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Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis

Tyler Pitre, Johnny Su, Sonya Cui, Ryan Scanlan, Christopher Chiang, Renata Husnudinov, Muhammad Faran Khalid, Nadia Khan, Gareth Leung, David Mikhail, Pakeezah Saadat, Shaneela Shahid, Jasmine Mah, Lisa Mielniczuk, Dena Zeraatkar, Sanjay Mehta
European Respiratory Review 2022 31: 220036; DOI: 10.1183/16000617.0036-2022
Tyler Pitre
1Division of Internal Medicine, McMaster University, Hamilton, ON, Canada
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Johnny Su
1Division of Internal Medicine, McMaster University, Hamilton, ON, Canada
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Sonya Cui
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Ryan Scanlan
1Division of Internal Medicine, McMaster University, Hamilton, ON, Canada
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Christopher Chiang
1Division of Internal Medicine, McMaster University, Hamilton, ON, Canada
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Renata Husnudinov
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Muhammad Faran Khalid
2Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
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Nadia Khan
3Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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Gareth Leung
4Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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David Mikhail
5Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
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Pakeezah Saadat
6Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
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Shaneela Shahid
7Health Research Methods Evidence and Impact, McMaster University, Hamilton, ON, Canada
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Jasmine Mah
8Dept of Medicine, Dalhousie University, Halifax, NS, Canada
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Lisa Mielniczuk
9University of Ottawa Heart Institute, Ottawa, ON, Canada
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Dena Zeraatkar
7Health Research Methods Evidence and Impact, McMaster University, Hamilton, ON, Canada
10Harvard Medical School, Harvard University, Boston, MA, USA
13D. Zeraatkar and S. Mehta contributed equally to this article as senior authors and supervised the work
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Sanjay Mehta
11Southwest Ontario PH Clinic, Division of Respirology, Dept of Medicine, Lawson Health Research Institute, London Health Sciences Centre, Schulich School of Medicine, Western University, London, ON, Canada
12PHA Canada, Vancouver, BC, Canada
13D. Zeraatkar and S. Mehta contributed equally to this article as senior authors and supervised the work
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  • FIGURE 1
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    FIGURE 1

    Preferred Reporting Items for Systematic Review and Meta-Analysis flow diagram for inclusion of randomised controlled trials. #: Cochrane Central Register of Controlled Trials.

  • FIGURE 2
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    FIGURE 2

    Network diagram for risk of clinical worsening in randomised controlled trials of pulmonary arterial hypertension treatments. Each node represents a drug or drug combination that has been tested in trials; the size of the nodes is proportional to the number of patients that have received that drug or drug combination; and the thickness of the connecting lines is proportional to the number of trials. PDE5i: phosphodiesterase-5 inhibitor; ERA: endothelin receptor antagonist; inh: inhalation; i.v.: intravenous; s.c.: subcutaneous; PRA: prostacyclin receptor agonist.

  • FIGURE 3
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    FIGURE 3

    Forest plot for dichotomous outcomes. The vertical line indicates any effect. Figure 4 presents data in absolute effects with minimally important difference thresholds and Grades of Recommendation, Assessment, Development, and Evaluation ratings. ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor; PRA: prostacyclin receptor agonist; inh: inhalation; i.v.: intravenous.

  • FIGURE 4
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    FIGURE 4

    Network estimates of the effects of pulmonary arterial hypertension medications versus placebo on clinical and haemodynamic outcomes, presented in absolute risk difference per 1000 patients (95% CI); negative values indicate fewer events and positive values indicate more events per 1000. Colour arrangement reflects certainty of evidence. All estimates are network estimates unless otherwise specified. Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) working group grades of evidence are as follows. Interpretation: each node estimate is compared against placebo; the comparative effectiveness of a treatment on an outcome versus another treatment can be assessed by comparing respective cells; 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). 6MWD: 6-min walk distance; SAE: serious adverse events; ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor; PRA: prostacyclin receptor agonist; inh: inhalation; i.v.: intravenous; s.c.: subcutaneous; MID: minimally important difference. GRADE rating: #: imprecision; ¶: inconsistency; +: rate down three times for imprecision; §: rate down twice for imprecision; ƒ: risk of bias.

  • FIGURE 5
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    FIGURE 5

    Forest plot for 6-min walk distance. The solid line indicates any effect; figure 4 presents data in absolute effects with minimally important difference thresholds and Grades of Recommendation, Assessment, Development, and Evaluation ratings. ERA: endothelin receptor antagonist; PDE5i: phosphodiesterase-5 inhibitor; PRA: prostacyclin receptor agonist; inh: inhalation; i.v.: intravenous.

Tables

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  • TABLE 1

    Basic demographic and clinical characteristics of participants across trials of pulmonary arterial hypertension (PAH) treatments

    Randomised participants124 (45–267)
    Trials53
    Age (years)48.7 (44.6–51.1)
    Female (%)78.8 (75.1–81.4)
    6MWD (m)349 (333.4–372)
    NYHA/WHO functional class (%)
     I0 (0–0.4)
     II34 (9.2–50.7)
     III60.7 (51–74.1)
     IV1.2 (0–5)
    PAH aetiology
     Idiopathic/heritable5400 (51)
     CTD-associated2832 (26.5)
     HIV-associated80 (1)
     Other2358 (21.5)

    Data are presented as median (interquartile range), n or n (%). Full details of the included trials in the network meta-analysis are given in supplementary material S5 and S6. 6MWD: 6-min walk distance; NYHA: New York Heart Association; WHO: World Health Organization; CTD: connective tissue disease.

    Supplementary Materials

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      Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

      Supplementary material ERR-0036-2022.SUPPLEMENT

      Supplementary figure S1 ERR-0036-2022.supplement_figure_S1

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    Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis
    Tyler Pitre, Johnny Su, Sonya Cui, Ryan Scanlan, Christopher Chiang, Renata Husnudinov, Muhammad Faran Khalid, Nadia Khan, Gareth Leung, David Mikhail, Pakeezah Saadat, Shaneela Shahid, Jasmine Mah, Lisa Mielniczuk, Dena Zeraatkar, Sanjay Mehta
    European Respiratory Review Sep 2022, 31 (165) 220036; DOI: 10.1183/16000617.0036-2022

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    Medications for the treatment of pulmonary arterial hypertension: a systematic review and network meta-analysis
    Tyler Pitre, Johnny Su, Sonya Cui, Ryan Scanlan, Christopher Chiang, Renata Husnudinov, Muhammad Faran Khalid, Nadia Khan, Gareth Leung, David Mikhail, Pakeezah Saadat, Shaneela Shahid, Jasmine Mah, Lisa Mielniczuk, Dena Zeraatkar, Sanjay Mehta
    European Respiratory Review Sep 2022, 31 (165) 220036; DOI: 10.1183/16000617.0036-2022
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