A Modern History RAAS Inhibition and Beta Blockade for Heart Failure to Underscore the Non-equivalency of ACEIs and ARBs

Beta blockers and renin-angiotensin-aldosterone-inhibitors (RAAS-i) including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been a mainstay of guideline-based medical therapy for heart failure with reduced ejection fraction (HFrEF) for decades. However, initial evidence supporting each of the aforenoted class of drug for heart failure indications was largely found independently of the other two classes with the exception of the addition of BBs to ACEIs. In the initial ACEI trials for HFrEF, few participants were on BBs as BBs were seen as contraindicated in HFrEF at the time. The seminal BB in HFrEF trials had high prevalence of ACEIs use as ACEIs for HF were standard of care by then, but ARBs as a class were still in their infancy. We closely examine the evidence for combinations of BB and ACEIs versus ARBs in HFrEF. In doing so, we demonstrate the lack of evidence for consideration of ARBs to be interchangeable with ACEIs when used in combination with BB and provide evidence that calls in to question the validity of assuming benefits from each drug class are independently cumulative, widening the gap between ACEIs and ARBs when used with BBs. Modern guidelines should emphasize this lack of evidence for the combination use of ARB and BB in HFrEF, except for candesartan. Even as practice moves towards the widespread uptake of angiotensin receptor-neprilysin inhibitors (which contain the ARB valsartan) in heart failure, the distinction has important implications for the ongoing role of combination therapy with BB, which thus far has been assumed, but not proven.