Although approximately 20% to 30% of patients with cancer will develop venous thromboembolism (VTE), clinicians continue to debate strategies for pharmacologic treatment and prevention.1 At the 2018 Debates and Didactics in Hematology and Oncology Conference, held on Sea Island, Georgia, Christine L. Kempton, MD, MSc, of Emory University, weighed the risks and benefits of using direct-acting oral anticoagulants, in the ambulatory setting and in patients undergoing major surgery.2
VTE Prevention: Perioperative Setting
Although a number of different predictive scoring systems can be applied to determine the risk of VTE, the Khorana system, which considers cancer type, prechemotherapy platelet counts, hemoglobin, white blood cell count, and body mass index, is the most well known. In patients deemed to be at low risk, said Dr. Kempton, the rate of VTE over the subsequent 2.5 months is 0.3%; in those classified as high risk, the rate increases to 6.7%.3
“Minimal improvement is seen with the addition of biomarkers such as D-dimer or prothrombin fragment 1+2, P-selectin, or the type of chemotherapy and the performance status,” Dr. Kempton added. “Generally, all scores have had only modest predictive capability.”
Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer.— Christine L. Kempton, MD, MSc
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In patients undergoing major cancer surgery (ie, general anesthesia for more than 30 minutes), the overall recommendation for pharmacologic prophylaxis is 7 to 10 days after surgery. For major abdominal or pelvic surgery with high-risk features, such as residual cancer, obesity, prior VTE, or immobility, however, prophylaxis is recommended up to 4 weeks, as the rate of VTE with intermittent pneumatic compression devices alone is up to 19%.4
“With extended pharmacologic prophylaxis of enoxaparin—40 mg administered subcutaneously—the risk can be reduced by half,” said Dr. Kempton. “Use of novel oral anticoagulants, however, is not currently recommended for patients with malignancy and VTE because of limited data in patients with cancer.”
VTE Prevention: Ambulatory Setting
When anticoagulation has been used for VTE prevention in patients with cancer undergoing chemotherapy in the ambulatory setting, the absolute risk reduction of VTE was approximately 2 to 2.5.
“If you do apply prophylaxis with an anticoagulant universally to your patients with cancer, you’re going to be treating 40 to 50 patients to prevent a clot and likely a lot of bleeding as well,” Dr. Kempton explained.
On the other hand, in high-risk patients with a Khorana score higher than 3, research has shown a modest benefit, though not a statistically significant benefit for those randomized to receive dalteparin (Fragmin; 12% VTE) vs placebo (21% VTE; hazard ratio = 0.69, 95% confidence interval: 0.23–1.89).5 The AVERT trial will test the effectiveness of apixaban, an orally administered anticoagulant, vs placebo in 574 newly diagnosed patients with cancer with planned chemotherapy and a Khorana score higher than 2.
“With the availability of anticoagulants at prophylactic doses that can be taken orally, I think there’s a real opportunity in this patient population,” noted Dr. Kempton. “These results will be very interesting.”
VTE Prevention: Multiple Myeloma
Patients receiving antiangiogenic agents with chemotherapy and/or dexamethasone are also at risk for VTE. Those who are at low risk can be treated with aspirin alone (81–325 mg), whereas those who are at high risk will need anticoagulation. The current recommendations are for enoxaparin or warfarin, said Dr. Kempton, who noted there are no current data on direct-acting oral anticoagulants in this setting.
“If a direct-acting oral anticoagulant is going to be used, I would favor using therapeutic doses of apixaban at 5 mg daily or rivaroxaban at 20 mg,” said Dr. Kempton, who added that ongoing trials will answer the question of whether lower doses should be used.
What Anticoagulant Should Be Used for Patients With Cancer?
As Dr. Kempton reported, the long-standing CLOT trial established the superiority of low–molecular-weight heparin over warfarin for the treatment of cancer-associated thrombosis, with a nearly 50% relative risk reduction with the use of dalteparin vs warfarin.6 The CATCH trial showed a similar benefit of tinzaparin (Innohep) over warfarin with associated reduction in the risk for bleeding.7 According to Dr. Kempton, however, the recent introduction of direct-acting oral anticoagulants has generated a great deal of clinical interest because “they are much simpler than the use of subcutaneous injection.”
“Overall, in patients without cancer, direct-acting oral anticoagulants have been shown to be slightly safer than warfarin for the treatment of VTE,” said Dr. Kempton. “For select patients, warfarin may still be more appropriate, but direct-acting oral anticoagulants are becoming the standard of care in this space.”
For select patients, warfarin may still be more appropriate, but direct-acting oral anticoagulants are becoming the standard of care in this space [treatment of cancer-associated thrombosis].— Christine L. Kempton, MD, MSc
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In an open-label, noninferiority trial, 1,050 patients with cancer who had acute symptomatic or incidental VTE were randomized to receive either low–molecular-weight heparin followed by oral edoxaban (60 mg once daily) or subcutaneous dalteparin (200 IU/kg) followed by dalteparin (150 IU/kg).8 In the composite outcome of recurrent VTE or major bleeding, oral edoxaban was shown to be noninferior to subcutaneous dalteparin. Although the rate of recurrent VTE was lower with edoxaban, 6.9% of patients had major bleeding with edoxaban, compared with 4.0% of patients who received dalteparin. The group with the greatest risk for gastrointestinal bleeding consisted of those with colorectal cancers, and bleeding was more likely to occur in the upper gastrointestinal tract.
In the Select-D pilot trial, recently published data showed that rivaroxaban was associated with a relatively low recurrence of VTE but higher clinically relevant nonmajor bleeding compared with dalteparin.9 For clinicians, added Dr. Kempton, the question now becomes whether to use low–molecular-weight heparin or a direct-acting oral anticoagulant.
“Clinicians deciding between a direct-acting oral anticoagulant and low–molecular-weight heparin should consider drug interactions with planned chemotherapy to make sure there are no contraindications,” said Dr. Kempton, who noted that substrates of CYP3A4 and P-glycoprotein interfere with direct-acting oral anticoagulants. “There’s also a bleeding risk in patients with active gastrointestinal cancers.”
Clinicians don’t have to make a decision about a therapy that will extend forever. You can choose the right therapy for now, and when the clinical situation changes, you can change therapies.— Christine L. Kempton, MD, MSc
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As Dr. Kempton explained, patients at high risk of bleeding, including the elderly, those with a history of bleeding, and those with uncontrolled hypertension, should avoid a direct-acting oral anticoagulant. Clinicians caring for patients with anticipated grade 3 or 4 thrombocytopenia may wish to avoid a direct-acting oral anticoagulant in the early cancer setting as well. The ease of use needs to be weighed against the increased risk of bleeding, particularly in the setting of gastrointestinal malignancies, she observed.
“One of the key take-home points is that clinicians don’t have to make a decision about a therapy that will extend forever,” noted Dr. Kempton. “You can choose the right therapy for now, and when the clinical situation changes—patients have received treatment and no longer have an active tumor in their gastrointestinal tract or have better controlled hypertension—you can change therapies. You can use low–molecular-weight heparin upfront and change to something that’s easier for the patient in the future.”
Current recommendations are for anticoagulation therapy to be given for a minimum of 6 months. However, future studies are needed to determine the optimal duration and whether lower doses are adequate for longer-term therapy, Dr. Kempton concluded. ■
DISCLOSURE: Dr. Kempton reported no conflicts of interest.
REFERENCES
1. Timp JF, Braekkan SK, Versteeg HH, et al: Epidemiology of cancer-associated venous thrombosis. Blood 122:1712-1723, 2013.
3. van Es N, Di Nisio M, Cesarman G, et al: Comparison of risk prediction scores for venous thromboembolism in cancer patients: A prospective cohort study. Haematologica 102:1494-1501, 2017.
4. Lyman GH, Bohlke K, Khorana AA, et al: Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol 33:654-656, 2015.
5. Khorana AA, Francis CW, Kuderer NM, et al: Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res 151:89-95, 2017.
6. Lee AY, Levine MN, 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 349:146-153, 2003.
7. Lee AYY, Kamphuisen PW, Meyer G, et al: Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial. JAMA 314:677-686, 2015.
8. Raskob GE, van Es N, Verhamme P, et al: Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 378:615-624, 2018.
9. 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 36:2017-2023, 2018.
