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

Abstract

Background: There is no consensus on the most effective treatments of pulmonary arterial hypertension (PAH). Our objective was to compare effects of medications for PAH.

Methods: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrials.gov from inception to December 2021. We performed a frequentist random-effects network meta-analysis on all included trials. We rated the certainty of the evidence using the Grades of Recommendation, Assessment, Development, and Evaluation approach.

Results: We included 53 randomised controlled trials with 10 670 patients. Combination therapy with endothelin receptor antagonist (ERA) plus phosphodiesterase-5 inhibitors (PDE5i) reduced clinical worsening (120.7 fewer events per 1000, 95% CI 136.8-93.4 fewer; high certainty) and was superior to either ERA or PDE5i alone, both of which reduced clinical worsening, as did riociguat monotherapy (all high certainty). PDE5i (24.9 fewer deaths per 1000, 95% CI 35.2 fewer to 2.1 more); intravenous/subcutaneous prostanoids (18.3 fewer deaths per 1000, 95% CI 28.6 fewer deaths to 0) and riociguat (29.1 fewer deaths per 1000, 95% CI 38.6 fewer to 8.7 more) probably reduce mortality as compared to placebo (all moderate certainty). Combination therapy with ERA+PDE5i (49.9 m, 95% CI 25.9-73.8 m) and riociguat (49.5 m, 95% CI 17.3-81.7 m) probably increase 6-min walk distance as compared to placebo (moderate certainty).

Conclusion: Current PAH treatments improve clinically important outcomes, although the degree and certainty of benefit vary between treatments.

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

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

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

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

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.