Switching to riociguat may be an effective strategy for pulmonary arterial hypertension (PAH) patients who respond inadequately to phosphodiesterase-5 inhibitors, results from a small open-label study demonstrated.
“This study represents an important step towards determining if this new treatment strategy is an effective approach to the management of patients with PAH, although additional data from larger, randomised, controlled studies are needed to further establish the safety and efficacy of this approach,” researchers led by Marius M. Hoeper, MD, wrote in a study published online Sept. 9, 2017, in the European Respiratory Journal.
Current clinical data indicate that many patients with PAH who receive phosphodiesterase-5 inhibitors do not reach treatment goals. “For example, in the AMBITION study, 73% of patients with PAH receiving tadalafil monotherapy and 61% of those receiving tadalafil in combination with ambrisentan did not achieve a satisfactory clinical response at week 24 of the study (N Engl J Med. 2015;373:834-44),” Dr. Hoeper of the Clinic for Respiratory Medicine at Hannover Medical School Germany and his associates wrote. “Furthermore, in the SERAPHIN study, event-free survival of patients receiving [phosphodiesterase-5 inhibitors] monotherapy was approximately 50% at 3 years (N Engl J Med. 2013;369:809-18).”
For the current trial, known as RESPITE, investigators from nine countries in Europe and North America enrolled 61 PAH patients in a 24-week, open-label uncontrolled analysis to investigate the safety, feasibility, and benefit of switching them from phosphodiesterase-5 inhibitors to riociguat. The patients underwent 1-3 days free of phosphodiesterase-5 inhibitors before receiving riociguat in a maximum dose of up to 2.5 mg t.i.d. Most patients (74%) were female, and 92% were Caucasian. In all, 51 patients (84%) completed all 24 weeks of treatment, while the remaining 10 discontinued treatment, 4 of whom due to adverse events.
Additionally, 54% of the patients studied experienced an improvement in their the World Health Organization Functional Class. However, 32 patients (52%) experienced study drug–related adverse events and 10 (16%) experienced serious adverse events, two of which were related to the drug being studied. Six patients (10%) experienced clinical worsening, including death in two, though the deaths were deemed to be unrelated to the drug being studied.
“Although not mechanistically studied, the findings of RESPITE support the hypothesis that a defective [nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate] pathway might explain why some patients have no sufficient or sustained response to [phosphodiesterase-5 inhibitors] therapy,” the researchers noted. “In such patients, direct stimulation of [soluble guanylate cyclase] may be more effective than inhibition of [phosphodiesterase-5], but this hypothesis is still unproven.”
They acknowledged certain limitations of the study, including its prospective design and the relatively homogenous patient population. “Other limitations include the lack of a long-term continuation phase, and the absence of mechanistic data allowing identification of patients likely to respond or not respond to switching,” they wrote. “Two deaths were observed in this study, which might raise concerns, although neither of the deaths (one due to pneumonia and one due to subdural haematoma) was considered by the investigators to be study drug-related or due to worsening PAH. Given the lack of a control group and the rate of study withdrawals and clinical worsening events, further evaluation to clarify the safety of switching is required.”
The study was funded by Bayer AG, Berlin. Dr. Hoeper and his coauthors disclosed having financial ties to numerous pharmaceutical companies, including Bayer, which makes riociguat.
PRIMARY SOURCE: Eur Respir J. 2017 Sep 9. doi: 10.1183/13993003.02425-2016.