The Use of Oral Anticoagulants for the Treatment of Venous Thromboembolism in Cancer Patients

Abstract

Background: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer, second to death caused by cancer itself. Guidelines from the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) support the use of low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) for treatment of VTE in cancer patients. The novel oral anticoagulants (NOACs) are increasingly being used for all types of VTE, but their safety and efficacy in cancer-associated VTE has not been established. In the CLOT trial of LMWH in cancer-associated VTE, the rate of recurrent VTE was 9.0%, compared to 5.1% among the subgroup of cancer patients who received rivaroxaban in the EINSTEIN trial; bleeding rates among cancer patients in the CLOT and EINSTEIN trials were 14% and 15.2%, respectively. Due to a paucity of data, at this point neither the NCCN nor ASCO supports the use of NOACs for treatment of cancer-associated VTE. Objective: Evaluate the efficacy and safety of NOACs in cancer-associated VTE. Methods: We performed a retrospective chart review of all patients with a diagnosis of active malignancy who received a prescription for a NOAC for treatment of VTE at Yale Cancer Center between February 1, 2012, and December 31, 2014. Patients with a heritable thrombophilia or bleeding disorder were excluded. Data collected included patient demographics, body mass index (BMI), cancer type and stage, type of VTE event (deep venous thrombosis (DVT), pulmonary embolism (PE), or both), type of NOAC, compliance with NOAC therapy, appropriate NOAC dose, and potential drug-drug interactions (DDI) with NOACs. Primary outcomes were recurrent VTE, defined as the finding of new or progressive DVT or PE on imaging with or without symptoms, and clinically relevant bleeding (CRB), defined as a decrease in hemoglobin of at least 2 g/dL in a 24-hour period, a requirement for red blood cell transfusion, any critical site bleeding event, or any type of bleeding event requiring increased physician monitoring. Fisher's exact test was used to calculate p-values where appropriate. Results: 75 patients met inclusion criteria; rivaroxaban was the only NOAC used in all cases. The incidence of recurrent VTE and CRB was 7.0% (n = 5) and 25.3% (n = 19), respectively. There were two fatal events, one due to recurrent VTE and one due to major gastrointestinal bleed; in neither case was NOAC compliance, dosing, or DDIs implicated in the fatality. Over half (n = 39) of all study patients were on a concomitant medication with a known DDI with NOAC therapy; the most common such agents were ciprofloxacin, fluconazole, azithromycin and voriconazole. In only one of the 80 DDI cases was anticoagulation therapy changed. NOAC dosing was inappropriate in 20 instances, mostly due to patients not receiving the recommended loading dose prior to beginning maintenance dosing. Among the 19 occurrences of CRB, advanced stage solid tumor emerged as a statistically significant (p = 0.0151) risk factor for bleeding while on rivaroxaban. Conclusion: Treatment of cancer-associated VTE with NOAC therapy is effective, but the risk of bleeding in our cohort was higher than in other published studies. Patients with advanced stage solid tumors may be at a particularly high risk of bleeding. Prescriber practices with NOACs may require modification based on high utilization of concomitant medications with DDIs and failure to prescribe appropriate loading doses of NOACs in treatment of VTE. Disclosures No relevant conflicts of interest to declare.

Use of Direct Oral Anticoagulants in Patients with Cancer: Practical Considerations for the Management of Patients with Nausea or Vomiting

“…In another study, although LMWHs were the dominant class of anticoagulant used during the first 6 months postevent in patients with active cancer, 21% of patients were switched to rivaroxaban therapy during the first 6 months after VTE diagnosis [102]. Perhaps because of a lack of clear guidelines, patients with cancer and VTE who eventually receive DOACs do not always receive doses of these drugs that are in line with those recommended by the product labels [100]. Adherence to anticoagulant therapy for VTE has been associated with a significant reduction in VTE recurrence in patients with VTE and concomitant cancer [124]; however, available evidence shows less than optimal adherence to anticoagulation strategies in this patient group.…”

“…When DOACs were compared with VKAs and LMWHs separately, DOACs were associated with higher rates of bleeding than LMWHs but were found to be as effective as and to have a similar safety profile to VKAs . Data from retrospective or observational studies in patients with cancer and VTE seem to indicate that DOACs have a similar efficacy and tolerability profile (including the risk of major bleeding) to LMWHs (Table ) . The vast majority of these clinical data was collected when specific reversal agents for the DOACs were not available.…”

“…In another study, although LMWHs were the dominant class of anticoagulant used during the first 6 months postevent in patients with active cancer, 21% of patients were switched to rivaroxaban therapy during the first 6 months after VTE diagnosis . Perhaps because of a lack of clear guidelines, patients with cancer and VTE who eventually receive DOACs do not always receive doses of these drugs that are in line with those recommended by the product labels .…”