Patients with cancer and a Khorana score ≥2 have an estimated risk of symptomatic venous thromboembolism (VTE) of 9.6% during the first 6 months of chemotherapy [1]. Patients with upper gastrointestinal cancers have a higher risk of VTE than patients with other malignancies [2, 3].
The use of direct oral anticoagulants (DOACs) as thromboprophylactic agents in patients with cancer offers important advantages over parenteral agents: DOACs have an easier route of administration with less inconvenience for the patients, and they allow a reduction in costs.
However, caution on using DOACs in patients with gastrointestinal cancers is mandatory since a few studies reported a higher rate of major bleeding complications among these patients [4, 5].
The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) guidelines recommended DOACs as the treatment of choice for patients without gastric or gastroesophageal cancer [6,7].
A recent study determined the efficacy and safety of apixaban in patients with gastrointestinal cancers performing a post-hoc analysis of the AVERT trial [8].
The AVERT trial
The AVERT trial (NCT02048865), a randomized, placebo-controlled, double-blind clinical trial, assessed the efficacy and safety of apixaban for thromboprophylaxis in intermediate- to high-risk (Khorana score ≥ 2) patients with cancer who were starting chemotherapy [9]. Eligible patients were randomized to receive either apixaban (2.5 mg twice daily) or a placebo in a 1:1 ratio up to 5 days before administering the first dose of chemotherapy. The primary efficacy outcome was objectively documented VTE over a follow-up period of 180 days. The main safety outcome was a major bleeding episode [9]. Among intermediate- to high-risk ambulatory patients with cancer who were starting chemotherapy, patients treated with apixaban had a significantly lower rate of VTE than those in the placebo group. The rate of major bleeding was significantly higher with apixaban than with placebo in the modified intention-to-treat analysis (3.5% and 1.8%, respectively; hazard ratio [HR]: 2.00; 95% CI: 1.01–3.95; number needed to harm: 59), but the rate was not significantly higher with apixaban than with placebo in the analysis of outcomes during the treatment period (2.1% and 1.1%, respectively; HR: 1.89; 95% CI: 0.39–9.24; number needed to harm: 100) [9].
Post-hoc analysis of the AVERT trial
The post-hoc analysis included patients with gastrointestinal cancers stratified into three groups: 1) upper gastrointestinal (esophageal, gastroesophageal junction and gastric cancers); 2) pancreatic/hepatobiliary cancers; and 3) colorectal cancers. In total, 133 patients had gastrointestinal cancer, and 130 were included in the modified intention-to-treat analysis. A total of 65 patients were allocated to each of the apixaban and placebo groups [8].
Some imbalances of baseline characteristics between apixaban and placebo groups existed. The apixaban cohort had a higher number of patients with upper gastrointestinal cancer (38.5% vs 27.9%) and a lower proportion of patients with pancreatic/hepatobiliary (56.9% vs 60.3%) and colorectal (4.6% vs 11.8%) cancers. More patients in the apixaban group had a higher Khorana score (3 or 4) than the placebo group. Last, the placebo cohort had a higher rate of previous VTE (2.9% vs 0%) and a significantly larger number of patients on concomitant antiplatelet medication (22.1% vs 7.7%) [8].
Patients with pancreatic/hepatobiliary cancer receiving apixaban had a non-significant higher risk of major bleeding complications. Major bleeding occurred in 2 (3.1%) patients in the apixaban group and 1 (1.5%) patient in the placebo group (HR: 2.39; 95% CI: 0.29–19.78; p=0.42; number needed to harm: 63), which was not statistically significant [8].
There were no major bleeding complications among patients with upper gastrointestinal or colorectal cancers [8].
Clinically relevant non-major bleeding occurred in 5 (7.7%) patients in the apixaban group and 3 (4.6%) patients in the placebo group (HR: 1.97; 95% CI: 0.64–6.06; p=0.24), a non-statistically significant higher risk [8].
Death occurred in 15 (23.1%) patients in the apixaban group and 11 (16.9%) in the placebo group. Many of these patients had advanced cancer, which was the most common cause of death [8].
In summary
The post-hoc analysis of the AVERT trial demonstrates that the rate of major bleeding complications with apixaban is relatively low in patients with gastrointestinal cancer, especially with upper gastrointestinal and colorectal cancers. The risk of major bleeding was also similar in the subgroup of patients with gastrointestinal cancers compared to the whole study population [8].
This study suggests that primary thromboprophylaxis with apixaban is safe and effective in patients with gastrointestinal cancers. However, the use of apixaban should be patient-tailored, weighing the benefits against the patient’s risk of bleeding with anticoagulation.
References
- Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116(24):5377-5382.
- 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.
- Kraaijpoel N, Di Nisio M, Mulder FI, et al. Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study. Thromb Haemost. 2018;118(8):1439-1449.
- Streiff MB, Holmstrom B, Angelini D, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Cancer-Associated Venous Thromboembolic Disease. Version 1.2020. April 16, 2020. www.nccn.org/professionals/physician_gls/pdf/vte.pdf.
- Kraaijpoel N, Di Nisio M, Mulder FI, et al. Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study. Thromb Haemost. 2018;118(8):1439-1449.
- Streiff MB, Holmstrom B, Angelini D, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Cancer-Associated Venous Thromboembolic Disease. Version 1.2020. April 16, 2020. www.nccn.org/professionals/physician_gls/pdf/vte.pdf.
- 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;38:496-520.
- Ladha D, Mallick R, Wang TF, Caiano L, Wells PS, Carrier M. Efficacy and safety of apixaban for primary prevention in gastrointestinal cancers: A post-hoc analysis of the AVERT trial. Thromb Res. 2021;202:151-154.
- 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.