Sequential Add-On Therapy and Risk Reclassification in PAH

Key Takeaways

• Both noninvasive risk tools shifted toward lower-risk categories during follow-up after macitentan was added to prior sildenafil.
• WHO functional class improved and BNP decreased, while 6-minute walk distance remained essentially unchanged over the same interval.
• COMPERA 2.0 and REVEAL Lite 2 showed strong correlation at baseline and follow-up.

COMPERA 2.0 low-risk classification rose from 19% to 43% over 24 weeks after macitentan was added to prior sildenafil in adults with PAH classified as Group 1.4. In this Mexican single-center retrospective cohort of 25 adults, that shift was accompanied by improvement in WHO functional class and lower BNP values. All patients had been receiving sildenafil alone before sequential add-on therapy began.

Investigators included 25 adults with right-heart-catheterization-confirmed PAH who had previously received sildenafil monotherapy and were classified as Group 1.4 under 2022 ESC/ERS criteria. Baseline was defined at macitentan initiation, and follow-up occurred 24 weeks after sequential add-on macitentan plus sildenafil. The median age was 37 years, 96% were female, 72% had congenital heart disease-associated PAH, 24% had connective tissue disease-associated PAH, and 64% had Eisenmenger syndrome.

WHO functional class improved significantly over follow-up, with p = 0.002. BNP declined from 510 to 184 pg/mL, with p = 0.003. By contrast, 6-minute walk distance remained similar at 332 versus 328 m, with p = 0.936, and tricuspid regurgitation jet velocity remained stable at 3.70 versus 3.52 m/s, with p = 0.326. The TAPSE/PASP ratio rose from 0.279 to 0.328 without reaching significance, with p = 0.089.

Risk reclassification was directionally similar with both noninvasive tools. REVEAL Lite 2 low-risk status increased from 40% to 68%, while high-risk status fell from 28% to 4%, with p = 0.009. COMPERA 2.0 also changed significantly, with p = 0.023, and no patients remained in the high-risk category at follow-up. Correlation between the tools was strong at baseline, with Spearman rho = 0.67, and at 24 weeks, with rho = 0.70; both p values were below 0.001. No significant time-by-group interaction was seen by Eisenmenger status.

Interpretation was limited by the retrospective, uncontrolled design, the small sample, and the absence of systematic hemodynamic follow-up. Follow-up was restricted to 24 weeks, and intermittent drug shortages affected consistent access to therapy during that period. The observed score changes were not a direct mortality analysis and do not establish causality for treatment effects.