DOACs to Treat Venous Thromboembolism in Cancer

MARCH 27, 2018
It is known that patients with cancer have an increased risk of venous thromboembolism (VTE). However, management of VTE is challenging, because the risk of recurrent VTE and bleeding are both increased in this patient population.1,2 The reported risk of thrombotic events is 4 times as high in patients with cancer and increases 6-fold if the patient is receiving chemotherapy, compared with the general population.3

Historically, subcutaneous low molecular weight heparin (LMWH) has been the treatment of choice to prevent VTE recurrence in cancer patients based on the CLOT trial.4 This trial compared the efficacy of subcutaneous LMWH to oral warfarin and found that LMWH had a significantly lower rate of VTE recurrence at 6 months compared with oral warfarin (8.0% vs. 15.8%; HR 0.48; 95% CI 0.30-0.77; P = 0.002). As a result, treatment with LMWH in patients with cancer is supported by clinical guidelines, including those by the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network.5-7 Despite the current recommendations, long-term management with LMWH can become burdensome, as it requires subcutaneous injections and is costly based on the price of these agents. Although the use of oral direct-acting oral anticoagulants (DOACs) is preferred for VTE treatment in patients without cancer, their role in therapy for patients with cancer remains controversial. To further investigate the role of DOACs in this subset of patients, new evidence comparing the use of DOACs to LMWH is emerging.

The largest trial published to date in this patient population, the HOKUSAI-VTE Cancer study, compared the use of dalteparin with edoxaban in patients with cancer diagnosed with an acute symptomatic or incidental VTE.2 This was an open-label, non-inferiority, randomized clinical trial of 1050 patients that assigned participants to receive either subcutaneous dalteparin for 5 days followed by oral edoxaban 60 mg once daily or a single subcutaneous dalteparin 200 units/kg injection daily for 1 month. After 1 month, the dalteparin dose was reduced to 150 units/kg once daily for the remainder of the study period. Both arms were treated for at least 6 months, up to a maximum of 12 months. The primary outcome was a composite of VTE recurrence or major bleeding, based on the International Society on Thrombosis and Hemostasis definition, during the 12-month study period. The study found that edoxaban was non-inferior to dalteparin in the primary composite outcome of recurrent VTE or in major bleeding at 12 months (12.8% edoxaban vs. 13.5% dalteparin group; P = 0.006). There was a non-significant reduction in the recurrence of VTE in the edoxaban group (7.9% vs. 11.3%; P = 0.09), coupled with a higher rate of major bleeding (6.9% vs. 4.0%; P = 0.04).  Bleeding was primarily seen in patients who entered the trial with gastrointestinal cancers. A subgroup analysis showed no difference in bleeding in patients without gastrointestinal cancers.

The Select-D trial was a prospective, randomized, open-label, pilot study that compared dalteparin to rivaroxaban in patients with cancer and VTE.8 The full Select-D trial has yet to be published but is anticipated to be released in 2018. The interventions used were subcutaneous dalteparin 200 units/kg daily for 1 month, later changed to 150 units/kg for months 2 to 6 or oral rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily up to 6 months. The study population consisted of 406 patients and showed that the rivaroxaban group had a lower rate of VTE recurrence at 6 months compared with the dalteparin group (4% vs. 11%). There was no difference in major bleeding between cohorts (3% vs, 4%), but the rate of clinically relevant non-major bleeding at 6 months was increased with rivaroxaban (12.3% vs. 3%). This risk was increased in patients with gastrointestinal (GI) cancers.1

Moreover, a recent systemic review and meta-analysis analyzed the effectiveness and safety of DOACs to LMWH for the prevention of VTE recurrence in patients with cancer.1 The results of the analysis showed that the rates of recurrent VTE in patients who received DOACs was lower when compared with LMWH, but this outcome was paired with an increased risk of bleeding, specifically in patients with GI cancers. Improved compliance with DOACs compared with LMWH was noted to explain the differences in effectiveness and safety of the 2 interventions.

Although, it is recommended that LMWH be used over vitamin K antagonists or DOACs to prevent VTE recurrence in patients with cancer in multiple guidelines, new data does suggest that edoxaban or rivaroxban may be reasonable alternatives to LMWH. Their use in this patient population will likely be increasing in the near future soon, but further investigation must be conducted to assess the efficacy and safety of the other DOAC agents used for this indication, along with further investigation into bleeding potential and use in patients with GI cancers.
This article was co-authored by Paulushi Patel, a PharmD candidate at Chicago State University College of Pharmacy.

References

1. Li A, Garcia DA, Lyman GH, Carrier M. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): a systematic review and meta-analysis. Thromb Res. 2018. pii: S0049-3848(18)30216-0. doi: 10.1016/j.thromres.2018.02.144. 
2. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624. doi: 10.1056/NEJMoa1711948.
3. Lyman GH, Eckert L, Wang Y, Wang H, Cohen A. Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis. Oncologist. 2013;18(12):1321-9. doi: 10.1634/theoncologist.2013-0226.
4.  Lee AY, Levine M, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53. 
5. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.
6. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189-204. doi: 10.1200/JCO.2013.49.1118. 
7. Streiff MB, Holmstrom B, Ashrani A, et al. Cancer-associated venous thromboembolic disease version 1.2015. J Natl Compr Canc Netw. 2015;13(9):1079-95
8. Young A, Marshall A, Thirwall J, et al. Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: Results of the Select-D Pilot trial. Blood. 2017;130:625.
 

Alexander Kantorovich, PharmD, BCPS
Alexander Kantorovich, PharmD, BCPS, is a Clinical Associate Professor of Pharmacy Practice at Chicago State University College of Pharmacy and Clinical Pharmacy Specialist at Advocate Christ Medical Center in Oak Lawn, Illinois. Dr. Kantorovich earned his Associate of Science degree with an emphasis in chemistry from William Rainey Harper College and received his Doctor of Pharmacy degree from the University of Illinois at Chicago College of Pharmacy. He went on to complete a 2-year pharmacotherapy residency with an emphasis in cardiology and critical care at the Cleveland Clinic and is board certified in pharmacotherapy. His research interests center around cardiovascular pharmacotherapy, anticoagulation, and anticoagulation reversal.
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