orientation to the ECG procedures, and training in completion and transfer of study forms.
  • Periodic refresher training will be held in conjunction with regularly scheduled Steering Committee meetings. These refresher sessions may include a review of correct blood pressure measurement procedures or any problem that may be identified through review of routine monitoring activities.
  • a patient's assigned treatment group may be revealed.
  • the Regional Coordinators will be the first line of advice in the decision of whether to break the blind or not. If the Regional Coordinator cannot be reached, the investigator should try to contact any of the other Regional Coordinators, or Dr. Davis or Dr. Goff at the Clinical Trials Center, or Dr. Payne or Dr. Cutler at NHLBI to discuss the relevant medical issues. If medically appropriate, an effort will be made to maintain the blinding of the patient and the clinical center investigator. If the regional coordinator agrees, or if the investigator is insistent, the investigator should contact the Clmical Trials Center to determine the unblinded treatment assignment. If there is an emergency and the Clinical Trials Center cannot be contacted, the investigator will reveal the unblinded treatment assignment by contacting a central unblinding facility.
  • the Regional Coordinators will be the first line of advice in the decision of whether to withdraw the patient from study treatment. If the Regional Coordinator agrees, or if the investigator is insistent, the investigator should contact the Clinical Trials Center to inform them that this action is being taken and the reasons for it.
  • the clinical sites will be reimbursed on a capitation basis for each randomization to the antihypertensive trial, randomization to the lipid-lowering trial, each protocol-required follow-up visit, and each completed study endpoint. These payments will be made monthly from the Clinical Trials Center.
  • a study form In order for a reimbursement to be authorized, a study form must be received at. the Clinical Trials Center, all questions regarding that form must be resolved, and the form must be entered onto the study database.
  • reimbursements will be in several parts made separately for the study form itself, the death certificate or discharge summary, and for additional documentation for the 10% sample for verification.
  • the primary endpoint of the antihypertensive component of ALLHAT is fatal plus nonfatal CHD.
  • the primary response variable is time from randomization to development of this event.
  • the log rank test [60] will be used to compare each of the non-diuretic treatment groups to the diuretic one.
  • the log rank test will also be used.
  • the log rank test will also be used to test if there are treatment differences in the following subgroups for the outcome of fatal and non-fatal CHD — 1) men and women, 2) > 65 years and ⁇ 65 years, 3) African Americans, and 4) diabetics and non-diabetics. ' For the outcomes of LVH by ECG, and health-related quality of life, comparison of proportions will be used to see if there are differences in the treatment groups. For the outcome of renal disease, the inverse of the slope of creatinine will be calculated for each participant. The weighted average of the participants' inverses in each treatment group will be calculated and these averages will be compared across groups using the longitudinal models of Laird ' and Ware [61].
  • the primary endpoint of the lipid-lowering component of ALLHAT is all-cause mortality.
  • the primary response variable is time from randomization to death.
  • the log rank test will be used to compare the group assigned to lipid-lowering ' therapy to the group assigned to no treatment.
  • the log rank test will also be used.
  • the log rank test will also be used to test if there are treatment differences in the following subgroups for the outcome of fatal and non-fatal CHD - 1) men and women, 2) > 65 years and ⁇ 65 years, 3) African Americans, and 4) diabetics and 'non-diabetics.
  • comparison of proportions will be used to see if there are differences in the treatment groups.
  • Interim monitoring will focus on patient intake - overall and within clinical center, center adherence to protocol, baseline comparability of treatment groups, sample size assumptions with regard to event rates, crossover rates, competing risk and lost to follow-up, adverse effects data, and effect of treatment on the primary and secondary study outcomes. Interim analyses will coincide with the meetings of the Data and Safety Monitoring Board (DSMB).
  • DSMB Data and Safety Monitoring Board
  • termination in favor of the alternative hypothesis- (H a ) may be considered if the conditional probability of rejecting the null hypothesis (H 0 ) at the scheduled end of the study given the current data and assuming H 0 is true, is greater than or equal to some pre-specified value ⁇ 0 .
  • termination in favor of the null hypothesis would be considered if the conditional probability of rejecting Ho under the design specified alternative hypothesis is less than some pre-specified value ⁇ a .
  • the .type I error is inflated slightly above ⁇ (depending on the number of looks at the data, the timing of the looks, and the value of ⁇ 0 ) and the type II error is slightly inflated above ⁇ (again, depending on the number of looks at the data, the timing of the looks, and the value of ⁇ a ).
  • the choice of the ⁇ 's will be determined by the DSMB.
  • the initial six months of the study will comprise a vanguard phase for the full-scale trial. Twenty practices will be selected to carry out this vanguard phase with the goal of randomizing six hundred (of the full complement of 40,000) patients. Objectives of the vanguard phase include:
  • StasonWB Cost and quality trade-offs in the treatment of hypertension. Hypertension 1989; 13 (SupplI): I-145-I-148.
  • SHEP Cooperative Research Group Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-3264.
  • Furberg CD Cutler JA. Diuretic agents versus beta-blockers: Comparisons of effects on mortality, stroke, and coronary events. Hypertension 1989; 13(Suppl I): 1-57— 1-61.
  • HMG CoA 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors in the treatment of hypercholesterolemia. J Am Med Assoc 1987; 258:3532-3536.
  • CHD rate in the diuretic arm was about 1.35% a year (a 6 year rate of approximately 7.8%). This was based on exponential regression models applied to data from Framingham 12, Framingham 16, and HDFP. We included from the Framingham data all hypertensives aged 45-75, excluding those with recent MI (within 2 years). The variables included in the model were age, sex, and whether or not the patient was at high risk (defined as meeting ALLHAT entry criteria). Rates were adjusted to a mean age of 67 and a 55% prevalence of males. A similar analysis was done on the HDFP data, which included those 50 years old and older. The stepped and referred care cohorts of HDFP were analyzed separately. The following reductions were applied for secular trends and the healthy volunteer effect.
  • Crossover rates were estimated from TOMHS. We fit a time-dependent Markov model to the data. A model assuming a 2.75% chance of crossing over to another medication during each of the first three years, and 6% for each of the last three years appears to fit well (see Figure 1). Under this model, about 24%> of all patients will cross over to another medication at least once in 6 years, and about 21% of all patients will be crossed over to another medication at the end of 6 years. A patient in the diuretic arm who crosses over to another active antihypertensive medication is assumed to have a reduced event rate even though some of the other antihypertensives may confer no benefit.
  • a patient in an active antihypertensive arm who crosses over to another antihypertensive medication is assumed to have an increased event rate consistent with the diuretic arm even though that patient may have crossed over to another antihypertensive medication that is as beneficial as that to which he/she was assigned.
  • A' patient may cross over and then cross back.
  • crossover rates 1, 2, and 3 correspond to approximately 20% and 22.5% of patients on another medication at the end of 6 years, respectively.
  • the latter rate ' appears to be quite conservative.
  • the three rates of 22%, 24%, and 26% for at least one crossover will henceforth be referred to as crossover rates 1, 2, and 3, respectively.
  • Loss from competing risks was estimated to be approximately 8% over 6 years. Tlis was composed of other cardiovascular mortality (2.6% over 6 years) and non-cardiovascular mortality (5.4% over 6 years). These rates were calculated in a manner similar to the way we computed event rates for the primary endpoint. The same healthy volunteer and secular trend adjustments were applied. We added about 1.5% per year for losses to follow-up, yielding a total loss rate of approximately 16.8% over 6 years. We considered two other loss rates of 16.8% ⁇ 5%. The three loss rates of 11.8%, 16.8%, and 21.8% will henceforth be referred to as loss rates 1, 2, and 3, respectively.
  • ⁇ (x) power can be shown to be:
  • the primary endpoint for the lipid lowering component is total mortality. W ⁇ assume that the vital status of all participants can be ascertained from the National Death Index, hence there will be no loss to follow-up.
  • Power for the LL total mortality component is depicted in Figure 7.
  • the power is almost exactly 80%o under dropin/dropout rate 1 and a 12.5% reduction in mortality from LL treatment. It drops to 68.6% if there is only an 11 % reduction in mortality (other assumptions as before).
  • the power will be 88.1% if there is a 14% reduction in mortality from LL treatment (other assumptions as before).
  • the power is 76.9% under a 2.35%/yr mortality rate and a 12.5% reduction in mortality from LL treatment (not shown in the graph).
  • CABG coronary bypass grafting
  • PTCA percutaneous transluminal coronary angioplasty
  • Coronary death will be subclassified as:
  • CHD no known non-atherosclerotic cause and one or both of the following: chest pain within 72 hours of death or a history of chronic ischemic heart disease in the absence of valvular heart disease or non- ischemic cardiomyopathy, or
  • coronary death will also be classified as rapid or non-rapid, based on whether death did or did not occur within 24 hours after the onset of symptoms (or the time at which the patient was last seen without symptoms).
  • MI myocardial infarction
  • Symptoms (such as chest pain) compatible with an acute MI of at least 20 minutes duration.
  • ECG changes compatible with an acute MI such as new persistent ST segment elevation of > 0.1 mV or new pathologic Q waves (QRS>0.04 sec), each in two contiguous leads.
  • a serum biochemical marker compatible with an acute MI such as:
  • the deficit must last more than 24 hours unless death supervenes or there is a demonstrable lesion compatible with acute stroke on CT orMRI scan.
  • Non-fatal stroke (either of the following):
  • Fatal stroke Death certificate listing stroke as consistent with, underlying, or immediate cause of death, plus any one or more of the following:
  • Appendix III Electrocardiographic Criteria for Silent Myocardial Infarction, Ischemia, Left Ventricular Hypertrophy, and Bundle Branch Block
  • the ALLHAT study records electrocardiographic information from baseline and biennial clinic visits and from a sample of acute hospitalizations that are designated as quality control events. Clinic ECGs are evaluated for prevalent and interim events including "silent" myocardial infarction.
  • a determination that an ALLHAT participant has prevalent MI, ischemia, LVH or bundle branch block can be made using Minnesota Code criteria.
  • Interim MI, ischemia, LVH or bundle branch block can be made using the criteria shown for simultaneous comparison of ECGs.
  • Baseline ECG coded a) 3-1 or 3-3 (soft LVH) b) 3-1 or 3-3 PLUS any 4-3 through 4-1-x, or 5-3 through 5-1 (hard
  • Interim Ml Any EDI through ED7
  • Interim ischemic event Any EVl -EV9 pattern
  • Interim bundle branch block .
  • An Equivocal Q-code is a 1-2-8 or any 1-3-x code.
  • a Diagnostic Q-code is any 1-1-x or any 1-2-x except 1-2-6 or 1-2-8. « The designation of "ED" means evolving diagnostic Q-code pattern. ⁇ All ED patterns are confirmed as significant increase by serial comparison.
  • ED2a An Equivocal Q-code (1-2-8 or any 1-3-x code) and no major ST depression in baseline ECG followed by a record with a Diagnostic Q-code (1-1 -1 to 1 -2-5 or 1-2-7) PLUS a major ST depression (4-1-X or 4-2), confirmed as a significant increase.
  • ED2b An Equivocal Q-code (1-2-8 or any 1-3-x code) with pre-existing major ST depression (4 1-X or 4-2) in baseline ECG followed by a record with a Diagnostic Q-code (1-1 - 1 to 1-2-5 or 1-2-7) PLUS more severe ST depression (4-1-X), confirmed by a significant increase.
  • E-BBB 1 No 7-1-1 in reference followed by an ECG with 7-1-1 with the QRS duration increased by > 0.02 sec, confirmed as a significant increase.
  • E-BBB 3 No 7-4 in reference followed by an ECG with 7-4 with the QRS duration increased by > 0.02 sec, confirmed as a significant increase.
  • E-LVH 1 No 3-1 in the reference ECG followed by an ECG with a 3-1, confirmed as a sigificant increase.
  • E-LVH 4 3-3 in the reference ECG followed by an ECG with 3-3 or no 3 code confirmed as a significant decrease.
  • E2 An ECG record with ST-segment depression (4-1-x, 4-2, or 4-3).
  • Appendix TS 7 Quality Control Evaluation of Hospitalized Myocardial Infarctions (MI)
  • Enzymes are classed as abnormal if any enzyme values recorded meet any of the following criteria:
  • CK-MB is "present”: ( if laboratory uses the criterion of "present” or “absent” without reporting a more specific value) or the CK-MB is greater than or equal to 10% of the total CK value, and b. There is no known non-ischemic cause (cardiac surgery, severe muscle trauma, rhabdomyolysis) for the elevated enzyme value. or
  • Total CK and LDH are both at least twice the upper limits of normal. (These increases do not have to occur on the same day). and b. There is no known non-ischemic cause (cardiac surgery, severe muscle trauma, rhabdomol sis) for the elevated enzyme value and no evidence of hemolytic disease.
  • Enzymes are classed as "equivocal" if the criteria for abnormal enzymes are not met and if: 1. Either total CK or total LDH are at least twice the upper limits of normal. or
  • Power for the lipid-lowering portion of ALLHAT was revised based on a total sample size of 10,000 and subgroups of size 4,000.
  • the dropout rate was taken as the more pessimistic of the two scenarios in the protocol-6% in the first year and 3% per year thereafter.
  • the dropin was also taken as the more pessimistic of the two protocol scenarios, namely 2.5% per year.
  • the loss for total mortality was taken to be 0, while for the CHD it was as specified in the protocol for the antihypertensive component (slightly over 3% per year).
  • the event rates shown are after accounting for benefits of antihypertensive therapy.
  • the power results are shown in Tables 1 and 2. A more pessimistic loss of 5% per year was also considered. This reduced power by about 2 percentage points.
  • the amount of type 1 error probability spent is inextricably linked to information time. This contrasts with the method of Slud and Wei (1982), which spends a fixed amount of type 1 error probability at each look at the data, regardless of the-information time. Serious inflation of the type 1 error rate can occur with the Slud and Wei procedure, but not with the Lan-DeMets procedure (Proschan, Follmann, and Waclawiw, 1992).
  • conditional power (Lan, Simon, and Halperin, 1982 or Lan and Wittes, 1988).
  • conditional probability of obtaining a statistically significant result at the end of the trial is computed under different hypothesized treatment effects. Unlike the O'Brien-Fleming or Lan-DeMets boundaries, conditional power is usually used to justify terminating a trial which has no realistic chance of producing a statistically significant result. The trial is stopped if the conditional power is very low even assuming a large treatment benefit for the remainder of the trial. Stochastic curtailment refers to stopping a trial because the conditional power crosses a pre-specified threshold value.
  • ⁇ is the two-sided type 1 error rate for a given comparison with diuretic
  • ⁇ is the standard normal distribution function
  • Z ⁇ 4 is its 100(l- ⁇ /4)th percentile.
  • ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
  • NALBI National Heart, Lung, and Blood Institute
  • the study has two components:
  • An antihypertensive component to determine whether newer antihypertensive agents, such as ACE inhibitors, calcium blockers, and alpha blockers, reduce incidence of coronary heart disease (CHD) in high-risk hypertensives when compared to diuretics.
  • CHD coronary heart disease
  • a lipid-lowering component to determine whether reduction of serum cholesterol with pravastatin, an HMG-CoA reductase inhibitor, reduces total mortality in moderately hypercholesterolemic older hypertensives.
  • African-Americans suffer disproportionately from hypertension. and its sequelae, a large percentage of participants will be African-American.
  • Antihypertensive Component in the early 1980's three new classes of antihypertensive agents, the calcium antagonists, angiotensin- converting enzyme (ACE) inhibitors, and alpha-adrenergic blockers, were developed and licensed for use in chronic antihypertensive therapy. Some of these agents can cost up to 30 times as much as older therapies such as diuretics and beta blockers. They are also believed to have fewer side effects and may have ancillary properties (in addition to their blood-pressure lowering effects) that could reduce morbidity and mortality from coronary heart disease (CHD).
  • CHD coronary heart disease
  • Elevated cholesterol is known to be a major CHD risk factor, but trials demonstrating a reduction in CHD from cholesterol lowering have not demonstrated a net reduction in all-cause mortality. Since these trials have been conducted primarily in middle-aged men, the extrapolation of their findings to older men and women has also been questioned.
  • ALLHAT hypertensive patients High-risk are randomly assigned to receive one of four drugs in a double- blind design. No patient receives placebo, and a limited choice of second step agents are provided for patients not controlled on first- line medication. Patients are followed every 3 months for the first year and every 4 months thereafter for an average of 6 years of follow-up.
  • Antihypertensive Component o Age 55 years or older o Known hypertensive with BP less than or equal 160/100 mmHg on treatment, or BP greater than or equal 140/90 mmHg and less than or equal 180/110 without treatment . o At least one of the following:
  • Chlorthalidone a common diuretic used to treat people The School of Public Health -with high blood pressure, The study followed 24,335 was awarded a $103.2 million dramatically decreases the risk patients age 55 and older with contract from the NHLBI to of cardiovascular disease high blood pressure and at least coordinate ALLHAT in 1993, compared to doxazosin, an one of several cardiovascular making it the largest contract alpha-blocker, say researchers disease risk factors, such as ever awarded to UT-Houston. at UT-Houston. diabetes and a history of stroke. . The patients were randomly More than 4.6 million assigned to receive one of four
  • a lipid-lowering ascertain to what extent the relative risk with doxazosin trial in a subset of 10 336 participants is designed to deversus chlorthalidone depends on 1) whether the assigned termine whether decreasing cholesterol levels with a hy- drugs were used as monotherapy or in combination with droxymethyl glutamyl coenzyme A reductase inhibitor other agents and 2) the difference in decreases in systolic (pravastatin) compared with usual care reduces all-cause and diastolic blood pressure. mortality in older, moderately hypercholesterolemic patients. In January 2000, the doxazosin arm of the trial was METHODS discontinued.
  • ALLHAT defined symptomatic heart failure as clear-cut-
  • the ALLHAT protocol specified a s ⁇ epped-care treatand women 55 years of age or older who had systolic or ment program for hypertension. Trained observers using diastolic hypertension ( ⁇ 140/90 mm Hg or hypertension standardized techniques measured blood pressures during controlled with medication) plus at least one additional the trial (1, 2). All blood pressures were calculated as the risk factor for coronary heart disease events. The risk facaverage of two measurements obtained with a 30-second tors included previous (>6 months) myocardial infarction interval between them. The blood pressure goal in all four or stroke, left ventricular hypertrophy on electrocardi ⁇ gra- study arms was less than 140/90 mm Hg.
  • This level was to phy or echocardiography, history of type 2 diabetes, curbe achieved with the lowest possible dose of blinded first- rent cigarette smoking, and a low high-density lipoprotein line drug, with addition of second- and third-line open- cholesterol level. Persons with a history of hospitalized or ' label therapy as needed after reaching the maximal dose of treated symptomatic heart failure or a known ejection fracfirst-line drug. tion less than 0.35 were excluded. Chlorthalidone and doxazosin were to be taken once
  • Type 2 diabetes % 35 4 35 0 36 2 35 1
  • Diastolic 83 8 ⁇ 9 8 83 9 £ 9 9 9 84 1 10 3 83 9 ⁇ 10 1
  • Serum potassium level, mmoM.* 4 1 ⁇ 07 4 4 i 0 8 4 3 0.7 4 3 ⁇ 0 6
  • Serum cholesterol level mmol/l (mgJdV
  • the Figure shows the number of patients who were Cox regression analyses of the entire cohort that included randomly assigned and followed to the time of each analfixed covariates of baseline systolic and diastolic blood presysis. It also shows the number of participants who reached sure and time-dependent covariates of follow-up systolic the maximal dose level of blinded step 1 drug and those and diastolic blood pressure were performed. who were stepped up to any open-label drug or any anti ⁇
  • Table 1 shows baseline characteristics of the chlortha ⁇
  • the doxazosin arm included more the dose of doxazosin was increased from 2 mg to 4 mg but black patients than white patients compared with the not when it was increased from 4 mg to 8 mg.
  • the chlorthalidone arm included more black patients dose of chlorthalidone was increased from 12.5 to 25 mg. than white patients.
  • the doxazosin arm included more Hispanic patients with the overall results. and more persons with atherosclerotic cardiovascular disThe results of the two outcome comparisons for the ease but.
  • Table 2 shows results of Cox regression analyses comyear, 20% at 3 years, and 16% at 5 years. paring the treatment groups with respect to heart failure
  • Table 4 shows event rates and relative risks of the outcomes for all patients as randomly assigned, those with treatment groups for heart failure outcomes beyond 1 year, no exposure to open-label medication, and those with exwith stratification to control for blood pressure at ] year. posure to such medication.
  • the 4-year event rates are The stratum with the lower systolic or diastolic blood preshigher among participants exposed to open-label medicasure had a higher relative risk and a smaller difference in tion than in those not exposed.
  • the stratum with the done treatment is substantial, in patients without and with best control (blood pressure ⁇ 140/90 mm Hg) had the exposure to open-label drugs.
  • the risk ratios in the monogreatest relative risk and only a small difference in mean therapy groups (3.1 for all cases of heart failure and 2.5 for systolic blood pressure. After adjustment for baseline and hospitalized or fatal heart failure) are greater than those in follow-up blood pressures, the results were essentially unthe as-randomized groups.
  • Table 3 shows the relative risk for all heart failure and beneficial, doxazosin was harmful, or both.
  • Chlorthalidone hospitalized or fatal heart failure in the treatment groups has been shown- to prevent and treat heart failure (9), according to dose levels of doxazosin and chlorthalidone. whereas doxazosin has not been shown to do either.
  • Tliis analysis is limited to duration of follow-up with no Systolic Hypertension in the Elderly Program, risk for exposure to open-label therapy. The increased risk was apheart failure was reduced by 50% with use of chlorthaliparent at all dose levels of doxazosin. At a fixed dose of done compared with placebo (9). chlorthalidone, an increase in relative risk was noted when In ALLHAT, not all participants continued to take
  • Indication bias happens when the invesases described above
  • tigator gives additional medication on the basis of signs the relative risk tended to increase with increasing doses of and symptoms, for example to control blood pressure or doxazosin
  • the rela- reduce perceived side effects Diagnostic bias can occur nve risk decreased with the increased dose of chlorthaliwhen the investigator or patient is influenced by knowldone Increasing doses of doxazosin relative to increasing edge about treatment Participants in the doxazosin group doses of chlorthalidone were associated with shorter durawere significantly more likely (relative risk, 1 31) than tion of treatment with the medication If doxazosin had no those in the chlorthalidone group to receive other drugs, effect on preven ⁇ on of heart failure, comparison of paand administration of other drugs tended to occur earlier tients taking a fixed
  • doxazosin recipients were more hkely Davis, J A. Cutler, C D Furberg, J T Wright, MA Father, J V Felicthan chlorthalidone recipients to be given additional drugs etta, J D Stokes.
  • the sample includes a high proportion of people with diabetes (36%), patients with existing cardiovascular disease (47%). and smokers (22%). There were no important differences between the randomized treatment groups at baseline. ALLHAT will add greatly to our understanding of the management of hypertension by providing an answer to the following question: are newer antihypertensive agents similar, superior, or inferior to traditional treatment with diuretics? ⁇ Hypertension. 2001;37:19-27.)
  • uiarly high-dose thiazide diuretics may have offset the the study was designed to recruit high proportions of groups potential benefit of BP reduction.
  • the trial also lin sensitivity, and, possibly, increased ventricular ectopic randomized a subset of participants to a lipid-lowering trial activity. 5-8 However, these side effects are minimal at curdesigned to compare iota!
  • the HAT are high-risk hypertensive paiients recraited at 625 clinical sites in the United States, Canada, Puerto Rico, and the US Virgin ACE inhibitor captopril has been compared with diuretics Islands. Recruitment took place between February 14, 1994, and and/or ⁇ -blockers in 2 large trials, the Captopril Prevention January 31. 1998. The trial ⁇ s scheduled to eD in March 2002, after Project (CAPPP) 10 and the UK Prospective Diabetes Study a mean follow-up of 6 years. However, in February 2000. the (UKDPS).
  • BP eligibility criteria were hased on the patient's current antihyfor preventing cardiovascular events in hypertensive patients pertensive treatment status and on the average of 2 seated BP with heart disease or diabetes l2 - 1; however, other data measurements at each of 2 visits.
  • the BP inclusion criteria at both visits were suggest that the commonly prescribed calcium antagonists are SBP of at least 140 ram Pig or DBP of at least 90 mm Hg.
  • SBP ⁇ i 80 mm Hg and DBP ⁇ i 10 mm Hg were required. For these groups of patients. 16 ⁇ 1 those who had been on treatment with 1 to 2 drugs for ⁇ 2 months,
  • STOP-2 pants into each arm was in the ratio of 1.7:1:1:1, with the largest did not include blacks, persons with stage 1 hypertension, or number assigned to chlorthalidone to maximize statistical powe ⁇ for the comparison of the diuretic arm to each of the 3 nondiurctic arms. ' anyone aged ⁇ 70 years. Furthermore, the results of this trial The initial doxazosin dose was 1 mg for 1 week, followed by 2 mg need confirmation in a larger trial with a broader population for 1 month and monthly titrations thereafter to achieve a BP goal of ⁇ of hypertensive persons. SBP ⁇ 140 and DBP ⁇ 90 mm Hg. Chlorthalidone, amlodipine, and
  • the step 2 Trial (ALLHAT) study was designed to deteimine whether medications provided include reserpine (0.05 to 0.2 mg daily), the combined incidence of fatal CHD and nonfatal MI differs clonidine (0.1 to 0.3 mg twice daily), and atenolol (25 to 100 mg once daily).
  • the step 3 medication is hydralazine (25 to 100 mg between diuretic treatment and 3 alternative antihypertensive , twice daily). All participants were given standard advice on lifestyle pharmacological treatments. To generalize the results of factors (sodium, alcohol, physical activity, and caloric intake), with ALLHAT to a broad population of people with hypertension. reinforcement as needed during the study.
  • ALLHAT The step 2 Trial (ALLHAT) study was designed to deteimine whether medications provided include reserpine (0.05 to 0.2 mg daily), the combined incidence of fatal CHD and nonfatal MI differs clonidine (0.1 to 0.3 mg twice daily), and atenolol (25 to 100 mg
  • HDL cholesterol ⁇ 090 mmol/L on 2 occasions within past 5 y Left ventricular hypertrophy on ECG or echocardiogram within past 2 y
  • Cell may not sum to total because of missing gender data on 2 white participants and 1 black participant
  • Results Table 4 The mean age of the participants ⁇ vas 67 years.
  • Table 2 provides the frequency distribution of ALLHAT both male and female white participants were older than the randomized participants by race, ethnicity, gender, age at black participants This difference resulted p ⁇ ma ⁇ ly from a entry, history of diabetes, and preexisting ASCVD.
  • 25 292 (59 6%) 59 age category (29 1% versus 15 8%, respectively) and a were white, and 15 09 4 (35 6%) were black Asians and larger proportion of whites compared with blacks the 70 to American Indians made up 1 1% and 0.2%, respectively 79 age category (32 0% versus 25.9%, respectively).
  • Pulse bpm 737 ⁇ 107 736 ⁇ ⁇ 07 73 5+108 735 + 107 736 107
  • +ECGs were available for only 38 955 participants, education was provided by 39538 participants, serum ootassium, creatmine, and cholesterol levels were available for 40126 participants, lasting glucose was available lor 31 255 participants, cLDL cholesterol was available for 3749B pa ⁇ icipants, HDL cholesterol was measured m 40099 participants, t ⁇ glyce ⁇ des were measured m 31 304 participants
  • %P ⁇ 001, ⁇ P ⁇ 005 for each characteristic, 2-propo ⁇ on or 2 sample mean difference tests were perrormed comparing each of the 3 ⁇ onoiuretic groups with chlorthalidone, respectively) smaller proportion of female participants compared with male males were more hk ⁇ ly to be current smokers, and blades participants was white (38 5% versus 54 6%, respectively), general w ere more likely to have a history of diabetes, had a and a larger proportion was black ( ⁇ l 5% versus 30 4%, higher resting pulse and had a higher glucose level Black respectively) women had higher body mass index, and blacks overall,
  • Ischemic ST T ave changes % 10 4 92 131 98 87 12 9 11 1 10 1 13 2
  • 'Cell may not sum to total because of missing gender data on 2 white participants and 1 black participant terol, HDL cholesterol, and markedly lower t ⁇ glyce ⁇ de years, 625 centers in the United States, Canada Puerto Rico, levels than did whites Women had higher total cholesterol and the US Viigm Islands enrolled ⁇ 2 4 ⁇ 8 high-nsk patients LDL cholesterol, and HDL cholesterol, whereas men had High nsk was determined on the basis of the presence of higher tnglycendes hypertension, age ⁇ 55 years and at least I additional
  • Table 5 lists the proportion oi participants with each of the cardiovascular ⁇ sk factor ⁇ sk factor criteria that quabf ⁇ ed participants for entrv m the Patients in ALLHAT were randomly assigned to 1 of ⁇ t ⁇ al Compared with black participants white participants treatment groups chlorthalidone, amlodipine hsmop ⁇ l or were more likely to be entered into the study on the basis of doxazosin The treatment groups were balanced at baseline, history of MI and/or stroke, revascularization procedures or with no clinically important differences any of the recorded other ASCVD Blacks more often qualified for the studv for vanables The studv by design included a high percentage of ischemic ECG changes, diabetes, smoking, and left vent ⁇ c African Amencans (35 6%) and nearlv equal proportions bv ul ⁇ ir hypertrophy on ECG Men were more hkel ⁇ to be gender (46 8% w omen) It also included a large cohort of entered into the studv because of previous MI,
  • ALLHAT also may be able to address some questions
  • ALLHAT is the largest randomized double-blind trial ever were randomized an open-label fashion to either convenconducted panents with hypertension Over a period of 4 tional therapy ( ⁇ iurehcs or ⁇ -blockers) or captopnl 10 Al- 26. Hypertension January 2001
  • ECGs were available for only 38 955 participants; serum potassium, creatinine, and cholesterol levels were available for 40 126 participants; fasting glucose was available for 31 255 participants: cLDL cholesterol was available for 37498 participants; HDL cholesterol was measured in 40099 participants; and triglycerides were measured in 31 304 participants.
  • ALLHAT still remains uniquely positioned to provide strokes were more frequent in the group treated with captoan answer to the primary question: are newer antihypertenpril. This finding was partially attributed to the fact that the sive agents superior, similar, or inferior to traditional therapy captopril group had higher baseline SBP and baseline DBP, with diuretics? which remained slightly higher than values in the convenALLHAT is an ongoing study examining the highest tional therapy group throughout the study. No such baseline priority hypertension treatment question at the turn of the BP differences exist in ALLHAT. century. The results of ALLHAT will significantly add to our
  • hypercholesterolemic patients (a subset of the which are currently more costly to purchase on 40,000) with a 3-hydroxymethylglutaryl coenzyme average, as good or better than diuretics in A (HMG CoA) ⁇ eductase inhibitor, pravastatin, reducing coronary heart disease incidence and will reduce all-cause mortality compared to a progression? Will lowering LDL cholesterol in control group receiving "usual care.”
  • moderately hypercholesterolemic older ALLHAT's main eligibility criteria are: 1) age 55 individuals reduce the incidence of cardiovascular or older; 2) systolic or diastolic hypertension; and disease and total mortality? 3) one or more additional risk factors for heart,
  • ALLHAT Prevent Heart Attack Trial
  • CHD Further fatal coronary heart disease
  • CHD Further fatal coronary heart disease
  • ALLHAT randomized to diuretic treatment ALLHAT
  • Am and each of three alternative treatments' — a J Hypertens 1996;9:342-360 calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an oi-adr ⁇ nergic blocker (doxazosin) .
  • ALLHAT also KEY ORDS: Hypertension, hypercholesterolemia, contains a randomized, open-label, lipid-lowering pharmacologic therapy, clinical trial, ALLHAT trial designed to determine whether lowering LDL trial, chlorthalidone, amlodipine, doxazosin, cholesterol in 20,000 moderately lisinopril, economics.
  • the ⁇ -blockers have been shown to have modercountries with documented CHD and cholesterol levately favorable effects on lipid profile, particularly on els between 212 and 309 mg / dL to treatment with HDL cholesterol, LDL cholesterol, and the LDL /HDL simvastatin or placebo.
  • the primary endpoint was toratio. 13,23 Improvements in insulin resistance also have tal mortality with a median follow-up of 5.4 years. been reported with ⁇ -blockers. 24 There is some eviThe results of the trial showed the following: 1 ) a dence that these agents may reduce platelet aggrega- reduction of 35% in the mean LDL cholesterol in the bility and stimulate tissue plasminogen activator.
  • myocardial infarction differs between diuretic (chlorTable 2. thalidone) treatment and three alternative antihyperOne of the main reasons for choosing all-cause mortensive pharmacologic treatments — a calcium antagotality as the primary endpoint was that this trial is unnist (amlodipine), an ACE inhibitor (lisinopril), and blinded. Further, the assessment of myocardial inan ⁇ -adrenergic blocker (doxazosin).
  • the lipid-lowfarction for this component will rely on the routine cenering component is a randomized, open-label trial detrally coded, electrocardiogram (ECG), rather than the signed to determine whether lowering serum cholespotentially biased assessment of the study physicians.
  • ECG electrocardiogram
  • CoA reductase inhibitor (pravastatin) will reduce all- While a blinded study would certainly have been cause mortality as compared to a control group receivpreferable in many ways, other factors did not make it ing "usual care.” feasible within the overall context of ALLHAT. Compli ⁇
  • Secof Visit 1 is to assess ehgibiUty for and interest in ondary hypotheses for this component are listed in ALLHAT and to begin withdrawing patients from ⁇ Table 2. blockers and central ⁇ -agonists if needed. It is antici ⁇
  • Renal disease a. Slope and reciprocal of serum creatinine b. End-stage rena] disease (initiation of chronic renal dialysis or kidney transplant)

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