Zofenopril and incidence of cough: a review of published and unpublished data

OBJECTIVE Cough is a typical side effect of angiotensin-converting enzyme (ACE) inhibitors, though its frequency quantitatively varies among the different compounds. Data on the incidence of cough with the lipophilic third-generation ACE inhibitor zofenopril are scanty and never systematically analyzed. The purpose of this paper is to give an overview on the epidemiology, pathophysiology, and treatment of ACE inhibitor-induced cough and to assess the incidence of cough induced by zofenopril treatment. METHODS Published and unpublished data from randomized and postmarketing zofenopril trials were merged together and analyzed. RESULTS Twenty-three studies including 5794 hypertensive patients and three studies including 1455 postmyocardial infarction patients exposed for a median follow-up time of 3 months to zofenopril at doses of 7.5-60 mg once-daily were analyzed. The incidence of zofenopril-induced cough was 2.6% (range 0%-4.2%): 2.4% in the hypertension trials (2.4% in the double-blind randomized studies and 2.4% in the open-label postmarketing studies) and 3.6% in the doubleblind randomized postmyocardial infarction trials. Zofenopril-induced cough was generally of a mild to moderate intensity, occurred significantly (P < 0.001) more frequently in the first 3-6 months of treatment (3.0% vs 0.2% 9-12 months), and always resolved or improved upon therapy discontinuation. Zofenopril doses of 30 mg and 60 mg resulted in significantly (P = 0.042) greater rate of cough (2.1% and 2.6%, respectively) than doses of 7.5 mg and 15 mg (0.4% and 0.7%, respectively). In direct comparison trials (enalapril and lisinopril), incidence of cough was not significantly different between zofenopril and other ACE inhibitors (2.4% vs 2.7%). CONCLUSION Evidence from a limited number of studies indicates a relatively low incidence of zofenopril-induced cough. Large head-to-head comparison studies versus different ACE inhibitors are needed to highlight possible differences between zofenopril and other ACE inhibitors in the incidence of cough.