Individual patient data were obtained from clinical trials of antihypertensive agents submitted to the Food and Drug Administration (FDA) as part of the pediatric exclusivity provision. Between January 1, 1998, and December 31, 2005, data from 6 ACEi and 2 ARB trials were submitted electronically to the FDA Division of Cardiovascular and Renal Products. Patients were excluded from the trials if they had severe hypertension, renal dysfunction, or therapy-related contraindications.
Trials were designed to include a lead-in phase during which all previously administered antihypertensive agents were discontinued (). Five of the trials were type C (enalapril, fosinopril, lisinopril, irbesartan, losartan), 2 were type D (benazepril and ramipril), and one was type A (quinapril). For type C studies, we only considered coughs reported as adverse events during the placebo-controlled period of the study. No patients in the 5 type C trials were discontinued from study drug during the double-blind period for cough-related adverse events.
We obtained study data sets from the FDA electronic document room. Data from the 8 antihypertension trials were merged using STATA 10.0 (College Station, TX). From each trial, the following common variables were assembled: study drug, study identification number, age, sex, race, therapy received during placebo-controlled phase of the study (placebo or active drug), start and stop dates for the placebo-controlled phase, start date of reported adverse event, and adverse event description. We used a categorical variable of “white/black/other” for race because several trials used this format to report race, and more specific information was unavailable.
Descriptors of adverse events that were defined as cough for this analysis included: cough, congestive cough, cough (intermittent), cough with emesis, cough/headache common cold, coughing, cough aggravated, cough increased, dry cough, hacking cough, headache and cough, intermittent cough usually at night, moist cough, night cough, persistent cough, productive cough, sporadic cough with mild expectoration, ear pain/sinus congestion/cough, and cough/red throat. Observations for subjects with missing dates for the start (n=10) or stop (n=16) date of the placebo-controlled portion of the trial were not considered in the analyses as the relationship of the adverse event to the study phase could not be determined. Only 1 of the excluded subjects reported cough as an adverse event (fosinopril study subject that received placebo).
Estimates of the proportion of children who reported cough were performed using the total number of subjects with cough divided by the total number subjects. Comparisons of proportions were performed using Fisher's exact test. Kaplan Meier curves were constructed with failure defined as time at first episode of cough. We used the Wilcoxon-Breslow-Gehan test of equality to compare the survivor functions between the subjects who received ACEi, ARB, and placebo therapy. Statistical significance was defined as P<0.05. Analysis was performed using STATA 10 (College Station, TX).