Cochrane Database Syst Rev

Combination therapy reduces clinical worsening in PAH patients

August 12, 2025

Study details: This Cochrane review included nine randomized trials (N = 1,807; median duration 16 weeks) comparing combination therapy with a PDE5i plus an endothelin receptor antagonist (ERA) to either agent alone in adults and adolescents (≥12 years) with group 1 pulmonary arterial hypertension (PAH). Outcomes assessed included clinical worsening, mortality, hospitalization, 6-minute walk distance (6MWD), WHO functional class, dyspnea, adverse events, and trial withdrawal.

Results:

• Combination vs. ERA: Combination therapy significantly reduced clinical worsening (risk ratio [RR], 0.53; number needed to treat for an additional beneficial effect [NNTB] 9; high-certainty) and likely reduced hospitalizations (RR, 0.32; NNTB 14; moderate-certainty). Mortality and 6MWD differences were minimal or uncertain. Serious adverse events and withdrawals were similar.
• Combination vs. PDE5i: Evidence was very uncertain for clinical worsening and hospitalization, though exclusion of high-bias studies suggested possible benefit (RR, 0.57). 6MWD improved modestly (MD, ~20 m; moderate-certainty). Serious adverse events and withdrawals were comparable, with a possible reduction in withdrawals favoring combination therapy.
• PDE5i vs. ERA: Little to no difference in clinical worsening, mortality, or 6MWD; all outcomes supported by low- or very low-certainty evidence.

Clinical impact: Combination therapy with PDE5i plus ERA offers a clear benefit over ERA monotherapy in reducing clinical worsening and likely hospitalizations in group 1 PAH. Benefits over PDE5i monotherapy are less certain but may exist when high-bias studies are excluded. Mortality and functional outcomes remain uncertain. Safety profiles are similar across regimens. These findings support the use of initial combination therapy in WHO functional class II/III PAH, but generalizability is limited by underrepresentation of Black patients.

Source:

Oba Y, et al. (2025, August 4). Cochrane Database Syst Rev. Phosphodiesterase type 5 inhibitor plus endothelin receptor antagonist compared to either alone for group 1 pulmonary arterial hypertension. https://pubmed.ncbi.nlm.nih.gov/40757552/