Can Angiotensin-Converting Enzyme (ACE) inhibitors induce a cough in patients who have been taking them for a long time?

From the Guidelines

Yes, ACE inhibitors can induce a cough in patients even after long-term use, affecting approximately 5-35% of patients taking these medications. This side effect, known as ACE inhibitor-induced cough, typically presents as a persistent, dry, non-productive cough that can develop at any time during treatment—from days to months or even years after starting the medication 1. The mechanism behind this side effect involves the accumulation of bradykinin and substance P in the lungs, as ACE inhibitors block the enzyme that would normally break down these compounds. These substances irritate the bronchial passages and trigger the cough reflex.

Key Points to Consider

• The incidence of ACE inhibitor-induced cough has been reported to be in the range of 5 to 35% among patients treated with these agents 1.
• The onset of ACE inhibitor-induced cough ranges from within hours of the first dose to months after the initiation of therapy 1.
• The cough usually resolves within 1-4 weeks after discontinuing the ACE inhibitor, but may linger for up to 3 months in some cases 1.
• For patients who need to remain on renin-angiotensin system blockade, switching to an angiotensin receptor blocker (ARB) like losartan or valsartan is typically recommended, as ARBs rarely cause cough while providing similar cardiovascular benefits 1.

Management of ACE Inhibitor-Induced Cough

• Discontinue ACE inhibitor therapy in patients presenting with chronic ACE inhibitor-induced cough, as this is the only uniformly effective treatment 1.
• Consider switching to an ARB or an appropriate agent of another drug class in patients who cannot tolerate ACE inhibitor-induced cough 1.
• Note that some patients may be able to tolerate ACE inhibitors again after a period of time, but this should be done with caution and under close monitoring 1.

From the FDA Drug Label

Cough Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough

• Yes, ACE inhibitors, including enalapril, can induce a cough in patients, and this side effect is presumably due to the inhibition of the degradation of endogenous bradykinin.
• The cough is described as persistent nonproductive, and it always resolves after discontinuation of therapy.
• Patients taking ACE inhibitors, including those who have been taking them for a long time, should be aware of this potential side effect, and ACE inhibitor-induced cough should be considered in the differential diagnosis of cough 2

From the Research

ACE Inhibitors and Cough

• ACE inhibitors can induce a cough in patients, with the incidence varying among individual ACE inhibitors 3, 4, 5, 6.
• The mechanisms underlying ACE inhibitor-induced cough are likely linked to suppression of kininase II activity, leading to an accumulation of kinins, substance P, and prostaglandins 6.
• The incidence of cough associated with ACE inhibitors can range from around 10% of patients, with half of these patients requiring discontinuation of the ACE inhibitor 6.

Management of ACE Inhibitor-Induced Cough

• Strategies for managing ACE inhibitor-induced cough include temporarily discontinuing the ACE inhibitor and reintroducing it after the cough has resolved, or adding a calcium channel blocker to the ACE inhibitor 3.
• Switching to an alternative drug, such as an angiotensin receptor blocker, may be necessary in cases where the cough is intolerable and other causes of cough have been excluded 3, 4, 5.
• A challenge/re-challenge approach can be used to determine if re-introduction of the ACE inhibitor is associated with recurrence of symptoms 4.

Comparison with Other Antihypertensives

• ACE inhibitors have a higher incidence of cough compared to angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) 5, 7.
• The incidence of cough with ACE inhibitors is higher than with placebo, with a pooled estimated relative risk of 2.21 (95% CI: 2.05-2.39) 5.
• Losartan, an ARB, has a lower incidence of cough compared to ACE inhibitors, although confounding factors may contribute to the observed differences 7.