CLOT

Published

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.
PubMed • Full text • PDF

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 and ONCENOX 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. However, this cost may be at least somewhat offset by reduction in high-cost care related to acute thromboses.

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.

The 2018 Hokusai VTE Cancer Trial showed edoxaban to be non-inferior to dalteparin in an open label study.

Guidelines

ACCP Antithrombotic Therapy for VTE Disease (2016, adapted):

• In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy (all Grade 2B)
• In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C)
• In patients with DVT of the leg or PE who receive extended therapy, recommend no need to change the choice of anticoagulant after the first 3 months (Grade 2C)
• In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching to treatment with LMWH at least temporarily (Grade 2C).
• In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer, time-limited period (eg, 6, 12, or 24 months) (Grade 1B).
• In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).
• In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B).
• In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).
• In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).

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 clinical centers in 8 countries
• Enrollment: 1999-2001
• Mean follow-up: 125 days (LMWH) and 115 days (oral anticoagulation)
• Analysis: Intention-to-treat
• Primary outcome: Recurrent VTE

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, 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%

Interventions

• 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

Outcomes

Comparisons are LMWH vs. oral anticoagulation.

Primary Outcome

Recurrent VTE

Defined as recurrent DVT, nonfatal PE, or fatal PE.

8.0% vs. 15.8% (HR 0.48; 95% CI 0.30-0.77; P=0.002)

DVT only: 14 vs. 37 events

Nonfatal PE: 8 vs. 9 events

Fatal PE: 5 vs. 7 events

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

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

Funding

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