Switch to riociguat may benefit PAH patients not at treatment goal on PDE5 inhibitor
Presenter: Marius Hoeper, MD
In patients with intermediate-risk pulmonary arterial hypertension (PAH) who have an inadequate response to stable treatment with a phosphodiesterase-5 (PDE5) inhibitor, switching to riociguat results in greater clinical improvement compared with maintenance PDE5 inhibitor therapy.
In the randomized, controlled, open-label phase IV REPLACE study (NCT02891850), conducted at 81 sites in 22 countries,1 a satisfactory clinical response was achieved by 41% in patients assigned to riociguat compared with 22% in those assigned to PDE5 inhibitor maintenance, said Marius Hoeper, MD, of the Clinic for Respiratory Medicine, Hannover Medical School, Germany.
“We believe that switching from PDE5 inhibitor to riociguat can benefit patients with PAH at intermediate risk and may serve as a strategic option for treatment escalation,” said Dr. Hoeper.
A total of 226 patients with intermediate-risk PAH treated with a stable dose of PDE5 inhibitor with or without an endothelin receptor antagonist for at least 6 weeks were randomized to continuation of their PDE5 inhibitor (oral sildenafil, ≥ 60 mg/day, or oral tadalafil, 20 to 40 mg/day) or a switch to riociguat (maximum dosage of 2.5 mg three times daily). Intermediate risk was defined as World Health Organization (WHO) functional class III and a 6-minute walk distance of 165 to 440 m.
A total of 155 patients (69%) had idiopathic PAH, heritable PAH, or drug- and toxin-induced PAH (DPAH); 26 (12%) had PAH associated with congenital heart disease or portal hypertension; and 43 (19%) had PAH associated with connective tissue disease. More than 80% in each arm had a 6-minute walk distance of 320 m or greater.
The primary end point was centrally adjudicated clinical improvement at week 24, defined as fulfillment of at least two of three efficacy parameters: at least a 10% or 30-m increase from baseline in 6-minute walk distance, improvement to WHO functional class I/II, or at least a 30% reduction from baseline in N-terminal-pro-brain natriuretic peptide, all in the absence of clinical worsening.
The advantage to riociguat on achievement of the primary end point was statistically significant (odds ratio 2.78; P = .0007). The primary end point favored riociguat in all PAH subgroups. Only one patient in the riociguat arm had clinical worsening compared with 10 in the PDE5 inhibitor maintenance arm (odds ratio 0.10; P = .0047).
No new safety signals were observed, and adverse events were equally common in the two treatment arms. Serious adverse events occurred at a rate of 17% in the PDE5 inhibitor maintenance arm vs 7% in the riociguat arm.
Three patients randomized to the PDE5 inhibitor maintenance arm had clinical worsening events leading to death, and an additional patient in this arm died in the safety follow-up. There were no deaths observed in the riociguat arm.
“In a disease state such as PAH, the bioavailability of nitric oxide may be reduced,” said Dr. Hoeper in explaining the potential rationale for the efficacy of a switch in intermediate-risk patients. “Especially in advanced disease, it’s possible that the PDE5 inhibitor is no longer active, where a compound like riociguat, which can directly stimulate the production of cyclic [guanosine monophosphate], in the absence or presence of nitric oxide, may still be efficacious.”
Reference
- Hoeper M, Ghofrani H, Al-Hiti H, et al. Switching to riociguat in patients with pulmonary arterial hypertension not at treatment goal with phosphodiesterase type-5 inhibitors: subgroup analysis results of the REPLACE study. CHEST 2020; 158(4 Suppl):A2156–A2159. doi:https://doi.org/10.1016/j.chest.2020.08.1857