Endothelin receptor antagonists for pulmonary arterial hypertension

Chao Liu; Junmin Chen; Yanqiu Gao; Bao Deng; Kunshen Liu

doi:10.1002/14651858.CD004434.pub6

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Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 1: Change from baseline in 6‐minute walk

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Analysis 1.2

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 2: Proportion of participants with improved functional class

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Analysis 1.3

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 3: Proportion of participants with deteriorated functional class

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Analysis 1.4

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 4: Change from baseline in Borg dyspnoea index

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Analysis 1.5

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 5: Mortality

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Analysis 1.6

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 6: Change from baseline in mean pulmonary artery pressure

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Analysis 1.7

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 7: Change from baseline in pulmonary vascular resistance

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Analysis 1.8

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 8: Pulmonary vascular resistance

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Analysis 1.9

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 9: Ratio of geometric mean PVR

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Analysis 1.10

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 10: Change from baseline in cardiac index

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Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO 2

Analysis 1.11

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 11: Change from baseline in SpO ₂

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Analysis 1.12

Comparison 1: Endothelin receptor antagonists versus placebo, Outcome 12: Hepatic toxicity

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Analysis 2.1

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 1: 6‐minute walk

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Analysis 2.2

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 2: Proportion of participants with improved functional class

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Analysis 2.3

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 3: Proportion of participants with deteriorated functional class

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Analysis 2.4

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 4: Symptoms

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Analysis 2.5

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 5: Mortality

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Analysis 2.6

Comparison 2: Endothelin receptor antagonists versus PDE5 inhibitor, Outcome 6: Cardiac index

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Analysis 3.1

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 1: Change from baseline in 6‐minute walk

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Analysis 3.2

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 2: Proportion of participants with improved functional class

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Analysis 3.3

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 3: Proportion of participants with deteriorated functional class

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Analysis 3.4

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 4: Mortality

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Analysis 3.5

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 5: Change from baseline in mean pulmonary arterial pressure

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Analysis 3.6

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 6: Change from baseline in pulmonary vascular resistance

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Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO 2

Analysis 3.7

Comparison 3: Endothelin receptor antagonists in Eisenmenger syndrome, Outcome 7: Change from baseline in SpO ₂

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Summary of findings 1. Endothelin receptor antagonists compared to placebo for pulmonary arterial hypertension

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Endothelin receptor antagonists compared to placebo for pulmonary arterial hypertension
Participant or population: pulmonary arterial hypertension Setting: clinics and hospitals Intervention: endothelin receptor antagonists Comparison: placebo
Outcomes	Risk with placebo	Risk with endothelin receptor antagonists	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Change from baseline in 6MWD (m) mean duration of study 16.3 weeks	The weighted mean change on control was −4.56 m.	MD 25.06 higher (17.13 higher to 32.99 higher)	‐	2739 (14 RCTs)	⊕⊕⊕⊝ Moderate¹	Higher is better for 6MWD.
Proportion of participants with improved functional class mean duration of study 16.8 weeks	175 per 1000	230 per 1000 (197 to 264)	OR 1.41 (1.16 to 1.70)	3060 (15 RCTs)	⊕⊕⊕⊝ Moderate¹	Participants with high OR are more likely to achieve functional improvement.
Change from baseline in BDI mean duration of study 14.3 weeks	The weighted mean change on control was 0.25 higher.	MD 0.43 lower (0.90 lower to 0.04 higher)	‐	788 (7 RCTs)	⊕⊕⊝⊝Low²	Symptoms are worse with higher score of BDI.
Mortality mean duration of study 30.2 weeks	73 per 1000	58 per 1000 (44 to 78)	OR 0.78 (0.58 to 1.07)	2889 (12 RCTs)	⊕⊕⊝⊝ Low³	Participants with lower OR are less likely to die.
Change from baseline in mean PAP (mmHg) mean duration of study 17.1 weeks	The weighted mean change on control was 0.53 higher.	MD 4.65 lower (6.05 lower to 3.26 lower)	‐	729 (8 RCTs)	⊕⊕⊕⊝ Moderate⁴	Participants are worse with higher pulmonary artery pressure.
Change from baseline in PVR (dyn/s/cm⁵) mean duration of study 15.7 weeks	The weighted mean change on control was 63.55 higher.	MD 236.24 lower (333.21 lower to 139.26 lower)	‐	586 (7 RCTs)	⊕⊕⊕⊝ Moderate⁴	Participants are worse with higher pulmonary vascular resistance.
Hepatic toxicity mean duration of study 25 weeks	37 per 1000	67 per 1000 (34 to 130)	OR 1.88 (0.91 to 3.90)	2250 (11 RCTs)	⊕⊕⊕⊝ Moderate¹	Participants with higher OR are more likely to suffer hepatic toxicity.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). 6MWD: 6‐minute walk distance; BDI: Borg dyspnoea index; CI: confidence interval; MD: mean difference; OR: odds ratio; PAP: pulmonary artery pressure; PVR: pulmonary vascular resistance; RCT: randomised controlled trial
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
¹Incomplete outcome data (attrition bias) due to missing data imbalanced between intervention and control groups in most of the included studies (−1 level). ²Attrition, publication bias and wide upper confidence interval (−2 levels). ³We downgraded the evidence for the outcome of mortality by 2 levels because the study period was relatively short and events in most of the studies few, and wide upper confidence interval of odds ratio. ⁴The pooled analysis used raw data from subgroups of the included studies.

Summary of findings 1. Endothelin receptor antagonists compared to placebo for pulmonary arterial hypertension

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Table 1. Main study characteristics across all studies

Study	N	Country	Intervention	Control	Outcomes
AMBITION	747	International	Ambrisentan + tadalafil or ambrisentan	Tadalafil + placebo	Primary outcome: time to the first event of clinical failure Secondary outcomes: change from baseline in NT‐proBNP level, 6MWD, WHO FC, and Borg dyspnoea index
ARIES‐1	201	International	Ambrisentan (5 mg/day or 10 mg/day)	Placebo	Primary outcome: change from baseline in 6MWD Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening, plasma BNP, and SF‐36 physical functioning scale
ARIES‐2	192	International	Ambrisentan (2.5 mg/day or 5 mg/day)	Placebo	Primary outcome: change from baseline in 6MWD Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening, plasma BNP, and SF‐36
BREATHE‐1	213	International	Bosentan	Placebo	Primary outcome: change from baseline in 6MWD Secondary outcomes: Borg dyspnoea index, WHO FC
BREATHE‐2	33	International	Bosentan	Placebo	Primary outcome: change from baseline to week 16 in TPR Secondary outcomes: change in cardiac index, PVR, mPAP, mRAP, 6MWD, NYHA FC and dyspnoea‐fatigue rating
BREATHE‐5	54	International	Bosentan	Placebo	Primary outcome: change from baseline in SpO₂ and PVR Secondary outcomes: change from baseline in 6MWD, WHO FC, cardiac index, PVR, mPAP, and mRAP
Channick 2001	32	International	Bosentan	Placebo	Primary outcome: change from baseline in 6MWD Secondary outcomes: cardiopulmonary haemodynamics (cardiac index, PVR, mPAP, mRAP), WHO FC
COMPASS‐2	334	International	Bosentan	Placebo	Primary outcome: time to the first morbidity/mortality event Secondary outcomes: change in 6MWD, WHO FC, time to the first occurrence of death from any cause, hospitalisation for PAH or start of intravenous prostanoid therapy, atrial septostomy, or lung transplant.
EARLY	185	International	Bosentan	Placebo	Primary outcomes: PVR and change from baseline in 6MWD Secondary outcomes: time to clinical worsening, change from baseline to month 6 in WHO FC, Borg dyspnoea index, mPAP, cardiac index, RAP, and SvO₂
EDITA	38	Germany	Ambrisentan	Placebo	Primary outcome: change in mPAP Secondary outcomes: change in WHO FC, change in cardiac index, change in PVR, symptoms of SSc, quality of life (SF‐36), lung function tests, right heart dimensions and function, NT‐proBNP, measures of disease‐related progression
MAESTRO	150	International	Macitentan	Placebo	Primary outcome: change from baseline in 6MWD Secondary outcomes: change from baseline in WHO FC and Borg dyspnoea index
PORTICO	85	International	Macitentan	Placebo	Primary outcome: change from baseline to PVR Secondary outcomes: change from baseline in RAP, mPAP, cardiac index, total pulmonary resistance, SvO₂, NT‐proBNP, 6MWD, and WHO FC
SERAPH	26	British	Bosentan	Sildenafil	Primary outcome: change in right ventricle mass from baseline Secondary outcomes: change from baseline in 6MWD, cardiac index, Borg dyspnoea index, quality of life, and plasma BNP level from baseline
SERAPHIN	742	International	Macitentan	Placebo	Primary outcome: time from the initiation of treatment to the first event related to pulmonary arterial hypertension Secondary outcomes: change from baseline in 6MWD, percentage of participants with an improvement in WHO FC, death due to PAH or hospitalisations for PAH, and death from any cause
STRIDE‐1	178	International	Sitaxsentan	Placebo	Primary outcome: peak oxygen consumption Secondary outcomes: change from baseline in 6MWD, NYHA FC, PAP, cardiac index, and PVR
STRIDE‐2	245	International	Sitaxsentan	Placebo	Primary outcome: change from baseline in 6MWD Secondary outcomes: change from baseline in WHO FC, Borg dyspnoea index and time to clinical worsening
STRIDE‐4	98	International	Sitaxsentan	Placebo	Primary efficacy endpoint was the change in 6MWD from baseline to week 18. Secondary outcomes: changes in WHO FC from baseline at each assessment and time to clinical worsening, Borg dyspnoea index
6MWD: 6‐minute walk distance; BNP: B‐type natriuretic peptide; mPAP: mean pulmonary artery pressure; mRAP: mean right atrial pressure; MVO₂: mixed venous oxygen saturation; NT‐proBNP: N‐terminal pro–brain natriuretic peptide; NYHA FC: New York Heart Association functional class; PAH: pulmonary arterial hypertension; PVR: pulmonary vascular resistance; SF‐36: 36‐item Short Form Health Survey; SpO₂: oxygen saturation; SSc: systemic sclerosis; SvO₂: mixed venous oxygen saturation; TPR: total pulmonary resistance; WHO FC: World Health Organization functional class

Table 1. Main study characteristics across all studies

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Table 2. Sensitivity analysis: including versus excluding combination therapy

Outcome	Including combination therapy	Excluding combination therapy
Change in 6MWD, mean with 95% CI	25.06 (17.13 to 32.99)	25.65 (16.80 to 34.49)
WHO/NYHA FC improvement, OR with 95% CI	1.41 (1.16 to 1.70)	1.52 (1.22 to 1.91)
Mortality, OR with 95% CI	0.78 (0.58 to 1.07)	0.82 (0.58 to 1.17)
6MWD: 6‐minute walk distance; CI: confidence interval; NYHA FC: New York Heart Association functional class; OR: odds ratio; WHO FC: World Health Organization functional class

Table 2. Sensitivity analysis: including versus excluding combination therapy

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Table 3. Sensitivity analysis: including versus excluding PAH participants associated with SSc, or CHD, or portal hypertension

Outcome	Including combination therapy	Excluding combination therapy
Change in 6MWD, mean with 95% CI	25.06 (17.13 to 32.99)	27.90 (20.96 to 34.83)
WHO/NYHA FC improvement, OR with 95% CI	1.41 (1.16 to 1.70)	1.46 (1.19 to 1.78)
Mortality, OR with 95% CI	0.78 (0.58 to 1.07)	0.77 (0.57 to 1.05)
6MWD: 6‐minute walk distance; CHD: congenital heart disease; CI: confidence interval; NYHA FC: New York Heart Association functional class; OR: odds ratio; PAH: pulmonary arterial hypertension; SSc: systemic sclerosis; WHO FC: World Health Organization functional class

Table 3. Sensitivity analysis: including versus excluding PAH participants associated with SSc, or CHD, or portal hypertension

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Comparison 1. Endothelin receptor antagonists versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Change from baseline in 6‐minute walk Show forest plot	14	2739	Mean Difference (IV, Random, 95% CI)	25.06 [17.13, 32.99]

1.1.1 Non‐selective ERA	8	1860	Mean Difference (IV, Random, 95% CI)	20.51 [10.03, 31.00]
1.1.2 Selective ERA	6	879	Mean Difference (IV, Random, 95% CI)	33.48 [23.12, 43.83]
1.2 Proportion of participants with improved functional class Show forest plot	15	3060	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [1.16, 1.70]

1.2.1 Non‐selective ERAs	9	1896	Odds Ratio (M‐H, Fixed, 95% CI)	1.45 [1.13, 1.87]
1.2.2 Selective ERAs	6	1164	Odds Ratio (M‐H, Fixed, 95% CI)	1.35 [1.01, 1.80]
1.3 Proportion of participants with deteriorated functional class Show forest plot	13	2347	Odds Ratio (M‐H, Random, 95% CI)	0.43 [0.26, 0.72]

1.3.1 Non‐selective ERA	7	1121	Odds Ratio (M‐H, Random, 95% CI)	0.65 [0.30, 1.42]
1.3.2 Selective ERAs	6	1226	Odds Ratio (M‐H, Random, 95% CI)	0.31 [0.17, 0.60]
1.4 Change from baseline in Borg dyspnoea index Show forest plot	7	788	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐0.90, 0.04]

1.4.1 Non‐selective ERAs	3	240	Mean Difference (IV, Random, 95% CI)	‐0.27 [‐1.58, 1.03]
1.4.2 Selective ERAs	4	548	Mean Difference (IV, Random, 95% CI)	‐0.43 [‐1.01, 0.14]
1.5 Mortality Show forest plot	12	2889	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.58, 1.07]

1.5.1 Non‐selective ERAs	7	1759	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.62, 1.23]
1.5.2 Selective ERAs	5	1130	Odds Ratio (M‐H, Fixed, 95% CI)	0.45 [0.21, 0.94]
1.6 Change from baseline in mean pulmonary artery pressure Show forest plot	8	729	Mean Difference (IV, Random, 95% CI)	‐4.65 [‐6.05, ‐3.26]

1.6.1 Non‐selective ERAs	6	519	Mean Difference (IV, Random, 95% CI)	‐5.79 [‐7.30, ‐4.27]
1.6.2 Selective ERAs	2	210	Mean Difference (IV, Random, 95% CI)	‐2.65 [‐5.31, 0.00]
1.7 Change from baseline in pulmonary vascular resistance Show forest plot	7	586	Mean Difference (IV, Random, 95% CI)	‐236.24 [‐333.21, ‐139.26]

1.7.1 Non‐selective ERAs	5	376	Mean Difference (IV, Random, 95% CI)	‐281.74 [‐395.85, ‐167.63]
1.7.2 Selective ERAs	2	210	Mean Difference (IV, Random, 95% CI)	‐173.73 [‐332.52, ‐14.94]
1.8 Pulmonary vascular resistance Show forest plot	2	175	Mean Difference (IV, Fixed, 95% CI)	‐288.59 [‐472.18, ‐104.99]

1.9 Ratio of geometric mean PVR Show forest plot	3		Ratio of Geometric mean (IV, Random, 95% CI)	Subtotals only

1.9.1 Selective ERAs	0		Ratio of Geometric mean (IV, Random, 95% CI)	Not estimable
1.9.2 Non‐selective ERAs	3		Ratio of Geometric mean (IV, Random, 95% CI)	0.69 [0.60, 0.80]
1.10 Change from baseline in cardiac index Show forest plot	7	718	Mean Difference (IV, Random, 95% CI)	0.50 [0.35, 0.65]

1.10.1 Non‐selective ERAs	5	509	Mean Difference (IV, Random, 95% CI)	0.55 [0.34, 0.77]
1.10.2 Selective ERAs	2	209	Mean Difference (IV, Random, 95% CI)	0.39 [0.23, 0.54]
1.11 Change from baseline in SpO ₂ Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

1.12 Hepatic toxicity Show forest plot	11	2250	Odds Ratio (M‐H, Random, 95% CI)	1.88 [0.91, 3.90]

1.12.1 Non‐selective ERAs	9	1888	Odds Ratio (M‐H, Random, 95% CI)	2.33 [0.98, 5.56]
1.12.2 Selective ERAs	2	362	Odds Ratio (M‐H, Random, 95% CI)	0.89 [0.31, 2.51]

Comparison 1. Endothelin receptor antagonists versus placebo

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Comparison 2. Endothelin receptor antagonists versus PDE5 inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 6‐minute walk Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.2 Proportion of participants with improved functional class Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.3 Proportion of participants with deteriorated functional class Show forest plot	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

2.4 Symptoms Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.5 Mortality Show forest plot	2	273	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.07, 1.36]

2.6 Cardiac index Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Endothelin receptor antagonists versus PDE5 inhibitor

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Comparison 3. Endothelin receptor antagonists in Eisenmenger syndrome

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Change from baseline in 6‐minute walk Show forest plot	2	280	Mean Difference (IV, Random, 95% CI)	21.49 [‐31.23, 74.21]

3.1.1 Non‐selective ERA	2	280	Mean Difference (IV, Random, 95% CI)	21.49 [‐31.23, 74.21]
3.1.2 Selective ERA	0	0	Mean Difference (IV, Random, 95% CI)	Not estimable
3.2 Proportion of participants with improved functional class Show forest plot	2	280	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.48, 1.90]

3.2.1 Non‐selective ERAs	2	280	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.48, 1.90]
3.2.2 Selective ERAs	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	Not estimable
3.3 Proportion of participants with deteriorated functional class Show forest plot	2	280	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.09, 4.85]

3.3.1 Non‐selective ERA	2	280	Odds Ratio (M‐H, Random, 95% CI)	0.67 [0.09, 4.85]
3.3.2 Selective ERAs	0	0	Odds Ratio (M‐H, Random, 95% CI)	Not estimable
3.4 Mortality Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.4.1 Non‐selective ERAs	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.4.2 Selective ERAs	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3.5 Change from baseline in mean pulmonary arterial pressure Show forest plot	2	90	Mean Difference (IV, Fixed, 95% CI)	‐4.63 [‐8.03, ‐1.23]

3.5.1 Non‐selective ERAs	2	90	Mean Difference (IV, Fixed, 95% CI)	‐4.63 [‐8.03, ‐1.23]
3.5.2 Selective ERAs	0	0	Mean Difference (IV, Fixed, 95% CI)	Not estimable
3.6 Change from baseline in pulmonary vascular resistance Show forest plot	2	93	Mean Difference (IV, Fixed, 95% CI)	‐480.07 [‐753.34, ‐206.79]

3.6.1 Non‐selective ERAs	2	93	Mean Difference (IV, Fixed, 95% CI)	‐480.07 [‐753.34, ‐206.79]
3.6.2 Selective ERAs	0	0	Mean Difference (IV, Fixed, 95% CI)	Not estimable
3.7 Change from baseline in SpO ₂ Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 3. Endothelin receptor antagonists in Eisenmenger syndrome

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