Adding Bosentan to Sildenafil for PAH: What's the Verdict?

Nicholas Gross, MD, PhD


December 16, 2015

Bosentan Added to Sildenafil Therapy in Patients With Pulmonary Hypertension

McLaughlin V, Channick RN, Ghofrani HA, et al
Eur Respir J. 2015;46:405-413

Combination Therapy for PAH

Pulmonary arterial hypertension (PAH) is a severe and progressive disorder that predisposes those who suffer from it to right-sided heart failure. Without treatment, the condition is fatal within 2-3 years.

Effective treatments, which have been available since the early 2000s, fall into three main categories: endothelin antagonists (eg, bosentan), phosphodiesterase type 5 (PDE-5) inhibitors (eg, sildenafil), and prostacyclin derivatives (eg, treprostinil). Although each treatment modality is beneficial, attempts to improve outcomes (eg, mortality) are now being made by using drug combinations.

Study Summary

McLaughlin and colleagues examined the benefits of adding bosentan to sildenafil for the treatment of PAH. In this prospective trial, 334 patients with severe PAH who had been receiving sildenafil (≥ 20 mg three times daily) for 3 months or more were randomly assigned to receive additional bosentan (125 mg twice daily) or matching placebo. The primary endpoint was time to the first occurrence of a composite of mortality from any cause or morbidity (worsening PAH, the need for additional therapy, or lung transplantation).

The two treatment groups were well-matched. Most patients were female, with a mean age of 53.9 years, and diagnosed predominantly with idiopathic PAH. Connective-tissue PAH was the next most common etiology. The primary endpoint occurred in 51.4% of the patients on sildenafil plus placebo and 42.8% of patients on sildenafil plus bosentan; this difference was not significant (P = .25).

However, an important secondary outcome—performance on the 6-minute walk—was significantly better in the dual therapy group, which showed an improvement of 7.2 m compared with a decline of 14.6 m in the placebo group (P = 0.01). Other endpoints (World Health Organization [WHO] functional class, hospitalization, atrial septostomy, or lung transplantation) did not significantly differ between groups. No subgroup of patients with respect to age at onset, sex, etiology, geographic location, or baseline WHO functional class responded significantly better to the combination therapy.

Adverse effects occurred in 12.6% and 24.5% of patients in the control vs bosentan groups, respectively. However, worsening of PAH occurred more often in the placebo group than the bosentan group (35% vs 25%, respectively). No new safety signals were observed.


Because the prognosis of PAH is dire despite the use of available monotherapies, it is appropriate to seek improvements by combining therapies. The results have been variable. A similar trial>[1] using the same combination of bosentan and sildenafil showed significantly improved clinical and hemodynamic parameters, together with improvements in functional status.[2]

Despite the failure of the present trial with respect to the primary endpoint, the improvement on the 6-minute walk suggests to the practicing physician that the sildenafil/bosentan combination may be worth a trial in a patient in whom monotherapy has not provided acceptable results. If the outcome does not improve function, the second medication can be dropped.

It should be mentioned that the use of sildenafil and bosentan is appropriate only for idiopathic or genetic forms of PAH and PAH caused by connective-tissue diseases. For other etiologies of PAH (eg, left-sided heart failure, arterial hypoxemia secondary to primary pulmonary disease, thromboembolism), the underlying cause of PAH should be addressed.



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