Cough and angiotensin II receptor antagonists: cause or confounding?

Aims Cough is one of the most frequent side effects associated with angiote nsin converting enzyme inhibitors (ACEIs) but is not thought to be associat ed with losartan, all angiotensin II receptor antagonist (ARA). This study compares reports of cough with losartan and three ACEIs used in general pra ctice. Methods Studies have been conducted for losartan, and three ACEIs enalapril , lisinopril and perindopril, using the technique of Prescription-Event Mon itoring. Patients were identified using dispensed prescription data. Questi onnaires were sent to patients' general practitioners 6 months after the da te of first prescription. Cases of cough within the first 60 days of treatm ent with losartan resulting in withdrawal of the drug were followed up with additional questionnaires. Incidence rates for reports of cough were calcu lated. in order to reduce the impact of carry-over effects, rate ratios wer e calculated for first reports of cough between days 8 and 60 using losarta n as the index: drug. Results The cohort fur each drug exceeded 9000 patients. Age and sex distri butions and indications for prescribing the four drugs were similar. Cough was the most frequent reason for discontinuation of losartan and the most f requently reported event in the first month of treatment. with this drug. W hen reports of cough between days 1-7 were excluded, rates of cough were si gnificantly higher for the three ACEIs when compared with losartan (rate ra tios 1.5, 4.8 and 5.7, all P<0.03). 101 patients had discontinued losartan due to cough. 92% of these had previously been prescribed an ACEI and 86% h ad previously experienced ACEI cough. Conclusions Carry-over accounted for the observed excess of reports of coug h with losartan. Rates of cough between days 8 and 60 were significantly hi gher for the three ACEIs compared with losartan. Confounding factors associ ated with comparative observational cohort studies are discussed.