Review of the long-term controlled trials of usefulness of therapy for systemic hypertension

Abstract

A number of long-term clinical trials involving over 40,000 patients have been performed to study the effectiveness of antihypertensive therapy in controlling high blood pressure and in reducing the morbidity and mortality associated with hypertension. Only diuretics and β blockers have been studied in long-term trials to determine their efficacy in reducing cardiovascular morbidity and mortality. The Hypertension Detection and Follow-Up Program (HDFP), Medical Research Council (MRC) trial, European Working Party on Hypertension in the Elderly (EWPHE) trial, Australian Therapeutic Trial in Mild Hypertension, and the Veterans Administration Cooperative Study all showed a reduction in stroke rate. The EWPHE and HDFP trials were the only studies to show a statistically significant reduction in mortality from myocardial infarction. All of these were diuretic-based; in addition, the MRC trial also used a β blocker as first-step therapy in 1 cohort. The International Primary Prospective Prevention Study in Hypertension and Heart Attack Primary Prevention in Hypertension (HAPPHY) trials compared β-blocker and non-β-blocker or diuretic-based therapies and found no significant difference between the treatment groups in the incidence of stroke or cardiac events. Neither study had a control group, so it was impossible to determine if there was any reduction in stroke or cardiac events. The Metoprolol Atherosclerosis Prevention in Hypertension trial, an extension of the HAPPHY trial, showed that smokers receiving the β blocker metoprolol had a significantly lower cardiovascular mortality rate than those randomized to a diuretic drug. However, subgroup analysis of the HAPPHY data showed no difference in the effect of β blockers and diuretics in smokers. The Multiple Risk Factor Intervention Trial had an unexpected result: Hypertensive men with electrocardiographic abnormalities at rest who were treated with diuretic drugs in the special intervention group had a higher mortality rate than similar men in the usual-care group. It has been suggested that this was due to arrhythmias from diuretic-induced hypokalemia, but the data do not support this hypothesis.