Meta-analysis supports combination therapy for PAH patients

By Eleanor McDermid

A meta-analysis shows that clinical worsening is significantly less likely in patients with pulmonary arterial hypertension (PAH) if they are given combination treatment, rather than monotherapy.

Overall, patients given combination therapy were 35% less likely to experience clinical worsening than those given monotherapy, show the findings published in The Lancet Respiratory Medicine.

The benefit was consistent across most subgroups, defined by treatment type, idiopathic or associated PAH, World Health Organization functional class and baseline 6-minute walk distance.

However, there was only a trend towards improved survival with combination therapy, with a nonsignificant 23% reduction in PAH-related mortality (p=0.06) and a 14% reduction in all-cause mortality (p=0.09).

"Hence, although combination therapy undoubtedly improves patient-relevant outcomes, we cannot yet claim that it also improves survival, although this seems likely", writes Marius Hoeper (Hannover Medical School and German Centre for Lung Research) in an accompanying commentary.

He notes that the meta-analysis, which involved 4095 patients, contains the same drawbacks as the original 17 studies, including that only four of the studies lasted longer than 24 weeks and the definition of clinical worsening varied.

Clinical worsening endpoints included PAH-related hospital admission, treatment escalation and symptomatic progression, and combination treatment versus monotherapy reduced the risk of these endpoints by 29%, 62% and 47%, respectively. But Steeve Provencher (Laval University, Québec City, Canada) and study co-authors found that the risks of all-cause mortality and lung transplantation were not significantly reduced by combination therapy.

Hoeper also stresses the "significant proportion of patients" who had disease progression while receiving combination therapy, with 17% experiencing clinical worsening.

"Therefore to further improve the outcome of patients with PAH, we either need new drugs or we must make better use of the drugs we already have", he says, pointing to research suggesting that upfront combination therapy may yield larger benefits than introducing additional drugs only after a patient's condition worsens.

Only two of the trials in the meta-analysis investigated upfront combination therapy, with the other 15 assessing sequential add-on therapy.

The results so far obtained from research into upfront combination therapy "suggest that patient outcomes might be determined by the physician's treatment choices at the beginning", says Hoeper.

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