Introduction: REPLACE will evaluate switching to riociguat in patients with pulmonary arterial hypertension (PAH) and an insufficient response to phosphodiesterase-5 inhibitors. The primary outcome is a composite clinical improvement endpoint (no clinical worsening and two of: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I/II; ≥30% decrease in N-terminal pro-brain natriuretic peptide). We assessed whether the endpoint could differentiate between the riociguat and placebo arms of the PATENT-1 study, and whether achieving the endpoint was associated with long-term outcomes.
Methods: In PATENT-1, patients received placebo or riociguat up to 2.5 mg three times/day (tid). In PATENT-2, former placebo patients received riociguat up to 2.5 mg tid. This post-hoc analysis applied the REPLACE composite endpoint to the PATENT-1 database and evaluated the association between achieving the composite endpoint in PATENT-1 and survival and clinical worsening-free survival in PATENT-2.
Results: The PATENT-1 analysis included 126 patients who received placebo and 254 who received riociguat up to 2.5 mg tid, with long-term outcomes assessed in 340 patients who entered PATENT-2. At Week 12, 50% of riociguat-treated and 25% of placebo-treated patients achieved the composite endpoint (odds ratio, 3.13; 95% confidence interval, 1.88–5.26; p<0.001). Similar results were observed irrespective of background therapy, although more treatment-naïve patients achieved the endpoint than pretreated patients in the riociguat arm. Patients who achieved the endpoint in PATENT-1 had a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2 compared with those who did not.
Conclusion: In this post-hoc analysis of PATENT-1 data, riociguat-treated patients were
more likely than placebo-treated patients to achieve the REPLACE composite endpoint of
improvement, which was associated with improved long-term outcomes. Use of this endpoint
in patients with PAH is a viable assessment of treatment response.