RAS inhibitors' dose-dependent efficacy: myth or reality?

Objective: Treatment of hypertension remains challenging in clinical practice. One major problem is incorrect utilization of the principal drug classes. Drugs from each class are currently used in accordance with an assumption that the blood pressure (BP) lowering effect is dose dependent. While this is true for most drugs, it is not appropriate for all drugs that block the renin angiotensin system (RAS). Methods: This review is based on a PubMed/Cochrane database search for articles on the dose-dependent effect of RAS blockers on BP and cardiovascular protection. Results: Of the RAS blockers, most angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have a flat dose response curve for BP decrease, meaning an increase in dose prolongs duration of action, but does not yield greater potency. Perindopril is the only ACE inhibitor to show a real dose response curve for BP decrease. While the effectiveness of RAS blockers on target organ damage is dose dependent and at least partially unrelated to BP control, there is evidence that the only way to obtain a beneficial effect is to use them at full dose. Thus, RAS blockers need to be used at the correct dose, based on the results of controlled clinical trials and meta-analysis. Furthermore, for all-cause mortality, ACE inhibitors have been shown to be better than ARBs, a specific efficacy supported by perindopril-based studies including ASCOT-BPLA (the Anglo-Scandinavian Cardiac Outcomes Trial BP Lowering Arm), ADVANCE (the Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation trial) and HYVET (HYpertension in the Very Elderly Trial). Conclusion: In hypertensive patients, a strategy based on ACE inhibitors with dose-dependent efficacy such as perindopril as optimal treatment should lead both to improved BP control and to a better protection from target organ damage, thereby reducing the incidence of cardiovascular events.