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Review Article

Direct Oral Anticoagulants: A User’s Guide

Suvash Shrestha, MD; On Chen, MD; Robert Frankel, MD; Yisachar Greenberg, MD; and Felix Yang, MD

Volume 57 - Issue 4 - April 2017

ABSTRACT: Direct oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—are available alternatives to warfarin for oral anticoagulation. Studies have proven the efficacy of DOACs in stroke prevention in nonvalvular atrial fibrillation, in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and as prophylaxis against DVT and PE in patients undergoing hip or knee replacement surgery. DOACs have fewer drug interactions than warfarin. Among DOACs, apixaban has a notably low rate of gastrointestinal tract bleeding, whereas dabigatran has demonstrated a significant reduction in the rate of ischemic stroke. This article reviews the data and practices regarding the use of DOACs.

KEYWORDS: Direct oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, stroke prevention, atrial fibrillation, deep vein thrombosis, pulmonary embolism, warfarin

 

For the past 60 years, warfarin had been the only oral anticoagulant available for the prevention and management of thromboembolic events. Warfarin is a vitamin K antagonist (VKA) that acts on vitamin K-dependent clotting factors II (prothrombin), VII, IX, and X, thus affecting the extrinsic and intrinsic pathways of coagulation. Although warfarin is an effective anticoagulant, its activity is affected by certain foods, certain drugs, and individual genetic variability. This interaction makes frequent monitoring and dose adjustment necessary in order to maintain therapeutic anticoagulation. The window for therapeutic anticoagulation is considerably narrow with warfarin. In addition, it is slow in onset and thus requires bridging with parenteral anticoagulation in certain situations.

In recent years, new oral anticoagulants have been developed as alternatives to warfarin. Different terms are used for these newer agents—novel oral anticoagulants, non-vitamin K-dependent oral anticoagulants, and direct oral anticoagulants (DOACs). We use the term DOAC in this article, as its use also has been proposed by the International Society on Thrombosis and Haemostasis.1 Currently, 4 DOACs are available for clinical use: dabigatran, rivaroxaban, apixaban, and edoxaban.

The mechanism of action of these agents is different from that of warfarin. Among the 4 DOACs, dabigatran is a direct and competitive thrombin inhibitor,2 whereas the other 3 are factor Xa inhibitors (Figure).3-5 These agents have predictable pharmacokinetic properties when they are administered at a fixed dosing. Additionally, DOACs have minimal interactions with food—rivaroxaban should be taken with the evening meal, and the absorption of dabigatran is delayed by approximately 2 hours if it is taken with a fatty meal.

Coagulation Cascade and DOACs

DOACs are rapidly acting, reaching peak activity in 3 to 4 hours. They do not require other forms of overlapping anticoagulation. Dabigatran is eliminated predominantly via the kidneys (Table 1).3,4,6-11 Only one-third of apixaban is eliminated by the kidneys, with the rest eliminated via the fecal route. In general, DOACs are contraindicated if creatinine clearance (CrCl) is less than 30 mL/min and should be used with extreme caution if the CrCl is between 15 and 30 mL/min.6,12-14

Table 1 Comparison of Warfarin and DOACs

The unavailability of reversal agents is a major concern in case of bleeding while on DOACs. Recently, the US Food and Drug Administration (FDA) approved idarucizumab, a humanized antibody fragment, as a reversal agent for dabigatran.15 Andexanet alfa, a recombinant, modified factor Xa molecule, is being developed as an antidote for rivaroxaban, apixaban, and edoxaban.16 Hemodialysis can also partially reverse the anticoagulant effect of dabigatran, since it is only 35% protein-bound, but not for the other 3 agents, which are highly protein-bound.7

Coagulation Assays and DOACs

DOACs do not need frequent routine monitoring of anticoagulation activity as with warfarin because of their fixed dosing and relatively predictable activity. The assessment of anticoagulation activity becomes necessary in situations such as suspected overdose, nonadherence, acute bleeding, preoperative state, and thrombosis while on a DOAC. However, this assessment is limited due to the lack of validated, standard, and universally approved methods of monitoring the drug activity (Table 2).17-19

Table 2 Effect of DOACs on Coagulation Studies

NEXT: Common Indications of DOACs, 

 

Common Indications of DOACs

Since their development, DOACs have been compared with conventional anticoagulation therapy in many major studies. These trials have shown that DOACs are noninferior to conventional therapy in the prevention of stroke and systemic embolism in atrial fibrillation (AF), in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and as prophylaxis for venous thromboembolic (VTE) events after total knee arthroplasty (TKA) and total hip arthroplasty (THA). These major trials excluded patients with active liver disease (aspartate aminotransferase or alanine aminotransferase levels more than twice the upper limit of the normal range), patients with severe renal insufficiency (CrCl, < 30 mL/min) and pregnant women.6,12,13

Atrial fibrillation. AF is among the most common supraventricular tachyarrhythmias, affecting more than 1.2 million people in the United States alone.20 AF has been reported to increase the risk of stroke by 4 to 5 times.21,22 Traditionally, warfarin had been the preferred anticoagulant for prevention of stroke and systemic embolism in these patients, reducing the risk of stroke by more than 50%.22 However, warfarin therapy requires dietary restrictions, frequent monitoring, and clinic visits for dose adjustment. Patient adherence is frequently difficult, and maintaining a time in therapeutic range beyond 60% to 70% is often challenging.

Based on the results of large phase 3, randomized, controlled trials, all 4 DOACs have been FDA-approved for the prevention of thromboembolic events associated with AF (Table 3).6,12-14 The RE-LY trial was a multicenter, randomized, controlled trial that compared 2 regimens of dabigatran, 110 mg twice daily and 150 mg twice daily, with dose-adjusted warfarin.6 After 2 years of follow-up, the study concluded that dabigatran in either dosing regimen is noninferior to warfarin. In fact, the 150-mg dosage of dabigatran was found to be superior to warfarin in the reduction of ischemic stroke and cardiovascular mortality but not in terms of major bleeding. It is noteworthy that the dose of 110 mg is not FDA-approved and thus is not available in the United States.

Table 3 Major Studies on the Use of DOACs in Nonvalvular AF

Likewise, the ROCKET-AF,12 ARISTOTLE,13 and ENGAGE AF-TIMI 4814 trials compared rivaroxaban, apixaban, and edoxaban, respectively, against warfarin for the prevention of AF-associated thromboembolic events. These trials concluded that any of these DOACs could be an effective alternative to warfarin. More specifically, rivaroxaban and edoxaban were found to be noninferior to warfarin in the prevention of stroke. Apixaban was found to be superior to warfarin in preventing stroke and systemic embolism. Rivaroxaban had a similar rate of major bleeding as warfarin, whereas edoxaban and apixaban had significantly lower rates of major bleeding.

VTE prophylaxis after elective TKA or THA. VTE is a serious and frequent complication among patients undergoing orthopedic procedures. Without prophylaxis, the incidence of proximal DVT 7 to 14 days after a major orthopedic procedure is approximately 10% to 30%.23 Likewise, among patients undergoing TKA or THA who had routine ventilation/perfusion lung scanning within 2 weeks of surgery, 3% to 28% had scan results suggesting a high probability of PE.23 Importantly, the mean time to symptomatic VTE after TKA or THA has been reported to be 21.5 and 9.7 days, respectively.24 Patients require inpatient as well as continued outpatient anticoagulation. Because of the convenient dosing regimen, DOACs have been an attractive choice for VTE prophylaxis among these patients (Table 4).

Table 4 Prophylaxis Against VTE After TKA and THA

Two major trials, RE-MODEL25 and RE-NOVATE,26 showed that a once-daily dose of dabigatran, either 150 mg or 110 mg, was noninferior to enoxaparin and also had a similar bleeding profile. Likewise, the series of trials under the name RECORD27-30 also concluded that 10 mg of rivaroxaban once daily was superior to enoxaparin, with similar rates of bleeding. Major VTE occurred in only 9 of 908 patients (1.0%) in the rivaroxaban group compared with 24 of 925 (2.6%) in enoxaparin group (absolute risk reduction, 1.6%). On the other hand, the ADVANCE trials,31-33 which compared apixaban against enoxaparin, produced mixed results. A regimen of apixaban, 2.5 mg twice daily, failed to meet noninferiority criteria when compared with 30 mg enoxaparin twice daily among patients undergoing TKA. But the same regimen of apixaban significantly reduced the absolute risk of VTE by 9.3% compared with 40 mg enoxaparin once daily. In all of these trials, treatment drugs were started within 3 to 4 hours of arthroplasty.

Treatment of VTE. All 4 of the DOACs have been evaluated for the management of acute VTE including DVT and PE (Table 5). RE-COVER,34 EINSTEIN,35,36 and Hokusai37 were noninferiority trials for dabigatran, rivaroxaban, and edoxaban, respectively. In these trials, DOACs were found to be noninferior to the standard treatment of dose-adjusted warfarin with an international normalized ratio (INR) between 2 and 3.

Table 5 Studies Supporting DOACs for Treatment of VTE

In RE-COVER and Hokusai, dabigatran and edoxaban, respectively, were started after a minimum of 5 days of parenteral anticoagulation, whereas in the EINSTEIN trials, rivaroxaban was started from the beginning. Similarly, in the AMPLIFY trial,38 the study group received apixaban from day 1, while the conventional-therapy group received parenteral anticoagulation along with warfarin until INR was in the therapeutic range. Thus, clinical guidelines suggest parenteral anticoagulation for at least 5 days before starting dabigatran or edoxaban.

In terms of dosage, the RE-COVER trial34 tested 2 regimens of dabigatran (220 mg twice daily and 150 mg twice daily), and both regimens were found to be noninferior to the conventional warfarin therapy. In EINSTEIN-PE,36 edoxaban was used at 60 mg once daily; however, it was reduced to 30 mg if a patient had a CrCl of 30 to 50 mL/min, had a body weight of less than 60 kg, or was on concomitant potent P-glycoprotein 1 inhibitors.

NEXT: Which DOAC When?

 

Which DOAC When?

Although each DOAC has been proven to be beneficial in the prevention and management of thromboembolic events (Table 6),6,25-39 some individual differences might favor the selection of one over another in certain situations. Dabigatran is reported to cause dyspepsia, so patients with a history of peptic ulcer disease may fare better with a different DOAC. Patients who have difficulty adhering to a twice-daily medication should benefit from the once-daily dosing of rivaroxaban and edoxaban. Also, rivaroxaban must be taken with food. Edoxaban has the fewest drug interactions, since its metabolism does not involve the cytochrome P-450 pathway, and no dose adjustments are required in AF patients on P-glycoprotein 1 inhibitors. Dabigatran has been shown to have a lower incidence of ischemic strokes. In terms of hemorrhagic stroke, all DOACs have a lower incidence than warfarin.

Table 6 Clinical Indications of DOACs

Before starting DOACs

Anticoagulation is initiated after a consideration of an individual patient’s bleeding risk and the risk for thromboembolic events (Table 7).40-42 The CHADS2 and CHA2DS2-VASc scoring systems are routinely used to estimate thromboembolic risk in patients with AF.40 The parameters included in CHA2DS2-VASc are congestive heart failure; hypertension; age; diabetes mellitus; stroke, transient ischemic attack, or thromboembolism; any vascular disease; and sex.

Table 7 CHA DS-VASc and HAS-BLED Scores

The HAS-BLED scoring system may be used to calculate bleeding risk among patients with AF. The score is easily calculated using the following risk factors: hypertension, abnormal renal or liver function, stroke, bleeding, labile INR, age, drugs, and alcohol. HAS-BLED scores range from 0 to 9; a score of 3 or higher indicates a high risk of bleeding.42

While switching between anticoagulants or in cases of interruptions, care should be taken to ensure that an appropriate state of anticoagulation is maintained. Caution is also warranted when the patient is on any medications that could interact with DOACs (Tables 8, 9, and 10).9-11,43

Table 8 Switching Between Anticoagulants

Table 9 Interruption of Therapy, Reinitiation of Therapy, and Missed Doses

Table 10 Interactions With Commonly Used Drugs

NEXT: Management of Bleeding, Conclusions

 

Management of Bleeding

With the use of any anticoagulant, bleeding is the most concerning adverse effect (Table 11). Among patients with AF, the incidence of major bleed was 3.36% with warfarin compared with 3.11% with standard dose of dabigatran.6 All the major trials on DOACs categorized bleeding as major, clinically relevant nonmajor, and minor, which are defined by International Society on Thrombosis and Haemostasis.44

Table 11 Classification and Management of Bleeding

As with any case of bleeding, supportive therapy should always be initiated, including fluid resuscitation, mechanical compression when feasible, surgical hemostasis, and transfusion of blood products if necessary. In addition, active medications should be carefully reviewed to ensure that agents such as antiplatelet agents and nonsteroidal anti-inflammatory drugs are discontinued.

With warfarin, prothrombin time-INR precisely reflects the extent of anticoagulation, and vitamin K along with fresh frozen plasma may be used to reverse its effect. With DOACs, although some literature suggests diluted thrombin time and anti-factor Xa activity as possible measures of evaluating drug activity, these tests are not readily available and lack clinical validation and universal approval. Only dabigatran is dialyzable, given that only 35% of it is protein-bound. The other 3 DOACs are not dialyzable.

The recent development of DOAC reversal agents has raised hope for the effective management of major bleeding associated with DOACs. Idarucizumab, recently FDA-approved to reverse dabigatran, reverses anticoagulation immediately after its administration.15 Andexanet alfa, which is in phase-3 clinical trials, reverses the 3 factor Xa inhibitors.16 Before these agents were available, prothrombin complex concentrate (PCC) and recombinant factor VIIa were considered in cases of severe life-threatening bleeding, although the evidence was not very strong.7 PCC either can be 4-factor-concentrate containing adequate amounts of vitamin K-dependent factors II, VII, IX, and X, or can be 3-factor-concentrate containing lower amounts of factor VII. PCCs are expected to provide more substrate to increase thrombin production, which is necessary for clot formation.45 Recombinant factor VIIa is another hemostatic agent developed initially for the management of patients with hemophilia. It activates factor X into factor Xa, enhancing thrombin generation on the activated platelet surface, even in the absence of factor VIII or factor IX.46

Antithrombotics in Patients With AF and ACS 

It is evident that VKAs and DOACs are important in stroke prevention in patients with AF. Likewise, aspirin provides significant benefits to patients with coronary artery disease, and clopidogrel prevents stent thrombosis. Patients who require percutaneous coronary intervention and who have AF present a therapeutic challenge. Continuing all 3 agents may be beneficial but reportedly increases the annual bleeding risk by as much as 45%.47 There is no clear answer, but the current literature favors dual therapy with VKA and clopidogrel vs triple therapy.

Recently, the WOEST trial compared dual therapy (VKA and clopidogrel) with triple therapy (VKA, clopidogrel, and aspirin) among 573 patients with AF who required percutaneous coronary intervention.48 The results showed that dual therapy significantly reduced bleeding events (hazard ratio, 0.36) compared with triple therapy. 

Supporting the findings of the WOEST trial, a clinical study of 12,165 patients in Denmark also reported no increase in the risk of recurrent coronary events with the use of dual therapy compared with triple therapy in a year.49

However, these studies involved VKAs but not DOACs. Whether the findings of these studies can be extrapolated to DOACs remains to be answered. Among the few studies available, one showed that by adding rivaroxaban in patients with a recent acute coronary syndrome (ACS), the composite end point of cardiac death, myocardial infarction, and stroke decreased, but the risk of major and intracranial bleeding simultaneously increased.50 The RE-DEEM trial showed that dabigatran added to dual antiplatelet therapy resulted in a dose-related increase in bleeding risk without reduction of ischemic events.51 The APPRAISE-2 study showed that after ACS, apixaban added to either aspirin alone or aspirin and clopidogrel increased the risk of bleeding without ischemic benefit.52 More studies are under way that are expected to shed more light on concomitant use of DOACs with dual antiplatelet therapy.

Conclusions

In recent years, the use of DOACs has been increasing. All of these agents have demonstrated efficacy in the reduction of stroke and thromboembolic end points. Compared with warfarin, DOACs do not have as many dietary restrictions and have a fixed dosing schedule, which eliminates the need for frequent blood testing for dose titration. Although as anticoagulants, DOACs carry risks for major bleeding, reversal agents have been developed.

Suvash Shrestha, MD, is an internal medicine physician at Rhode Island Hospital in Providence, Rhode Island.

On Chen, MD, is a cardiologist in the Department of Cardiology at Maimonides Medical Center in Brooklyn, New York.

Robert Frankel, MD, is the director of Interventional Cardiology in the Department of Cardiology at Maimonides Medical Center in Brooklyn, New York.

Yisachar Greenberg, MD, is the director of Electrophysiology and Pacing in the Department of Cardiology at Maimonides Medical Center in Brooklyn, New York.

Felix Yang, MD, is the associate director of Electrophysiology and Pacing in the Department of Cardiology at Maimonides Medical Center in Brooklyn, New York.

Disclosure: Felix Yang, MD, has received consulting fees from Daiichi Sankyo.

References:

  1. Barnes GD, Ageno W, Ansell J, Kaatz S; Subcommittee on the Control of Anticoagulation of the International Society on Thrombosis and Haemostasis. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(6):1154-1156.
  2. van Ryn J, Goss A, Hauel N, et al. The discovery of dabigatran etexilate. Front Pharmacol. 2013;4:12. doi:10.3389/fphar.2013.00012
  3. Samama MM. The mechanism of action of rivaroxaban—an oral, direct factor Xa inhibitor—compared with other anticoagulants. Thromb Res. 2011;​127(6):​497-504.
  4. Wong PC, Jiang X. Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro: comparison with direct inhibitors of factor VIIa, XIa and thrombin. Thromb Haemost. 2010;104(2):​302-310.
  5. Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014;35(28):1844-1855.
  6. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
  7. 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(6):1116-1127.
  8. Holford NHG. Clinical pharmacokinetics and pharmacodynamics of warfarin: understanding the dose-effect relationship. Clin Pharmacokinet. 1986;11(6):​483-504.
  9. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc; 2014.
  10. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2015.
  11. Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo Inc; 2015.
  12. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;​365(10):883-891.
  13. Granger CB, Alexander JH, McMurray JJV, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
  14. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.
  15. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 373(6):511-520.
  16. Enriquez A, Lip GYH, Baranchuk A. Anticoagulation reversal in the era of the non-vitamin K oral anticoagulants. Europace. 2016;18(7):955-964.
  17. Pollack CV Jr. Coagulation assessment with the new generation of oral anticoagulants. Emerg Med J. 2016;33(6):423-430.
  18. Baglin T, Hillarp A, Tripodi A, Elalamy I, Buller H, Ageno W. Measuring oral direct inhibitors (ODIs) of thrombin and factor Xa: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013;11(4):756-760.
  19. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128-1139.
  20. Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112(8):1142-1147.
  21. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-988.
  22. Björck S, Palaszewski B, Friberg L, Bergfeldt L. Atrial fibrillation, stroke risk, and warfarin therapy revisited a population-based study. Stroke. 2013;​44(11):​3103-3108.
  23. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S-400S.
  24. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br. 2007;89(6):799-807.
  25. Eriksson BI, Dahl OE, Rosencher N, et al; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178-2185.
  26. Eriksson BI, Dahl OE, Rosencher N, et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949-956.
  27. Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
  28. Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39.
  29. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
  30. Turpie AG, Lassen MR, Davidson BL, et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-1680.
  31. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
  32. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;​375(9717):807-815.
  33. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-2498.
  34. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352.
  35. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
  36. EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297.
  37. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415.
  38. Agnelli G, Buller HR, Cohen A, et al. AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;​369(9):799-808.
  39. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817.
  40. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):​e1-e76.
  41. Lip GYH, Skjøth F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol. 2015;65(14):1385-1394.
  42. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):​1093-1100.
  43. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2015.
  44. Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202-204.
  45. Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran. Emerg Med J. 2014;31(2):163-168.
  46. Hedner U, Lee CA. First 20 years with recombinant FVIIa (NovoSeven). Haemophilia. 2011;17(1):e172-e182.
  47. Dewilde WJM, Janssen PWA, Verheugt FWA, et al. Triple therapy for atrial fibrillation and percutaneous coronary intervention: a contemporary review. J Am Coll Cardiol. 2014;64(12):1270-1280.
  48. Dewilde WJM, Oirbans T, Verheugt FWA, et al; WOEST Study Investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115.
  49. Lamberts M, Gislason GH, Olesen JB, et al. Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. J Am Coll Cardiol. 2013;62(11):981-989.
  50. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19.
  51. Oldgren J, Budaj A, Granger CB, et al; RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;​32(22):2781-2789.
  52. Hess CN, James S, Lopes RD, et al. Apixaban plus mono versus dual antiplatelet therapy in acute coronary syndromes: insights from the APPRAISE-2 trial. J Am Coll Cardiol. 2015;66(7):777-787.