Stop the Shots: Edoxaban vs. Dalteparin in Cancer-Associated VTE Treatment

At least 180 shots. That is minimum number of injections a cancer patient would face if diagnosed with cancer-associated venous thromboembolism (VTE). But oral treatment with a direct oral anticoagulant (DOAC) now may be an option. A recently published study demonstrated that oral edoxaban is non-inferior to the injectable low-molecular weight heparin (LMWH) agent dalteparin.¹ The implications of this study could potentially increase cancer patients’ quality of life by eliminating the need for injectable LMWH. And potentially lower health care costs!

Cancer patients are at high risk for VTE for several reasons. Cancer is an acquired thrombophilic condition that predisposes patients to a four to seven-fold higher risk of developing VTE.² Additional risk factors for VTE including frequent hospital admissions, immobilization, indwelling central catheters, chemotherapy (especially newer molecular-targeted agents), and erythropoiesis-stimulating agents.

For the treatment of cancer-associated VTE, LMWHs are recommended over warfarin (Grade 2B) and DOACs (all Grade 2C).³ This recommendation is stems from the Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism (affectionately called the CLOT) study, which showed the rate of recurrent VTE was 8.0% in the dalteparin arm vs. 15.8% in the warfarin arm (p=0.002).⁴  Moreover, warfarin therapy in cancer-associated VTE is often made more difficult by wildly fluctuating international normalized ratios, procedure-related interruptions, as well as numerous drug-drug and drug-food interactions.

While DOACs have been widely used in the treatment of VTE, there is very little data supporting their use in patients with active cancer. Several studies are ongoing including the use of rivaroxaban in the SELECT-D Trial and apixaban in CARAVAGGIO trial.  For now, the only available data we have to support the use of DOACs in this population comes from the recently published Hokusai VTE Cancer study.¹

Raskob and colleagues conducted a randomized, open-label, non-inferiority trial to evaluate edoxaban vs. dalteparin for the treatment of cancer-associated VTE.¹ The primary outcome of the study was a composite of recurrent VTE and major bleeding during the 12 months after randomization, regardless of treatment duration. The study was conducted from July 2015 to December 2016. Included patients were adults (age 18 or older), with a confirmed symptomatic DVT or PE, and with a cancer being actively treated or diagnosed within 2 years of randomization. Patients with a diagnosis of basal- or squamous-cell skin cancers were NOT included. All patients had to be willing to give SQ injections for at least 6 months.

The patient population (n=1050) was very comparable to those enrolled in the CLOT study.  Edoxaban was started after a therapeutic-dose of LMWH had been given for at least 5 days. The initial LMWH need not be dalteparin. Oral edoxaban was given at a fixed dose of 60 mg once daily, irrespective to food. In patients whose creatinine clearance (CrCl) was 30 to 50 mL/min or body weight was under 60 kg or treated with a concomitant potent p-glycoprotein inhibitor, the dose was decreased to 30 mg daily. Dalteparin was given subcutaneously at a dose of 200 IU per kilogram of body weight once daily for 30 days, with a maximum daily dose of 18,000 IU. Afterwards, dalteparin was given at a dose of 150 IU per kilogram once daily. If the platelet count dropped to less than 100,000/µl during treatment, the dose of dalteparin was temporarily reduced per the product labeling. The investigators used a modified intention-to-treat (mITT) analysis whereby patients who had undergone randomization and received at least one dose of the assigned treatment were included in the results.

Baseline characteristics were generally similar between the two groups. However, notably, patients in the edoxaban group were more likely to have gastrointestinal cancer (33 vs. 21 patients in the dalteparin group). All patients were followed for 12 months or until the study was terminated.  Many subjects did not complete the trial due to death; 205 participants in the edoxaban group (39.5%) vs. 192 in the dalteparin group (36.6%). Patients were assessed either in clinic or over by phone on day 31 and at months 3, 9, and 12.  

The primary outcome (recurrent VTE or major bleeding) occurred in 67 of 522 patients (12.8%) in the edoxaban arm compared to 71 of the 524 patients (13.5%) in the dalteparin arm (HR= 0.97, 95% CI 0.70 to 1.36; p = 0.006 for non-inferiority and p= 0.87 for superiority). Recurrent venous thromboembolism favored edoxaban, occurring in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, −3.4%; 95% CI, −7.0 to 0.2). Conversely, major bleeding was less frequent with dalteparin, occurring in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, +2.9%; 95% CI, 0.1 to 5.6, NNH = 34). Secondary outcomes are detailed in Table 1.

Table 1. Secondary Outcomes During Overall Trial Period– no. (%)

^{*Category 1 bleeding events were not considered to be a clinical emergency; category 2 bleeding events led to some treatment but were not considered a clinical emergency; category 3 bleeding events were considered a clinical emergency requiring urgent treatment; and category 4 bleeding events led to death before or almost immediately after the patient entered the hospital.}

^{**For patients who had more than one event, only the first counted}

These results are promising, but it must be noted that the rate of major bleeding and clinically relevant nonmajor bleeding was higher in the edoxaban group vs. the dalteparin group. The severity of bleeding events differed significantly between the two groups. In the edoxaban group, 66.7% of the bleeds were severity category 2 (less severe) while the majority (13/21 – 61.9%) of dalteparin major bleeding events were category 3 or greater.

A notable difference was that the rate of gastrointestinal (GI) bleeding (3.8% for edoxaban vs. 1.1% dalteparin; p= 0.02). Seventeen of the 20 edoxaban events were upper GI bleeds. This could have been due to the higher number of patient with GI cancer in the edoxaban group, potentially confounding the result. There are no published head-to-head comparisons of DOACs; therefore, determining which DOAC confers the lowest (or highest) risk for GI bleeds is difficult.⁵ DOAC associated GI bleeds may be due inhibition of GI mucosal healing.  Risk factors for DOAC associated GI bleeds include concurrent ulcerogenic drug use, older age, renal impairment, H. pylori infection, and a prior history of GI bleeds.⁶

It is important to point out the significant difference in the treatment duration in the two the study arms. The average duration of therapy in the edoxaban group was 211 days and the average duration for dalteparin was 184 days (p=0.01). The longer duration could be due to provider inexperience with edoxaban and the desire to lengthen therapy to assure adequate treatment. However, the longer exposure to edoxaban likely contributed to the higher incidence of bleeding. Per ACCP guidelines, patients with DVT and cancer should receive a LMWH for 3 to 6 months (Grade 1A). ³ Thereafter, anticoagulant therapy should be given indefinitely or until the cancer is resolved (Grade 1C). Although the average patient in both arms of this study received more than 6 months of therapy, a larger portion of edoxaban patients completed extended therapy (38.3% vs. 29.4%, respectively).

These results provide sound evidence to support the use of edoxaban for cancer-associated VTE treatment. Several other studies using DOACs for cancer-associated VTE are ongoing.  The SELECT-D trial is evaluating the use of rivaroxaban. Apixaban is being used in the CARAVAGGIO trial.  Offering patients with cancer a non-injectable treatment option will likely result in improved quality of life and, perhaps, adherence. Moreover, the cost of using a DOAC is substantially lower than a LWMH in most health systems.  Not all patients are good candidates for DOAC therapy including those with sub-optimal kidney function (CrCl < 30 mL/min), a diagnosis of GI cancer, and those at high-risk for GI bleeding.  A LMWH may be preferred in these patients. If edoxaban is used, patient monitoring is still required (e.g. adherence, bleeding, and renal function) but it’s not as cumbersome as warfarin.  Should edoxaban become the preferred choice to treatment VTE in patients with cancer?  What do you think?