Fight PAH in Systemic Sclerosis With Combination Therapy

LISBON, Portugal — Combination therapy is better than monotherapy for the initial treatment of pulmonary arterial hypertension in patients with systemic sclerosis, according to a post hoc analysis of data from the AMBITION trial.

This provides evidence rheumatologists and pulmonologists have been waiting for.

In fact, the relative risk for treatment failure was 57% lower with initial combination therapy than with initial monotherapy for patients with connective tissue disease, and 56% lower in a subset of patients with systemic sclerosis.

"It's really the first confirmatory study to look at combination therapy in pulmonary artery hypertension," Jonathan Langley, BSc, clinical investigation leader at the GlaxoSmithKline Global Rare Disease Unit in London, United Kingdom, said here at the Systemic Sclerosis World Congress (SSWC) 2016. The study was funded by GlaxoSmithKline and Gilead Sciences.

In the AMBITION trial, patients with New York Heart Association functional class II and III pulmonary arterial hypertension were randomly assigned to receive ambrisentan (Volibris, GlaxoSmithKline) plus tadalafil (Adcirca, Eli Lilly) in combination or either agent alone. (Ambrisentan was approved as Letairis [Gilead Sciences] in the United States in October 2015.)

Early results from the AMBITION trial showed that there were fewer hospitalizations with combination therapy than with monotherapy, and that 6-minute walking was better with the combination, as previously reported by Medscape Medical News.

Of the 610 patients in the AMBITION trial, 187 had connective tissue disease. Of these, 118 presented with scleroderma.

Langley and his colleagues evaluated outcomes in the subgroup of patients with connective tissue disease. Time to clinical failure was better with the combination than with monotherapy, which served as the reference group (relative risk, 0.44 vs 1.0).

Table. Outcomes in Patients With Connective Tissue Disease

Outcome	Combination (n = 103)	Monotherapy (n = 84)
Any event, %	21	40
Improvement in 6-minute walking, m	40	12

"We get approximately three times the walk distance with combination compared with monotherapy, perhaps indicating the 6-minute walk test might be useful in connective tissue disease and scleroderma patients," Langley said.

In addition, most secondary end points favored combination therapy over monotherapy, including hospitalization related to pulmonary arterial hypertension, disease progression, and clinical response, he reported.

"If a patient is no better after 6 months, we consider that a failure, and treatment really should be escalated," he said. All-cause death rates did not differ significantly between groups.

This is "a really important study," said Christopher Denton, PhD, from Royal Free Hospital/University College London in the United Kingdom, who was not involved with the AMBITION study.

"These findings look quite robust, especially the data for the connective tissue disease subgroup," he told Medscape Medical News.

"It's analogous to other areas of rheumatology, such as rheumatoid arthritis, where you generally get a larger and more sustainable response with combination therapy," he pointed out.

Adverse events more common in the combination group included peripheral edema and nasal congestion. Serious adverse events more common in the monotherapy group included dyspnea and anemia.

'We can see we have a pretty consistent treatment effect in the connective tissue disease and scleroderma patients," Langley said.

The findings are "very consistent based on etiology," he added. "It doesn't matter what functional class you are, what age, or what region you're from, you still benefit from initial combination therapy."

"This is an encouraging finding and is consonant with studies in other diseases where treating by blocking more than one mechanism of action improves response," said Daniel Furst, MD, from the University of California, Los Angeles (emeritus), the University of Washington in Seattle, and the University of Florence in Italy.

"I would like to see this replicated in another study, even a registry or cohort study, to be sure that the results are robust. Remember that the term research is just that — "re" and "search". Corroboration is important to lend credibility to the result," Dr Furst explained.

Mr Langley is an employee of GlaxoSmithKline. Dr Denton is a consultant for GlaxoSmithKline. Dr Furst has disclosed no relevant financial relationships.

Systemic Sclerosis World Congress (SSWC) 2016. Presented February 19, 2016.

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Cite this: Fight PAH in Systemic Sclerosis With Combination Therapy - Medscape - Feb 20, 2016.