A Review of Clinical Trial Endpoints of Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension and How They Relate to Patient Outcomes in the United States.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are subgroups of pulmonary hypertension and are considered rare diseases. Understanding how endpoints of clinical trials (and patient registry studies) of patients with PAH and CTEPH are associated with patient outcomes is important in order to address the concerns of patients, health care providers, decision makers, and payers. The purpose of this review was to examine how endpoints used in clinical trials and patient registry studies are associated with outcomes of patients with PAH and CTEPH. A PubMed literature search was conducted to retrieve published studies, including randomized phase III clinical trials and observational studies, from years 2000 to May 2015 that evaluated the associations between change in 6-minute walking distance (6MWD), 6MWD thresholds, change in World Health Organization functional class (WHO-FC), and time to clinical worsening with outcomes of patients with PAH and CTEPH. Based on this review of published literature, a reduction in 6MWD as a criterion for PAH worsening, a deterioration in WHO-FC, and delay in the time to clinical worsening are clinically meaningful trial endpoints and are associated with outcomes of patients with PAH and CTEPH. Utilization and standardization of these endpoints will be useful for comparing interventions of clinical trials and therapies. Hospitalizations are frequent among patients with PAH and CTEPH, and total health care costs are high. From a U.S. payer perspective, clinical worsening is an important composite endpoint in that it includes hospitalization, which can be transformed into a preventative cost value associated with efficacious treatment of patients with PAH and CTEPH. In view of the greater number of medications available to treat PAH, the introduction of the first approved therapy to treat CTEPH, and the increasing use of combination pharmacotherapy, reliable prognostic markers of treatment responsiveness are important to help guide appropriate management. As new clinical trials and observational studies are conducted, it will be important to maintain universal endpoints so that health care providers, decision makers, and payers can better understand the value of targeted pharmacotherapies and combination therapies for the treatment of patients with PAH and CTEPH. DISCLOSURES Sponsorship for this review and article processing charges were funded by Bayer HealthCare Pharmaceuticals. Divers and Platt are employees of Bayer HealthCare Pharmaceuticals. Wang is an employee of Bayer HealthCare Pharmaceuticals and owns stock in the company. Lin and Lingohr-Smith are employees of Novosys Health, which received research funds from Bayer HealthCare Pharmaceuticals in connection with conducting this review and developing this manuscript. Mathai is a consultant to Bayer HealthCare Pharmaceuticals and also reports consulting fees from Actelion and Gilead. Study concept and design were contributed by Divers, Platt, Lin, and Mathai. Lin and Lingohr-Smith collected the data, and data interpretation was performed by Divers, Platt, Wang, and Matthai. The manuscript was written primarily by Lingohr-Smith, with assistance from the other authors, and revised by Divers, Platt, Wang, and Mathai.