Racial Differences in Blood Pressure Response to Angiotensin-Converting Enzyme Inhibitors in Children: A Meta-Analysis

Abstract

Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension in children (1). ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and cardiac hypertrophic properties of angiotensin II and the vasodilatory and natriuretic properties of bradykinin; they also alter the metabolism of other vasoactive substances (2). Through these mechanisms, ACE inhibitors decrease systemic vascular resistance and promote natriuresis without increasing heart rate. They have proven efficacy in the treatment of hypertension, congestive heart failure, and left ventricular dysfunction and also delay the progression of diabetic nephropathy (2). In adults, ACE inhibitors are less potent in blacks than in whites (3,4). Although racial differences in response to ACE inhibitors are established in adults, data in children are limited by small sample sizes of individual trials (5,6). We evaluated results of 6 trials of ACE inhibitors submitted to the US Food and Drug Administration (FDA) for pediatric exclusivity using meta-analytic techniques to estimate the effect of race on blood pressure response. METHODS The cohortBetween January 1, 1998, and December 31, 2005, efficacy data from 12 antihypertensive products were submitted to the FDA's Division of Cardiovascular and Renal Products. We used the randomized, blinded efficacy trials for this analysis (7). One efficacy trial and at least 1 pharmacokinetic-pharmacodynamic (PK-PD) trial were completed for each agent. Summaries of medical and clinical pharmacology reviews of several of the studies are publicly available (8). Except for demonstrating differences in clearance and half-life for benazepril, the PK trials did not indicate differential dosing from adult data and did not suggest differences in absorption, bioavailability, clearance, or differential response by age or development. PK-PD samples were not obtained in the efficacy trials; therefore, we did not include PK-PD results in this analysis. The PK trials were performed in children ages 1 month to 16 years with the exception of the quinapril trial which was performed in children ages 2.5 months to 6 years and the ramipril trial which was performed in children ages 2 years to 6 years (8-11). In our Of the 12 efficacy trials, 6 were conducted with ACE inhibitors. Inclusion and exclusion criteria among trials were similar. The studies enrolled children 6-16 years of age. The trials excluded children with severe hypertension (because of a placebo phase), low glomerular filtration rates (< 30 mL/min/1.73 m 2 ), electrolyte abnormalities, renal disease, and other substantive medical problems including clinically significant cardiac disease (5). The trial design (12) and dosing strata of each study are shown in Table 1. Data managementThe data, protocols, and case report forms from these 6 trials were submitted electronically to the FDA. Source data were available in SAS datasets, which we converted to STATA datasets via STAT Transfer. We combined patient-level data to obtain 1...

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