Chest 2005: Combination drug therapies may improve efficacy, reduce side effects in PAH

Because several molecular pathways are relevant in the pathogenesis and progression of pulmonary arterial hypertension (PAH), combinations of therapies are being explored to better manage the disease.

Attacking as many of the targets as possible through combination therapy may improve efficacy and reduce side effects by allowing reduced doses of 1 or both therapies, said presenters at the 71st annual scientific assembly of the American College of Chest Physicians.

Current guidelines for the treatment of PAH do not address combination therapy because no studies were published at the time the guidelines were written.

The double-blind study included 65 patients with PAH who were being treated with bosentan. Patients had New York Heart Association class III or IV heart failure and had to be on a stable dose of bosentan for at least 16 weeks to be eligible. They were randomized to iloprost, 5 mg (titrated down to 2.5 mg if not tolerated) or placebo added to bosentan. Compliance with scheduled doses was more than 90% in each arm, with most patients taking 6 inhalations per day.

At week 12, 6-minute walk distance improved by 30 m in patients randomized to iloprost (P=.001 compared with baseline) and by 4 m in the patients randomized to placebo. The improvement in the iloprost group relative to the placebo group did not quite reach statistical significance (P=.051).

Thirty-four percent of the iloprost recipients improved by at least 1 functional class compared with only 6% of placebo recipients (P=.002).

None of the iloprost patients experienced clinical worsening compared with 15% of the placebo group (P=.02). Clinical deterioration was defined as any 1 of the following: death due to worsening PAH, receipt of lung transplant or atrial septostomy, hospitalization for worsening PAH, or any early discontinuation from the study drug due to worsening PAH.

"There were also significant improvements in post-inhalation hemodynamics," Dr McLaughlin said. These included significant improvements in mean pulmonary artery pressure, pulmonary vascular resistance, and myocardial oxygen consumption.

Headache and cough occurred significantly more often in the iloprost recipients, consistent with previous studies of iloprost.

According to Dr McLaughlin, combination therapy may be considered for patients who remain in functional class III or IV despite bosentan monotherapy.