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(Chest. 2005;128:1475-1482.)
© 2005 American College of Chest Physicians

Anticoagulant Therapy for Idiopathic Pulmonary Fibrosis*

Hiroshi Kubo, MD, FCCP; Katsutoshi Nakayama, MD; Masaru Yanai, MD; Tomoko Suzuki, MD; Mutsuo Yamaya, MD; Mika Watanabe, MD and Hidetada Sasaki, MD, PhD

* From the Departments of Geriatric and Respiratory Medicine (Drs. Kubo, Nakayama, Suzuki, Yamaya, and Sasaki) and Pathology (Dr. Watanabe), Tohoku University School of Medicine, Sendai; and Divisions of Respiratory Medicine (Dr. Yanai), Ishinomaki Red Cross Hospital, Ishinomaki, Japan.

Correspondence to: Hidetada Sasaki, MD, PhD, Professor and Chairman, Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.

Key Words: acute exacerbation • anticoagulant therapy • idiopathic pulmonary fibrosis • low-molecular-weight heparin • prognosis • survival • warfarin


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Idiopathic pulmonary fibrosis (IPF) is a chronic, diffuse interstitial pulmonary disease associated with a histologic appearance of usual interstitial pneumonia. IPF has a worse prognosis, and the median survival is 4 to 5 years after symptoms of cough or breathlessness develop.1 IPF is characterized by progressive injury, inflammation, and fibrosis of the lung parenchyma.1 The prognosis of acute exacerbations of IPF was reported to be very poor.2345 There is no effective therapy with proven and unequivocal benefits currently available, and the nature and appropriate therapy for this condition are still to be established.

Fibrotic lung diseases are accompanied by inflammation and vascular injury.678 Abundant neointimal tissue factor, a maximal prothrombotic stimulus, is exposed to circulating blood following endothelial disruption, thereby triggering rapid coagulation. Thus, thrombosis in the pulmonary vasculature might exist especially where alveolitis and/or fibrotic processes of the lung are present. In fact, although pulmonary embolism is a documented cause of death in IPF patients,9 few reports focus on the role of the coagulation system in IPF. The aims of the present study were to evaluate whether a coagulation disorder occurs in IPF patients, and whether the administration of anticoagulant agents has a beneficial effect on the survival of patients with IPF.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
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 age at the time of hospital admission was 69.4 years (range, 47 to 89). The diagnosis of IPF was determined previously by either histologic evaluation of open-lung biopsy or transbronchial lung biopsy specimens, or radiologic evaluation using high-resolution CT (HRCT), or both. Histologic evidence demonstrated the characteristics of usual interstitial pneumonia and showed the various stages of interstitial lung disease including alveolitis, fibrosis, honeycombing, and a patchy reticular pattern that was predominantly evident in the basal region of the periphery of the lung field and was associated with traction bronchiectasis. HRCT-based diagnosis was performed by two radiologists who did not know the purpose of the present study. The typical HRCT appearance demonstrated honeycombing, intralobular reticulations, and traction bronchiectasis with or without ground-glass opacification.101112 Nonspecific interstitial pneumonia was excluded based on histologic findings or HRCT appearance. Patients were excluded if they had clinical or serologic evidence of collagen vascular disease, a history of exposure to known fibrogenic agents, active infection, malignancy, hemoptysis, hypersensitive pneumonitis, GI bleeding, or ARDS. Patients were also excluded if they had obvious signs of preexisting pulmonary embolism, pulmonary hypertension due to pulmonary thromboembolism, or phlebitis by color Doppler ultrasonography or enhanced CT. All patients were nonsmokers. Pulmonary function tests (percentage of predicted FVC [%FVC] and carbon monoxide diffusing capacity) and blood gas analysis (PaO2) were performed on enrollment in this study.

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 the dose required to keep the values of the international normalized ratio between 2.0 and 3.0. All patients were informed of the protocol of this study on enrollment. We used random-number tables for simple randomization. As a result of random allocation, there were 33 patients in the nonanticoagulant group and 31 patients in the anticoagulant group. Among the 31 patients in the anticoagulant group, 6 patients declined participation because they were afraid of side effects and disliked the extra blood sampling required for monitoring the international normalized ratio. One patient stopped the study due to purpura. One patient dropped out because he moved to another prefecture. Our final enrolled cohort included 33 patients in the nonanticoagulant group and 23 patients in the anticoagulant group.

During follow-up, approximately 60% of all patients were rehospitalized due to severely progressive respiratory failure secondary to various causes including acute exacerbation of IPF, bacterial pneumonia, heart failure, or sepsis. During the period of hospitalization for these crises, patients in the anticoagulant group received IV low-molecular-weight heparin, dalteparin sodium instead of oral warfarin, at a dose of 75 IU/kg/d for 1 to 2 weeks. No serious complications, such as bleeding, were observed with the anticoagulant agents. Steroid therapy was stopped for patients readmitted with obvious bacterial infection or heart failure. Conversely, patients readmitted with an acute exacerbation of IPF were treated with high doses of methylprednisolone (500 to 1,000 mg/d) for 3 days. All patients in both groups who were readmitted received oxygen therapy and antibiotic treatment. Acute exacerbations were defined as previously described with a slight modification2: (1) exacerbation of dyspnea within a few weeks; (2) newly developing diffuse pulmonary infiltrates on chest radiographs or HRCT; (3) deterioration of hypoxemia (PaO2/fraction of inspired oxygen < 300); and (4) absence of infectious pneumonia, heart failure, and sepsis.

The primary end points of this study were overall survival time to death and hospitalization-free period. Survival time to death was calculated from the initial visit until death or censoring. The hospitalization-free period was also calculated from initial visit until the second hospitalization due to severely progressive respiratory failure or censoring.

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 high-molecular-weight fibrin degradation products are thought to be useful markers of abnormal coagulation balance.17 However, to our knowledge, there is no report on the plasma d-dimer level in patients with acute exacerbation of IPF. The d-dimer assay was performed in all participants at entry to this study. The plasma d-dimer was also measured in patients with an acute exacerbation of IPF (21 patients in the nonanticoagulant group and 11 patients in the anticoagulant group) on the first and 14th days following readmission to the hospital.

For the measurement of plasma d-dimer levels, blood samples were collected by clean venous puncture into tubes containing 3.8% trisodium citrate (9:1, volume/volume). Platelet-poor plasma was obtained by centrifuging at 3,000g for 15 min. Plasma d-dimer levels were measured using an enzyme immunosorbent assay (Boehringer; Mannheim, Germany).18 The normal level for plasma d-dimer in our laboratory is < 0.5 µg/mL.

Statistical Analysis
Comparisons of baseline characteristics between the nonanticoagulant group and the anticoagulant group were tested by an unpaired t test and {chi}2 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 survival curves between patients with and without anticoagulant therapy. Cox regression analysis was also performed to assess the relative risk of survival curves between the anticoagulant group and the nonanticoagulant group, which was adjusted for age and baseline %FVC. Statistical software (StatView version 5.0; SAS Institute; Cary, NC) was used for analysis.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
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).


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  		Table 1.. Baseline Characteristics of the Patients*

 
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 significant difference between the survival curves of the two groups (Fig 1 ; p = 0.049, log-rank test). According to the Cox regression model, the hazard ratio, which was adjusted for age and baseline %FVC, was 2.9 (95% confidence interval, 1.0 to 8.0; p = 0.04) for death in the nonanticoagulant group compared to the anticoagulant group (Fig 1).


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  		Table 2.. Clinical Outcome During Follow-up*

 


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  		Figure 1.. Kaplan-Meier survival estimate with censoring ({perp}) between the nonanticoagulant group and the anticoagulant group in regard to overall survival. Open circles indicate the survival curve in the anticoagulant group. Closed circles indicate the survival curve in the nonanticoagulant group. There was a statistical significance between survival curves of the anticoagulant group and the nonanticoagulant group (p = 0.049, log-rank test). According to the Cox regression model, the hazard ratio for death was 2.9 in the nonanticoagulant group compared to the anticoagulant group (adjusted for age and baseline %FVC; 95% confidence interval, 1.0 to 8.0; p = 0.04).

 
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 hospitalization was 39% for the nonanticoagulant group and 74% for the anticoagulant group, but this was not statistically significant (p = 0.3, log-rank test) [Fig 2 ].



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  		Figure 2.. Kaplan-Meier estimate with censoring ({perp}) between the nonanticoagulant group and the anticoagulant group in regard to hospitalization-free period. Open circles indicate the survival curve in the anticoagulant group. Closed circles indicate the survival curve in the nonanticoagulant group. There was no statistical significance of probability of hospitalization-free period between the anticoagulant group and the nonanticoagulant group (p = 0.3, log-rank test).

 
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 was the most frequent cause of readmission to the hospital in both the nonanticoagulant group and the anticoagulant group (72% and 73%, respectively). However, the mortality from acute exacerbation of IPF in the anticoagulant group was significantly reduced compared to that in the nonanticoagulant group (15 deaths in 21 acute exacerbations vs 2 deaths in 11 acute exacerbations, respectively; p = 0.008, Fisher Exact Test; Table 2).

The plasma d-dimer levels in the anticoagulant group were reduced by oral warfarin administration before readmission to hospital (1.1 ± 1.2 µg/mL). However, the plasma d-dimer levels on the first day of readmission to hospital with acute exacerbation were slightly elevated in both groups (2.2 ± 1.1 µg/mL in the nonanticoagulant group vs 2.1 ± 1.0 µg/mL in the anticoagulant group). The plasma d-dimer level in the anticoagulant group with acute exacerbation was significantly reduced by IV administration of dalteparin sodium (2.1 ± 1.0 µg/mL on day 1, vs 0.8 ± 1.0 µg/mL on day 14 (p = 0.01, paired t test; Fig 3 ). Conversely, no significant difference between the plasma d-dimer levels on day 1 and day 14 following readmission to the hospital was evident in the nonanticoagulant group with acute exacerbation. The changes in plasma d-dimer levels of the patients before and during readmission to hospital with acute exacerbation are summarized in Table 3 . Finally, 17 of 32 patients with an acute exacerbation of IPF died during hospitalization (15 of 21 patients in the nonanticoagulant group and 2 of 11 patients in the anticoagulant group; Fig 3). The plasma d-dimer level on day 14 in the deceased patients was significantly higher than that in the survivors of an acute exacerbation of IPF (3.3 ± 2.3 µg/mL vs 0.9 ± 0.7 µg/mL, p < 0.0001).



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  		Figure 3.. Comparisons of plasma d-dimer levels on day 1 and day 14 during hospitalization due to acute exacerbation of IPF in the nonanticoagulant group (left, A) and the anticoagulant group (right, B). Open circles indicate the values from survivors with acute exacerbation of IPF. Closed circles indicate those from patients who died during hospitalization. The bold black bars indicate the mean values of groups; *p = 0.01, paired t test. The dashed line indicates the upper limit of the plasma d-dimer level (< 0.5 µg/mL).

 

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  		Table 3.. Changes in Plasma D-dimer Levels*

 
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 membranes. Furthermore, a few small clots were detected in the alveolar capillary bed in 1 patient (Fig 4, bottom left, C), and there was evidence of fibrin deposition in the alveolar space of another patient; stained red with Elastica-Masson staining (Fig 4, bottom right, D). However, no evidence of massive pulmonary embolism was found in these samples.



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  		Figure 4.. Histopathologic analysis of lung tissue derived from patients who died due to exacerbation of IPF in the nonanticoagulant group. All samples were stained with Elastica-Masson staining. Each bar in the panel indicates 50 µm. Top left, A: fibrosing stage of IPF, with marked fibrosis and dilatation of residual airspaces with glandular metaplasia and a honeycomb appearance. Top right, B: acute exacerbation of IPF, revealing histologic features of diffuse alveolar damage including edematous thickening and hyperemia of the alveolar wall with marked swelling of reactive type II pneumocytes. Note the extensive hyaline membrane formation and focal intra-alveolar organization with an active mesenchymal cell reaction (fibroblastic foci). Bottom left, C: an area of the alveolar capillary bed with large magnification from one patient who died due to acute exacerbation of IPF. A small clot was detected in the dilated capillary (arrows). Bottom right, D: fibrin deposition in an alveolar space from another patient. The fibrin deposition was stained red with Elastica-Masson staining (arrows).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
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 study. Although corticosteroids exert a potent anti-inflammatory effect, they may induce a hypofibrinolytic state.20 It is possible that anticoagulation cancels out the adverse effect of corticosteroid on the intravascular coagulation balance. We did not have a patient group treated with anticoagulation alone, and it is therefore unclear if the improved prognosis resulted from the effects of anticoagulation alone or the combined effect of both corticosteroid and anticoagulant. Although the number of patients and the observation period in the present study were limited, our data support a new therapeutic approach using anticoagulants in patients with IPF.

According to this study, the major cause of death in patients with IPF was acute exacerbation, in which the plasma d-dimer level was elevated. The acute exacerbation is defined clinically after excluding infection and heart failure. IV administration of dalteparin sodium significantly decreased the plasma d-dimer level and mortality during rehospitalization with exacerbation of IPF. Interestingly, the plasma d-dimer level was slightly elevated in IPF patients at entry to this study (Table 1). Since an elevated plasma d-dimer level is thought to be a marker for intravascular coagulation, these results suggests the presence of an activated coagulation system in patients with IPF and a relationship between intravascular coagulation and mortality in acute exacerbations of IPF. Panos et al9 described that pulmonary embolism is an important cause of death in IPF patients. However, Kotani et al21 reported that an increased procoagulant activity was observed in BAL fluid from IPF patients. Tissue factor expression and fibrin deposition were detected by specific antibodies in the alveoli from patients with IPF.22 Since d-dimer is derived from fibrin, plasma d-dimer may be influenced by increased intra-alveolar fibrin deposition. Thus, careful hemostatic analysis might reveal important prognostic factors in IPF patients.

The exact mechanism of the beneficial effect of anticoagulation therapy for IPF is not known. Histologic analysis on the patients who died due to exacerbation of IPF in the nonanticoagulant group revealed the usual interstitial pneumonia with superimposed features of acute lung injury. There was a honeycomb appearance and an exudative or organizing phase of diffuse alveolar damage. These findings were compatible with previous reports23 showing a pattern of usual interstitial pneumonia and acute lung injury with or without hyaline membranes. Although evidence of massive pulmonary embolisms was not found in the samples, a few small clots were detected in the alveolar capillary bed and there was evidence of fibrin deposition in the alveolar space. Furthermore, it is described that extravascular fibrin deposition and coagulation play an important role in the pathogenesis of acute lung injury and related fibrosis.23 The extravascular function as well as the intravascular function of anticoagulant therapy might be associated with the beneficial effects evident in this study.

There was a tendency for a longer hospitalization-free state in the anticoagulant group compared to the nonanticoagulant group, but this was not statistically significant. This suggests that anticoagulation with oral warfarin in the outpatient setting is insufficient to prevent risk of acute exacerbation of IPF. However, anticoagulant therapy following readmission to the hospital, ie, IV heparin administration, could reduce the mortality of patients with acute exacerbation. The reason for the discrepancy between the beneficial effect of heparin on mortality of acute exacerbations of IPF and the ineffectiveness of oral warfarin in preventing the risk of acute exacerbation is not clear. One possibility is the absence of rigid control of anticoagulation in outpatients. It is more difficult to rigidly control the intravascular coagulation by means of oral warfarin administration compared to IV heparin therapy that can be used in hospitalized patients. Another possibility is that heparin exerts additional effects compared to anticoagulation with warfarin. Several in vitro studies2425 indicate that heparin may directly down-regulate the expression of various factors implicated in the progression of interstitial fibrosis such as transforming growth factor-ß1, endothelin-1, and fibroblast growth factor-2. These reports suggest the existence of important differential effects between oral warfarin and IV heparin (dalteparin sodium injection) administration.

In summary, we demonstrated the beneficial effect of combined anticoagulant and corticosteroid therapy on the survival of IPF patients. Increased plasma d-dimer level was observed in patients with IPF, suggesting the presence of an activated hemostasis system. The main effect of anticoagulant therapy is lowering the mortality rate after acute exacerbation of IPF. Anticoagulant therapy may be an additional new strategy to treat IPF patients.


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


   Footnotes
 
Abbreviations: %FVC = percentage of predicted FVC; HRCT = high-resolution CT; IPF = idiopathic pulmonary fibrosis

Received for publication August 23, 2004. Accepted for publication January 31, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Use of Anticoagulation in Idiopathic Pulmonary Fibrosis: too early to say
Imran Mohammed, et al.
Chest Online, 21 Nov 2005 [Full text]
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