ALLHAT, the largest hypertensive trial ever conducted, randomized 15,255 patients to chlorthalidone, 9061 to doxazosin (Cardura), 9048 to amlodipine, and 9054 to lisinopril (Prinivil/Zestril).10,11 (The arm involving doxazosin was terminated after 3.2 years.11,22)
Compared with the beta-blocker, more patients achieved target blood pressure control on chlorthalidone (63% vs 58%), and systolic blood pressure was about 2 mm Hg lower. Although the primary outcome of fatal coronary heart disease and nonfatal MI was equal in both groups (doxazosin=7.91%; chlorthalidone=7.76%; RR=1.03 [95% CI, 0.93–1.15]; P=.62), the doxazosin arm had more stroke, heart failure, and combined cardiovascular events.
Patients on amlodipine and lisinopril had a longer follow-up of 4.9 years. Systolic blood pressure was higher on amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P<.001) than on chlorthalidone. The primary endpoint (fatal coronary heart disease and nonfatal MI) was similar on the diuretic (11.5%), calcium channel blocker (11.3%; RR=0.98 [95% CI, 0.90–1.07]; P=.65), and ACE inhibitor (11.4%; RR=0.99 [95% CI, 0.91–1.08]; P=.81).
Compared with the diuretic arm, the calcium channel blocker arm had a higher incidence of heart failure, while the ACE inhibitor arm had a higher incidence of heart failure, stroke, and combined cardiovascular disease. The results were similar whatever the initial glycemic state, renal function status, and racial makeup of the patients studied.23-26 More than 60% of patients in ALLHAT required 2 or more drugs for good blood pressure control.27
“Diuretics first” for patients with or without diabetes?
In ALLHAT, although diabetes occurred more frequently and fasting glucose rose in patients on diuretics, these metabolic abnormalities did not result in more cardiovascular events. Even among patients with diabetes, heart failure was more common on doxazosin, amlodipine, and lisinopril compared with those on chlorthalidone.23,24
Given that the ultimate aim of hypertensive therapy is to reduce clinical disease—not just to improve laboratory profiles—ALLHAT should put to rest any apprehension physicians have about diuretic use. These findings have even led to suggestions that diuretics be the first line antihypertensive agent, in both diabetic and nondiabetic patients.28-30
FAST TRACK
There is evidence that beta-blockers are less useful in the older hypertensive patient
ACE inhibitor vs diuretic
ANBP2 randomized hypertensive patients to initial treatment with an ACE inhibitor (n=3044) or a diuretic (n=3039).12 With similar blood pressure reduction in both arms (26/12 mm Hg), treatment with the ACE inhibitor resulted in a lower incidence of the composite primary end-point of cardiovascular events or total death that was of borderline significance (ACE inhibitor=22.8%; diuretic=24.2%; RR=0.89 [95% CI, 0.79–1.00]; P=.05).
Among women, there was no difference between the ACE inhibitor and diuretic groups. In the overall population, there was also no difference individually of total mortality or incidence of first cardiovascular event or death.
Thus ANBP2 actually confirms the results from ALLHAT by showing that ACE inhibitors and diuretics are equivalent in reducing cardiovascular events in hypertension.31
Losartan vs atenolol
In the LIFE study, 9193 hypertensive patients with left ventricular hypertrophy were randomized to either losartan (Cozaar) or atenolol.9 Losartan treatment resulted in a marked reduction in stroke incidence, which produced a significant reduction in the composite primary end-point of death, MI, or stroke (11% vs 13%; RR=0.87 [95% CI, 0.77–0.98]; P=.021).
When only the 1195 patients with diabetes were assessed, there was a significant reduction not only in the primary endpoint but also in cardiovascular and total mortality.32 Surprisingly, the reduction of stroke incidence did not reach statistical significance in this diabetic population (RR=0.79 [95% CI, 0.55–1.14]; P=.204).
A word of caution, though: The results of LIFE should be taken together with data from other trials. No other study has demonstrated a special benefit from the renin-angiotensin antagonists in preventing stroke. In fact, ACE inhibitors were weaker than the comparator drugs in preventing stroke in both CAPPP (TABLE) and ALLHAT.5,10 Various reviews have suggested that among antihypertensive drugs, it is the diuretics and calcium channel blockers that may be more useful in stroke reduction.33,34
Chalk the benefit up to the drop in blood pressure
In the LIFE study, the treated mean systolic blood pressure was lower with losartan in the overall (1.1 mm Hg; P=.017) and diabetic (2 mm Hg; P value not stated) populations, and thus the clinical benefit could possibly have been from the better blood pressure reduction on losartan. Furthermore, there is evidence that beta-blockers are less useful in the older hypertensive patient, and are especially weak in preventing stroke incidence.35,36
Rather than showing the superiority of the ARB, it is fair to say that LIFE actually confirms the importance of blood pressure reduction, and reveals the weaker cardiovascular protective effect of atenolol in older hypertensive patients.
