Stephan Moll, MD
Associate Professor, Hemophilia and Thrombosis Center, University of North Carolina School of Medicine, Department of Medicine, Division of Hematology-Oncology, Chapel Hill, NC
Dr. Moll has consulted for OrthoMcNeil.
A 48-year-old man taking warfarin long-term for recurrent venous thromboembolism asks during his annual follow-up clinic about switching to dabigatran. He has had fluctuating INRs requiring testing approximately every two weeks and states that he is tired of dealing with frequent dose adjustments and clinic visits. He has tried to stabilize his INR by taking a daily 100 mcg vitamin K tablet for the last three months and switching from generic warfarin to brand-name Coumadin®, with no beneficial effects. Would you switch him to dabigatran? What would be your management strategy if major bleeding were to occur while taking dabigatran?
Background Information on Dabigatran
Dabigatran (Pradaxa®), a new oral anticoagulant, is a synthetic direct thrombin inhibitor that does not require monitoring of its anticoagulant effect by blood tests and is not influenced by dietary vitamin K intake. It was approved by the FDA in October 2010 for the prevention of stroke and systemic arterial thromboembolism in patients with atrial fibrillation based on a large trial showing that, at the approved dose (150 mg twice daily), it was more effective than warfarin in preventing stroke and systemic embolism, and equally safe.1
Dabigatran Use in DVT and PE
Dabigatran is not FDA-approved for the prevention or treatment of venous thromboembolism (VTE), so any such use would be considered off-label. However, a key phase III trial of 2,539 patients with acute deep-vein thrombosis (DVT) or pulmonary embolism (PE) showed that dabigatran (150 mg twice daily) taken for at least six months after a diagnosis of acute DVT or PE was as effective and safe as warfarin.2 These solid data make me comfortable considering off-label use of dabigatran for VTE treatment. It is important to realize, though, that in this trial dabigatran was not given as first-line treatment in patients with newly diagnosed VTE, but rather only after at least five days of a parenteral anticoagulant. Therefore, if I were to use dabigatran in patients with VTE, I would not use it first-line in the first few days after an acute clot. I would feel comfortable, however, switching from warfarin to dabigatran in the non-acute setting in select patients.
In Which Patients Might I Consider Off-Label Dabigatran Use?
Some patients tolerate warfarin quite poorly and/or dislike the therapy to such a degree that they would consider stopping treatment and accepting a significant risk of recurrent VTE. Reasons include: (a) wide fluctuations of INRs creating stress and need for frequent dose adjustments; (b) significant side effects (hair loss, fatigue); (c) decreased quality of life due to need for frequent blood tests, dietary restrictions, fear of bleeding, or recurrent thrombosis when non-therapeutic; and (d) cost of anticoagulation management, including clinic visits and INR testing. For these patients, I would consider a switch to off-label dabigatran.
In patients tolerating warfarin well and having stable INRs I would not yet consider a switch to dabigatran. It is a relatively new drug, and even though it has been used in a large number of patients (more than 20,000 in the phase III VTE2 and atrial fibrillation3 trials), I would like to see more real-life experience with the drug, more published data in the peer-reviewed literature on optimal management of major bleeding complications, and a comprehensive FDA review of the VTE trial data during the approval process for the VTE indication.
Management of Major Bleeding
One major reason for me not to prescribe dabigatran more frequently off label in VTE patients is that neither a reversal agent nor an established evidence-based strategy exist for management of major bleeding. In patients on warfarin who have a major bleed, established treatment options include vitamin K, fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), and recombinant factor VIIa, depending on the degree of bleeding.4 For bleeding on dabigatran, suggested management strategies are based on ex vivo plasma mixing studies, rat-tail bleeding models, or limited studies on healthy volunteers, and are mostly published only in abstract form.5-8 I am not aware of any peer-reviewed, full-length, patient-data-based publications on management of major bleeding in patients on dabigatran. Major bleeding occurred at rates of one in 32 patients and one in 63 patients in the atrial fibrillation2 and VTE trial3, respectively. It would be helpful to have data from these trials reporting how major bleeding was managed and what the clinical outcomes were, so that clinicians would have at least some clinical data to go by in their decisions about how to manage such patients.
In the event of bleeding in patients on dabigatran, management strategies should be individualized according to the severity and location of the bleed. Dabigatran is predominantly (80%) cleared by the kidney. It has a plasma half-life of 13 hours (range 11-22 hours) in individuals with normal renal function (creatinine clearance greater than 80 mL/min). This increases to 18 hours (range 13-23 hours) and 27 hours (range 22-35 hours) in patients with creatinine clearances of 30-50 mL/min and less than 30 mL/min,5 highlighting the need to maintain good renal output and consider hemodialysis in cases of major and life-threatening bleeding. Supportive measures, such as mechanical compression, surgical intervention, and fluid replacement, should of course be employed. Beyond that, treatment options include activated charcoal to prevent absorption of residual drug if the last drug intake was within two to four hours; PCCs with or without additional FFP; activated PCCs; recombinant factor VIIa; or antifibrinolytic drugs (aminocaproic acid or tranexamic acid). As major bleeding is likely to occur in some patients taking dabigatran, emergency departments and hematologists may want to proactively establish a management strategy for their institutions. To assist in the development of these approaches, I have provided suggestions for drug selection and dosing through Clot Connect, the educational resource of the University of North Carolina Blood Clot Education Outreach Program.9
- U.S. Food and Drug Administration. Dabigatran Label and Approval History. Dabigatran Label and Approval History. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist. (last accessed March 24, 2011).
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
- 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.
- Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:160S-198S.
- van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.
- Eerenberg ES, Sijpkens MK, Kamphuisen PW, et al. Prothrombin complex concentrate reverses the anticoagulant effect of rivaroxaban in healthy volunteers. (Abstract 1094; ASH annual meeting Dec 4-7, 2010, Orlando, FL).
- Morishima Y, Honda Y, Shibano T. Anti-inhibitor coagulant complex, prothrombin complex concentrate, and recombinant factor VIIa reverse prothrombin time prolonged by edoxaban in human plasma. (Abstract 3319; ASH annual meeting Dec 4-7, 2010, Orlando, FL).
- van Ryn J, Ruehl D, Priepke H, et al. Reversability of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIa or activated prothrombin complex concentrate. (Abstract 0370). Haematologica 2008;93(Suppl 1):148.
- Clot Connect MD. http://clotconnectmd.wordpress.com/2010/12/06/pradaxa®-management-of-major-bleeding. (last accessed March 24, 2011).
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