Abstract
To the Editor:
We appreciate Doctors Darracq and Young’s thoughtful response to our article. Our goal was to raise awareness of this potential issue for medical screeners and wilderness providers—an issue that is rapidly evolving but for which there is little evidence or consensus to guide their decision-making. Given the novelty of these agents, the wide diversity of ability and baseline health in potential consumers using these agents, and the minimal evidence for their safe or unsafe usage in austere environments, we appreciate that well-meaning practitioners can arrive at different conclusions and recommendations. In that context we respect Darracq and Young’s conclusions, but disagree with their contention that alternative opinions are “dangerous and inappropriate.”
In general we agree with their final assessment that “additional studies…are necessary before recommendations for patients undergoing high risk activities should be considered.” In fact, our conclusion states “There are inadequate resources in the literature for consultant wilderness physicians to advise organizations on risk management or to follow evidence-based practices in treating coagulopathic patients in wilderness settings. This case study and literature review begins to address that paucity of resources, and includes recommendations based on the research currently available. More research is required to fully understand the role and risks of anticoagulation in the wilderness.” In addition, at least rivaroxaban is being specifically marketed in widely disseminated advertising as applicable for wilderness or austere environments (
In the context of making those recommendations, we think Darracq and Young’s broad categorization of all outdoor and backcountry activities as “high-risk” is both impractical and erroneous. Not all wilderness activities carry the same level of risk. The risks associated with specific activities and the lack of supporting evidence regarding these risks should not be overlooked as discussion of specific anticoagulants ensues. There remains a paucity of evidence addressing risk stratification for those using anticoagulants in outdoor activities, and more research is needed.
We believe the most important element to caregiver or screener decision-making is that the limited data available be accurately and correctly characterized. In that context, we’d like to clarify specific issues regarding anticoagulants raised by Darracq and Young: In RE-LY, dabigatran was not associated with a “suggested” decrease in intracranial hemorrhages (ICHs), but rather with a statistically significant decrease (relative risk 0.40, P < .001). This marked decrease in ICH is a uniform finding in all atrial fibrillation trials of the direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban).
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RE-LY did not show a significant increase in myocardial infarction (MI) with dabigatran (P = .07). It is true that two meta-analyses have shown an increase in MI with dabigatran. However, in both papers this risk was outweighed by an overall mortality benefit.2,3 In the atrial fibrillation trials, increased gastrointestinal (GI) bleeding was seen with both dabigatran and rivaroxaban (absolute increase in this elderly population of 0.5–1%/y), but this increased bleeding was not seen with apixaban.4,5 Also, the increase in GI bleeding with dabigatran was not seen in a US Food and Drug Administration mini-sentinel review.
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Although it is true that all the direct oral anticoagulants have an element of renal clearance, it would seem improbable for someone in the backcountry to unexpectedly and abruptly decrease their creatinine clearance to the extent where dose adjustment for dabigatran (<30 mL/min), rivaroxaban (<50 mL/min), or apixaban (<15 mL/min) would be required. Patients on these new agents will have elevations of common laboratory tests, including activated partial thromboplastin time (dabigatran) and the international normalized ratio (INR; rivaroxaban, apixaban).
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Levels for monitoring are available at reference laboratories. Only drugs that are strong inhibitors of both CYP3A4 and P-glycoprotein interact with rivaroxaban and apixaban. For most patients these are HIV antiviral agents and azoles.
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We agree this would be an important screening and treatment consideration. Although prothrombin complex concentrates do make the INR look better in warfarin-induced bleeding, this does not seem like a practical or widely available drug in the backcountry. In addition, although Darracq and Young seem to believe that readily available reversal is a sine qua non to anticoagulant drug use, there are no robust data that outcomes are improved with its use. Given that 75% of patients with warfarin-induced ICH end up dead or disabled, it would seem better to use drugs with a lower incidence of this devastating complication. Also, analysis of clinical trials to date have not shown worse outcomes with bleeding as a result of direct oral anticoagulants when compared with warfarin.9,10 Given that aspirin, clopidogrel, prasugrel, ticagrelor, fondaparinux, and low-molecular-weight heparin also do not have reversal agents, the new agents are not unique in this regard. As we pointed out in our published discussion, clopidogrel may carry even more risk than warfarin for immediate ICH and has no reversal agent; however, like aspirin, it has been available for years and would likely not be routinely flagged in the medical screening process as a drug that would exclude participation in outdoor activities.
In conclusion, it is important to recognize that our discussion did not mandate use of new anticoagulation agents, but suggested some of their properties may be more convenient and safer than alternatives for those who want to enjoy the outdoors. Specific situations and activities should also be taken into consideration. Most importantly, we are in agreement with Darracq and Young that more research is needed to clarify these questions.