ACE and ARB Combination

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are both commonly used in hypertension, heart failure, diabetic nephropathy and for the prevention of progressive renal failure in patients with persistent proteinuria. There has been some debate over whether the use of ACE/ARB combination therapy offers any advantage over the single agents.

ACE inhibitors and ARBs work at different steps of the renin-angiotensin system, as shown in Figure 1. ACE inhibitors block the conversion of angiotensin I to angiotensin II, whereas ARBs competitively block the binding of angiotensin II to type I angiotensin (AT₁) receptors.

Figure 1. Renin-angiotensin-aldosterone system (Copied with permission of A. Rad)

Angiotensin II has numerous effects, including stimulation of the sympathetic nervous system, vasoconstriction, increasing aldosterone release and sodium retention, which can result in hypertension.

Beneficial effects on morbidity and mortality from ACE inhibitor/ARB combination therapy in the treatment of renal disease has been inconsistent. The combination is not recommended for routine use and should be reserved for patients with resistant congestive heart failure, renal disease, or severe unresponsive hypertension, following specialist advice.

The objective of the randomised double-blind CALM (candesartan and lisinopril microalbuminuria) study was to assess and compare the effects of each drug, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension and type 2 diabetes. It was concluded that candesartan 16mg and lisinopril 20mg once daily were equally effective in reducing blood pressure and microalbuniuria. Combination treatment was well tolerated and more effective in lowering blood pressure.

Two trials, CHARM-added (Candesartan in Heart Failure – Assessment of Reduction in Mortality & Morbidity – added) trial, the ‘added’ leg included patients with left ventricular ejection fraction ≤40% who were treated with an ACE inhibitor, and ValHeFT (Valsartan Heart Failure Trial), looked at the addition of an ARB (candesartan and valsartan respectively) in patients with congestive heart failure currently on an ACE inhibitor. The CHARM-added study showed a significant reduction in cardiovascular death in patients with congestive heart failure (NYHA functional class II-IV).

There was improved left ventricular ejection fraction and reduced hospital admissions. The ValHeFT study showed no significant difference in mortality between the placebo and valsartan groups. Candesartan is consequently the only ARB registered as add-on therapy to ACE inhibitors in patients with congestive heart failure and left ventricular systolic dysfunction.

The ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study compared ramipril, telmisartan and the combination therapy in patients with vascular disease or high-risk diabetes. ACE inhibitors are known to reduce mortality and morbidity from cardiovascular causes but the role of ARBs is unknown in both aforementioned patient groups.

Although the combination group did show an improved reduction in blood pressure, there wasn’t a significant benefit in the primary outcome of reducing the composite outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalisation for heart failure. The combination group showed a significantly increased risk of hypotension, syncope, hyperkalaemia, and renal dysfunction compared to ramipril alone. There was also a trend towards an increased risk of renal dysfunction requiring dialysis. These results contrast with those of the CHARM and ValHeFT trials, however, in these trials the choice of ACE inhibitor was left up to individual physicians and there was no attempt to titrate the ACE inhibitor to the maximum dose.

In conclusion, there have been conflicting results when using the combination treatment of an ACE inhibitor and an ARB. An increased risk of symptomatic hypotension and hyperkalaemia as well as a decline in renal function were noted. The combination did not improve survival in patients with left ventricular dysfunction post myocardial infarction or provide additional benefit in patients at high risk of vascular disease. However, this therapy may have a place for those patients with congestive heart failure or renal disease resistant to other treatments, or severe unresponsive hypertension, but only under specialist advice. Candesartan is the only ARB registered at present for combination treatment in patients with low left ventricular ejection fraction.