Is an ACE inhibitor plus an ARB more effective than either drug alone?

Heart failure

The bulk of data on dual RAS blockade in heart failure patients comes from three large randomized trials: CHARM-Added (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity),¹⁴ VALIANT (Valsartan in Acute Myocardial Infarction Trial),¹⁵ and VAL-HeFT (Valsartan Heart Failure Trial).¹⁶

CHARM-Added¹⁴ was the only trial that showed a reduction in cardiovascular deaths with dual RAS therapy (absolute risk reduction 3.6%). It also showed a lower rate of hospitalization for heart failure (absolute risk reduction 4%). However, the rate of allcause mortality was not different between the groups. Of note, more patients receiving dual RAS blockade had to stop taking the study drug because of adverse effects.

Val-HeFT¹⁶ showed, in a post hoc analysis, higher rates of morbidity (cardiac arrest, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least 4 hours) and death when the ARB valsartan (Diovan) was added to the combination of an ACE inhibitor plus a beta-blocker.

A recent meta-analysis¹⁷ of safety and tolerability of dual RAS blockade compared with an ACE inhibitor alone found a higher risk of discontinuation because of adverse effects such as hyperkalemia, renal dysfunction, and hypotension in patients on dual RAS blockade. The authors concluded that, given the adverse effects and the lack of consistent survival benefit, the available data do not support the routine addition of an ARB to ACE inhibitor therapy in heart failure patients.

WHAT ABOUT DIRECT RENIN INHIBITORS?

Another class of RAS blockers is available: direct renin inhibitors. Therefore, dual RAS blockade can be achieved by combining an ACE inhibitor with an ARB, an ACE inhibitor with a direct renin inhibitor, or an ARB with a direct renin inhibitor.

We have some outcome data on the combination of an ACE inhibitor plus an ARB,^3,4,17 but none for the other two possible dual RAS combinations. Thus far, we know that dual RAS blockade with an ARB and an ACE inhibitor is not beneficial in patients like those in ONTARGET, and that it has questionable benefit in heart failure. However, little is known about combining a direct renin inhibitor with either an ACE inhibitor or an ARB.

Since ARBs and ACE inhibitors both increase plasma renin activity and only partially block the RAS, the argument has been put forward that the addition of a drug such as a direct renin inhibitor, which really decreases plasma renin activity, has the potential to be more beneficial than blockade with either an ACE inhibitor or an ARB. In theory, this is an attractive concept and certainly deserves scrutiny in outcome studies such as ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints).¹⁸

SURROGATE END POINTS: A CAVEAT

As defined by Temple,¹⁹ a surrogate end point of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful end point that measures directly how patients feel or function, or if they survive. Effects on surrogate end points often fail to predict the true clinical effects of an intervention, as the ONTARGET data demonstrated. Among several explanations for this failure is that interventions may affect the clinical outcome by unintended, unanticipated, and unrecognized mechanisms that operate independently of the disease process.²⁰ Nonetheless, surrogate end point cosmetics remains attractive for many clinicians.

The ONTARGET findings indicate that there is no clinically important benefit in adding an ARB for patients with hypertension, proteinuria, heart failure, or coronary artery disease if they are already being treated with an ACE inhibitor. This would indicate that dual RAS blockade should be avoided in clinical practice until we are provided with better evidence.