Warfarin in Idiopathic Pulmonary Fibrosis: Friend or Foe, Is It a Matter of Genes and Heparin? To the Editor: In the past 2 years, we have witnessed a publication ...
Correspondence Warfarin in Idiopathic Pulmonary Fibrosis: Friend or Foe, Is It a Matter of Genes and Heparin? To the Editor:
In the past 2 years, we have witnessed a publication burst in both the diagnostic and therapeutic field of idiopathic pulmonary fibrosis (IPF). Starting with the documentation of the recent American Thoracic Society/European Respiratory Society/ Japanese Respiratory Society/Latin American Thoracic Association guidelines for IPF (1) and ending with the emergence of four hallmark studies (2–5) investigating the efficacy of different treatment agents, it is now widely accepted that IPF represents the most challenging disease entity for respiratory physicians overcoming obstructive lung diseases and lung cancer. Based on recent evidence, derived from randomized controlled trials, treatment guidelines for IPF need to be cautiously reassessed because several weak recommendations are now considered to be strong, either against or in favor of certain pharmaceutical agents. Warfarin represents one of them. In the recent ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) study (4), investigating the anticoagulant effectiveness in patients with IPF, authors clearly demonstrated that warfarin use had more detrimental rather than beneficial effects, accelerating disease progression and leading a significant number of patients enrolled toward either sudden death, or acute exacerbation and respiratory failure. On the basis of these negative results, investigators speculated that coagulation cascade may exert a protective role during fibrogenesis, and thus its inhibition resulted in fatal outcomes (6). With regard to this conclusion, we would like to make the following comments: 1. Warfarin is an anticoagulant that acts by inhibiting the vitamin K–dependent synthesis of biologically active forms of the calcium-dependent clotting factors II, VII, IX, and X, as well as the regulatory factors protein C, protein S, and protein Z (7). Nevertheless, when warfarin is newly and rapidly started in high-dosage regimens to achieve international normalized ratios between 2.0 and 3.0, especially in treatment-naive patients like those enrolled in the ACE study, it may promote a prothrombotic state mainly due to the fact that in the first 36 hours after its administration, warfarin reduces the levels of protein C, leading to a diminished degradation of factors Va and VIIIa. Consequently the hemostasis system becomes biased toward thrombus formation. Therefore, it has been proposed that when warfarin is loaded rapidly in doses larger than 5 mg per day, it is beneficial to coadminister heparin, which acts on antithrombin-factor II inhibition, exerting a protective effect for the first 4–5 days of warfarin usage (7). Based on the ACE study design, investigators did not report any prophylactic coadministration of heparin with high doses of warfarin. If heparin was not coadministered with warfarin, then this evidence may provide a possible explanation for the excessive number of deaths in the warfarin arm, especially when all deaths were not provoked by hemorrhagic episodes. In line with this notion, it is conceivable to speculate that deaths due to myocardial infarction, accelerated pulmonary hypertension, and respiratory failure or disease acute exacerbation could be attributed to occult myocardial and pulmonary embolic episodes resulting from high warfarin loading doses, in patients with a fragile balance between
oxygen supply and metabolic tissue demands. Although none of the fatal episodes did occur on an acute basis, nevertheless the triggering of the coagulation cascade may have been initialized weeks before, by the time warfarin was started and elicited clinically meaningful outcomes several days after. Further supporting our premise, Kubo and colleagues (8) documented that oral warfarin was insufficient to prevent disease acute exacerbation, whereas intravenous heparin administration clearly reduced the mortality in hospitalized patients with acute deterioration. 2. Finally, it is worth mentioning that major outcome discrepancies between ACE trial and the study by Kubo and coworkers (8), where a beneficial effect of use of anticoagulants (both warfarin and heparin) was reported, could also be explained by different pharmacogenetic backgrounds of the studied population because 92% of patients enrolled in the ACE trial were white, whereas in the Kubo study, all patients were of Asian origin (Japanese). In particular, Asian and white subjects present with major differences regarding polymorphisms in VKORC1 and CYP2C9 genes encoding for the major enzymes responsible for coumarin targets and metabolism (9). The latter evidence could partially explain distinct drug responsiveness among different ethnic groups as happens with Asian patients with lung adenocarcinoma and mutations in epidermal growth factor receptor (EGFR) that exhibit a favorable clinical response to tyrosine kinase inhibitors, including erlotinib and gefitinib. In conclusion, given disease phenotypic and pathogenetic complexity, we highlight the need for cautious interpretation of the results emerging from the ACE study, because anticoagulants and especially heparin may be proven beneficial in patients with IPF, if administered in a selective group of patients including those experiencing acute exacerbation on the basis of pharmacogenetically tailored treatment. Further studies encapsulating molecular and histological staging of different IPF patterns are sorely needed to support this notion. Author disclosures are available with the text of this letter at www.atsjournals.org.
Argyris Tzouvelekis, M.D., Ph.D. George Margaritopoulos, M.D., Ph.D. Stylianos Loukides, M.D., Ph.D. Demosthenes Bouros, M.D., Ph.D. Democritus University of Thrace Alexandroupolis, Greece
References 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824. 2. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760–1769. 3. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079–1087. 4. Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186:88–95.
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5. Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:1968–1977. 6. Muller-Quernheim J, Wells A. Evidence-based recommendations in idiopathic pulmonary fibrosis: a year is a long time in interstitial lung disease. Am J Respir Crit Care Med 2012;186:5–7. 7. Litin SC, Gastineau DA. Current concepts in anticoagulant therapy. Mayo Clin Proc 1995;70:266–272. 8. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:1475–1482. 9. Oldenburg J, Bevans CG, Fregin A, Geisen C, Muller-Reible C, Watzka M. Current pharmacogenetic developments in oral anticoagulation therapy: the influence of variant VKORC1 and CYP2C9 alleles. Thromb Haemost 2007;98:570–578.
The call for a cautious constant reassessment of guidelines of treatment options in idiopathic pulmonary fibrosis is correct, and at least for now, as practicing clinicians, we need to view warfarin as a strong no. We would argue that there simply isn’t enough evidence to place a call for a vote on alternative anticoagulants at this time. Author disclosures are available with the text of this letter at www.atsjournals.org.
Imre Noth, M.D. University of Chicago Chicago, Illinois
Reply
Mitchell Olman, M.D. Cleveland Clinic Cleveland, Ohio
From the Authors:
1. The authors point out the prothrombotic effects of high-dose early warfarin usage when not conducted in conjunction with intravenous heparin. It was a study design concern and one of our first questions upon seeing the results, but upon review of the data, we believe that this is an unlikely cause as the patients were initiated at a dose of no higher than 5 mg per day in anticipation of this issue. Additionally, none of the mortality events occurred within the early time frame suggested. The mortality plot was included in the paper to help address this issue. The argument that the coagulation cascade was initialized weeks before by the warfarin seems unsupported. 2. The authors point out the beneficial effect noted in the Kubo and colleagues study (2), and argue that Kubo and coworkers demonstrated that warfarin was insufficient and therefore instituted heparin. However, the protocol called for all subjects to receive dalteparin, independent of warfarin use upon rehospitalization. 3. Although there is little doubt that genetics play a role in idiopathic pulmonary fibrosis and in the pharmacologic responses, we think it unlikely that potential mutations or polymorphisms in warfarin metabolism enzymes explain the detrimental effects of warfarin. As the home monitoring system allowed patients to perform international normalized ratio monitoring 1–2 times per week, any warfarin resistance or sensitivity was rapidly identified and appropriate dose adjustments made. Lastly, as pointed out by Tzouvelekis and colleagues, clinically overt bleeding or thromboses did not account for any mortality increase in the warfarin-treated group. Determining whether genetic differences contributed to the results observed through as yet unknown mechanisms of action will require further exploration. 4. As highlighted in the ACE paper, there are many methodological differences between our study design and that of
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Kubo and colleagues that could explain the difference in the results. We agree that future consideration other anticoagulation drugs such as heparin or factor Xa inhibitors remains warranted (3, 4). Given the complex interplay of the coagulation cascade, at this time we are simply not in a position to address the potential benefits of these other agents.
Copyright ª 2013 by the American Thoracic Society
We greatly appreciate the call for cautious interpretation of the Anticoagulation Effectiveness (ACE) results by Dr. Tzouvelekis and colleagues. As we highlighted in the DISCUSSION section of the paper, the ACE study (1) was not designed to address mechanism and this remains to be elucidated. As the hazard ratio was nearly 5 in the treatment arm, there is no question that the use of warfarin was harmful in this group. Dr. Tzouvelekis and colleagues do an outstanding job of explaining the complexity of action of warfarin and its downstream effects and suggest several possible etiologies for this outcome. We would like to take this opportunity to address several key points made in the letter:
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For the IPFnet References 1. Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186:88–95. 2. Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe M, Sasaki H. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128:1475–1482. 3. Markart P, Nass R, Ruppert C, Hundack L, Wygrecka M, Korfei M, Boedeker RH, Staehler G, Kroll H, Scheuch G, et al. Safety and tolerability of inhaled heparin in idiopathic pulmonary fibrosis. J Aerosol Med Pulm Drug Deliv 2010;23:161–172. 4. Scotton CJ, Krupiczojc MA, Konigshoff M, Mercer PF, Lee YC, Kaminski N, Morser J, Post JM, Maher TM, Nicholson AG, et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J Clin Invest 2009;119:2550–2563. Copyright ª 2013 by the American Thoracic Society
Severe Vitamin D Deficiency: A Biomarker of Exacerbation Risk? To the Editor:
With great interest, we have read the article of Kunisaki and colleagues reporting in a large chronic obstructive pulmonary disease (COPD) cohort the absence of relationships between baseline serum vitamin D (25OHD) levels and the risk for acute exacerbations during 1 year of follow-up (1). Although the authors acknowledged some weaknesses of their observational design, we think that another important bias may have troubled their findings. The authors studied all patients from whom baseline blood samples were available, including those taking vitamin D supplementation at baseline. Most patients with COPD taking vitamin D supplements in a clinical setting have a documented deficiency or suffer from osteopenia or osteoporosis. In general, these patients have worse pulmonary function, more comorbidities, and exacerbations compared with a nonsupplemented group because they just represent a more severe stage of the disease. Once supplemented, 25OHD levels no longer reflect the underlying COPD severity. That these patients were included in the analysis of Kunisaki and colleagues may explain why the subgroup with highest 25OHD levels (.40 ng/ml, n ¼ 11%) had more exacerbations and a shorter interval to first exacerbation than the groups with low to normal 25OHD levels. In our Belgian intervention study,
