Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Condition: Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus; Heart Diseases; Hypercholesterolemia; Hypertension; Myocardial Infarction; Myocardial Ischemia; Heart Failure
MeSH terms: Cardiovascular Diseases; Heart Diseases; Myocardial Infarction; Coronary Disease; Myocardial Ischemia; Hypercholesterolemia; Infarction; Ischemia
Study type: Interventional
Phase: Phase 3

Summary: 
      To determine if the combined incidence of nonfatal myocardial infarction and coronary heart
      disease death differs between diuretic-based and each of three alternative antihypertensive
      pharmacological treatments. Also, to determine, in a subset of this population, if lowering
      serum cholesterol with a HMG CoA reductase inhibitor in older adults reduces all-cause
      mortality compared to a control group receiving usual care. Conducted in conjunction with the
      Department of Veterans' Affairs.
    

Detailed description: 
      BACKGROUND:

      An estimated 58 million people in the United States have elevated blood pressure (systolic
      blood pressure (SBP) of 140 mmHg or greater and/or diastolic blood pressure (DBP) of 90 mmHg
      or greater on initial examination) or are taking antihypertensive medication. Perhaps
      one-half to two-thirds of these have sustained hypertension.

      Despite the known etiologic relationship of hypertension to coronary heart disease,
      large-scale randomized clinical trials in mild to moderate hypertension have failed to
      demonstrate conclusively that antihypertensive drug treatment, largely based on thiazide-like
      diuretics, reduces the occurrence of coronary heart disease death or non-fatal myocardial
      infarction. The pooled results of nine such trials, using primarily thiazide-like diuretics
      and involving over 43,000 subjects, suggest a 9 percent benefit, with 95 percent confidence
      limits consistent with a 19 percent benefit or 1 percent adverse outcome. This observed
      treatment effect compares with a maximum predicted effect on coronary heart disease of
      approximately 23 percent for an equivalent blood pressure difference, as derived from
      epidemiologic data. In contrast, the observed beneficial effect on stroke in these trials, 36
      percent, is almost exactly that which would be predicted from epidemiologic data. A more
      recent overview of 14 trials in participants with all levels of hypertension estimated a
      somewhat larger benefit of 14 percent. While this may be an over-estimate of benefit, these
      overviews do not include the strongly positive results of the Systolic Hypertension in the
      Elderly Program (SHEP), in which diuretic-based treatment reduced stroke incidence by 36
      percent and major coronary heart disease events by 27 percent.

      In the early 1980s, two new classes of antihypertensive agents, the calcium antagonists and
      ACE inhibitors, were developed and licensed for use in chronic antihypertensive therapy.
      These agents cost more than older agents such as diuretics and beta-blockers, and evidence
      was limited that might justify their use despite the increased cost. The 1988 Joint National
      Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommended
      beta-blockers, calcium antagonists, ACE-inhibitors, and diuretics as equally acceptable
      first-line therapy. All four classes of drugs have been found to control diastolic blood
      pressure as single agents in 50 percent or more of patients with mild hypertension.

      Of these drug classes, only beta-blockers have been compared directly to diuretics in
      large-scale, long-term clinical trials in hypertension. Three such trials completed in Europe
      in 1985-1986 showed approximate equivalence of effects on morbidity and mortality in
      diuretic- and beta-blocker-based regimens. Pooled analysis of these trials yields a 6 percent
      lower coronary heart disease mortality from beta-blockers. These data are in contrast to the
      recent Medical Research Council (MRC) Trial in the Elderly, in which patients treated with a
      thiazide diuretic had significantly lower rates of coronary heart disease compared to
      beta-blocker treatment or placebo, both by about 45 percent.

      Circulating levels of cholesterol, specifically cholesterol associated with the low-density
      lipoprotein (LDL) fraction, have been established as a major etiologic factor in coronary
      heart disease in observational epidemiologic studies, in metabolic, pathologic, and genetic
      studies in humans and selected animal models, and in randomized clinical trials. The clinical
      trials that have demonstrated a reduction in coronary heart disease incidence from lowering
      LDL-cholesterol levels have been conducted primarily in middle-aged men with
      hypercholesterolemia or established 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. The paucity of clinical trial data
      led the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and
      Treatment of High Blood Cholesterol in Adults in their 1987 Guidelines to allow for
      considerable physician judgement regarding the elderly.

      DESIGN NARRATIVE:

      Patients were recruited through office-based practices and hypertension clinics which were
      reimbursed by the Clinical Trials Center on a per-patient basis. Six hundred patients were
      entered into the vanguard or feasibility phase and a total of 42,448 were entered into the
      full-scale trial. The primary hypothesis of the antihypertensive trial was that the combined
      incidence of fatal coronary heart disease and nonfatal myocardial infarction would be lower
      in hypertensive patients randomized to amlodipine (a calcium antagonist), lisinopril (an
      angiotensin-converting enzyme (ACE) inhibitor), or doxazosin (an alpha adrenergic blocker) as
      compared to those randomized to chlorthalidone (a thiazide-like diuretic). Secondary
      endpoints were total cardiovascular mortality, major morbidity, all-cause mortality, and
      health-related quality of life.

      The primary hypothesis of the cholesterol-lowering trial was that mortality from all causes
      would be lower in the subset of hypertensive patients with LDL cholesterol levels between 120
      and 189 mg/dl (between 100 and 159 mg/dl for those with known coronary heart disease) who
      were randomized to receive pravastatin (a HMG CoA reductase inhibitor) plus the National
      Cholesterol Education Program Step I cholesterol-lowering diet than those randomized to
      receive usual care plus diet. Secondary endpoints were the combined incidence of nonfatal
      myocardial infarction and coronary heart disease death, major non-cardiovascular heart
      disease morbidity and mortality, and health-related quality of life.

      Recruitment for the feasibility phase began in February 1994. The clinical phase of the
      feasibility study ended in September 1994. Recruitment for the full-scale trial began in
      October 1994 and ended in January, 1998. The mean follow-up was 4.9 years. There were over
      600 clinics in 47 states, Puerto Rico, Virgin Islands and Canada.
    

Intervention name(s): Inhibitors, ACE; amlodipine; lisinopril; doxazosin; chlorthalidone; pravastatin; diet, fat-restricted
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Behavioral
Intervention MeSH terms: Amlodipine; Lisinopril; Chlorthalidone; Doxazosin; Pravastatin; Angiotensin-Converting Enzyme Inhibitors
Allocation: Randomized
Primary purpose: Prevention