The Role of Noninvasive Endpoints in Predicting Long-Term Outcomes in Pulmonary Arterial Hypertension

BACKGROUND: Until recently, many clinical trials in patients with pulmonary arterial hypertension (PAH) evaluated exercise capacity with 6-minute walk distance (6MWD) as the primary endpoint. Common secondary endpoints include PAH functional class (FC), which assesses symptoms, and either brain natriuretic peptide (BNP) or the inactive N-terminal cleavage product of its prohormone (NT-proBNP), which assesses cardiac function. OBJECTIVE: Examine the relationships among 6MWD, FC, and BNP/NT-proBNP measured at baseline or follow-up with long-term outcomes in PAH studies. METHODS: Relevant literature from January 1990 to April 2018 were obtained by searching PubMed, Embase, and Cochrane. Articles in English reporting on associations between 6MWD, FC, or BNP/NT-proBNP and outcomes in PAH were identified. Each endpoint was evaluated individually. Prespecified inclusion and exclusion criteria were applied at level 1 (titles/abstracts) and level 2 (full-text review). RESULTS: The database search yielded 836 unique records; 65 full-text articles were reviewed. Twenty-five studies were eligible for inclusion. Findings supported the importance of measuring PAH noninvasive endpoints in predicting long-term outcomes. Patients with shorter or decreased 6MWD, poor (III/IV) or declining FC (e.g., from II to III), or elevated or increasing BNP/NT-proBNP had a higher risk of death and costly events (e.g., hospitalization, lung transplant). FC also predicted health care resource utilization and costs. Collectively, these endpoints establish risk groups that predict likelihood of complications from PAH or death. CONCLUSION: Assessment of 6MWD, FC, and BNP/NT-proBNP provides low-cost, efficient, and noninvasive means of predicting long-term health and economic outcomes in patients with PAH.