Clinical Outcomes with Direct Oral Anticoagulants Compared to Low Molecular Weight Heparins in the Treatment of Cancer-Associated Venous Thromboembolism

Abstract

Background: Emerging data suggest that treatment of cancer-associated venous thromboembolism (VTE) with direct oral anticoagulants (DOACs) results in lower recurrence rate compared to low molecular weight heparins (LMWHs) at 6 months but with concern for increase in bleeding risks. The objective of this study was to determine occurrence of major bleeding as well as recurrent VTE events on treatment with DOACs or LMWHs in a cohort study. Methods: The cancer-associated thrombosis (CAT) clinic is a centralized service for care of cancer patients with suspected deep venous thrombosis (DVT) and/or pulmonary embolism (PE) established at the Tausig Cancer Institute of the Cleveland Clinic. We conducted a prospective cohort study of patients referred to this clinic between 8/2014 through 1/2018. The demographics, cancer types, VTE characteristics, treatment courses, and outcomes (VTE recurrence, major or clinically relevant nonmajor [CRNM] bleeding) were recorded for these patients. Standards of treatment at the CAT clinic shifted in late 2017 from use of LMWH, enoxaparin, to a DOAC, rivaroxaban for cancer-associated VTE. Current exclusion criteria for rivaroxaban use include recent active bleeding, GFR < 30 mL/min, severe hepatic impairment, thrombocytopenia (platelet count < 50,000), and/or expected malabsorption at the level of stomach or small bowel. For cancer patients considered at higher risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary; cancers at risk of bleeding from genitourinary tract, bladder or nephrostomy tubes; or patients with active mucosal abnormalities such as duodenal ulcers, gastritis/esophagitis or colitis, treatment with LMWHs is preferred. Major or CRNM bleeding was determined according to definitions outlined by the International Society on Thrombosis and Haemostasis. Results: The study population included 258 patients with acute VTE. Of these, 239 patients had DVT (93%), 34 had PE (14%), 15 had both (6.2%), and 3 had visceral vein thromboses (1.2%). The patients were 53% male with a median age of 65 ± 16 years. The most common cancer types were hematologic malignancies (19.5%, n = 50), primary brain tumors (11.2%, n = 29), lung (8.5%, n = 22), breast (7.0%, n = 18), and pancreatic cancers (6.6%, n = 17). Enoxaparin monotherapy was prescribed for 72.1% (n = 179 of 248) of patients. Other treatments included rivaroxaban (17.3%, n = 43), apixaban (0.8%, n = 2), warfarin (2.8%, n = 7), dalteparin (0.4%, n = 1), or no anticoagulation (3.2%, n = 8). Major bleeding occurred in 5% (n = 12 of 241) of patients treated with anticoagulation at 6 months of the initial event, including 5.0% (n = 9 of 179) of patients on enoxaparin and 4.7% (n = 2 of 43) of patients on rivaroxaban, and these differences were not significant (p > 0.95) (Figure 1). CRNM bleeding was observed in 16.2% (n = 29 of 179) of patients on enoxaparin and 11.6% (n = 5 of 43) of patients on rivaroxaban. The common cancer types for patients with major bleeding events included primary brain tumors (n = 4), genitourinary cancers (n = 2) and gastrointestinal cancers (n = 2) (Table 1). The 1-year incident rate of recurrent VTE was 11% for patients treated with enoxaparin and 9% for those treated with DOACs, and 2-year rate was 13% and 11%, respectively (Figure 2). Overall, there was no significant difference in the VTE recurrence rate calculated by the competing risk model between patients on enoxaparin compared to rivaroxaban (p = 0.19). Conclusions: Bleeding events of patients treated with enoxaparin was comparable to rivaroxaban for both major and CRNM bleeding events in this carefully selected real-world population. Patients receiving rivaroxaban reported a statistically insignificant but lower rate of recurrent VTE compared to those receiving enoxaparin. These findings support a recent change in ISTH guidance recommending rivaroxaban or edoxaban as initial treatment of cancer-associated VTE in selected patients. Disclosures Khorana: Sanofi: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Pfizer: Consultancy.

Clinical outcomes of isolated distal deep vein thrombosis versus proximal venous thromboembolism in cancer patients: The Cleveland Clinic experience

“…As a centralized cancer thrombosis clinic, our care path recommended LMWH until December 2017 when we changed our preferred drug to rivaroxaban in light of new data supporting the use of DOACs for the treatment of cancer‐associated thrombosis . However, for cancer patients considered to have high risk of bleeding on a DOAC (including patients with luminal gastrointestinal cancers with an intact primary, cancers arising from the genitourinary tract, or patients with active mucosal abnormalities such as duodenal ulcers, gastritis/esophagitis, or colitis), treatment with LMWHs was preferred . We kept patients on anticoagulation for as long as 6 months and continued thereafter if patients had active cancer or continued on systemic antineoplastic therapy.…”

“…15,16 However, for cancer patients considered to have high risk of bleeding on a DOAC (including patients with luminal gastrointestinal cancers with an intact primary, cancers arising from the genitourinary tract, or patients with active mucosal abnormalities such as duodenal ulcers, gastritis/esophagitis, or colitis), treatment with LMWHs was preferred. 17 We kept patients on anticoagulation for as long as 6 months and continued thereafter if patients had active cancer or continued on systemic antineoplastic therapy. Standard anticoagulant treatment with enoxaparin was a subcutaneous dose of 1 mg/kg twice daily or 1.5 mg/kg once daily because both of these dosing regimens are considered to be adequately therapeutic.…”

Multiple Myeloma and Thrombosis: Prophylaxis and Risk Prediction Tools

“…Their profile is favorable, as secondary to safety and efficacy, they are administered orally and do not require routine monitoring. They are currently licensed for use in the treatment of cancer-associated thrombosis [93,107,108]. Ongoing trials will most likely establish their use in VTE prophylaxis in ambulatory cancer patients as well, and the results are much anticipated [107].…”