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Introduction and Objectives In the randomized controlled TRITON (NCT02558231) study, both initial triple oral (macitentan, tadalafil, selexipag) and initial double oral (macitentan, tadalafil, placebo) therapy improved pulmonary vascular resistance (primary endpoint; by 54% and 52%) and 6-minute walk distance (secondary endpoint; by 55 and 56 m) at week 26 in patients with newly diagnosed PAH, with no difference between groups. This analysis further explored long-term outcome data in patients initiated on triple versus double oral therapy in TRITON. Methods We analysed the treatment effect on the secondary endpoint of time to first disease progression event (centrally adjudicated) until end of the observation period +7 days and time to all-cause death (post-hoc) until end of the observation period (Cox regression model). Results Baseline characteristics were balanced between the initial triple (n=123) and initial double therapy (n=124) groups, median follow-up was 77.6 and 75.8 weeks, respectively. There was a 41% reduction in the risk of first disease progression event with initial triple vs initial double therapy (hazard ratio 0.59, 95% CI 0.32–1.09; figure 1), driven by PAH-related hospitalisation and all-cause death. Adverse events were consistent with known safety profiles of study drugs. Two patients died in the initial triple therapy group and 9 in the initial double therapy group (hazard ratio 0.23, 95% CI 0.05–1.04). Conclusions Exploratory analysis indicated a signal for improved long-term outcome with initial triple versus initial double therapy. Please refer to page A240 for declarations of interest related to this abstract.

Background Primary mitral regurgitation (MR) is one of the most common heart valvular pathologies. However, optimum timing of surgery remains controversial. Purpose To describe changes in cardiopulmonary exercise testing (CPET) parameters after surgery for severe primary MR. Methods In a single centre prospective study, patients undergoing surgery under current ESC guidelines for severe primary MR underwent assessment with transthoracic echocardiogram, CPET, cardiac MRI and quality of life questionnaire pre-operatively and at six months after surgery. The primary outcome was a per protocol analysis of impaired post-operative functional capacity (defined as post-operative left ventricular ejection fraction on transthoracic echocardiogram Results 43 of the 50 patients recruited between February 2017 and October 2018 were included in the per protocol analysis. Thirty five patients (72.9%) had impaired post-operative functional capacity. In the overall cohort (n=43), there was a significant fall post-operatively in percentage predicted peak VO2 (ppVO2) (81.8±15.7% vs. 76.2±16.2%, p In the multivariable analysis, pre-operative left ventricular ejection fraction ≤60% (hazard ratio, 1.69; 95% confidence interval, 1.56 to 480.1, p=0.04) and pre-operative percentage predicted peak VO2 ≤84% (hazard ratio, 1.22; 95% confidence interval, 2.13 to 107.1, p Conclusions Pre-operative percentage predicted peak VO2 ≤84% is an independent predictor of impaired post-operative functional capacity. Subject to a confirmatory study, this may help to refine current ESC guidelines for intervention for severe primary MR. Change in ppVO2 after surgery Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Rosetrees Trust and Friends of Hammersmith Hospital

Introduction Long-term outcomes are important in PAH. Purpose To evaluate the long-term efficacy and safety of initial triple oral therapy with selexipag, macitentan and tadalafil vs initial double oral therapy with macitentan and tadalafil in PAH. Methods TRITON, a multicentre, double-blind, placebo-controlled, phase 3b study, randomised 1:1 newly diagnosed, treatment-naïve PAH patients to initial triple vs double therapy. Macitentan and tadalafil were initiated at randomisation and selexipag/placebo at day 15 (uptitrated to wk 12). Efficacy and safety were assessed in a blinded manner until the last patient randomised completed wk 26 (end of observation period). Pulmonary vascular resistance (PVR; primary endpoint) and 6-minute walk distance (6MWD) were assessed at wk 26. Other secondary endpoints included time to first disease progression event (centrally adjudicated) to end of observation period +7 days. Time to all-cause mortality up to end of observation period was analysed post-hoc. Results 247 patients were randomised to initial triple (n=123) or initial double therapy (n=124); baseline characteristics were balanced between groups. Median follow-up was 77.6 (initial triple) and 75.8 wks (initial double). Initial triple and initial double therapy improved PVR (by 54% and 52%) and 6MWD (by 55 and 56 m), with no difference between groups. A 41% reduction in the risk of first disease progression event driven by PAH-related hospitalisation and all-cause death was observed with initial triple vs initial double therapy (hazard ratio 0.59, 95% CI 0.32–1.09, p=0.087; Figure). Two patients died in the initial triple vs 9 in the initial double therapy group (hazard ratio 0.23, 95% CI 0.05–1.04). Adverse events were consistent with the known safety profiles of the study drugs. Conclusions In TRITON, assessments at wk 26 showed marked improvements in both treatment arms, with no difference between groups. Exploratory analysis indicated a signal for improved long-term outcome with initial triple versus initial double therapy. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Actelion Pharmaceuticals Ltd.

Purpose In TRITON (NCT02558231), initial triple (macitentan, tadalafil, selexipag) and initial double (macitentan, tadalafil, placebo) oral therapy in newly diagnosed PAH patients markedly improved hemodynamic and functional parameters at week 26, with no difference between groups. Main analysis up to end of main observation period suggested that initial triple therapy reduced the risk of disease progression vs initial double therapy. Here, we present data from a longer follow-up period (up to end of study [EOS]). Methods In this multicenter, double-blind, randomized, placebo-controlled, phase 3b study, end of the main observation period occurred when the last patient randomized completed week 26. Unblinding occurred after end of main observation period, and patients were further followed-up to EOS, which occurred 30 days after last intake of study treatment. Time to first disease progression event (pre-specified) and all-cause death (post-hoc) were analyzed with Cox regression; all disease progression events were analysed (post-hoc) using a negative binomial model. Events were centrally adjudicated in a blinded fashion. Results Median follow-up time at EOS was 100 weeks in the initial triple therapy group (n=123) and 95 weeks in the initial double therapy group (n=124) (Table). The hazard ratio for the risk of a first disease progression event and the rate of all disease progression events for initial triple vs initial double therapy were similar at end of main observation period and at EOS (Table). Four patients in the initial triple and 12 in the initial double therapy groups died before EOS. Safety up to EOS was consistent with findings at end of main observation period. Conclusion Results at EOS and at end of main observation period are consistent and suggest a signal for improved long-term outcome with initial triple vs initial double oral therapy.

Introduction A major breakthrough in the understanding the pathobiology of pulmonary arterial hypertension (PAH) was the identification of heterozygous disease-causing mutations in the BMPR2gene. Recently, mutations were also identified in GDF2, which encodes the ligand for BMPR2 (Graf S et al.,2018). We hypothesised that patients harbouring mutations in BMPR2and GDF2show distinct phenotypes from patients without mutations in previously established disease genes. Methods A total of 1077 cases of idiopathic and heritable PAH were recruited to NIHR Bioresource-Rare Diseases PAH study and underwent whole genome sequencing. Phenotypic diagnostic information was prospectively collected. Results Of 1077 patients recruited, 162 had heterozygous mutations in BMPR2 and 10 patients had heterozygous GDF2 mutations, including 2 patients with large deletions at the GDF2 locus not previously described. Plasma GDF2 levels were significantly lower in GDF2mutation carriers than in healthy controls (79.2 (22.3)vs.202 (35.2);p Conclusions We report deletions at the GDF2 locus and reduced plasma GDF2 levels in patients with pathogenic mutations, supporting the functional significance of these mutations. BMPR2 mutation carriers had earlier disease onset, more severe haemodynamics and altered blood test parameters. GDF2 mutation carriers were indistinguishable from PAH patients without disease-causing mutations and showed no features of HHT or vascular anomaly syndromes. On behalf of UK PAH Cohort Study Consortium, NIHR BioResource – Rare Disease Consortium

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter ≤2.5 μm3 (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK PAH national Cohort study. Associations with transplant-free survival and pulmonary hemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (Unadjusted hazard ratio (HR) 2.68; 95% CI 1.11-6.47 per 3 μg·m-3, p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38; 95% CI 1.44-13.36 per 3 μg·m-3, p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the ERS/ESC risk categories as well as pulmonary hemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

[Eur Heart J 2014; 35 :3033–73, doi:10.1093/eurheartj/ehu283] The published version of these Guidelines referred to 317 000 VTE-related deaths related in …