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Original Research: Pulmonary Vascular Disease |

Comparative Effectiveness of Pharmacologic Interventions for Pulmonary Arterial Hypertension: A Systematic Review and Network Meta-Analysis

Snigdha Jain, MD; Rohan Khera, MD; Saket Girotra, MD, SM; David Badesch, MD; Zhen Wang, PhD; Mohammad Hassan Murad, MD; Amy Blevins, MALS; Gregory A. Schmidt, MD; Siddharth Singh, MD; Alicia K. Gerke, MD
Author and Funding Information

Drs Jain and Khera contributed equally as co-first authors.

FUNDING/SUPPORT: A. K. G. and S. G. are supported by career development awards from the National Heart, Lung, and Blood Institute [grants K23HL114640 and K08HL122527]. S. S. is supported by the National Library of Medicine/National Institute of Health [training grant T15LM011271]. R. K. received support from the National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001105]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

aDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX

bDivision of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX

cDivision of Cardiology, University of Iowa Carver College of Medicine, Iowa City, IA

dHardin Library for the Health Sciences, University of Iowa Carver College of Medicine, Iowa City, IA

eDivision of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Carver College of Medicine, Iowa City, IA

fDivision of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO

gKnowledge and Evaluation Research Unit and the Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN

hDivision of Biomedical Informatics, Department of Internal Medicine, University of California San Diego, La Jolla, CA

CORRESPONDENCE TO: Snigdha Jain, MD, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(1):90-105. doi:10.1016/j.chest.2016.08.1461
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Background  We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH).

Methods  MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016). Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected.

Results  Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA + PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA + PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo.

Conclusions  Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy.

Registration  PROSPERO CRD42016036803

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