Anticoagulation: Updated Guidelines for Outpatient Management


Anticoagulation therapy is recommended for preventing, treating, and reducing the recurrence of venous thromboembolism, and preventing stroke in persons with atrial fibrillation. Direct oral anticoagulants are first-line agents for eligible patients for treating venous thromboembolism and preventing stroke in those with nonvalvular atrial fibrillation. Vitamin K antagonists are recommended for patients with mechanical valves and valvular atrial fibrillation. Vitamin K antagonists inhibit the production of vitamin K-related factors and require a minimum of five days overlap with parenteral anticoagulants, whereas direct oral anticoagulants directly inhibit factor II or factor Xa, providing more immediate anticoagulation. The immediate effect of direct oral anticoagulants permits select patients at low risk to initiate treatment in the outpatient setting for venous thromboembolism, including pulmonary embolism. Low-molecular-weight heparin continues to be recommended as a first-line treatment for patients with venous thromboembolism and active cancer, although there is growing evidence of effectiveness for the use of direct oral anticoagulants in this patient population. Validated bleeding risk assessments such as HAS-BLED should be performed at each visit and modifiable factors should be addressed. Major bleeding should be treated with vitamin K and 4-factor prothrombin complex concentrate for patients already being treated with a vitamin K antagonist. Idarucizumab has been effective for reversing the anticoagulant effects of dabigatran, and andexanet alfa has been effective for reversing the effects of rivaroxaban and apixaban.

Vitamin K antagonists (e.g., warfarin [Coumadin]), unfractionated heparin, low-molecular-weight heparin (LMWH), and direct oral anticoagulants are commonly used for the prevention and treatment of systemic embolism associated with atrial fibrillation, stroke, and venous thromboembolism (VTE). LMWH and select direct oral anticoagulants can be used for anticoagulation therapy initiation on an outpatient basis.


Compared with vitamin K antagonists, direct oral anticoagulants have fewer overall drug-drug interactions, a comparable (if not lower) bleeding rate, a shorter half-life, and fixed dosing based on indication, drug interactions, and renal or hepatic function.

American Academy of Family Physicians guidelines recommend the use of oral anticoagulants in patients with a CHADS2 score greater than 1 for the prevention of stroke in atrial fibrillation. The American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines recommend a direct oral anticoagulant over a vitamin K antagonist, unless the patient has moderate-to-severe mitral stenosis or a mechanical heart valve.

In May 2018, andexanet alfa (Andexxa) was approved to reverse the anticoagulant effects of rivaroxaban (Xarelto) and apixaban (Eliquis) in patients with life-threatening or uncontrolled bleeding. Optimal dose, duration, need for repeat dosing, and mitigation of thromboembolic risk is yet to be delineated.

 Enlarge     Print


Clinical recommendationEvidence ratingComments

Direct oral anticoagulants should be used as first-line agents for the treatment of venous thromboembolism and the prevention of stroke in patients with nonvalvular atrial fibrillation and a CHA2DS2-VASc score of 2 or higher in men and 3 or higher in women.20


Consensus guideline on the management of venous thromboembolism and atrial fibrillation

Bleeding risk assessment should be performed and any modifiable risk factors addressed during each visit.1,21


Expert opinion and consensus guidelines

Vitamin K antagonists should be used for the prevention of stroke in patients with atrial fibrillation with moderate-to-severe mitral stenosis and a CHA2DS2-VASc score of 2 or higher in men and 3 or higher in women.20,21


Consensus guidelines and a two-dose validation study

Low-molecular-weight heparin is recommended as the anticoagulant of choice in patients with cancer and venous thromboembolism; however, direct oral anticoagulants may be appropriate in select situations.1


Consensus guideline

CHA2DS2-VASc = congestive heart failure; hypertension; age 75 years or older [doubled]; diabetes mellitus; prior stroke, transient ischemic attack, or thromboembolism [doubled]; vascular disease; age 65 to 74 years; sex category.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to


Clinical recommendationEvidence ratingComments

Direct oral anticoagulants should be used as first-line agents for the treatment of venous thromboembolism and the

The Authors

show all author info

PATRICIA WIGLE, PharmD, BCPS, BCACP, FCCP, is a professor in the Division of Pharmacy Practice and Administrative Sciences at the University of Cincinnati (Ohio) and is an ambulatory care clinical pharmacy specialist at The Christ Hospital, Cincinnati....

BRAD HEIN, PharmD, BS, BCPS, is the associate dean for professional education and assessment at the University of Cincinnati and is an internal medicine clinical pharmacy specialist at The Christ Hospital.

CHRISTOPHER R. BERNHEISEL, MD, is the director of the University of Cincinnati/The Christ Hospital Family Medicine Residency Program and is an associate professor in the Department of Family and Community Medicine at the University of Cincinnati.

Address correspondence to Patricia Wigle, PharmD, BCPS, BCACP, FCCP, University of Cincinnati James L. Winkle College of Pharmacy, 3225 Eden Ave., 285 Kowalewski Hall, Cincinnati, OH 45267-0004 (email: Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.


show all references

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report [published correction appears in Chest. 2016;150(4):988]. Chest. 2016;149(2):315–352....

2. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol. 2018;36(20):2017–2023.

3. Raskob GE, van Es N, Verhamme P, et al.; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615–624.

4. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(suppl 2):e152S–e184S.

5. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257–3291.

6. University of Washington Anticoagulation Services. Simplified nomogram for warfarin maintenance dosing. Accessed September 8, 2018.

7. Ebell MH. Evidence-based adjustment of warfarin (Coumadin) doses. Am Fam Physician. 2005;71(10):1979–1982.

8. Liu A, Stumpo C. Warfarin-drug interactions among older adults. Geriatrics & Aging. 2007;10(10):643–646.

9. Pradaxa (dabigatran etexilate mesylate) capsules for oral use [prescribing information]. Ridgefield, Conn.: Boehringer Ingelheim Pharmaceuticals; 2018. Accessed May 2, 2019.

10. Xarelto (rivaroxaban) tablets, for oral use [prescribing information]. Janssen Pharmaceuticals, Inc.; 2018. Accessed May 2, 2019.

11. Eliquis (apixaban) tablets, for oral use [prescribing information]. Bristol-Myers Squibb Co.; 2018. Accessed May 2, 2019.

12. Savaysa (edoxaban) tablets, for oral use [prescribing information]. Daiichi Sankyo, Inc.; 2017. Accessed May 2, 2019.

13. Bevyxxa (betrixaban) capsules, for oral use [prescribing information]. Portola Pharmaceuticals, Inc.; 2017. Accessed May 2, 2019.

14. Lutz J, Jurk K, Schinzel H. Direct oral anticoagulants in patients with chronic kidney disease: patient selection and special considerations. Int J Nephrol Renovasc Dis. 2017;10:135–143.

15. Proietti M, Romanazzi I, Romiti GF, et al. Real-world use of apixaban for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 2018;49(1):98–106.

16. Kirchhof P, Radaideh G, Kim YH, et al.; Global XANTUS program Investigators. Global prospective safety analysis of rivaroxaban. J Am Coll Cardiol. 2018;72(2):141–153.

17. Otite FO, Khandelwal P, Chaturvedi S, et al. Increasing atrial fibrillation prevalence in acute ischemic stroke and TIA. Neurology. 2016;87(19):2034–2042.

18. Mazurek M, Shantsila E, Lane DA, et al. Secondary versus primary stroke prevention in atrial fibrillation. Stroke. 2017;48(8):2198–2205.

19. American Academy of Family Physicians. Updated clinical practice guideline: pharmacologic management of newly detected atrial fibrillation. April 2017. Accessed February 4, 2019.

20. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. January 21, 2019. Accessed May 2, 2019.

21. Lip GY, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation. Chest. 2018;154(5):1121–1201.

22. Connolly SJ, Ezekowitz MD, Yusuf S, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010;363(19):1877]. N Engl J Med. 2009;361(12):1139–1151.

23. Granger CB, Alexander JH, McMurray JJ, et al.; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992.

24. 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.

25. 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.

26. Mentias A, Shantha G, Chaudhury P, et al. Assessment of outcomes of treatment with oral anticoagulants in patients with atrial fibrillation and multiple chronic conditions. JAMA Netw Open. 2018;1(5):e182870.

27. Burgess S, Crown N, Louzada ML, et al. Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. J Thromb Haemost. 2013;11(9):1647–1654.

28. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants. J Am Coll Cardiol. 2017;70(24):3042–3067.

29. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–520.

30. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al.; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131–1141.

31. Monreal M, Falgá C, Valdés M, et al.; Riete Investigators. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism. J Thromb Haemost. 2006;4(9):1950–1956.

32. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100(10):3484–3488.

33. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Medicine (Baltimore). 1999;78(5):285–291.

34. Streiff MB, Holmstrom B, Angelini D, et al. NCCN Clinical Practice Guidelines in Oncology: Cancer-Associated Venous Thromboembolic Disease. Version 1.2019. Accessed August 2, 2019.

35. Streiff MB, Holmstrom B, Angelini D, et al. NCCN guidelines insights: cancer-associated venous thromboembolic disease, version 2.2018. J Natl Compr Canc Netw. 2018;16(11):1289–1303.

36. Wigle P, Hein B, Bloomfield HE, et al. Updated guidelines on outpatient anticoagulation. Am Fam Physician. 2013;87(8):556–566.

37. du Breuil AL, Umland EM. Outpatient management of anticoagulation therapy. Am Fam Physician. 2007;75(7):1031–1042.



Copyright © 2019 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions

More in Pubmed


Jul 2021

Access the latest issue of American Family Physician

Read the Issue

Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.

Sign Up Now

Navigate this Article