The key differentiating factors between the endpoints of morbidity and mortality and time to clinical worsening (TTCW) are the way in which these endpoints are defined and the design of the studies in which they are captured.
Although TTCW has been included in almost all trials of targeted pulmonary arterial hypertension (PAH) therapies, this has only been as a secondary or exploratory endpoint1,2 (see slide 1) and these trials were powered to show differences in the primary endpoint, typically change in 6-minute walk distance (6MWD)3. These trials included small numbers of patients (between 200 to 400) and were typically short-term (ranging from 12-24 weeks)4; therefore, the assessment of TTCW was based on a limited number of worsening events5 (see slide 2). In addition, no extrapolation can be made to infer an effect on true long-term outcomes.
In contrast, ‘time to first morbidity or mortality event’ was used as the composite primary endpoint in SERAPHIN, the first long-term, randomised controlled trial (RCT) in PAH, enrolling more than 700 patients6. SERAPHIN was an event-driven study that continued until the pre-specified, statistically relevant number of 285 primary endpoint events were reached6. As a long-term RCT, SERAPHIN has provided prospective and controlled data on the long-term treatment benefit of macitentan in patients with PAH.
In PAH, events such as death or lung transplantation very rarely occur as first events, given that sudden death is uncommon and patients usually deteriorate before dying or being listed for transplantation. It is, therefore, essential that the definition of ‘other worsening of PAH’ is robust, well defined and able to capture significant clinical deterioration7. In previous trials, the definition of TTCW has been inconsistently defined8,9 (see slide 3) and the definition of ‘other worsening of PAH’ has typically been based on a single parameter8. In addition, there has been no independent adjudication of the disease progression that has taken place in trials using TTCW in PAH (see slide 4). Due to the subjective nature of disease progression, this allows the potential for inconsistent event classification between different sites and investigators3.
The morbidity-mortality composite endpoint used in SERAPHIN reflects the progression of PAH2. The definition used for ‘other worsening of PAH’ in the SERAPHIN trial employed the recommendations from the proceedings of the 4th World Symposium on Pulmonary Hypertension8 and included an additional criterion6 (see slide 5). As such, all of the following criteria had to be met in order to count as an ‘other worsening’ event: a decrease in 6MWD of at least 15%, confirmed by two tests on different days; worsening of PAH symptoms, which must include either an increase in functional class (FC) or appearance or worsening of symptoms of right heart failure; and the need for a new PAH treatment6. In accordance with recommendations from the 4th World Symposium on pulmonary hypertension, and in order to ensure that all criteria were met and the events were clinically meaningful7, 8, all morbidity and mortality events were adjudicated by an independent and blinded Clinical Event Committee6 (see slide 6). This results in a highly robust primary outcome measure that directly reflects disease progression.