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Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease and coronary artery disease with left ventricular dysfunction.
ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,6 and all-cause mortality in patients with HFrEF.7
This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.8 Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.6 Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.
Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.
The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.10
In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.11 Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.11 Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.12,13
An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.14 There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.9,15
In my medical practice, I try to make sure patients with HFrEF, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction receive an inhibitor of the renin-angiotensin-aldosterone system.
I prefer ARBs because patients tolerate them better. I continue ACE inhibitors in patients who are already taking them without adverse effects, and I change to ARBs in patients who later become unable to tolerate ACE inhibitors.
Most antihypertensive agents increase the risk of incident gout, except for calcium channel blockers and losartan.16 Losartan is the only ARB with a uricosuric effect, although a mild one,17,18 due to inhibition of the urate transporter 1,19 and therefore I prefer to use it instead of other ARBs or ACE inhibitors in patients who have a concomitant diagnosis of gout.
The addition of beta-blockers and mineralocorticoid receptor blockers to ACE inhibitors or ARBs is associated with a further decrease in the mortality risk for patients with HFrEF,20–22 but some patients cannot tolerate these combinations or optimized doses of these medications because of worsening hypotension or increased risk of developing acute kidney injury or hyperkalemia.
In most cases, I try not to combine ACE inhibitors with ARBs. This combination may be useful in nondiabetic patients with proteinuria refractory to maximum treatment with 1 class of these agents, but it is associated with an increased risk of hyperkalemia or acute kidney injury in patients with diabetic nephropathy without improving rates of the clinical outcomes of death or cardiovascular events.23 I prefer adding a daily low dose of a mineralocorticoid receptor blocker to an ACE inhibitor or an ARB, which is more effective in controlling refractory proteinuria.24 This regimen is associated with decreased rates of mortality, cardiovascular mortality, and hospitalization for heart failure in patients with HFrEF,22 although it can lead to a higher frequency of hyperkalemia,25 and patients on it require frequent dietary education and monitoring of serum potassium.
I avoid combining direct renin inhibitors with ACE inhibitors or ARBs, since this combination has been contraindicated by the US Food and Drug Administration due to lack of reduction in target-organ damage and an associated increased risk of hypotension, hyperkalemia, and kidney failure, and a slight increase in the risk of stroke or death in patients with diabetic nephropathy.26
Neprilysin is a membrane-bound endopeptidase that degrades vasoactive peptides, including B-type natriuretic peptide and atrial natriuretic peptide.27 The combination of the ARB valsartan and the neprilysin inhibitor sacubitril is associated with a 20% further decrease in rates of cardiovascular mortality and hospitalization and a 16% decrease in total mortality for patients with HFrEF compared with an ACE inhibitor, although there can also be more hypotension and angioedema with the combination.27,28
Very importantly, an ACE inhibitor cannot be used together with valsartan-sacubitril due to increased risk of angioedema and cough. I change ACE inhibitors or ARBs to valsartan-sacubitril in patients with HFrEF who still have symptoms of heart failure. Interestingly, a network meta-analysis showed that the combination of valsartan-sacubitril plus a mineralocorticoid receptor blocker and a beta-blocker resulted in the greatest mortality reduction in patients with HFrEF.7 A word of caution, though: one can also expect an increased risk of hypotension, hyperkalemia, and kidney failure.
It is crucial to monitor blood pressure, serum potassium, and renal function in patients receiving ACE inhibitors, ARBs, mineralocorticoid receptor blockers, valsartan-sacubitril, or combinations of these medications, particularly in elderly patients, who are more susceptible to complications. I use a multidisciplinary approach in my clinic: a patient educator, dietitian, pharmacist, and advanced practice nurse play key roles in educating and monitoring patients for the development of possible complications from this therapy or interactions with other medications.
A recent population-based cohort study found an association of ACE inhibitor use with a 14% relative increase in lung cancer incidence after 10 years of use, compared with ARBs,29 but this may not represent a large absolute risk (calculated number needed to harm of 2,970 after 10 years of ACE inhibitor use) and should be balanced against the improvement in morbidity and mortality gained with use of an ACE inhibitor. Additional studies with long-term follow-up are needed to investigate this possible association.
This article was adapted from Cleveland Clinic Journal of Medicine. 2019 September;86(9):608-611
Dr. Rincon-Choles practices in the Department of Nephrology and Hypertension within Cleveland Clinic Glickman Urological and Kidney Institute. He is also Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and Medical Director of the East Cleveland Dialysis Center, Ohio Renal Care Group.