Chest
Volume 128, Issue 3, September 2005, Pages 1475-1482
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Clinical Investigations
Anticoagulant Therapy for Idiopathic Pulmonary Fibrosis

https://doi.org/10.1378/chest.128.3.1475Get rights and content

Study objective

To evaluate the effect of anticoagulant therapy on the survival of patients with idiopathic pulmonary fibrosis (IPF).

Design

Prospective study.

Setting

Five hospitals located in the Miyagi prefecture in Japan, including a university hospital, a Red Cross hospital, two public general hospitals, and a municipal hospital.

Patients

Fifty-six patients with IPF (mean age, 69.4 years; range, 47 to 89) admitted to the hospitals from April 2001 to April 2004.

Interventions

Patients were assigned to receive prednisolone alone or prednisolone plus anticoagulant therapy. The anticoagulants included oral warfarin in an outpatient setting and low-molecular-weight heparin for rehospitalized patients with severely progressive respiratory failure.

Measurements and results

There was no difference in baseline characteristics, including age, gender, clinical condition, pulmonary function, and plasma d-dimer level between the nonanticoagulant group and the anticoagulant group. The overall survival and hospitalization-free periods were assessed. There was a significant difference between survival curves of the nonanticoagulant group and the anticoagulant group, with a 2.9 hazard ratio (p = 0.04, Cox regression model). There was no significant difference in the probability of a hospitalization-free period between groups. The major cause of clinical deterioration was acute exacerbation during follow-up in the present study. Therefore, the mortality and plasma d-dimer levels in patients with an acute exacerbation were also assessed. The mortality associated with acute exacerbations of IPF in the anticoagulant group was significantly reduced compared to that in the nonanticoagulant group (18% vs 71%, respectively; p = 0.008, Fisher Exact Test). Furthermore, the plasma d-dimer levels in patients who died were significantly higher than those in survivors during acute exacerbation of IPF (3.3 ± 2.3 μg/mL vs 0.9 ± 0.7 μg/mL, p < 0.0001). Histologic analysis performed in three patients who died due to an exacerbation of IPF in the nonanticoagulant group demonstrated the features of usual interstitial pneumonia and acute lung injury.

Conclusions

Our data suggested that plasma d-dimer levels are associated with mortality in patients with an acute exacerbation of IPF, and that anticoagulant therapy has a beneficial effect on survival in patients with IPF.

Section snippets

Patients

We conducted a prospective study of 56 patients with IPF who were admitted to five hospitals located in the Miyagi prefecture in Japan from April 2001 to April 2004. The hospitals were a university hospital, a Red Cross hospital, two public general hospitals, and a municipal hospital. Before enrollment in this study, all patients had received a diagnosis of IPF and had demonstrated progressive deterioration of IPF in varying degrees, despite conventional therapy without prednisolone. The mean

Intervention

To evaluate the effect of anticoagulant therapy on the survival of patients with IPF, participants were randomly assigned to receive oral prednisolone alone (nonanticoagulant group) or oral prednisolone plus oral warfarin (anticoagulant group). The oral prednisolone therapy in both groups was performed initially at a dosage of 0.5 to 1.0 mg/kg/d for 4 weeks, with subsequent tapering of the dose to 10 to 20 mg/d over a 1-month period. Warfarin was used for patients in the anticoagulant group at

Plasma D-dimer

D-dimer is a final product of cross-linked fibrin degradation and is released into the circulation during the process of endogenous fibrinolysis. D-dimer has been reported to be elevated in acute myocardial infarction,13 unstable angina,14 and deep venous thrombosis,15 as well as in patients with suspected pulmonary embolism.16 Furthermore, the procedure for d-dimer is simple, inexpensive, and noninvasive, compared to angiography or scintigraphic examination. Therefore, d-dimer and

Statistical Analysis

Comparisons of baseline characteristics between the nonanticoagulant group and the anticoagulant group were tested by an unpaired t test and χ2 test. Values are reported as mean ± SD. Significance was accepted at p < 0.05. Survival time to death was calculated from the initial visit until death or censoring. Patients were censored if they were still alive at the last contact. Survival estimates were computed using standard Kaplan-Meier estimates with the log-rank test for the p value of

Patient Characteristics

There was no difference in baseline characteristics, including age at enrollment, gender, clinical condition, pulmonary function, and plasma level of d-dimer, between the nonanticoagulant group and the anticoagulant group (Table 1). The overall mean age was 69.4 years. There were 31 men and 25 women. The overall %FVC was 70%. All participants were nonsmokers. The mean plasma d-dimer level was increased at the time of the initial visit (2.02 ± 1.3 μg/mL).

Survival to Death

Twenty of the 33 patients in the nonanticoagulation group died during follow-up (median, 399 days; range, 35 to 1,106). Five of the 23 patients in the anticoagulant group died during follow-up (median, 347 days; range, 55 to 1,106) [Table 2]. The 1-year survival rates for the nonanticoagulant group and the anticoagulant group were 58% and 87%, respectively. The 3-year survival rates for the nonanticoagulant group and the anticoagulant group were 35% and 63%, respectively. There was a

Rehospitalization and Hospitalization-Free Period

Twenty-two patients in the nonanticoagulant group were rehospitalized with acute respiratory failure during follow-up. Since some patients were rehospitalized several times, the total number of rehospitalizations in this group was 29. Thirteen patients in the anticoagulant group were hospitalized with a total of 15 hospitalizations (Table 2). The hospitalization-free period was calculated from the initial visit until the second hospitalization. The probability of a 1-year period without

Acute Exacerbation of IPF and Plasma D-dimer Level

At readmission to the hospital with progressive respiratory failure, all patients underwent ultrasonic cardiography, HRCT scanning with enhancement, blood biochemical analysis, and blood and sputum microbiological analysis together with a physical examination. The causes of readmission to the hospital included acute exacerbation of IPF, pneumonia, heart failure, and sepsis (Table 2). There were no cases with obvious pulmonary thromboembolism or deep venous thrombosis. Acute exacerbation of IPF

Pathology Findings

We performed postmortem examinations in three patients with an exacerbation of IPF in the nonanticoagulant group. All exhibited similar histologic characteristics with the usual interstitial pneumonia and superimposed features of acute lung injury (Fig 4, top left, A, and top right, B). There was a honeycomb appearance in the subpleural zone and diffuse consolidation of lung parenchyma by septal fibrosis. There was also a diffuse and exudative alveolar damage with varying degrees of hyaline

Discussion

In this study, we found a beneficial effect of combined anticoagulant and prednisolone therapy on the survival of IPF patients. Corticosteroids are the mainstay of therapy in IPF patients. However, medication with corticosteroid alone resulted in a poor prognosis, with a 3-year survival of 35% in the present study as previously reported.19 In contrast, combined therapy with combined anticoagulant and prednisolone therapy gave a better prognosis, with a 3-year survival of 63% in the present

Acknowledgement

We thank Mr. Grant Crittenden for the English correction. We also thank Dr. Toru Takahashi for advice on pathology.

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