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The effectiveness and safety of valsartan have not been assessed in hypertensive children. Therefore, hypertensive patients aged 6 to 16 years (n=261) were randomized to receive weight-stratified low- (10/20 mg), medium- (40/80 mg), or high-dose (80/160 mg) valsartan for 2 weeks. After 2 weeks, patients were randomized to a 2-week placebo-controlled withdrawal phase. Dose-dependent reductions in sitting systolic blood pressure (SSBP) and sitting diastolic blood pressure (SDBP) were observed after 2 weeks (low dose, −7.9/−4.6 mm Hg; medium dose, −9.6/−5.8 mm Hg; high dose, −11.5/−7.4 mm Hg [P<.0001 for all groups]). During the withdrawal phase, SSBP and SDBP were both lower in the pooled valsartan group than in the pooled placebo group (SSBP, −2.7 mm Hg [P=.0368]; SDBP, −3.0 mm Hg [P=.0047]). Similar efficacy was observed in all subgroups. Valsartan was well tolerated and headache was the most commonly observed adverse event during both the double-blind and 52-week open-label phases. J Clin Hypertens (Greenwich). 2011;13:357–365. ©2011 Wiley Periodicals, Inc.
Hypertension is a significant health concern in the pediatric population. Children with hypertension may not manifest any overt signs; however, target organ damage similar to that seen in adults has been reported widely.1–5 Prevention of target organ damage is preferable, and in children with persistent hypertension despite aggressive nonpharmacologic therapy, antihypertensive agents are recommended.6,7 In patients with end-organ damage at the time of presentation, drug treatment to lower blood pressure (BP) is indicated.6–8
The safe and effective use of antihypertensive agents in children and adolescents has emerged as an important unmet medical need recognized by primary care physicians who treat these patients, academic subspecialists to whom these patients are referred frequently, and the US Food and Drug Administration (FDA) that has issued a number of written requests calling for study of marketed agents in this vulnerable patient population.6,9 The resulting studies have yielded mixed results. While all have shown some effect on either systolic or diastolic BP compared with placebo or baseline measurements, when evaluation is limited to marketed agents using the same experimental design, some have been shown to meet regulatory requirements for effectiveness while others have not.10 At the heart of this ambiguity are issues of incorrect dosing and, often, an inability to demonstrate clearly an exposure-response relationship. For these reasons, each agent with the potential for use in pediatric patients must be studied in this target population to ensure that effectiveness and safety can be demonstrated.
The angiotensin-converting enzyme (ACE) inhibitors have been among those most extensively evaluated in children and adolescents.11,12 Angiotensin II (A-II) receptor inhibition is perceived to have a physiologic advantage over inhibition of the converting enzyme alone since the latter does not inhibit tissue and serum enzymes that convert A-I to A-II, thus circumventing the ACE inhibitor–induced blockade of the renin-angiotensin-aldosterone system.13–15 Blocking the receptor mitigates the effects of A-II–induced vasoconstriction and aldosterone-dependent and aldosterone-independent sodium reabsorption.16
This study was designed to evaluate the efficacy and safety of valsartan, an angiotensin receptor blocker (ARB), in hypertensive children and adolescents using a randomized, dose-ranging, controlled-withdrawal design. The drug has recently been reported to be safe and effective in children aged 1 to 5 years with no negative effects on growth and development.17 In this trial, the age range is extended to patients aged 6 to 16 years.
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The FDA Modernization Act, enacted in 1997, has resulted in a significant increase in pediatric trials of hypertensive medications in recent years. As a result, many commonly prescribed antihypertensive medications, such as ACE inhibitors, ARBs, and calcium channel blockers, have been evaluated in hypertensive children aged 6 to 16 years in well-controlled, prospective, multicenter studies.11,12,17,19,20 The results from most of these studies have demonstrated that these agents were effective in lowering BP and were well tolerated in children. The safety profiles observed in children were not different from those observed in adult patients. Results from the current study demonstrated that a dose-dependent SSBP reduction was observed with valsartan in hypertensive children aged 6 to 16 years. The efficacy of valsartan in reducing BP was further confirmed in a randomized 2-week, placebo-withdrawal period. The antihypertensive effect of valsartan was not influenced by the demographic make-up of the patient population. Valsartan was well tolerated, and no unexpected AEs were reported during the study.
The mean daily dose of valsartan administered to patients in phases 1 and 2 of the study ranged from 0.4 mg/kg to 2.7 mg/kg. Valsartan was shown to reduce SSBP and SDBP in a dose-dependent fashion in children aged 6 to 16 years. The reduction in BP appeared to be maximal within 2 weeks after starting therapy. No further reduction in mean SSBP or SDBP was observed in patients who continued on valsartan during phase 2. Randomized withdrawal to active drug or placebo confirmed the antihypertensive effectiveness of valsartan, especially in the medium- and high-dose groups.
It has been reported that black patients with hypertension respond poorly to certain classes of antihypertensive medications.21 To assess the impact of demographic make-up of the patient population on the efficacy and safety of valsartan in hypertensive children, an adequate number of patients from predefined subgroups were enrolled, including school children (50% older than 12 years), black children (46.8%), female patients (39.5%), and children from the United States and outside the United States (50% each). Approximately one half (54%) of the children were obese (body mass index ≥95th percentile for sex and age), a finding not surprising considering the accepted relationship between obesity and hypertension. (Previous reports have demonstrated hypertension prevalence of up to 30% in obese adolescents.22) Subgroup analyses revealed few differences between groups. The magnitude of the response to valsartan increased with dose in all subgroups. Weight group, race, sex, and maturation did not appear to influence response to valsartan. There were no differences in response based on age group (6–11 years vs 12–16 years) in phase 1. However, the younger children appeared to have lower placebo-corrected SDBP (but not SSBP) than the older patients. This observation might be explained by the greater likelihood that hypertension is caused by renal diseases in younger children.23,24 Renal diseases are a common cause of resistant hypertension in adults.25,26 Less is known about the impact of renal disease on hypertension treatment in children; however, in the recent multicenter observational Chronic Kidney Disease in Children study,27 antihypertensive treatment failed to control hypertension in nearly half (48.5%) of children (mean age, 11 years) with hypertension and chronic kidney disease.
Plasma renin and A-II activities were not measured in this study. No assertions can be made regarding correlation of response to baseline activity of the RAAS. Since there were relatively few patients in the subgroups, caution is indicated when generalizing from these results.
Although direct comparisons cannot be made, the response observed in children is comparable with that seen in the adult population.28–30 Valsartan treatment in adults resulted in a dose-dependent reduction in both SSBP and SDBP when compared with placebo over a dose range of 10 mg to 320 mg.31 In this study, the valsartan 20-mg dose was not different from placebo. The magnitude of response was similar to that seen after 4 weeks of therapy using comparable doses in adults.28 AEs in adults were similar to those observed in children. Dizziness was significantly more common in adult patients who received 320 mg of valsartan than in those who received lower doses (9.3% vs 2.1%–3.4% at doses of 20–160 mg).29
BP reductions were also comparable with those seen in children aged 6 to 16 years treated with losartan.19 Comparable reductions in mean SSBP and SDBP were observed in adults treated with either valsartan (80–160 mg) or losartan (50–100 mg) for up to 8 weeks.32
Overall, valsartan was well tolerated. Short-term data from phase 2 suggests that the AEs observed in valsartan-treated patients are similar to those observed with placebo, although the number of patients studied was relatively small and AEs in the placebo group might still be attributable to valsartan during the first few days of phase 2. Headaches were observed in >5% of patients. Headaches are a relatively common complaint in children with and without hypertension. It is difficult to know whether the headaches observed in the patients in this study were due to valsartan or other causes. Dose-related dizziness seen in adults29 was also observed in a small number of children. New-onset diabetes was uncommon in this study, and no patient discontinued the study prematurely as a result of diabetes development. Other AEs were relatively uncommon, generally mild to moderate in severity, and rarely resulted in discontinuation of therapy. AEs that occur with a very low frequency may not have been detected in this study.
Only two AEs were both serious and deemed to be related to therapy. Of these AEs, hyperkalemia has been described in the adult population and is a predictable effect of A-II receptor blockade. In patients with renal or renovascular disease, serum potassium levels should be monitored, especially in patients who are concurrently treated with ACE inhibitors or potassium-sparing diuretics.
Acknowledgments and disclosures: The authors acknowledge all investigators and study coordinators at the participating centers and all patients for their commitment to the study, which was sponsored by Novartis Pharmaceuticals Corporation. Editorial assistance was provided on the final draft of this manuscript by a professional medical writer, Joanne Bentley (ACUMED, Tytherington, UK); this support was funded by Novartis Pharmaceuticals Corporation. Thomas Wells, Jeffrey Blumer, Kevin E.C. Meyers, Jose Pacheco Ribeiro Neto, Rejane Meneses, and Mieczysław Litwin have no conflicts of interest to disclose and all have participated or are participating in other trials sponsored by Novartis. Johan Vande Walle has acted as a consultant for Novartis and has participated in other trials sponsored by Novartis. Guangyang Han, Susan Solar-Yohay, and Victor Shi are employees of Novartis Pharmaceuticals Corporation.