Hokusai VTE Cancer
Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism
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Overview
In cancer-associated VTE, edoxaban was noninferior to dalteparin for recurrent VTE or major bleeding; major bleeding was higher with edoxaban.
Clinical takeaway
Edoxaban is an oral option that met noninferiority on the composite of recurrence or major bleeding. It was not superior. Major bleeding was higher; the VTE risk-difference interval included no difference.
Key result
The 12-month composite of recurrent VTE or major bleeding was 12.8% with edoxaban versus 13.5% with dalteparin (HR 0.97; 95% CI 0.70-1.36; P=0.006 for noninferiority; P=0.87 for superiority).
Practice impact
An oral Xa inhibitor can replace dalteparin for many cancer-associated VTEs if you accept more major bleeding for similar composite risk.
Evidence
Study design
Open-label, noninferiority randomized trial of edoxaban versus dalteparin.
Enrollment
1,050
Follow-up
Primary outcome counted for 12 months after randomization, regardless of treatment duration.
Geography
Not listed
Clinical question
Is oral edoxaban noninferior to dalteparin for the composite of recurrent VTE or major bleeding in cancer-associated VTE?
Population
- Patients with cancer and acute symptomatic or incidental venous thromboembolism.
Intervention
Low-molecular-weight heparin for at least 5 days, then oral edoxaban 60 mg once daily, given for at least 6 months and up to 12 months.
Comparator
Subcutaneous dalteparin 200 IU per kilogram once daily for 1 month, then 150 IU per kilogram once daily, given for at least 6 months and up to 12 months.
Primary outcome
Composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration.
Edoxaban was noninferior to dalteparin on the composite (P=0.006 for noninferiority). It was not superior (P=0.87).
Hazard ratio / 0.97 / 95% CI 0.70-1.36 / p=0.006
Key results
- Of 1050 randomized patients, 1046 were included in the modified intention-to-treat analysis.
- Primary composite: 67 of 522 (12.8%) with edoxaban versus 71 of 524 (13.5%) with dalteparin; HR 0.97 (95% CI 0.70-1.36; P=0.006 for noninferiority; P=0.87 for superiority).
- Recurrent VTE (secondary component): 41 patients (7.9%) versus 59 patients (11.3%); risk difference -3.4 percentage points (95% CI -7.0 to 0.2).
- Major bleeding (secondary component): 36 patients (6.9%) versus 21 patients (4.0%); risk difference 2.9 percentage points (95% CI 0.1 to 5.6).
Harms
- Major bleeding was higher with edoxaban than with dalteparin (6.9% versus 4.0%; risk difference 2.9 percentage points, 95% CI 0.1 to 5.6).
Clinical Use
Practice impact
- Edoxaban is a reasonable oral alternative to dalteparin for cancer-associated VTE when the composite of recurrence or major bleeding is the decision metric.
- Counsel that major bleeding was higher with edoxaban in this trial.
Applicability
- Most applicable to patients with cancer and acute symptomatic or incidental VTE who can take oral edoxaban after at least 5 days of LMWH.
Limitations
- Open-label design.
- The primary result is noninferiority of a composite that mixes benefit and harm.
- Modified intention-to-treat used 1046 of 1050 randomized patients.
Common misinterpretations
- Noninferiority is not superiority; the superiority p-value was 0.87.
- Do not call recurrent VTE significantly lower; the risk-difference interval was -7.0 to 0.2 percentage points.
- The authors described VTE as lower and bleeding as higher; only the bleeding difference excluded no effect.
Related evidence
Citation
Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378(7):615-624. doi:10.1056/NEJMoa1711948
Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding.
- PMID
- 29231094