Since their relatively recent introduction, a major concern over NOAC use has been the lack of available reversal agents akin to vitamin K or fresh frozen plasma used to reverse anticoagulation effect of warfarin.
Fortunately, there are currently 2 FDA-approved NOAC reversal agents (idarucizumab and andexanet alfpha) and 1 NOAC on breakthrough or fast-track status at the FDA (1,2):
- Idarucizumab, a humanized mouse antibody fragment, or Fab, targeted specifically for reversal of dabigatran. FDA approved
- Andexanet alfa, a class-specific antidote for reversal of direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), as well as an indirect factor Xa inhibitor, enoxaparin. FDA approved
- Ciraparantag (PER977), a synthetic water-soluble compound that reverses direct thrombin (dabigatran), direct factor Xa (apixaban, rivaroxaban, edoxaban), and indirect factor Xa inhibitors (enoxaparin). Currently under investigation.
1. Ansell JE. Universal, class-specific, and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2016;41:248-52. https://www.ncbi.nlm.nih.gov/pubmed/26449414
2. Connolly SJ, Milling TJ, Eikelboom JW, etal. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Eng J Med 2016;375:1131-41. https://www.nejm.org/doi/full/10.1056/NEJMoa1607887
Contributed in part by William L. Hwang, MD, Mass General Hospital, Boston, MA.
Although warfarin has long been the standard treatment for venous thromboembolism (VTE) and thomboprophylaxis in atrial fibrillation (AF), the need for its frequent monitoring, potential drug interactions, and narrow therapeutic window made it far from ideal.
Since 2009, DOACs have become viable alternative agents owing to their more predictable and safer pharmacological profiles. DOACs include several direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and a direct thrombin inhibitor (dabigatran). Approved indications include: (1) thromboprophylaxis in nonvalvular AF; (2) treatment of deep venous thrombosis or pulmonary embolism; and (3) primary prevention of postoperative VTE.
Compared to warfarin, DOACs are associated with a reduced risk of intracranial hemorrhage, and in the case of apixaban, lower risk of gastrointestinal bleeding; rivaroxaban and edoxaban have been associated with a higher risk of gastrointestinal bleeding.
Apixaban is also the only NOAC whose dose can be safely reduced in chronic kidney disease, including those on hemodialysis.
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Contributed by William L. Hwang, MD, Mass General Hospital, Boston, MA
The short answer is “yes” when deep veins, such as brachial, axillary or subclavian are involved; cephalic and basilic veins are superficial. Although some have suggested that isolated brachial vein thrombosis may be considered at low risk of complication, this assumption has not been corroborated by objective research (1).
There are no randomized trials of AC therapy in patients with upper extremity deep vein thrombosis (UEDVT). However, the American College of Chest Physicians has recommended a 3-month course of AC therapy similar to that of leg DVT for several reasons (1,2):
- UEDVT has generally been reported to have complications and consequences comparable to that of leg DVT
- Several small cohort studies suggest lower rates of recurrent DVT, PE, and bleeding when UEDVT is treated similar to leg DVT
- Known demonstrated benefit of AC therapy in leg DVT
In addition, post-thrombotic syndrome is relatively common (~1 in 5) among patients with UEDVT (3)
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1. Hingorani A, Ascher E, Marks N, et al. Morbidity and mortality associated with brachial vein thrombosis. Ann Vasc Surg 2006; 20:297-299. https://www.ncbi.nlm.nih.gov/pubmed/16779509
2. Kearon C, Akl EA, Comerato AJ, et al. Antithrombotic therapy for VTE disease: American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(suppl):419S-494S. https://www.ncbi.nlm.nih.gov/pubmed/22315268
3. Maynard G. Upper extremity deep vein thrombosis:A call to arms. JAMA Intern Med 2014;696-698. https://www.ncbi.nlm.nih.gov/pubmed/24638129
Until recently, there were no randomized-controlled trials (RCTs) available to help guide our decision. A 2015 RCT, however, demonstrated that foregoing bridging anticoagulation was not inferior to bridging with low-molecular-weight heparin in patients with chronic or paroxysmal AF for the prevention of arterial thromboembolism and decreased the risk of major bleeding (1).
It’s important to keep in mind the ineligibility criteria in this study before you consider not bridging perioperatively. The following were listed as exclusion criteria in this study:
- Mechanical valve
- Systemic embolism or transient ischemic attack within the previous 12 weeks
- Major bleeding within the previous 6 weeks
- Creatinine clearance < 30 ml/min
- Platelet count < 100,000/ cubic ml
- Planned cardiac, intracranial, or intraspinal surgery.
Another important caveat of the BRIDGE study is that it included relatively few patients (<5%) with CHADS-2 score >4.
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- Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015 (published June 22 at NEJM.org).
Not really! Many of the commonly used antibiotics have the potential for increasing the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.
Although there may be some inconsistencies in the reports, generally quinolones (e.g. ciprofloxacin, levofloxacin), sulonamides (e.g. trimethoprim-sulfamethoxazole), macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk (1,2). Metronidazole can also be a culprit (2).
1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf