RAAS inhibitors in the cardiovascular continuum: what is still missing?

Recently, clinical trials evaluating cardiovascular outcomes with antihypertensive drugs that target the renin-angiotensin-aldosterone system have been dramatically increasing in size. The CONSENSUS trial in 1987 enrolled 253 patients, while Val-HeFT in 1999 enrolled 5,010 patients; indeed, the Val-HeFT subgroup of patients not receiving angiotensin-converting enzyme inhibitors was bigger than the whole CONSENSUS trial even though the 366 patients were only 7% of the total trial population. More recent and ongoing cardiovascular trials have even greater patient numbers with 14,703 patients enrolled in VALIANT, 15,314 in VALUE, 23,400 in ONTARGET and 33,357 in ALLHAT. Part of the reason is that in modern trials, patients in the control group are already receiving optimal therapy. Therefore, in order to be adequately powered to detect any benefit of new drugs, trials must recruit thousands of patients. This expanding trend cannot continue forever because of time and economic constraints and as a result, trials are shifting their design to include composite and surrogate endpoints. In addition, more predefined substudies are being carried out to analyze possible benefits in specific patient populations such as those with type 2 diabetes or renal impairment. Modern trials are also placing more emphasis on protection as a long-term strategy to control cardiovascular risks. Examples of these points, particularly regarding the size of modern cardiovascular trials to have the power to show protective effects, are illustrated by Val-HeFT, LIFE, ELITE II, VALIANT, VALUE, CHARM and NAVIGATOR.