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.

Condition	Treatment or Intervention	Phase
Cardiovascular Diseases Coronary Disease Diabetes Mellitus Heart Diseases Hypercholesterolemia Hypertension Myocardial Infarction Myocardial Ischemia Heart Failure	Drug: Inhibitors, ACE  Drug: amlodipine  Drug: lisinopril  Drug: doxazosin  Drug: chlorthalidone  Drug: pravastatin  Behavior: diet, fat-restricted	Phase III

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 angiogensin-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 enpoints 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.

Ages Eligible for Study:  55 Years and above,  Genders Eligible for Study:  Both

Criteria

Men and women hypertensive patients, ages 55 and above. A total of 36 percent were diabetics.

Study chairs or principal investigators

Barry Davis,  University of Texas   

Study ID Numbers:  85
Record last reviewed:  August 2004
Record first received:  October 27, 1999
ClinicalTrials.gov Identifier:  NCT00000542
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-29