Direct-Acting Oral Anticoagulants: Consider Risk Factors for Thrombosis and Bleeding in Decision to Use, Dosing

Pearls for using direct oral anticoagulants (DOACs) in different scenarios were offered by Stephan Moll, MD, professor of medicine, University of North Carolina School of Medicine, Chapel Hill.

The recommendation by the American College of Chest Physicians1 and American Society of Hematology2 to treat venous thromboembolism (VTE) with a DOAC (instead of warfarin) may not apply to certain subgroups, such as those with renal insufficiency, moderate to severe liver disease, or antiphospholipid syndrome (APS).2

DOAC dosing for the treatment of VTE consists of an acute phase, treatment phase, and long-term phase. In the acute phase of VTE, recommended apixaban dosing is 10 mg twice daily for 7 days; in the treatment phase (up to 6 months), 5 mg twice daily; and in the long-term phase, 2.5 mg twice daily. The corresponding recommended dosing for rivaroxaban is 15 mg twice daily for 3 weeks in the acute phase; 20 mg daily in the treatment phase; and 10 mg daily in the long-term phase. Dabigatran dosing is 150 mg twice daily for all three phases.

Treat “as long as needed, but not longer than necessary,” he said. If patients have a VTE due to a major transient risk factor (ie, hip or knee replacement) and are at low risk for recurrence of VTE, he suggests 3 months of treatment. In contrast, if a patient has an unprovoked VTE and a high risk for recurrence, the recommendation is to treat with long-term anticoagulation. Obtaining a D-dimer level can be helpful to guide duration of DOAC for those patients in between (equipoise). In addition, a strong thrombophilia or repeatedly positive antiphospholipid antibodies would warrant long-term anticoagulation. In general, the duration of anticoagulation is a conglomerate decision weighing the risk of recurrent VTE with the risk for bleeding.

Intermediate-dose is as effective as full-dose DOAC and may be slightly safer in patients with equipoise. Some patients clearly need full-dose anticoagulation (ie, men with unprovoked VTE). “I think about intermediate dose, after 6 months of full-dose treatment, in the elderly person, those with a lower body weight, and those with a higher risk for bleeding, who may have comorbidities,” said Dr. Moll.

DOACs can be considered in patients with unusual clots (ie, splenic vein thrombosis, renal vein thrombosis, ovarian vein thrombosis, Budd-Chiari syndrome, portal vein thrombosis), although data are limited for any type of anticoagulation for this indication. As with VTE, consider VTE risk factors in making the decision to treat long term.

For patients with superficial thrombophlebitis, short-term anticoagulation (2 to 6 weeks) is appropriate although no gold standard exists.

For patients with a body mass index (BMI) up to 40 kg/m2 and a body weight up to 120 kg, all DOACS are reasonable options. For the severely obese, defined as those with a BMI >40 kg/m2 and a body weight >120 kg, data are strongest with rivaroxaban but apixaban is also a reasonable choice of DOAC, he said. 

Following bariatric surgery, absorption of DOACs is impaired. Therefore, in the acute postoperative phase, use a parenteral anticoagulant. At ≥4 weeks, once the gastrointestinal tract has adapted to the gastric surgery, a switch to warfarin or a DOAC may be considered. If a DOAC is used, obtain a trough blood level.

In patients with renal failure, apixaban is appropriate to use but not rivaroxaban. The dosing of apixaban would be 5 mg twice daily in younger and heavier patients and those with a lower risk of bleeding; and 2.5 mg twice daily in those who are low weight, are older, have comorbidities, and those at higher risk of bleeding.

The DOACs are good treatment options for patients with cancer and VTE, said Dr. Moll. Apixaban is as effective and safe in this setting as low molecular weight heparin (LMWH).3,4 Rivaroxaban and edoxaban are more effective than LMWH but are associated with higher bleeding risk.5,6

In patients with antiphospholipid antibodies, thrombosis recurrence is elevated in patients switched from warfarin to a DOAC compared with patients remaining on warfarin.7,8 High-risk features of patients with APS in whom warfarin instead of a DOAC is indicated are triple positivity, arterial thrombosis, small-vessel thrombosis or organ involvement, and heart valve disease. However, “if a patient with APS is doing well on a DOAC [ie, has been on it for 2 or more years], I don’t necessarily switch to warfarin, even if they are triple positive,” he said, as no clinical studies enrolled such patients. The best anticoagulant is not clear in patients with de novo APS.

In patients scheduled for surgery, the bleeding risk associated with the surgery should guide the interruption schedule of the DOAC. In patients with normal renal function undergoing surgery associated with a high bleeding risk, stop the DOAC 2 days before and resume on day 2 or 3 after surgery. With a low-risk intervention, stop the DOAC 1 day prior and restart 1 day after the surgery. The exception is dabigatran in patients with CrCl <50 mL/min, in which case dabigatran should be interrupted 4 days prior to surgery associated with a high risk of bleeding, and restarted on day 2 or 3, and in such patients undergoing surgery with a low bleeding risk, stop dabigatran 2 days prior and resume the day after surgery. Bridging with LMWH is never needed when interrupting a DOAC.

Disclosure

Consultant for Bristol‐Myers Squibb 

References

  1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315-52.
  2. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4:4693-4738.
  3. McBane RD 2nd, Wysokinski WE, Le-Rademacher JG, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial. J Thromb Haemost 2020;18:411-21.
  4. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382:1599-1607.
  5. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-24.
  6. Young AM, Marshall A, Thirwall 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;36:2017-23.
  7. Pengo V, Denas G, Zoppellaro G, et al.  Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018;132:1365-71.
  8. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med 2019;171:685-94.

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