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High-dose Acetylcysteine in Idiopathic Pulmonary Fibrosis

Demedts M, Behr J, Buhl R, et al. N Engl J Med. 2005;353(21):2229-2242.

Introduction:

• Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by the inexorable deposition of extracellular matrix in regions of the lung where gas exchange occurs. IPF leads to death from respiratory failure in the majority of patients within 5 years of diagnosis.
• The only therapeutic intervention that is known to prolong survival is orthotopic lung transplantation.
• Over the last 25 years, the majority of IPF patients have been treated with oral corticosteroids, often in conjunction with an immunosuppressive or cytotoxic medication, such as azathioprine or cyclophosphamide. Although immunosuppressive therapy has been used extensively in patients with IPF, there are no controlled studies that demonstrate efficacy. The rationale for immunosuppressive therapy is based largely on its efficacy in patients with interstitial lung disease (ILD) occurring with autoimmune disease, such as rheumatoid arthritis or polymyositis.
• The high resolution chest CAT (HRCT) scan has improved the diagnostic accuracy in patients with ILD. It is now possible to predict the histologic pattern of usual interstitial pneumonia (UIP) based on the pattern of parenchymal lung disease present on HRCT. The improved diagnostic accuracy and the identification of nonspecific interstitial pneumonia (NSIP) that carries a better prognosis and for which patients can improve with oral corticosteroids have led to the increasing concern among practicing clinicians that corticosteroids are not beneficial in UIP.
• This article reports a clinical trial in which the combination of prednisone, azathioprine, and N-acetylcysteine (PANAC) was compared to prednisone and azathioprine (PA) in patients with IPF.

Findings:

• This one-year study was a double-blind, randomized, placebo-controlled multicenter study of oral acetylcysteine (600 mg three times daily) added to prednisone and azathioprine.
• 182 patients were randomized for treatment. Before treatment began, 27 patients (15%) were excluded for a variety of reasons, including diagnosis not being confirmed or consent being withdrawn. 57/80 patients (71%) in the PANAC arm and 51/75 (68%) in the PA arm completed one year of treatment.
• The primary endpoints of the study were the mean change from baseline in forced vital capacity (FVC) and in single-breath carbon monoxide diffusing capacity (DL_CO).
• Diagnosis of IPF was established either on clinical grounds with an HRCT that was very suggestive or consistent with a probable diagnosis of UIP, or by surgical lung biopsy demonstrating a UIP pattern. 48% of patients in the PANAC arm and 47% of the patients in the PA arm received a surgical lung biopsy.
• The baseline vital capacity (VC) was 2.29L for the PANAC arm and 2.36L for the PA arm. The baseline DL_CO was 3.85 and 3.90 mmol/min/kPa, respectively for the two arms.
• The main results of the study were that the VC fell from 2.29 to 2.22L when the missing data due to drop out or death were imputed by the last observation carried forth in the PANAC group compared to a fall of 2.36 to 2.17L in the PA arm. This difference was statistically significant (P = 0.02). The DL_CO fell from 3.85 to 3.74 mmol/min/kPa in the PANAC arm and from 3.90 to 3.20 mmol/min/kPa in the PA arm. This difference was also statistically significant (P = 0.003). Thus, both pre-specified primary endpoints met statistical significance.
• The absolute changes, however, are small and would be undetected as clinically significant by patients. Several retrospective studies have suggested that a decline in FVC of 10% is predictive of mortality. A post hoc analysis showed that there was no difference between the two groups in the numbers of patients that exhibited a decline in FVC by 10%. Furthermore, there was no difference in mortality or in indices of reported dyspnea between the two groups.
• Side effects were apparent in both groups and notably there were fewer myelotoxic events in the PANAC (P = 0.03) arm suggesting that this recognized side effect of azathioprine was prevented by NAC.

Expert Opinion:

The diagnostic accuracy of IPF drops between the category of a “confident” diagnosis and a “probable” or “consistent with” description. The number of patients with a diagnosis made without a surgical biopsy that had a CAT scan that was “very suggestive” as compared to “consistent with a probable diagnosis” was not delineated by the authors. This may be relevant because patients with NSIP could have been included and might be expected to have a better response to PA. It would be helpful to know if the categories of HRCT diagnosis were equally distributed between the two groups. Randomization was excellent and there were no disparities between the two treatment arms. It is not possible, however, to conclude from this study that PANAC is efficacious in the treatment of IPF, since the "control" arm (PA alone) has not been compared to placebo. Nonetheless, this study provides critical information to discuss with patients when therapy with PA is considered. It is possible to give some information on the progression of lung disease as measured by lung function over one year. From these data, it is reasonable to include NAC in the regimen when PA is used, however, it is not possible to determine from this study whether NAC alone would be efficacious in IPF. Future studies sponsored by the National Institutes of Health are being designed to test these therapeutic modalities in the management of patients with IPF. Enrollment in clinical trials is essential for this effort. NAC is a promising therapy worthy of further investigation.

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