Riociguat An Option For Pulmonary Arterial Hypertension When PDE-5 Inhibitors Fail

Patients with pulmonary arterial hypertension (PAH) at intermediate risk of death within a year may be switched from a phosphodiesterase-5 (PDE-5) inhibitor to riociguat to reduce risk, researchers suggest.

"Decision making regarding treatment of PAH has become increasingly complex," Dr. Marius Hoeper of Hanover Medical School in Germany told Reuters Health by email. "This reflects availability of an increased number of drugs . . . combined with clear evidence that the vast majority of patients are best treated with a combination of medications from at least two classes, and often all three."

Riociguat and PDE-5 inhibitors act on the nitric oxide pathway via different mechanisms. However, Dr. Hoeper said, "No randomized double-blind placebo-controlled comparisons of riociguat to PDE-5 inhibitors have been done, and probably never will be, given the logistic complexity of such a study."

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Therefore, as reported in The Lancet Respiratory Medicine, the team conducted REPLACE, an open-label, randomized controlled trial in 81 hospital-based pulmonary hypertension centers in 22 countries.

Patients with symptomatic PAH at intermediate risk of one-year mortality (mean age, 49; 21% men; 78% white) were randomly assigned to remain on PDE-5 inhibitor treatment (oral sildenafil, at least 60 mg per day, or oral tadalafil 20-40 mg per day) or to switch to oral riociguat (up to 2.5 mg three times per day).

Two hundred and eleven patients completed the study and seven in each group discontinued; 225 patients were included in the safety analysis and 224 in the full analysis set.

Forty-one percent of patients in the riociguat group and 20% of those in the PDE-5 inhibitor group met the primary endpoint of clinical improvement by week 24 (odds ratio, 2.78; P=0.0007).

Clinical worsening, a secondary endpoint, occurred in one (1%) patient in the riociguat group (hospitalization due to worsening PAH) and 10 (9%) in the PDE-5 inhibitor group (nine hospitalizations due to worsening PAH, and one disease progression), a significant difference.

In the riociguat group, the most frequent adverse events were hypotension (14%), headache (13%) and dyspepsia (9%); in the PDE-5 inhibitor group, the most frequent AEs were headache (7%), cough (6%) and upper respiratory tract infection (6%).

Serious adverse events were reported in 7% of those in the riociguat group and in 17% of patients in the PDE-5 inhibitor group, including four deaths.

"Switching to riociguat from (PDE-5 inhibitor) 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 authors write.

Dr. Hoeper said, "Conversion to riociguat in patients not meeting treatment goals on a PDE-5 inhibitor (usually already with an endothelin receptor antagonist) is a reasonable approach, particularly if there is a desire not to add a prostanoid. It is also reasonable instead to add a nonparenteral prostanoid, given the strength of evidence for that approach."

"Prostanoids are the most potent available agents, so it is important that this option also be carefully considered periodically if patients are not staying adequately compensated on lesser therapies," he said. "There is the risk of waiting too long before adding parenteral therapy, resulting in irreversible right ventricular failure and premature death.

"An opinion at a pulmonary hypertension center of excellence to assist in making the best possible decisions in this highly complex field is highly recommended," he added.

Dr. Robert Frantz of Mayo Clinic in Rochester, Minnesota, author of a related editorial, commented in an email to Reuters Health, "In my personal view, these data do not indicate that riociguat is generally more efficacious than PDE-5 inhibitors, and they should not change current recommendations to initiate PAH therapy with a combination of an endothelin-receptor antagonist and a PDE-5 inhibitor."

"However," he said, "the switching strategy provides a new treatment option for patients with PAH who are not achieving the treatment goal - i.e., a low-risk status - with a PDE-5 inhibitor-based treatment. As these patients are common and as we have only limited treatment options for such patients, having more options is good news."

Bayer AG, which sells riociguat as Adempas, and Merck Sharpe and Dohme Corp. co-funded the study and reviewed the manuscript. Bayer paid for medical writing. Dr. Hoeper has financial ties to both companies.

—Marilynn Larkin

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