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

2014-07-10 14:01:18 | BioPortfolio



Patients with cancer and a first deep venous thrombosis of the leg or pulmonary embolism (venous thromboembolism, VTE) are generally treated with low molecular weight heparin (LMWH)injections for 6 months, since this treatment is associated with a reduced incidence of recurrent VTE compared to vitamin K antagonists (VKA). It is recommended that patients with active malignancy (metastatic cancer and/or ongoing cancer treatment)continue anticoagulant treatment. However, it is unknown whether LMWH is still superior compared to VKA for the long-term anticoagulant treatment.


The aim of this study is to evaluate whether low-molecular-weight heparin more effectively reduces recurrent VTE compared to vitamin K antagonists in patients with cancer who have already completed 6 to 12 months of anticoagulant treatment because of deep venous thrombosis of the leg or pulmonary embolism.


The investigators hypothesize that LMWH is more effective compared to VKA in the long-term treatment of VTE in cancer patients who have already been treated for 6-12 months with anticoagulants.


This is a multicenter, multinational, randomized, open label trial.


Patients with a malignancy (all types, solid and hematological) who have received 6-12 months of anticoagulation for VTE and have an indication for continuing anticoagulation, will be randomly assigned to six additional months of LMWH or VKA. LMWH will be administered in a weight-adjusted scheme, with 65-75% of therapeutic doses. All types of LMWH and VKA are allowed, as long as weight adjusted dosing is possible for LMWH. The target INR will be 2.0-3.0. The primary efficacy outcome is symptomatic recurrent VTE, i.e. deep vein thrombosis and pulmonary embolism. The primary safety outcome is major bleeding.

Sample size

A total of 65 to 87 recurrent VTE events are needed to show a 50% reduction with LMWH as compared to VKA (type I error 0.05, two-sided, power respectively 80 and 90%). To observe 75 events, with a 10% event rate per half year in the VKA arm and 5% in the LMWH arm a total of 1000 patients will need to be included.


Outcomes will be adjudicated by a central adjudication committee. A steering committee will be formed, preferably consisting of one member of every participating center. An electronic case report form will be used for data collection. Also, an electronic trial master file will be used.


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 indicated.

Study Design

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


Venous Thromboembolism


low molecular weight heparin, vitamin K antagonists


George Washington University
District of Columbia
United States




University Medical Centre Groningen

Results (where available)

View Results


Published on BioPortfolio: 2014-07-10T14:01:18-0400

Clinical Trials [3568 Associated Clinical Trials listed on BioPortfolio]

Heparin Antibodies in Intensive Care Unit Patients (HAICU)

Intensive care unit patients have multiple risk factors for venous thromboembolism. Venous thromboembolism leads to significant morbidity and can be fatal. Unfractionated heparin and low...

Long-Term Low-Molecular-Weight Heparin Versus Oral Anticoagulants in Deep Venous Thrombosis

The purpose of this study is to evaluate whether low-molecular-weight heparin could be equally or more effective than oral anticoagulation in the long-term treatment of deep venous thrombo...

Anti Xa Activity in Cancer Patients Receiving Low-molecular-weight Heparin for Venous Thromboembolism

Low molecular weight heparins (LMWH) are the reference molecule for the long term treatment of venous thromboembolism (VTE) in cancer patients but remains, however, associated with a high ...

Efficacy of Sodium Heparin for Prophylaxis of Venous Thromboembolism in Surgical Patients

The aim of this study is to verify, through clinical examination and doppler, the non-inferiority of the drug test (heparin sodium 5.000UI/0.25 mL - HIPOLABOR) in relation to the drug comp...

Once Weekly Subcutaneous Ports for the Administration of Anticoagulants

The purpose of this study is to ascertain whether subcutaneous ports are an effective and reliable way to administer the low molecular weight heparin (LMWH) enoxaparin to patients for the ...

PubMed Articles [13712 Associated PubMed Articles listed on BioPortfolio]

Decreased Bleeding Incidence with Direct Oral Anticoagulants Compared to Vitamin K Antagonist and Low-Molecular-Weight Heparin in Patients with Sickle Cell Disease and Venous Thromboembolism.

Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD), yet the optimal pharmacologic anticoagulant is unknown.

Risk factors for and clinical management of venous thromboembolism during pregnancy.

Venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism, is one of the leading causes of non-obstetric maternal death in the United States. Physiologic and anatomic c...

D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with non-vitamin K anticoagulants.

D-dimer levels measured during and after vitamin K antagonist withdrawal may be used in clinical practice to assess the individual risk of recurrent venous thromboembolism. Currently, direct oral anti...

Apixaban and Dalteparin in Active Malignancy Associated Venous Thromboembolism: The ADAM VTE Trial.

Low molecular weight heparin is the guideline-endorsed treatment for cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, limited data support its...

Direct Oral Anticoagulants for the Treatment of Cerebral Venous Thrombosis.

Cerebral venous thrombosis (CVT) is an uncommon neurological condition usually treated with heparin followed by oral vitamin K antagonists (VKAs). In patients with venous thromboembolism (VTE), compar...

Medical and Biotech [MESH] Definitions

Heparin fractions with a molecular weight usually between 4000 and 6000 kD. These low-molecular-weight fractions are effective antithrombotic agents. Their administration reduces the risk of hemorrhage, they have a longer half-life, and their platelet interactions are reduced in comparison to unfractionated heparin. They also provide an effective prophylaxis against postoperative major pulmonary embolism.

A low-molecular-weight fragment of heparin, prepared by nitrous acid depolymerization of porcine mucosal heparin. The mean molecular weight is 4000-6000 daltons. It is used therapeutically as an antithrombotic agent. (From Merck Index, 11th ed)

A heparin fraction with a mean molecular weight of 4500 daltons. It is isolated from porcine mucosal heparin and used as an antithrombotic agent. (From Merck Index, 11th ed)

Low-molecular-weight fragment of heparin, having a 4-enopyranosuronate sodium structure at the non-reducing end of the chain. It is prepared by depolymerization of the benzylic ester of porcine mucosal heparin. Therapeutically, it is used as an antithrombotic agent. (From Merck Index, 11th ed)

Coagulant substances inhibiting the anticoagulant action of heparin.

More From BioPortfolio on "Long-term Treatment for Cancer Patients With Deep Venous Thrombosis or Pulmonary Embolism"

Quick Search

Relevant Topics

Cancer Disease
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...

Cardiology is a specialty of internal medicine.  Cardiac electrophysiology : Study of the electrical properties and conduction diseases of the heart. Echocardiography : The use of ultrasound to study the mechanical function/physics of the h...

Searches Linking to this Trial