ACE inhibitor and ARB therapy: Practical recommendations

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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.

Which agent?

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.

Which combinations of agents?

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.


  • Blockade of the renin-angiotensin-aldosterone system is a cornerstone in the therapy of cardiovascular disease.
  • ARBs are as effective as ACE inhibitors and have a better tolerability profile.
  • ACE inhibitors cause more angioedema in African Americans and more cough in Chinese Americans than in the rest of the population.
  • ACE inhibitors and most ARBs (except for losartan) increase the risk of gout.
  • The combination of beta-blockers and mineralocorticoid receptor blockers with ACE inhibitors or ARBs and, lately, the use of the valsartan-sacubitril combination have been increasingly beneficial for patients with HFrEF.

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