The ALLHAT Collaborative Research Group. JAMA 2002; 288: 2981–2997

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind, active controlled, clinical trial conducted with a view to determine which antihypertensive treatment decreased the risk of coronary artery disease (CAD) or other cardiovascular disease (CVD) events. It enrolled 33 357 hypertensive subjects, both men and women, >55 years of age, with at least one other risk factor for CAD from 623 North American centers. The patients were randomized to receive chlorthalidone 12.5–25 mg/day (n=15 255), amlodipine 2.5–10 mg/day (n=9048), or lisinopril 10–40 mg/day (n=9054), and followed up for 8 years. The primary end-point was a combination of CAD deaths plus nonfatal myocardial infarction (MI). The secondary end-points were all-cause mortality, stroke, combined CAD end-point (CAD death, nonfatal MI, coronary revascularization, or angina requiring hospitalization), and combined CVD (combined CAD end-point, stroke, treated angina without hospitalization, CHF and peripheral arterial disease). At a mean follow-up of 4.9 years, the primary outcome of CAD death plus nonfatal MI was not different in any of the treatment groups. Compared with chlorthalidone (6-year rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI: 0.90–1.07) for amlodipine (6-year rate, 11.3%) and 0.99 (95% CI: 0.91–1.08) for lisinopril (6-year rate, 11.4%). Similarly, all-cause mortality was also not different. Chlorthalidone was more effective in controlling systolic BP as compared to amlodipine and lisinopril (p<0.05 for both). On the other hand, amlodipine was more effective in lowering the diast olic BP (p<0.01). Among the secondary end-points, occurrence of CHF was commoner in the amlodipine group as compared to the chlorthalidone group (10.2% v. 7.7%, RR 1.38; 95% CI: 1.25–1.52). Similarly, combined CAD end-points (33.3% v. 30.9%, RR 1.10; 95% CI: 1.05–1.16), stroke (6.3% v. 5.6%, RR 1.15; 95% CI: 1.02–1.30), and CHF (8.7% v. 7.5%, RR 1.19; 95% CI: 1.07–1.31) were all higher in the lisinopril group compared to chlorthalidone group. The authors concluded that diuretics are superior to amlodipine or lisinopril in reducing the cardiovascular morbidity and are much less expensive.

For decades, the search for an ideal antihypetensive has been on. An ideal antihypertensive is one which not only controls the blood pressure but also reduces cardiovascular morbidity and, even more importantly, mortality, without causing side-effects. The cost of drug therapy is also important, especially because it has to be continued lifelong. Classically, diuretics and beta-blockers have been considered drugs of first choice, primarily because of their effect in reducing mortality. However, these drugs are not without side-effects, and are besieged with the problems of diuresis, impotence, and depression, as well as dyslipidemia and metabolic abnormalities. Angiotensin-converting enzyme inhibitors (ACE-I) have emerged as a credible alternative because of their efficacy and ability to prevent complications such as the progression of renal disease and stroke. However, till date, no large study has shown reduction in overall mortality with ACE-I. Calcium-channel blockers (CCB), on the other hand, though efficacious, have actually shown increased mortality with the use of shortacting ones. Unfortunately, very few large studies have undertaken head-to-head comparison of various antihypertensive agents. In this context, the ALLHAT study is a landmark one. The major finding of this study was a striking and unequivocal null result in reducing the primary end-point, i.e. CAD death plus nonfatal MI (except doxazocin which was discontinued earlier on in the study). Because of the large number of subjects involved in the study, the mortality benefit with diuretics, if at all, is likely to be very small. However, in the context of reduction of cardiovascular morbidity, therapy with chlorthalidone does seem superior to that with amlodipine or lisinopril. In fact, chlorthalidone was found to be superior to even lisinopril in reducing 6-year CHF rates (8.7% v. 7.7%; CI: 1.07–1.31), a risk reduction of 1.19. However, despite being pathbreaking, the study is still fraught with certain limitations. The blood pressure control achieved was not similar in all the groups (SBP was better controlled with chlorthalidone, while DBP was better controlled with amlodipine). Newer antihypertensive agents such as ramipril, angiotensin receptor blockers, selective aldosterone antagonists, and beta-blockers have not been studied. The most important message from this study is that, as of now, thiazide-type diuretics should still be considered first-line therapy because of their excellent efficacy, low long-term morbidity and mortality rates, and low cost.