Key result
Add-on tadalafil or inhaled treprostinil improves 6MWD by up to ~27 meters vs ERA monotherapy.
Why the study?
Previously published meta-analyses did not distinguish between drug agents used for initial and sequential combination therapy in PAH.
Do add-on PAH-specific drug therapies improve 6-minute walk distance in adult patients with PAH?
Meta-Analysis (n=4,112)
Do add-on PAH-specific drug therapies improve 6-minute walk distance in adult patients with PAH?
Mean Difference: 27 (95% CI 11–43)
Sequential combination therapy with add-on PAH-specific drugs significantly improves 6-minute walk distance compared to monotherapy, supporting current guideline recommendations.
Supports add-on tadalafil or inhaled treprostinil in PAH on ERAs; reinforces guideline recommendations for sequential combination therapy.
Background: Recently published meta-analyses did not discriminate between drug agents used for initial and sequential combination therapy. Objective: To assess the comparative efficacy of drugs specific for the treatment of pulmonary arterial hypertension (PAH) as add-on therapies based on 6-minute walk distance (6MWD), all-cause mortality, and discontinuation due to adverse events (AEs). Methods: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched until December 9, 2018, for the randomized, placebo-controlled clinical trials (RCTs) conducted on primarily adult patients diagnosed with PAH. Data extracted from applicable RCTs were as follows: for 6MWD mean change from baseline, the total number of patients, and the number of patients with events, per treatment. Network meta-analysis (NMA) was conducted in a Bayesian framework. Results: A total of 16 RCTs were eligible for analysis, with 4112 patients. Add-on therapy with tadalafil or inhaled treprostinil performed better than endothelin receptor antagonists alone [27 m; 95% credible interval (CrI): (11, 43); and 19 m; 95% CrI: (10, 27); respectively]. Add-on therapy with macitentan or bosentan performed better than phosphodiesterase type 5 inhibitors alone [26 m; 95% CrI: (6.4, 45); and 22 m; 95% CrI: (5.1, 38); respectively]. Differences in all-cause mortality and discontinuation due to AEs were nonsignificant. Conclusion and Relevance: Our NMA evaluated efficacy and safety of add-on therapies in patients with PAH. None of the previous meta-analyses evaluated RCTs focusing solely on patients pretreated with another PAH-specific drug therapy. Our results support guideline recommendations on combination therapy in PAH patients and add the quantitative perspective on which sequential therapy demonstrated the greatest effect size.
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Petrovič et al. (2019) conducted a meta-analysis in Pulmonary arterial hypertension (PAH) (n=4,112). Add-on PAH-specific drug therapies vs. Monotherapy (endothelin receptor antagonists or phosphodiesterase type 5 inhibitors) was evaluated on 6-minute walk distance (6MWD) mean change from baseline (MD 27, 95% CI 11-43). Add-on therapy with tadalafil or inhaled treprostinil improved 6-minute walk distance compared to endothelin receptor antagonists alone (mean difference 27 m [95% CrI 11-43] and 19 m [10-27]).
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