Update: What evidence supports the use of direct-acting oral anticoagulants in patients with cancer-related VTE?

Introduction

Venous thromboembolism (VTE) is the second leading cause of death in cancer patients, increasing their risk 4 to 6 times those of patients without cancer.^1,2 For patients who develop a VTE, they must be monitored closely for VTE recurrence and bleeding and should be placed on an anticoagulant for secondary prophylaxis.^1-3 Treatment recommendations for these patients can be difficult due to the amount of drug-drug interactions with anti-cancer treatments or thrombocytopenia from those treatments, increasing their risk of bleeding. Previous guidelines preferred low molecular weight heparin (LMWH) for acute treatment and secondary prophylaxis.^1,4 However, greater evidence is emerging on the use of direct-acting oral anticoagulants (DOACs), which are being incorporated into more contemporary guidelines.

Acute cancer related VTE treatment options

Updated guideline recommendations for antithrombotic therapy in patients with cancer and VTE have come forth as data on the safety and efficacy on DOACs have become available. When DOACs were first introduced, they were not preferred over LMWH or vitamin K antagonists (VKAs) due to a lack of data. Generally, guidelines on antithrombotic therapy for VTE disease historically supported the use of LMWH as first-line therapy for treatment and secondary prophylaxis and VKAs in those who do not receive LMWH in patients with cancer.^3-6 However, as more data in patients with cancer became available the recommendations have become more favorable for using DOACs. The Table summarizes current recommendations for managing VTE in patients with cancer.^7-9

Trials of DOACs in cancer related VTE

A previous frequently asked question (FAQ) on this topic from January 2019 summarized information from the HOKUSAI-VTE Cancer and SELECT-D trials, which evaluated edoxaban and rivaroxaban, respectively, for the treatment of cancer-related VTE, along with subgroup analyses from DOAC landmark trials. A summary of those can be found here. Since then, several randomized controlled trials evaluating the efficacy and safety of DOACs in patients with cancer have been published. A summary of the more recent trials is presented below along with 1 observational study, which provided a direct comparison between 2 DOAC agents.

Treatment/secondary prophylaxis

The Apixaban and Dalteparin in Active Malignancy-associated VTE (ADAM-VTE) trial (n=287) compared 6 months of therapy with dalteparin (200 IU/kg daily for 1 month, then 150 IU/kg daily) to oral apixaban (10 mg twice daily for 7 days, then 5 mg twice daily).¹⁰ All patients were randomized after the VTE event and were excluded if they had already received more than 7 days of anticoagulation. The trial was powered on a safety endpoint, with any episode of major bleeding as the primary endpoint. The primary safety endpoint of any episode of major bleeding showed that 0% of patients in the apixaban group versus 1.4% (n=2) of patients in the dalteparin group experienced any episode of major bleeding (hazard ratio [HR] not estimable; p= 0.138). For efficacy, VTE recurrence was significantly higher in the dalteparin group (6.3%, n=9) versus the apixaban group (0.7%, n=1) (HR, 0.099; 95% confidence interval [CI], 0.013 to 0.78; p=0.0281). The composite endpoint of major or clinically relevant non-major bleeding (CRNMB) was not significantly different between the 2 groups (apixaban vs dalteparin: 6.2% vs 6.3%; HR, 0.931; 95% CI,0.43 to 2.02; p=0.88). Deaths were not significant between the 2 groups and were not attributed to major bleeding or thromboembolism (apixaban vs dalteparin: 16% vs 11%; p=0.3078).

The Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer (CARAVAGGIO) trial (n=1155) compared treatment with apixaban and dalteparin in patients presenting with a newly diagnosed VTE. Patients were randomized to apixaban (10 mg twice daily for 7 days, then 5 mg twice daily) or dalteparin (200 IU/kg daily for 1 month, then 150 IU/kg daily) for 6 months.¹¹ This was a noninferiority trial with an established non-inferiority margin of 2.0 for the primary outcome of recurrent VTE. The primary outcome occurred in 32 patients in the apixaban group and 46 patients in the dalteparin group (5.6% vs 7.9%; HR, 0.63; 95% CI, 0.37 to 1.07; p<0.001 for non-inferiority; p=0.09 for superiority). Rates of major bleeding occurred in 22 patients of the apixaban group and 23 patients of the dalteparin group (3.8% vs 4%; HR, 0.82; 95% CI, 0.40 to 1.69; p=0.60). Rates of CRNMB occurred in 9% of the apixaban group and 6% in the dalteparin group. Death from any cause occurred in 135 (23.4%) of the apixaban group and 153 (26.4%) in the dalteparin group. These deaths were mostly cancer-related; 4 deaths due to VTE and 2 deaths due to bleeding occurred in each group.

Lastly, one observational cohort is also worth discussing as it allowed for the direct comparison of more than 1 DOAC, along with a LMWH, in a prospective setting.¹² Wysokinski et al evaluated consecutive patients presenting with acute cancer-related VTE who received apixaban, rivaroxaban, or enoxaparin for treatment and completed at least 3 months of therapy. During the study period, 224 patients were treated with apixaban, 163 patients were treated with rivaroxaban, and 363 were treated with enoxaparin. The primary outcome was VTE recurrence, which occurred in 11 patients of 224 in the apixaban group, 7 patients of 163 in the rivaroxaban group, and 17 patients of 363 in the enoxaparin group. This translated into a recurrence rate of 7.74 and 3.82 per 100 person-years (PY) for the apixaban and rivaroxaban groups, respectively; this difference was not statistically significant (HR, 1.31; 95% CI, 0.51 to 3.36), nor were the recurrence rates for each DOAC compared to enoxaparin (recurrence rate, 5.56 per 100 PY). Major bleeding occurred in 11 patients in the apixaban group, 12 patients in the rivaroxaban group and 21 patients in the enoxaparin group, which translates to 7.73, 6.74, and 6.99 per 100 PY, respectively. CRNMB occurred in 5 patients of the apixaban group, 13 patients in the rivaroxaban group, and 10 patients in the enoxaparin, which translates to 3.45, 7.46, and 3.20 per 100 PY, respectively. The rate of CRNMB was significantly lower with apixaban compared to rivaroxaban (HR, 0.31; 95% CI, 0.11 to 0.91). Mortality rates per 100 PY in the apixaban, rivaroxaban, and enoxaparin groups were 55.7, 39.31, and 53.80, respectively. The mortality rate for rivaroxaban was statistically significantly lower compared to both the apixaban and the enoxaparin groups.

Primary prophylaxis

The Apixaban to Prevent Venous Thromboembolism in Patients with Cancer (AVERT) trial (n = 563) evaluated the utility of apixaban for thromboprophylaxis in ambulatory patients with cancer who were initiating a new course of chemotherapy and were deemed at a high risk for VTE, as measured by a Khorana score of at least 2. Patients were randomized to apixaban 2.5 mg twice daily or placebo for 180 days. The primary endpoint of first episode of major VTE during the treatment period occurred in 12/288 (4.2%) apixaban patients versus 28/275 (10.2%) placebo patients. Significantly fewer patients experienced their first major VTE within 180 days with apixaban (HR, 0.41; 95% CI, 0.26 to 0.65; p<0.001).¹³ The rate of major bleeding experienced was 3.5% in the apixaban group versus 1.8% in the placebo group (HR, 2.00; 95% CI, 1.01 to 3.95; p=0.046). Rates of CRNMB were 7.3% in the apixaban group and 5.5% in the placebo group (HR 1.28; 95% CI 0.89 to 1.84). Death from any cause occurred in 12.2% of the apixaban group and 9.8% in the placebo group (HR, 1.29; 95% CI, 0.98 to 1.71). Of those deaths, 87% were attributed to cancer.

The Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer (CASSINI) trial (n=841) evaluated the efficacy and safety of rivaroxaban as thromboprophylaxis in patients with a solid tumor or lymphoma who were initiating a new course of chemotherapy and were deemed at a high risk for VTE, as measured by a Khorana score of at least 2. Patients were randomized to rivaroxaban 10 mg daily or placebo for 180 days.¹⁴ The primary efficacy composite endpoint (including confirmed symptomatic or asymptomatic DVT or PE and VTE-related death) occurred in 25 (6%) in the rivaroxaban group and 37 (8.8%) in the placebo group (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.10) during the 180-day treatment period. In the pre-specified treatment interval from first dose to last dose plus 2 days, the primary composite outcome occurred in 2.6% and 6.4% of patients in the rivaroxaban and placebo groups, respectively (HR, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 (2%) of the rivaroxaban group and 4 (1%) of the placebo group (HR, 1.96; 95% CI, 0.59 to 6.49; p=0.26). CRNMB occurred in 11 (2.7%) of the rivaroxaban group and 8 (2%) of the placebo group (HR, 1.3; 95% CI, 0.54 to 3.32; p=0.53) and was also not significantly different.  Eighty-four (20%) deaths from any cause were seen in the rivaroxaban group compared to 100 (23.8%) deaths in the placebo group (HR, 0.83; 95% CI, 0.62 to 1.11). Death from VTE only contributed marginally to the primary end point (3 and 1 patients in the placebo and rivaroxaban groups, respectively). However, since most patients died at home with the suspected cause being cancer, the true rate of death from VTE may be underestimated.

Overall findings from recent trials

Apixaban and dalteparin for the treatment and secondary prophylaxis of VTE were compared in 2 studies: ADAM-VTE and CARAVAGGIO.^10,11 ADAM-VTE showed significantly less recurrent VTE rates with apixaban.¹⁰ While CARAVAGGIO found comparable, noninferior rates between the therapies.¹¹ Rates of major bleeding were not significantly different between interventions in both trials.^10,11 Interestingly, the observational study found similar rates of VTE recurrence between apixaban, rivaroxaban, and enoxaparin, but found apixaban to be associated with lower rates of CRNMB and rivaroxaban to be associated with lower rates of all-cause mortality.¹²

For primary prophylaxis of VTE in high-risk ambulatory cancer patients initiating a new chemotherapy regimen, 2 trials addressed the efficacy and safety of DOACs.^13,14 AVERT evaluated apixaban versus placebo wherein apixaban showed significantly fewer patients experiencing their first major VTE within 180 days after initiation of therapy.¹³ CASSINI evaluated rivaroxaban versus placebo and found no significant improvement in the rate of VTE or VTE-related death in the 180-day trial period.¹⁴ However, during the pre-specified intervention period, rivaroxaban substantially reduced VTE without increasing major bleeding.

Conclusion

With these new studies and the updated guidelines, there are new recommendations for antithrombotic therapy in patients with cancer and VTE, specifically regarding DOAC safety and efficacy. The American Society of Clinical Oncology (ASCO) and the International Initiative on Thrombosis and Cancer (ITAC) guidelines provide recommendations for use of rivaroxaban and edoxaban (after initial parenteral anticoagulation) for patients with cancer-associated VTE based on the ADAM VTE and CARAVAGGIO trials, along with the HOKUSAI-VTE Cancer and SELECT-D trials which were summarized in the previous FAQ. For primary thromboprophylaxis, the ASCO, ITAC, and International Society for Thrombosis and Hemostasis (ISTH) guidelines all suggest that apixaban and rivaroxaban can be used in select high-risk outpatients with cancer who are initiated a new chemotherapy. Generally, DOACs are not recommended in patients with significant drug-drug interactions or with impaired GI absorption. Further, DOACs are not recommended in patients with pregnancy, severe renal failure, or in patients undergoing neurosurgery. Uncertainty still surrounds patients with certain types of cancer or other patient-specific factors due to the exclusion of these populations from clinical trials. Some examples include patients with brain tumors, active central nervous system metastases, and those who are more vulnerable either by being higher risk for bleeding or who are sicker. In those cases, LMWH is still recommended due to the lack of data addressing those populations.

References

1. Rodriguez R. What evidence supports the use of direct-acting oral anticoagulants in patients with cancer-related VTE? University of Illinois at Chicago Drug Information Group. Published January 2019. Accessed August 15, 2020. https://dig.pharmacy.uic.edu/faqs/2019-2/january-2019-faqs-2/#
2. Franco-Moreno A, Cabezon-Gutierrez L, Palka-Kotlowsa M, Villamayor-Delgado M, Garcia-Navarro M. Evaluation of direct oral anticoagulants for the treatment of cancer-associated thrombosis: an update. J Thromb Thrombolysis. 2019;47(3):409-419. doi: 10.1007/s11239-018-1783-2
3. 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):2189-2204. doi: 10.1200/JCO.2013.49.1118
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6. Guyatt GH, Eikelboom JW, Gould MK, et al. Approach to outcome measurement in the prevention of thrombosis in surgical and medical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e185S-e194S. doi:10.1378/chest.11-2289
7. Key NS, Khorana AA, Kuderer, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38(5):496-520. doi: 10.1200/JCO.19.01461
8. Wang T, Zwicker JI, Ay C, et al. The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: Guidance from the SSC of the ISTH. J Thromb Haemost. 2019;17(10):1772-1778. doi:10.1111/jth.14564
9. Farge D, Frere C, Connors JM, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2019;20(10):e566-e581. doi: 10.1016/S1470-2045(19)30336-5
10. McBane RD, 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(2):411-421. doi:10.1111/jth.14662
11. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382(17):1599-1607. doi:10.1056/NEJMoa1915103
12. Wysokinski WE, Houghton DE, Casanegra AI, et al. Comparison of apixaban to rivaroxaban and enoxaparin in acute cancer-associated venous thromboembolism. Am J Hematol. 2019;94(11):1185-1192. doi:10.1002/ajh.25604
13. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380(8):711-719. doi:10.1056/NEJMoa1814468
14. Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban for thromboprophylaxis in high risk ambulatory patients with cancer. N Engl J Med. 2019;380(8):720-728. doi:10.1056/NEJMoa1814630

Prepared by:
Erin Hermes, PharmD
PGY1 Pharmacy Resident
University of Illinois at Chicago College of Pharmacy

October 2020

The information presented is current as September 15, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.