Johannes M. Douwes

Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension : occurrence and prognostic value when comparing three response criteria

AIMS To assess the occurrence and prognostic value of acute vasodilator response (AVR) in paediatric vs. adult pulmonary arterial hypertension, and idiopathic/hereditary pulmonary arterial hypertension (iPAH/HPAH) vs. pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) using three different response criteria. METHODS AND RESULTS Ninety-nine PAH patients underwent AVR testing (37 children, 62 adults; 70 iPAH/HPAH, 29 PAH-CHD). Three response criteria from clinical practice were used to define AVR. The number of responders was evaluated separately in subgroups based on age, diagnosis, and presence of a non-restrictive post-tricuspid shunt. Numbers of responders varied importantly using the different criteria but were always higher in iPAH/HPAH, compared with PAH-CHD. The number of responders did not differ between paediatric and adult iPAH/HPAH. No responders were identified in patients with a post-tricuspid shunt. Acute vasodilator response was associated with improved survival using all three criteria. Low baseline mean right atrial pressure (mRAP) was associated with improved survival in adults (P< 0.001). High baseline mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure (mSAP) and pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) were associated with worse survival, statistically independent from age, diagnosis, and the presence of a post-tricuspid shunt. CONCLUSION The proportion of patients with AVR highly depends on the used criteria, but did not differ between paediatric and adult iPAH/HPAH. Current response criteria are not suitable for patients with a post-tricuspid shunt. In both children and adults without post-tricuspid shunts, AVR was associated with improved survival independent of the used criteria. Nevertheless, prognostic value in the individual patient was limited. Baseline mRAP showed a good correlation with survival for adult PAH patients, but not for children. High baseline mPAP/mSAP and PVR/SVR was associated with worse prognosis independent from age, diagnosis, or the presence of a post-tricuspid shunt.

Identification of treatment goals in paediatric pulmonary arterial hypertension

To be able to design goal-oriented treatment strategies in paediatric pulmonary arterial hypertension (PAH), we aimed to identify treatment goals by investigating the prognostic value of treatment-induced changes in noninvasive predictors of transplant-free survival. 66 consecutive, treatment-naïve paediatric PAH patients in the Dutch National Network for Paediatric Pulmonary Hypertension who started taking PAH-targeted drugs between January 2000 and April 2013 underwent prospective, standardised follow-up. Clinical, biochemical and echocardiographic measures were longitudinally collected at treatment initiation and follow-up, and their respective predictive values for transplant-free survival were assessed. Furthermore, the predictive values of treatment-induced changes were assessed. From the identified set of baseline predictors, the variables World Health Organization functional class (WHO-FC), N-terminal pro-brain natriuretic peptide (NT-proBNP) and tricuspid annular plane systolic excursion (TAPSE) were identified as follow-up predictors in which treatment-induced changes were associated with survival. Patients in whom these variables improved after treatment showed better survival (p<0.002). Therefore, WHO-FC, NT-proBNP and TAPSE are not only predictors of transplant-free survival in paediatric PAH but can also be used as treatment goals, as treatment-induced improvements in these variables are associated with improved survival. The identification of these variables allows for the introduction of goal-oriented treatment strategies in paediatric PAH. Improving WHO-FC, NT-proBNP and TAPSE are valid treatment goals in paediatric pulmonary arterial hypertension http://ow.ly/y4GJn

Sildenafil add-on therapy in paediatric pulmonary arterial hypertension, experiences of a national referral centre

Objective In paediatric pulmonary arterial hypertension (PAH), the effectiveness of add-on combination PAH-therapy has not yet been systematically studied. The purpose of this study was to determine the effect of sildenafil add-on therapy in paediatric PAH patients treated with bosentan. Methods In this observational study within a national paediatric patient cohort, follow-up data of 24 consecutive paediatric PAH patients initially treated with bosentan monotherapy and prospectively followed at the Dutch national referral centre for paediatric PAH in 2007–2013, were reviewed. Patients received add-on sildenafil therapy in case of clinical worsening. Results Fifteen children received add-on sildenafil therapy; nine remained on bosentan monotherapy. Patient characteristics, 6-minute walk distance (6MWD), WHO functional class (WHO-FC), N-terminal pro-Brain Natriuretic Peptide (NT-proBNP), and haemodynamic measurements at bosentan start were similar in both patient groups. In children with clinical worsening, sildenafil add-on therapy improved 6MWD at 5, 10, 15 and 21 months of follow-up, improved WHO-FC at 10, 15 and 21 months and stabilised NT-proBNP. Patients who received add-on sildenafil therapy had more advanced disease progression during bosentan monotherapy. Despite that, they had better or, at least, no worse survival compared to patients who remained on bosentan monotherapy. Conclusions In children with PAH, sildenafil add-on therapy indicated by clinical deterioration on bosentan monotherapy, was associated with a significant improvement of WHO-functional class and 6MWD. Despite clinical deterioration on bosentan monotherapy, patients receiving sildenafil add-on therapy, had either better or, at least, no worse survival than patients remaining on bosentan monotherapy.

Prognostic factors in pediatric pulmonary arterial hypertension: A systematic review and meta-analysis

BACKGROUND Despite the introduction of targeted therapies in pediatric pulmonary arterial hypertension (PAH), prognosis remains poor. For the definition of treatment strategies and guidelines, there is a high need for an evidence-based recapitulation of prognostic factors. The aim of this study was to identify and evaluate prognostic factors in pediatric PAH by a systematic review of the literature and to summarize the prognostic value of currently reported prognostic factors using meta-analysis. METHODS AND RESULTS Medline, EMBASE and Cochrane Library were searched on April 1st 2014 to identify original studies that described predictors of mortality or lung-transplantation exclusively in children with PAH. 1053 citations were identified, of which 25 were included for further analysis. Hazard ratios (HR) and 95% confidence intervals were extracted from the papers. For variables studied in at least three non-overlapping cohorts, a combined HR was calculated using random-effects meta-analysis. WHO functional class (WHO-FC, HR 2.7), (N-terminal pro-) brain natriuretic peptide ([NT-pro]BNP, HR 3.2), mean right atrial pressure (mRAP, HR 1.1), cardiac index (HR 0.7), indexed pulmonary vascular resistance (PVRi, HR 1.3) and acute vasodilator response (HR 0.3) were identified as significant prognostic factors (p ≤ 0.001). CONCLUSIONS This systematic review combined with separate meta-analyses shows that WHO-FC, (NT-pro)BNP, mRAP, PVRi, cardiac index and acute vasodilator response are consistently reported prognostic factors for outcome in pediatric PAH. These variables are useful clinical tools to assess prognosis and should be incorporated in treatment strategies and guidelines for children with PAH.

Pulsatile haemodynamic parameters are predictors of survival in paediatric pulmonary arterial hypertension

BACKGROUND There is a need for reliable prognostic parameters in pulmonary arterial hypertension (PAH), especially in children. Pulsatile components of the right ventricular afterload, represented by pulmonary arterial compliance (PACi) and pulmonary stroke volume (PSVi), may provide important additional prognostic information to conventional static haemodynamic parameters. The aim of this study was to determine the prognostic value of PACi and PSVi in paediatric PAH. METHODS Right heart catheterization data of 52 consecutive paediatric idiopathic/hereditary PAH and PAH associated with congenital heart disease patients with full haemodynamic evaluation seen at the Dutch national referral centre for paediatric pulmonary hypertension between 1993 and 2010 were reviewed. A control group was composed of patients with normal pulmonary vascular resistance. PSVi and PACi were calculated and tested for predictive value for transplant-free survival. RESULTS PAH patients had significantly lower PSVi and PACi compared to control patients. PSVi and PACi were lower in patients with higher WHO-functional class compared to those with lower functional classes. Higher PSVi, PACi and mSAP and lower mPAP/mSAP and heart rate were associated with improved survival, independent from WHO-functional class and PAH-targeted therapy. In multivariate analyses PSVi, heart rate and mSAP emerged as the strongest haemodynamic predictors of survival. The effect of vasodilator challenge on the haemodynamic variables did not provide additional prognostic information. CONCLUSIONS The parameters of both the pulsatile and static pulmonary circulations are strong independent predictors for transplant-free survival, and therefore can be of complementary value in assessing disease severity, predicting survival and guiding treatment in paediatric PAH.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension)

BACKGROUND The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcome

Background—The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH. Methods and Results—Forty-three consecutive children (median age, 8.0 years; range, 0.4–21.5) with idiopathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation–free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics (P<0.05), whereas left ventricular dimensions correlated with hemodynamics and survival (P<0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival (P<0.05). Right ventricular ejection time correlated with hemodynamics and survival (P<0.05) and tended to correlate with WHO-FC (P=0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival (P<0.05). Conclusions—This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH.Background— The value of echocardiography in assessing disease severity and predicting outcome in pediatric pulmonary arterial hypertension (PAH) is insufficiently defined. The aim of this study was to describe correlations between echocardiography and disease severity and outcome in pediatric PAH. Methods and Results— Forty-three consecutive children (median age, 8.0 years; range, 0.4–21.5) with idiopathic/hereditary PAH (n=25) or PAH associated with congenital heart disease (n=18) were enrolled in a prospective single-center observational study. Anatomic and right ventricular-functional variables were obtained by two-dimensional echocardiography and Doppler-echocardiography at presentation and at standardized follow-up and were correlated with measures of disease severity (World Health Organization functional class [WHO-FC], N-terminal-pro-B-type natriuretic peptide, hemodynamics) and lung-transplantation–free survival. Right atrial and right ventricular dimensions correlated with WHO-FC and hemodynamics ( P <0.05), whereas left ventricular dimensions correlated with hemodynamics and survival ( P <0.05). Right-to-left ventricular dimension ratiocorrelated with WHO-FC, hemodynamics and survival ( P <0.05). Right ventricular ejection time correlated with hemodynamics and survival ( P <0.05) and tended to correlate with WHO-FC ( P =0.071). Tricuspid annular plane systolic excursion correlated with WHO-FC, mean right atrial pressure and survival ( P <0.05). Conclusions— This early descriptive study shows that echocardiographic chararacteristics of both the right and the left heart correlate with disease severity and outcome in pediatric PAH, both at presentation and during the course of the disease. The preliminary data from this study support the potential value of echocardiography as a tool in guiding management in children with PAH.

Acute Vasodilator Response in Pediatric Pulmonary Arterial Hypertension: Current Clinical Practice From the TOPP Registry

BACKGROUND In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied. OBJECTIVES This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH. METHODS From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT. RESULTS Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB. CONCLUSIONS The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.

Clinical Worsening as Composite Study End Point in Pediatric Pulmonary Arterial Hypertension

BACKGROUND Clinical worsening (CW), an increasingly used composite end point in adult pulmonary arterial hypertension (PAH), has not yet been evaluated in pediatric PAH. This study aims to evaluate the usefulness of CW in pediatric PAH by assessing the event incidence and prognostic value of each separate component of CW and of the composite CW end point. METHODS Seventy pediatric patients with PAH from the Dutch National Network for Pediatric Pulmonary Hypertension, who started PAH-targeted therapy between January 2000 and January 2014, were included in the study and underwent standardized follow-up. The following CW components were prospectively registered: death, lung transplantation (LTx), PAH-related hospitalizations, initiation of IV prostanoids, and functional deterioration (World Health Organization functional-class deterioration, ≥ 15% decrease in 6-min walk distance, or both). The longitudinal event incidence and prognostic value were assessed for each separate component and their combination. RESULTS The end-point components of death, LTx, hospitalizations, initiation of IV prostanoids, and functional deterioration occurred with a longitudinal event rate of 10.1, 2.5, 21.4, 9.4 and 48.1 events per 100 person-years, respectively. The composite CW end point occurred 91.5 times per 100 person-years. The occurrences of either hospitalization, initiation of IV prostanoids, or functional deterioration were predictive of death or LTx (P < .001 for each component). In this cohort, 1-, 3-, and 5-year transplant-free survival was 76%, 64%, and 56%, respectively. Freedom from CW at 1, 3, and 5 years was 43%, 22%, and 17%, respectively. CONCLUSIONS CW occurred with a high event incidence and each of the soft end-point components was predictive of death or LTx. This supports the usefulness of CW as a study end point in clinical trials in pediatric PAH.

Clinical classification in pediatric pulmonary arterial hypertension associated with congenital heart disease

Congenital heart disease (CHD) is a frequent cause of pediatric pulmonary arterial hypertension (PAH), with diverse etiology and outcome. We aimed to describe phenotypic heterogeneity in pediatric PAH associated with CHD (PAH-CHD), assess the applicability of the Nice CHD classification, and explore whether this classification accurately reflects patient/disease characteristics and survival. All children with CHD from a contemporary cohort of consecutive pediatric PAH patients followed in three major referral centers (Denver, New York, the Netherlands) were characterized and classified on the basis of the latest proposed clinical classification for PAH-CHD (World Symposium on Pulmonary Hypertension, Nice, 2013). According to this classification, 24% of 134 children were classified into group 1, 14% into group 2, 19% into group 3, and 30% into group 4; 11% could not be classified. Types of CHD and hemodynamic profile differed between groups, with the highest right atrial pressure in group 4 (P < 0.040). Group 3 children had Down syndrome less frequently (P = 0.011) but other (un)defined syndromes most frequently (P = 0.063) and received most intense PAH-targeted therapy (P = 0.003). With 15 deaths and one lung transplant (12%; median follow-up: 4.3 years), survival differences could not be demonstrated between the groups in the Nice CHD classification. Pediatric PAH-CHD is a heterogeneous condition frequently associated with extracardiac, developmental factors that are believed to affect disease development. The Nice CHD classification identifies groups with specific patient/disease characteristics. However, a substantial proportion of children could not be classified. Group 3 forms a distinct disease entity. Its prognostic value could not be determined because of the low number of events. The Nice CHD classification supports clinical characterization of PAH-CHD; however, further refinement is needed to classify all children with PAH-CHD.