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Anticoagulant Therapy and Idiopathic Pulmonary Fibrosis FREE TO VIEW

Brent W. Kinder, MD; Harold R. Collard, MD; Talmadge E. King, Jr, MD, FCCP
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San Francisco General Hospital, San Francisco, CA

Correspondence to: Talmadge E. King Jr, MD, FCCP, San Francisco General Hospital, 1001 Potrero Ave, 5H22, San Francisco, CA 94110; e-mail: tking@medsfgh.ucsf.edu



Chest. 2006;130(1):302-303. doi:10.1378/chest.130.1.302-a
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To the Editor:

We read with interest the report by Kubo and colleagues1 of a randomized controlled trial of anticoagulation and corticosteroids vs corticosteroids alone in 56 Japanese patients with idiopathic pulmonary fibrosis (IPF). The authors should be commended for applying sound biological rationale in developing a promising hypothesis, and the results provide hope that anticoagulation may benefit patients with IPF. However, there are three substantial methodologic issues in this study, and physicians should not rush to adopt this treatment as a new standard of care.

First, this cohort is not representative of the general IPF population. All patients were nonsmokers who were identified during a hospitalization. IPF has a marked association with smoking. In addition, choosing hospitalized patients may result in a spectrum bias toward acutely ill or deteriorating patients. There are several observations that make this likely: the incidence of acute exacerbation was extraordinary high (57% overall and 64% in the placebo group). Also, the median survival for the placebo arm was 399 days, a distinctly shorter period of time than previously reported.2

Second, several issues raise concerns regarding a potential misclassification bias. Only nine patients had surgical lung biopsy-confirmed IPF. Furthermore, the inclusion of radiographic ground-glass attenuation in the case definition of IPF differs from the recommended criteria. High-resolution CT is accurate in the diagnosis of IPF when specific criteria are met: bilateral basal predominant subpleural reticulation (with our without traction bronchiectasis), honeycombing, and the absence of atypical features such as significant ground-glass opacity.34 Commentary on the percentage of patients with significant ground-glass opacity on high-resolution CT would be informative.

Finally, the study was unblinded, and eight patients (26%) randomized to anticoagulation therapy withdrew after randomization. Such a high percentage of differential dropouts eliminate the benefit of randomization, as those who withdrew may somehow be different from those who did not (perhaps they were more ill). Consequently, the differences between groups could be due to confounding variables and not a true treatment effect. A better approach would have been to include those patients who withdrew as part of the “treatment group” in an intention to treat analysis. Less robust but still valid, the investigators could have analyzed the data using a Cox proportional hazards model including well-characterized covariates that may influence mortality in IPF patients such as age, smoking status, and baseline FVC. The results of this trial are dramatic but must be interpreted with caution and confirmed by future studies addressing the concerns outlined above before anticoagulation is adopted as a new standard of care in IPF.

The authors have no conflicts of interest to disclose.

Kubo, H, Nakayama, K, Yanai, M, et al (2005) Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest128,1475-1482
 
Bjoraker, JA, Ryu, JH, Edwin, MK, et al Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1998;157,199-203
 
Hunninghake, G, Zimmerman, MB, Schwartz, DA, et al Utility of lung biopsy for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2001;164,193-196
 
Raghu, G, Mageto, YN, Lockhart, D, et al The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study.Chest1999;116,1168-1174
 

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References

Kubo, H, Nakayama, K, Yanai, M, et al (2005) Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest128,1475-1482
 
Bjoraker, JA, Ryu, JH, Edwin, MK, et al Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1998;157,199-203
 
Hunninghake, G, Zimmerman, MB, Schwartz, DA, et al Utility of lung biopsy for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2001;164,193-196
 
Raghu, G, Mageto, YN, Lockhart, D, et al The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study.Chest1999;116,1168-1174
 
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