Riociguat may be a useful option for patients with pulmonary arterial hypertension (PAH) in whom phosphodiesterase-5 inhibitor (PDE5i) treatment is insufficient, according to the results of a recent study published in the journal Lancet Respiratory Medicine.

Researchers evaluated clinical improvement, defined as an absence of clinical worsening and prespecified improvements in at least 2 of 3 variables, in patients with symptomatic PAH at intermediate risk for 1-year mortality in the REPLACE open-label, randomized controlled trial ( Identifier: NCT02891850). Patients were randomly assigned to either remain on PDE5i treatment or switch to riociguat therapy. The 3 variables for clinical improvement were 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP).

Among the 293 patients screened, 226 met the inclusion criteria and were enrolled as study participants. Of these 226 individuals, 211 completed the study (104 in the riociguat group and 107 to the PDE5i group). An absence of clinical worsening was seen in 41% of patients in the riociguat group and 20% of patients in the PDE5-i treatment group. Furthermore, clinical worsening events occurred in 1% of patients in the riociguat group and 9% of patients in the PDE5i treatment group.

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From baseline to 24 weeks, riociguat improved mean 6MWD, from 374 meters to 410 meters while PDE5i therapy improved 6MWD to a lesser extent, from 367 meters to 381 meters (mean treatment difference, 23 m; P =.054). Improvements in WHO functional class were also reported in patients treated with riociguat compared with patients treated with PDE5i therapy (mean difference, -0.26; P =.0007).

The most frequently reported adverse event was hypotension, followed by headache and dyspepsia. A total of 7% (n=8) and 17% (n=19) of patients in the riociguat and PDE5i groups experienced serious adverse events. In addition, 4 patients in the PDE5i group died during the study.

“Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality,” the study authors.

Disclosure: This clinical trial was supported by Bayer AG, Merck Sharp & Dohme. Please see the original reference for a full list of authors’ disclosures.


Hoeper MM, Al-Hiti H, Benza RL, et al; on behalf of the REPLACE investigators. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. Published online March 24, 2021. doi:10.1016/S2213-2600(20)30532-4