Background and Methods:Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, there is a lack of randomized controlled trials comparing these two treatments. The study aimed to evaluate the efficacy and safety of BPA and riociguat in patients with inoperable CTEPH. A phase 3 multicenter, open-label, parallel-group randomized controlled trial was conducted in 23 specialized centers for pulmonary hypertension in France. The study included inoperable CTEPH-naïve patients aged 18 to 80 years, newly diagnosed, with pulmonary vascular resistance>320 dyn·s·cm-5. Patients were randomly assigned 1:1 to BPA or riociguat groups through a network randomization system using block randomization without stratification (2 or 4 cases in one group). The primary study endpoint was change in pulmonary vascular resistance at week 26, expressed as a percentage of baseline pulmonary vascular resistance in the intent-to-treat population. Safety analyses were performed in all patients who received at least 1 dose of riociguat or at least 1 dose of BPA. Patients who completed the RACE trial continued to receive adjuvant follow-up for 26 weeks, during which symptomatic patients with pulmonary vascular resistance still exceeding 320 dyn·s·cm-5 could benefit from either riociguat after BPA or riociguat after BPA.Results:Between January 19, 2016 and January 18, 2019, 105 patients were randomized to either riociguat (53) or BPA (52). At week 26, mean pulmonary vascular resistance decreased to 39.9% (95% CI: 36.2-44.0) of baseline pulmonary vascular resistance in the BPA group and 66.7% (95% CI: 60.5-73.5, mean ratio 0.60, 95% CI: 0.52-0.69; P<0.000 1）。 Treatment-related serious adverse events occurred in 22 of 52 (42%) in the BPA group, compared with 5 of 53 (9%) in the riociguat group. The most common treatment-related serious adverse events were lung injury in the BPA group [18/52 (35%)] and severe hypotension with syncope in the riociguat group (2/53, 4%). No treatment-related deaths occurred. At week 52, patients receiving either first-line riociguat or first-line BPA had a similar reduction in pulmonary vascular resistance (ratio of geometric means, 0.91, 95% CI, 0.79 to 1.04). The incidence of serious adverse events associated with BPA was lower in patients pretreated with riociguat (5/36, 14%, 22/52, 42%).Conclusion:Reduction in pulmonary vascular resistance was more pronounced in BPA than in riociguat at week 26, but treatment-related serious adverse events were more common in BPA. Patients pretreated with riociguat in subsequent studies had fewer BPA-related serious adverse events compared to patients receiving BPA as first-line therapy, suggesting the potential benefit of a multimodal therapeutic approach in patients with inoperable CTEPH. Further exploration of the efficacy of one or two drugs combined with BPA sequential therapy in inoperable CTEPH patients needs to be further explored in the future.
