A Bayesian network meta-analysis on the efficacy and safety of eighteen targeted drugs or drug combinations for pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) can be relieved by pharmacological interventions, especially the targeted drug, which is classified into endothelin receptor antagonist, phosphodiesterase 5 inhibitor, prostaglandin I2, soluble guanylate cyclase stimulator and selective non-prostanoid prostacyclin receptor agonist. To solve the contradictions existing in reported trials and provide a comprehensive guideline for clinical practice. PubMed, Embase, Cochrane library, and clinicaltrials.gov were searched. The basic information about the article, trial, arm, intervention, and the detailed data of outcome, including 6 minutes walking distance (6MWD) change, WHO functional class (FC) improvement, Borg dyspnea score (BDS) change, cardiac index (CI) change, mean pulmonary arterial pressure (mPAP) change, mean right arterial pressure (mRAP) change, pulmonary vascular resistance (PVR) change, clinical worsening, hospitalization, death, severe adverse events (SAEs), and withdrawal were extracted. The rank of treatments was estimated. 10,230 cases provided the firsthand comparison data about targeted drugs for treating PAH. For 6MWD, ambrisentan + tadalafil, vardenafil, and sildenafil + bosentan were better than others. Epoprostenol, macitentan, and sildenafil represented a greater WHO FC improvement. Vardenafil and treprostinil were better for BDS. So were bosentan + epoprostenol and bosentan alone for CI. Iloprost plus bosentan, bosentan + epoprostenol, and epoprostenol were better for mPAP. Iloprost plus bosentan, bosentan alone, and selexipag could reduce PVR. Sildenafil, epoprostenol, and vardenafil had the highest probability to reduce the incidence of death and withdrawal. To conclude, vardenafil and iloprost + bosentan showed relatively better performance in both efficacy and safety. However, the therapeutic choice should be made according to both the feature of each therapy and the individual condition.

The pathogenesis, diagnosis and management of congenital dyserythropoietic anaemia type I

“…For patients with sickle cell disease, this is screened by tricuspid jet velocity followed by right heart catheterization in patients with tricuspid jet velocity >2·5 m/s. A recent meta‐analysis (Wang et al , ) compared different types of treatment for all types of idiopathic pulmonary hypertension including endothelin receptor antagonists, phosphodiesterase type‐5 inhibitors, prostaglandin I2, soluble guanylate cyclase stimulator and selective non‐prostanoid prostacyclin receptor agonists or combination treatment. Results differed depending on the outcome used to measure response but the best responses appeared to be for vardenafil (taken orally) and iloprost + bosantan (inhaled).…”

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.…”

“…Further critical appraisal performed based on input from clinical experts. Vizza 2018 [ 56 ] Patients with PAH MA 6 Oral bosentan, oral ambrisentan, oral riociguat, oral tadalafil and oral/inhaled treprostinil 6MWD Not reported Wang 2018 e [ 57 ] Patients with PAH NMA 45 Oral ERAs (ambrisentan, bosentan, macitentan, sitaxsentan), oral PDE5Is (sildenafil, tadalafil, vardenafil d ), prostanoids (IV epoprostenol, oral/IV/inhaled/SC treprostinil, inhaled iloprost, oral beraprost), sGCSs (oral riociguat), sPRA (oral selexipag) 6MWD, WHO FC, BDI, cardiac index, PAP, RAP, PVR, clinical worsening, hospitalization, death, SAEs, and withdrawal Not reported Wei 2016 [ 58 ] Patients with different diseases including PAH MA 24 Oral ERAs (bosentan, ambrisentan and macitentan); EU authorised AEs Cochrane’s risk of bias and GRADE for evidence Xing 2011 [ 59 ] Patients with PAH (including idiopathic PAH, familial PAH, as well as CTD-associated PAH, pulmonary shut, portal hypertension, HIV infection and thyroid disease) MA 10 Prostanoids (IV epoprostenol, IV/SC treprostinil, oral beraprost and inhaled iloprost) 6MWD, BDI, cardiac index, mean PAP, PVR, mortality, clinical worsening and AEs Jadad scores Zhang 2015 [ 60 ] Patients with PAH MA 21 Oral treatments (ambrisentan, bosentan, macitentan, sitaxentan, sildenafil, tadalafil, riociguat, beraprost, epoprostenol, treprostinil, terbogrel d and imatinib d ) CCW or at least all-cause mortality Cochrane’s risk of bias Zhang 2016 [ 61 ] Patients with PAH NMA 14 Prostanoids (IV epoprostenol, inhaled/IV/oral/SC treprostinil, oral beraprost and inhaled iloprost) 6MWD, mortality, Functional Class, and discontinuation Not reported Zhang 2019 [ 62 ] Patients with PAH NMA 10 Oral ERAs (bosentan, ambrisentan, macitentan) Safety outcomes: abnormal li...…”

“…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 ].…”

“…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].…”