Clinical trial

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

N Engl J Med · 20181050 patients randomised (1046 patients in the modified intention-to-treat analysis: 522 edoxaban, 524 dalteparin)

Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. N Engl J Med. 2018. 378:615-624

Study type: Clinical trial
Study name: Hokusai VTE Cancer
Design: Open-label randomised non-inferiority trial
Sample size: 1050 patients randomised (1046 patients in the modified intention-to-treat analysis: 522 edoxaban, 524 dalteparin)
Source: N Engl J Med · 2018
Trial registration: NCT02073682

In plain words

Until this study, the standard treatment for blood clots in people with cancer was a daily injection of low-molecular-weight heparin (such as dalteparin). In this study, more than 1000 patients either took edoxaban tablets daily after at least 5 days of heparin injections, or received daily dalteparin injections. For the combined total of repeat clots and serious bleeding, edoxaban tablets were no worse than dalteparin injections. Repeat clots were less common with edoxaban (7.9% versus 11.3%), but serious bleeding was more common (6.9% versus 4.0%). The choice between tablets and injections depends on the type of cancer, your risk of bleeding and your other medicines, and should be made with your doctor.

Key results

12.8% vs 13.5%

Recurrent venous thromboembolism or major bleeding at 12 months (primary endpoint)

67 of 522 patients with edoxaban vs 71 of 524 with dalteparin; HR 0.97 (95% CI 0.70–1.36); P=0.006 for non-inferiority; P=0.87 for superiority

7.9% vs 11.3%

Recurrent venous thromboembolism

41 patients with edoxaban vs 59 with dalteparin; risk difference −3.4 percentage points (95% CI −7.0 to 0.2)

6.9% vs 4.0%

Major bleeding

36 patients with edoxaban vs 21 with dalteparin; risk difference 2.9 percentage points (95% CI 0.1–5.6)

Dose and schedule cards

Edoxaban after LMWH (Hokusai VTE Cancer)

Cancer-associated VTE in a patient without a high risk of GI bleeding, after at least 5 days of parenteral anticoagulationCycle length: DailyOn the page “Venous thromboembolism in cancer: risk assessment, prevention and treatment” · Treatment of cancer-associated VTE

Cancer-associated VTE in a patient without a high risk of GI bleeding, after at least 5 days of parenteral anticoagulation

Drug	Dose	Route	Schedule
Day 1 to at least day 5
LMWH	Therapeutic dose	Subcutaneous	At least 5 days (label: 5 to 10 days)
After that
Edoxaban	60 mg once a day (30 mg with CrCl 15 to 50, weight ≤60 kg or use of certain P-gp inhibitors)	Oral, with or without food	Continuous

Cycle length: Daily
Duration: At least 6 and at most 12 months in the trial

The dose and dose-reduction criteria are from the edoxaban label. In Hokusai VTE Cancer, recurrence was lower (7.9% vs 11.3%) but major bleeding higher (6.9% vs 4.0%) than with dalteparin; the excess bleeding was mainly gastrointestinal and in GI cancers, and advanced cancer and low haemoglobin were associated with GI bleeding.

On the page “Venous thromboembolism in cancer: risk assessment, prevention and treatment” · Treatment of cancer-associated VTE

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Low-molecular-weight heparin followed by edoxaban

Low-molecular-weight heparin (LMWH) for at least 5 days, then oral edoxaban 60 mg once daily. Treatment duration at least 6 months and at most 12 months. The type and dose of heparin in the initial period and the edoxaban dose-reduction criteria in the trial itself: further details in the full text of the paper.

FDA label for edoxaban (SAVAYSA): the recommended dose is 60 mg orally once daily after 5 to 10 days of initial treatment with a parenteral anticoagulant; in patients with creatinine clearance (CrCL) 15 to 50 mL/min, body weight 60 kg or less, or concomitant use of certain P-gp inhibitors, the dose is reduced to 30 mg once daily.

2Dalteparin (comparator group)

Dalteparin subcutaneously 200 IU/kg once daily for 1 month, then 150 IU/kg once daily. Treatment duration at least 6 months and at most 12 months.

FDA label for dalteparin (FRAGMIN), venous thromboembolism in patients with cancer: 200 units/kg of total body weight subcutaneously once daily for the first 30 days, then about 150 units/kg once daily in months 2 to 6; the total daily dose should not exceed 18,000 units.

Source of the regimen details: Abstract of the paper (N Engl J Med 2018); recommended dose and dose-reduction criteria from the FDA label for edoxaban (SAVAYSA, DailyMed, section 2.2); weight-based dose and maximum daily dose from the FDA label for dalteparin (FRAGMIN, DailyMed, section 2.3)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with cancer and acute symptomatic or incidental venous thromboembolism (VTE). Other eligibility criteria are not given in the abstract.

Endpoints

Primary endpoint (non-inferiority): composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomisation, regardless of treatment duration.

Components of the primary endpoint reported separately: recurrent venous thromboembolism and major bleeding.

Safety and side effects

Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and 21 patients (4.0%) in the dalteparin group (risk difference 2.9 percentage points; 95% CI 0.1–5.6). Bleeding sites and other adverse events are not reported in the abstract.

Clinical significance and place in guidelines

This trial showed that oral edoxaban (after at least 5 days of low-molecular-weight heparin) is non-inferior to dalteparin for the composite of recurrent venous thromboembolism or major bleeding, with fewer recurrences but more major bleeding. The 2020 update of the ASCO guideline reported that edoxaban and rivaroxaban carry a higher bleeding risk than low-molecular-weight heparin in gastrointestinal and possibly genitourinary cancers (Key NS et al., J Clin Oncol 2020). The 2022 international ITAC guideline recommends direct oral anticoagulants (rivaroxaban, apixaban, edoxaban) for cancer-associated thrombosis in patients with creatinine clearance ≥30 mL/min who are not at high risk of gastrointestinal or genitourinary bleeding and have no strong drug interactions (grade 1A), and advises caution in gastrointestinal cancers, especially of the upper gastrointestinal tract (Farge D et al., Lancet Oncol 2022). The edoxaban dose in this trial (60 mg once daily after at least 5 days of low-molecular-weight heparin) matches the dose recommended in the FDA label for edoxaban (SAVAYSA; 60 mg once daily after 5 to 10 days of initial treatment with a parenteral anticoagulant).

Limitations

Based on the abstract: the trial was open-label. The primary endpoint was a composite whose components differed in opposite directions (fewer recurrences but more major bleeding with edoxaban), so the result should be interpreted component by component. Superiority of edoxaban for the primary endpoint was not shown (P=0.87). All patients in the edoxaban group first received at least 5 days of low-molecular-weight heparin. Cancer types and bleeding sites are not given in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.