Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials

Abstract

Background: Pulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH.

Methods: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD).

Results: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003) vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008) vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028) vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001) vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001) vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023) vs PDE-5Is, and 3.94 mmHg (95% CI: -6.99, -0.88; P=0.012) vs sGCS. There were no significant differences in all-cause mortality and severe adverse events between prostanoids, ERAs, PDE-5Is, sGCS, combination therapy, and placebo.

Conclusion: All targeted drugs for PAH are associated with improved clinical outcomes, especially combination therapy. However, all these drugs seem to show less favorable effects on survival in the short-term follow-up, suggesting further clinical trials are required.

Keywords: 6-minute walk distance; network meta-analysis; prostanoids; pulmonary arterial hypertension; targeted drugs.

Figure 1

Network of available drugs for PAH. Note: The size of nodes is proportional to the number of individuals randomized to each treatment, and the thickness of lines to the number of direct comparisons in trials. Abbreviations: ERAs, endothelin receptor antagonists; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator.

Figure 2

Pooled WMD and 95% CIs determined by network meta-analysis for 6MWD of targeted drugs (A) or oral targeted drugs (B) for PAH. Abbreviations: 6MWD, 6-minute walk distance; CI, confidence interval; ERAs, endothelin receptor antagonists; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator; WMD, weighted mean difference.

Figure 3

Pooled WMD and 95% CIs determined by network meta-analysis for mean pulmonary artery pressure of targeted drugs (A) or oral targeted drugs (B) for PAH. Pooled WMD and 95% CIs determined by network meta-analysis for pulmonary vascular resistance of targeted drugs (C) or oral targeted drugs (D) for PAH. Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; PVR, pulmonary vascular resistance; sGCS, soluble guanylate cyclase stimulator; WMD, weighted mean difference.

Figure 3

Pooled WMD and 95% CIs determined by network meta-analysis for mean pulmonary artery pressure of targeted drugs (A) or oral targeted drugs (B) for PAH. Pooled WMD and 95% CIs determined by network meta-analysis for pulmonary vascular resistance of targeted drugs (C) or oral targeted drugs (D) for PAH. Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; PVR, pulmonary vascular resistance; sGCS, soluble guanylate cyclase stimulator; WMD, weighted mean difference.

Figure 4

Pooled OR and 95% CIs determined by network meta-analysis for all-cause mortality of targeted drugs (A) or oral targeted drugs (B) for PAH. Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; OR, odds ratio; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator.

Figure 5

Pooled OR and 95% CIs determined by network meta-analysis for clinical worsening events of targeted drugs (A) or oral targeted drugs (B) for PAH. Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; OR, odds ratio; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; sGCS, soluble guanylate cyclase stimulator.

Figure 6

Pooled OR and 95% CIs determined by network meta-analysis for SAEs of targeted drugs (A) or oral targeted drugs (B) for PAH. Abbreviations: CI, confidence interval; ERAs, endothelin receptor antagonists; OR, odds ratio; PAH, pulmonary arterial hypertension; PDE-5Is, phosphodiesterase 5 inhibitors; SAE, serious adverse event; sGCS, soluble guanylate cyclase stimulator.