Safety and Efficacy of Combination Treatment for CTD-PAH

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Combination therapy decreased the risk for a first clinical failure event compared with pooled monotherapy.
Combination therapy decreased the risk for a first clinical failure event compared with pooled monotherapy.

Initial combination therapy with ambrisentan and tadalafil may improve treatment response in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the CTD-PAH subtype systemic sclerosis (SSc)-associated PAH (SSc-PAH), according to a subgroup analysis from the Ambrisentan and Tadalafil in Patients With Pulmonary Arterial Hypertension (AMBITION) trial. The study was published in the Annals of the Rheumatic Diseases.

"CTD-PAH has been associated with a worse response to therapy when compared to idiopathic PAH," John Gerry Coghlan, MD, from the Royal Free Hospital, London, United Kingdom, told Rheumatology Advisor. Short-term monotherapy and combination therapy targeting PAH have been shown to produce a reduced response to treatment in CTD-PAH compared with idiopathic PAH (iPAH). Limited data also suggest that patients with CTD-PAH caused by SSc do not respond as well to PAH-targeted therapy as those with non-SSc CTD-PAH.

High Yield Data Summary

  • Among patients with CTD-PAH or SSc-PAH, initial combination therapy with ambrisentan and tadalafil reduced the risk for a first clinical failure event compared with monotherapy with either drug.

Dr Coghlan and the investigators of the AMBITION study performed a post hoc analysis of the CTD-PAH subgroup in AMBITION to examine the response to initial combination therapy (ambrisentan plus tadalafil) compared with initial monotherapy (ambrisentan or tadalafil).

Of 500 patients with PAH, 187 patients had CTD-PAH; of these, 103 were assigned to initial combination therapy and 84 to pooled monotherapy (ambrisentan plus placebo or tadalafil plus placebo). More than half (63%) of patients with CTD-PAH had SSc-PAH. The primary end point was time to first clinical failure event, defined as first occurrence of hospitalization for worsening PAH, disease progression, unsatisfactory long-term clinical response, or death.

Combination therapy decreased the risk for a first clinical failure event compared with pooled monotherapy in the CTD-PAH (hazard ratio, 0.43) and SSc-PAH (hazard ratio, 0.44) populations.

Peripheral edema occurred more frequently in the combination therapy group than in the monotherapy groups. The rates of other adverse events, including headache and diarrhea, as well as serious adverse events, were similar among treatment groups in both the CTD-PAH and SSc-PAH populations.

Summary & Clinical Applicability

Previous data suggest that PAH-targeted therapy may produce lower response rates in patients with CTD-PAH than in patients with iPAH. In this post hoc analysis of the AMBITION trial, investigators found that among patients with CTD-PAH or SSc-PAH, initial combination therapy with ambrisentan and tadalafil reduced the risk for a first clinical failure event compared with monotherapy with either drug.

"The data from the more recent 'outcome' trials suggests that these patients have a more aggressive form of vasculopathy and benefit from an aggressive therapeutic strategy," Dr Coghlan said. "In contrast to the relatively high event rate in the monotherapy arms, when treated with combination therapy, patients with CTD-PAH have a similar medium-term outcome to that seen in patients with iPAH."

Study Limitations

  • This was a post hoc analysis of subgroups of patients with CTD-PAH and SSc-PAH from the AMBITION trial
  • The number of patients with CTD-PAH not caused by SSc was small, so response rates could not be compared between the CTD-PAH subsets

Disclosures 

This study was funded by Gilead Sciences and GlaxoSmithKline.

Reference

Coghlan JG, Galiè N, Barberà JA, et al; AMBITION Investigators. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial [published online December 30, 2016]. Ann Rheum Dis. doi:10.1136/annrheumdis-2016-210236

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