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Research Article
17 December 2019

Comparative effectiveness of pulmonary arterial hypertension drugs in treatment-naive patients: a network meta-analysis

Abstract

Aim: No network meta-analysis has been conducted to study efficacy of drug therapies specific for treatment of pulmonary arterial hypertension in treatment-naive patients only. Methods: Randomized controlled trials on pulmonary arterial hypertension-specific drug therapies were searched and a Bayesian network meta-analysis was performed. The 6-min walking distance (6MWD) and all-cause mortality were efficacy outcomes, whereas discontinuation due to adverse events was a safety-related outcome. Results: Analysis included 3.713 patients from 21 trials. Combination of ambrisentan and tadalafil showed the greatest impact on 6MWD, followed by epoprostenol and intravenous treprostinil (high dose). The latter two demonstrated marked effect size on mortality, although not statistically significant. Conclusion: According to 6MWD, ambrisentan/tadalafil combination was considered as most effective among all comparisons.
Prospero ID: CRD42019110832.

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References

Papers of special note have been highlighted as: • of interest; •• of considerable interest
1.
Galie N, Humbert M, Vachiery JL et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the 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. 37(1), 67–119 (2016).
•• Guidelines summarize and evaluate all available evidence on pulmonary hypertension, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with pulmonary hypertension. Guidelines represent the official position of the European Society of Cardiology.
2.
Benza RL, Miller DP, Gomberg-Maitland M et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 122(2), 164–172 (2010).
3.
Sitbon O, Channick R, Chin KM et al. Selexipag for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 373(26), 2522–2533 (2015).
4.
Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N. Engl. J. Med. 369(4), 330–340 (2013).
5.
Taichman DB, Ornelas J, Chung L et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest 146(2), 449–475 (2014).
•• The guideline was supported by American College of Chest Physicians and provides clinicians advice regarding pharmacology therapy for adult patients with pulmonary arterial hypertension (PAH) according to available evidence.
6.
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 145(5), 1055–1063 (2014).
7.
Duo-Ji MM, Long ZW. Comparative efficacy and acceptability of endothelin receptor antagonists for pulmonary arterial hypertension: a network meta-analysis. Int. J. Cardiol. 234, 90–98 (2017).
8.
Fox BD, Shtraichman O, Langleben D, Shimony A, Kramer MR. Combination therapy for pulmonary arterial hypertension: a systematic review and meta-analysis. Can. J. Cardiol. 32(12), 1520–1530 (2016).
9.
Gao XF, Zhang JJ, Jiang XM et al. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials. Patient Prefer. Adherence 11, 871–885 (2017).
10.
Jain S, Khera R, Girotra S et al. Comparative effectiveness of pharmacologic interventions for pulmonary arterial hypertension: a systematic review and network meta-analysis. Chest 151(1), 90–105 (2017).
• A recent and extensive network meta-analysis evaluating comparative efficacy and safety PAH-specific therapies in patients with PAH.
11.
Lajoie AC, Lauziere G, Lega JC et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. Lancet Respir. Med. 4(4), 291–305 (2016).
• Compares efficacy of combination of PAH-specific therapies with monotherapies using the Mantel–Haenszel method.
12.
Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] (2008). https://training.cochrane.org/handbook/archive/v5.1/
13.
Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat. Med. 23(20), 3105–3124 (2004).
• Addresses issues and assumptions underlying modeling of mixed treatment comparisons, and the role of Bayesian deviance analysis.
14.
Sutton A, Ades AE, Cooper N, Abrams K. Use of indirect and mixed treatment comparisons for technology assessment. Pharmacoeconomics 26(9), 753–767 (2008).
• Reviews pair-wise meta-analysis and indirect and mixed treatment comparison approaches to synthesis, clearly outlining the assumptions involved in each approach.
15.
Jonas DE, Wilkins TM, Bangdiwala S et al. Findings of Bayesian Mixed Treatment Comparison Meta-Analyses: Comparison and Exploration Using Real-World Trial Data and Simulation. MD, USA (2013). www.effectivehealthcare.ahrq.gov/reports/final.cfm
16.
Spiegelhalter DJ, Best NG, Carlin BP, Van Der Linde A. Bayesian measures of model complexity and fit. J. R. Stat. Soc. Series B Stat. Methodol. 64(4), 583–639 (2002).
17.
Jansen JP, Cope S. Meta-regression models to address heterogeneity and inconsistency in network meta-analysis of survival outcomes. BMC Med. Res. Methodol. 12, 152 (2012).
18.
Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat. Med. 29(7–8), 932–944 (2010).
19.
Galie N, Barbera JA, Frost AE et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N. Engl. J. Med. 373(9), 834–844 (2015).
20.
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 127(5), 624–633 (2013).
21.
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 Transpl. 29(2), 137–149 (2010).
22.
Galie N, Rubin L, Hoeper M et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371(9630), 2093–2100 (2008).
23.
Galie N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 119(22), 2894–2903 (2009).
24.
Galie N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117(23), 3010–3019 (2008).
25.
Galie N, Beghetti M, Gatzoulis MA et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 114(1), 48–54 (2006).
26.
Galie N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N. Engl. J. Med. 353(20), 2148–2157 (2005).
27.
Wilkins MR, Paul GA, Strange JW et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am. J. Respir. Crit. Care Med. 171(11), 1292–1297 (2005).
28.
Barst RJ, Mcgoon M, Mclaughlin V et al. Beraprost therapy for pulmonary arterial hypertension. J. Am. Coll. Cardiol. 41(12), 2119–2125 (2003).
29.
Mclaughlin VV, Gaine SP, Barst RJ et al. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J. Cardiovasc. Pharmacol. 41(2), 293–299 (2003).
30.
Galie N, Humbert M, Vachiery 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. 39(9), 1496–1502 (2002).
31.
Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N. Engl. J. Med. 346(12), 896–903 (2002).
32.
Olschewski H, Simonneau G, Galie N et al. Inhaled iloprost for severe pulmonary hypertension. N. Engl. J. Med. 347(5), 322–329 (2002).
33.
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. 165(6), 800–804 (2002).
34.
Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 358(9288), 1119–1123 (2001).
35.
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. 132(6), 425–434 (2000).
36.
Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med. 334(5), 296–301 (1996).
37.
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. 112(7), 485–491 (1990).
38.
Lin H, Wang M, Yu Y et al. Efficacy and tolerability of pharmacological interventions for pulmonary arterial hypertension: a network meta-analysis. Pulmon. Pharmacol. Ther. 50, 1–10 (2018).
39.
Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 186(5), 428–433 (2012).
40.
Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary arterial hypertension. Eur. Respir. Rev. 25(142), 408–417 (2016).
41.
Gaine S, Mclaughlin V. Pulmonary arterial hypertension: tailoring treatment to risk in the current era. Eur. Respir. Rev. 26(146), 170095 (2017).
42.
Savarese G, Paolillo S, Costanzo P et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension?: A meta-analysis of 22 randomized trials. J. Am. Coll. Cardiol. 60(13), 1192–1201 (2012).
43.
Tonelli AR, Arelli V, Minai OA et al. Causes and circumstances of death in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 188(3), 365–369 (2013).
44.
Rival G, Lacasse Y, Martin S, Bonnet S, Provencher S. Effect of pulmonary arterial hypertension-specific therapies on health-related quality of life: a systematic review. Chest 146(3), 686–708 (2014).
45.
Mclaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J. Am. Coll. Cardiol. 53(17), 1573–1619 (2009).
46.
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 126(3), 349–356 (2012).