ACE-inhibitor, AT1-receptor-antagonist, or both? A clinical pharmacologist`s perspective after publication of the results of ONTARGET

Abstract

Clinical Pharmacology is commonly accepted to be a bridging discipline between basic science observations and clinical practice. Today, it should be a major task of the clinical pharmacologist in academia to provide support in the interpretation of preclinical and clinical study data, to develop evidence-based treatment guidelines and to serve as drug expert supporting all disciplines of clinical medicine with specific pharmacological and therapeutic knowledge. The results of the ONTARGET-trial confront both researchers and clinicians with the unexpected truth that AT1-receptor-blockade with an angiotensin-receptor-blocker (ARB) does not seem to have superior therapeutic benefit compared with an ACE-inhibitor (ACE-I) at reducing fatal and nonfatal cardiovascular events. The combination of the two drugs was associated with more adverse events without an increase in benefit. Therefore, the crucial question `ACE-I, ARB, or both?' requires a new and critical appraisal depending on the medical indication for which these renin-angiotensin-system (RAS)-inhibitors are used: In a population of high-risk patients suffering from cardiovascular disease or diabetes mellitus, the evidence to favor an ARB over an ACE-I is still limited after ONTARGET and because of the higher costs for ARBs one can rather support the old therapeutic advice that ARBs are equally effective as ACE-Is and therefore therapeutic alternatives for patients with ACE-I intolerance. With respect to a very moderate additive BP-lowering effect of dual therapy with an ACE-I and an ARB seen in metaanalysis which was not even clearly attributable to dual RAS-inhibition and the increased adverse event rate in the combination treatment group of ONTARGET, this regimen seems not to be recommendable for the treatment of hypertension. Dual-RAS-blockade using an ACE-I-ARB-combination is an effective therapy to treat proteinuria and might be of therapeutic benefit especially in diabetic patients without concomitant diseases. There may be a therapeutic rationale to prefer ARBs over ACE-Is in well-selected patients with congestive heart failure (CHF) because a considerable amount of angiotensin II (Ang II) is produced independent of angiotensin-conversion-enzyme (ACE) in the failing heart and is therapeutically unaffected by ACE-I treatment. The results of the Val-HeFt and the CHARM-added-study revealed additive effects of an ARB on heart failure related morbidity and mortality when added to existing therapy with an ACE-I suggesting a role for ACE-I-ARB-combination treatment in well selected heart failure patients. Independent of the medical indication for its use, the concept of dual RAS-blockade with an ARB-ACE-I-combination should clinically be used with caution and a close monitoring of potassium levels and kidney function. Although the results of ONTARGET revealed equity of ramipril and telmisartan at reducing fatal and nonfatal cardiovascular events, we should not forget that pharmacologically not all ARBs are the same and the question if the study results of ONTARGET with telmisartan are transferable to the complete class of ARBs still merits further investigation.