Combination therapy for pulmonary fibrosis appears to increase risk of death, hospitalization

A combination of prednisone, azathioprine and N-acetylcysteine (NAC) for pulmonary fibrosis prompted a trial to stop early after it showed an increased risk of death and hospitalization compared with NAC alone and with placebo.

The randomized, double-blind, placebo-controlled trial examined patients ages 35 to 85 with idiopathic pulmonary fibrosis who had mild-to-moderate lung function impairment, defined as forced vital capacity of less than 50% and a carbon dioxide diffusing capacity of less than 30%. They were randomized equally into one of three groups: combination therapy, NAC alone or placebo.

Prednisone was started at 0.5 mg/kg of ideal body weight and was tapered to 0.15 mg/kg over 25 weeks. Azathioprine was given at a maximum of 150 mg/d, while NAC was given at 600 mg orally three times a day. The primary study outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.

After about half the data had been collected (with 77 patients on combination therapy and 78 in the placebo group), a planned interim analysis revealed that combination therapy patients had an increased rate of death compared with placebo (81 vs. 1; P=0.01) and hospitalization (23 vs. 7; P<0.001).

There was no evidence of physiological or clinical benefit for combination therapy. Forced vital capacity was −0.24 L in the combination-therapy group and −0.23 L in the placebo group (P=0.85).

The data and safety monitoring board recommended ending the combination therapy group. “Our data that show increased rates of death and hospitalization provide compelling evidence against the use of the combination of azathioprine, prednisone and NAC for patients with idiopathic pulmonary fibrosis who have mild-to-moderate impairment in pulmonary function,” they concluded. The trial was published online May 20 by the New England Journal of Medicine.