Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials

Figures & data

Figure 1 Network of available drugs for PAH.

Note: The size of nodes is proportional to the number of individuals randomized to each treatment, and the thickness of lines to the number of direct comparisons in trials.
Abbreviations: ERAs, endothelin receptor antagonists; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator.

Figure 2 Pooled WMD and 95% CIs determined by network meta-analysis for 6MWD of targeted drugs (A) or oral targeted drugs (B) for PAH.

Abbreviations: 6MWD, 6-minute walk distance; CI, confidence interval; ERAs, endothelin receptor antagonists; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator; WMD, weighted mean difference.

Figure 3 Pooled WMD and 95% CIs determined by network meta-analysis for mean pulmonary artery pressure of targeted drugs (A) or oral targeted drugs (B) for PAH. Pooled WMD and 95% CIs determined by network meta-analysis for pulmonary vascular resistance of targeted drugs (C) or oral targeted drugs (D) for PAH.

Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; PVR, pulmonary vascular resistance; sGCS, soluble guanylate cyclase stimulator; WMD, weighted mean difference.

Figure 4 Pooled OR and 95% CIs determined by network meta-analysis for all-cause mortality of targeted drugs (A) or oral targeted drugs (B) for PAH.

Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; OR, odds ratio; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator.

Figure 5 Pooled OR and 95% CIs determined by network meta-analysis for clinical worsening events of targeted drugs (A) or oral targeted drugs (B) for PAH.

Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; OR, odds ratio; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator.

Figure 6 Pooled OR and 95% CIs determined by network meta-analysis for SAEs of targeted drugs (A) or oral targeted drugs (B) for PAH.

Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; OR, odds ratio; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; SAE, serious adverse event; sGCS, soluble guanylate cyclase stimulator.

Figure S1 Study selection flow chart.

Abbreviation: RCT, randomized controlled trial.

Table S1 General characteristics of the included studies

Reference/study acronym, year	Treatment (n)	Control (n)	Age(mean age)	Female(%)	Etiology (%)	Period (wk)	Active drug	Comparator	Primary end point	Jadad score
Rubin et al,^Citation1 1990	11	12	36	70	IPAH (100)	8	Epoprostenol (IV)	Conventional therapy	TPR	2
AIR,^Citation2 2002	101	102	52	67.5	IPAH (50), APAH (22), CTEPH (28)	12	Iloprost (INH)	Placebo	6MWD, NYHA	4
ALPHABET,^Citation3 2002	65	65	45	61.5	IPAH (48), APAH (52)	12	Beraprost (PO)	Placebo	6MWD	3
ARIES1,^Citation4 2008	67	67	51	85.8	IPAH (63), APAH (37)	12	Ambrisentan (PO)	Placebo	6MWD	3
ARIES1,^Citation4 2008	68	67	49	83.6	IPAH (63), APAH (37)	12	Ambrisentan (PO)	Placebo	6MWD	3
ARIES2,^Citation4 2008	64	65	51	71.3	IPAH (65), APAH (35)	12	Ambrisentan (PO)	Placebo	6MWD	3
ARIES2,^Citation4 2008	63	65	51	74.2	IPAH (65), APAH (35)	12	Ambrisentan (PO)	Placebo	6MWD	3
Badesch et al,^Citation5 2000	56	55	55	91	APAH (100)	12	Epoprostenol (IV)	Conventional therapy	6MWD	2
Barst et al,^Citation6 1996	41	40	40	72.8	IPAH (100)	12	Epoprostenol (IV)	Conventional therapy	6MWD	2
Barst et al,^Citation7 2003	60	56	42	85.6	IPAH (74), APAH (26)	48	Beraprost (PO)	Placebo	Disease progression	3
BREATHE-1,^Citation8 2002	144	69	48	78.9	IPAH (70), APAH (30)	16	Bosentan (PO)	Placebo	6MWD	3
BREATHE-2,^Citation9 2004	22	11	46	69.7	IPAH (82), APAH (18)	16	Bosentan (PO) + epoprostenol (IV)	Epoprostenol (IV)	TPR	3
BREATHE-5,^Citation10 2006	37	17	39	61.1	APAH (100)	16	Bosentan (PO)	Placebo	SpO2, PVR	3
Channick et al,^Citation11 2001	21	11	51	87.5	IPAH (84), APAH (16)	12	Bosentan (PO)	Placebo	6MWD	4
EARLY,^Citation12 2008	93	92	45	69.7	IPAH (61), APAH (39)	24	Bosentan (PO)	Placebo	PVR, 6MWD	4
EVALUATION,^Citation13 2011	44	22	31	82.8	IPAH (61), APAH (39)	12	Vardenafil (PO)	Placebo	6MWD	4
FREEDOM-C,^Citation14 2012	174	176	51	82.3	IPAH/FPAH (66), APAH (34)	16	Treprostinil (PO)	Placebo	6MWD	3
FREEDOM-C2,^Citation15 2013	157	153	51	77.7	IPAH/FPAH (65), APAH (35)	16	Treprostinil (PO)	Placebo	6MWD	3
FREEDOM-M,^Citation16 2013	233	116	41	75.1	IPAH/FPAH (74), APAH (26)	12	Treprostinil (PO)	Placebo	6MWD	3
COMBI,^Citation17 2006	19	21	52	77.5	IPAH (100)	12	Iloprost (INH) + bosentan (PO)	Bosentan (PO)	6MWD	3
McLaughlin et al,^Citation18 2003	17	9	37	81	IPAH (100)	8	Treprostinil (SC)	Placebo	6MWD	2
STEP,^Citation19 2006	34	33	50	79	IPAH (55), APAH (45)	12	Iloprost (INH) + bosentan (PO)	Bosentan (PO)	6MWD	4
PATENT-1,^Citation20 2013	254	126	51	79	IPAH (61), FPAH (2), APAH (37)	12	Riociguat (PO)	Placebo	6MWD	3
PATENT-1,^Citation20 2013	63	126	51	79	IPAH (61), FPAH (2), APAH (37)	12	Riociguat (PO)	Placebo	6MWD	3
PHIRST-1,^Citation21 2011	45	45	51	79	IPAH (62), APAH (38)	16	Tadalafil (PO) + bosentan (PO)	Bosentan (PO)	6MWD	3
PHIRST-1,^Citation21 2011	42	45	51	78	IPAH (61), APAH (39)	16	Tadalafil (PO) + bosentan (PO)	Bosentan (PO)	6MWD	3
PHIRST-1,^Citation21 2011	37	37	58	76	IPAH (64), APAH (36)	16	Tadalafil (PO)	Placebo	6MWD	3
PHIRST-1,^Citation21 2011	37	37	57	76	IPAH (64), APAH (36)	16	Tadalafil (PO)	Placebo	6MWD	3
SERAPH,^Citation22 2005	14	12	43	81	IPAH (88), APAH (12)	16	Sildenafil (PO)	Bosentan (PO)	RVM	4
SERAPHIN,^Citation23 2013	250	250	46	75	IPAH (55), FPAH (2), APAH (43)	115	Macitentan (PO)	Placebo	TTCW	3
SERAPHIN,^Citation23 2013	242	250	46	77	IPAH (53), FPAH (1), APAH (46)	115	Macitentan (PO)	Placebo	TTCW	3
SIMONNEAU,^Citation24 2002	233	236	44	81	IPAH (58), APAH (42)	12	Treprostinil (SC)	Placebo	6MWD	4
PACES,^Citation25 2008	133	134	48	80	IPAH (79), APAH (21)	16	Sildenafil (PO) + epoprostenol (IV)	Epoprostenol (IV)	6MWD	4
SUPER,^Citation26 2005	69	70	48	76	IPAH (62), APAH (38)	12	Sildenafil (PO)	Placebo	6MWD	4
SUPER,^Citation26 2005	67	70	50	76	IPAH (62), APAH (38)	12	Sildenafil (PO)	Placebo	6MWD	4
SUPER,^Citation26 2005	71	70	48	80	IPAH (63), APAH (37)	12	Sildenafil (PO)	Placebo	6MWD	4
TRIUMPH,^Citation27 2010	115	120	53	81	IPAH/FPAH (56), APAH (44)	12	Treprostinil (INH)	Placebo	6MWD	3
TRUST,^Citation28 2010	30	14	32	61	IPAH/FPAH (95), APAH (5)	12	Treprostinil (IV)	Placebo	6MWD	3
AMBITION,^Citation29 2015	253	126	54	76	IPAH (53), FPAH (3), APAH (44)	24	Ambrisentan (PO) + tadalafil (PO)	Ambrisentan (PO)	Clinical failure	4
AMBITION,^Citation29 2015	253	121	55	77	IPAH (52), FPAH (3), APAH (45)	24	Ambrisentan (PO) + tadalafil (PO)	Tadalafil (PO)	Clinical failure	4
Zhuang et al,^Citation30 2014	60	64	51	79	IPAH (63), APAH (37)	16	Tadalafil (PO) + ambrisentan (PO)	Ambrisentan (PO)	6MWD	3
PATENT PLUS,^Citation31 2015	12	6	59	67	IPAH (50), APAH (50)	12	Riociguat (PO) + sildenafil (PO)	Sildenafil (PO)	Supine SBP	4
COMPASS-2,^Citation32 2015	159	175	54	76	IPAH (64), FPAH (2), APAH (34)	16	Bosentan (PO) + sildenafil (PO)	Sildenafil (PO)	TTCW	3

Abbreviations: 6MWD, 6-minute walk distance; APAH, acquired pulmonary arterial hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; FPAH, familial pulmonary arterial hypertension; INH, inhaled; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; PO, per os [orally]; SC, subcutaneous; TTCW, time to clinical worsening.

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