Background: The 2002 ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) generated attention and controversy with its finding that thiazide diuretics were at least as effective as newer drug classes in preventing cardiovascular disease (CVD), including heart failure and stroke, in high-risk patients with hypertension. Wright Jr. and colleagues reevaluated the initial ALLHAT findings in light of subsequent published studies.
The Study: ALLHAT was a randomized, double-blind, multicenter clinical trial that examined whether fatal and nonfatal coronary heart disease events were reduced in high-risk patients with hypertension (e.g., patients with CVD risk factors such as current cigarette smoking, diabetes, or previous atherosclerotic CVD) using a thiazide diuretic (chlorthalidone), an angiotensin-converting enzyme inhibitor (lisinopril [Zestril]), a calcium channel blocker (amlodipine [Norvasc]), or an alpha blocker (doxazosin [Cardura]).
More recent trials examining two or more of the drug classes for similar outcomes were reviewed, including the Second Australian National Blood Pressure Study (ANBP2), International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. Findings from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) meta-analysis were also reevaluated.
Results: ALLHAT initially reported that the risk of new coronary heart disease was similarly reduced by the four drug classes tested; however, chlorthalidone was more effective in preventing one or more major forms of CVD, including stroke and heart failure. The INSIGHT and CONVINCE trials concurred that thiazides were equivalent to calcium channel blockers in preventing CVD, but that thiazides were more effective in preventing fatal and nonfatal heart failure events (relative risk of calcium channel blocker use = 2.20 and 1.30, for the respective trials).
ANBP2 reported fewer CVD events with angiotensin-converting enzyme-inhibitor therapy compared with diuretics, but the results were not directly comparable with ALLHAT because of ANBP2's open-label design, attrition, and inconsistent dosing protocols.
ASCOT found fewer CVD events with amlodipine with or without an angiotensin-converting enzyme inhibitor compared with atenolol (Tenormin) with or without the thiazide bendroflumethiazide (Naturetin). However, the thiazide dose used was up to one half the amount used in other relevant antihypertensive trials, and the study lacked appropriate randomization and was inconsistent in adding drug therapy. The ACCOMPLISH trial reported that a combination benazepril/hydrochlorothiazide (Lotensin HCT) agent was less effective in preventing CVD than benazepril/amlodipine (Lotrel); however, the maximum hydrochlorothiazide dose of 25 mg used in the ACCOMPLISH trial has elsewhere been reported to be less effective at reducing blood pressure than chlorthalidone, which was used in ALLHAT.
The BPLTTC meta-analysis reported that CVD events were similarly reduced by thiazides and the other drug classes, but calcium channel blockers were less effective than the other agents in preventing heart failure.
Conclusion: Reanalysis of the initial 2002 ALLHAT data confirmed that neither alpha blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers are more effective than thiazide diuretics as initial therapy to reduce cardiovascular or renal risk in high-risk patients with hypertension. Thiazides are superior to calcium channel blockers in preventing fatal and nonfatal heart failure.