Clinical worsening in trials of pulmonary arterial hypertension: results and implications

PURPOSE OF REVIEW: Time to clinical worsening (TTCW) can be used to assess disease progression associated with pulmonary arterial hypertension (PAH). As a consequence, it is highly relevant to patients, clinicians, and regulatory agencies. The majority of clinical trials of PAH-specific drug therapies have included TTCW as a secondary endpoint; this article summarizes the results of randomized controlled clinical trials in PAH, specifically with respect to the clinical worsening endpoint. RECENT FINDINGS: Some trials have demonstrated a treatment-related delay in TTCW and others have not. Recent results suggest that TTCW shows particular promise in detecting disease progression, even in mildly affected patients. Definitions of clinical worsening have also varied across clinical trials; although all have agreed on the inclusion of all-cause death and hospitalization due to PAH in the definition, the inclusion of additional parameters defining 'disease progression' has differed. SUMMARY: There is a need for a clear and uniform definition of TTCW that can be tailored to the study population being investigated; the endpoint may require adaptation for patients in different functional classes and with different causes. Consistency of event reporting within a trial may be improved by employing a committee to adjudicate events. Trials are beginning to include TTCW as a primary endpoint; the results will be important in establishing the validity of whether this parameter should become the endpoint of choice in PAH trials in the future.