Pharmacological Treatment of Arterial Hypertension in Children and Adolescents: A Network Meta-Analysis

Pharmacological treatment is indicated in children and adolescents with hypertension unresponsive to lifestyle modifications, but there is not enough evidence to recommend 1 class of antihypertensive drugs over others. We performed a network meta-analysis to compare the results of available randomized clinical trials on pharmacological treatment of pediatric hypertension. From a total of 554 potentially relevant studies, 13 randomized placebo-controlled clinical trials enrolling ≥50 patients and a follow-up ≥4 weeks were included. The reduction of systolic blood pressure (SBP) and diastolic BP (DBP) after treatment were the coprimary end points. A total of 2378 pediatric patients, with a median age of 12 years, were included in the analysis. After a median follow-up of 35 days, lisinopril and enalapril were found to be superior to placebo in reducing SBP and DBP, whereas only for DBP, losartan was found to be superior to placebo and lisinopril and enalapril were found to be superior to eplerenone. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were associated with a greater SBP and DBP reduction compared with placebo, likewise the mineralocorticoid receptor antagonist was inferior to angiotensin-converting enzyme inhibitors in DBP reduction. The analysis was adjusted for study-level mean age, percentage of women, mean baseline blood pressure, and mean weight, only the latter significantly affected DBP reduction. According to the present analysis, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers could represent the best choice as antihypertensive treatment for pediatric hypertension. However, because of the paucity of available data for the other classes of antihypertensive drugs, definitive conclusions are not allowed and further randomized controlled trials are warranted.

[1]  Wilbert S Aronow,et al.  2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. , 2018, Hypertension.

[2]  J. Ioannidis,et al.  Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis , 2018, The Lancet.

[3]  S. Daniels,et al.  Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents , 2017, Pediatrics.

[4]  Josemir W Sander,et al.  Antiepileptic drug discontinuation by people with epilepsy in the general population , 2017, Epilepsia.

[5]  M. Vervloet,et al.  Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. , 2017, Kidney international.

[6]  S. Bangalore,et al.  Optimal Systolic Blood Pressure Target After SPRINT: Insights from a Network Meta-Analysis of Randomized Trials. , 2017, The American journal of medicine.

[7]  A. Dominiczak,et al.  2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. , 2016, Journal of hypertension.

[8]  M. Flechtner-Mors,et al.  Blood pressure in 57,915 pediatric patients who are overweight or obese based on five reference systems. , 2015, The American journal of cardiology.

[9]  Harry Hemingway,et al.  Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people , 2014, The Lancet.

[10]  Stephen G. Miller,et al.  Anti-hypertensive drugs in children and adolescents. , 2014, World journal of cardiology.

[11]  N. Welton,et al.  Evidence Synthesis for Decision Making 3 , 2013, Medical decision making : an international journal of the Society for Medical Decision Making.

[12]  Jeroen P Jansen,et al.  Network meta‐analysis of individual and aggregate level data , 2012, Research synthesis methods.

[13]  J. Flynn,et al.  Antihypertensive Drug Use By Children: Are the Drugs Labeled and Indicated? , 2012, Journal of clinical hypertension.

[14]  D. Blowey,et al.  Update on the Pharmacologic Treatment of Hypertension in Pediatrics , 2012, Journal of clinical hypertension.

[15]  Shannon Cope,et al.  Meta-regression models to address heterogeneity and inconsistency in network meta-analysis of survival outcomes , 2012, BMC Medical Research Methodology.

[16]  Nicky J Welton,et al.  Evidence Synthesis for Decision Making in Healthcare: Welton/Evidence Synthesis for Decision Making in Healthcare , 2012 .

[17]  H. Sesso,et al.  Blood pressure in early adulthood, hypertension in middle age, and future cardiovascular disease mortality: HAHS (Harvard Alumni Health Study). , 2011, Journal of the American College of Cardiology.

[18]  V. Shi,et al.  The Efficacy and Safety of Valsartan in Obese and Non‐Obese Pediatric Hypertensive Patients , 2011, Journal of clinical hypertension.

[19]  N. Welton,et al.  Heterogeneity: Subgroups, Meta-Regression, Bias And Bias-Adjustment , 2011 .

[20]  M. Litwin,et al.  Effectiveness and Safety of Valsartan in Children Aged 6 to 16 Years With Hypertension , 2011, Journal of clinical hypertension.

[21]  F. Rasmussen,et al.  Association of blood pressure in late adolescence with subsequent mortality: cohort study of Swedish male conscripts , 2011, BMJ : British Medical Journal.

[22]  M. Litwin,et al.  Regression of target organ damage in children and adolescents with primary hypertension , 2010, Pediatric Nephrology.

[23]  R. Portman,et al.  Safety, Efficacy, and Pharmacokinetics of Telmisartan in Pediatric Patients With Hypertension , 2010, Clinical pediatrics.

[24]  A. Rudich,et al.  Progression of Normotensive Adolescents to Hypertensive Adults: A Study of 26 980 Teenagers , 2010, Hypertension.

[25]  J. Flynn,et al.  The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension: a randomized, double-blind, dose-response study. , 2010, The Journal of pediatrics.

[26]  R. Heyrman,et al.  A Double-Blind, Dose-Response Study of the Efficacy and Safety of Olmesartan Medoxomil in Children and Adolescents with Hypertension , 2010, Hypertension.

[27]  R. Hanson,et al.  Childhood obesity, other cardiovascular risk factors, and premature death. , 2010, The New England journal of medicine.

[28]  J. Ioannidis,et al.  The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration , 2009, Annals of Internal Medicine [serial online].

[29]  Youfa Wang,et al.  Tracking of Blood Pressure From Childhood to Adulthood: A Systematic Review and Meta–Regression Analysis , 2008, Circulation.

[30]  T. Seeman,et al.  Regression of left-ventricular hypertrophy in children and adolescents with hypertension during ramipril monotherapy. , 2007, American journal of hypertension.

[31]  Michael Böhm,et al.  2013 ESH/ESC Guidelines for the management of arterial hypertension , 2007, Blood pressure.

[32]  B. Falkner,et al.  Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience. , 2007, The Journal of pediatrics.

[33]  F. Assadi.  Effect of Microalbuminuria Lowering on Regression of Left Ventricular Hypertrophy in Children and Adolescents with Essential Hypertension , 2006, Pediatric Cardiology.

[34]  M. Litwin,et al.  Left ventricular hypertrophy and arterial wall thickening in children with essential hypertension , 2006, Pediatric Nephrology.

[35]  David Toll,et al.  How Do You Improve Compliance? , 2005, Pediatrics.

[36]  Zhongxin Zhang,et al.  A double-blind, dose-response study of losartan in hypertensive children. , 2005, American journal of hypertension.

[37]  G. Lu,et al.  Combination of direct and indirect evidence in mixed treatment comparisons , 2004, Statistics in medicine.

[38]  R. Califf,et al.  Is the Extrapolated Adult Dose of Fosinopril Safe and Effective in Treating Hypertensive Children? , 2004, Hypertension.

[39]  S. Daniels,et al.  A randomized, placebo-controlled trial of amlodipine in children with hypertension. , 2004, The Journal of pediatrics.

[40]  Paul Landais,et al.  Meta-regression detected associations between heterogeneous treatment effects and study-level, but not patient-level, factors. , 2004, Journal of clinical epidemiology.

[41]  S. Shahinfar,et al.  A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. , 2003, American journal of hypertension.

[42]  Thomas Lumley,et al.  Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. , 2003, JAMA.

[43]  R. Portman,et al.  Clinical trial of extended-release felodipine in pediatric essential hypertension , 2003, Pediatric Nephrology.

[44]  S. Shahinfar,et al.  A Double‐Blind, Placebo‐Controlled, Dose‐Response Study of the Effectiveness and Safety of Enalapril for Children with Hypertension , 2002, Journal of clinical pharmacology.

[45]  J. Sorof,et al.  β-Blocker/thiazide combination for treatment of hypertensive children: a randomized double-blind, placebo-controlled trial , 2002, Pediatric Nephrology.

[46]  J. Sorof,et al.  Ambulatory Blood Pressure and Left Ventricular Mass Index in Hypertensive Children , 2002, Hypertension.

[47]  I. Olkin,et al.  Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement , 1999, The Lancet.

[48]  T. Ruddy,et al.  Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators. , 1998, American journal of hypertension.

[49]  A Whitehead,et al.  Borrowing strength from external trials in a meta-analysis. , 1996, Statistics in medicine.

[50]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[51]  V. Bykerk,et al.  Consensus Statement , 2004, Pediatric Clinical Practice Guidelines & Policies.

[52]  T. Lehtimäki,et al.  The Cardiovascular Risk in Young Finns Study , 2008 .