New Trial Designs and Potential Therapies for Pulmonary Artery Hypertension

A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH. A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances over the past 2 decades in treatment of this disorder. However, these treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Because PAH is considered an orphan disease that is uniformly progressive and fatal, prior clinical trials evaluating novel therapies were relatively short in duration and were comprised of small populations of affected patients. These studies provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Accordingly, clinical development of novel therapies for PAH in the future will require trials of larger and perhaps more diverse patient cohorts who are studied for longer periods and with more robust and meaningful efficacy endpoints. The challenges posed by these requirements are substantial, and include From th

Long-term safety and outcome of intravenous treprostinil via an implanted pump in pulmonary hypertension

BACKGROUND: We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH). METHODS: Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics. RESULTS: We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11-34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 peri-procedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11-3.28; p = 0.019; n=95). CONCLUSIONS: Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed. (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved