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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)". Journal of Clinical Oncology. 2018. 36(20):2017-23.
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Clinical Question

In patients with cancer-associated VTE, how does rivaroxaban compare to dalteparin in terms of efficacy and safety?

Bottom Line

Among patients with cancer-associated VTE, rivaroxaban decreased the risk of recurrent VTE as compared to dalteparin at the expense of an increased rate of bleeding.

Major Points

Low-molecular weight heparin (LMWH) was established as the standard of care for treating patients with cancer-associated VTE after CLOT (2003) demonstrated the superiority of dalteparin over warfarin in this patient group. Newer direct-acting oral anticoagulants (DOACs) including dabigatran, edoxabain, rivaroxaban, and apixaban, have similar if not improved outcomes versus warfarin, but the pivotal trials leading to their approval only included a small number of patients with cancer-associated VTE and thus LMWH has remained the standard of care. Meta-analyses provided encouraging evidence that DOACs were likely safe and efficacious in this population, but randomized studies were needed to demonstrate the efficacy and safety of DOACs versus LMWH in patients with cancer-associated VTE.

Published in 2018, the Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D) trial was a pilot study which randomized 406 patients with known cancer and concurrent VTE in a 1:1 fashion to either rivaroxaban or dalteparin. Follow-up imaging was performed as clinically indicated. The primary endpoint was recurrent VTE defined as proximal DVT or symptomatic/incidental PE at 6 months of follow-up, and secondary outcomes included independently adjudicated major bleeding and clinically relevant nonmajor bleeding (CRNMB) events. The statistical plan of this pilot study was to enroll 530 patients to allow estimation of VTE recurrence to within 8% of the 95% CI, but due to slow accrual target enrollment was decreased to 400; this would yield recurrent VTE estimates within 9% of the 95% CI. In addition, the investigators planned a second randomization to either 6 additional months of rivaroxaban or placebo for selected patients, but this was abandoned as insufficient patients met the criteria for second randomization. Ultimately 406 patients were enrolled, predominantly ECOG PS 0-1, >90% with solid tumors (58% of which were metastatic; about 25% of all patients had gastric or colorectal cancer), and half of patients had symptomatic VTE while half had incidental PE. At 6-month of follow-up, recurrent VTE was seen in 4% of patients in the rivaroxaban group versus 11% in the dalteparin group (HR 0.43; 95% CI 0.19-0.99). Cumulative rates of major bleeding were 6% with rivaroxaban and 4% with dalteparin (HR 1.83; 95% CI 0.68-4.96); among patients with esophageal or gastroesophageal cancer, major bleeding was more common with rivaroxaban than with dalteparin (36% versus 11%). Similarly, rates of CRNMB were higher with rivaroxaban than with dalteparin (13% versus 4%). The authors acknowledge study limitations including slow accrual, overly optimistic attempts at a second randomization, and lack of generalizability beyond 6 months. Ultimately they conclude that among patients with cancer-associated VTE, rivaroxaban is a safe and efficacious alternative to LMWH, with caveats around bleeding in patients with esophageal cancer.

SELECT-D adds to a growing body of evidence supporting the use of DOACs in patients with cancer-associated VTE. Previously Hokusai-VTE demonstrated the efficacy and safety of edoxaban versus dalteparin in this patient population. Together, these two studies demonstrate that DOACs are effective — perhaps even more efficacious than LMWH — at the expense of increased rates of major and clinically relevant nonmajor bleeding.


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.[1] The ISTH released a guidance statement in 2018.[2]


  • Multicenter, prospective, randomized, open label, pilot trial
  • N=406 patients with first episode of cancer-associated VTE
    • Rivaroxaban (n=203)
    • Dalteparin (n=203)
  • Setting: 58 sites in the United Kingdom
  • Enrollment: 2013-2016
  • Follow-up: 6 months
  • Analysis: Intent-to-treat
  • Primary outcome: Recurrent VTE


Inclusion Criteria

  • Age ≥18 years
  • Weight ≥40 kg
  • ECOG performance status ≤2
  • Adequate hematologic, hepatic, and renal function
  • Active solid tumor or hematologic malignancy
    • Cancer defined as cancer other than basal cell or non-squamous cell skin cancer
    • Active defined as diagnosis or treatment within prior 6 months, recurrent/metastatic cancer, or cancer not in complete remission

Exclusion Criteria

  • Current anticoagulation or antiplatelet therapy
  • More than 72 hours pre-treatment with anticoagulant for this episode.
  • Clinically significant liver disease
  • Bacterial endocarditis
  • Active bleeding or a high risk of bleeding, contraindicating anticoagulant treatment
  • Blood pressure ≥180/110
  • Childbearing age without appropriate contraception
  • Pregnant or breastfeeding
  • Use of strong CYP3A4 inhibitors/inducers or P-gp inhibitors/inducers

Baseline Characteristics

From the rivaroxaban group.

  • Demographics: median age 67, female 43%, median BMI 26.7, non-White ethnicity 6%
  • ECOG score: 0 (29%), 1 (44%), 2 (26%)
  • Stage of disease: early (40%), metastatic (58%), hematologic malignancy (2%)
  • Platelets ≤350 K/μL: 83%
  • Qualifying VTE: symptomatic VTE (47%), incidental PE (53%)
  • VTE high-risk tumor type: 83%
  • Anticoagulation for VTE prior to randomization: 78%
  • Time since diagnosis of primary tumor to randomization: 6.4 months
  • Active cancer therapy: 69%
  • Selected tumor types:
    • Colorectal 27%
    • Lung 11%
    • Breast 10%
    • Pancreas 9%
    • Prostate 7%
    • Esophageal/gastroesophageal 5%


Randomization in 1:1 fashion:

  • Rivaroxaban 15 mg twice daily for 3 weeks then 20 mg/d for the remainder of the 6 months
  • Dalteparin 200 IU/kg/d for month 1 and 150 IU/kg/d for months 2-6


  • Every 3 months until month 12
  • Then every 6 months until month 24
  • Patients with DVT at study entry had repeat ultrasound of the lower limbs at approximately month 5
  • Ultrasound and CT imaging was otherwise performed only as clinically indicated


Comparisons are rivaroxaban vs. dalteparin.

Primary Outcomes

VTE recurrence at 6 months
4% vs. 11% (HR 0.43; 95% CI 0.19-0.99)

Secondary Outcomes

Major bleeding at 6 months
6% vs. 4% (HR 1.83; 95% CI 0.68-4.96)
Clinically relevant nonmajor bleeding at 6 months
13% vs. 4% (HR 3.76; 95% CI 1.63-8.69)
Overall survival at 6 months
75% vs. 70%


  • Slow recruitment
  • Pilot study lacking power to definitively compare efficacy and safety of two therapies
  • Poor accrual and high early mortality precluded answering questions about duration of therapy


Funded by Bayer, who makes rivaroxaban. Multiple authors with research funding from Bayer.

Further Reading