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:

• pulmonary arterial hypertension
• targeted drugs
• 6-minute walk distance
• prostanoids
• network meta-analysis

Supplementary materials

Figure S1 Study selection flow chart.

Abbreviation: RCT, randomized controlled trial.

Table S1 General characteristics of the included studies

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Author contributions

CSL had the original idea and designed the study. GXF and ZJJ performed the systematic literature search, study identification, data extraction, and quality assessment. JXM and GZ undertook the statistical analysis. WZM, LB, and MWX drafted the article. All authors revised and approved the final report. All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Acknowledgments

The study is supported by the Jiangsu Provincial Special Program of Medical Science (BL2013001).