OBJECTIVES: Evaluating overall survival in randomized controlled trials (RCT) can often be confounded by bias introduced by treatment switching. Macitentan is an endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. In the phase 3 RCT SERAPHIN study (N=742), a decrease in the risk of all-cause mortality in an intent-to-treat (ITT) analysis up to study closure was reported with macitentan 10mg versus placebo; this was not statistically significant. As patients were allowed to switch treatment when experiencing symptoms of disease progression, this analysis attempts to adjust for the confounding effects of the switch on overall survival.

METHODS: The inverse probability of censoring weighted (IPCW) and rank-preserving structural failure time (RPSFT) models were used to estimate the treatment effect on overall mortality had there been no switching in SERAPHIN. Time to all-cause death was evaluated up to study closure. Treatment switching was defined as placebo patients switching to open-label macitentan 10mg, and macitentan patients prematurely discontinuing macitentan.

RESULTS: Up to study closure, 183/250 patients (73.2%) in the placebo group switched to macitentan 10mg; among these patients, macitentan exposure-time represented 28.2% of total study treatment exposure (cumulative exposure 134.6 patient-years). The adjusted hazard ratios for overall survival using the IPCW and RPSFT methods were lower (0.42, [95% CI 0.22, 0.81]; p=0.009, and 0.33 [0.04, 2.83], respectively) than the ITT unadjusted hazard ratio (0.80 [0.51, 1.24]).

CONCLUSION: Treatment switching in SERAPHIN confounded the standard ITT analysis and resulted in a substantial underestimation of the benefit of macitentan 10mg on overall survival, confirming results from a previous analysis integrating real-world and SERAPHIN data (Torbicki et al, Circ Cardiovasc Qual Outcomes;2019;12:e005095). Adjusting for switching, while acknowledging the related assumptions, can provide more reliable treatment effect estimates than standard/confounded ITT analyses, especially when there are high rates of treatment switching, as in SERAPHIN.