Showing papers by "Lewis J. Rubin published in 2019"

An overview of the 6th World Symposium on Pulmonary Hypertension

Abstract: State of the art summary on diagnosis, prognosis, therapy and future perspectives of pulmonary hypertensionhttp://ow.ly/8MHN30mGtqs

Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients With Pulmonary Arterial Hypertension.

Abstract: Background: NT-proBNP (N-terminal pro brain natriuretic peptide) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidel...

Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial

Abstract: BACKGROUND The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction. METHODS Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event. RESULTS Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35–0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35–1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients. CONCLUSIONS Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients.

Selexipag treatment for pulmonary arterial hypertension associated with congenital heart disease after defect correction: insights from the randomised controlled GRIPHON study.

Abstract: Aims Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD‐PAH) after defect correction have a poor prognosis compared with other CHD‐PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD‐PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD‐PAH patients from the GRIPHON study and examine the response to selexipag.

Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial

Abstract: Purpose This phase 2 study was designed to assess the efficacy, safety and tolerability of immediate-release orally administered ralinepag, a selective, non-prostanoid prostacyclin receptor agonist with a 24-h terminal half-life, compared to placebo in adult patients with symptomatic pulmonary arterial hypertension (PAH). Methods 61 PAH patients who were receiving standard care, including mono or dual PAH-targeted background therapy were randomised 2:1 to ralinepag (n=40) or placebo (n=21). The starting dose of ralinepag was 10 μg twice daily. Dosage was then up-titrated as tolerated over the course of the 9-week dose-titration period, to a maximum total daily dose of 600 μg (300 μg twice daily). The primary efficacy end-point was the absolute change in pulmonary vascular resistance (PVR) from baseline to week 22. Additional end-points included percentage change in PVR from baseline, other haemodynamic parameters, 6-min walk distance (6MWD) and safety and tolerability. Results Ralinepag significantly decreased PVR by 163.9 dyn·s·cm−5 compared to an increase of 0.7 dyn·s·cm−5 with placebo (p=0.02); the least-squares mean change from baseline PVR was −29.8% compared with placebo (p=0.03). 6MWD increased from baseline by 36.2 m with ralinepag and 29.4 m with placebo (p=0.90). Serious adverse events occurred in 10% of ralinepag patients and 29% of placebo patients. Study discontinuations occurred in 13% of ralinepag patients and 10% of placebo patients. Summary Ralinepag reduced PVR compared with placebo in PAH patients on mono (41%) or dual combination (59%) background therapy.

Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension‒related hospitalization in the AMBITION trial.

Abstract: BACKGROUND In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression , or unsatisfactory long-term clinical response) vs pooled monotherapy . These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.

Pulmonary artery denervation using catheter-based ultrasonic energy.

Abstract: Aims Pulmonary arterial hypertension is a devastating disease characterised by pulmonary vascular remodelling and right heart failure. Radio-frequency pulmonary artery denervation (PDN) has improved pulmonary haemodynamics in preclinical and early clinical studies; however, denervation depth is limited. High-frequency non-focused ultrasound can deliver energy to the vessel adventitia, sparing the intima and media. We therefore aimed to investigate the feasibility, safety and efficacy of ultrasound PDN. Methods and results Histological examination demonstrated that innervation of human pulmonary arteries is predominantly sympathetic (71%), with >40% of nerves at a depth of >4 mm. Finite element analysis of ultrasound energy distribution and ex vivo studies demonstrated generation of temperatures >47oC to a depth of 10 mm. In domestic swine, PDN reduced mean pulmonary artery pressure induced by thromboxane A2 in comparison to sham. No adverse events were observed up to 95 days. Histological examination identified structural and immunohistological changes of nerves in PDN-treated animals, with sparing of the intima and media and reduced tyrosine hydroxylase staining 95 days post procedure, indicating persistent alteration of the structure of sympathetic nerves. Conclusions Ultrasound PDN is safe and effective in the preclinical setting, with energy delivery to a depth that would permit targeting sympathetic nerves in humans.

Integrating Data From Randomized Controlled Trials and Observational Studies to Assess Survival in Rare Diseases.

Abstract: Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.