Prednisone, Azathioprine, and NAC for IPF

Published - Written by Rachel Wolfson

In your office is a 54-year-old man with a non-productive cough and months of worsening dyspnea. He has inspiratory crackles and clubbing. His chest x-ray and CT scan show the patterns typical of interstitial lung disease. After a long work up, you decide he has idiopathic pulmonary fibrosis (IPF).  Now comes the crucial question: what can you do to treat him?

If you were to survey your pulmonologist colleagues, there would be a variety of answers. Many of them would suggest a three-drug combination of prednisone, azathioprine, and N-acetylcysteine (NAC). Most of the experts have used this regimen, and many have confidence that it helps patients with IPF. But a bit more research would reveal that international guidelines gave this treatment plan a “weak-YES” recommendation in 2000 and a “weak-NO” recommendation in 2011. After scanning the literature, you would find that no randomized control trials have proved the efficacy of this three-drug regimen in comparison to placebo. You might start to wonder, should I prescribe this treatment?

A new article in this week’s NEJM shows the results of the interim analysis of a clinical trial run by the Idiopathic Pulmonary Fibrosis Clinical Network that provides some insight into your question. This group performed a three-armed prospective trial that compared the three-drug regimen vs. NAC alone (with placebos for the other two drugs) or no treatment (with placebos for all three drugs). Across 25 clinical centers, a total of 77 patients were enrolled in the three-drug regimen and 78 were enrolled in the placebo only group. Half way through the trial, a planned interim analysis showed that there were increased rates of mortality (8 deaths vs. 1 death) and hospitalizations (23 vs. 7) in the group treated with the three-drug regimen as compared to those treated with three placebos. The results were so surprising that the three-drug group was terminated early—the trial continues to test the efficacy of NAC alone vs. placebo.

For years the standard treatment for IPF has been considered by many to be the combination therapy of prednisone, azathioprine, and NAC, with over half of pulmonologists recommending using either this three-drug regimen or a combination of prednisone and azathioprine to treat such patients. It turns out that you were right to hesitate prescribing the combination to the 54-year-old man in your office.

“This study shows that the current therapies for IPF have actually been harming our patients, which is unsettling for physicians, but is an important finding that drastically impacts the field,” said Dr. Jeffrey Drazen, pulmonologist and NEJM editor-in-chief. Clearly, the three-drug approach is a mistake, but this study doesn’t help us decide what, if anything, can help patients with IPF.

In addition to altering the management of IPF, this study raises questions about this difficult disease. Since prednisone and azathioprine were thought to be effective in IPF due to their ability to inhibit the inflammatory response, do these results indicate that inflammation is not as important of a mediator of IPF as we thought? Should this change how we think about the pathogenesis of IPF? Or is the inflammation just not sensitive to this therapeutic combination? We know that it did not help, but why did the three-drug regimen actually worsen patients’ outcomes?  This brings up an even bigger question. Many other treatment regimens that we commonly use to treat of a number of diseases have not been properly tested in randomized, placebo controlled clinical trials. Which of these regimens may, in fact, be harming our patients? Even the experts can be wrong.