Prostacyclin drugs for pulmonary arterial hypertension: a systematic review and meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 ZHAO Honglin ¹ , HUI Xu ² , LU Zhenxing ³ , ZHOU Biao ³ , LIANG Fuxiang ¹ , YAO Liang ⁴

1. Department of Cardiovascular Surgery, the First Hospital of Lanzhou University, Lanzhou, 730000, P.R.China;
2. School of Public Health, Lanzhou University, Lanzhou, 730000, P.R.China;
3. School of the First Clinical Medical College, Lanzhou University, Lanzhou, 730000, P.R.China;
4. Chinese Medicine Faculty of HongKong Baptist University, HongKong, 999077, P.R.China;

Corresponding author：

ZHAO Honglin, Email: ebm2018@sina.com

Keywords：

Prostacyclin; Pulmonary arterial hypertension; Systematic review; Meta-analysis; RCT

DOI：

10.7507/1672-2531.201807086

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ObjectiveTo systematically review the efficacy and safety of prostacyclin for patients with pulmonary arterial hypertension (PAH).MethodsWe searched PubMed, EMbase, The Cochrane Library, WanFang Data, CBM and CNKI databases for randomized controlled trials (RCTs) compared prostacyclin with placebo from inception to April 2018. Two reviewers independently screened literature, extracted the data and assessed the risk of bias of included studies. Then meta-analysis was performed using RevMan 5.3 software.ResultsEleven RCTs including 2 549 participants were included. The results of meta-analysis showed that, compared with placebo group, prostacyclin group was superior to the placebo group in 6-min walk distance (MD=31.10, 95%CI 16.89 to 45.30, P<0.001), mortality (RR=0.62, 95%CI 0.41 to 0.94,P=0.03), Brog score (MD=–0.88, 95%CI –1.28 to –0.49, P<0.001), mean pulmonary arterial pressure (MD=–3.31, 95%CI –4.34 to –2.29,P<0.001) and cardiac index (MD=0.32, 95%CI 0.14 to 0.51,P<0.001). However, there were no differences between two groups in reducing delaying time to clinical deterioration (RR=1.27, 95%CI 0.99 to 1.63,P=0.06), tolerability (RR=0.74, 95%CI 0.42 to 1.31, P=0.30) and pulmonary vascular resistance (MD=–4.35, 95%CI –8.85 to 0.15, P=0.06).ConclusionsCurrent evidence reveals that prostacyclin therapy appears to be superior to the placebo in reducing the mortality, improving excise capacity, respiratory and cardiac function, and ameliorating mean pulmonary arterial pressure for pulmonary arterial hypertension. However, the efficacy of prostacyclin in delaying time to clinical deterioration, tolerability and pulmonary vascular resistance for PAH is not clear. Due to the limited quality and quantity of included studies, more high quality RCTs are required for further verification.

Citation： ZHAO Honglin, HUI Xu, LU Zhenxing, ZHOU Biao, LIANG Fuxiang, YAO Liang. Prostacyclin drugs for pulmonary arterial hypertension: a systematic review and meta-analysis. Chinese Journal of Evidence-Based Medicine, 2018, 18(11): 1257-1266. doi: 10.7507/1672-2531.201807086 Copy

1.	Weatherald J, Boucly A, Chemla D, et al. Prognostic value of follow-up hemodynamic variables after initial management in pulmonary arterial hypertension. Circulation, 2018, 137(7): 693.
2.	Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertensionthe joint 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: Association for european paediatric and congenital cardiology (aepc), international society for heart and lung transplantation (ishlt). Eur Heart J, 2016, 37(1): 67-119.
3.	Lau EMT, Tamura Y, McGoon MD, et al. The 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: A practical chronicle of progress. Eur Respir J, 2015, 46(4): 879-882.
4.	Hoeper MM, McLaughlin VV, Dalaan AMA, et al. Treatment of pulmonary hypertension. Lancet Respir Med, 2016, 4(4): 323-336.
5.	Dodson MW, Brown LM, Elliott CG. Pulmonary arterial hypertension. Heart Fail Clin, 2018, 14(3): 255-269.
6.	Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: A reappraisal of the nih risk stratification equation. Eur Respir J, 2010, 35(5): 1079.
7.	刘嫄, 胡欣, 史爱欣. 肺动脉高压新型靶向治疗药物的临床研究进展. 中国药房, 2017, 28(32): 4589-4592.
8.	Coghlan JG, Channick R, Chin K, et al. Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: Insights from the randomized controlled griphon study. Am J Cardiovasc Drugs, 2018, 18(1): 37-47.
9.	Galiè N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med, 2003, 2(2): 123-137.
10.	何建国, 黄丽. 肺动脉高压靶向药物治疗进展. 中国循环杂志, 2017, 32(12): 1145-1148.
11.	Ruan CH, Dixon RAF, Willerson JT, et al. Prostacyclin therapy for pulmonary arterial hypertension. Tex Heart Inst J, 2010, 37(4): 391-399.
12.	Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med, 2000, 132(6): 425-434.
13.	Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol, 2003, 41(12): 2119-2125.
14.	Galiè N, Humbert M, Vachiéry JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol, 2002, 39(9): 1496-1502.
15.	Hiremath J, Thanikachalam S, Parikh K, et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant, 2010, 29(2): 137-149.
16.	Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation, 2013, 127(5): 624-633.
17.	McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol, 2003, 41(2): 293-299.
18.	Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med, 2002, (5): 322-329.
19.	Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med, 1990, 112(7): 485-491.
20.	Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med, 2002, 165(6): 800-804.
21.	Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J, 2012, 40(4): 874-880.
22.	Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med, 2015, 373(26): 2522-2533.
23.	The Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Available at://www.cochrane.org/.
24.	Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: chest guideline and expert panel report. Chest, 2014, 146(2): 449-475.
25.	Lin H, Wang M, Yu Y, et al. Efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension: a network meta-analysis. Pulm Pharmacol Ther, 2018, 50: 1-10.
26.	Zhang H, Li X, Huang J, et al. Comparative efficacy and safety of prostacyclin analogs for pulmonary arterial hypertension: a network meta-analysis. Medicine (Baltimore), 2016, 95(4): e2575.
27.	Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation, 2012, 126(3): 349-356.
28.	Paramothayan NS, Lasserson Toby J, Wells A, et al. Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev, 2005, (2): CD002994.
29.	Li T, Chen Y, Zang W, et al. Prostacyclin and its analogues in pulmonary artery hypertension: a meta-analysis. Curr Med Res Opin, 2013, 29(8): 889-899.
30.	Zheng Y, Yang T, Chen G, et al. Prostanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomes. Eur J Clin Pharmacol, 2014, 70(1): 13-21.
31.	Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med, 2013, 369(9): 809-818.
32.	Coeytaux RR, Schmit KM, Kraft BD, et al. Comparative effectiveness and safety of drug therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Chest, 2014, 145(5): 1055-1063.
33.	He B, Zhang F, Li X, et al. Meta-analysis of randomized controlled trials on treatment of pulmonary arterial hypertension. Circ J, 2010, 74(7): 1458-1464.

1. Weatherald J, Boucly A, Chemla D, et al. Prognostic value of follow-up hemodynamic variables after initial management in pulmonary arterial hypertension. Circulation, 2018, 137(7): 693.
2. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertensionthe joint 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: Association for european paediatric and congenital cardiology (aepc), international society for heart and lung transplantation (ishlt). Eur Heart J, 2016, 37(1): 67-119.
3. Lau EMT, Tamura Y, McGoon MD, et al. The 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: A practical chronicle of progress. Eur Respir J, 2015, 46(4): 879-882.
4. Hoeper MM, McLaughlin VV, Dalaan AMA, et al. Treatment of pulmonary hypertension. Lancet Respir Med, 2016, 4(4): 323-336.
5. Dodson MW, Brown LM, Elliott CG. Pulmonary arterial hypertension. Heart Fail Clin, 2018, 14(3): 255-269.
6. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: A reappraisal of the nih risk stratification equation. Eur Respir J, 2010, 35(5): 1079.
7. 刘嫄, 胡欣, 史爱欣. 肺动脉高压新型靶向治疗药物的临床研究进展. 中国药房, 2017, 28(32): 4589-4592.
8. Coghlan JG, Channick R, Chin K, et al. Targeting the prostacyclin pathway with selexipag in patients with pulmonary arterial hypertension receiving double combination therapy: Insights from the randomized controlled griphon study. Am J Cardiovasc Drugs, 2018, 18(1): 37-47.
9. Galiè N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med, 2003, 2(2): 123-137.
10. 何建国, 黄丽. 肺动脉高压靶向药物治疗进展. 中国循环杂志, 2017, 32(12): 1145-1148.
11. Ruan CH, Dixon RAF, Willerson JT, et al. Prostacyclin therapy for pulmonary arterial hypertension. Tex Heart Inst J, 2010, 37(4): 391-399.
12. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med, 2000, 132(6): 425-434.
13. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol, 2003, 41(12): 2119-2125.
14. Galiè N, Humbert M, Vachiéry JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol, 2002, 39(9): 1496-1502.
15. Hiremath J, Thanikachalam S, Parikh K, et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant, 2010, 29(2): 137-149.
16. Jing ZC, Parikh K, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation, 2013, 127(5): 624-633.
17. McLaughlin VV, Gaine SP, Barst RJ, et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol, 2003, 41(2): 293-299.
18. Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med, 2002, (5): 322-329.
19. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med, 1990, 112(7): 485-491.
20. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med, 2002, 165(6): 800-804.
21. Simonneau G, Torbicki A, Hoeper MM, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J, 2012, 40(4): 874-880.
22. Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med, 2015, 373(26): 2522-2533.
23. The Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions. Available at://www.cochrane.org/.
24. Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: chest guideline and expert panel report. Chest, 2014, 146(2): 449-475.
25. Lin H, Wang M, Yu Y, et al. Efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension: a network meta-analysis. Pulm Pharmacol Ther, 2018, 50: 1-10.
26. Zhang H, Li X, Huang J, et al. Comparative efficacy and safety of prostacyclin analogs for pulmonary arterial hypertension: a network meta-analysis. Medicine (Baltimore), 2016, 95(4): e2575.
27. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation, 2012, 126(3): 349-356.
28. Paramothayan NS, Lasserson Toby J, Wells A, et al. Prostacyclin for pulmonary hypertension in adults. Cochrane Database Syst Rev, 2005, (2): CD002994.
29. Li T, Chen Y, Zang W, et al. Prostacyclin and its analogues in pulmonary artery hypertension: a meta-analysis. Curr Med Res Opin, 2013, 29(8): 889-899.
30. Zheng Y, Yang T, Chen G, et al. Prostanoid therapy for pulmonary arterial hypertension: a meta-analysis of survival outcomes. Eur J Clin Pharmacol, 2014, 70(1): 13-21.
31. Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med, 2013, 369(9): 809-818.
32. Coeytaux RR, Schmit KM, Kraft BD, et al. Comparative effectiveness and safety of drug therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Chest, 2014, 145(5): 1055-1063.
33. He B, Zhang F, Li X, et al. Meta-analysis of randomized controlled trials on treatment of pulmonary arterial hypertension. Circ J, 2010, 74(7): 1458-1464.

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