Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study.

INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

Pharmacotherapeutic management of paediatric heart failure and ACE-I use patterns: a European survey.

OBJECTIVE: To characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting. METHODS: A Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology. RESULTS: Out of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination. CONCLUSIONS: Despite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children.

Use of subcutaneous treprostinil in pediatric pulmonary arterial hypertension-Bridge-to-transplant or long-term treatment?

PAH is a progressive life-threatening disease in children. While parenteral prostacyclin therapy improves survival in patients with severe PAH, central line-related complications are common. Our aim was to assess the efficacy, safety, and tolerability of subcutaneous treprostinil treatment in pediatric PAH patients. Eight patients were treated with subcutaneous treprostinil at the Pediatric Heart Center Budapest. Indications for subcutaneous treprostinil therapy were clinical worsening and/or echocardiographic progression or switch from intravenous to subcutaneous therapy. Following treprostinil initiation, clinical status improved or did not change in four of eight patients. Two patients were lost early during treprostinil therapy, parenteral treprostinil as a rescue therapy being insufficient in these cases. The final dose in long-term treated patients was between 60 and 100 ng/kg/min. Aside from thrombocytopenia, other severe side effects were not observed. Potts shunt was performed as palliative treatment in two cases. Three patients had successful lung transplantation, and one died while on the waiting list. Long-term subcutaneous treprostinil could be a safe and well-tolerated therapy in children with severe PAH even at higher doses. It may serve as an alternative to intravenous prostacyclin treatment allowing to avoid the potential complications of permanent central line placement.

Frequency of Miscarriage/Stillbirth and Terminations of Pregnancy Among Women With Congenital Heart Disease in Germany, Hungary and Japan.

BACKGROUND: The 2011 guidelines of the European Society of Cardiology (ESC) on the management of cardiovascular diseases during pregnancy define the maternal predictors for neonatal complications. The aim of this study was to determine whether these are associated with an increased number of miscarriages/stillbirths and terminations of pregnancy (TOPs) also in patients with congenital heart defects (CHD). METHODS AND RESULTS: The 634 women from Germany, Hungary and Japan were surveyed concerning the issues of sexuality and reproductive health, as well as their general life situation and medical care. 25% of the recorded pregnancies in women with CHD resulted in miscarriage, stillbirth or TOP. Affecting 16.8% of all recorded pregnancies, miscarriages or stillbirths occurred more frequently than in the general population and more than previously recorded for patients with CHD. TOP occurred in 8% of the surveyed pregnancies. Underlying maternal predictors for neonatal events had an influence on the number of TOP; among those with underlying predictors, TOP was recorded 3-fold more than in those without such predictors (15.6% vs. 5.5%). Remarkably, a significant deficit regarding the level of information on potential pregnancy-associated risks was observed in all 3 participating countries. CONCLUSIONS: Pregnant women with CHD should always be treated and counseled individually by cardiologists, gynecologists, obstetricians and anesthetists with appropriate expert knowledge. (Circ J 2016; 80: 1846-1851).

Fluid Overload Is Associated With Higher Mortality and Morbidity in Pediatric Patients Undergoing Cardiac Surgery.

OBJECTIVES: Fluid overload after pediatric cardiac surgery is common and has been shown to increase both mortality and morbidity. This study explores the risk factors of early postoperative fluid overload and its relationship with adverse outcomes. DESIGN: Secondary analysis of the prospectively collected data of children undergoing open-heart surgery between 2004 and 2008. SETTING: Tertiary national cardiac center. PATIENTS: One thousand five hundred twenty consecutive pediatric patients (<18 years old) were included in the analyses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the first 72 hours of the postoperative period, the daily fluid balance was calculated as milliliter per kilogram and the daily fluid overload was calculated as fluid balance (L)/weight (kg) × 100. The primary endpoint was in-hospital mortality; the secondary outcomes were low cardiac output syndrome and prolonged mechanical ventilation. One thousand three hundred and sixty-seven patients (89.9%) had a cumulative fluid overload below 5%; 120 patients (7.8%), between 5% and 10%; and 33 patients (2.1%), above 10%. After multivariable analysis, higher fluid overload on the day of the surgery was independently associated with mortality (adjusted odds ratio, 1.14; 95% CI, 1.008-1.303; p = 0.041) and low cardiac output syndrome (adjusted odds ratio, 1.21; 95% CI, 1.12-1.30; p = 0.001). Higher maximum serum creatinine levels (adjusted odds ratio, 1.01; 95% CI, 1.003-1.021; p = 0.009), maximum vasoactive-inotropic scores (adjusted odds ratio, 1.01; 95% CI, 1.005-1.029; p = 0.042), and higher blood loss on the day of the surgery (adjusted odds ratio, 1.01; 95% CI, 1.004-1.025; p = 0.015) were associated with a higher risk of fluid overload that was greater than 5%. CONCLUSIONS: Fluid overload in the early postoperative period was associated with higher mortality and morbidity. Risk factors for fluid overload include underlying kidney dysfunction, hemodynamic instability, and higher blood loss on the day of the surgery.

Left circumflex coronary artery occlusion due to a left atrial appendage closure device.

Nowadays, percutaneous left atrial appendage (LAA) closure is spreading, and a large number of patients with this procedure have concomitant coronary artery disease. With the presented case it could be concluded that coronary angiography is recommended before LAA closure.

Assessment of global tissue perfusion and oxygenation in neonates and infants after open-heart surgery.

OBJECTIVES: Monitoring and preserving adequate perfusion and oxygen balance is a primary objective of critical care. This prospective observational study aimed to assess the relationship between global haemodynamic parameters and variables reflecting tissue oxygenation during the early period following corrective cardiac surgery in neonates and infants. The postoperative time course of oxygen delivery and consumption was evaluated. As surrogate markers of oxygen balance, the central venous oxygen saturation (ScvO2) and venoarterial PCO2 difference (PvaCO2) were thoroughly investigated. METHODS: Thirteen children <1 year of age who underwent open-heart surgery were prospectively enrolled. In addition to conventional postoperative monitoring, transpulmonary thermodilution (TPTD) was used to monitor cardiac output and calculate oxygen delivery and consumption. In parallel with each TPTD measurement, arterial and central venous blood gas values were recorded. Global haemodynamic parameters and oxygenation measurements were compared with weighted linear regression statistics and Pearson's correlation coefficient. RESULTS: Data from 145 TPTD measurements and 304 blood gas samples were recorded. The early postoperative period was characterized by a supply-dependent oxygen consumption, as demonstrated by the direct correlation between the change in oxygen delivery and consumption (r = 0.62, P < 0.001). Regarding haemodynamic parameters, none of the heart rate, mean arterial pressure or cardiac index correlated with the measured ScvO2. However, the ScvO2 and PvaCO2 were found to correlate significantly (r = -0.49, P < 0.001), and both strongly related to oxygen extraction. CONCLUSIONS: Both the ScvO2 and PvaCO2 are reliable and comparable parameters in following tissue oxygen balance during the early postoperative course after open-heart surgery in neonates and infants. As part of multiparameter monitoring, our data highlight the importance of regular ScvO2 measurements and PvaCO2 calculations in paediatric intensive care.

A comparison of the systems for the identification of postoperative acute kidney injury in pediatric cardiac patients.

BACKGROUND: The pediatric-modified Risk, Injury, Failure and Loss, and End-Stage (pRIFLE) criteria and a different but conceptually similar system termed Acute Kidney Injury Network (AKIN) were created to standardize the definition of acute kidney injury (AKI) in children. Kidney Disease: Improving Global Outcomes (KDIGO) currently recommends a combination of AKIN and pRIFLE in AKI. This study aimed to compare the three classifications for predicting AKI in pediatric patients undergoing cardiac operations. METHODS: We analyzed the prospectively collected data of 1,489 consecutive pediatric patients undergoing cardiac operations between January 2004 and December 2008. AKI presence and severity was assessed for each classification using the change in serum creatinine and estimated creatinine clearance levels calculated by the Schwartz equation. RESULTS: AKI was present in 285 (20%), 481 (34%), and 409 (29%) patients according to the AKIN, pRIFLE, and KDIGO systems, respectively. The KDIGO classification categorized 121 patients (8%) who were placed in the AKIN 0 category, whereas the pRIFLE system categorized 74 (5%) in KDIGO 0 and 200 (14%) in AKIN 0 stages as having an AKI. The overall mortality rate was 3.9%. The KDIGO stage III (odds ratio [OR], 18.8; 95% confidence interval [CI], 9.6 to 36.6, p < 0.001), the AKIN stage III (OR, 38.3; 95% CI, 20.6 to 70.9, p < 0.001), and pRIFLE failure group (OR, 13.6, 95% CI, 7 to 26.3; p < 0.001) were associated with increased mortality. CONCLUSIONS: The pRIFLE system was the most sensitive test in detecting AKI, and this was especially so in the infant age group and also in the early identification of AKI in low-risk patients. The AKIN system was more specific and detected mostly high-risk patients across all age groups. The KDIGO classification system fell between pRIFLE and AKIN in performance. All three had increasing severity of AKI associated with mortality.

Impact of the insulin and glucose content of the postoperative fluid on the outcome after pediatric cardiac surgery.

INTRODUCTION: The aim of this study was to investigate the role of the insulin and glucose content of the maintenance fluid in influencing the outcomes of pediatric patients undergoing heart surgery. METHODS: A total of 2063 consecutive pediatric patients undergoing cardiac surgery were screened between 2003 and 2008. A dextrose and an insulin propensity-matched group were constructed. In the dextrose model, 5% and 10% dextrose maintenance infusions were compared below 20 kg of weight. RESULTS: A total of 171 and 298 pairs of patients were matched in the insulin and glucose model, respectively. Mortality was lower in the insulin group (12.9% vs. 7%, p = 0.049). The insulin group had longer intensive care unit (ICU) stay [days, 10.9 (5.8-18.4) vs. 13.7 (8.2-21), p = 0.003], hospital stay [days, 19.8 (13.6-26.6) vs. 22.7 (17.6-29.7), p < 0.01], duration of mechanical ventilation [hours, 67 (19-140) vs. 107 (45-176), p = 0.006], and the incidence of severe infections (18.1% vs. 28.7%, p = 0.01) and dialysis (11.7% vs. 24%, p = 0.001) was higher. In the dextrose model, the incidence of pulmonary complications (13.09% vs. 22.5%, p < 0.01), low cardiac output (17.11% vs. 30.9%, p < 0.01), and severe infections (10.07% vs. 20.5%, p < 0.01) was higher, and the duration of the hospital stay [days, 16.4 (13.1-21.6) vs. 18.1 (13.8-24.6), p < 0.01] was longer in the 10% dextrose group. CONCLUSIONS: Insulin treatment appeared to decrease mortality, and lower glucose content was associated with lower occurrence of adverse events.

NT-proBNP correlated with strain and strain rate imaging of the right ventricle before and after transcatheter closure of atrial septal defects.

BACKGROUND: Atrial septal defects (ASD) account for 10% of all congenital heart lesions and represent the third most congenital cardiac defect seen in adults. OBJECTIVES: Using strain and strain rate imaging (SRI) to assess right ventricular (RV) function in patients with ASD and correlate the results with the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) before and after transcatheter closure. METHODS: At the Hungarian Institute of Cardiology, 27 females and 18 males (mean age 21.53 years) were diagnosed with ASD and admitted for percutaneous closure. Echocardiography was done to assess theleft ventricular (LV), RV and left atrial (LA) diameters. For assessment of systolic RV function, we measured Tricuspid annular plane systolic excursion (TAPSE), strain, and SRI. Amplatzer ASD closure was done under general anesthesia. NT-proBNP levels were measured before and three months after closure. RESULTS: ASD closure was achieved in all patients. The mean ASD diameter was 15.15 mm. The size of the occluder ranged from 10 to 24 mm. The mean LA diameter in the pre-closure group was significantly higher than the control; mean left ventricular end diastolic diameter (LVEDD) showed a non-significant difference from either the control group or the post-closure group, while the mean right ventricular end diastolic diameter (RVEDD) markedly reduced post-closure, and it was significantly higher than the control group. Global RV strain and peak systolic strain rate (PSSR) were significantly higher in ASD group than in the control. The NT-proBNP levels were found to be correlated with pulmonary arterial pressure (PAP), TAPSE, global RV strain and PSSR. CONCLUSION: Volume overload induced by ASD is associated with increased strain values, which return to normal after closure. NT-proBNP is a parameter which correlates to RV pressure, PAP and the amount of shunt volume caused by an ASD.

Postoperative differences between colonization and infection after pediatric cardiac surgery-a propensity matched analysis.

BACKGROUND: The objective of this study was to identify the postoperative risk factors associated with the conversion of colonization to postoperative infection in pediatric patients undergoing cardiac surgery. METHODS: Following approval from the Institutional Review Board, patient demographics, co-morbidities, surgery details, transfusion requirements, inotropic infusions, laboratory parameters and positive microbial results were recorded during the hospital stay, and the patients were divided into two groups: patients with clinical signs of infection and patients with only positive cultures but without infection during the postoperative period. Using propensity scores, 141 patients with infection were matched to 141 patients with positive microbial cultures but without signs of infection. Our database consisted of 1665 consecutive pediatric patients who underwent cardiac surgery between January 2004 and December 2008 at a single center. The association between the patient group with infection and the group with colonization was analyzed after propensity score matching of the perioperative variables. RESULTS: 179 patients (9.3%) had infection, and 253 patients (15.2%) had colonization. The occurrence of Gram-positive species was significantly greater in the colonization group (p=0.004). The C-reactive protein levels on the first and second postoperative days were significantly greater in the infection group (p=0.02 and p=0.05, respectively). The sum of all the positive cultures obtained during the postoperative period was greater in the infection group compared to the colonization group (p=0.02). The length of the intensive care unit stay (p<0.001) was significantly longer in the infection group compared to the control group. CONCLUSIONS: Based on our results, we uncovered independent relationships between the conversion of colonization to infection regarding positive S. aureus and bloodstream results, as well as significant differences between the two groups regarding postoperative C-reactive protein levels and white blood cell counts.

Down syndrome and postoperative complications after paediatric cardiac surgery: a propensity-matched analysis.

OBJECTIVES: The incidence of congenital heart disease is ~50%, mostly related to endocardial cushion defects. The aim of our study was to investigate the postoperative complications that occur after paediatric cardiac surgery. METHODS: Our perioperative data were analysed in paediatric patients with Down syndrome undergoing cardiac surgery. We retrospectively analysed the data from 2063 consecutive paediatric patients between January 2003 and December 2008. After excluding the patients who died or had missing data, the analysed database (before propensity matching) contained 129 Down patients and 1667 non-Down patients. After propensity matching, the study population comprised 222 patients and 111 patients had Down syndrome. RESULTS: Before propensity matching, the occurrences of low output syndrome (21.2 vs 32.6%, P = 0.003), pulmonary complication (14 vs 28.7%, P < 0.001) and severe infection (11.9 vs 22.5%, P = 0.001) were higher in the Down group. Down patients were more likely to have prolonged mechanical ventilation [median (interquartile range) 22 (9-72) h vs 49 (24-117) h, P = 0.007]. The total intensive care unit length of stay [6.9 (4.2-12.4) days vs 8.3 (5.3-13.2) days, P = 0.04] and the total hospital length of stay [17.3 (13.3-23.2) days vs 18.3 (15.1-23.6) days, P = 0.05] of the Down patients were also longer. Mortality was similar in the two groups before (3.58 vs 3.88%, P = 0.86) and after (5.4 vs 4.5%, P = 1.00) propensity matching. After propensity matching, there was no difference in the occurrence of adverse events. CONCLUSIONS: After propensity matching Down syndrome was not associated with increased mortality or complication rate following congenital cardiac surgery.

[Percutaneous left atrial appendage closure after resolution of left atrial appendage thrombi with dabigatran]. / Percutan bal pitvari fülcsezárás dabigatrannal való fülcsethrombus feloldását követoen.

The "gold standard" of the prevention of atrial fibrillation related thromboembolic events is anticoagulation therapy with oral vitamin K antagonists. A certain proportion of high-risk patients with atrial fibrillation are not receiving effective antithrombotic therapy because of problems associated with its use. Resolution of subsequent left atrial appendage thrombi is quite a great challenge in patients who are not tolerating "standard" antithrombotic drugs. According to the knowledge of the authors, this is the first report of a patient with non-valvular persistent atrial fibrillation and high stroke risk, who was intolerant to "standard" anticoagulant therapy and had persistent left atrial appendage thrombi following the use of a wide variety of "standard" anticoagulants. Successful resolution of left atrial appendage thrombi with dabigatran and successful percutaneous left atrial appendage closure were performed in this case.

[Right ventricular outflow tract reconstruction in adolescents and adults after previous repair of congenital heart defects]. / A jobbkamra-kifolyási pálya rekonstrukciója elozoleg korrigált veleszületett szívhibák esetén fiatal- és felnottkorban.

UNLABELLED: Due to successful surgical treatment of congenital heart defects in infants and children, the number of patients who reach the adolescent/adult age is continuously increasing. AIMS: The authors sought to identify the short- and medium-term outcomes of reconstruction of right ventricular outflow tract in adolescents and adults who underwent surgical intervention for congenital heart defect in infancy or early childhood. METHODS: Between 2001 and 2012, 48 patients (age: 15-39, mean 21 years) (30 tetralogy of Fallot, 11 pulmonary atresia + ventricular septal defect, 6 transposition of great arteries + ventricular septal defect + left ventricular outflow tract obstruction, and 1 truncus arteriosus) had repeat operation because of right ventricular dysfunction. All patients previously underwent right ventricular outflow tract procedures in early childhood. RESULTS: In 31 patients, the small homograft, and in 9 patients the transannular-paths were replaced for "adult-size" homograft. Bioprosthetic pulmonary valve replacement was performed in pulmonary (6 patients) and homograft annuli (2 patients). In 14 patients, resection of the right ventricular outflow tract aneurism was also necessary to be performed. There was no early and mid-time (10 years) mortality. In 97.5% of patients with homograft-re-implantation, there was no need for repeat intervention for 5 years. CONCLUSIONS: The right ventricular outflow tract restoration in adolescents and adults is an effective procedure. The reconstruction should be performed in early adolescent period to prevent right ventricular dysfunction. The authors prefer using bioprosthetic pulmonary valve replacement in patients with adult-size pulmonary or homograft annulus.

Acute kidney injury is associated with higher morbidity and resource utilization in pediatric patients undergoing heart surgery.

BACKGROUND: The RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification system was developed to standardize the definition of acute kidney injury (AKI) in adults. We hypothesized that AKI was associated with increased mortality and morbidity. METHODS: Acute kidney injury was defined as a decrease in the amount of estimated creatinine clearance based on pediatric-modified RIFLE (pRIFLE) criteria. Using propensity score analysis, 325 patients who had AKI were matched to 325 patients who did not have AKI from a database of 1,510 consecutive pediatric patients who underwent cardiac surgery between January 2004 and December 2008 at a single center. The association between AKI and outcome was analyzed after propensity score matching of perioperative variables. RESULTS: Four hundred eighty-one patients (31.9%) had AKI according to the RIFLE categories. Of those 1,510, 173 (11.5%) reached pRIFLE criteria for risk; 26 (1.7%) reached the criteria for injury; and 282 (18.7%) reached the criteria for failure. Fifty-five patients (3.6%) died. The 2 matched groups were well balanced in terms of measured perioperative variables. Mortality rate was 5.2% in the AKI and 2.5% in the matched control group (p=0.09). Occurrence of low cardiac output syndrome (p=0.002), need for dialysis (p<0.001), and infection (p=0.03) were significantly higher, and duration of mechanical ventilation (p<0.001) and length of intensive care unit stay (p<0.001) were significantly longer compared with the matched control group. CONCLUSIONS: Acute kidney injury was independently associated with an increased occurrence of postoperative complications but not with mortality after pediatric cardiac surgery.

Ventricular septal rupture caused by myocardial bridge, solved by interventional closure device.

Myocardial bridging is a common coronary anomaly, which is generally described as a benign phenomenon. However, a growing number of studies consider this anomaly a relevant pathophysiological phenomenon with serious pathological consequences. Here we report on the case of an 88-year-old woman suffering from myocardial infarction and ventricular septal rupture, lacking any recognizable coronary disease except for a myocardial bridge causing the systolic compression of the left anterior descending coronary artery. A wide range of diagnostic procedures, including coronarography, echocardiography, and magnetic resonance imaging were used. The septal rupture was finally closed by using a percutaneous closure device. This event indicates that myocardial bridges - at least in some cases - may have notable clinical relevance.

A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension.

BACKGROUND: Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. METHODS AND RESULTS: Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. CONCLUSIONS: Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00159913.