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Risk of Cancer-Associated Thrombosis and Bleeding in Veterans With Malignancy Who Are Receiving DOACs

The low incidence of venous thromboembolism formation in this study and similar rates of bleeding in other clinical trials indicate that direct oral anticoagulant agents are safe alternatives in patients with cancer.

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Patients with cancer are at an increased risk of both venous thromboembolism (VTE) and bleeding complications. Risk factors for development of cancer-associated thrombosis (CAT) include indwelling lines, antineoplastic therapies, lack of mobility, and physical/chemical damage from the tumor.1 Venous thromboembolism may manifest as either deep vein thrombosis (DVT) or pulmonary embolism (PE). Cancer-associated thrombosis can lead to significant mortality in patients with cancer and may increase health care costs for additional medications and hospitalizations.

Zullig and colleagues estimated that 46,666 veterans received cancer care from the US Department of Veteran Affairs (VA) health care system in 2010. This number equates to about 3% of all patients with cancer in the US who receive at least some of their health care from the VA health care system.2 In addition to cancer care, these veterans receive treatment for various comorbid conditions. One such condition that is of concern in a prothrombotic state is atrial fibrillation (AF). For this condition, patients often require anticoagulation therapy with aspirin, warfarin, or one of the recently approved direct oral anticoagulant agents (DOACs), depending on risk factors.


Due to their ease of administration, limited monitoring requirements, and proven safety and efficacy in patients with AF requiring anticoagulation, the American Heart Association (AHA) and American College of Cardiology recently switched their recommendations for rivaroxaban and dabigatran for oral stroke prevention to a class 1/level B recommendation.3

The American College of Chest Physicians (ACCP) recommends treatment with DOACs over warfarin therapy for acute VTE in patients without cancer; however, the ACCP prefers low molecular-weight heparin (LMWH) over the DOACs for treatment of CAT.4 Recently, the National Comprehensive Cancer Network (NCCN) updated its guidelines for the treatment of cancer-associated thromboembolic disease to recommend 2 of the DOACs (apixaban, rivaroxaban) for treatment of acute VTE over warfarin. These guidelines also recommend LMWH over DOACs for treatment of acute VTE in patients with cancer.5 These NCCN recommendations are largely based on prespecified subgroup meta-analyses of the DOACs compared with those of LMWH or warfarin in the cancer population.

In addition to stroke prevention in patients with AF, DOACs have additional FDA-approved indications, including treatment of acute VTE, prevention of recurrent VTE, and postoperative VTE treatment and prophylaxis. Due to a lack of head-to-head, randomized controlled trials comparing LMWH with DOACs in patients with cancer, these agents have not found their formal place in the treatment or prevention of CAT. Several meta-analyses have suggested similar efficacy and safety outcomes in patients with cancer compared with those of LMWH.6-8 These meta-analysis studies largely looked at subpopulations and compared the outcomes with those of the landmark CLOT (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer Investigators) and CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trials.9,10

As it is still unclear whether the DOACs are effective and safe for treatment/prevention of CAT, some confusion remains regarding the best management of these at-risk patients. In patients with cancer on DOAC therapy for an approved indication, it is assumed that the therapeutic benefit seen in approved indications would translate to treatment and prevention of CAT. This study aims to determine the incidence of VTE and rates of major and clinically relevant nonmajor bleeding (CRNMB) in veterans with cancer who received a DOAC.


This retrospective, single-center chart review was approved by the local institutional review board and research safety committee. A search within the VA Corporate Data Warehouse identified patients who had an active prescription for one of the DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) along with an ICD 9 or ICD 10 code corresponding to a malignancy.

Patients were included in the final analysis if they were aged 18 to 89 years at time of DOAC receipt, undergoing active treatment for malignancy, had evidence of a history of malignancy (either diagnostic or charted evidence of previous treatment), or received cancer-related surgery within 30 days of DOAC prescription with curative intent. Patients were excluded from the final analysis if they did not receive a DOAC prescription or have any clear evidence of malignancy documented in the medical chart.

Patients’ charts were evaluated for the following clinical endpoints: patient age, height (cm), weight (kg), type of malignancy, type of treatment for malignancy, serum creatinine (SCr), creatinine clearance (CrCl) calculated with the Cockcroft-Gault equation using actual body weight, serum hemoglobin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, indication for DOAC, type of VTE, presence of a prior VTE, and diagnostic test performed for VTE. Major bleeding and CRNMB criteria were based on the definitions provided by the International Society on Thrombosis and Haemostasis (ISTH).11 All laboratory values and demographic information were gathered at the time of initial DOAC prescription.

The primary endpoint for this study was incidence of VTE. The secondary endpoints included major bleeding and CRNMB. All data collection and statistical analysis were done using Microsoft Excel 2016 (Redmond, WA). Comparisons of data between trials were done using the chi-squared calculation.


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