Should DOACs be Used for Treatment of Cancer-Related Thromboembolism?

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Author: Sandeep Devabhakthuni, PharmD, BCCP

Patients with active cancer are at 7-fold increased risk of venous thromboembolism (VTE) and have a 2- to 6-fold increased likelihood of VTE-related death.^1,2 Up to one-third of VTE diagnoses have been documented as cancer-associated, a known marker of poor prognosis in this population.^3,4 Low molecular weight heparins (LMWH) are considered first-line for cancer-associated VTE given previous studies demonstrating superior efficacy over warfarin in reducing risk of recurrent VTE.^5,6 However, one limitation with LMWH therapy is the need for parenteral administration, which is not always ideal in the outpatient setting. In the past decade, oral anticoagulation has evolved with the widespread use of direct oral anticoagulants (DOACs) in both VTE and atrial fibrillation and are often recommended over warfarin in specific populations.^7-9 This blog summarizes the available data and provides recommendations for VTE treatment in patients with cancer.

Patients with active cancer are at increased risk of venous thromboembolic events, particularly in those with certain characteristics.¹⁰ Patients with aggressive solid tumors at advanced stages are at higher risk for VTE. Additionally, cancer type (e.g., pancreatic, brain, and lung) and specific gene mutations (e.g., JAK2 mutations) are strongly correlated with thrombotic risk.^11,12 Moreover, numerous chemotherapy agents are also associated with increased risk of VTE, including platinum-based (e.g., cisplatin), hormonal (e.g., tamoxifen), anti-VEGF (e.g., bevacizumab), and immunomodulator (e.g., thalidomide) therapies.¹³

DOAC Evidence in VTE Treatment
Low molecular weight heparins have previously been the standard of care in cancer-associated VTE. Evidence supporting LMWH over vitamin K antagonists (VKAs) is based on two large randomized, controlled trials.^5,6 However, patients may not prefer LMWH over oral anticoagulation due to parenteral administration.^14,15 To-date, there have been three head-to-head randomized, controlled trials that have compared DOAC with LMWH in cancer patients newly diagnosed with VTE and 3 subgroup analyses of cancer patients published from the landmark phase III trials evaluating DOACs.^16-21 These trials have been summarized in Table 1.

Edoxaban
Edoxaban was the first DOAC to be studied in cancer patients newly diagnosed with VTE. The Hokusai VTE Cancer trial was an open-label, randomized, non-inferiority trial that included 1050 cancer patients with VTE who received LMWH for at least 5 days followed by either edoxaban or dalteparin.¹⁶ Edoxaban was non-inferior to dalteparin in the primary composite endpoint (HR 0.97; 95% CI, 0.7-1.36; p = 0.006 for non-inferiority, p = 0.87 for superiority). Edoxaban had a nonsignificantly lower rate of recurrent VTE (HR 0.71; 95% CI, 0.48 to 1.06) but significantly higher rate of bleeding (HR 1.77; 95% CI, 1.03 to 3.04) driven by higher bleeding rates in patients with gastrointestinal cancers (13.2% vs. 2.4%, p = 0.02). Significant limitations included low incidence of primary outcome events and higher median duration with edoxaban compared to dalteparin (211 days vs. 184 days, p = 0.01).

Rivaroxaban
The SELECT-D Pilot trial was a multicenter, randomized, open-label trial of 406 patients with active cancer and symptomatic VTE who received either dalteparin or rivaroxaban for 6 months.¹⁷ Rivaroxaban reduced the primary outcomes of VTE recurrence compared to dalteparin (HR 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was similar between groups (HR 1.83; 95% CI, 0.68 to 4.96). However, rivaroxaban was associated with higher rates of clinically relevant nonmajor bleeding (HR 3.76; 95% CI, 1.63-8.69). Limitations of this trial included short follow-up period of 6 months, lower event rate, and small sample size given that it was a pilot study.

There was also a published pooled subgroup analysis of 655 patients with active cancer from the landmark phase III EINSTEIN-PE/DVT trials.¹⁹ The rate of recurrent VTE was similar between groups (HR 0.67; 95% CI, 0.35 to 1.3), and rivaroxaban had lower risk of major bleeding (HR 0.42; 95% CI, 0.18 to 0.99). However, it is important to note that only 7.9% of the patients enrolled in the two phase III trials had active cancer, which limits these findings. There are also ongoing trials comparing rivaroxaban with LMWH including CONKO-11, CASTA-DIVA, and PRIORITY trials.^22-24

Apixaban
The ADAM VTE trial, which was a multicenter, randomized, open-label, superiority trial, included 300 patients with cancer-associated VTE who received either apixaban or dalteparin for 6 months.¹⁸ The primary outcome of major bleeding was similar between the two groups (0% in apixaban group vs. 1.4% in dalteparin group, p = 0.138). Recurrent VTE was significantly lower with apixaban compared to dalteparin (HR 0.099; 95% CI, 0.013 to 0.78). Also, more patients randomized to dalteparin switched therapy compared to apixaban (22 vs. 6; p = 0.0012). Significant limitations include small sample size, high discontinuation rate in both groups due to patient dissatisfaction, and low event rates.

There was also a subgroup analysis of the phase III AMPLIFY trial that compared apixaban with enoxaparin followed by warfarin for VTE in 169 patients with active cancer.²¹ Apixaban had a similar rate of recurrent VTE (relative risk [RR] 0.56; 95% CI, 0.13 to 2.37) and major bleeding (RR 0.45; 95% CI, 0.08 to 2.46). Of note, only 3.1% of the patients in this trial had active cancer. There is another ongoing randomized trial called the CARAVAGGIO trial comparing apixaban to dalteparin.²⁵

Dabigatran
A pooled subgroup analysis from two phase III trials (RE-COVER I and II) compared dabigatran to warfarin for acute VTE in 355 patients with cancer, representing 7% of patients included.²⁰ There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95% CI, 0.2 to 2.8) or diagnosed during the study (HR 0.63; 95% CI, 0.2 to 2.8). Major bleeding was also similar in both groups during the study (HR 0.53; 95% CI, 0.29 to 1.1). The ongoing CANVAS trial will be comparing four DOACs (dabigatran, rivaroxaban, apixaban, or edoxaban) to LMWH, which will provide further insight into the composite efficacy and safety profile and drug-specific versus class effects.²⁶

Guideline Recommendations for DOAC Use in Treatment of VTE
Until recently, guidelines recommended LMWH as the only first-line option for treatment of cancer-associated VTE. With the emerging data on DOAC use, the latest International Society on Thrombosis and Haemostasis guidance support use of DOACs in this population with preference for edoxaban and rivaroxaban if acute VTE and low risk of bleeding.²⁷ For those at high risk of bleeding (e.g., gastrointestinal and genitourinary cancers), LMWH remains preferred for acute VTE.

Figure 1 summarizes the recent addition of recommendations for DOAC use in cancer-associated thromboembolism in the 2019 National Comprehensive Cancer Network (NCCN) Cancer-Associated Venous Thromboembolic Disease guidelines and 2019 American Society of Clinical Oncology (ASCO) VTE Prophylaxis and Treatment guidelines.^28,29

Recommendations:
Despite the emerging data for DOACs, LMWH remains a first-line option in cancer-associated VTE given the robust evidence supporting its use.^5,6 However, recent data from the Hokusai VTE, SELECT-D Pilot, and ADAM VTE trials suggest that edoxaban, rivaroxaban, and apixaban have similar efficacy compared to dalteparin, respectively.^16-18 These data also suggest that patients with gastrointestinal cancer are at higher risk of bleeding when a DOAC is used. Therefore, it is reasonable to limit use of DOACs in cancer patients to those with low risk of bleeding. Data for therapeutic anticoagulation in the treatment of cancer-associated VTE beyond 6 months are limited to LMWH only.³⁰ No recommendations for dabigatran can be made at this time due to limited data.

Special Considerations:
In cancer patients with progressive renal disease (CrCl < 15 mL/min), switching from a DOAC to an alternative anticoagulant with less renal cleance is preferred over anti-Xa level monitoring until further research is conducted.³¹ Finally, in those who develop thrombocytopenia, which is commonly associated with chemotherapy, anticoagulation should be avoided when platelet counts fall below 50,000 to 70,000/µL.³²

Bottom Line:
Patients with active cancer are at a higher risk of VTE depending on cancer type and cancer therapies used.^1-3 Until recently, LMWH therapy was the mainstay for VTE treatment in patients with active cancer given its superiority over VKAs.^5,6 However, real-world data suggest that patients have suboptimal medication adherence with LMWH therapy.^14,15 Recently published data suggests that edoxaban, rivaroxaban, and apixaban may have similar efficacy to LMWH.^16-18 Therefore, DOACs represent a convenient alternative for VTE treatment in patients with active cancer at low risk of bleeding.²⁷ Ultimately, a discussion between the patient and the multidisciplinary healthcare team is necessary; anticoagulation strategies should be highly individualized based on patient preferences and thrombotic and bleeding risk factors.

Sandeep Devabhakthuni, PharmD, BCCP

Sandeep Devabhakthuni is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @deepdev511