Are ACE Inhibitor/ARB Combinations Beneficial?

Darrell Hulisz, PharmD


May 16, 2012


Do hypertensive patients benefit from an ACE inhibitor/ARB combination?

Response from Darrell Hulisz, PharmD
Associate Professor, Case Western Reserve University School of Medicine; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

Hypertension is a prominent risk factor for cardiovascular disease events, with studies demonstrating a doubling of mortality from ischemic heart disease and stroke for every 20-mm Hg systolic or 10-mm Hg diastolic increase in blood pressure (BP).[1] More than two thirds of patients require 2 or more antihypertensive medications for optimal control.[1]

The renin-angiotensin-aldosterone system (RAAS) maintains BP via angiotensin II-induced vasoconstriction and aldosterone-mediated sodium retention in the collecting duct. Angiotensin-converting enzyme (ACE) inhibitors interact with the RAAS by inhibiting the formation of angiotensin II, causing vasodilation and decreased BP. However, an accurate understanding of the RAAS should include alternative pathways of producing angiotensin II, in addition to ACE activity. Angiotensin receptor blockers (ARBs) were developed to more completely inhibit the RAAS, bypassing the "ACE escape" phenomenon. A systematic review by Matchar and colleagues[2] found that ACE inhibitors and ARBs provide similar levels of BP control and appear to have an equivalent effect on mortality and cardiovascular events.

The combination of an ACE inhibitor plus an ARB should, in theory, enhance RAAS blockade. A dual-blockade approach of the RAAS has been shown to be effective in reducing BP in patients with essential HTN.[3,4,5,6,7] In a pilot study by Azizi and colleagues,[3] patients with mild to moderate hypertension demonstrated a statistically significant decrease in diastolic BP (3-4 mm Hg), but not systolic BP, with combination (enalapril and losartan) therapy vs with either drug alone after 6 weeks of treatment. Another study, by Stergiou and colleagues,[4] observed decreases in the average 24-hour systolic (6.8 mm Hg; 95% confidence interval [CI], 2.2-11.4) and diastolic (4.9 mm Hg; 95% CI, 1.7-8.1) BP with combination therapy (valsartan and benazepril), compared with benazepril alone after 6 weeks of treatment.

The AMAZE (A Multicenter Trial Using Atacand and Zestril vs. Zestril to Evaluate the Effects on Lowering Blood Pressure) trial was a randomized controlled trial in hypertensive patients, designed to determine whether the addition of candesartan to lisinopril is more effective in lowering BP than titration of lisinopril to 40 mg in patients uncontrolled on lisinopril 20 mg [5] Results from 1096 patients found that the combination treatment produced a greater reduction in BP compared with the high-dose monotherapy group (3.1/1.7 mm Hg) after 8 weeks of treatment.

A meta-analysis found that the combination of an ACE inhibitor and an ARB reduced ambulatory BP by 4.7 systolic/3.0 diastolic mm Hg (95% CI, 2.9-6.5/1.6-4.3) compared with ACE inhibitor monotherapy, and by 3.8/2.9 mm Hg (95% CI, 2.4-5.3/0.4-5.4) compared with ARB monotherapy.[6] Results from the trials reviewed in this study were slightly misleading, however, as the majority used doses that were below the maximum or once-daily dosing of shorter-acting ACE inhibitors. The investigators noted that when larger doses of short-acting ACE inhibitors were given, or when a longer-acting ACE inhibitor was used, there was generally no additive BP lowering seen with the ARBs.Of note, proteinuria was reduced by combination treatment compared with monotherapy with either drug, independent of BP in several studies. This suggests that the combination could have benefits in hypertensive nephropathy in patients with proteinuria.[6]

The candesartan and lisinopril microalbuminuria (CALM) study compared the effects of candesartan and lisinopril on BP and urinary albumin excretion and evaluated the effects of the combination of both drugs in 199 patients with hypertension, microalbuminuria, and type 2 diabetes.[7] Results from the study showed that the combination group had a 5- to 6-mm Hg reduction in diastolic BP and a 9- to 11-mm Hg reduction in systolic BP compared with the monotherapy groups at 24 weeks of treatment. Combination therapy was associated with a greater reduction in urinary albumin excretion vs with candesartan or lisinopril alone.

The CALM II study was designed to compare the effects of lisinopril 40 mg once daily vs dual-blockade treatment with candesartan 16 mg and lisinopril 20 mg in 75 hypertensive patients with diabetes over 12 months.[8] Results of the study showed a nonsignificant reduction in 24-hour systolic and diastolic BP between groups. Reduction was obtained in both treatment arms, with mean reduction from dual blockade of 6 mm Hg vs 2 mm Hg with lisinopril (P = .10).

One important underlying question is whether these very modest reductions in BP with combination therapy correlate with better outcomes. The ONTARGET trial attempted to evaluate this question.[9]The trial evaluated whether telmisartan (80 mg/day) was noninferior to ramipril (10 mg/day) and whether a combination of the drugs was superior to ramipril alone as a treatment to prevent vascular events in patients with coronary artery disease or diabetes, but not heart failure. Patients were excluded from the trial if they had uncontrolled hypertension on treatment (> 160/100 mm Hg).[10] However, the mean BP at run-in was 143/82 mm Hg, and approximately 69% of patients had hypertension at baseline.[9,10] Results of the trial showed that despite a reduction in systolic blood pressure of 2-3 mm Hg in the combination therapy group as compared with the ramipril group, no significant benefit was seen in the primary composite outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure.[9]

In conclusion, several trials comparing ACE inhibitor monotherapy vs combined treatment with an ARB used suboptimal doses of ACE inhibitors, were relatively short in duration, and had small sample sizes. Combination therapy may have a benefit in reducing proteinuria in patients with hypertensive nephropathy. Whether the long-term BP effects of ACE inhibitors and ARBs are additive or synergistic is still not completely confirmed. Nonetheless, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study demonstrated that reductions in BP, as seen with combination ACE inhibitor and ARB treatment, does not necessarily correlate to improved morbidity and mortality, even in high-risk patients.

The author wishes to thank Keith Anderson for providing technical assistance.