Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial

Abstract

BackgroundFew controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH).MethodsPatients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; ≥325 m), and baseline aetiology; sensitivity analyses were subsequently performed.ResultsIn sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil–placebo], −2.4 m [90% CI: –21.8 to 17.1 m]; P = 0.6); mean ± SD changes from baseline were 26.4 ± 45.7 versus 11.8 ± 57.4 m, respectively, in IPAH (65% of population) and −18.3 ± 82.0 versus 17.5 ± 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil.ConclusionsSildenafil, in addition to stable (≥3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study.Trial registrationClinicalTrials.gov NCT00323297 (registration date: May 5, 2006).Electronic supplementary materialThe online version of this article (10.1186/s12872-017-0674-3) contains supplementary material, which is available to authorized users.

Efficacy and safety of oral targeted therapies in pulmonary arterial hypertension: a meta‐analysis of randomized clinical trials

“…5,8,9,15–24,26,29 In the other five trials that did not report this endpoint as defined, we extracted the data according to the definition. 16,25,27,30,31 If the study did not report all the relevant endpoints of clinical worsening, we combined the reported endpoints together as clinical worsening.…”

The Clinical Efficacy of Endothelin Receptor Antagonists in Patients with Pulmonary Arterial Hypertension

“…and demonstrated that sildenafil provided no additional benefit versus placebo on 6 MWT at 12 weeks when added to the bosentan monotherapy. 21) Compared with bosentan, ambrisentan does not strongly induce CYP and therefore does not reduce the blood concentrations of PDE5-Is. 22,23) With respect to the pharmacokinetic interactions between ERAs and PDE5-Is, one RCT demonstrated that the combination of PDE5-I with macitentan or ambrisentan should be preferable to a combination with bosentan due to maintaining the targeted plasma PDE-5I concentration.…”

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

“…Among them, according to exclusion criteria, another 13 trials involving patients with non-Group 1 PH were excluded. Eventually data from 45 trials were retrieved as primary evidence for further analysis (Rubin, 1990 ; Barst et al., 1996 ; Badesch, 2000 ; Channick et al., 2001 ; Badesch et al., 2002 ; Galie et al., 2002 ; Rubin et al., 2002 ; Barst et al., 2003 ; McLaughlin et al., 2003 ; Barst et al., 2004 ; Humbert et al., 2004 ; Oudiz et al., 2004 ; Galie et al., 2005 ; Wilkins et al., 2005 ; Barst et al., 2006 ; Galie, 2006 ; McLaughlin et al., 2006 ; Hoeper et al., 2006b ; Badesch et al., 2007 ; Simonneau, 2008 ; Galie et al., 2008a ; 2008b ; 2009 a; Hiremath et al., 2010 ; Iversen et al., 2010 ; McLaughlin et al., 2010 ; Jing et al., 2011 ; Sandoval et al., 2012 ; Simonneau et al., 2012 ; Tapson et al., 2012 ; Ghofrani et al., 2013 ; Jing et al., 2013 ; Pulido et al., 2013 ; Tapson et al., 2013 ; Zhuang et al., 2014 ; Chin et al., 2015 ; Hoendermis et al., 2015 ; McLaughlin et al., 2015 ; Rosenkranz et al., 2015 ; Rubin et al., 2015 ; Sitbon et al., 2015 ; Webb et al., 2015 ; Galie et al., 2015a ; 2015b ; Vizza et al., 2017 ). Characteristics of included trials.…”