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Treatment of VTE: Warfarin and parenteral anticoagulation still have a role
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Vitamin K antagonists have been extensively used as the standard of care in the treatment of venous thromboembolism for the past 60 years. The known limitations of vitamin K antagonists have been widely recognized; thus, alternatives have been sought after for decades.
In recent years, novel oral anticoagulants such as dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Janssen), apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and edoxaban (Savaysa, Daiichi Sankyo) have emerged as alternatives to vitamin K antagonists (VKAs).
RE-COVER, EINSTEIN, AMPLIFY and Hokusai-VTE are recent trials that have compared novel oral anticoagulants vs. VKAs in the setting of acute VTE. In the randomized, double blind, controlled, noninferiority-designed RE-COVER study, researchers compared the efficacy and safety of dabigatran vs. standard therapy with enoxaparin and VKA for 6 months. Results published in The New England Journal of Medicine in 2009 demonstrated that dabigatran was noninferior to standard therapy. The EINSTEIN researchers compared rivaroxaban vs. enoxaparin and VKA in patients presenting with acute deep vein thrombosis and pulmonary embolism and found similar results. Researchers for the AMPLIFY study evaluated apixaban vs. the standard of care for acute VTE and found that apixaban was noninferior to VKA during 6 months of follow-up. Most recently, in the Hokusai-VTE study, edoxaban therapy for 3 to 12 months was noninferior to warfarin for the treatment of VTE.
Michael R. Jaff
Ido Weinberg
As a result of these trials, the tissue-specific oral anticoagulants seem to have the potential to replace VKAs for the management of DVT and PE. The question remains, however: With the emergence of tissue-specific oral anticoagulants, what is the modern relevance of VKA therapy in the treatment of VTE?
Pros and cons of available therapies
Widely recognized limitations of VKAs include the prolonged onset of action, the need for frequent laboratory monitoring, the requirement of an overlap of therapy at initiation and variations in patient response to therapy. Additionally, VKAs have a narrow therapeutic index and many drug-drug and food-drug interactions. Furthermore, despite monitoring, 30% to 50% of international normalized ratio values fall outside the therapeutic range for patients anticoagulated with VKAs, as demonstrated by Jones and colleagues in Heart in 2005. Even in the controlled environment of a clinical trial, it is estimated that only 55% to 60% of patients regularly achieve target INR.
Source: Jaff MR, et al.
Many characteristics of the tissue-specific oral anticoagulants are advantageous compared with the well-known disadvantages of VKAs. Contrary to VKAs, tissue-specific oral anticoagulants have a rapid onset of action, allowing initiation of apixaban and rivaroxaban without bridging with a parenteral agent; this has not been observed with dabigatran and edoxaban. For many patients, this means eliminating the need for subcutaneous injections, which reduces discomfort and stress among patients, as well as medical office staff in ensuring appropriate subcutaneous drug-delivery techniques.
Although VKAs achieve steady state plasma levels after 4 to 5 days, rivaroxaban arrives at peak levels within 2 to 4 hours and apixaban within 1 to 2 hours, each with a significantly shorter half-life as compared with VKAs. Furthermore, tissue-specific oral anticoagulants have predictable pharmacokinetics that allow fixed dosing without monitoring. A clinically relevant comparison between VKAs and novel oral anticoagulants is provided in Table 1.
Specific scenarios dictate treatment
Nevertheless, despite many areas in which tissue-specific oral anticoagulants are superior to VKAs, there remain several scenarios in which VKAs continue to be a necessary therapy in the anticoagulation armamentarium.
First, VKAs are predominantly cleared through non-renal mechanisms, whereas tissue-specific oral anticoagulants are all at least partially excreted by the kidneys (see Table 2). The extent of renal clearance varies depending on the agent (80% of dabigatran, 33% of rivaroxaban, 25% of apixaban, 33% of edoxaban). Although dabigatran has the greatest degree of creatinine clearance, it is the only tissue-specific oral anticoagulant that is able to be removed by dialysis. It follows that currently available tissue-specific oral anticoagulants need to be used with caution in patients with creatinine clearance less than 15 cc/min. Second, the lack of an antidote for the tissue-specific oral anticoagulants is especially concerning in this patient population, although data concerning clinically relevant bleeding events appear minor.
More data needed
There are several clinical scenarios in which the tissue-specific oral anticoagulants should be avoided until more data become available to guide therapy.
The trials that have compared these drugs with conventional anticoagulation included very few patients with cancer-associated VTE, and there have been no trials comparing tissue-specific oral anticoagulants with low–molecular-weight heparin in patients with cancer-associated VTE.
Source: Jaff MR, et al.
Other conditions in which tissue-specific oral anticoagulant use is currently discouraged include VTE and pregnancy, heparin-induced thrombocytopenia, concomitant use of thrombolytic therapy and antiphospholipid antibody syndrome. Patients who exhibit poor compliance with VKA monitoring are not ideal candidates for the tissue-specific oral anticoagulants. In these patients, inability to monitor the impact of the agent and the short half-life may be disadvantageous. As treating clinicians, we will have no way to monitor if patients are indeed taking their medication.
Finally, the cost of the tissue-specific oral anticoagulants is higher compared with generic warfarin, even with the need for repeated laboratory testing. Robust cost-effectiveness analyses are important to determine the widespread adoption of the tissue-specific oral anticoagulants, particularly in the Accountable Care Organization model.
VKAs still alive
In conclusion, tissue-specific oral anticoagulants are appealing, but we must not forget that VKAs have been time-tested and effective in many patients during the past 6 decades. Although the newer agents overcome many of shortcomings of VKAs, they too have their own set of limitations and long-term data are still lacking.
We have long been awaiting the demise of VKAs, but they still seem to be very much alive. With the opportunity that tissue-specific oral anticoagulants present, there also is new responsibility for clinicians to use them judiciously and in appropriately selected patients.
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For more information:
Michael R. Jaff, DO, is medical director of the Massachusetts General Hospital Vascular Center.
Jessica Mintz, MD, is a fellow in vascular medicine at Massachusetts General Hospital.
Ido Weinberg, MD, is associate director of the Vascular Medicine and Intervention Fellowship at Massachusetts General Hospital. They can be reached at 55 Fruit St., Boston, MA 02114.
Disclosure: Jaff reports serving as a board member for VIVA Physicians, a 501(c)3 not-for-profit education and research organization. Mintz and Weinberg report no relevant financial disclosures.