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Is monotherapy as effective as combination therapy in improving long-term outcomes in PAH?

The use of combination therapy has already been adopted in many pulmonary arterial hypertension (PAH) centres1,2 and is likely to become an increasingly important component of care in the future.

Until recently, randomised controlled trials (RCTs) investigating the use of combination therapy in PAH have been short-term3-7, and the majority of these trials have failed to show a significant improvement in their primary endpoint associated with the use of combination therapy compared with monotherapy. The primary endpoint assessed in all but two of these trials was change from baseline in 6 minute walk distance (6MWD), and the effects on time to clinical worsening, investigated as a secondary endpoint in a number of these short-term trials, have also been variable8.

The SERAPHIN study is the first large-scale RCT to provide long-term data on the effect of combination therapy in PAH. Pre-specified sub-group analysis of the composite primary endpoint (time to first morbidity-mortality event) in patients who were on stable background therapy provides novel data assessing the long-term benefit of administering macitentan in combination with background therapy.

In the SERAPHIN study, 64% (n = 471) of patients were on a PAH-specific background therapy, and 96% of these patients were on phosphodiesterase type 5 inhibitors (PDE5-i; see slide 1). In the pre-specified sub-group analysis of patients on background PAH therapy at baseline, macitentan 10 mg reduced the risk of occurrence of morbidity-mortality events, as measured by the composite endpoint, up to end of treatment versus placebo by 38% (p = 0.009)9 (see slide 3).

As a result of these novel data, regulatory agencies have included macitentan in combination with other PAH-specific therapies, excluding other endothelin receptor antagonists, in the therapeutic indication of the European and US label (SmPC and USPI)10,11.

Experts at the recent 5th World Symposium on PH reviewed the existing data on sequential combination therapy, identifying 13 RCTs incorporating background therapy, including the long-term SERAPHIN study (see slide 4)12. More recently, a further three trials on combination therapy have been completed: COMPASS-213 AMBITION14 and NCT0032329715. Additionally, the combination therapy results from GRIPHON have been announced in a recent press release16. In light of this increased experience, it has been recommended to increase the grade of recommendation and level of evidence for combination therapy in patients with an inadequate response to initial monotherapy, in the updated treatment algorithm (slide 5)12.

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Show References

1. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30:2493-537.

2. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34:1219-63.

3. Galiè N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008; 371:2093-100.

4. Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119:2894-903.

5. McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Resp Crit Care Med 2006; 174:1257-63.

6. McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010; 55:1915-22.

7. Simonneau G, Rubin LJ, Galiè N et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008; 149:521-30.

8. Vachiéry JL and Gaine S. Challenges in the diagnosis and treatment of pulmonary arterial hypertension. Eur Respir Rev 2012; 21:313-20.

9. Pulido T, Adzerikho I, Channick R, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369:809-18.

10. Opsumit® (macitentan). Summary of Product Characteristics, May 2014.

11. Opsumit® (macitentan). US Prescribing Information, October 2013.

12. Galiè N, Corris PA and Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62:D60-72.

13. McLaughlin VV, Channick R, Ghofrani HA, et al. Effect of bosentan and sildenafil combination therapy on morbidity and mortality in pulmonary arterial hypertension (PAH): Results from the COMPASS-2 study. Chest 2014; 146:860A.

14. Galiè N, Barbera JA, Frost A, et al. AMBITION: A randomised, multicenter study of first-line ambrisentan and tadalafil combination therapy in subjects with pulmonary arterial hypertension (PAH). Eur Respir J 2014; 44(Suppl. 58):2916.

15. NCT00323297. Assess the efficacy and safety of sildenafil when added to bosentan in the treatment of pulmonary arterial hypertension. www.clinicaltrials.gov.

16. Actelion Pharmaceuticals Ltd. Selexipag meets primary endpoint in pivotal Phase III GRIPHON outcome study in patients with pulmonary arterial hypertension. Press Release, June 2014.

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