A Bayesian Network Meta-analysis of Add-on Drug Therapies Specific for Pulmonary Arterial Hypertension

Abstract

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.

Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal

“…The publication year ranged between 2007 [ 43 ] and 2020 [ 39 , 41 , 48 , 67 ] with most studies published in recent years. MAs were conducted in 35 studies [ 17 , 19 , 20 , 22 , 23 , 26 – 29 , 31 , 35 – 41 , 43 – 47 , 49 – 51 , 53 , 56 , 58 – 60 , 63 – 66 , 69 ], NMAs in 15 studies [ 18 , 21 , 24 , 25 , 30 , 32 , 33 , 42 , 48 , 52 , 54 , 57 , 61 , 62 , 67 ], both NMA and MA in one study [ 55 ], and MA and disproportionality analysis in one study [ 34 ]. Of 52 studies, 47 evaluated the impact of PAH interventions in patients with PAH and PAH subgroups (based on aetiology, e.g.…”

“…With a number of exceptions [ 17 , 20 , 24 , 25 , 34 , 35 , 39 – 41 , 45 , 47 , 54 , 58 , 59 , 61 , 62 , 64 ], most studies investigated treatments targeting all three pathways. All the approved treatments (ERA, PDE-5Is, PRAs, prostacyclin and sGCS) were investigated in nine recent studies [ 27 , 30 , 38 , 42 , 46 , 48 , 57 , 63 , 67 ]. Some studies included treatments approved in limited markets such as beraprost [ 38 , 40 , 48 , 50 , 51 , 57 , 61 , 65 , 67 ].…”

“…The outcomes evaluated included clinical, hemodynamics, health-related-quality-of -life (HRQoL) and safety. Frequently investigated clinical endpoints were 6MWD (as a standalone or within combined events) in 43 studies [ 17 , 19 , 20 , 22 – 33 , 35 , 36 , 39 – 44 , 46 – 50 , 52 – 61 , 63 – 67 ] followed by mortality (all-cause or disease-specific) in 37 studies [ 18 – 21 , 23 , 25 – 30 , 33 , 37 , 40 – 53 , 55 , 58 – 61 , 63 – 67 ], clinical worsening (standalone or in combined events) in 25 studies [ 18 – 21 , 24 – 27 , 30 , 31 , 33 , 35 , 37 , 38 , 42 , 46 , 52 , 55 , 57 , 59 , 60 , 63 – 66 ] and WHO functional class improvement or deterioration in 24 studies [ 18 – 20 , 24 , 27 , 29 , 31 – 33 , 35 , 37 , 40 , 42 – 44 , 46 , 47 , 53 , 55 ,…”

“…The most commonly employed tool for quality assessment was Cochrane’s risk of bias tool, employed in 21 studies [ 20 , 21 , 27 , 32 – 39 , 41 , 46 – 49 , 58 , 60 , 62 , 67 ] followed by Jadad scores used in 12 studies [ 17 , 25 , 26 , 30 , 40 , 42 , 47 , 49 , 59 , 63 – 65 ]. There was no mention of quality appraisal being conducted in 10 studies [ 18 , 24 , 28 , 29 , 43 , 44 , 53 , 56 , 61 , 62 ].…”

“…All the approved treatments (ERA, PDE-5Is, PRAs, prostacyclin and sGCS) were investigated in nine recent studies [27,30,38,42,47,49,50,59,65]. Some studies included treatments approved in limited markets such as beraprost [38,40,49,50,52,53,59,63,67]. In nine studies, drugs targeting one pathway only were investigated: prostacyclins in five studies [40,48,61,63,66] and ERAs in four studies [25,46,60,64].…”