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Lee AY, et al. "Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer". The New England Journal of Medicine. 2003. 349(2):146-53.
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Clinical Question

In patients with cancer and acute symptomatic VTE, how does LMWH compare with warfarin in preventing VTE recurrence?

Bottom Line

In patients with cancer, dalteparin reduced VTE recurrence without increasing bleeding risk or deaths compared to warfarin.

Major Points

Prior to the CLOT trial, standard therapy for venous thromboembolism (VTE) consisted of a brief period of unfractionated heparin or low molecular weight heparin (LMWH) followed by long-term oral anticoagulation. The 2003 Comparison of Low Molecular Weight Heparin Versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients With Venous Thromboembolism (CLOT) trial demonstrated superiority of dalteparin (LMWH) over oral anticoagulants among patients with cancer. Dalteparin was associated with a reduction in the rate of recurrent VTE at 6 months without any significant differences in the rate of bleeding or mortality as compared with warfarin. These findings were confirmed in the 2006 LITE[1] and ONCENOX[2] trials.

Despite the clinical evidence, adoption of LMWH for VTE in the setting of malignancy has been slow because of the considerable cost of the therapy.[3] However, this cost may be at least somewhat offset by reduction in high-cost care related to acute thromboses.[4]

Novel oral anticoagulants have not yet been compared to LMWH in a head-to-head trial but a pooled subgroup analysis of other RCTs found rivaroxaban to be similar to vitamin K antagonist therapy for secondary prevention of VTE in patients with cancer.[5]


ACCP Antithrombotic therapy for VTE (2012, adapted):[6]

  • In patients with PE and no cancer, recommend VKA over LMWH for long-term therapy (Grade 2C).
  • In patients with PE and no cancer who are not treated with VKA, recommend LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C).
  • In patients with PE and cancer, recommend LMWH over VKA (Grade 2B).
  • In patients with PE and cancer who are not treated with LMWH, recommend VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C).


  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=676 patients with cancer and acute symptomatic VTE
    • LMWH (n=338)
    • Oral anticoagulation (n=338)


Inclusion Criteria

  • Adult patients
  • Active cancer, defined as:
    • any cancer other than basal cell or squamous cell carcinoma of skin within 6 months prior to enrollment,
    • any treatment for cancer within the prior 6 months, or
    • recurrent or metastatic cancer
  • Newly diagnosed, symptomatic proximal deep vein thrombosis (popliteal or more proximal veins based upon ultrasound or contrast venography), pulmonary embolism (by CT angiogram, V/Q scan, or pulmonary angiogram), or both

Exclusion Criteria

  • Weight <40kg
  • ECOG (Eastern Cooperative Oncology Group) status 3 or 4
  • Receipt of therapeutic heparin for more than 48h before randomization
  • Receipt of oral anticoagulant therapy
  • Active or serious bleeding within prior 2 weeks
  • Conditions associated with high bleeding risk (active peptic ulcer disease, recent neurosurgery, etc.)
  • Thrombocytopenia (<75k)
  • Contraindications to heparin such as HIT
  • Use of contrast medium
  • Creatinine >3 times the upper limit of the normal range
  • Pregnancy

Baseline Characteristics

From the LMWH group.

  • Demographics: Age 62 years, female sex 53%
  • ECOG score:
    • 0. 24%
    • 1. 40%
    • 2. 35%
    • 3. 1%
      • Enrolled before protocol amended to exclude ECOG 3-4
  • Outpatient: 50%
  • Inpatient: 50%
  • Hematologic cancer: 12%
  • Solid tumor disease: No clinical disease 11%, localized only 12%, metastatic 66%
  • Chemo, XRT, or surgery: 79%
  • Current smoker: 10%
  • History of DVT/PE: 12%
  • Recent major surgery: 18%
  • Central line: 14%
  • Type of VTE: DVT 70%, PE 30%


  • Randomized to dalteparin (LMWH) or warfarin
  • Dalteparin group treated with 200 IU/kg/day SQ for 1 month followed by 150 IU/kg/day for the subsequent 5 months
    • Measuring anti-Xa levels discouraged except in patients with renal insufficiency
    • Dose held for platelets <50k and adjusted for platelets 50-100k
    • Max dose 18,000 IU/day
  • Oral anticoagulation group treated with warfarin (acenocoumarol in Spain and Netherlands)
    • Goal INR 2-3 except for platelets 50-100k, in which goal INR was 1.5-2.5


Comparisons are LMWH vs. oral anticoagulation.

Primary Outcomes

Recurrent DVT, nonfatal PE, or fatal PE at 6 months
8% vs. 15.8% (HR 0.48; 95% CI 0.30-0.77; P=0.002)

Secondary Outcomes

Major: 6% vs. 4% (P=0.27)
Any: 14% vs. 19% (P=0.09)
39% vs. 41% (P=0.53)


  • Patients in the oral anticoagulant group had an INR above goal 24% of the time[7]
  • Unclear how compliant patients will be with subcutaneous injections in clinical practice[7]
  • No cost analysis[7]


Funding provided by Pharmacia, Peapack, NJ, which also supplied the study drug.

Further Reading

  1. Hull RD, et al. "Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer." American Journal of Medicine. 2006;119(12):1062-1072.
  2. Deitcher SR, et al. "Secondary prevention of venous thromboembolic events in patients with active cancer: Enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period." Clin Appl Thromb Hemost. 2006;12(4):389-396.
  3. Linkins Lori-Ann. "Management of venous thromboembolism in patients with cancer: Role of dalteparin." Vascular health and risk management. 2008;4(2):279-287.
  4. Bick RL. "Perspective: Cancer-associated thrombosis." The New England Journal of Medicine. 2003;349:109-111.
  5. Prins MH, et al. "Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): A pooled subgroup analysis of two randomised controlled trials." The Lancet Haematology. 2014;1(1):e37-e46.
  6. Kearon C, et al. "Antithrombotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines." Chest. 2012;141 supp:E419S-494S.
  7. 7.0 7.1 7.2 Multiple authors. "Correspondence: Dalteparin compared with an oral anticoagulant for thromboprophylaxis in patients with cancer." The New England Journal of Medicine. 2003;349:1385-1387.