VKAThe title represents the ultimate alphabet soup, no? Most practicing physicians, however, would recognize these acronyms and have probably committed to one or the other as a preferred agent in their own patient management decisions. VKAs and NOACs are anticoagulants—that is, they prevent blood from clotting properly, which is a desirable effect in patients with or at risk for pathological blood clots, hopefully—hopefully, without contributing to or worsening pathologic bleeding. That razor’s edge difference is always there—no matter how safe the anticoagulant on which you put a patient, that patient’s risk of having abnormal bleeding or a frank hemorrhage is higher than it would be if that same patient were not on an anticoagulant. Therefore, this represents a perfect example of the need to individualize a benefit:risk analysis in patient care. In order to prescribe an anticoagulant for a given patient, the healthcare provider should

(1) be reasonably certain that the benefit from treatment of an existing clot or the prevention of a potential clot in an at-risk patient outweighs the likelihood of contributing to or causing serious bleeding, and

(2) practice shared decision-making1—that is, the decision to initiate anticoagulation is one that should be thoroughly discussed and made with the patient and his/her family or caregiver, explaining that risk:benefit “calculation” for that patient. Bleeding risk—patients and caregivers must be made to understand—increases with age, many comorbid illnesses (especially renal insufficiency), prior history of bleeding, subsequent need for an invasive procedure or surgery, and several other well-recognized factors.2

Unlike healthcare providers practicing between the 1940s and the 2010s, today’s prescribers have a choice: yes, between VKAs (vitamin K antagonists) and NOACs (non-vitamin-K-dependent oral anticoagulants, also called DOACs [direct oral anticoagulants], the latter comprised of the oral antithrombin dabigatran [Pradaxa®] and the oral anti-Factor Xa agents apixaban [Eliquis®], betrixaban [BevyxXa®], edoxaban [Savaysa®], and rivaroxaban [Xarelto®]). All but one of these drugs (betrixaban) came to market after a pivotal Phase 3 study comparing each with VKA for safe suppression of stroke risk in atrial fibrillation. Dabigatran (in RE-LY3), rivoraxaban (in ROCKET-AF4), apixaban (in ARISTOTLE5), and edoxaban (in ENGAGE-AF TIMI-486) all were at least as effective and at least as safe overall, compared to VKA in that indication. Notably, only apixaban was significantly better than VKA in major bleeding safety, and only apixaban and dabigatran showed a mortality benefit on the efficacy side. To some extent, dabigatran, edoxaban, and rivaroxaban showed more frequent major GI bleeding than VKA, but not major bleeding overall and not fatal GI bleeds.

All four drugs then followed with pivotal Phase 3 trials, again against VKA, for the safe treatment and secondary prevention of venous thromboembolism (VTE). Apixaban was approved based on the AMPLIFY trial,7 rivaroxaban on the EINSTEIN trials,8 dabigatran on the RE-COVER trials,9,10 and edoxaban in the HOKUSAI-VTE trial.11 It is critical to note that because of the way these studies were designed, both dabigatran and edoxaban require a heparinoid (generally low-molecular-weight heparin, or LMWH, like enoxaparin) lead-in (not a bridge, but a monotherapy lead-in) to NOAC treatment of VTE. Both rivaroxaban and apixaban may be initiated without lead-in for these patients. Studies of prevention of VTE by these agents followed, particularly for post-operative VTE prophylaxis.

It must be noted that there have been no randomized, controlled studies of one NOAC vs another . . . only NOAC vs VKA. There is a great deal of “real world” observational data now coming out that purports to compare these newer agents to one another, but those data should be appreciated more for their consistent results with those of the RCTs than for any significant difference demonstrated in practice. It is safe to say that ALL of these agents represent a pharmacologic advance over the decades-old standard of VKA, and that, in general, new starts on oral anticoagulation, whether for stroke protection in atrial fibrillation or for prevention or treatment of venous thromboembolism, should be on a NOAC.

In future posts we’ll discuss the “special status” of betrixaban and “medically ill prophylaxis,” as well as provide some guidance about choosing a specific NOAC for your patient, and of course we’ll discuss anticoagulation reversal. No matter how safe an anticoagulant (or an antiplatelet agent) is, the prescriber is increasing that patient’s risk of bleeding!


  1. MacLean S, Mulla S, Akl EA, et al. Patient Values and Preferences in Decision Making for Antithrombotic Therapy: A Systematic Review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2, Supplement):e1S-e23S. doi:10.1378/chest.11-2290
  2. Proietti M, Lane DA, Boriani G, Lip GYH. Stroke Prevention, Evaluation of Bleeding Risk, and Anticoagulant Treatment Management in Atrial Fibrillation Contemporary International Guidelines. Can J Cardiol. 2019;35(5):619-633. doi:10.1016/j.cjca.2019.02.009
  3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561
  4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638
  5. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039
  6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907
  7. Agnelli G, Buller HR, Cohen A, et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2013;369(9):799-808. doi:10.1056/NEJMoa1302507
  8. Cohen AT, Bauersachs R. Rivaroxaban and the EINSTEIN clinical trial programme. Blood Coagul Fibrinolysis. 2019;30(3):85-95. doi:10.1097/MBC.0000000000000800
  9. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361(24):2342-2352. doi:10.1056/NEJMoa0906598
  10. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772. doi:10.1161/CIRCULATIONAHA.113.004450
  11. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med. 2013;369(15):1406-1415. doi:10.1056/NEJMoa1306638

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