CLOT

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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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Contents

Clinical Question

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

Bottom Line

Compared to warfarin, dalteparin reduced VTE recurrence without increasing the risk of bleeding or mortality among patients with cancer.

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.

Guidelines

ASCO (2007, adapted)[1]

  • LMWH as the preferred therapy for the first 5-10 days after diagnosis of VTE in patients with cancer followed by at ≥6 months of LMWH as the "preferred approach," though vitamin K antagonists with INR 2-3 is acceptable for long-term anticoagulation if LMWH is unavailable.
  • After 6 months, indefinite anticoagulant therapy should be considered for certain patients (i.e. those with metastatic disease and chemotherapy recipients)

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=676 patients with cancer and acute symptomatic VTE
    • LMWH (n=338)
    • Oral anticoagulation (n=338)
  • Setting: 48 centers in eight countries
  • Enrollment: 2001-1999
  • Follow-up: 6 months
  • Analysis: Intention-to-treat
  • Primary outcome: Recurrent DVT, nonfatal PE, or fatal PE at 6 months

Population

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, RT, 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%

Interventions

  • Randomized to a group:
  • LMWH - 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
  • Warfarin - 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

Outcomes

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; NNT 13)

Secondary Outcomes

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

Criticisms

  • Participants on warfarin had a supratherapeutic INR 24% of the time, potentially introducing bias[2]
  • Unclear patient perspective with this medication and compliance with the treatment[2]
  • Unclear cost/benefit ratio[2]

Funding

Funding provided by Pharmacia Corporation (now merged with Pfizer), the manufacturer of Fragmin, the brand name of dalteparin.

Further Reading

  1. 2007 Anticoagulation guidelines from the American Society of Clinical Oncology
  2. 2.0 2.1 2.2 Multiple authors. "Dalteparin compared with oral anticoagulation for thromboprophylaxis in patients with cancer." The New England Journal of Medicine. 2003;349:1385-1387.