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

Purpose of the study:

The primary purpose of the study is to compare the pharmacokinetics of anti-Xa activity in patients with cancer and patients without cancer treated with curative dose of low molecular weight heparins (LMWH) for venous thromboembolism (VTE).

The secondary purposes are 1/ to study the correlation between anti-Xa LMWH and concentration of plasma heparanase and 2/ to evaluate the predictive nature of the anti-Xa activity on the occurrence of thromboembolic recurrence in cancer patients treated with LMWH for VTE.

Study design:

Multicentre cohort study of patients hospitalized with VTE:

1. Observational case-control study to compare the pharmacodynamics of anti-Xa activity between patients cancer patients (n = 50) and non-cancer patients (n = 50) matched (1-1) for age, renal function and LMWH
2. A prospective cohort study including 320 cancer patients with a 6 months follow-up.

Study hypothesis:

Venous thrombosis and pulmonary embolism are a common complication of cancer. They complicate up to 10% of cancers and are the cause of fatality, morbidity and significant impaired quality of life. The treatment of these diseases is difficult in this context. Low molecular weight heparins (LMWH) are the reference molecule for the long term treatment of venous thromboembolism (VTE) in cancer patients. Outside this context, their pharmacological properties allow to administer a fixed dose without measuring anti-Xa activity. In the presence of cancer, their use remains, however, associated with a high risk of recurrent thromboembolism up to 9% after 6 months of treatment.

This high rate of recurrence may result from alterations in the pharmacokinetics of LMWH in the presence of a cancer. The synthesis of heparanase by tumor cells might cause a decrease in anti-Xa activity of LMWH and reduce their effectiveness. If this hypothesis is verified, it could result in a change in the management of thrombosis in cancer patients and lead to a dose adjustment of LMWH through the measurement of anti-Xa activity, which may allow reduce the incidence of thromboembolic relapses during treatment.

Enrollment (Target or Actual Number of Subjects):

1. Pharmacokinetics study In a preliminary unpublished study of 37 cancer and non-cancer subjects with the highest concentration of anti-Xa activity was measured. Included 100 subjects (50 cancer patients and 50 non-cancer) would detect a maximum level difference of anti-Xa activity in plasma of 0.20 between cancer patients and cancer-with a power of 90% and a risk of the first kind 5%.

   A difference of 0.20 seems relevant from these preliminary data (median 0.46 vs 0.65), and returns to show that a cancer patient has over 70% chance of having a maximum concentration of anti-Xa activity below that of a free cancer patient (nonparametric Wilcoxon test).

2. Cohort study (cancer patients) The risk of recurrent thromboembolism was estimated between 5 and 10% in cancer patients. By including 200 subjects, around twenty events would be observed and corresponds to a reasonable number of subjects can be recruited over 18 months (50 would already enroll in the pharmacodynamic study). The event rate will be assessed on the first 100 patients that will have been followed for 6 months, if event rate is lower than expected, the number of participants will be reassessed.

After over 2 years of inclusion, the event rate is lower than expected (7%). The number of subjects required was therefore reassessed. To reach the number of 20 events necessary to our analysis, a total of 320 cancer subjects must therefore be included.

Target Follow-Up, duration :

Study duration: 5 years and 6 months (inclusion: 5 years follow-up: 6 months). Duration of participation: 3 a 10 days for non-cancer patients, 6 months for cancer patient.

Performance of the study:

1. Pharmacokinetics study Inclusion (as soon as the diagnosis is confirmed VTE): 1 tube of blood taken before the start of treatment (at the time of another blood sample) for determination of heparanase. After the start of treatment: 3 tubes of blood drawn for determination of anti-Xa activity.

   Assays will be centrally performed, blinded from the clinical data and from the group knowledge of the group patient.

2. Prospective cohort study of cancer patients Followed for 6 months with consultation at 1, 3, and 6 months (normal monitoring).

Follow-up visits: Collection of clinical data (recurrent thromboembolism, hemorrhage, death, tumor progression, cancer treatment since last visit, interruption of treatment with LMWH, thrombocytopenia, anemia), and removal of 1 tube of blood (at the time of a another sample) for determination of anti-Xa activity.

Thromboembolic recurrences will be validated centrally by an independent committee.

Prospects:

Reduce the incidence of thromboembolic recurrence in cancer patients treated with LMWH for VTE by adapting the dose of LMWH with anti-Xa activity in this population if the hypothesis is verified.