JS ISH-ESH-4 WHAT DO CLINICAL TRIALS TEACH US ABOUT SELECTION OF ANTIHYPERTENSIVE DRUGS.

Beginning with the Veterans Administration (VA) Cooperative Hypertension Study of the 1960 s, blood pressure (BP) lowering with antihypertensive medications has been shown to reduce major cardiovascular (CV) outcomes, including coronary heart disease, stroke, heart failure (HF) and CV and all-cause mortality in randomized controlled CV outcome trials. Multiple drugs were usually required in these trials to lower BP in treated participants. Medication regimens in the early trials, including the VA trial, included a thiazide-type diuretic (TTD) as initial therapy. Some later trials used a beta-blocker (BB) as initial therapy or compared BBs with other agents and the benefits of BBs were less consistent. One major trial showed benefit comparing a calcium channel blocker (CCB) with placebo. Several trials compared classes against one another as initial therapy. BBs and alpha blockers were less effective than several other major classes. Each of four drug classes, TTDs, CCBs, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) usually had comparable effects on mortality and CV and cerebrovascular outcomes, with one primary exception: HF. Initial treatment with a TTD was more effective than a CCB, ACEI, or alpha blocker, and an ACEI was more effective than a CCB in improving HF outcomes. In black patients, TTDs or CCBs appear to be more effective in reducing CV outcomes than ACEIs or ARBs. Although ACEIs or ARBs appear to preserve renal function better than other classes in patients with chronic kidney disease (CKD), they are not superior in reducing CV outcomes or mortality in patients with CKD. In clinical trials and practice at least 3 drugs in combination have been needed to control BP to <140/90 mmHg in at least half the time. Dosing of antihypertensive medications also appears important - full doses of the initial drug were used and needed to control BP in 70-80% of patients in hypertension CV outcome trials. Outcomes have been less robust when less than full doses have been allowed in trials. It is reasonable for the first three classes used to control BP in a patient be a TTD, CCB, and either an ACEI or ARB in most patients with hypertension, although other classes may be included if there is a strong indication, e.g., a BB in patients with coronary artery disease. In resistant hypertension, it is not clear whether adding one drug class will lower CV events more than others, but the addition of spironolactone lowered BP better than a BB or alpha blocker in a randomized trial. Amiloride or direct arterial vasodilators may also be effective.