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Long-term Treatment for Cancer Patients With Deep Venous Thrombosis or Pulmonary Embolism

Phase 3
18 Years
Open (Enrolling)
Venous Thromboembolism, Neoplasms

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Trial Information

Long-term Treatment for Cancer Patients With Deep Venous Thrombosis or Pulmonary Embolism

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism
(PE), represents a major cause of morbidity and mortality in cancer patients. 1 The risk of
VTE is increased several-fold in patients with cancer with incidences ranging between 4% and
20%. 2 Treatment of VTE aims at preventing recurrent events, including potentially fatal PE,
which in turn could reduce the morbidity, use of health care resources and, above all,
mortality for cancer patients.

Standard treatment for VTE consists of an initial course of heparin followed by vitamin K
antagonists (VKAs) with doses adjusted to maintain an international normalized ratio (INR)
between 2.0 and 3.0. Several unique aspects related to the cancer itself and its management
make VKA therapy more complex than in non cancer patients. Chemotherapy induced
thrombocytopenia and invasive procedures, for instance, may require a temporary interruption
of anticoagulant therapy and a prompt reversal of the anticoagulant effect. On the other
side, poor nutrition, concomitant medications, and impaired liver function can cause
unpredictable changes in the dose response of VKAs. In addition, VKAs seem less effective
and safe in cancer patients who experience a 3-fold higher risk of VTE recurrence and a
3-fold higher risk of bleeding during anticoagulation compared to patients without cancer.
3-5 Most bleeding and thrombotic complications occur with anticoagulant parameters within
the therapeutic range. Therefore, more aggressive anticoagulant therapy would have the
potential to reduce the risk of recurrent VTE, but at the price of an increase in bleeding.

Recently, randomized clinical trials and prospective cohort studies in cancer patients with
acute VTE have shown that low-molecular-weight heparin (LMWH) may be more effective in
preventing VTE recurrences at a comparable bleeding risk as compared to VKA's. 6-9 In
addition, LMWH offer the advantages of being easier to administer, more flexible, and not
influenced by nutrition problems or liver impairment.

In the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant
Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer)
study, cancer patients with acute, symptomatic proximal DVT, PE, or both, were randomly
assigned to receive dalteparin (200 IU/kg of body weight subcutaneously once daily for 5 to
7 days) followed by a coumarin derivative for 6 months, or dalteparin alone for 6 months
(200 IU/kg of body weight once daily for 1 month followed by 150 IU/kg body weight once
daily for 5 months). During the 6-month study period, 27 of 336 patients (9%) in the
dalteparin group had symptomatic, objectively documented recurrent VTE as compared to 53 of
336 patients (17%) in the VKAs group, hazard ratio 0.48 (95% CI: 0.30, 0.77, p=0.002). There
was no statistically significant difference in major bleeding (6% versus 4%, p=0.27) nor in
any bleeding (14% and 19%, respectively, p=0.09) between the two study groups. 6 In a
randomized, open-label multicenter trial, subcutaneous enoxaparin sodium (1.5 mg/kg once
daily) was compared with warfarin given for 3 months in 146 cancer patients with VTE. 7
Fifteen (21.1%) of the 71 assessable patients assigned to receive warfarin had one major
bleeding or a recurrent VTE within 3 months compared with seven patients (10.5%) of the 67
assessable patients assigned to receive enoxaparin (p=0.09). There were six deaths as a
result of hemorrhage in the warfarin group compared with none in the enoxaparin group.

In a RCT of 122 cancer patients with acute symptomatic VTE, no significant differences in
major and minor bleeding rates were observed between patients assigned to subcutaneous
enoxaparin given for up to 180 days and those receiving enoxaparin followed by warfarin. 8
In the LITE (Longitudinal Investigation of Thromboembolism Etiology) study, cancer patients
with acute symptomatic proximal DVT were randomized to intravenous UFH followed by VKAs for
3 months or tinzaparin (175 U/kg once daily) alone for 3 months. During the 1-year
observational period, recurrent VTE occurred in 16 of 100 (16%) patients assigned to
UFH-VKAs compared with 7 of 100 cancer patients (7%) treated with tinzaparin. 9 The American
Society of Clinical Oncology and the American College of Chest Physicians guidelines advice
LMWH for acute and long-term treatment in cancer patients with acute VTE. 10-11 The US Food
and Drug Administration has recently approved dalteparin sodium for long-term treatment of
symptomatic VTE in cancer patients. 12 Long-term anticoagulant therapy with VKAs is
suggested when LMWH is not available.

After 6 months of LMWH, indefinite anticoagulant therapy is suggested for patients with
active cancer, such as those with metastases or receiving chemotherapy. These patients are
considered to be at a greater risk for recurrent VTE. For most patients, this means lifelong
anticoagulation. The relative benefits and risks of continuing LMWH beyond 6 months versus
switching to oral VKAs, remains a clinical judgment in the individual patient. Some experts
in the field recommend VKAs in patients with less advanced disease. 13 The risks of
long-term LMWH therapy include bleeding, heparin-induced thrombocytopenia and osteoporosis.
While heparin-induced thrombocytopenia and clinically relevant osteoporosis seems relatively
uncommon, the incidence of major and overall bleeding appears to be comparable between LMWH
and VKAs at least for the first 3-6 months of therapy. 6-8 The costs of long-term LMWH
administration which exceeds by far that of VKAs 14 as well as the patient's preference
should be taken into account when deciding on the optimal long-term VTE prophylaxis.

The optimal anticoagulant prophylaxis in cancer patients with VTE who have completed 6
months of LMWH remains a dilemma. While current guidelines by the American Society of
Clinical Oncology and the American College of Chest Physicians advice lifelong LMWH, these
recommendations remain based solely on expert consensus in the absence of clinical trial
data. A recent worldwide survey has shown that VKAs remain the most commonly used long-term
in cancer patients. 15 The aim of this study is to evaluate whether LMWHs are superior to
VKAs in the long-term treatment of symptomatic VTE in cancer patients who completed 6 to 12
months of anticoagulant treatment. As stated above, both medicines have been used for over a
decade and their side-effects are widely known. In this study, we will only dictate which
anticoagulant should be used for long-term treatment, not whether anticoagulant treatment is

Inclusion Criteria:

1. Patients with cancer and confirmed pulmonary embolism (PE) or deep vein thrombosis
(DVT) of the leg who have been treated for minimally 6 and maximally 12 months with
therapeutic doses of anticoagulants, i.e. LMWH or VKA or a new anticoagulant in a

2. Written informed consent

3. Indication for long-term anticoagulant therapy (e.g. because of metastasized disease,

Exclusion Criteria:

1. Legal age limitations (country specific), minimum age at least 18 years

2. Indications for anticoagulant therapy other than DVT or PE

3. Any contraindication listed in the local labeling of LMWH or VKA

4. Childbearing potential without proper contraceptive measures, pregnancy or

5. Life expectancy <3 months

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Symptomatic recurrent VTE, i.e. the composite of recurrent deep venous thrombosis and fatal or non-fatal pulmonary embolism

Outcome Description:

Primary efficacy outcome

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Pieter W. Kamphuisen, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Medical Centre Groningen


Netherlands: Medical Ethics Review Committee (METC)

Study ID:

EudraCT nr: 2009-015336-15



Start Date:

August 2010

Completion Date:

July 2014

Related Keywords:

  • Venous Thromboembolism
  • Neoplasms
  • anticoagulants
  • Heparin, Low-Molecular-Weight
  • 4-Hydroxycoumarins
  • recurrent venous thrombosis
  • Neoplasms
  • Embolism
  • Pulmonary Embolism
  • Thromboembolism
  • Thrombosis
  • Venous Thrombosis
  • Venous Thromboembolism