Long-term treatment for cancer patients with deep vein thrombosis or pulmonary embolism - a randomized open label study

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and
pulmonary embolism (PE), represents a major cause of morbidity and mortality in
cancer patients. The risk of VTE is increased several-fold in patients with
cancer with incidences ranging between 4% and 20%. 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. Recently, randomized clinical trials and
prospective cohort studies in cancer patients with acute VTE have shown that
low-molecular-weight heparin (LMWH) is more effective in preventing VTE
recurrences at a comparable bleeding risk as compared to oral anticoagulants.
In the large CLOT study, dalteparin treatment was associated with a 50%
reduction in recurrent VTE compared to Vitamin K antagonists (VKA). The
guidelines of the American Society of Clinical Oncology and the American
College of Chest Physicians, and also the recently published Dutch guideline of
the CBO all advice LMWH for acute and long-term treatment in cancer patients
with acute VTE. Generally, after six months of LMWH, indefinite anticoagulant
therapy is recommended for patients with active cancer, such as those with
metastases or receiving chemotherapy, because of the greater risk for recurrent
VTE. For most patients, this means lifelong anticoagulant therapy. The relative
benefits and risks of continuing LMWH beyond 6 months versus switching to oral
VKA are unknown and therefore remain a clinical judgment in the individual
patient.
Therefore, there is an urgent need for a randomized trial that directly
compares LMWH and VKA as extended anticoagulant treatment in cancer patients to
assess which has the best risk-benefit ratio.

The primary efficacy objective is to evaluate whether LMWH is superior to VKAs
in the long-term treatment of symptomatic VTE in cancer patients who completed
6 to 12 months of anticoagulant treatment. Two aspects are important: the
efficacy with which it prevents recurrent DVT/PE and the bleeding risk.

This is a multicenter, randomized, open, superiority trial for efficacy.

Cancer patients with confirmed DVT or PE who have completed 6-12 months of
treatment with LMWH are eligible for this trial. After randomization, patients
will be allocated to VKA or LMWH. The treatment duration will be 6 months.
Allocation to treatment will be done by block randomization via a web based
application and will be stratified by country.
All outcomes will be evaluated by a central, blinded, independent adjudication
committee. Adjudication results will be the basis for the final analysis.
An independent data and safety monitoring board will monitor the patient*s
safety during the study and give recommendations to the executive committee.

For all patients, contacts are scheduled at regular time intervals. Including
the screening/randomization visit, 4 visits and one phone call are planned.
Patients who are randomized but who did not receive study treatment or did
discontinue anticoagulant treatment prematurely will at least be seen at the
end of the respective treatment periods. During all contacts, the treatment and
the clinical course of the patient will be evaluated using a contact report.
Patients with suspected efficacy outcomes or bleeding will undergo confirmatory
testing. All outcomes are adjudicated by the central independent adjudication
committee.

Patients will be treated for 6 months with either LMWH or VKA. The type of LMWH
or VKA used, is up to preferences of the local physician and the local
guidelines. In case of treatment with VKA, INR values will be monitored. A
target INR of 2.5 will be used. LMWH will be used in 2/3 of normal doses
(conform the treatment regime in the CLOT study).

There is no additional risk associated with participation, because the decision
to give long-term (sometimes life long) anticoagulation has already been made
prior to participation in the study. Doctors and patients can then choose
between LMWH and VKA, based on the current literature there is no preference
for one of them. This study only dictates whether LMWH or VKA should be given.
Participation will not interfere with the oncological treatment.
The burden of this study is minimally. Next to the screening/randomization
visit, there are only 3 visits and 1 phone call. Visits will take maximally 30
minutes (probably much less) and will probably be interwoven with a standard
clinical care.
Information from this study will benefit future patients with cancer and PE or
DVT and an indication for long-term anticoagulant treatment.