The Art of Managing Cancer-Associated Thrombosis: Caravaggio and Beyond

Venous thromboembolism (VTE) is a frequent complication and the second leading cause of death in cancer patients. Cancer-associated thromboembolism (CAT) accounts for 9% of deaths associated with early mortality during chemotherapy and 47-fold increased risk of mortality from VTE^1,2.

The high risk of recurrent VTE and bleeding in patients with cancer requires specific studies on anticoagulant treatment.

For almost 20 years, injectable low-molecular-weight heparins (LMWHs) have been the mainstay of VTE treatment in patients with malignancies, based on the efficacy and safety of these drugs compared to oral VKA, as determined by the CLOT and CATCH trials^3,4. Following the demonstration of therapeutic benefits of direct oral anticoagulants (DOACs) in the management of  VTE in the general population, recent randomized clinical trials (RCTs) focused on the assessment of DOACs in the CAT setting.

In the Hokusai VTE Cancer Trial, 1050 cancer patients with symptomatic or incidentally diagnosed VTE were randomized to receive either edoxaban (dalteparin for at least 5 days, followed by edoxaban 60 mg once daily) or dalteparin (200 IU/kg once daily for 1 month, followed by 150 IU/kg daily) for 6-12 months⁵. The primary outcome was a composite of recurrent VTE or major bleeding within 12 months after randomization, regardless of treatment duration. While edoxaban was non-inferior to LMWH, an increased risk of major bleeding was observed, especially in the gastrointestinal (GI) tract.  Likewise, in the SELECT–D trial, the anti-Xa rivaroxaban yielded good efficacy, but lower safety compared to dalteparin in terms of major bleeding⁶. These results precluded the use of DOACs in certain categories of cancer patients according to recent International Clinical Practice Guidelines for the Treatment of Venous Thromboembolism in Patients with Cancer⁷.

Given that the anti-Xa apixaban demonstrated a good safety profile in previous VTE studies⁸, the aim of the randomized, open-label Caravaggio trial was to assess whether oral apixaban was non-inferior to subcutaneous dalteparin for the treatment of symptomatic or incidental proximal lower-limb deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in patients with any type of cancer apart from basal-cell or squamous-cell carcinoma of the skin, primary brain tumor or known cerebral metastases and acute leukemia⁹. Notably, patients with thrombocytopenia, concomitant use of strong inhibitors or inducers of both CYP-3A4 and P-gp were excluded from the study. After randomization, apixaban was given orally at a dose of 10 mg bid for 1 week, followed by 5 mg bid for up to 6 months. Subcutaneous dalteparin was administered according to the CLOT regimen.

The outcome was determined by objectively confirmed recurrent symptomatic or incidental proximal lower limb DVT or PE or symptomatic DVT of the upper limbs occurring during the study treatment period. Major bleeding was assessed according to the European Medicines Agency (EMA) definition. The study population included 1170 patients, 80% with symptomatic VTE; 97% had active cancer and 68% presented with advanced disease. The vast majority of patients had solid tumors with about one third GI, pancreatic or hepatobiliary cancer. The primary composite efficacy outcome (recurrent DVT, recurrent or fatal PE) occurred in 32/576 (5.6%) patients in the apixaban group compared to 46/579 (7.9%) patients in the dalteparin group [HR 0.63 (95%CI 0.37-1.07); p <0.001 for non-inferiority and p=0.08 for superiority]. The primary safety outcome of major bleeding occurred in 22/576 (3.8%) in the apixaban group, which did not differ in the dalteparin group – 23/579 (4.0%) [HR 0.82 (95%CI 0.40-1.69); p =0.60]. Likewise, there was no intergroup difference in major GI or non-GI bleeding. A total of major bleeding and clinically relevant non-major bleeding events amounted to 12.2% in the apixaban group relative to 9.7% in the dalteparin group [HR 1.16 (95%CI 0.77-1.75)]. The findings of the Caravaggio study demonstrate the safety and efficacy of oral apixaban in the treatment of cancer-associated venous thromboembolism and foster the use of this DOAC in such challenging clinical setting, including patients with GI cancer. Notably, the ADAM VTE trial showed similar favorable outcomes¹⁰.

While the results of the Caravaggio study are practice-changing, several issues related to the management of CAT remain to be addressed. Further studies are needed in patients with primary brain tumor or known cerebral metastases, and acute leukemia who were excluded as well as patients with other hematological malignancies who were underrepresented in this study. Guidelines for managing patients beyond 6 months warrant extended studies, potentially based on the experience gained in the general VTE population¹¹. Although DOACs are likely to be increasingly employed in patients with CAT, LMWHs still have an important role in particular clinical settings, including that of cancer patients with COVID-19.

References

1. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634.
2. Kuderer NM, Culakova E, Lyman GH, Francis C, Falanga A, Khorana AA. A Validated Risk Score for Venous Thromboembolism Is Predictive of Cancer Progression and Mortality. Oncologist. 2016;21(7):861-867.
3. 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. 2003;349(2):146-153.
4. 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. 2015;314(7):677-686.
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(7):615-624.
6. 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.
7. 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.
8. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
9. 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.
10. 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(2):411-421.
11. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708.