Endothelin receptor antagonists for pulmonary arterial hypertension

Chao Liu; Junmin Chen

doi:10.1002/14651858.CD004434.pub2

Endothelin receptor antagonists for pulmonary arterial hypertension

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Referencias

References to studies included in this review

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estudios excluidos
estudios a la espera de valoración
otras referencias

Barst RJ, Langleben D, Frost E, Horn EM, Oudiz R, Shapiro S, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Amercian Journal of Respiratory and Critical Care Medicine 2004;169:441‐7.

Badesch DB, Bodin F, Channick FR. Effects of the dual endothelin‐receptor antagonist, in pulmonary hypertension. Current Therapeutic Research ‐ Clinical and Experimental 2002;63:227‐46.

Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF. Effects of the dual endothelin‐receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo‐controlled study. Lancet 2001;358(9288):1119‐23.

Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension. A 1‐year follow‐up study. Chest 2003;124(1):247‐54.

Galie, N. Hinderliter, A. L. Torbicki, A. Fourme, T. Simonneau, G. Pulido, T, et al. Effects of the oral endothelin‐receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension. Journal of the American College of Cardiology 2003;41(8):1380‐6.

Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A. Bosentan therapy for pulmonary arterial hypertension. The New England Journal of Medicine 2002;346(12):896‐03.

References to studies excluded from this review

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estudios incluidos
estudios a la espera de valoración
otras referencias

Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of sitaxsentan, an endothelin‐A receptor antagonist, in patients with pulmonary arterial hypertension: open‐label pilot study.[comment]. Chest 2002;121(6):1860‐8.

Barst RJ, Ivy D, Dingemanse J, Widlitz A, Schmitt K, Doran A, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clinical Pharmacology & Therapeutics 2003;73(4):372‐82.

Hoeper MM, Taha N, Bekjarova A, Gatzke R, Spiekerkoetter E. Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. European Respiratory Journal 2003;22(2):330‐4.

Krum H, Charlon V, Widmann T, Packer M. Long‐term, open‐label experience with an endothelin receptor antagonist, Bosentan, in patients with severe heart failure. Circulation 1999;100(Suppl. 1):1646.

Packer M. Effects of the endothelin receptor antagonist bosentan on the morbidity and mortality in patients with chronic heart failure: results of the Enable 1 and 2 trial program. American College of Cardiology 51 st Annual Scientific Session, Atlanta, GA. 2002.

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Williamson DJ, Wallman LL, Jones R, Keogh AM, Scroope F, Penny R, et al. Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation 2000;102(4):411‐8.

References to studies awaiting assessment

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estudios incluidos
estudios excluidos
otras referencias

Humbert M, Barst RJ, Robbins IM, Channick R, Manes A, Rubin LJ, et al. Safety & efficacy of bosentan combined with epoprostenol in patients with severe pulmonary arterial hypertension. American Thoracic Society 99th International Conference (http://www.abstracts2view.com) 2003.

Google Scholar

Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE‐2 Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE‐2.. European Respiratory Journal 2004;24(3):353‐9.

Additional references

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estudios excluidos
estudios a la espera de valoración

Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Annals of internal medicine 2000;132(6):425‐34.

Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. The New England Journal of Medicine 1996;334(5):296‐302.

D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Annals of Internal Medicine 1991;115:343‐9.

Filep JG, Fournier A, Foldes‐Filep E. Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ETA and ETB receptors. British journal of pharmacology 1995;115(2):227‐36.

Fuster V, Steele PM, Edwards ED, Gersh DJ, McGoon MD, Frye RL. Primary pulmonar hypertension: natural history and importance of thrombosis. Circulation 1984;70(4):580‐587.

Gater PR, Wasserman MA, Renzetti LM. Effects of Ro 47‐0203 on endothelin‐1 and sarafotoxin S6c‐induced contractions of human bronchus and guinea‐pig trachea. European journal of pharmacology 1996;304(1‐3):123‐8.

Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin‐1 in the lungs of patients with pulmonary hypertension. New England Journal of Medicine 1993;328:1732‐39.

Hasuda T, Satoh T, Shimouchi A, Sakamaki F, Kyotani S, Matsumoto T. Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension. Circulation 2000;101(17):2066‐70.

Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovascular research 1993;27:2125‐9.

Kim H, Yung GL, Marsh JJ, Konopka RG, Pedersen CA, Chiles PG, et al. Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase. Experimental Lung Research 2000;26(4):287‐301.

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Mansoor AM, Honda M, Saida K, Ishinaga Y, Kuramochi T, Maeda A, et al. Endothelin induced collagen remodeling in experimental pulmonary hypertension. Biochemical and Biophysical Research Communications 1995;215(3):981‐6.

Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, et al. Clinical correlates and prognostic significance of six‐minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. American journal of respiratory and critical care medicine 2000;161:487‐92.

Paramothayan NS, Lasserson TJ, Wells AU, Walters EH. Prostacyclin for pulmonary hypertension (Cochrane Review). The Cochrane Library 2003, (2).

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Reeves JT, Groves BM, Turkevich D. The case for treatment of selected patients with primary pulmonary hypertension. The American Review of Respiratory Disease 1986;134:342‐46.

Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium‐channel blockers on survival in primary pulmonary hypertension. The New England journal of medicine 1992;327(2):76‐81.

Rich S, editor. Primary Pulmonary Hypertension: executive summary from the World Symposium ‐ Primary Pulmonary Hypertension 1998. Evian, France: World Health Organization, 1998. http://www.who.int/ncd/cvd/pph.html.

Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP. Big endothelin‐1 and endothelin‐1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120 (5):1562‐9.

Rubin L. ACCP consensus statement: primary pulmonary hypertension. Chest 1987;104:236‐50.

Google Scholar

Sitbon O, Humbert M, Jagot JL, Taravella O, Fartoukh M, Parent F, Herve P, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium‐channel blockers in primary pulmonary hypertension. The European respiratory journal 1998;12:265‐70.

Wort SJ, Woods M, Warner TD, Evans TW, Mitchell JA. Endogenously released endothelin‐1 from human pulmonary artery smooth muscle promotes cellular proliferation: relevance to pathogenesis of pulmonary hypertension and vascular remodeling. American Journal of Respiratory Cell and Molecular Biology 2001;25:104‐10.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Barst 2004

Methods	Multi‐centre randomised placebo parallel double blind trial.Randomisation conducted centrally according to a computer‐generated random number table.Allocation concealment adequate.Blinding of treater, participants and assessors were all blinded.Dropout and withdraw were described. Intention to treat analysis was conducted. Study duration (12 weeks).
Participants	Total n = 178 (60 in placebo group; 118 in sitaxsentan group) enrolled. Total 166 completed (55 in placebo group; 111 in sitaxsentan group). Women (47 in placebo group; 94 in sitaxsentan group)Men (13 in placebo group; 17 in sitaxsentan group)Age (48+/14 in placebo group; 45+/‐14 in sitaxsentan 100 mg once daily group; 44+/‐12 in 300 mg sitaxsentan daily group)PPH (37 in placebo group, 57 in sitaxsentan group) PAH secondary to collagen vascular disease (9 in placebo group; 33 in sitaxsentan group)PAH secondary to congenital heart disease (14 in placebo group; 28 in sitaxsentan group)NYHA functional class II (22 in placebo group, 37 in sitaxsentan group)NYHA functional class III (36 in placebo group; 81 in sitaxsentan group)NYHA functional class IV (2 in placebo group, 0 in sitaxsentan group)
Interventions	Intervention group: 100 mg once daily or 300 mg once dailyControl group: placebo
Outcomes	Primary outcome: Peak oxygen consumption (Peak O2) Sedentary outcomes:Exercise capacity (six minute walk distance)NYHA functional class (I for no symptoms on exertion, IV for symptoms at rest)Pulmonary artery pressure (PAP)Cardiac index (CI)Pulmonary vascular resistance (PVR) Cardiac index was cardiac output (L/min) divided by body surface area.Pulmonary vascular resistance was calculated by (mean pulmonary artery pressure [mm Hg]‐ pulmonary capillary wedge pressure [mm Hg])/cardiac output (L/min)*80.
Notes	Data reported as mixed population, Specific data for PPH or PAH secondary to collagen vascular disease not available. Authors and Pharmaceutical company has been contacted, yet no detailed data obtained.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Barst 2004a

Methods	As above.
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Barst 2004b

Methods	As above.
Participants
Interventions
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Channick 2001

Methods	Multi‐centre randomised parallel trial comparing bosentan with placebo for 12 weeks. Randomisation conducted by computer using the Almedica Drug Labelling System. Allocation concealment adequate.Participants, treaters and outcome assessors were blinded.Dropout and withdraw were described. Intention to treat analysis was conducted. Study duration (12 weeks).
Participants	Total n = 32 enrolled (30 completed protocol; 21 in bosentan group; 11 in placebo group). Men (4 in bosentan group, 0 in placebo group)Women (11 in placebo group, 17 in bosentan group)Age (47.4+/‐14.0 in placebo group; 52.2+/‐12.2 in bosentan group)All patients were in WHO functional class III. PPH (10 in placebo group, 17 in bosentan group).PAH secondary to scleroderma (1 in placebo group, 4 in bosentan group)
Interventions	Intervention group: 62.5 mg bosentan twice daily for the first 4 weeks followed by the target dose (125 mg twice daily) unless drug related adverse events arose, or matching doses of placebo.Control group: placebo
Outcomes	The primary outcome:Exercise capacity (six‐min walk test) at week of 12 and was measured the distance a patient could walk in 6 minutes.Secondary outcomes:Cardiopulmonary haemodynamics (pulmonary vascular resistance, cardiac index, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and mean right atrial pressure)Cardiac index was cardiac output (L/min) divided by body surface area.Pulmonary vascular resistance was calculated by (mean pulmonary artery pressure [mm Hg]‐ pulmonary capillary wedge pressure [mm Hg])/cardiac output (L/min)*80.Borg dyspnoea index (0 for nothing at all; 10 for most difficult)WHO functional class (I for no symptoms on exertion, IV for symptoms at rest)
Notes	All patients (n = 32) were entered into the meta‐analysis. Specific data for PPH or PAH secondary to scleroderma were not available.The article just provided mean and standard error; and we converted standard error into standard deviation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Galiè 2003

Methods	Multi‐centre randomised placebo parallel triple arms trial comparing bosentan with placebo.Randomisation method not clear. Allocation concealment not clear. Blinding of participants, treaters and outcome assessors not clear. Dropout and withdraw were described. Intention to treat was performed.Study duration (16 weeks).
Participants	Total n = 85 enrolled (81 completed study; 26 in placebo group; 55 in bosentan group). Men (5 in placebo group; 8 in bosentan group)Women (24 in placebo group; 48 in bosentan group)Age (44.9 +/‐19.2 in placebo group; 45.1 +/‐ 16.2 in bosentan group)PAH secondary to scleroderma (4 in placebo group; 7 in bosentan group)Other (2 in placebo group; 1 in bosentan group)WHO functional class III (28 in placebo group; 49 in bosentan group)WHO functional class IV (1 in placebo group; 7 in bosentan group)
Interventions	Same as study carried out by Rubin 2002.
Outcomes	Cardiac index
Notes	Data are from Rubin 2002. The study reports data from 13/27 study centres who volunteered to participate in an echocardiography sub‐study. The article provided mean and standard error only; we converted standard error into standard deviation.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Rubin 2002

Methods	Multi‐centre randomised placebo parallel triple arms trial comparing bosentan with placebo.Randomisation method not clear. Allocation concealment not clear. Blinding of participants, treaters and outcome assessors not clear. Dropout and withdraw were described. Intention to treat was performed.Study duration (16 weeks).
Participants	Total n = 213 (69 in placebo group; 144 in bosentan group)Man (15 in placebo group, 30 in bosentan group)Women (54 in placebo group; 114 in bosentan group)Age (47.2+/‐16.2 in placebo group; 48.7+/‐15.8 in bosentan group)PPH (48 in placebo group; 102 in bosentan group)PAH secondary to collagen vascular disease (21 in placebo group; 42 in bosentan group)WHO functional class III (65 in placebo group; 130 in bosentan group) WHO functional class IV (4 in placebo group; 14 in bosentan group)
Interventions	Intervention group: 62.5 mg bosentan twice daily for the first 4 weeks followed by the target dose (125 mg or 250 mg twice daily) for 12 weeks.Control group: placebo
Outcomes	Primary outcomes:Exercise capacity by week of 16 measured by six‐min walk testThe secondary outcome: Borg dyspnoea index;WHO functional class
Notes	The article just provided mean and standard error; and we converted standard error into standard deviation. All patients (n = 213) were entered into the meta‐analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos

Study	Reason for exclusion
Barst 2002	Not a RCT.
Barst 2003b	Not a RCT.
Hoeper 2003	Non‐randomised assessment of the additive effects of ERAs to prostacyclin
Krum 1999	Trial participants had heart failure; not a RCT.
Packer 2002	Trial participants had heart failure.
Williamson 2000	Not a RCT.

Data and analyses

Open in table viewer

Comparison 1. Endothelin receptor antagonists versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Six minute walk Show forest plot	2		Metres (Fixed, 95% CI)	46.24 [23.96, 68.53]
Open in figure viewer Analysis 1.1 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 1 Six minute walk.
2 Number of patients who improved their classification (WHO or NYHA functional class) Show forest plot	3	423	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [1.17, 2.32]
Open in figure viewer Analysis 1.2 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 2 Number of patients who improved their classification (WHO or NYHA functional class).
2.1 Nonselective ERAs	2	245	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [1.02, 2.26]
2.2 Selective ERAs	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	1.98 [1.02, 3.84]
3 Symptoms Show forest plot	2		Borg dyspnoea score (Random, 95% CI)	‐0.83 [‐1.65, ‐0.01]
Open in figure viewer Analysis 1.3 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 3 Symptoms.
4 Mortality Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 4 Mortality.
5 Pulmonary artery pressure (change from baseline) Show forest plot	3	208	Mean Difference (IV, Fixed, 95% CI)	‐4.36 [‐6.77, ‐1.94]
Open in figure viewer Analysis 1.5 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 5 Pulmonary artery pressure (change from baseline).
5.1 Nonselective ERAs	1	30	Mean Difference (IV, Fixed, 95% CI)	‐6.70 [‐12.67, ‐0.73]
5.2 Selective ERAs	2	178	Mean Difference (IV, Fixed, 95% CI)	‐3.90 [‐6.54, ‐1.25]
6 Pulmonary vascular resistance (change from baseline) Show forest plot	3	208	Mean Difference (IV, Fixed, 95% CI)	‐286.73 [‐369.10, ‐204.36]
Open in figure viewer Analysis 1.6 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 6 Pulmonary vascular resistance (change from baseline).
6.1 Nonselective ERAs	1	30	Mean Difference (IV, Fixed, 95% CI)	‐414.0 [‐595.77, ‐232.23]
6.2 Selective ERAs	2	178	Mean Difference (IV, Fixed, 95% CI)	‐253.84 [‐346.24, ‐161.44]
7 Cardiac Index (change from baseline) Show forest plot	4	289	Mean Difference (IV, Random, 95% CI)	0.51 [0.22, 0.81]
Open in figure viewer Analysis 1.7 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 7 Cardiac Index (change from baseline).
7.1 Nonselective ERAs	2	111	Mean Difference (IV, Random, 95% CI)	0.68 [0.06, 1.30]
7.2 Selective ERAs	2	178	Mean Difference (IV, Random, 95% CI)	0.35 [0.18, 0.52]
8 Hepatic toxicity Show forest plot	3	422	Odds Ratio (M‐H, Random, 95% CI)	1.62 [0.57, 4.55]
Open in figure viewer Analysis 1.8 Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 8 Hepatic toxicity.
8.1 Nonselective ERAs	2	245	Odds Ratio (M‐H, Random, 95% CI)	1.45 [0.22, 9.71]
8.2 Selective ERAs	1	177	Odds Ratio (M‐H, Random, 95% CI)	1.53 [0.30, 7.81]

Analysis 1.1

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 1 Six minute walk.

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Analysis 1.2

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 2 Number of patients who improved their classification (WHO or NYHA functional class).

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Analysis 1.3

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 3 Symptoms.

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Analysis 1.4

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 4 Mortality.

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Analysis 1.5

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 5 Pulmonary artery pressure (change from baseline).

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Analysis 1.6

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 6 Pulmonary vascular resistance (change from baseline).

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Analysis 1.7

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 7 Cardiac Index (change from baseline).

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Analysis 1.8

Comparison 1 Endothelin receptor antagonists versus placebo, Outcome 8 Hepatic toxicity.

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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 Six minute walk Show forest plot	2		Metres (Fixed, 95% CI)	46.24 [23.96, 68.53]

2 Number of patients who improved their classification (WHO or NYHA functional class) Show forest plot	3	423	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [1.17, 2.32]

2.1 Nonselective ERAs	2	245	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [1.02, 2.26]
2.2 Selective ERAs	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	1.98 [1.02, 3.84]
3 Symptoms Show forest plot	2		Borg dyspnoea score (Random, 95% CI)	‐0.83 [‐1.65, ‐0.01]

4 Mortality Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Pulmonary artery pressure (change from baseline) Show forest plot	3	208	Mean Difference (IV, Fixed, 95% CI)	‐4.36 [‐6.77, ‐1.94]

5.1 Nonselective ERAs	1	30	Mean Difference (IV, Fixed, 95% CI)	‐6.70 [‐12.67, ‐0.73]
5.2 Selective ERAs	2	178	Mean Difference (IV, Fixed, 95% CI)	‐3.90 [‐6.54, ‐1.25]
6 Pulmonary vascular resistance (change from baseline) Show forest plot	3	208	Mean Difference (IV, Fixed, 95% CI)	‐286.73 [‐369.10, ‐204.36]

6.1 Nonselective ERAs	1	30	Mean Difference (IV, Fixed, 95% CI)	‐414.0 [‐595.77, ‐232.23]
6.2 Selective ERAs	2	178	Mean Difference (IV, Fixed, 95% CI)	‐253.84 [‐346.24, ‐161.44]
7 Cardiac Index (change from baseline) Show forest plot	4	289	Mean Difference (IV, Random, 95% CI)	0.51 [0.22, 0.81]

7.1 Nonselective ERAs	2	111	Mean Difference (IV, Random, 95% CI)	0.68 [0.06, 1.30]
7.2 Selective ERAs	2	178	Mean Difference (IV, Random, 95% CI)	0.35 [0.18, 0.52]
8 Hepatic toxicity Show forest plot	3	422	Odds Ratio (M‐H, Random, 95% CI)	1.62 [0.57, 4.55]

8.1 Nonselective ERAs	2	245	Odds Ratio (M‐H, Random, 95% CI)	1.45 [0.22, 9.71]
8.2 Selective ERAs	1	177	Odds Ratio (M‐H, Random, 95% CI)	1.53 [0.30, 7.81]

Comparison 1. Endothelin receptor antagonists versus placebo

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Referencias

References to studies included in this review

Barst 2004 {unpublished data only}

Barst 2004a {published data only}

Barst 2004b {published data only}

Channick 2001 {published data only}

Galiè 2003 {published data only}

Rubin 2002 {published data only}

References to studies excluded from this review

Barst 2002 {published data only}

Barst 2003b {published data only}

Hoeper 2003 {published data only}

Krum 1999 {published data only}

Packer 2002 {published data only}

Williamson 2000 {published data only}

References to studies awaiting assessment

Humbert 2004 {published data only}

Additional references

Badesch 2000

Barst 1996

D'Alonzo 1991

Filep 1995

Fuster 1984

Gater 1996

Giaid 1993

Hasuda 2000

Katwa 1993

Kim 2000

Mansoor 1995

Miyamoto 2000

Paramothayan 2003

Reeves 1986

Rich 1992

Rich 1998

Rubens 2001

Rubin 1987

Sitbon 1998

Wort 2001

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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