Angiotensin receptor blockers and cardiovascular protection: are we ONTARGET?

It is well known that activation of the renin-angiotensin system (RAS) plays a crucial role in the initiation and progression of cardiovascular disease (CVD) and target organ damage in patients with hypertension. There is growing recognition that RAS inhibition provides protection against cardiovascular damage, irrespective of blood pressure (BP) levels. Angiotensin-converting enzyme (ACE) inhibitors have been shown to prevent cardiovascular, neurologic, and renal complications in high-risk patients. With the realization that ACE inhibitors do not provide optimal blockade of the RAS, angiotensin receptor blockers (ARBs) have been developed. Although the efficacy of ARBs in the treatment of hypertension is comparable with that of ACE inhibitors, the former class of drugs has not yielded consistent or superior effects on target organ protection. Therefore, an unsettled issue in preventive medicine has been whether ARBs are as effective as (or superior to) ACE inhibitors in high-risk populations. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), evaluating whether the ARB telmisartan is as least as effective as (noninferior to) the ACE inhibitor ramipril and whether the combination of the 2 drugs is superior to ramipril, was recently reported at the 2008 American College of Cardiology meeting and published. 1 Although ARBs have demonstrated efficacy in other cardiovascular and renal protection therapeutic trials, the clinical outcomes have been limited to special patient populations, such as patients with acute myocardial infarctions in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) 2 and patients with heart failure in the Valsartan Heart Failure Trial (Val-HeFT) 3 and the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) trial. 4 Therefore, the findings of these highly specialized research studies may not be applicable to the relatively large segment of asymptomatic patients who are at high risk for CVD. The significance of the ONTARGET trial is that it was conducted in a large high-risk patient population similar to most patients treated in community practice. The ONTARGET results establish that an ARB (telmisartan) is noninferior to and preserves cardioprotective effects compared with ramipril, the “gold standard” of ACE inhibitors, with much better overall tolerability. The study also confirms that ARBs offer significant vascular protection. As a result, blockade of the RAS with ARBs is now validated to be as effective as with ACE inhibitors for reducing cardiovascular risk in patients with multiple risk factors. Although not universally accepted, it has been widely postulated that the vascular protection offered by ACE inhibitors may be independent of BP. 5,6 The Heart Outcomes Prevention Evaluation (HOPE) trial 5 and the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA), 6 for example, showed that long-term therapy with ACE inhibitors (ramipril and perindopril, respectively) in high-risk patients who are not necessarily hypertensive provides vascular protection. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial 7 provided evidence in support of similar BP-independent results for the ARB losartan. In general, these results suggest that the cardiovascular protection conferred by the therapies was not necessarily or always based on reductions in BP. Recent studies suggest that RAS blockade may also reduce the incidence of cerebrovascular events in high-risk groups. The risk for stroke was reduced with ramipril in the HOPE trial. 5 Subsequently, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 8 showed that treatment