PANTHER-IPF negative, stopped early for harm from steroids, Imuran in IPF (RCT)

(image: Wikipedia)

As we reported a few months ago, the PANTHER-IPF trial was stopped early for safety, when it became clear that the combination of prednisone and azathioprine was hurting people with idiopathic pulmonary fibrosis (IPF). Ganesh Raghu (U-Washington), Kevin Anstrom (Duke), Talmadge King (UCSF) et al report the final results in the May 24 New England Journal of Medicine.

A little history: Although evidence was lacking, a 2000 American Thoracic Society (ATS) consensus guideline suggested using prednisone and either azathioprine (Imuran) or cyclophosphamide (Cytoxan) for some patients with IPF. Surveys in the mid-2000s suggested that almost half of pulmonologists were doing so -- sometimes adding N-acetylcysteine, as well. N-acetylcysteine ("NAC" or Mucomyst) got into the mix after a randomized trial in NEJM 2005 showed a benefit in protecting lung function by adding N-acetylcysteine to prednisone + azathioprine, as compared to azathioprine and prednisone alone. However, the lack of a real control group (i.e., placebo) made its conclusions unreliable.

The most recent ATS recommendation guidelines for idiopathic pulmonary fibrosis (IPF) do not advise using any specific agent to treat patients with IPF, and suggest not using immunotherapy. Reliable evidence to guide therapy for IPF -- or the withholding of it -- remained scant.

What They Did

Randomized 236 patients with mild-to-moderate IPF (diagnosed by CT criteria or biopsy, with forced vital capacity >= 50% predicted) to receive one of three medication regimens for 6 months (with 60 month follow-up):

• N-acetylcysteine (NAC) alone (81 patients);

• NAC, prednisone, and azathioprine/Imuran (77 patients);

• Placebo (78 patients)

The primary outcome was change in FVC during the study period, with numerous secondary outcomes (death, exacerbations, etc.).

What They Found

Bad things happened to people taking prednisone and azathioprine with NAC:

• 8 died, vs. 1 in the placebo group (p=0.01), almost all due to respiratory causes.

• 23 were hospitalized, vs. 7 in the placebo group (p<0.001)

• 5 had acute exacerbations of IPF, vs. none in the placebo group.

• 24 serious adverse events, vs. 8 in placebo (p=0.001).

Periodic safety reviews were designed into PANTHER-IPF, and after the interim analysis, the prednisone/azathioprine/NAC arm was stopped for safety on October 14, 2011.

There was no difference in forced vital capacity (FVC) / lung function between groups at the time of trial stoppage between the prednisone/azathioprine/NAC arm and placebo (both had lost ~240 mL of FVC).

Clinical Takeaway: Providing prednisone and azathioprine to patients with IPF looks like a very bad idea. As a reminder, the ATS guidelines for management of IPF do not recommend prednisone alone, either. The N-acetylcysteine and placebo arms of PANTHER-IPF will continue on; we and our patients can hold out hope that this benign medication might help people with this so-far untreatable disease.

The IPF Clinical Research Network authors. Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis. N Engl J Med 2012;366:1968-1977.