Book Review

Clinical Trials in Hypertension

N Engl J Med 2001; 345:1217-1218October 18, 2001

Article

Clinical Trials in Hypertension
Edited by Henry R. Black. 643 pp. New York, Marcel Dekker, 2001. $225. ISBN: 0-8247-0270-0

One of the highlights among the remarkable achievements in medicine over the past four decades has been the development of antihypertensive agents. Since the introduction of these agents into clinical practice, cardiovascular mortality in this country has been reduced from a rate above 54 percent to a rate below 50 percent, an astounding and impressive statistic. This reduction in the overall rate of death due to cardiovascular causes can be attributed primarily to a reduction of more than 70 percent in the rate of death due to stroke and a reduction of more than 50 percent in the rate of death due to coronary heart disease. Moreover, the number of patients with hypertensive emergencies, which once accounted for a large number of hospital admissions, has been reduced so dramatically that hospitalizations for the related diagnoses are clinical rarities.

Coincident with the appearance of longer-acting diuretics, of which chlorothiazide was the first, Edward D. Freis conceived the idea of the multicenter, placebo-controlled trial designed to determine whether less potent agents (reserpine and hydralazine) would reduce cardiovascular morbidity and mortality. Until that time, it was perhaps only in the multicenter trials of antituberculosis therapy that effective reductions in morbidity and mortality had been demonstrated.

Freis demonstrated the feasibility of such multicenter trials as well as the efficacy of ganglionic-blocking drugs and other agents in reducing arterial pressure. Perhaps even more important, he showed that such studies could be conducted in patients with less severe hypertension. The first trial involved patients whose diastolic pressures ranged from 115 to 129 mm Hg; 70 patients received placebo and 73 received active antihypertensive therapy. The follow-up study involved patients whose diastolic pressures ranged from 90 to 114 mm Hg, which showed that the tested therapy was safe and efficacious and that it was associated with reduced morbidity and mortality. This was demonstrated in only 186 patients who received placebo and only 104 who received active therapy. Still more remarkable, these findings were obtained within a five-year follow-up period.

These pioneering studies demonstrated to investigators worldwide the problems associated with the long-term observation of patients in a blinded fashion. They provided techniques to determine whether patients had taken their medications, how studies could be assessed at long distance by a monitoring committee, how the patients' safety could be ensured, how the conduct of the investigators and their team members could be monitored closely, and how such studies could be designed and monitored in cooperation with biostatistical support at yet another location remote from the principal investigators.

This story is presented in the first chapter of Clinical Trials in Hypertension. The subsequent chapters were written (for the most part) by the senior investigators responsible for the multicenter trials that made antihypertensive therapy what it is today. The chapters include discussions of beta-adrenergic–receptor blockers and newer classes of agents. Chapter by chapter, we learn of differences in the responses of patients with diastolic hypertension according to demographic characteristics; the importance of treating elderly patients with isolated systolic hypertension; the value of the beta-adrenergic–receptor antagonists in preventing a second myocardial infarction; the importance of angiotensin-converting–enzyme inhibitors in treating congestive heart failure, reducing recurrent hospitalization for cardiac failure, preventing cardiac failure, death due to cardiac failure, and recurrence of myocardial infarction; the use of angiotensin-converting–enzyme inhibitors in preventing the progression of end-stage renal disease in patients with diabetes mellitus; and the value of calcium-channel antagonists in treating hypertension.

This important reference work collates the major therapeutic and medical milestones of cardiovascular pharmacotherapy. It is easily readable and is suitable for a broad audience, one that includes epidemiologists, biostatisticians, and interested students of cardiovascular, hypertensive, and renal diseases.

Edward D. Frohlich, M.D.
Alton Ochsner Medical Foundation, New Orleans, LA 70121