Are Hemodynamics Surrogate Endpoints in Pulmonary Arterial Hypertension?
Background—While frequently assessed in trials and clinical practice, hemodynamic response to therapy has never been validated as a surrogate endpoint for clinical events in pulmonary arterial hypertension (PAH).
Methods and Results—We performed a patient-level pooled analysis of four randomized placebo-controlled trials to determine if treatment-induced changes in hemodynamic values at 12 weeks accounted for the relationship between treatment assignment and the probability of early clinical events (death, lung transplantation, atrial septostomy, PAH hospitalization, withdrawal for clinical worsening, escalation in PAH therapy). We included 1119 subjects with PAH. The median (interquartile range) age was 48 (37 - 59), and 23% were men. 656 (59%) received active therapy (101 [15%] iloprost, 118 [18%] sitaxsentan, 204 [31%] sildenafil, and 233 [36%] subcutaneous treprostinil). Active treatment significantly lowered right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), and pulmonary vascular resistance and increased cardiac output and index (p < 0.01 for all). Changes in hemodynamic values (except for RAP and mPAP) were significantly associated with the risk of a clinical event (p ≤ 0.01 for all). While active treatment approximately halved the odds of a clinical event compared to placebo (p < 0.001), changes in hemodynamics accounted for only 1.2 - 13.9% of the overall treatment effect.
Conclusions—Treatment-induced changes in hemodynamics at 12 weeks only partially explain the impact of therapy on the probability of early clinical events in PAH. These findings suggest that resting hemodynamics are not valid surrogate endpoints for short-term events in PAH clinical trials.
- Received February 24, 2014.
- Revision received May 27, 2014.
- Accepted June 16, 2014.