Journal of Human Hypertension (1999) 13, 413–417 1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Double-blind comparison of eprosartan and enalapril on cough and blood pressure in unselected hypertensive patients WJ Elliott, for the Eprosartan Study Group The effects of a new angiotensin receptor antagonist, with a 3.45-fold higher risk of definite cough (14/261 vs -Overall cough incidence (from spon .(0.018 ؍ eprosartan (200 or 300 mg b.i.d.) and enalapril (5–20 mg 4/259, P u.i.d.) on cough and blood pressure were compared in taneous reports from patients, or investigator’s a 26-week, double-blind, randomised, parallel-group, observation) was also more frequent with enalapril, as multicentre, international study involving 528 patients compared to eprosartan. Both agents reduced blood with hypertension. Uptitration of doses was based on pressure significantly compared to baseline, although clinic blood pressure measurements during the first 12 the eprosartan-treated group had a slightly higher weeks, after which hydrochlorothiazide (12.5–25 response rate (defined as sitting diastolic blood press- mg/day) could be added. The frequency and intensity of ure Ͻ90 mm Hg, or at least a 10 mm Hg reduction from cough was assessed by a standardised questionnaire baseline), both at end of titration (70.3% vs 62.6%, administered at each clinic visit. The primary end-point P Ͻ 0.05) and after 26 weeks (81.7% vs 73.5%, These data suggest that, in unselected .(0.018 ؍ was the incidence of persistent, dry cough not due to P upper respiratory infection; change in sitting diastolic hypertensive patients, eprosartan is associated with blood pressure and overall incidence of cough were less cough and a somewhat higher responder rate secondary end-points. During the first 12 weeks of dou- than enalapril. ble-blind therapy, enalapril treatment was associated Keywords: angiotensin II receptor antagonist; ACE inhibitor Introduction Patients and methods Angiotensin-coverting enzyme (ACE)-inhibitors are Study design useful in treating hypertension, heart failure, and renal impairment, but are most often discontinued because of the development of a persistent, dry This 41-centre, international double-blind, double- cough, the prevalence of which has been reported dummy, parallel-group study consisted of three as high as 25–69%.1–6 Unlike ACE-inhibitors, angi- treatment periods: a 3- to 5-week single-blind pla- otensin II receptor antagonists do not inhibit brady- cebo run-in (‘baseline’) period, an 18-week double- kinin degradation in vitro, and have been associated blind titration period, and an 8-week maintenance with a lower incidence of cough in carefully selec- period. Initially, patients were randomised to ted patients who demonstrated the cough response receive either eprosartan 200 mg twice daily or enal- to an ACE-inhibitor.7–10 Eprosartan is a new, highly- april 5 mg once daily. At 3-week intervals, the office selective non-peptide, non-biphenyl, non-tetrazole blood pressure was measured and the dose titrated angiotensin II receptor blocker with few effects on as needed to a maximum dosage of 300 mg twice 11 the cyctochrome P450 system. This paper describes daily eprosartan or 20 mg once daily enalapril. At the results of a large clinical study designed to com- the end of week 12, the maximum doses of double- pare the effects of eprosartan and enalapril on cough blind medication were supplemented with HCTZ and blood pressure (BP) in unselected hyperten- 12.5 mg once daily, and increased if needed to a sive patients. maximum of 25 mg daily. This study was conducted in accordance with the Declaration of Helsinki as amended. The protocol and informed consent signed by each participant Correspondence: William J Elliott, Rush Presbyterian-St. Luke’s were approved by the Institutional Review Board or Medical Center, Department of Preventive Medicine, 1725 Harri- son Street, #117, Chicago, IL 60612, USA Ethics Committee at each study site. Received 21 July 1998; revised 8 January 1999; accepted 4 Febru- ary 1999 Cough: eprosartan vs enalapril WJ Elliott 414 Patients tarily discontinued medication because of coughing. Maximum cough was defined as the sum of definite, Patients were eligible if they were at least 18 years of probable, and possible cough, and tickle in throat. age and had essential hypertension. Premenopausal Antihypertensive efficacy was measured at trough as women of childbearing potential were required to be the mean change from baseline in sitting and stand- using hormonal, barrier, or intrauterine contracep- ing systolic blood pressure (SBP) and diastolic blood tion. pressure (DBP). Responders were patients whose Patients with secondary forms of hypertension, SitDBP was less than either 90 mm Hg, or 100 advanced hypertensive retinopathy, average sitting Ͼ mm Hg and had decreased from baseline by at least systolic blood pressure (SitSBP) 200 mm Hg, 10 mm Hg. advanced atrioventricular conduction defects, ven- Baseline values were obtained at the last visit of tricular tachyarrhythmias requiring therapy, brady- the placebo run-in period, before randomisation. For cardia, prior myocardial infarction or cerebrovascu- blood pressure only, baseline was the mean of the lar accident within the past 90 days, congestive last two visits prior to randomisation. Comparisons heart failure being treated with ACE inhibitors or at baseline with respect to categorical demographic diuretics, angina being treated with nitrates, beta- and clinical characteristics were performed using blockers, or calcium channel blockers, unstable dia- the chi-square technique with adjustment for sam- betes mellitus, or presence of clinically significant pling differences across centres. For continuous renal or hepatic disease or another concurrent sev- variables, baseline differences were assessed by ere disease, were excluded. Patients were also analysis of variance (PROC GLM in SAS), which excluded if they had conditions which could inter- included terms for centre, medication regimen, and fere with the assessment of cough: emphysema, interaction with centre. Centralised data collection asthma or chronic bronchitis, or upper respiratory and statistical analysis were performed by full-time infection within 2 weeks of screening. Use of antico- employees of the sponsor (SmithKline Beecham agulants or another investigational drug within 30 Pharmaceuticals, Inc, Philadelphia, PA, USA). days of enrolment, chronic sympathomimetic amine For the categorical variables of cough incidence, or nonsteroidal anti-inflammatory drugs (other than cough severity, and response rate, comparisons low-dose aspirin) within 7 days of enrolment, and between the eprosartan and enalapril regimens dur- concomitant use of antidepressants or medications ing the double-blind periods were performed using a known to affect blood pressure or cough were not Cochran-Mantel-Haenszel (CMH) statistic adjusting allowed. for centre interaction with regimen, which was assessed with the Breslow-Day test (PROC FREQ in Assessments of cough and blood pressure SAS). For vital signs, an analysis of variance was performed at each visit, which included terms for A pulmonary assessment (physician’s physical centre, medication regimen, and regimen-by-centre examination of the chest by auscultation and per- interaction. If the latter was not significant cussion, if abnormal) was performed at screening, at (P Ͼ 0.10), it was removed from the model. Sub- randomisation, at weeks 6 and 12 of the titration groups of age, gender, race, prior use of antihyper- phase, and at the end of the maintenance phase. No tensives, and baseline severity of hypertension were pulmonary function testing was performed. The compared using similar techniques for cough, blood presence and character of cough were assessed by pressure, and response rate. the investigator regarding type, duration, severity, frequency, and probable cause of cough. Cough was categorised according to a hierarchy of severity as Results definite, probable, possible, or a ‘tickle in throat’. At Patient demographics and treatment regimens each visit, the patient completed a quality-of-life questionnaire, which included a five-point toler- The demographic and clinical characteristics of the ability rating scale of both frequency (never, seldom, patients are shown in Table 1; there were no signifi- occasional, frequent, or constant) and severity for cant differences between groups in any of these each of 10 commonly-experienced adverse effects parameters. In the eprosartan group, 138 patients with antihypertensive medications (one of which were titrated to the maximum dose of 300 mg twice was cough). Cough that occurred at any time during daily, whereas 151 patients in the enalapril group the trial was recorded as an adverse experience. were titrated to the maximum dose of 20 mg once Blood pressure and heart rate were measured in trip- daily. In each group, 81 patients initially received licate at each visit during the four study periods, HCTZ 12.5 mg once daily, and then 51 patients from according to standard techniques. the eprosartan group and 50 patients from the enala- pril group received the maximum dose plus HCTZ 25 mg once daily. Statistical analyses The primary end-point was definite cough of inter- Incidence of cough est, defined as the incidence of persistent, non-pro- ductive (dry) cough associated with treatment and A significantly higher incidence of definite cough not due to an upper respiratory infection