Dechallenge and rechallenge method showed different incidences of cough among four ACE-Is Bernadette A. Tumanan-Mendoza a, * , Antonio L. Dans b , Lourdes Lucienne Villacin c , Victor L. Mendoza d , Sofia Rellama-Black e , Moises Bartolome f , Jimmy Ragual f , Benjamin Flor, Josephine Valdez g a Department of Internal Medicine, Manila Doctors Hospital, U.N. Avenue, Manila, Philippines 1000 b Department of Internal Medicine, University of the Philippines e Philippine General Hospital, Taft Avenue, Manila, Philippines 1000 c Department of Medicine, Riverside Medical Center, Bacolod City, Philippines d Department of Internal Medicine, De La Salle University, Health Sciences Campus, Dasmarin˜as, Cavite 4114, Philippines e Department of Medicine, St. Louis University Hospital, Baguio City, Philippines f Department of Medicine, Quezon City General Hospital, Quezon City, Philippines g Department of Internal Medicine, De La Salle University, Health Sciences Campus, Dasmarinas, Cavite 4114, Philippines Accepted 26 June 2006 Abstract Objective: To determine the incidence of cough secondary to (1) Cilazapril, (2) Enalapril, (3) Imidapril, and (4) Perindopril and their efficacy in the control of hypertension. Study Design and Setting: Randomized double-blind study conducted in selected medical centers in the Philippines from the first quar- ter of 1999 to March, 2001. Results: A total of 301 patients, aged 28e86 years with stage I or II hypertension were included. Patients were randomized to Cilazapril 2.5e5.0 mg/day (n 5 70), Enalapril 10e20 mg/day (n 5 82), Perindoril 4e8 mg/day (n 5 73), or Imidapril 10e20 mg/day (n 5 76). Hydro- chlorothiazide 12.5 mg/day was added if needed. Using a dechallenge and rechallenge method, a strict criteria to attribute cough to angio- tensin converting enzyme inhibitors (ACE-Is) not yet used in previous reports, the cough incidence were as follows: (1) Cilazaprild22.86% (16/70), (2) Enalaprild21.95% (18/82), (3) Perindoprild10.96% (6/73), and (4) Imidaprild13.16% (10/76) (P 5 0.041). Control of hypertension was significantly better with Enalapril during the first follow-up period. Conclusion: Statistically significant differences in the incidence of cough among the studied ACE-Is were noted. Control of hyperten- sion was observed to be better in those with a higher incidence of cough; however, the mean change of both systolic and diastolic blood pressure levels were not significantly different. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Cough; ACE-inhibitors; Dechallenge/rechallenge method; Randomized trial 1. Introduction Persistent dry cough is a common side effect of angio- tensin converting enzyme inhibitors (ACE-Is). This is often troublesome and can sometimes lead to the discontinuation of the drug. Data about the incidence of cough are conflict- ing [1]. It has been reported to be as low as 1e2% in retro- spective or postmarketing studies. Highs of 37e39% have been reported in controlled trials although a 0.9% incidence was reported in one [2e7]. The incidence also varied among the different predisposing disorders. In a study by Ravid et al. [8], the incidence was reported to be higher among patients with congestive heart failure as compared to hypertensives (P ! 0.001). Elliot [9], on the other hand, suggested that the difference might be related to race or ethnic factors. It was found that among blacks, the occur- rence of cough poses a 2.5 times risk of discontinuing the use of ACE-Is (relative risk [RR] 5 2.58; 95% confidence interval [CI]: 1.21, 4.65). Another study showed a higher incidence of cough among Chinese in Hong Kong (53% among those taking ACE-I, 10% among controls) as com- pared to Caucasians in Auckland (18% among those taking ACE-I, 5% among controls) [10]. With regard to other antihypertensives, Lacourciere et al. [11] reported a higher incidence of cough among patients given Lisinopril com- pared to those given either Losartan or hydrochlorthiazide. * Corresponding author. Tel.: þ63-2-521-1704. E-mail address: bernadette.tumanan@gmail.com (B.A. Tumanan- Mendoza). 0895-4356/07/$ e see front matter Ó 2007 Elsevier Inc. All rights reserved. doi: 10.1016/j.jclinepi.2006.06.017 Journal of Clinical Epidemiology 60 (2007) 547e553