May 302014
NAC for IPF: Fail (PANTHER-IPF Wrap-Up)

Long ago, when pulmonologists were more ingenuous (in 2000), flawed clinical trials convinced the American Thoracic Society to recommend prednisone and either azathioprine or cyclophosphamide in its consensus guideline for some patients with idiopathic pulmonary fibrosis (IPF). By not including a true control arm, the also-flawed follow-up 2005 IFIGENIA trial reinforced this informal standard of care, and further suggested N-acetylcysteine (NAC) might "help" even more. Soon around half of pulmonologists were using some combination of these drugs on at least some patients with idiopathic pulmonary fibrosis. Editor's note: PulmCCM is not affiliated with ATS.

Twelve years later, the PANTHER-IPF trial put (almost) all that to rest in an epic demonstration of what I call the Ioannidis Principle (after his landmark paper, "Why Most Published Research Findings Are False.") The more rigorously conducted PANTHER-IPF was stopped early in 2012 due to clear harm resulting from prednisone and azathioprine given to people with idiopathic pulmonary fibrosis.

But one appendage of PANTHER-IPF was allowed to live on: the 81 patients taking N-acetylcysteine (which seemed safe enough), and their placebo-taking controls. Those results were announced at the American Thoracic Society 2014 meeting, and published in the New England Journal in May 2014:

N-acetylcysteine showed no benefit over placebo in the treatment of idiopathic pulmonary fibrosis.

After over one year of follow-up, there was no difference in lung function decline (change in forced vital capacity), mortality, or rates of acute exacerbations of IPF. Almost twice as many patients taking N-acetylcysteine for IPF died as those taking placebo (4.9% vs. 2.5%), but this was not statistically significant.

Taken together with the rest of PANTHER-IPF, it's a cautionary epilogue to the previous decade of aggressive anti-inflammatory treatment for IPF, a convincing refutation of the inflammation hypothesis and a reminder that consensus is only as good as the evidence it's based on. On the up side, the same national meeting and journal issue announced the exciting success of pirfenidone and nintedanib for slowing lung function decline in IPF, and possibly even preventing IPF exacerbations and extending life for people with idiopathic pulmonary fibrosis.

PANTHER-IPF. Randomized Trial of Acetylcysteine in Idiopathic Pulmonary Fibrosis. N Engl J Med 2014; 370:2093-2101.

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N-acetylcysteine: no benefit in idiopathic pulmonary fibrosis