What is the clinical evidence from this study?

Study design: RCT. Population: Cancer-associated venous thromboembolism (n=1050). Intervention: Edoxaban vs. Dalteparin. Primary outcome: Composite of recurrent venous thromboembolism or major bleeding (HR 0.97, 95% CI 0.70-1.36, p=0.006 for non-inferiority).

July 30, 2018Open Access

Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study

Key Result

Edoxaban was non-inferior to dalteparin for the composite of recurrent venous thromboembolism or major bleeding (HR 0.97), with excess major bleeding confined to patients with gastrointestinal cancer.

Study Design

Type

RCT (n=1,050)

Blinding

Open-label, blinded outcome evaluation

Randomization

Randomized

Multicenter

Yes

Structured PICO

Does edoxaban compared to dalteparin affect the risk, site, and severity of major bleeding in patients with cancer-associated VTE?

Population

1,050 adult patients with cancer-associated acute VTE (symptomatic or incidental proximal deep vein thrombosis of the lower extremity, symptomatic or incidental pulmonary embolism or both) requiring low-molecular-weight heparin therapy for at least 6 months, mean age ~64, ~51% male, multinational (13 countries).

Intervention

Edoxaban 60 mg orally once daily (or 30 mg once daily for dose reduction) after an initial 5-day course of subcutaneous low-molecular-weight heparin, for at least 6 months and up to 12 months.

Comparator

Dalteparin 200 IU/kg subcutaneously once daily (max 18,000 IU) for 30 days, then 150 IU/kg once daily, for at least 6 months and up to 12 months.

Outcome

Composite outcome of recurrent venous thromboembolism (VTE) and major bleeding at 12 months.safety

Oral edoxaban is an appropriate alternative to subcutaneous dalteparin for cancer-associated VTE, but requires careful benefit-risk weighting in patients with gastrointestinal cancer due to an increased risk of major bleeding.

Main Result

Effect estimate: HR 0.97 (95% CI 0.70-1.36)

Absolute Event Rate: 12.8% vs 13.5%

p-value: p=0.006 for non-inferiority

Limitations

Open-label design may have impacted clinical decisions on red blood cell transfusion or hospitalization
Lack of stratification by centre, possibly leading to an imbalance in the number of gastrointestinal cancers in the two treatment groups

Abstract

In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.

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