Recurrent venous thromboembolism (VTE) and major bleeding are the two major challenges in managing cancer-associated thrombosis (CAT). Despite anticoagulation, recurrent VTE is common among patients with cancer, and anticoagulation therapy increases the risk of bleeding in this population [1].
Low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) are currently recommended for the short- (3–6 months) and long-term (>6 months) management of CAT in clinical practice guidelines [2].
However, the duration of anticoagulation beyond 6 months in patients with CAT is still a matter of debate and should be evaluated individually based on each patient’s risk [1].
Anticoagulation beyond 6 months
Two studies, the DALTECAN (NCT00942968) and TiCAT studies suggest the safety of LMWH in patients with CAT beyond 6 months.
In the DALTECAN study, the incidence of major bleeding was 0.7% (95% CI: 0.3–1.4) at 7–12-months compared with 1.7% (95% CI: 1.1–2.4) during the initial 6 months of the study [3].
In the TiCAT study, clinically relevant bleeding during months 1–6 and 7–12 was 0.9% (95% CI: 0.5–1.6) and 0.6% (95% CI: 0.2–1.4) per patient and month, respectively [4].
The SELECT-D trial evaluated the efficacy and safety of rivaroxaban at 12 months in patients with PE or residual DVT. VTE recurrence was lower in the rivaroxaban arm (4%) than the placebo arm (14%) at month 12; however, the difference was not statistically significant due to the small sample size.
Two (5%) patients experienced major bleeding in the rivaroxaban arm compared with none (0%) in the placebo arm. The rate of CRNMB was 4% in the rivaroxaban arm and 0% in the placebo arm [5].
In all these studies, patients were treated with full-dose anticoagulation. However, no data exist about low-dose anticoagulation as secondary prophylaxis in CAT, and guidelines recommend full-dose if patients need more than 6 months of treatment [1].
The CAP study
In an attempt to fill this gap, the CAP study (NCT02581176, an investigator-initiated, single-arm, interventional, multicenter study, assessed the efficacy and safety of apixaban as secondary prophylaxis for VTE in patients with cancer [6].
After full-dose treatment for up to 6 months, the primary endpoints are recurrent VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB). The secondary endpoints are recurrent VTE, major bleeding, and CRNMB after secondary prophylaxis with low-dose apixaban for up to 30 months [6].
In total, 298 patients received full-dose apixaban for up to 6 months. From month 7, 196 patients received 2.5 mg twice daily as secondary VTE prophylaxis for up to 30 months [6].
During the first 6 months of full-dose anticoagulation, 12/298 patients had recurrent VTE (4.0%, 95% CI: 2.1–6.9). In the next 30 months with low-dose apixaban, 14/196 (7.1%, 95% CI: 4.0–11.7) patients experienced recurrent VTE [6].
Recurrent VTE had the highest incidence rate during the first month of full-dose anticoagulation (1.4%, 95% CI: 0.5–3.6, per person-month), which decreased at 2–6 months (0.8%, 95% CI: 0.4–1.6), and increased again slightly at 7–12 months, after the dose of apixaban was reduced (1.0%, 95% CI: 0.5–1.9) [6].
During the first 6 months of full-dose anticoagulation, 5.4% of patients experienced major bleeding, and 8.7% experienced one or more episodes of CRNMB. During the next 30 months of low-dose apixaban treatment, 3.1% of patients experienced major bleeding, and 8.2% experienced CRNMB [6].
The incidence rate of major bleeding peaked in the first month of full-dose treatment (1.7%, 95% CI: 0.7–4.1, per person-month). It declined after dose reduction at 7–12 months (0.3%, 95% CI: 0.1–1.0, per person-month) and remained low during the subsequent 30 months [6].
These results show that dose reduction of apixaban to 2.5 mg twice daily is reasonably safe and effective after 6 months of treatment with full-dose apixaban. Furthermore, even though the incidence of recurrent VTE increased slightly after dose reduction, the risk of VTE might be outweighed by the reduction in major bleedings [6].
Despite these promising findings, proper investigation through randomization between full and reduced anticoagulation doses should be performed to assess the safety and efficacy of apixaban dose reduction after 6 months [6].
In the CAP study, the incidence of recurrent VTE and major bleeding greatly diminished after 9–12 months of treatment. For this reason, it is not clear the best time to reduce the apixaban dose, which might be after 6 months of full-dose [6].
Ongoing clinical trials
Currently, two randomized trials are trying to shed some light on this matter.
The API-CAT (NCT03692065) is an ongoing randomized, double-blind, multicenter, international, prospective, and parallel-group study. It assesses two dose regimens of apixaban (2.5 vs 5 mg) to prevent recurrent VTE in patients with cancer who have completed at least 6 months of anticoagulant treatment [7].
The EVE trial (NCT03080883) is an investigator-initiated phase III, multicenter, randomized, double‐blind trial. It will estimate the difference in the bleeding rates using two doses of apixaban for secondary prevention of cancer‐associated VTE over 12 months for patients who have already received 6 months (but no more than 12 months) of anticoagulant treatment [8].
In the general population, the AMPLIFY-EXT trial (NCT00633893) showed that secondary prophylaxis with low-dose apixaban protects against recurrent VTE without increasing the rate of major bleeding [9].
Because of the increased bleeding risk in patients with cancer, exploring the efficacy and safety of dose reduction in anticoagulation is of utmost importance in this population also.
References
Falanga A, Le Gal G, Carrier M, et al. Management of Cancer-Associated Thrombosis: Unmet Needs and Future Perspectives. TH Open. 2021;5(3):e376-e386.
Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2020;38(5):496-520.
Francis CW, Kessler CM, Goldhaber SZ, et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015;13(6):1028-1035.
Jara-Palomares L, Solier-Lopez A, Elias-Hernandez T, et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res. 2017;157:90-96.
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.
Larsen TL, Garresori H, Brekke J, et al. Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients – 30 months follow-up [published online ahead of print, 2022 Feb 3]. J Thromb Haemost. 2022;10.1111/jth.15666.
Mahé I, Agnelli G, Ay C, et al. Extended Anticoagulant Treatment with Full- or Reduced-Dose Apixaban in Patients with Cancer-Associated Venous Thromboembolism: Rationale and Design of the API-CAT Study. Thromb Haemost. 2021;10.1055/a-1647-9896.
McBane RD 2nd, Loprinzi CL, Ashrani A, et al. Extending venous thromboembolism secondary prevention with apixaban in cancer patients: The EVE trial. Eur J Haematol. 2020;104(2):88-96.
Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708. doi:10.1056/NEJMoa1207541