Table 2. Summary of clinical trial for combination therapy in PAH.

Randomized, controlled short-term studies
	Study N design key results
	PACES 87	267	Sildenafil in patients previously treated with epoprostenol	Significant improvement in 6MWT distance, hemodynamics, and time to clinical worsening
	STEP 88	37	Inhaled iloprost in patients previously treated with bosentan	Trend toward increase in 6MWT distance, but significant improvement in WHO-FC and clinical deterioration
	COMBI 89	40	Inhaled iloprost in patients previously treated with bosentan	Study prematurely ended after interim analysis; no clinical improvement observed.
	TRIUMPH 80	255	Inhaled iloprost in patients previously treated with bosentan	Significant improvement in 6MWT distance, but no improvement in WHO-FC or time to clinical worsening.
	FREEDOM-C 82	350	Oral treprostinil in addition to ERAs and/or PDE-5 inhibitors	No significant improvement in 6MWT distance, WHO-FC, or time to clinical deterioration
	FREEDOM-C2 83	310	Oral treprostinil in addition to ERAs and/or PDE-5 inhibitors	No significant improvement in 6MWT distance, WHO-FC, or time to clinical deterioration
	PHIRST 63	216	Subgroup analysis of patients who were given tadalafil + bosentan	No significant improvement in 6MWT distance. No improvement in WHO-FC or time to clinical deterioration in patients previously treated with bosentan
	IMPRES 90	202	Imatinib in addition to dual or triple combination therapy	Significant improvement in 6MWT distance, PVR and NT-proBNPNo effect on time to clinical worsening. High dropout rate because of adverse effectsUnexpectedly high rate of subdural hematoma
	PATENT 66	222	Riociguat in addition to ERAs and/or prostacyclin analogues	Significant improvement in 6MWT distance and PVR in previously treated patients
	PATENT-plus 91	18	Riociguat in addition to sildenafil	No change in systolic blood pressure (primary end point), no efficacy signals, increased hypotensive episodes in the extension phase of the study
Event-driven randomized, controlled studies
	Study N design key results
	COMPASS-2 56	334	Bosentan in addition to sildenafil	• No significant improvement in progression-free survival (primary end point) • Significant improvement in 6MWT distance and NT-proBNP after 16 weeks
	SERAPHIN 59	471	Macitentan in previously treated patients (predominantly with PDE-5 inhibitors)	• Significant improvement in progression-free survival (HR 0.62; p  = 0.009) • Significant improvement in 6MWT distance, WHO-FC and PVR after 6 months
	AMBITION 86	500	Initial combination therapy with ambrisentan and tadalafil versus monotherapy with one of these substances	• 50% risk reduction in time to therapy failure with initial combination therapy • Significant improvement in 6MWT distance and NT-proBNP after 6 months
	GRIPHON 84	925	Selexipag in addition to ERAs and/or PDE-5 inhibitors	• 40% reduction in risk for disease progression, almost independently of pre-existing therapy • No improvement in WHO-FC

Abbreviations: 6MWT, 6-minute walking test; ERA, endothelin receptor antagonist; NT-proBNP, N-terminal pro-brain natriuretic peptide; PDE-5, phosphodiesterase type 5; PVR, pulmonary vascular resistance; WHO-FC, World Health Organization functional class.

Adapted with permission from Hoeper MM et al, Targeted therapy of pulmonary arterial hypertension, Int J cardiol, 2018. ⁴⁹