Intermediate-risk pulmonary arterial hypertension (PAH) patients may see their symptoms improve after switching from phosphodiesterase-5 inhibitors (PDE-5i) to Adempas (riociguat), results from the Phase 4 REPLACE clinical trial show.
The transition to Adempas also appears to be a safer option than with PDE-5i maintenance therapy.
The study, “Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial,” was published in The Lancet Respiratory Medicine.
Adempas, marketed by Bayer in the U.S., is a soluble guanylate cyclase (sGC) stimulator approved for the treatment of PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Adempas was developed though a collaboration between Bayer and Merck, known as MSD outside the U.S. and Canada.
Both Adempas and PDE-5 inhibitors, such as Adcirca (taladafil) and Revatio (sildenafil), are vasodilator medications that induce blood vessel widening and relaxation. Although PDE-5i treatments are commonly used for PAH, some patients do not respond well enough and other treatment options are necessary.
Since PDE-5i and Adempas act on the same pathway via different mechanisms, researchers hypothesized that PAH patients who do not respond sufficiently to treatment with PDE-5i could benefit from switching to Adempas.
To test their hypothesis, researchers conducted the Phase 4 trial REPLACE (NCT02891850, Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy), in which the effects of switching to Adempas from PDE-5i treatment were compared to continued PDE-5i therapy in patients with PAH at intermediate risk. The trial was sponsored by Bayer and was conducted in 81 sites in 22 countries.
“The scientific rationale for the REPLACE study comes from ESC/ERS [European Society of Cardiology/European Respiratory Society] guidelines suggesting the need to set a treatment goal of low-risk status in patients with pulmonary arterial hypertension, and from clinical practice where many intermediate-risk patients do not reach or maintain specific treatment goals when treated with a PDE5i-based regimen,” Sameer Bansilal, MD, executive director, U.S. Medical Affairs at Bayer, said in a press release.
PAH patients from 18 to 75 years old at intermediate risk of one-year mortality — defined as World Health Organization (WHO) functional class III. That means patients who were enrolled were experiencing no symptoms at rest, but felt limited in normal activities, and the results of their six-minute walk distance test (6MWD, a functional capacity assessment) were 165–440 meters (180–481 yards). All patients enrolled showed an insufficient clinical response to stable treatment with PDE-5i.
Participants were either maintained on the same PDE-5i medication regimen (Revatio, more than 60 milligrams per day, or Adcirca, 20 to 40 milligrams per day, with or without an endothelin-receptor antagonist), or transitioned to Adempas (up to 2.5 milligrams, three times per day).
In total, 226 patients were selected; 111 were assigned to Adempas treatment and 115 to the PDE-5i group. Of these, 211 completed the study.
The study’s primary goal was clinical improvement by week 24.
Clinical improvement was defined as an absence of clinical worsening and a favorable outcome in at least two of the following criteria: at least a 10% or 30- meter (32-yard) increase in the 6MWD; a decrease in WHO functional class; and a reduction of at least 30% in the N‐terminal pro B-type natriuretic peptide (NT-proBNP), a prognostic marker of PH.
Clinical improvement was achieved by more patients on Adempas, 45 of 111 patients (41%), than those in the PDE-5i group, 23 of 113 patients (20%). Switching to Adempas increased by 2.78 times the chances of attaining clinical improvement.
The trial’s secondary goal was to evaluate clinical worsening events, defined as hospitalization and disease progression. Clinical worsening was observed in 10 of the 114 patients (9%) in the PDE-5i group as opposed to one of the 111 patients (1%) in the Adempas group. Of the 10 people with clinical worsening in the PDE-5i group, nine were hospitalized because of PAH worsening and one due to disease progression. The only person with clinical worsening in the Adempas group was hospitalized because of PAH worsening.
Regarding safety, in the Adempas group the most common adverse events (side effects) were low blood pressure (14%), headaches (13%), and indigestion (9%). Patients in the PDE-5i group experienced headaches (7%), cough (6%), and upper respiratory tract infections (6%). These results were in line with those observed in the pivotal PATENT trial (NCT00810693), in which researchers studied the efficacy and safety of Adempas in PAH patients.
Serious adverse events were more frequent in the PDE-5i group, 19 of 114 patients (17%), compared to eight of 111 patients (7%) in the Adempas group. Four deaths were reported during the study, all in the PDE-5i group.
Overall, “switching to riociguat from PDE5i treatment … could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality,” the researchers concluded.
Part of these results were presented previously at the 2020 virtual annual meeting of the European Respiratory Society.
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