Safety and Tolerability of Angiotensin-Converting Enzyme Inhibitor Versus the Combination of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker in Patients With Left Ventricular Dysfunction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: The addition of an angiotensin receptor blocker (ARB) to an angiotensin-converting enzyme inhibitor (ACEI) in patients with heart failure remains controversial. A recent meta-analysis showed that the combination therapy reduces hospitalization without improved survival. Whether excess risk is associated with this strategy has not been fully explored. We sought to quantify the risk of adverse events of combination therapy (ACEI+ARB) versus ACEI alone. Methods: MEDLINE, EMBASE, BIOSIS, and Cochrane databases were searched. Eligible studies were randomized, placebo-controlled trials of ACEI versus the combination of ACEI+ARB in patients with heart failure or left ventricular dysfunction. Included studies were reviewed to determine the frequency of adverse effects leading to discontinuation of therapy. Results: Nine trials that enrolled 18,160 patients met the inclusion criteria. A total of 9199 patients received combination therapy, and 8961 patients received an ACEI only. Patients receiving combination therapy had an increased risk of developing any adverse effect by 2.3% (relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.15-1.40, P < .00001, I² = 15.9%, number needed to harm [NNH] = 42), hypotension by 1.1% (RR = 1.91, 95% CI = 1.37-2.66, P = .0002, I² = 26.6%, NNH = 89), worsening renal function by 1% (RR = 2.12, 95% CI = 1.30-3.46, P = .003, I² = 67.3%, NNH = 100), and hyperkalemia by 0.6% (RR = 4.17, 95% CI = 2.31-7.53, P < .00001, I² = 0%, NNH = 149). There was no difference in angioedema (RR = 0.88, 95% CI = 0.43-1.80, P = .72, I² = 0%) or cough (RR = 0.84, 95% CI = 0.65-1.09, P = .19, I² = 0%). Conclusion: The current cumulative evidence suggests that patients with left ventricular dysfunction have an increased risk of adverse events leading to discontinuation on ACEI+ARB combination therapy compared with ACEI alone. This excess risk, coupled with a lack of consistent mortality benefit, suggests that ARBs should not routinely be added to ACEI therapy for left ventricular dysfunction. If chosen, the combination strategy may warrant closer patient monitoring to detect adverse effects.