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Rationale: The development of evidence-based treatment guidelines for pediatric pulmonary arterial hypertension (PAH) is hampered by lack of pediatric clinical trials. Trial design is hampered by lack of a feasible clinical endpoint in this population. Objectives: To evaluate the use of accelerometry for measuring physical activity (PA) in pediatric PAH and to investigate its correlation with clinical disease severity markers. Methods: We included children from the Dutch National Network for Pediatric Pulmonary Hypertension. Control patients were recruited from the outpatient cardiology clinic of the Beatrix Children's Hospital. Children were asked to wear the accelerometer for 7 days. Vector magnitude counts per minute (VMCPM) and time per day spent in different PA intensity levels were defined as accelerometer outcomes. Measurements and Main Results: VM CPM was lower in children withPAH(n = 29) than in controls (n = 60; 647 vs. 921; P

Background: Despite increasing recognition of the value of real-world data (RWD), consensus on the definition of RWD is lacking. Objectives: To review definitions publicly available for RWD to shed light on similarities and differences between them. Methods: A literature review and stakeholder interviews were used to compile data from eight groups of stakeholders. Data from documents and interviews were subjected to coding analysis. Definitions identified were classified into four categories: 1) data collected in a non-randomized controlled trial setting, 2) data collected in a non-interventional/non-controlled setting, 3) data collected in a non-experimental setting, and 4) others (i.e., data that do not fit into the other three categories). The frequency of definitions identified per category was recorded. Results: Fifty-three documents and 20 interviews were assessed. Thirty-eight definitions were identified: 20 out of 38 definitions (53%) were category 1 definitions, 9 (24%) were category 2 definitions, 5 (13%) were category 3 definitions, and 4 (11%) were category 4 definitions. Differences were identified between, and within, definition categories. For example, opinions differed on the aspects of intervention with which non-interventional/non-controlled settings should abide. No definitions were provided in two interviews or identified in 33 documents. Conclusions: Most of the definitions defined RWD as data collected in a non-randomized controlled trial setting. A considerable number of definitions, however, diverged from this concept. Moreover, a significant number of authors and stakeholders did not have an official, institutional definition for RWD. Persisting variability in stakeholder definitions of RWD may lead to disparities among different stakeholders when discussing RWD use in decision making.

Background: \ud \ud Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy.\ud \ud Methods: \ud \ud We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model. Treatment response was survival from all-cause mortality through day 180.\ud \ud Results: \ud \ud In the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82–1.28, p = 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum score model included TNF-R1α, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF-R1α, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40–0.92, p = 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68–18.13, p = 0.005; treatment by score interaction p

Aim:\ud Improved prediction of early post-discharge death or rehospitalization after admission for acute heart failure is a major unmet need. We evaluated the value of biomarkers to predict either low or high risk for early post-discharge events.\ud \ud Methods and results:\ud A total of 1653 patients enrolled in the PROTECT trial who were discharged alive and with available blood samples were included. Forty-seven biomarkers were serially evaluated in these patients. Measurement closest to discharge was used to evaluate the predictive value of biomarkers for low and high post-discharge risk. Patients were classified as ‘low risk’ if post-discharge 30-day risk of death or heart failure rehospitalization was 20% was used to define ‘high risk’. Cut-off values that yielded a 95% negative predictive value and a 20% positive predictive value were identified for each biomarker. Partial area under the receiver operating characteristic curve (pAUC) in the high-sensitivity and high-specificity regions was calculated to compare low-risk and high-risk predictive values. Of patients analysed, 193 (11.7%) patients reached the 30-day death or heart failure rehospitalization outcome. We found marked differences between low-risk and high-risk predictors. Cardiac-specific troponin I was the strongest biomarker for low-risk prediction (pAUC = 0.552, 95% confidence interval 0.52–0.58) while endothelin-1 showed better performance for high-risk prediction (pAUC = 0.560, 95% confidence interval 0.53–0.59). Several biomarkers (individually and in combination) provided added predictive value, on top of a clinical model, in both low-risk and high-risk regions.\ud \ud Conclusion:\ud Different biomarkers predicted low risk vs. high risk of early post-discharge death or heart failure readmission in patients hospitalized for acute heart failure.

Aims: \ud \ud It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways.\ud Methods and results: \ud \ud We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial. In patients with and without diabetes, we performed a network analysis to identify correlations between measured biomarkers. Compared with patients without diabetes (n = 1111), those with diabetes (n = 922) had a higher prevalence of ischaemic heart disease and traditional coronary risk factors. After multivariable adjustment, patients with and without diabetes had significantly different levels of biomarkers across a spectrum of pathophysiological domains, including inflammation (TNFR-1a, periostin), cardiomyocyte stretch (BNP), angiogenesis (VEGFR, angiogenin), and renal function (NGAL, KIM-1) (adjusted P-value

Background: Randomized controlled trials provide robust data on the efficacy of interventions rather than on effectiveness. Health technology assessment (HTA) agencies worldwide are thus exploring whether real-world data (RWD) may provide alternative sources of data on effectiveness of interventions. Presently, an overview of HTA agencies' policies for RWD use in relative effectiveness assessments (REA) is lacking. Objectives: To review policies of six European HTA agencies on RWD use in REA of drugs. A literature review and stakeholder interviews were conducted to collect information on RWD policies for six agencies: the Dental and Pharmaceutical Benefits Agency (Sweden), the National Institute for Health and Care Excellence (United Kingdom), the Institute for Quality and Efficiency in Healthcare (Germany), the High Authority for Health (France), the Italian Medicines Agency (Italy), and the National Healthcare Institute (The Netherlands). The following contexts for RWD use in REA of drugs were reviewed: initial reimbursement discussions, pharmacoeconomic analyses, and conditional reimbursement schemes. We identified 13 policy documents and 9 academic publications, and conducted 6 interviews. Results: Policies for RWD use in REA of drugs notably differed across contexts. Moreover, policies differed between HTA agencies. Such variations might discourage the use of RWD for HTA. Conclusions: To facilitate the use of RWD for HTA across Europe, more alignment of policies seems necessary. Recent articles and project proposals of the European network of HTA may provide a starting point to achieve this. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.

INTRODUCTION: In 2007, the National Healthcare Institute (ZIN) initiated conditional financing (CF) of expensive hospital drugs as an example of conditional reimbursement schemes (CRS). CF is a 4-year procedure encompassing initial HTA assessment (T = 0) followed by additional data collection via outcomes research (separately assessing appropriate use & cost-effectiveness in routine practice) and re-assessment (T = 4). This study aims to review performance and experiences with CF in the Netherlands to date. METHODS: All dossiers for drugs that underwent the full CF procedure were reviewed. Using a standardized data abstraction form, two researchers independently extracted information on procedural, methodological and decision-making aspects (that is, related to implemented outcomes research, evidence assessment and appraisal). A scoring algorithm was used to assess all three aspects. RESULTS: Fourty-seven candidates were nominated for CF; fourty-four underwent T = 0 assessments and eleven T = 4 assessments. The procedure extended beyond 4 years for 10/11 candidates. For the eleven candidates, applicants clearly defined study designs and data collection methods for outcomes research proposals addressing 16/22 research questions posed in T = 0 reports. ZIN provided discussion points and recommendations regarding research proposals for 18/22 research questions. Applicants implemented recommendations fully in 8/22 cases and partially in 12/22. Sufficient data was available at T = 4 to answer 15/22 research questions posed at T = 0. However, discussion points remained regarding implemented outcomes research for all eleven candidates at T = 4. ZIN advised to continue reimbursement for nine candidates and to stop reimbursement for two. For six of the nine candidates, reimbursement was continued on the basis of conditions relating to additional evidence generation beyond T = 4. CONCLUSIONS: Theoretically, CF provides a valuable option for enabling quick but conditional access to medicines in the Netherlands. However, procedural, methodological and decision-making considerations related to scheme design and implementation may affect its value in decision-making practice.

Aims\ud \ud Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF.\ud Methods and results\ud \ud BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction ≤35%, estimated glomerular filtration rate ≥30 mL/min/1.73 m2, K+ ≤5.0 mmol/L). The mean age was 66.1 ± 12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were younger, more often male, had higher body mass index, lower sodium, higher proportion of hypertension history and ACEi/ARB prescription (all P < 0.05). Of the 1049 patients who completed the baseline plus the 9 month visit, 585 (56%) had an MRA prescribed at baseline and 662 (63%) had an MRA prescribed at 9 months. Among the 585 patients with MRA at baseline, 91 (16%) had discontinued therapy and among the 461 (44%) patients without MRA at baseline 168 (36%) had initiated therapy subsequently. MRA discontinuation was more likely in subjects with higher left ventricular ejection fraction and NYHA class III/IV (P < 0.05 for both). MRA prescription both at baseline and 9 months was not associated with the outcome of death or heart failure hospitalization (adjusted hazard ratio 1.02, 95% confidence interval 0.66–1.58; P = 0.93).\ud Conclusions\ud \ud In this prospective observational study across Europe, MRAs were largely under-prescribed and frequently discontinued. Owing to these dynamic changes, outcome inferences are inconclusive.

AimImproved prediction of early post-discharge death or rehospitalization after admission for acute heart failure is a major unmet need. We evaluated the value of biomarkers to predict either low or high risk for early post-discharge events. Methods and resultsA total of 1653 patients enrolled in the PROTECT trial who were discharged alive and with available blood samples were included. Forty-seven biomarkers were serially evaluated in these patients. Measurement closest to discharge was used to evaluate the predictive value of biomarkers for low and high post-discharge risk. Patients were classified as low risk' if post-discharge 30-day risk of death or heart failure rehospitalization was 20% was used to define high risk'. Cut-off values that yielded a 95% negative predictive value and a 20% positive predictive value were identified for each biomarker. Partial area under the receiver operating characteristic curve (pAUC) in the high-sensitivity and high-specificity regions was calculated to compare low-risk and high-risk predictive values. Of patients analysed, 193 (11.7%) patients reached the 30-day death or heart failure rehospitalization outcome. We found marked differences between low-risk and high-risk predictors. Cardiac-specific troponin I was the strongest biomarker for low-risk prediction (pAUC = 0.552, 95% confidence interval 0.52-0.58) while endothelin-1 showed better performance for high-risk prediction (pAUC = 0.560, 95% confidence interval 0.53-0.59). Several biomarkers (individually and in combination) provided added predictive value, on top of a clinical model, in both low-risk and high-risk regions. ConclusionDifferent biomarkers predicted low risk vs. high risk of early post-discharge death or heart failure readmission in patients hospitalized for acute heart failure.

Background— Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes. Methods and Results— We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A 1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen >35 mg/dL and increase in creatinine >0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk. Conclusions— Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00328692 and NCT00354458.

Introduction: \ud \ud From a prospective multicentre multicountry clinical trial, we developed and validated risk models to predict prospective all-cause mortality and hospitalizations because of heart failure (HF) in patients with HF.\ud Methods and results: \ud \ud BIOSTAT-CHF is a research programme designed to develop and externally validate risk models to predict all-cause mortality and HF hospitalizations. The index cohort consisted of 2516 patients with HF from 69 centres in 11 European countries. The external validation cohort consisted of 1738 comparable patients from six centres in Scotland, UK. Patients from the index cohort had a mean age of 69 years, 27% were female, 83% were in New York Heart Association (NYHA) class II–III and the mean left ventricular ejection fraction (LVEF) was 31%. The full prediction models for mortality, hospitalization owing to HF, and the combined outcome, yielded c-statistic values of 0.73, 0.69, and 0.71, respectively. Predictors of mortality and hospitalization owing to HF were remarkably different. The five strongest predictors of mortality were more advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide, lower haemoglobin, and failure to prescribe a beta-blocker. The five strongest predictors of hospitalization owing to HF were more advanced age, previous hospitalization owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate. Patients from the validation cohort were aged 74 years, 34% were female, 85% were in NYHA class II–III, and mean LVEF was 41%; c-statistic values for the full and compact model were comparable to the index cohort.\ud Conclusion: \ud \ud A small number of variables, which are usually readily available in the routine clinical setting, provide useful prognostic information for patients with HF. Predictors of mortality were remarkably different from predictors of hospitalization owing to HF.