Comparison of Treatment Response in Idiopathic and Connective Tissue Disease–associated Pulmonary Arterial Hypertension

Rhee, Rennie L.; Gabler, Nicole B.; Sangani, Sapna; Praestgaard, Amy; Merkel, Peter A.; Kawut, Steven M.

doi:10.1164/rccm.201507-1456oc

Cited by 82 publications

(82 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent meta-analysis comparing the response to treatment in iPAH and CTD-PAH concluded that the treatment of CTD-PAH was less effective than that of iPAH in terms of both increasing 6MWD and reducing the occurrence of clinical worsening. 11 Observational data in patients with SSc-PAH indicate that survival also appears reduced compared with iPAH despite more modest haemodynamic dysfunction. 12 By contrast, non-SSc-CTD-PAH patients exhibit similar survival curves to patients with iPAH when receiving PAH-targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

et al. 2016

View full text Add to dashboard Cite

BackgroundPatients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.ObjectiveTo explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.MethodsThis was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).ResultsIn the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.ConclusionsThis post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.Trial registration number NCT01178073, post results.

show abstract

Section: Introductionmentioning

confidence: 99%

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In a separate, open-label multicenter study of 24 patients with CTD-PAH, upfront combination treatment similar to that in the AMBITION trial decreased RV mass, PVR, and PA compliance significantly at 36 weeks, as well as NT-BNP, which decreased as early as 4 weeks into therapy (37). The possibility that a specific treatment plan may influence disease trajectory has important ramifications in CTD-PAH, which is a particularly high-risk PAH subgroup characterized by impaired treatment response to conventional therapeutic strategies, as highlighted in a meta-analysis (38).…”

Section: Paradigm-shifting Clinical Trial Resultsmentioning

confidence: 93%

Update in Pulmonary Vascular Disease 2015

Maron

Gladwin

Simon

2016

Am J Respir Crit Care Med

View full text Add to dashboard Cite

“…An IPD meta-analysis included 11 placebo-controlled RCTs that evaluated drugs for pulmonary arterial hypertension (PAH) [17]. For the improvement in 6-minute walk distance, the IPD meta-analysis found that treatment for connective tissue disease-associated PAH was less effective than for idiopathic PAH (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Two cases were presented in detail to illustrate the usefulness of cumulative subgroup analysis. The first case study used data from an IPD meta-analysis of beta blockers for heart failure [16], and the second case study used data from an IPD meta-analysis that compared treatment effects for connective tissue disease-associated pulmonary arterial hypertension (PAH) and for idiopathic PAH [17]. Data from the two case studies were used to conduct cumulative subgroup analyses.…”

Section: Methodsmentioning

confidence: 99%

Cumulative subgroup analysis to reduce waste in clinical research for individualised medicine

Bachmann

2016

BMC Med

View full text Add to dashboard Cite

BackgroundAlthough subgroup analyses in clinical trials may provide evidence for individualised medicine, their conduct and interpretation remain controversial.MethodsSubgroup effect can be defined as the difference in treatment effect across patient subgroups. Cumulative subgroup analysis refers to a series of repeated pooling of subgroup effects after adding data from each of related trials chronologically, to investigate the accumulating evidence for subgroup effects. We illustrated the clinical relevance of cumulative subgroup analysis in two case studies using data from published individual patient data (IPD) meta-analyses. Computer simulations were also conducted to examine the statistical properties of cumulative subgroup analysis.ResultsIn case study 1, an IPD meta-analysis of 10 randomised trials (RCTs) on beta blockers for heart failure reported significant interaction of treatment effects with baseline rhythm. Cumulative subgroup analysis could have detected the subgroup effect 15 years earlier, with five fewer trials and 71% less patients, than the IPD meta-analysis which first reported it. Case study 2 involved an IPD meta-analysis of 11 RCTs on treatments for pulmonary arterial hypertension that reported significant subgroup effect by aetiology. Cumulative subgroup analysis could have detected the subgroup effect 6 years earlier, with three fewer trials and 40% less patients than the IPD meta-analysis. Computer simulations have indicated that cumulative subgroup analysis increases the statistical power and is not associated with inflated false positives.ConclusionsTo reduce waste of research data, subgroup analyses in clinical trials should be more widely conducted and adequately reported so that cumulative subgroup analyses could be timely performed to inform clinical practice and further research.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0744-x) contains supplementary material, which is available to authorized users.

show abstract

Comparison of Treatment Response in Idiopathic and Connective Tissue Disease–associated Pulmonary Arterial Hypertension

Cited by 82 publications

References 53 publications

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

Update in Pulmonary Vascular Disease 2015

Cumulative subgroup analysis to reduce waste in clinical research for individualised medicine

Contact Info

Product

Resources

About