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Hokusai VTE Cancer

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

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Year of Publication: 2018

Authors: Gary E. Raskob, Nick van Es, Peter Verhamme, ..., Harry R. Büller

Journal: New England Journal of Medicine

Citation: N Engl J Med 2018;378:615-24

Clinical Question

Is oral edoxaban noninferior to subcutaneous dalteparin for treatment of cancer-associated venous thromboembolism?

Bottom Line

Oral edoxaban was noninferior to subcutaneous dalteparin for the composite outcome of recurrent VTE or major bleeding, with lower recurrent VTE but higher major bleeding rates.

        Major Points
        Open-label, noninferiority randomized controlled trial comparing edoxaban vs dalteparin
1050 cancer patients with acute symptomatic or incidental VTE enrolled from 114 centers
Primary composite outcome of recurrent VTE or major bleeding occurred in 12.8% vs 13.5% (noninferiority achieved)
Recurrent VTE was numerically lower with edoxaban (7.9% vs 11.3%, HR 0.71)
Major bleeding was significantly higher with edoxaban (6.9% vs 4.0%, HR 1.77, p=0.04)
Higher bleeding risk mainly due to upper GI bleeding, especially in patients with GI cancer

      

Design

Study Type: Open-label, randomized, noninferiority trial

Randomization: 1

Blinding: Open-label (no blinding), but independent clinical events committee was blinded to treatment assignments

Enrollment Period: July 2015 through December 2016

Follow-up Duration: 12 months (minimum 9 months)

Centers: 114

Countries: Canada, Netherlands, Belgium, Italy, United States, United Kingdom, France

Sample Size: 1050

Analysis: Modified intention-to-treat analysis using Cox proportional-hazards model with stratification factors as covariates

Inclusion Criteria

Adult patients with cancer (other than basal-cell or squamous-cell skin cancer)
Active cancer or cancer diagnosed within previous 2 years
Acute symptomatic or incidentally detected DVT involving popliteal, femoral, iliac vein or IVC
Acute symptomatic PE confirmed by diagnostic imaging
Incidentally detected PE involving segmental or more proximal pulmonary arteries
Treating physician intended to administer LMWH for at least 6 months

Exclusion Criteria

Details provided in Supplementary Appendix (specific exclusions not detailed in main text)

Arms

Field	Control	Edoxaban
Intervention	Subcutaneous dalteparin 200 IU/kg once daily for 30 days (max 18,000 IU), then 150 IU/kg once daily	Oral edoxaban 60mg once daily (30mg if creatinine clearance 30-50 ml/min, weight ≤60kg, or potent P-glycoprotein inhibitors) after at least 5 days of therapeutic LMWH
Duration	At least 6 months, up to 12 months	At least 6 months, up to 12 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of recurrent venous thromboembolism or major bleeding during 12 months after randomization	Primary	71/524 (13.5%)	67/522 (12.8%)	0.97	0.006 for noninferiority; 0.87 for superiority
Recurrent venous thromboembolism	Secondary	59/524 (11.3%)	41/522 (7.9%)	0.71	0.09
Major bleeding	Secondary	21/524 (4.0%)	36/522 (6.9%)	1.77	0.04
Recurrent deep-vein thrombosis	Secondary	35/524 (6.7%)	19/522 (3.6%)	0.56
Recurrent pulmonary embolism	Secondary	28/524 (5.3%)	27/522 (5.2%)	1
Death from any cause	Secondary	192/524 (36.6%)	206/522 (39.5%)	1.12
Major bleeding	Adverse	21/524 (4.0%)	36/522 (6.9%)	1.77	0.04
Clinically relevant nonmajor bleeding	Adverse	58/524 (11.1%)	76/522 (14.6%)	1.38

Subgroup Analysis

Patients with gastrointestinal cancer had significantly higher bleeding risk with edoxaban than dalteparin (P=0.02 for interaction). No other statistically significant interactions between subgroups and treatment were observed.

Criticisms

Open-label design may introduce bias, though events were adjudicated by blinded committee
Lower than expected number of primary outcome events
Median treatment duration was shorter with dalteparin than edoxaban, potentially influencing relative efficacy
Sample size limitations for definitive conclusions about individual tumor types
Higher major bleeding rate with edoxaban, particularly upper GI bleeding in patients with GI cancer

Funding

Daiichi Sankyo

Based on: Hokusai VTE Cancer (New England Journal of Medicine, 2018)

Authors: Gary E. Raskob, Nick van Es, Peter Verhamme, ..., Harry R. Büller

Citation: N Engl J Med 2018;378:615-24

Content summarized and formatted by NeuroTrials.ai.

Hokusai VTE Cancer

(2018)

Objective

To compare oral edoxaban with subcutaneous dalteparin for treatment of cancer-associated venous thromboembolism

Study Summary

• Edoxaban was noninferior to dalteparin for the composite outcome of recurrent VTE or major bleeding (12.8% vs 13.5%)
• Recurrent VTE was lower with edoxaban (7.9% vs 11.3%) but major bleeding was higher (6.9% vs 4.0%)
• Oral edoxaban provides an effective alternative to subcutaneous dalteparin for cancer-associated VTE

Intervention

Oral edoxaban 60mg daily (after 5 days of LMWH) vs subcutaneous dalteparin 200 IU/kg daily for 1 month then 150 IU/kg daily

Inclusion Criteria

Adult patients with cancer and acute symptomatic or incidental VTE (DVT or PE) confirmed by imaging, with active cancer or cancer diagnosed within 2 years

Study Design

Arms: Edoxaban group vs Dalteparin group

Patients per Arm: 522 vs 524

Outcome

• Primary composite outcome occurred in 12.8% edoxaban vs 13.5% dalteparin (HR 0.97, 95% CI 0.70-1.36)
• Recurrent VTE: 7.9% vs 11.3% (HR 0.71, 95% CI 0.48-1.06)
• Major bleeding: 6.9% vs 4.0% (HR 1.77, 95% CI 1.03-3.04, p=0.04)

Bottom Line

Oral edoxaban was noninferior to subcutaneous dalteparin for the composite outcome of recurrent VTE or major bleeding, with lower recurrent VTE but higher major bleeding rates.

Major Points

Open-label, noninferiority randomized controlled trial comparing edoxaban vs dalteparin
1050 cancer patients with acute symptomatic or incidental VTE enrolled from 114 centers
Primary composite outcome of recurrent VTE or major bleeding occurred in 12.8% vs 13.5% (noninferiority achieved)
Recurrent VTE was numerically lower with edoxaban (7.9% vs 11.3%, HR 0.71)
Major bleeding was significantly higher with edoxaban (6.9% vs 4.0%, HR 1.77, p=0.04)
Higher bleeding risk mainly due to upper GI bleeding, especially in patients with GI cancer

Study Design

Study Type: Open-label, randomized, noninferiority trial
Randomization: Yes
Blinding: Open-label (no blinding), but independent clinical events committee was blinded to treatment assignments
Sample Size: 1050
Follow-up: 12 months (minimum 9 months)
Centers: 114
Countries: Canada, Netherlands, Belgium, Italy, United States, United Kingdom, France

Primary Outcome

Definition: Composite of recurrent venous thromboembolism or major bleeding during 12 months after randomization

Control	Intervention	HR/OR	P-value
71/524 (13.5%)	67/522 (12.8%)	0.97 (0.70-1.36)	0.006 for noninferiority; 0.87 for superiority

Limitations & Criticisms

Open-label design may introduce bias, though events were adjudicated by blinded committee
Lower than expected number of primary outcome events
Median treatment duration was shorter with dalteparin than edoxaban, potentially influencing relative efficacy
Sample size limitations for definitive conclusions about individual tumor types
Higher major bleeding rate with edoxaban, particularly upper GI bleeding in patients with GI cancer

Citation

N Engl J Med 2018;378:615-24

View Original Publication →

Hokusai VTE Cancer

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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