A Double‐Blind, Placebo‐Controlled, Dose‐Response Study of the Effectiveness and Safety of Enalapril for Children with Hypertension

Abstract

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectively in 110 hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24-h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose-dependent manner. During a 2-week, double-blind, randomized, dose-response period, patients were stratified by weight (< 50 kg or > or = 50 kg), then assigned to one of three dosing groups: low(0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight-adjusted basis. On completion of the dose-response phase of the study, patients entered a 2-week, double-blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose-response relationship for enalapril had a negative slope and was linear over the chosen dosing range, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug orplacebo confirmed the antihypertensive effectiveness of enalapril in the middle- and high-dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well-tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing > 50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose-dependent fashion, with larger doses resulting in a greater reduction.

Atherosclerosis in childhood and adolescent type 1 diabetes: early disease, early treatment?

“…No long-term randomised trials have investigated the effect of kidney function and cardiovascular disease in children or adolescents with diabetes, and the consensus statements are based on extrapolations from adult studies. In short-term studies, ACE inhibitors have been effective and safe in non-diabetic hypertensive children [58,59], but long-term studies are lacking.…”

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

“…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.…”

Pharmacologic Management of Pediatric Hypertension

“…ACE inhibitors are generally well-tolerated, and the common adult side-effect of chronic cough was seen in less than 3% of a pediatric population treated with enalapril [39]. Given the beneficial effects on cardiac function and remodeling, these drugs are considered the drug of choice for patients with diminished cardiac function or left ventricular hypertrophy.…”