Clinical Trials In Pulmonary Arterial Hypertension Research Articles

The sine transform is the sine qua non of the pulmonary and systemic pressure relationship.

Assessment of therapeutic interventions in patients with pulmonary arterial hypertension (PAH) suffers from several commonly encountered limitations: (1) patient studies are often too small and short-term to provide definitive conclusions, (2) there is a lack of a universal set of metrics to adequately assess therapy and (3) while clinical treatments focus on management of symptoms, there remain many cases of early loss of life in a seemingly arbitrary distribution. Here we provide a unified approach to assess right and left pressure relationships in PAH and pulmonary hypertension (PH) patients by developing linear models informed by the observation of Suga and Sugawa that pressure generation in the ventricle (right or left) approximately follows a single lobe of a sinusoid. We sought to identify a set of cardiovascular variables that either linearly or via a sine transformation related to systolic pulmonary arterial pressure (PAPs) and systemic systolic blood pressure (SBP). Importantly, both right and left cardiovascular variables are included in each linear model. Using non-invasively obtained cardiovascular magnetic resonance (CMR) image metrics the approach was successfully applied to model PAPs in PAH patients with an r2 of 0.89 (p < 0.05) and SBP with an r2 of 0.74 (p < 0.05). Further, the approach clarified the relationships that exist between PAPs and SBP separately for PAH and PH patients, and these relationships were used to distinguish PAH vs. PH patients with good accuracy (68%, p < 0.05). An important feature of the linear models is that they demonstrate that right and left ventricular conditions interact to generate PAPs and SBP in PAH patients, even in the absence of left-sided disease. The models predicted a theoretical right ventricular pulsatile reserve that in PAH patients was shown to be predictive of the 6 min walk distance (r2 = 0.45, p < 0.05). The linear models indicate a physically plausible mode of interaction between right and left ventricles and provides a means of assessing right and left cardiac status as they relate to PAPs and SBP. The linear models have potential to allow assessment of the detailed physiologic effects of therapy in PAH and PH patients and may thus permit cross-over of knowledge between PH and PAH clinical trials.

Heterogeneity of treatment effects by risk in pulmonary arterial hypertension.

It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening. Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

"It's that invisible illness":Patient and clinician perspectives on outcomes in pulmonary arterial hypertension treatment.

Knowledge of what outcomes are most meaningful to pulmonary arterial hypertension (PAH) stakeholders is limited. In this qualitative study, patients and clinicians endorsed personalized physical activity, symptoms, and psychosocial well-being as key outcomes to assess PAH treatment response, yet few are routinely measured in PAH clinical trials.

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Second International Pulmonary Hypertension/Heart Failure Symposium—Structural heart disease, right ventricular dysfunction, and stem cell therapy: The European Pediatric Pulmonary Vascular Disease Network

Abstract 15151: Identification of Novel Right Ventricular Function Phenotypes in Pulmonary Arterial Hypertension Using Unbiased K-Means Clustering

Introduction: Survival in pulmonary arterial hypertension (PAH) is associated with right ventricular (RV) function rather than pulmonary vascular resistance (PVR). At present, RV function is not incorporated in current risk assessment models and studies evaluating RV function are generally limited to single-center studies. The aim was to identify novel RV function phenotypes using unbiased k-means clustering in patients with PAH. Methods: Baseline clinical and hemodynamic data in patients with PAH were harmonized data from 5 PAH clinical trials (COMPASS3: n=98, EARLY: n=176, GRIPHON: n=720, MAESTRO: n=44, and SERAPHIN: n=728). Pearson correlation analysis was used to select variables that reduce the co-linearity (|r| &lt; 0.7) between hemodynamic variables used in the models. K-means clustering methods were applied to advanced RV hemodynamics including end-systolic pressure (ESP), arterial elastance (Ea), single-beat end-diastolic elastance (Eed), Pulse pressure (PP), stroke volume (SV) and RV stroke work (RVSW). Survival analysis was used to compare all-cause mortality among each cluster group. Results: Participants in the harmonized dataset (n=1766) had a mean PAP of 53 ± 17 mmHg, a cardiac output of 4.3±1.4 L/min, a wedge pressure of 9±4 mmHg and a PVR of 11.8±7.4 WU. K-means clustering identified four distinct RV cluster phenotypes that range from mild to severe RV dysfunction (Fig. A). Participants in RV cluster 1 (RV C1) have severe RV dysfunction with increased pressure/afterload, decreased cardiac function, and increased diastolic stiffness compared to RV cluster 4 (RV C4). (Fig. A) RV C1 had decreased six-minute walk distance compared to other clusters. RVC1 and RVC2 had increased risk of mortality compared to RV C4 (Fig. B). Conclusion: Applying K-means clustering to harmonized hemodynamic data from PAH clinical trial data identified 4 unique RV function phenotypes with different clinical outcomes.

Risk assessment tools for survival prognosis: An era of new surrogacy endpoints for clinical outcome measurement in pulmonary arterial hypertension clinical trials?

Developing a new medication in a rare disease indication like pulmonary arterial hypertension (PAH) is very challenging. This is especially true now that clinical trials often employ time to clinical worsening (TTCW) as an endpoint (thus requiring a relatively large and lengthy trial) and since patients are more frequently prescribed combination therapy. During the last few decades, several tools have been developed to predict mortality in PAH and have demonstrated generally good discrimination. The objective of this review article is to assess the available data on the different tools and methods described in the literature and identify potential candidates that could be used as surrogate endpoints in pivotal randomized clinical trials in future. Some of these tools have been validated in various registries and in post-hoc analyses of clinical trial data, but none have been assessed in a prospective clinical trial and we still lack the evidence necessary for endorsement by health authorities. In this review, we identify several promising options that warrant further investigation as potential surrogate endpoints in clinical trials to replace TTCW or 6-minute walk distance. Prospective inclusion of such tools in new clinical trials may help build a stronger surrogacy for prognosis of disease progression and mortality.

The Association of N-Terminal Pro-Brain Natriuretic Peptide With Time to Clinical Worsening in Hispanic Patients With Pulmonary Arterial Hypertension.

BackgroundMeasurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) level is an important parameter in the risk assessment of patients with pulmonary arterial hypertension (PAH). Data about the prognostic value of NT-proBNP in the Hispanic PAH population are lacking. Historically, clinical trials in PAH have only included a minority of Hispanic patients. It has been reported that baseline NT-proBNP levels differ between different ethnicities. Furthermore, NT-proBNP levels can be impacted by declining renal function, making its interpretation difficult regarding clinical decision making.MethodsIn a retrospective single-center cohort analysis, Hispanic patients with PAH had a baseline outpatient NT-proBNP level drawn during a period of clinical stability and were followed for 1 year to monitor for time to clinical worsening (TTCW). The association of baseline NT-proBNP and TTCW was assessed in patients with normal and abnormal renal function.ResultsA total of 26 patients (22%) met the clinical endpoint of clinical worsening. Twenty-seven patients (24%) had chronic kidney disease (CKD). At baseline NT-proBNP levels showed a significant inverse correlation with 6-min walk test (6MWD, r = -0.382, P = 0.02), and a significant positive correlation with renal function (r = 0.273, P = 0.05). NT-proBNP levels did not correlate with age (r = 0.19, P = 0.11) or body mass index (BMI) (r = -0.292, P = 0.061). NT-proBNP levels of > 1,415 ng/L were significantly associated with shorter TTCW (P < 0.01) in all patients and in patients with CKD (P = 0.03). A stepwise increase in NT-proBNP levels by 100 ng/L was associated with a higher risk of meeting the clinical endpoint of TTCW in patients with normal renal function (hazard ratio (HR) = 1.8, P < 0.01) and CKD (HR = 1.5, P < 0.01).ConclusionsIn Hispanic patients with PAH, NT-proBNP is a valuable tool to predict 1-year TTCW, independent of renal function.

A Semi-Automated Term Harmonization Pipeline Applied to Pulmonary Arterial Hypertension Clinical Trials.

Data harmonization is essential to integrate individual participant data from multiple sites, time periods, and trials for meta-analysis. The process of mapping terms and phrases to an ontology is complicated by typographic errors, abbreviations, truncation, and plurality. We sought to harmonize medical history (MH) and adverse events (AE) term records across 21 randomized clinical trials in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. We developed and applied a semi-automated harmonization pipeline for use with domain-expert annotators to resolve ambiguous term mappings using exact and fuzzy matching. We summarized MH and AE term mapping success, including map quality measures, and imputation of a generalizing term hierarchy as defined by the applied Medical Dictionary for Regulatory Activities (MedDRA) ontology standard. Over 99.6% of both MH (N = 37,105) and AE (N = 58,170) records were successfully mapped to MedDRA low-level terms. Automated exact matching accounted for 74.9% of MH and 85.5% of AE mappings. Term recommendations from fuzzy matching in the pipeline facilitated annotator mapping of the remaining 24.9% of MH and 13.8% of AE records. Imputation of the generalized MedDRA term hierarchy was unambiguous in 85.2% of high-level terms, 99.4% of high-level group terms, and 99.5% of system organ class in MH, and 75% of high-level terms, 98.3% of high-level group terms, and 98.4% of system organ class in AE. This pipeline dramatically reduced the burden of manual annotation for MH and AE term harmonization and could be adapted to other data integration efforts.

The REPAIR Study: Effects of Macitentan on RV Structure and Function in Pulmonary Arterial Hypertension

ObjectivesThe REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study evaluated the effect of macitentan on right ventricular (RV) and hemodynamic outcomes in patients with pulmonary arterial hypertension (PAH), using cardiac magnetic resonance (CMR) and right heart catheterization (RHC). BackgroundRV failure is the primary cause of death in PAH. CMR is regarded as the most accurate noninvasive method for assessing RV function and remodeling and CMR measures of RV function and structure are strongly prognostic for survival in patients with PAH. Despite this, CMR is not routinely used in PAH clinical trials. MethodsREPAIR was a 52-week, open-label, single-arm, multicenter, phase 4 study evaluating the effect of macitentan 10 mg, with or without phosphodiesterase type-5 inhibition, on RV remodeling and function and cardiopulmonary hemodynamics. Primary endpoints were change from baseline to week 26 in RV stroke volume, determined by CMR; and pulmonary vascular resistance, determined by RHC. Efficacy measures were assessed for all patients with baseline and week 26 data for both primary endpoints. ResultsAt a prespecified interim analysis in 42 patients, both primary endpoints were met, enrollment was stopped, and the study was declared positive. At final analysis (n = 71), RV stroke volume increased by 12 mL (96% confidence level: 8.4-15.6 mL; P < 0.0001) and pulmonary vascular resistance decreased by 38% (99% confidence level: 31%-44%; P < 0.0001) at week 26. Significant positive changes were also observed in secondary and exploratory CMR (RV and left ventricular), hemodynamic, and functional endpoints at week 26. Improvements in CMR RV and left ventricular variables and functional parameters were maintained at week 52. Safety (n = 87) was consistent with previous clinical trials. ConclusionsIn the context of this study, macitentan treatment in patients with PAH resulted in significant and clinically-relevant improvements in RV function and structure and cardiopulmonary hemodynamics. At 52 weeks, improvements in RV function and structure were sustained. (REPAIR: Right vEntricular remodeling in Pulmonary ArterIal hypeRtension [REPAIR]; NCT02310672)

Abstract 13420: Machine Learning for Risk Stratification in Pulmonary Arterial Hypertension - Can It Achieve the Gold Standard?

Background: Pulmonary arterial hypertension (PAH) is a fatal and difficult to treat disease due to patient inter-variability. Accurate risk stratification is necessary for guiding treatment but no PAH risk calculator has achieved "excellent performance" (receiver-operator AUC &gt; 0.8). Conversion of REVEAL 2.0 to a Bayesian network has shown promising results (Pulmonary Hypertension Outcomes Risk Assessment or PHORA). In this study, a new Bayesian network model (PHORA 2.0) was developed with a novel network structure and optimal feature selection. Methods: Patient-level data had been previously aggregated and harmonized across six PAH clinical trials (AMBITION, PATENT-1/2, GRIPHON, SERAPHIN, FREEDOM-EV, ARIES-1/2); all patients were assessed at baseline. Forty-one variables were initially considered based on p-value ranking from previous meta-analyses, availability across trials, and expert opinion. Training data was created by random sampling of 80% of the harmonized dataset, dropping early censored patients (N = 2531), leaving 20% of the data as a test set (N = 626). Continuous variables were discretized through univariate decision trees using 10-fold cross-validation maximizing Brier score. Genetic search selected combinations of features that maximized ranked correlation (Kendall’s tau) with one-year survival, with increasing penalty for redundant features. Feature combinations were evaluated in augmented naïve Bayesian networks, the best model was selected by 10-fold cross-validation on training data. Final performance is reported as performance on the test set. Results: The final model achieved the best cross-validation AUC using 16 variables. Performance on the test set was an AUC = 0.85. The final model outperformed multiple risk calculators at test time (Figure 1). Conclusion: Bayesian network modeling coupled with genetic feature selection has discovered for the first time a one-year mortality model for PAH with excellent performance.

LAB PARAMETERS IN PREDICTING SURVIVAL IN PULMONARY ARTERIAL HYPERTENSION

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: Lab values are essential sets of parameters for the prognosis of the patients with pulmonary arterial hypertension (PAH). METHODS: We analyzed the lab variables obtained at baseline in 7 PAH clinical trials: SERAPHIN, BREATHE, CHEST-2, PATENT-2, FREEDOM, TRIUMPH, and the subcutaneous treprostinil study. The outcome of the analysis was mortality at a time to event of each individual trial. We selected only the significant Lab variables (p-value<0.05) to be aggregated across the clinical trials using Stouffer’s method, weighed by their ‘N’ in the clinical trials. RESULTS: Collective data from 3,387 patients were available at baseline with a total of 45 lab variables. Out of the 45, only 24 variables were still significant (p-value<0.05) after the aggregation of p-values. Elevated Uric acid, leukocyte/neutrophil count, red blood cell count, neutrophil/lymphocyte ratio, bilirubin (direct & total), AST, and BUN are the most predictive of adverse outcomes. Higher Albumin, lymphocyte count, and renal function (Cr, Creatine clearance) are the most predictive of improved outcome. CONCLUSIONS: To our knowledge, this is the largest aggregated attempt to analyze lab parameters in predicting survival. This analysis will be used to select features for the derivation of machine-learned PAH patient risk stratification models CLINICAL IMPLICATIONS: Our long-term goal is to generate a comprehensive personalized risk assessment tool from the data-driven variable selections to aid clinical decisions. DISCLOSURES: No relevant relationships by James Antaki, source=Web Response Grants relationship with Actelion Please note: 2019-2021 Added 04/29/2021 by Raymond Benza, source=Web Response, value=Grant/Research Support Grants relationship with Bayer AG Please note: 2019-2021 Added 04/29/2021 by Raymond Benza, source=Web Response, value=Grant/Research Support Grants relationship with Bellerophon Please note: 2019-2021 Added 04/29/2021 by Raymond Benza, source=Web Response, value=Grant/Research Support Grants relationship with EIGER Please note: 2019-2021 Added 04/29/2021 by Raymond Benza, source=Web Response, value=Grant/Research Support No relevant relationships by Allen Everett, source=Web Response Advisory Committee Member relationship with Bayer Please note: 2016-2019 Added 04/30/2021 by Manreet Kanwar, source=Web Response, value=Consulting fee No relevant relationships by Jidapa Kraisangka, source=Web Response No relevant relationships by Shili Lin, source=Web Response No relevant relationships by Zilu Liu, source=Web Response No relevant relationships by Faezeh Movahedi, source=Web Response Advisory Committee Member relationship with Blue Spark Technologies Please note: 2020-Present Added 04/16/2021 by Adam Perer, source=Web Response, value=Consulting fee Consultant relationship with Johnson & Johnson Please note: 2021-Present Added 04/16/2021 by Adam Perer, source=Web Response, value=Consulting fee No relevant relationships by Jacqueline Scott, source=Web Response

REVEAL LITE 2 RISK ASSESSMENT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION FROM THE GRIPHON STUDY: A POST-HOC ANALYSIS DEMONSTRATES ASSOCIATION OF RISK STATUS WITH LONG-TERM OUTCOMES

REVEAL LITE 2 RISK ASSESSMENT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION FROM THE GRIPHON STUDY: A POST-HOC ANALYSIS DEMONSTRATES ASSOCIATION OF RISK STATUS WITH LONG-TERM OUTCOMES

Hemodynamic Parameters in Predicting Survival in Pulmonary Arterial Hypertension

<h3>Purpose</h3> Hemodynamics are considered to be extremely relevant when clinically assessing patients with pulmonary arterial hypertension (PAH), especially for estimating prognosis. Yet, inclusion of hemodynamic data in PAH risk-stratification remains inconsistent and controversial, having been derived from limited data-sets. <h3>Methods</h3> We analyzed hemodynamic variables obtained at baseline in 4 PAH clinical trials: SERAPHIN, BREATHE-1, PATENT-2 and the subcutaneous treprostinil study; and at follow-up from SERAPHIN (week 26), PATENT-2 (week12), and the subcutaneous treprostinil study (week12). Primary outcome analyzed was mortality at <i>time to event</i> noted in each individual trial. Only the significant p-values (p-value<0.05) of each hemodynamic variable were aggregated across the clinical trials using Stouffer's method, weighed by their ‘n' in clinical trials. Then, we converted the aggregated p-value for each hemodynamic into a prioritization matrix (a sig. Stouffer's w) using the logarithmic function, for visualization. A sig. Stouffer's w of 1.3 is equivalent to a p-value = 0.05, with higher values being increasingly significant. <h3>Results</h3> Collective data from 2,211 patients were available at baseline and for 1,487 patients at follow-up. 30 hemodynamic variables (a combination of calculated and derived data) were considered for this analysis. At baseline, the most significant variables predictive of primary outcomes were PA sat, stroke work, stroke volume, stroke volume index and pulmonary arterial elastance (more reflective of output). At follow-up, the most predictive variables were PA sat, total pulmonary resistance, pulmonary vascular resistance, pulmonary arterial elastance, and right atrial pressure (more reflective of RV afterload) <h3>Conclusion</h3> To our knowledge, this is the largest aggregated attempt to analyze hemodynamic parameters in predicting survival. This analysis will be used to select features for derivation of machine-learned PAH patient risk stratification models.

Pulmonary Hypertension Roundtable: Drug Development and Negative Clinical Trial Results

Pulmonary Hypertension Roundtable: Drug Development and Negative Clinical Trial Results

Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire: feasibility of utilizing one-day versus seven-day symptom reporting.

Patient-reported outcomes are important measures to include in pulmonary arterial hypertension clinical trials but are not widely utilized in clinical practice. Pulmonary Arterial Hypertension—Symptoms and Impact Questionnaire (PAH-SYMPACT) is the only pulmonary arterial hypertension-specific patient-reported outcomes instrument developed and validated in accordance with the US Food and Drug Administration guidance on patient-reported outcomes development. The PAH-SYMPACT tool measures pulmonary arterial hypertension-related symptoms and impact of pulmonary arterial hypertension on daily life. Symptoms are reported each day for seven consecutive days, and the impact of pulmonary arterial hypertension over one week is recalled and reported on day 7; however, daily symptom reporting may overburden patients and healthcare resources, limiting the practicality of PAH-SYMPACT outside of clinical trials. To determine the practicability of an abridged version of PAH-SYMPACT for which all reporting is completed on one day, symptom data from the SYMPHONY trial (NCT01841762; PAH-SYMPACT validation study) were retrospectively analyzed to assess whether symptoms reported on each day correlated with the weekly average and whether one-day symptom scores were sensitive to disease severity. Correlation coefficients comparing the weekly average and individual day symptom scores were mostly high or very high regardless of the day they were measured. Findings were similar when using either Spearman's rank correlation or weighted kappa method. One-day symptom scores differentiated well between World Health Organization functional classes II and III/IV pulmonary arterial hypertension and were sensitive to change in disease severity as measured by the Patient Global Assessment of Disease Severity. These data suggest that the one-day PAH-SYMPACT is feasible and appropriate for routine implementation in clinical practice.

4973Efficacy and safety of selexipag in pulmonary arterial hypertension (PAH) patients with and without significant cardiovascular (CV) comorbidities

Abstract Introduction Many PAH patients today have a number of CV comorbidities, yet data on the efficacy and safety of therapies in such patients remain scarce. Most recent PAH clinical trials also include patients with comorbidities. Purpose To assess the long-term efficacy and safety of the oral, selective IP prostacyclin receptor agonist, selexipag, in PAH patients with and without significant CV comorbidities using post hoc analysis of GRIPHON data. Methods GRIPHON enrolled 1156 PAH patients randomised 1:1 to placebo:selexipag. The present analysis includes patients with right heart catheterisation within 1 year of randomisation who were categorised as with or without CV comorbidities. Patients with CV comorbidities were defined as having ≥3 of the following: body mass index (BMI) &gt;30 kg/m2, history of essential hypertension, diabetes mellitus, or historical evidence of significant coronary artery disease; if PAWP/LVEDP was &gt;12 but &lt;15 mmHg, pulmonary vascular resistance (PVR) had to be &gt;500 dyn.sec/cm5; if PAWP/LVEDP was &lt;12, then PVR had to be &gt;300 dyn.sec/cm5. Selexipag effect on time to first morbidity/mortality (M/M) event up to end of treatment was assessed for both subgroups. Baseline (BL) adjusted treatment hazard ratios with 95% CIs were calculated using Cox models. Model building involved stepwise backward elimination of BL covariates. Results 752 PAH patients could be categorised based on these criteria (99 with CV comorbidities, 653 without). At BL, patients with CV comorbidities were older (median [range] 60 [28–80] vs 46 [18–78] yrs), had higher BMI (mean [SD] 33.3 [7.23] vs 26.0 [5.64] kg/m2) and lower 6-minute walk distance (mean [SD] 319 [95.7] vs 354 [79.3] m) vs those without. A greater proportion were from Western Europe/Australia/North America (60.6% vs 38.9%) and in WHO functional class III (69.7% vs 49.9%). At BL, 82.8% of patients with CV comorbidities were receiving PAH therapies vs 75.7% of those without. As expected, at BL a higher proportion of patients with CV comorbidities (vs without) had previous/concomitant cardiac disease (62.6% vs 43.0%), metabolism/nutrition disorders (75.8% vs 31.2%), respiratory/thoracic/mediastinal disorders (59.6% vs 37.5%) and vascular disorders (76.8% vs 37.4%). Selexipag reduced the risk of M/M events vs placebo in both subgroups (Figure), with no evidence of an inconsistent treatment effect (interaction p-value=0.1544). Adverse events leading to treatment discontinuation were reported in 35.4% (25.9% selexipag, 46.7% placebo) of patients with CV comorbidities and 35.0% (32.0% selexipag, 38.0% placebo) of those without. Common prostacyclin associated side effects observed with selexipag (headache, diarrhoea, nausea) were reported at a similar incidence in both subgroups. Conclusions Selexipag had a beneficial effect on long-term outcome in PAH patients both with and without CV comorbidities. Safety in both groups was consistent with the known profile of selexipag. Acknowledgement/Funding Actelion Pharmaceuticals Ltd

Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension.

Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension in male and female obese mice.We depleted endogenous oestrogen in leptin-deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS).ob/ob mice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated pulmonary hypertension in male ob/ob mice. Intra-thoracic fat from ob/ob mice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress, effects that are attenuated by both ANA and TMS.Obesity can induce pulmonary hypertension and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.

THE EFFECT OF TREPROSTINIL DOSE ON TIME TO ALL CAUSE AND PULMONARY ARTERIAL HYPERTENSION-RELATED HOSPITALIZATIONS

SESSION TITLE: Cardiovascular Disease SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/10/2018 01:00 PM - 02:00 PM PURPOSE: Treprostinil (TRE) is a prostacyclin vasodilator indicated for treatment of pulmonary arterial hypertension (PAH). Oral and parenteral TRE are titrated based on tolerability and clinical response, with no established maximum dose. Due to disease progression and dose individualization, dose-response studies are difficult to conduct. Recent PAH clinical trials employed a composite endpoint of clinical worsening, with results largely driven by hospitalization and disease progression. The purpose of this analysis is to evaluate the effect of TRE dose on time to first PAH-related and all-cause hospitalization in patients with PAH. METHODS: The manufacturer’s global drug safety database was retrospectively analyzed for hospitalizations (Hs) that occurred after initiation of oral or subcutaneous (SC) TRE in the randomized, pivotal or open-label extension (OLE) studies. Hs were adjudicated for relatedness to PAH by a team of pharmacovigilance physicians employed by the manufacturer. Hs were considered not related to PAH if the patient was treated for another underlying etiology or experienced a decompensation due to an acute medical problem. Patients with available dosing data at last OLE study visit were included and grouped into unbiased tertiles based on this dose. Oral TRE doses were converted to ng/kg/min equivalents. Pairwise comparisons were made between dose groups to evaluate differences in time to first PAH-related and all-cause H. RESULTS: 759 oral TRE and 860 SC TRE patients were included in this long-term analysis. 381 (50.2%) oral TRE patients were hospitalized, including 236 (31.1%) due to PAH. Oral TRE dose groups were <15.7, 15.7-37.4, and >37.4 ng/kg/min (Groups 1/2/3). Median time to PAH-related and all-cause H was 339/412/658 days and 293/400/552 days for Groups 1/2/3, respectively. There was a significant difference between Groups 1 and 3 for both PAH-related and all-cause H (p<0.001, both) and between Groups 1 and 2 for all-cause H (p=0.003). 349 (40.6%) SC TRE were hospitalized, including 160 (18.6%) due to PAH. SC TRE dose groups were <8.3, 8.3-30, and >30 ng/kg/min (Groups 1/2/3). Median time to PAH-related and all-cause H was 83/318/428 days and 95/266/310 days in Groups 1/2/3, respectively. There were significant differences between Groups 1 and 2 and Groups 1 and 3 for both PAH-related and all-cause H (p<0.001, all). CONCLUSIONS: Patients receiving higher oral and SC TRE doses have a significantly longer time to first PAH-related and all-cause H, as compared to those receiving lower doses. CLINICAL IMPLICATIONS: Results suggest the importance of aggressive oral and SC TRE dose up titration in patients with PAH. DISCLOSURES: Employee relationship with United Therapeutics Please note: >$100000 Added 02/09/2018 by Erick Borg, source=Web Response, value=Salary Employee relationship with United Therapeutics Please note: >$100000 Added 03/02/2018 by Meredith Broderick, source=Web Response, value=Salary Employee relationship with United Therapeutics Please note: >$100000 Added 03/02/2018 by Andrew Nelsen, source=Web Response, value=Salary No relevant relationships by Gautam Ramani, source=Web Response Employee relationship with United Therapeutics Please note: >$100000 Added 03/02/2018 by Amanda Saunders, source=Web Response, value=Salary My spouse/partner as a Employee relationship with GlaxoSmithKline Please note: >$100000 Added 03/02/2018 by Amanda Saunders, source=Web Response, value=Salary

Using Real-World Data to Optimize Strategic Planning for Pulmonary Arterial Hypertension Clinical Trials

Introduction Pulmonary arterial hypertension (PAH) clinical trials are evolving from small, surrogate endpoint studies based primarily in North America (NA) and Western Europe (WE), to larger, clinical endpoint trials with investigative sites around the world. Limited clinical trial experience with PAH beyond NA and WE presents a challenge to planning key elements of a study such as determining country and site selection and predicting event rates. We sought to develop a data-driven approach to estimate event rates and optimize strategic planning for PAH clinical trials. Methods We used the IMS prescription database, which includes prescription data from hospital, retail, mail service, and long-term care pharmacies in over 90 countries. We reviewed global prescription data to characterize the use of cornerstone PAH therapies in various countries as days of treatment per population count. We used this information to determine which countries had a higher use of PAH drugs and where combination therapy vs. monotherapy was most likely to be used. We reviewed previous PAH clinical trials to estimate time to clinical worsening (TTCW) rates for patients receiving monotherapy (∼25-30% events/yr.) vs. combination therapy (∼15-20% events/yr.). Results Regions and countries with the highest consumption of PAH specific drugs were NA, WE, and Japan ( Figure ). The lowest use of PAH specific drugs was in Latin America (LA). Endothelin receptor antagonists (ERAs) were used in countries throughout NA, WE, Eastern Europe (EE), and Asia. Use of newer therapies occurred only in select regions: riociguat, a soluble guanylate cyclase stimulator, was used mostly in WE, EE, Canada, Japan, and Taiwan, and selexipag, a prostacyclin receptor agonist, was used mostly in NA, WE, and Japan. Conclusions Our analysis showed that greater use of PAH specific drugs occurred in higher income regions such as NA, WE, and Japan; therefore, we predicted greater use of combination PAH therapy in these areas. There was lower use of PAH specific drugs in EE, LA, and Asia; thus, we predicted a higher prevalence of monotherapy in these regions. Understanding global prescription patterns and associated estimated event rates may allow for a more data-driven approach to developing enrollment timelines and selecting countries and sites for PAH clinical trials.

Clinical trials in pulmonary arterial hypertension: a glimpse of history

Clinical trials have remarkably changed the natural history of pulmonary arterial hypertension (PAH). Despite the relevant progresses achieved in terms of prognosis, PAH is still burned by high mortality rates, disability and low levels of quality of life. The aim of this review is to look over the history of clinical trials in PAH, starting from the little studies with prostacyclin analogues to the recent large randomized placebo-controlled trials. Moreover, the future perspectives of PAH management are addressed.