WILDERNESS & ENVIRONMENTAL MEDICINE, ], ]]]–]]] (2014)

Letter to the Editor Novel Anticoagulants Should NOT Be Recommended for High-Risk Activity To the Editor: We read with interest the recent article “Participation of Iatrogenically Coagulopathic Patients in Wilderness Activities” by Hawkins et al1 and commend the authors for the excellent synopsis of the issues regarding anticoagulation and participation in sports and backcountry activities. However, we would like to comment on several of the recommendations made regarding the use of new anticoagulants such as the coagulation cascade factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis) and factor IIa inhibitor dabigatran (Pradaxa). The authors list advantages of these medications over traditional anticoagulation with warfarin (Coumadin). However, in our opinion, the authors do not appropriately address the significant risks associated with these medications. There is currently no way to reliably reverse the anticoagulant effects of these antithrombotic agents in the event of major bleeding,2,3 nor is there a reliable method for determining the extent of anticoagulation when using these medications. This has profound implications for patients undertaking already high-risk activities, such as those involved in backcountry recreation or sports, and is the biggest weakness of these medications as compared with warfarin. The RE-LY trial4 suggested a decreased risk of spontaneous intracranial hemorrhage in patients taking dabigatran compared with warfarin; however, an increased risk of gastrointestinal bleeding was seen in the 2 dabigatran treatment groups. This has important implications for backcountry activity as gastrointestinal bleeding in a remote backcountry location could be life threatening. Hawkins et al1 similarly do not mention other adverse events that occurred in patients taking dabigatran during the RELY trial,4 including a greater number of patients withdrawing from the dabigatran group for serious adverse events and more myocardial infarctions.5 A myocardial infarction in a remote backcountry location is also potentially life threatening. The RE-LY,4 RECOVER,6 ROCKET AF,7 and apixaban ARISTOLE8 trials involved patients who were not engaged in high-risk activities. Intracranial bleeds in these studies were spontaneous or as a result of minor trauma such as falls from standing. It is therefore not appropriate to apply the results of these clinical studies to patients who are engaging in backcountry

activities in which significant falls or other trauma may occur. Bleeding risks of factor Xa inhibitors, factor IIa inhibitors, and warfarin in high-risk contexts are unknown. Without reliable reversal agents or methodologies, any bleeding, whether spontaneous or traumatic, represents a greater risk of morbidity or mortality with these novel anticoagulants. Warfarin carries significant disadvantages including food and drug–drug interactions and the need for regular anticoagulation monitoring. However, in the event of bleeding, reversal of anticoagulation is possible. The authors also fail to mention that dabigatran is renally cleared and dosing adjustments are made for patients with renal impairment. Factors associated with backcountry recreation, including dehydration, strenuous physical activity, or increased use of nonsteroidal antiinflammatory drugs as analgesia may adversely affect renal function, leading to impaired clearance and an increased risk of adverse events. Studies leading to the approval of rivaroxaban excluded patients with renal disease, leading to similar concerns for renal impairment and toxicity from “therapeutic” rivaroxaban dosing. In addition, drug–drug interactions (cytochrome P450 3A4 and P-glycoprotein inhibitors/inducers) have been reported with rivaroxaban and apixaban, which negate some of the reported benefit of this medication. In our opinion, it is dangerous and inappropriate to recommend these anticoagulants to patients who place themselves at higher risk for significant intracranial hemorrhage, gastrointestinal hemorrhage, other major bleeding, and other adverse effects as a result of their activities. These activities are often in a setting where resources are already severely limited and access to emergency medical care may take hours if not days. These novel anticoagulants currently lack a reliable method for determining the extent of anticoagulation or methods to reverse anticoagulation. Additional longitudinal studies and the development of methods to reverse anticoagulation are necessary before recommendations for patients undergoing high-risk activities should be considered.

Michael A. Darracq, MD, MPH UCSF Fresno Medical Education Program Department of Emergency Medicine Division of Medical Toxicology and Division of Wilderness Medicine Fresno, CA, USA

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Letter to the Editor Megann Young, MD UCSF Fresno Medical Education Program Department of Emergency Medicine Division of Wilderness Medicine Fresno, CA, USA

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References 1. Hawkins SC, Caudell MJ, Deloughery TG, Murray W. Participation of iatrogenically coagulopathic patients in wilderness activities. Wilderness Environ Med. 2013;24:257–266. 2. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–1579. 3. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate —a novel, reversible, oral direct thrombin inhibitor:

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interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2011;103:1116–1127. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. Therapeutics Initiative. Dabigatran for atrial fibrillation: why we can not rely on RE-LY. Therapeutics Letter Issue 80. Available at: http://www.ti.ubc.ca/letter80. Accessed January 5, 2014. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992.

Novel anticoagulants should NOT be recommended for high-risk activity.

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