ASCO Guidelines Strongly Recommend Apixaban for VTE in Cancer

“Apixaban is one of three direct inhibitors of factor Xa, but unlike rivaroxaban or edoxaban, it is administered twice daily. Currently, there are no studies that have directly compared direct oral anticoagulants on a head-to-head basis in this clinical setting," according to the guideline authors.

Apixaban (Eliquis) is now strongly recommended by the American Society of Clinical Oncology (ASCO) Venous Thromboembolism (VTE) guidelines as a prophylactic treatment option for patients with cancer based on high quality of evidence, according to a guideline update published in Journal of Clinical Oncology.¹ Additionally, the updated guidelines recommended apixaban and rivaroxaban (Xarelto) as options for extended thromboprophylaxis following surgery for cancer, although the strength of this recommendation was weak.

A multidisciplinary expert panel convened to provide updated recommendations addressing 2 of 6 clinical questions from the 2019 guidelines. The questions queried as to whether patients with cancer undergoing surgery should receive perioperative VTE prophylaxis, and what is the optimal treatment method for preventing recurrence in patients with cancer with established VTE.

Panelists conducted a literature search identifying 176 publications, which included findings from 5 eligible randomized clinical trials that investigated VTE treatment. Data from 2 of these trials evaluating rivaroxaban did not change any recommendations established in the 2019 guidelines, and the remaining trials investigated apixaban.

Is Perioperative VTE Prophylaxis Appropriate?

One of the clinical questions asked as to whether patients with cancer undergoing surgery should be treated with perioperative VTE prophylaxis. The corresponding recommendation indicated that patients who are eligible for post-surgical extended pharmacologic thromboprophylaxis may be able to receive prophylactic doses of low molecular weight heparin (LMWH). The quality of evidence for this is high, and the strength of the recommendation is strong.

Moreover, patients can also receive prophylactic rivaroxaban or apixaban following an initial period of LMWH or unfractionated heparin (UFH) as an alternative option. Notably, the quality of evidence supporting the recommendation is low, and the strength of the recommendation is weak.

The authors of the guidelines updates cited several studies supporting the use of prophylactic agents for VTE.

In the double-blind phase 3 PROLAPS-II trial (NCT03055026), investigators compared rivaroxaban with placebo in 582 patients with colorectal cancer (CRC) undergoing laparoscopic surgery.² In total, 1% of patients receiving rivaroxaban and 3.9% of patients receiving placebo experienced symptomatic VTE, asymptomatic deep vein thrombosis (DVT), or VTE-related deaths in the first 28 days following surgery (P = .03). Additionally, major bleeding occurred in 0.7% (95% CI, 0-1.0) and 0.0% of patients in each respective group.

Additionally, a separate, open-label, randomized phase 2 study (NCT02366871) compared postoperative thromboprophylaxis with apixaban vs enoxaparin in 400 patients with gynecologic cancer receiving surgery.³ Overall, 1 patient from each treatment arm experienced major bleeding, and clinically nonmajor bleeding affected 5.4% of those receiving apixaban vs 9.7% of those receiving enoxaparin (P = .11). Investigators also reported that 1.0% and 1.5% of patients in each respective arm subsequently developed VTE (P = .68), and that 84.8% and 83.7% of patients adhered to their respective regimens.

“The two studies differ in the design, type of surgery—[laparoscopic or open]; type of cancer—[CRC or gynecological cancer]; comparator—[placebo or LMWH];and primary outcome,” the guideline authors wrote. “Additional data from randomized clinical trials are necessary to strengthen this recommendation.”

Treating Patients with Cancer and Established VTE to Prevent Recurrence

The authors also addressed the best possible method for treating established VTE in patients with cancer with the goal of preventing recurrence. For this, 2 recommendations were added.

Initial coagulation can include LMWH, UFH, fondaparinux (Arixtra), rivaroxaban, or apixaban. LMWH is the preferred treatment vs UFH for the first 5 to 10 days of anticoagulation for those who have started treatment with parenteral anticoagulation, newly diagnosed VTW, and don't have severe renal impairment. The evidence quality for this recommendation is high, and the strength of recommendation is strong.

In the case of anticoagulation being administered in the long term, LMWH, edoxaban (Lixiana), rivaroxaban, or apixaban for at least 6 months are the recommended options vs vitamin K antagonists (VKAs). Authors indicated that this is due to the boost in efficacy that the aforementioned drugs yield. That being said, VKAs are a viable option when LMWH or direct factor Xa inhibitors cannot be used.

Notably, although direct factor Xa inhibitors can yield a decrease in recurrent thrombosis, they also have a high chance of causing clinically relevant nonmajor bleeding risk vs LMWH. Because of this, direct factor Xa inhibitors need to be utilized with caution in populations with gastrointestinal (GI) and genitourinary (GU) malignancies, as well as in any other diseases that have a higher risk of mucosal bleeding. The evidence quality for this recommendation is high, and the strength of recommendation is strong.

The authors cited 3 randomized phase 3 trials, assessing apixaban as a therapy for VTE in those with cancer.

In the open-label, non-inferiority phase 3 CARAVAGGIO trial (NCT03045406), investigators assessed apixaban as a VTE treatment in 1170 patients with cancer and symptomatic or incidental acute proximal DVT or pulmonary embolism.⁴

Recurrent VTE occurred in 5.6% of patients receiving apixaban compared with 7.9% of patients receiving dalteparin (Fragmin; P for noninferiority <.001; P for superiority = .09). Additionally, 3.8% and 4.0% of patients in each respective treatment arm experienced major bleeding. In the CARAVAGGIO trial, 4.3% of patients with incidental VTE experienced recurrence vs 7.3% of those with symptomatic VTE, and the risk of major bleeding was 5.2% vs 3.6% in each respective group.

Recurrent VTE most occurred in patients with gynecologic cancers (10.9%), GI cancers (8.8%), GU cancers (6.5%), urinary cancers (6.5%), and lung cancers (5.5%).⁵ Moreover, 7.2% of patients with GU cancers and 4.8% of those with GI cancers experienced major bleeding.

In the open-label, randomized phase 3 ADAM VTE trial (NCT02585713), investigators evaluated apixaban among 287 patients with cancer-related VTE.⁶ Major bleeding occurred in 0.0% patients receiving apixaban vs 1.4% of patients receiving dalteparin (P = .138). Additionally, recurrent VTE affected 0.7% and 6.3% of patients in each respective treatment arm (P = .0281).

Lastly, in another phase 3 trial (NCT04462003), investigators compared treatment with apixaban vs enoxaparin in a population with cancer and acute DVT.⁷ Data from an analysis including 100 of 138 patients who had active malignancies and acute DVT. Patients were randomly assigned to treatment with either oral apixaban or subcutaneous LMWH. Notably, results from the study indicated that the risks of recurrent VTE and major bleeding were not significantly different between treatment groups.

“Apixaban is one of three direct inhibitors of factor Xa, but unlike rivaroxaban or edoxaban, it is administered twice daily,” the guideline authors wrote. “Currently, there are no studies that have directly compared direct oral anticoagulants on a head-to-head basis in this clinical setting.”

References

1. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO guideline update. J Clin Oncol. Published online April 19, 2023. doi:10.1200/JCO.23.00294
2. Becattini C, Pace U, Pirozzi F, et al. Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Blood. 2022;140(8):900-908. doi:10.1182/blood.2022015796
3. Guntupalli SR, Brennecke A, Behbakht K, et al. Safety and efficacy of apixaban vs enoxaparin for preventing postoperative venous thromboembolism in women undergoing surgery for gynecologic malignant neoplasm: a randomized clinical trial. JAMA Netw Open. 2020;3(6):e207410. doi:10.1001/jamanetworkopen.2020.7410
4. Giustozzi M, Connors JM, Ruperez Blanco AB, et al. Clinical characteristics and outcomes of incidental venous thromboembolism in cancer patients: insights from the Caravaggio study. J Thromb Haemost. 2021;19(11):2751-2759. doi:10.1111/jth.15461
5. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382:1599-1607. doi:10.1056/NEJMoa1915103
6. 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
7. Mokadem ME, Hassan A, Algaby AZ. Efficacy and safety of apixaban in patients with active malignancy and acute deep venous thrombosis. Vascular. 2021;29(5):745-750. doi:10.1177/1708538120971148