September 24, 2020
2 min read
Hoeper MM, et al. ALERT: Pneumothorax, cough, PAH, alveolar proteinosis. Presented at: European Respiratory Society International Congress; Sept. 7-9, 2020 (virtual meeting).
The REPLACE study was co-funded by Bayer AG and Merck Sharp & Dohme Corp. Hoeper reports receiving fees from Acceleron, Actelion, Bayer, Janssen, Merck and Pfizer.
Patients with pulmonary arterial hypertension at intermediate risk who switched from phosphodiesterase type 5 inhibitors to riociguat experienced clinical improvement at 24 weeks, according to results of the REPLACE study.
Marius M. Hoeper, MD, senior physician in the department of respiratory medicine and professor of pulmonary hypertension at Hannover Medical School and the German Center for Lung Research, and colleagues conducted REPLACE, a prospective, randomized, open-label, 24-week, phase 4, multicenter study to investigate switching from a phosphodiesterase type 5 (PDE5) inhibitor to riociguat (Adempas, Bayer), an oral guanylate cyclase stimulator, or maintaining PDE5 inhibitor treatment. The study enrolled 226 patients with PAH at intermediate risk. At baseline, patients had WHO functional class 3 and a 6-minute walking distance of 165 m to 440 m.
Patients were randomly assigned to continue PDE5 inhibitors, including oral sildenafil and tadalafil (n = 115; mean age, 49 years; 83% women), or switch to riociguat 2.5 mg thrice daily (n = 111; mean age, 49 years; 74% women) for 24 weeks. Primary endpoint was clinical improvement at 24 weeks, which was defined by reaching two or more of the following: 6-minute walk distance improvement of at least 30 m or 10% from baseline, WHO functional class status 1 or 2 or N-terminal pro-B-type natriuretic peptide (NT-proBNP) reduction of at least 30% from baseline.
More patients met the primary endpoint after switching to riociguat compared with maintaining PDE5 inhibitors (41% vs. 20%; P = .0007).
At 24 weeks, 1% of patients who switched to riociguat vs. 9% who maintained PDE5 inhibitors experienced an adjudicated clinical worsening event (OR = 0.1; 95% CI, 0.013-0.725; P = .0046). Time to first clinical worsening event was significantly longer in those who switched to riociguat compared with those who maintained PDE5 inhibitors (P = .007). These findings were consistent across PAH subtypes, whether the patient started with monotherapy or combination therapy, or whether the patient received sildenafil or tadalafil.
WHO functional class improved from baseline to 24 weeks in 44% of patients who switched to riociguat vs. 23% of patients who maintained PDE5 inhibitors. The mean treatment difference between groups was 23 m (P = .0542). Researchers also observed improvement in NT-proBNP with riociguat vs. continued PDE5 inhibitors, with a mean treatment difference of –170 pg/mL (P = .01067). Hoeper also reported significant improvements in WHO functional class in the group that switched to riociguat, with a mean difference between groups of –0.26 (95% CI, –0.42 to –0.11; P = .0007).
The frequency of adverse events was similar in both groups, at 71% in the riociguat group vs. 66% in the PDE5 group. The frequency of serious adverse events was also similar, at 7% in the riociguat group vs. 17% in the PDE5 group. Seven patients in each treatment arm discontinued drug treatment and four patients in the PDE5 inhibitor arm died during the study period.
“Patients switching from PDE5 inhibitors to riociguat had a significantly higher likelihood of clinical improvement and also a significantly reduced rate of clinical worsening compared with patients [who] remained on PDE5 inhibitors,” Hoeper said during his presentation. “At the same time, riociguat was well tolerated in patients switching from PDE5 inhibitors and the safety data that we’ve seen were consistent with the known safety profile of the drug. Overall, switching from PDE5 inhibitors to riociguat seems to benefit some patients with PAH at intermediate risk and it may become a new treatment option for these patients.”