Special article: 2014 Pediatric Clinical Trials Forum.

In November 2014, the American Academy of Pediatrics convened key stakeholders to discuss the feasibility of accelerating children's medical advances by creating an independent global Pediatric Clinical Trials Network. The Forum identified challenges posed by the U.S. and global clinical trial systems regarding testing and disseminating drugs and devices for pediatric patients. Stakeholders mapped a vision to improve the safety and efficacy of pediatric drugs, biological products, and medical devices by creating a global Pediatric Clinical Trials Network. Such a Network would act as a central infrastructure for pediatric subspecialties and enable dedicated staff to provide clinical research sites with scientific, medical, and operational support. A Network would facilitate development and availability of innovative, high-quality therapies to extend and enhance the lives of neonates, infants, children, adolescents, and young adults. Participants expressed strong interest in forming such a Network, since drugs and devices still come to market without adequate pediatric indications-particularly in neonatology and rare diseases. Participants developed a Consensus Statement expressing their shared vision for a Network: Attendees of the Pediatric Clinical Trials Stakeholder Forum resolved to establish a Global Pediatric Clinical Trials Network and are committed to engage in the work to create and sustain it.

Detection of early diastolic alterations by tissue Doppler imaging in untreated childhood-onset essential hypertension.

The aim of the study was to determine the presence of preclinical diastolic dysfunction in hypertensive children relative to normotensive children by Tissue Doppler Imaging (TDI). We prospectively enrolled children with untreated essential hypertension in absence of any other disease and a matched healthy control group with normal blood pressure (BP); both groups confirmed by clinic BP and a 24-hour ambulatory BP monitoring. Echocardiographic diastolic parameters were determined using spectral transmitral inflow Doppler, flow propagation velocity, TDI, and systolic parameters were determined via midwall shortening fraction and ejection fraction. A total of 80 multiethnic children were prospectively enrolled for the study: 46 hypertensive (median age, 13 years; 72% males) and 34 control (median age, 14 years; 65% males). The only echocardiography parameters that had a statistically significant change compared with the control children, were regional mitral Ea, Aa, and the E/Ea ratio by TDI. In comparison with controls, hypertensive children had lower Ea and Aa velocities of anterior and posterior walls and higher lateral wall E/Ea ratio. The decrease in posterior wall Ea and Aa remained significant after adjustment for gender, age, body mass index, ethnicity, and left ventricular hypertrophy on multivariate analysis. The lateral and septal wall E/Ea ratios correlated significantly with fasting serum insulin levels on similar multivariate analysis. Decreased regional TDI velocities were seen with preserved left ventricular systolic function even when other measures of diastolic dysfunction remained unchanged in untreated hypertensive children. Hypertension and serum insulin levels had strong associations with preclinical diastolic alterations in children.

Evaluation of serum creatinine concentration-based glomerular filtration rate equations in pediatric patients with chronic kidney disease.

STUDY OBJECTIVE: To evaluate the accuracy of four equations based on serum creatinine concentration-the original Schwartz equation and the Leger, Bedside Chronic Kidney Disease in Children (CKiD), and Counahan-Barratt equations-for determining glomerular filtration rate (GFR) in pediatric patients with chronic kidney disease. DESIGN: Retrospective, observational, cross-sectional study. SETTING: Single-center, academic, outpatient pediatric nephrology clinic. PATIENTS: Fifty-three pediatric patients with stages 2-5 chronic kidney disease who completed GFR assessment with (125) I-iothalamate between January 2002 and January 2005. MEASUREMENT AND MAIN RESULTS: Data were collected from each patient's medical record. Glomerular filtration rate data were analyzed using 59 evaluations from the 53 pediatric patients. (125) I-iothalamate clearance was used as the index GFR. The Bedside CKiD and Counahan-Barratt equations outperformed the Schwartz and Leger equations when the index GFR was less than 60 ml/minute/1.73 m(2) ; the Schwartz and Counahan-Barratt equations performed best for index GFRs of 60 ml/minute/1.73 m(2) or greater. Overestimation was highest with the Schwartz and Leger equations (> 20% index GFR in 57.6% and 62.7% of patients, respectively). Underestimation was highest with the Bedside CKiD and Counahan-Barratt equations (> 20% index GFR in 30.5% and 28.8%, respectively). CONCLUSION: The new Bedside CKiD equation performed well for pediatric patients with moderate-to-severe chronic kidney disease, but less well for pediatric patients with mild disease. Additional studies are needed to develop more precise GFR equations using serum creatinine concentration.

Development of hypertension in adolescents with pre-hypertension.

OBJECTIVE: To evaluate the risk for developing incident hypertension (HTN) in adolescents with pre-hypertension. STUDY DESIGN: A secondary analysis of students participating in multiple school-based blood pressure (BP) screens from 2000 to 2007 was completed. At each screen, height, weight, and 2 to 4 BPs were measured on as many as 3 occasions when BP remained ≥ 95th percentile. Students with confirmed HTN at their initial screen were excluded, and incident HTN was defined as having a BP ≥ 95th percentile at all 3 visits of a later screen. Incidence rates (IR) and hazard ratios (HR) were calculated by using Cox Proportional models. RESULTS: Of 1006 students, HTN developed in 11 (IR 0.5%/year) in a mean of 2.1 years of observation. IRs were higher in "at-risk" students (pre-hypertensive or hypertensive with follow-up BP <95th percentile), 1.4%/year (HR, 4.89; 1.48-16.19) and students with a BP ≥ 90th percentile at 3 baseline visits, 6.6%/year HR 24.33 (5.68-104.29)]. Although not significant, students with pre-hypertension by the 2004 Task Force definition also had an increased IR of 1.1%/year (HR, 2.98; 0.77-11.56)]. CONCLUSION: Elevated BP increases the risk for the development of HTN during adolescence. Effective strategies for preventing HTN in at-risk adolescents are needed.

Prevalence of persistent prehypertension in adolescents.

OBJECTIVE: To measure the prevalence of persistent prehypertension in adolescents. STUDY DESIGN: We collected demographic and anthropometric data and 4 oscillometric blood pressure (BP) measurements on 1020 students. The mean of the second, third, and fourth BP measurements determined each student's BP status per visit, with up to 3 total visits. Final BP status was classified as normal (BP <90th percentile and 120/80 mm Hg at the first visit), variable (BP ≥ 90th percentile or 120/80 mm Hg at the first visit and subsequently normal), abnormal (BP ≥ 90th percentile or 120/80 mm Hg at 3 visits but not hypertensive), or hypertensive (BP ≥ 95th percentile at 3 visits). The abnormal group included those with persistent prehypertension (BP ≥ 90th percentile or 120/80 mm Hg and <95th percentile on 3 visits). Statistical analysis allowed for comparison of groups and identification of characteristics associated with final BP classification. RESULTS: Of 1010 students analyzed, 71.1% were classified as normal, 15.0% as variable, 11.5% as abnormal, and 2.5% as hypertensive. The prevalence of persistent prehypertension was 4.0%. Obesity similarly affected the odds for variable BP (OR, 3.9; 95% CI, 2.5-6.0) and abnormal BP (OR, 3.4; 95% CI, 2.0-5.9), and dramatically increased the odds for hypertension (OR, 38.4; 95% CI, 9.4-156.6). CONCLUSION: Almost 30% of the students had at least one elevated BP measurement significantly influenced by obesity. Treating obesity may be essential to preventing prehypertension and/or hypertension.

Apixaban or enoxaparin for thromboprophylaxis after knee replacement.

BACKGROUND: The optimal strategy for thromboprophylaxis after major joint replacement has not been established. Low-molecular-weight heparins such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin. Apixaban, a specific factor Xa inhibitor, may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use. METHODS: In a double-blind, double-dummy study, we randomly assigned patients undergoing total knee replacement to receive 2.5 mg of apixaban orally twice daily or 30 mg of enoxaparin subcutaneously every 12 hours. Both medications were started 12 to 24 hours after surgery and continued for 10 to 14 days. Bilateral venography was then performed. The primary efficacy outcome was a composite of asymptomatic and symptomatic deep-vein thrombosis, nonfatal pulmonary embolism, and death from any cause during treatment. Patients were followed for 60 days after anticoagulation therapy was stopped. RESULTS: A total of 3195 patients underwent randomization, with 1599 assigned to the apixaban group and 1596 to the enoxaparin group; 908 subjects were not eligible for the efficacy analysis. The overall rate of primary events was much lower than anticipated. The rate of the primary efficacy outcome was 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk, 1.02; 95% confidence interval, 0.78 to 1.32). The composite incidence of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P=0.03). CONCLUSIONS: As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement, apixaban did not meet the prespecified statistical criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse-event profile. (ClinicalTrials.gov number, NCT00371683.)

Left ventricular hypertrophy in hypertensive adolescents: analysis of risk by 2004 National High Blood Pressure Education Program Working Group staging criteria.

The National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents recently recommended staging hypertension (HTN) in children and adolescents based on blood pressure severity. The use of blood pressure staging and its corresponding therapeutic approach was examined in this pooled analysis assessing the risk for end-organ damage, specifically left ventricular hypertrophy among hypertensive adolescents stratified by working group criteria. Newly diagnosed hypertensive adolescents and normotensive control subjects similar in age, race/ethnicity, gender, and body mass index completed casual and 24-hour ambulatory blood pressure measurements, M-mode echocardiography, and fasting serum laboratories. Hypertensive subjects had higher insulin and cholesterol but similar glucose levels as compared with control subjects. Among subjects with stage 1 HTN by casual blood pressure, 34% had white-coat HTN as opposed to 15% of stage 2 hypertensive subjects. Of the subjects with normal casual measurements, 20% had HTN by ambulatory monitoring. Subjects with stage 2 HTN by casual measurement alone (odds ratio: 4.13; 95% CI: 1.04 to 16.48) and after 24-hour ambulatory confirmation (odds ratio: 7.23; 95% CI: 1.28 to 40.68) had increased odds for left ventricular hypertrophy. In addition, the risk for left ventricular hypertrophy was similar for subjects with masked and confirmed stage 1 HTN, whereas subjects with white-coat HTN had a risk comparable to normotensive subjects. Thus, recommendations that adolescents with stage 2 HTN by casual measurements alone receive medication initially along with therapeutic lifestyle counseling are reasonable, though ambulatory blood pressure monitoring remains a valuable tool for evaluating children with stage 2 HTN, because >10% have white-coat HTN.

Ambulatory blood pressure monitoring: what a pediatrician should know.

PURPOSE OF REVIEW: Ambulatory blood pressure monitoring is a useful tool for the evaluation and management of hypertension in children and adolescents. This review provides a basic overview of ambulatory blood pressure monitoring and summarizes the most recent available knowledge regarding its use in the pediatric population. RECENT FINDINGS: Evaluation and validation of ambulatory blood pressure monitoring equipment in children remains limited, although advances in the interpretation of results for this age group have been reported specifically in the area of circadian (24 h) and ultradian (<24 h) variability. Blood pressure is a dynamic phenomenon that varies not only with time but also with changing patient and environmental circumstances. Growing evidence regarding conditions identified when this variability is considered, specifically white coat and masked hypertension, suggests that office blood pressure measurement may not be a sufficient screening test for hypertension-related target-organ damage. SUMMARY: Information regarding ambulatory blood pressure monitoring use in children is increasing, although due to its limitations and expense, it remains a tool primarily utilized by the pediatric sub-specialist.

Prevalence of hypertension and pre-hypertension among adolescents.

OBJECTIVE: To determine the prevalence of hypertension and pre-hypertension on the basis of the 2004 National High Blood Pressure Education Program Working Group guidelines in an adolescent school-screening population. STUDY DESIGN: Cross-sectional assessment of blood pressure (BP) in 6790 adolescents (11-17 years) in Houston schools was conducted from 2003 to 2005. Initial measurements included height, weight, and 4 oscillometric BP readings. Repeat measurements were obtained on 2 subsequent occasions in students with persistently elevated BP. Final prevalence was adjusted for loss to follow-up and logistic regression used to assess risk factors. RESULTS: BP distribution at initial screen was 81.1% normal, 9.5% pre-hypertension, and 9.4% hypertension (8.4% Stage 1; 1% Stage 2). Prevalence after 3 screenings was 81.1% normal, 15.7% pre-hypertension, and 3.2% hypertension (2.6% Stage 1; 0.6% Stage 2). Hypertension and pre-hypertension increased with increasing body mass index. Sex, race, and classification as either at-risk for overweight or overweight were independently associated with pre-hypertension. Only classification as overweight was associated with hypertension. CONCLUSIONS: Application of new classification guidelines for adolescents with elevated BP reveals approximately 20% are at risk for hypertension. Further research determining the significance of each BP category and refining definitions to account for BP variability is warranted.

Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience.

OBJECTIVE: To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension. STUDY DESIGN: Patients were randomized to one of four treatment arms: placebo or ER metoprolol (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg). Data were analyzed on 140 intent-to-treat patients. RESULTS: Mean age (+/-SD) was 12.5 +/- 2.8 years and mean baseline BP was 132/78 +/- 9/9 mmHg. Following 4 weeks of treatment, mean changes in sitting BP were: placebo = -1.9/-2.1 mmHg; ER metoprolol 0.2 mg/kg = -5.2/-3.1 mmHg; 1.0 mg/kg = -7.7/-4.9 mmHg; 2.0 mg/kg = -6.3/-7.5 mmHg. Compared with placebo, ER metoprolol significantly reduced systolic blood pressure (SBP) at the 1.0 and 2.0 mg/kg dose (P = .027 and P = .049, respectively), reduced diastolic blood pressure (DBP) at the 2.0 mg/kg dose (P = .017), and showed a statistically significant dose response relationship for the placebo-corrected change in DBP from baseline. There were no serious adverse events or adverse events requiring study drug discontinuation among patients receiving active therapy. CONCLUSION: These data indicate that ER metoprolol is an effective and well-tolerated treatment for hypertension in children.

Population pharmacokinetics of amlodipine in hypertensive children and adolescents.

A population pharmacokinetic study was conducted in 74 hypertensive children (mean age 10.4 +/- 4.4 years [mean +/- SD]) receiving amlodipine (mean dose 0.17 +/- 0.13 mg/kg/d) chronically. Multiple blood samples were obtained from each subject to characterize amlodipine pharmacokinetics. Plasma amlodipine concentrations were determined by liquid chromatography/mass spectrophotometry with multiple-reaction monitoring detection. Population pharmacokinetic analysis was performed using NONMEM. Amlodipine concentrations were similar in subjects dosed either once or twice daily. Amlodipine pharmacokinetics were well described by a 1-compartment model with first-order absorption and elimination. For a subject at the population median weight (45 kg), predicted apparent clearances (CL/F) were 23.7 L/h for males and 17.6 L/h for females, and the apparent volume of distribution (V/F) was 25.1 L/kg. Dosing frequency did not appear to affect amlodipine concentrations in children. Weight-adjusted CL/F and V/F of amlodipine in younger children were significantly greater than in older children, suggesting a need for higher doses when treating young children with amlodipine.

A randomized, placebo-controlled trial of amlodipine in children with hypertension.

OBJECTIVES: Evaluation of the efficacy and safety of amlodipine in hypertensive children. STUDY DESIGN: A randomized, double blinded, placebo-controlled, parallel-group, dose-ranging study was conducted at 49 centers in North and South America. The primary end point was the effect of amlodipine on systolic blood pressure (BP); secondary end points included the effect of amlodipine on diastolic BP, the effect of amlodipine as a function of dose and body size, and evaluation of safety. RESULTS: We enrolled 268 hypertensive children (mean age, 12.1 +/- 3.3 years); 84 (31.3%) had primary hypertension, and 177 (66%) were boys. Amlodipine produced significantly greater reductions in systolic BP than placebo; these were -6.9 mm Hg for 2.5 mg daily (P=.045 vs placebo) and -8.7 mm Hg for 5 mg daily (P=.005 vs placebo). The underlying cause of hypertension had no effect on the response to amlodipine. There was a significant dose-response effect of amlodipine on both systolic and diastolic BP beginning at doses > or =0.06 mg/kg per day. Systolic BP < or =95(th) percentile was achieved in 34.6% of subjects with systolic hypertension. Amlodipine was well tolerated, with just 6 children withdrawn from treatment because of drug-related adverse events. CONCLUSIONS: Amlodipine effectively lowers systolic BP in a dose-dependent manner in hypertensive children who require drug treatment.

Measurement and treatment of elevated blood pressure in the pediatric patient with chronic kidney disease.

Hypertension, as in adults, is a frequent complication found in children with chronic kidney disease (CKD). Indeed, hypertension has now become one of the most prevalent chronic diseases of childhood. The most recent data available (2003) indicate that at least 38% of children with CKD in the United States are receiving antihypertensive therapy. Only recently has it been shown in children that hypertension, traditionally considered a marker for disease severity in children, is additionally a significant and independent risk factor for accelerated deterioration of kidney function and progression of CKD and a significant risk factor for cardiovascular disease. The following review outlines the differences and similarities of childhood versus adult hypertension with respect to measurement, diagnosis, treatment, and consequence in CKD. The definition of hypertension changes continually as a child grows with or without CKD. Despite numerous guidelines, the diagnosis of childhood hypertension continues to be based on epidemiologic data rather than evidence. For children, the current definition includes 2 categories: high normal, which is blood pressure (BP) between the 90th and 95th percentile, and hypertensive, which is BP above the 95th percentile. The evaluation of all hypertensive children should include a complete assessment of end-organ damage, including eyes, cardiovascular system (including blood vessels), kidneys, and nervous system. For children with CKD and end-stage renal disease (ESRD), a high percentage have left ventricular hypertrophy (LVH). The finding of end-organ damage or comorbidity (CKD, diabetes) in any child is an absolute indication for immediate pharmacologic therapy, whereas the presence of hypertension above the 95th percentile in children without CKD warrants initial intervention such as life style modification. The guidelines for measurement of BP in children with CKD are similar to those in children without CKD and include casual BP measurement, self-measured BP, and ambulatory BP monitoring. The recommendation for BP measurement in children is, when permitted, by auscultative method with a well-calibrated mercury manometer. Most casual BP measurements are performed with an automated oscillometric device whose validation has not been confirmed in children with CKD. The ambulatory BP monitor (ABPM) has 2 advantages: it significantly correlates with the presence of end-organ damage, and it identifies abnormal BP patterns that are frequently present in CKD patients, such as hypertension during the sleep period. An abnormal ABPM pattern can also be predictive of the development of end-organ damage. Treatment of hypertension in children, with and without CKD, is based on 3 factors: degree of BP elevation, the presence of cardiovascular risk factors, and the presence of end-organ damage. Additionally, the initial antihypertensive agent may be selected on available and age-appropriate formulations (eg, suspension and dosage selection). A physician treating a hypertensive child with CKD faces multiple challenges. They include selecting the convenience of available automated devices and the ABPM versus traditional auscultatory techniques upon which all normative standards have been based. Current research initiatives propose to develop pharmacokinetic and pharmacodynamics properties of antihypertensive medications and to study the effect of early intervention on end-organ damage.