Hokusai VTE Cancer Trial

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Raskob GE, et al. "Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism". The New England Journal of Medicine. 2018. 378(7):615-624.
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Clinical Question

Among patients with cancer-associated VTE, how does the factor Xa inhibitor edoxaban compare with the low-molecular-weight heparin agent dalteparin in terms of recurrent VTE and bleeding complications?

Bottom Line

Among patients with cancer-associated VTE, edoxaban reduces the risk of recurrent VTE but increases the bleeding risk compared to dalteparin.

Major Points

Venous thromboembolism (VTE) is a common complication of cancer and its treatment.[1] Patients with cancer-associated VTE have a higher risk of recurrent VTE and encounter more bleeding when on anticoagulation compared to patients without cancer, and thus the management of these patients poses particular challenges. The CLOT trial (2003) demonstrated that low molecular weight heparin (LMWH) reduced the risk of recurrent VTE among patients with cancer-associated VTE when compared to vitamin K antagonist (VKA) therapy, establishing LMWH as the standard of care for this patient population.[2] As the direct-acting anticoagulants (DOACs) became available, a logical question was whether DOACs would be effective in patients with cancer-associated VTE. The randomized DOAC versus VKA trials included few patients with malignancy and subsequent meta-analyses of patients from these and other randomized trials demonstrated favorable effects on recurrence and bleeding rates with DOACs compared to VKAs and LMWH in patients with cancer-associated VTE.[3] Randomized trials in patients with cancer-associated VTE were needed.

The Hokusai VTE Cancer Trial randomized 1,050 patients with cancer-associated VTE to the anti-Xa agent edoxaban or to the LMWH dalteparin. Cancer-associated VTE was defined as acute symptomatic or incidental proximal lower extremity DVT or pulmonary embolism involving segmental or more proximal pulmonary arteries, occurring in patients with malignancy that was active within the prior 6 months. Approximately 90% had solid tumor malignancies, most commonly colorectal, lung, genitourinary, and breast, with the remaining 10% harboring a hematologic malignancy. Patients were observed for the primary composite outcome of recurrent VTE or major bleeding, testing the hypothesis that edoxaban would be noninferior to dalteparin for this measure. With a minimum of 9 months of follow-up for each patient, the rate of the primary outcome was 12.8% in the edoxaban group versus 13.5% in the dalteparin group (HR 0.97; P=0.006 for noninferiority). There were fewer recurrent VTE episodes in the edoxaban group compared to the dalteparin group (7.9% vs. 11.3%; P=0.09), but major bleeding was significantly increased with edoxaban compared to dalteparin (6.9% vs. 4.0%; HR 1.77; P=0.04) and was driven primarily by GI bleeding among patients with GI malignancies.

This is the first large randomized study evaluating a DOAC versus LMWH in cancer-associated VTE. The small, open-label Select-D trial[4] compared rivaroxaban versus dalteparin among ~400 patients of similar profile to those in Hokusai and found a 57% reduction in VTE with rivaroxaban (HR 0.43; 95% CI 0.19-0.99) with an increase in clinically relevant non-major bleeding. Together, these provide evidence of the efficacy and safety of these agents in patients with cancer-associated VTE, and suggest that these may be reasonable alternatives to standard LMWH.

Guidelines

As of July 2018, no guidelines have been published that reflect the results of this trial. The current Chest guidelines on antithrombotic therapy for VTE were published in 2016.[5] The ISTH released a guidance statement in 2018.[6]

Design

  • Randomized, open-label, noninferiority trial
  • N=1,050 patients with cancer-associated VTE
    • Edoxaban (n=525)
    • Dalteparin (n=525)
  • Setting: 114 centers in 13 countries
  • Enrollment: 2015-2016
  • Follow-up: ≥9 months
  • Analysis: Intention-to-treat
  • Primary outcome: Recurrent VTE or major bleeding

Population

Inclusion Criteria

  • Age ≥18 years
  • Non-basal or squamous-cell skin cancer either active within the prior 6 months or diagnosed within the prior 2 years
  • Qualifying VTE, either:
    • Acute symptomatic or incidentally detected DVT involving the popliteal, femoral, iliac veins, or IVC, or
    • Symptomatic PE or asymptomatic segmental or more proximal PE
  • Intent to administer LMWH for ≥6 months

Exclusion Criteria

  • Treatment of VTE with thrombectomy, IVC filter placement, or fibrinolytic therapy
  • Anticoagulation for ≥72 hours prior to randomization
  • Therapeutic anticoagulation for a non-VTE indication prior to randomization
  • Active bleeding or contraindication to study drug
  • ECOG PS 3-4 at the time of randomization
  • CrCl <30 mL/min
  • History of HIT
  • Acute hepatitis, chronic active hepatitis, liver cirrhosis
  • AST/ALT >3×ULN and bilirubin >2×ULN in the absence of a clinical explanation
  • Life expectancy <3 months
  • Platelets <50K
  • Uncontrolled hypertension
  • Women of childbearing potential without proper contraceptive measures, and women who are pregnant or breastfeeding
  • NSAID therapy anticipated during the study
  • Aspirin >100 mg/d or dual antiplatelet therapy anticipated during the study
  • Treatment with P-gp inhibitors (eg, ritonavir) anticipated during the study
  • Systemic use of P-gp inhibitors (eg, ketoconazole) at the time of randomization; subsequent use permitted

Baseline Characteristics

From the edoxaban group.

  • Demographics: Age 64 years, 47% female
  • Weight: 79 kg
  • CrCl 30-50 ml/min: 7%
  • Platelets 50-100K: 6%
  • Met criteria for lower dose edoxaban: 23%
  • Qualifying VTE diagnosis: PE 63%, DVT only 37%, symptomatic DVT or PE 68%, incidental DVT or PE 32%
  • Active cancer: 98%
  • Metastatic disease: 52%
  • Recurrent cancer: 31%
  • Cancer treatment within prior 4 weeks: 72%
  • ECOG PS: 0 30%, 1 47%, 2 24%
  • Prior VTE: 9%
  • Risk factors for bleeding: 0 18%, 1 28%, 2 33%, ≥3 21%

Interventions

  • Patients were randomized 1:1 to edoxaban or dalteparin, and patients were stratified according to the presence of absence of bleeding risk factors and whether the patient met criteria for an edoxaban dose reduction. Risk factors for bleeding included surgery within prior 2 weeks, use of antiplatelet therapy, primary or metastatic brain cancer, regionally advanced or metastatic cancer, GI or urothelial cancer diagnosed within prior 6 months, or treatment with bevacizumab within prior 6 weeks.
    • Edoxaban: Patients received ≥5 days of therapeutic LMWH followed by edoxaban 60 mg PO daily; the dose was reduced to 30 mg/d in patients with CrCl 30-50 ml/min, body weight ≤60 kg, or in those receiving P-gp inhibitors.
    • Dalteparin: Patients received dalteparin 200 IU/kg SC daily for 30 days, then reduced to 150 IU/kg/d. The dose was capped at 18,000 IU per day. The dose was temporarily reduced if the platelet count declined to <100K.
  • In all patients, treatment was to continue for 6-12 months; therapy beyond 6 months was at the discretion of the treating physician.
  • Patients were followed for up to 12 months or until the end of the trial, with assessments on day 31 after randomization, and then at months 3, 6, 9, and 12.
  • Patients were followed for recurrent VTE (defined as symptomatic new DVT or PE, incidental new DVT or PE involving segmental or more proximal arteries, or fatal PE or unexplained death for which PE could not be excluded as the cause) and major bleeding (defined by overt bleeding associated with a 2-g/dL hemoglobin drop or requirement for ≥2 units of RBCs transfused, bleeding at a critical site, or that contributed to death).

Outcomes

Comparisons are edoxaban versus dalteparin.

Primary Outcome

Recurrent VTE or major bleeding
12.8% vs. 13.5% (HR 0.97; 95% CI 0.70-1.36; P=0.006 for noninferiority, 0.87 for superiority)

Secondary Outcomes

Recurrent VTE
7.9% vs. 11.3% (HR 0.71; 95% CI 0.48-1.06; P=0.09)
Recurrent DVT
3.6% vs. 6.7% (HR 0.56; 95% CI 0.32-0.97)
Recurrent PE
5.2% vs. 5.3% (HR 1.00; 95% CI 0.59-1.69)
Event-free survival
55.0% vs. 56.5% (HR 0.93; 95% CI 0.77-1.11)

Subgroup Analysis

Patients with GI malignancy were more likely to have an increased risk of bleeding during therapy with edoxaban than with dalteparin (P=0.02 for interaction). Other statistically significant interactions between subgroup and treatment were not observed.

Adverse Events

Major bleeding
6.9% vs. 4.0% (HR 1.77; 95% CI 1.03-3.04; P=0.04)
Clinically relevant nonmajor bleeding
14.6% vs. 11.1% (HR 1.38; 95% CI 0.98-1.94)
Major or clinically relevant nonmajor bleeding
18.6% vs. 13.9% (HR 1.40; 95% CI 1.03-1.89)
Death from any cause
39.5% vs. 36.6% (HR 1.12; 95% CI 0.92-1.37)

Criticisms

  • Open-label design potentially led to confounders
  • Anticoagulation was stopped after 12 months, which is not consistent with the guideline-based recommendation to continue anticoagulation indefinitely for patients with active cancer. Indefinite anticoagulation may result in a reduction in VTE recurrence and an increase in bleeding risk compared to those values reported in this study.

Funding

Supported by Daiichi Sankyo, the maker of edoxaban.

Further Reading

  1. Khorana AA et al. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013. 119:648-55.
  2. Lee AY et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N. Engl. J. Med. 2003. 349:146-53.
  3. Posch F et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb. Res. 2015. 136:582-9.
  4. Young AM et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J. Clin. Oncol. 2018. 36:2017-2023.
  5. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.
  6. Khorana AA, et al. "Role of direct oral anticoagulants in the treatment of cancer‐associated venous thromboembolism: guidance from the SSC of the ISTH." JTH 2018. e-pub 29 June 2018.