ACE Inhibitor and ARB Combination Therapy: Rational and Fashionable, But Does It Work?

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), direct renin inhibitors, and aldosterone antagonists—which specifically block the renin-angiotensinaldosterone system (RAAS)—are a valuable adjunct in the treatment of organ pathologies complicated by hypertension, as well as a variety of heart conditions (eg, remodeling and failure) and kidney diseases (eg, diabetic renal disease). ARBs were initially developed because ACE inhibitors were associated with “escape.” That is, after initial blockade of the RAAS with ACE inhibitors (at the step of angiotensin I to II conversion), renin levels rebounded, and as a result, so did angiotensin II and aldosterone levels (the latter called aldosterone synthesis escape).
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In the Randomized Aldactone Evaluation Study (RALES), adding spironolactone to standard heart failure therapy with an RAAS-blocking agent (either an ACE inhibitor or an ARB) further lowered mortality, which suggests that aldosterone synthesis escape with ACE inhibitors or ARBs could be harmful. Several heart failure regimens now include more than 1 agent directed at the RAAS—either an ACE inhibitor or an ARB in combination with an aldosterone antagonist. Two questions remain, however. First, are such combinations appropriate in other clinical settings (eg, hypertension)? Second, how effective is combining an ACE inhibitor with an ARB instead of combining either agent with spironolactone? This month’s “Top Paper” summarizes the available data.¹

COMBINATION RAAS-BLOCKING THERAPY: WHAT THE DATA SHOW
Holdiness and colleagues¹ provide some background statistics. In the authors’ hypertension referral practice, about 9% of new patients are already receiving dual RAAS-blocking therapy—a percentage that has doubled over the past decade. This specific demographic prompted them to ask whether combination therapy (more specifically, an ACE inhibitor and an ARB) had demonstrable benefit in patients with hypertension, heart disease, and/or renal disease. In those with hypertension, the authors concluded that adding an aldosterone antagonist (eg, spironolactone) to an ACE inhibitor or an ARB may lower systolic blood pressure (BP) by an additional 25 mm Hg and diastolic BP by an additional 12 mm Hg.

There are 2 important caveats to this observation. First, older patients as well as those with diabetes or chronic kidney disease or who are concurrently taking an ACE inhibitor, ARB, or NSAID are at increased risk for hyperkalemia. Second, if dual therapy consists of an ACE inhibitor plus an ARB (neither with spironolactone added), benefits in BP lowering are not supported by the evidence. Adding non-RAAS blockers to ACE inhibitor or ARB monotherapy lowers BP more effectively than both agents in combination. In the setting of heart failure, the authors agree with the latest American College of Cardiology guidelines.² ACE inhibitors and b-blockers arefirst-line agents for symptomatic systolic heart failure. ARBs are recommended for patients who are unable to tolerate ACE inhibitors. Combination therapy with an ACE inhibitor and an ARB should be reserved for patients who remain symptomatic while receiving standard therapy. Routine combination of an ACE inhibitor, an ARB, or an aldosterone antagonist is not recommended (see below for the newest evidence about spironolactone and eplerenone).

In regard to renal protection, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) demonstrated a lack of benefit from RAAS combination therapy (again, an ACE inhibitor and an ARB).³ Any benefit accrued was related to BP lowering per se, not dual RAAS blockade. The use of ACE inhibitor and ARB combination therapy in this study did not improve the primary end points of cardiovascular death, myocardial infarction, stroke, or heart failure hospitalizations. Holdiness and colleagues¹ conclude, “Based on the evidence, there is a limited role for combination ACE inhibitor–ARB therapy in the treatment and management of hypertension, heart failure, and nephropathy. In general, combinations of either an ACE inhibitor or ARB with other classes of medications designed for treatment of these diseases will provide a more effective and synergistic approach. Aldosterone antagonists clearly have a role as RAAS combination therapy in these diseases.” In fact, for those who want additional and timely information on aldosterone antagonists (spironolactone and eplerenone), a recent article and accompanying editorial have expanded indications for their use to systolic heart failure with mild symptoms.^4,5

THE EVIDENCE-BASED BOTTOM LINE
ACE inhibitors and ARBs in combination have become fashionable and may be rational in concept, but empiric evidence does not support their combined use at this time. However, there seems to be an expanding role for aldosterone antagonists in combination with other drugs that affect the RAAS.