Renin-angiotensin system inhibition: how much is too much of a good thing?

Inhibitors of the renin-angiotensin system (RAS) are valuable therapeutic agents for a wide range of clinical conditions. Increasingly, consideration is being given to the combination of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor (AR) antagonists to obtain more complete inhibition of the RAS than can be achieved by either agent alone. Beta-blockers also inhibit the RAS by inhibiting renin secretion. Whereas the combination of an ACE inhibitor and AR antagonist represents dual RAS inhibition, the combination of both of these agents with beta-blocker therapy represents triple RAS inhibition. Animal studies indicate that complete blockade of the RAS produces adverse effects. Moreover, post-hoc analysis of the recent Valsartan Heart Failure Trial study suggests that the combination of ACE inhibitor and AR antagonist therapies may have an adverse effect in heart failure when combined with beta-blocker therapy. There is therefore a need for caution in the combination of ACE inhibition and AR antagonism, particularly in patients receiving beta-blockers, until the impact of this strategy is evaluated.