Is There a Role for β-Adrenergic Blockers in Treating Hypertension in Children?
Article Outline
Over the past decade, it has been recognized that hypertension exists in children and adolescents, that pediatricians should screen for and evaluate it, and that the ideal goal is to prevent the long-term cardiovascular consequences of elevated blood pressure. Two parallel developments have influenced the choice of antihypertensive agent for children with persistent elevated blood pressure. The first development is the concept that drug testing is needed to ensure the efficacy and safety of any drug in children.1 A mechanism to accomplish this goal is patent extension to induce a company marketing a drug under a patent to support drug trials that may lead to improved labeling.2 This extension has been applied to antihypertensive agent studies.3 The second development is the recommendations emanating from a report on the diagnosis, evaluation, and treatment of hypertension in children and adolescents recommending that certain classes of antihypertensive agents be used as therapy.4
See related article, p 134
In this issue of The Journal, Batisky et al5 evaluate a class of antihypertensive drugs recommended by that report: the cardioselective β-blocker metoprolol.4 The importance of this study lies in the fact that it is well designed; previously, few well-conducted trials of β-blockers had been performed in children.5, 6 The study evaluates metoprolol extended-release tablets, which can be given once daily. The findings are from a 4-week double-blind dose-range study and a 52-week open-label extension study. Children age 6 to 16 years were evaluated.
The report provides evidence that extended-release metoprolol significantly reduced systolic blood pressure at 1.0 and 2.0 mg/kg compared with placebo. Only the 2.0 mg/kg dose significantly reduced diastolic blood pressure. The drug was well tolerated in the 52-week trial, and only 5% of study participants had to drop out due to adverse events. The response rate increased significantly, from 41% at the beginning of the study to 64% at week 52.
The principal value of this study lies in the assessment of the safety and efficacy of a β-blocker in a short-term trial. This assessment is important because this class of agents has not been extensively evaluated.5, 6 From these 2 studies, it appears that this agent is generally safe. However, a majority of subjects in each trial did not achieve target blood pressure control (55% and 59%, respectively) over the short term. The open-label study found that many more patients achieved the target blood pressure.5
A limitation of this study is that it fails to define precisely the circumstances in which a β-blocker would be chosen. All patients with hypertension secondary to coarctation of the aorta, pheochromocytoma, hyperthyroidism, and Cushing syndrome were excluded, and most patients in both trials had essential hypertension. Patients with other forms of hypertension were not generally evaluated.
The studies by Batisky5 and Sorof et al6 are placebo-controlled trials. Although the drug caused a greater drop in both systolic and diastolic pressure than placebo, there was a substantial placebo effect. This effect could be explained by 2 factors: the Hawthorne effect and the oft-made observation that hypertensive children may improve over time.7 The Hawthorne effect is a well-established phenomenon wherein the very fact of entering a study has an effect on patient behavior and may influence the symptoms or findings in a patient. Moreover, the data from these 2 trials and other studies indicate that children with mild primary hypertension followed over time may experience normalization of blood pressure without treatment. A clear implication is that such patients may need several months of observation before initiation of pharmaceutical intervention.
The use of a placebo arm in childhood hypertension trials is controversial. Many hypertensive trials in both children and adults do not have a placebo arm so as to avoid the well-established consequences of untreated hypertension.8 The International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline E10 concluded that “when a new treatment is tested for a condition for which no effective treatment is known, there is usually no ethical problem with a study comparing the new treatment to placebo.”9 The situation in antihypertensive trials falls outside this guideline, especially because so many effective agents are available.3, 4, 9 Flynn et al8 and Chesney et al3 have made the argument that a placebo control can be justified if the hypertension is mild, if the subjects do not have hypertension-related target organ damage, and if the study duration is short.
In the study by Batisky et al,5 adverse effects were uncommon, and even in the long-term open label component of the study, only 5 children dropped out because of side effects. This represents just 5% of the 100 patients in this phase of the trial. Reported side effects included fatigue, nightmares, anxiety, dizziness, and asthma. Traditional contraindications to β-adrenergic inhibition, such as asthma and diabetes, also are relevant; however, a β1 receptor antagonist should largely affect the cardiogenic receptors. The present study does not comment on the use of β-blockers in competitive athletes or runners, in whom the need to raise the heart rate is pertinent.
A recent survey review of 438 North American pediatric nephrologists indicated that most used angiotension-converting enzyme inhibitors (ACEIs), followed by calcium-channel blockers (47% and 37%, respectively), in the first-line treatment of primary hypertension.10 β-blockers were used as a first-line agent by only 7% of respondents, but in second-line therapy by 17%. In children with hypertension associated with renal insufficiency, ACEIs were used by 84% of respondents in first-line therapy, and β-blockers were used only as second-line agents. The study of Batisky et al5 shows that the β-blocker metoprolol can be used safely in patients with primary hypertension, with the target pressure reached in approximately 70% of subjects. This is valuable new information.
References
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- Efficacy and safety of extended-release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience. J Pediatr. 2007;150:134–139
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- . ICH Harmonised Tripartite Guideline E10: Choice of control group and related issues in clinical trials. 2000;July. Available at http://www.ich.org/pdfICH/e10step4.pdf. Accessed September 2006
- . How are hypertensive children evaluated and managed? (A survey of North American pediatric nephrologists). Pediatr Nephrol. 2005;20:791–797
PII: S0022-3476(06)01173-5
doi:10.1016/j.jpeds.2006.11.064
© 2007 Mosby, Inc. All rights reserved.
Refers to article:
- Efficacy and Safety of Extended Release Metoprolol Succinate in Hypertensive Children 6 to 16 Years of Age: A Clinical Trial Experience
