Combination therapy
Another therapeutic option is to combine drugs with different mechanisms of action, in order to optimize clinical benefit while minimizing side effects. The two possible strategies for combination therapy are either to add a new medication to an ongoing treatment (sequential combination) or in first intention by starting from the beginning with a combination treatment. The BREATHE-2 trial compared the association of i.v. epoprostenol and oral bosentan with i.v. epoprostenol and placebo among 33 patients with severe PAH over a 12 weeks period [227]. Reduction in pulmonary vascular resistance was greater with combination therapy, although it did not reached statistical significance. Furthermore, no benefit could be shown on the 6-MWD with combination therapy compared to epoprostenol alone (+ 68 m and + 74 m, respectively). These results however may be related to the small number of patients and the short term follow up in the context of the addition of a treatment to a drug already known to bring an important benefit in severe PAH patients. In a recent controlled trial, the sequential addition of oral sildenafil 80 mg three times daily for patients already receiving i.v. epoprostenol with insufficient improvement, proved to be more effective than the placebo on the 6-MWD and hemodynamic parameters. Indeed, there was a significant reduction in the number of patients showing clinical worsening and an improvement of survival among most severe patients [239]. There is currently no data on the addition of bosentan in such context. The combination of iloprost to bosentan in patients with idiopathic PAH or associated PAH in NYHA functional class III was shown to be significantly better than placebo and bosentan in terms of 6-MWD (+ 26 m), NYHA functional class and on post inhalation hemodynamic parameters (PVR −26.4%) [240].
Several uncontrolled studies evaluated the efficacy of other associations with encouraging results. The open-label sequential addition of bosentan or sildenafil to epoprostenol, treprostinil or iloprost was shown to be of interest [241-243]. Also, the association of ERA and PDE5, both available in oral form, offers an interesting option [244,245]. Currently, the limited data precludes consensus on which combined treatment or strategy should be preferred. Also, no long term evaluation of combination therapy is available.
The best strategy of combination therapy should be discussed in the next world symposium of Pulmonary Hypertension. Current ERS/ESC guidelines propose sequential combination therapy without any recommendation regarding the best way to associate available specific PAH therapies.