Blood pressure lowering, not vascular mechanism of action, is the primary determinant of clinical outcome.

A number of placebo-controlled randomized clinical trials have clearly established that blood pressure (BP) lowering, based on all antihypertensive drugs studied, lowers the risk of all major BP-related cardiovascular events. However, this does not exclude that some antihypertensive agents are more or less effective in preventing cardiovascular events than to be expected from the extent of BP lowering. Indeed, clinical trials of thiazide diuretics using 'high' doses demonstrated marked prevention of strokes, but little to no prevention of coronary events. Subsequent studies using thiazides at 'lower' doses showed prevention of both strokes and coronary events. Angiotensin converting enzyme inhibitors and calcium channel blockers exert direct vascular effects which may inhibit atherosclerosis and prevent cardiovascular events, in addition to their benefits related to BP lowering. After the publication of the results of Heart Outcome Prevention Evaluation (HOPE) trial, this concept has become widely accepted for angiotensin-converting enzyme inhibitors. However, placebo-controlled trials, such as HOPE and, recently, the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), are confounded by the difference in BP and its impact on outcome. Indeed, as a mirror image of these trials, the blacks subgroup in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) exhibited a 4 to 5 mmHg higher systolic BP on ACE inhibitor as compared with the diuretic, associated with 19% higher combined cardiovascular disease and 40% higher stroke rate. Recent overviews of randomized clinical trials comparing outcomes with different antihypertensive drug classes concluded that outcome benefits beyond BP lowering remain unproven.