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evident
Original paper
2003NEJMHematology/Oncology

CLOT

Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer

RCTCancer-associated VTE

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Overview

In cancer-associated VTE, 6 months of dalteparin reduced recurrent thrombosis versus a coumarin (HR 0.48) without a significant increase in bleeding.

Clinical takeaway

Use extended dalteparin rather than a coumarin when the goal is fewer recurrent clots after cancer-associated VTE. Six-month death was similar, so do not promise a survival gain.

Key result

Recurrent VTE occurred in 27 of 336 patients on dalteparin versus 53 of 336 on a coumarin (HR 0.48; P=0.002).

Practice impact

Extended LMWH became the reference regimen for cancer-associated VTE against which later DOAC trials were judged.

Evidence

Study design

Randomized comparison of six months of dalteparin versus a short course of dalteparin overlapped with a coumarin.

Enrollment

672

Follow-up

Six-month study period.

Geography

Not listed

Clinical question

Does six months of dalteparin reduce recurrent VTE compared with a coumarin in patients with cancer and acute VTE?

Population

  • Patients with cancer and acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both.

Intervention

Dalteparin 200 IU per kilogram subcutaneously once daily for one month, then about 150 IU per kilogram daily for five months.

Comparator

Dalteparin 200 IU per kilogram subcutaneously once daily for five to seven days plus a coumarin derivative for six months (target INR 2.5).

Primary outcome

Recurrent venous thromboembolism during the six-month study period.

Dalteparin reduced recurrent VTE compared with a coumarin (27 of 336 versus 53 of 336).

Hazard ratio / 0.48 / p=0.002

Key results

  • Recurrent VTE: 27 of 336 patients in the dalteparin group versus 53 of 336 in the oral-anticoagulant group (HR 0.48; P=0.002).
  • The six-month probability of recurrent thromboembolism was 9% with dalteparin versus 17% with a coumarin.
  • Six-month mortality was 39% with dalteparin and 41% with a coumarin.

Harms

  • Major bleeding was 6% with dalteparin versus 4% with a coumarin; the difference was not significant.
  • Any bleeding was 14% with dalteparin versus 19% with a coumarin; the difference was not significant.

Clinical Use

Practice impact

  • For cancer-associated VTE, prefer extended dalteparin over a coumarin when reducing recurrence is the goal.
  • Later DOAC trials used dalteparin as the active comparator because of this result.

Applicability

  • Most applicable to patients with cancer and acute symptomatic proximal DVT, PE, or both who can receive six months of injected LMWH.

Limitations

  • The abstract does not report a confidence interval for the recurrent-VTE hazard ratio.
  • The oral comparator is a coumarin, not a DOAC.
  • Mortality was similar, so the trial does not show that dalteparin prolongs survival.

Common misinterpretations

  • This is a recurrence result, not a survival trial; six-month death was 39% versus 41%.
  • Bleeding was not significantly lower or higher with dalteparin.
  • The comparator is a vitamin K antagonist, not a direct oral anticoagulant.

Related evidence

Hokusai VTE Cancer - Later TrialCaravaggio - Later TrialAMPLIFY - Context

Citation

Lee AY, Levine MN, Baker RI, 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(2):146-153. doi:10.1056/NEJMoa025313

In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.