Zofenopril and incidence of cough: a review of published and unpublished data

Abstract

ObjectiveCough 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ACE inhibitor-induced cough and to assess the incidence of cough induced by zofenopril treatment.MethodsPublished and unpublished data from randomized and postmarketing zofenopril trials were merged together and analyzed.ResultsTwenty-three studies including 5794 hypertensive patients and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%).ConclusionEvidence 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.

Efficacy of Zofenopril vs. Irbesartan in Combination with a Thiazide Diuretic in Hypertensive Patients with Multiple Risk Factors not Controlled by a Previous Monotherapy: A Review of the Double-Blind, Randomized “Z” Studies

“…All these side effects could be expected with these classes of drugs. Interestingly, the prevalence of cough with zofenopril in the “Z” studies (1.8%) was very close to that observed in previous double-blind or open-label post-marketing studies including 5794 hypertensive patients (2.4%) [31]. The relatively low incidence of cough in patients receiving zofenopril might be related to its limited ACE inhibitor potency at the lung level, responsible for a lesser accumulation of bradykinin and a reduced synthesis of prostaglandins in this tissue, as found in some experimental and animal studies [31].…”

Effects of Treatment with Zofenopril in Men and Women with Acute Myocardial Infarction: Gender Analysis of the SMILE Program

“…As far as zofenopril is regarded this confirms results of a previous pooled analysis in hypertensive patients, in which significantly more women than men experienced cough [39]. In the same meta-analysis, a slightly lower occurrence of cough was reported under zofenopril as compared to enalapril or lisinopril [39]. The incidence of angioedema, was low and similarly distributed in women and men, regardless of the type of ACE-inhibitor taken into account, suggesting no intra-class effect for this adverse drug reaction.…”

Off-Target Effects of Angiotensin-Converting Enzyme Inhibitors: Additional Therapeutic Benefits

“…По результатам мета-анализа 26 исследований 7249 пациентов, получавших зофеноприл, сухой кашель при приеме низких доз (7,5-15 мг/сут) развивался в 2,4% случаев, и в 2,6% при применении максимальных доз (30-60 мг/ сут). Эти данные, как минимум, не превышают показатели других ИАПФ, в частности лизиноприла и эналаприла [9]. Для более определенного ответа, как указывают авторы, необходимо проведение прямого сопоставления.…”