ALLHAT: definitive answers or continuing uncertainty?

JRAAS 2003;4:3–5 The long awaited Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT), the results of which were published recently, generates rather more questions than it provides answers, to key outstanding issues in hypertension management. In a sense, ALLHAT was yesterday’s trial addressing today’s questions. It was designed in the late 1980s as a follow-on from the Treatment Of Mild Hypertension Study (TOMHS), where the question was: what is the best first-line drug to treat hypertension? Subsequently, the study was developed to evaluate the use of different first-line treatments in prespecified subgroups, such as those with high cardiovascular risk and those of Afro-American ethnicity. The primary question was: which first-line drug treatment confers the greatest protection against coronary heart disease (CHD) events? This was an important question based on earlier placebo-controlled trials in hypertension, in which the protection of hypertensive subjects against CHD was less than that predicted from prospective observational studies, which contrasts with stroke outcome, where the results were compatible with the predicted reduction in incidence for a given fall in blood pressure (BP). ALLHAT randomised over 40,000 patients in a double-blind study comparing three first-line therapies of newer agents, the calcium channel blocker (CCB), amlodipine (2.5–10 mg daily), the angiotensin-converting enzyme (ACE) inhibitor, lisinopril (10–40 mg daily) and the α-blocker, doxazosin (1–8 mg daily) with the reference older drug, the diuretic chlorthalidone (12.5–25 mg daily). The study was planned for an average follow-up period of six years but the α-blocker limb was terminated early, on the grounds that there was an excess of secondary endpoints (cardiovascular disease and ‘heart failure’) in the doxazosin limb compared with chlorthalidone, but no difference in the primary endpoint of CHD. One of the initial problems in extrapolating results from ALLHAT to contemporary hypertension management is that the trial design necessitated the use of a variety of largely obsolete addon drugs, such as reserpine, clonidine and hydralazine, to achieve target BP, whilst at the same time avoiding contamination of one treatment regimen with drugs from another limb of the trial. Many of these drugs have little or no place in today’s practice and, indeed, could have confounded the main results. The patients enrolled in ALLHAT were highrisk hypertensives, many of whom had either diabetes or who had previously experienced a myocardial infarct (MI). ALLHAT was therefore a secondary prevention trial. The patients also had very mildly elevated BP, at randomisation, contrasting with the levels of BP of patients recruited into many other recently reported hypertension trials.