Analysis of Risk Assessment Tools in the REPLACE Study

Purpose The REPLACE study showed that switching to riociguat (rio) can benefit pulmonary arterial hypertension (PAH) patients treated with phosphodiesterase type 5 inhibitors (PDE5i) but still at intermediate risk. Improvements to lower risk status with rio versus PDE5i were seen with all three risk assessment tools analyzed, although the difference was not statistically significant with the modified REVEAL risk score (mRRS). Here, we report changes in the components of the mRRS, COMPERA, and FPHN non-invasive risk assessment tools, and a post hoc analysis of RRS Lite 2 in REPLACE. Methods Individual components of mRRS, COMPERA, and FPHN non-invasive assessment tools, and RRS Lite 2 risk scores and risk strata were calculated for the rio group (n=111) and PDE5i group (n=113) at REPLACE baseline and Week 24. WHO/NYHA functional class (FC), 6MWD, and NT-proBNP were components of all risk scores. Vital signs (systolic blood pressure [SBP] and heart rate [HR]) and renal insufficiency were additional components for mRRS and RRS Lite 2. PAH etiology and demographics were also components of mRRS. Results For mRRS, COMPERA, and FPHN, 44% of patients in the rio group vs 23% in the PDE5i group improved their WHO/NYHA FC component score at Week 24. Similar results were found for the 6MWD component (1 point removed from mRRS: rio 41% vs PDE5i 27%; COMPERA grade 1/FPHN low risk at Week 24: rio 37% vs PDE5i 27%). The incidences of lowest-risk NT-proBNP component scores at Week 24 were rio 41% vs PDE5i 40% for mRRS, rio 21% vs PDE5i 12% for COMPERA, and rio 41% vs PDE5i 40% for FPHN. At baseline, mRRS vital sign scores were similar between the two groups. At Week 24, more patients in the rio group (50%) versus the PDE5i group (36%) had 1−2 points added to their mRRS score due to SBP 96 bpm. The overall result was similar for the mRRS and the RRS Lite 2. With RRS Lite 2, the proportion of patients achieving a low-risk stratum from baseline to Week 24 was 41% to 61% for rio and 37% to 50% for PDE5i. Conclusion Risk assessment tools showed similar trends in shared components between treatment groups at baseline and Week 24. Results with RRS Lite 2 were similar to mRRS. Differences in discrimination of the risk sores, weighting of components, and differences in the vital signs component of mRRS could explain between score differences at baseline and Week 24 in REPLACE. SBP and HR will be individually analyzed in future.