Management of Atrial Fibrillation in Patients With Cancer (MAFIC Study)

Sponsor

AHEPA University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04508855

Collaborator

Theagenio Cancer Hospital (Other)

240

Enrollment

Locations

Anticipated Duration (Months)

120

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective is to assess the safety and efficacy of switching from direct oral anticoagulants to low molecular weight heparin in cancer patients during antineoplastic therapy

Condition or Disease	Intervention/Treatment	Phase
Cancer Atrial Fibrillation	Drug: Low molecular weight heparin

Detailed Description

This is a single-arm prospective observational study aiming to explore the safety and efficacy of switching from direct oral anticoagulants (DOAC) to low molecular weight heparin (LMWH) in cancer patients with atrial fibrillation (AF) during antineoplastic therapy or for a maximum time period of 6 months.

AF is the most common sustained arrhythmia; it affects 1.5% to 2% of the general population, and this prevalence increases to 10% at 80 years of age and to 18% at 85 years of age. Given the increasing occurrence of malignancies in the elderly and the coexistence of other conditions predisposing to AF in cancer patients, an association between those 2 conditions would be expected. A study including 24,125 patients estimated a prevalence of AF of 2.4% at the time of cancer diagnosis. A recent prospective study of 34,691 middle-aged women without AF or cancer at baseline showed that new-onset AF was a risk marker of subsequent diagnosis of cancer (HR 1.48, 95% CI 1.25 to 1.75; p <0.001).

Moreover, patients with cancer are at significantly higher risk of developing venous thromboembolism (VTE) which sometimes may precede the diagnosis of the malignancy. The risk is even higher when the patient is poorly mobilized or hospitalized. On the other hand, some anticancer therapies and especially the novel angiogenesis inhibitors are associated with increased thrombogenicity.

According to current Guidelines, DOACs are preferred over vitamin K antagonist (VKA) therapy and LMWH in both AF and VTE in the general population. However, in the presence of active cancer the administration of LMWH is advised for patients who are hospitalized for any reason and/or receiving chemotherapy, unless there is a high bleeding risk. LMWH has more favorable outcomes in cancer patients than VKAs, both in the setting of primary or secondary thromboembolic prophylaxis while extended anticoagulation (beyond the first 6 months) may be considered for an indefinite period or until the cancer is cured. This is possibly related with the fact that LMWH present antitumour and antimetastatic effects and confer an increased survival benefit. It should be noted that currently there is no conclusive evidence regarding the safety and efficacy of DOACs in cancer patients and the first results seem contradictory.

A number of recent studies with the use of DOACs in cancer-associated venous thromboembolism have demonstrated that these drugs are effective with similar rates of recurrent VTE but higher rates of major bleeding compared to LMWH. However, there are particular disadvantages, especially during the period of chemotherapy, such as interactions between these agents and anticancer therapies (eg, potential interactions between DOACs and azole-antimycotic agents), as well as unknown pharmacokinetics from chemotherapy-related vomiting.

Putting things together, many patients who are under a DOAC due to AF or previous VTE/pulmonary embolism (PE) may be diagnosed with cancer. Moreover, the risk of VTE is 6-fold higher on intravenous chemotherapy. For this reason, current clinical practice suggests that LMWH is continued during treatment with intravenous chemotherapy. However, data on the efficacy and safety of this common approach is lacking. This is important, especially in the setting of gastrointestinal tumors (especially gastric and pancreatic disease) which pose a high bleeding risk and especially during the chemotherapy active period.

Study Design

Study Type:

Observational

Anticipated Enrollment :

240 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Safety and Efficacy of Switching From Direct Oral Anticoagulants to Low Molecular Weight Heparin in Cancer Patients With Atrial Fibrillation During Antineoplastic Therapy

Actual Study Start Date :

Aug 1, 2020

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Cancer patients with atrial fibrillation All patients will be assigned to receive subcutaneous LMWH in therapeutic doses More specifically the regimens will be as follows: Tinzaparin 175 units/Kg once daily; Enoxaparin 1unit/kg twice daily; Fondaparinux <50 kg, 5 mg SC once daily, 50-100 kg, 7.5 mg SC once daily, >100 kg, 10 mg SC once daily; Bemiparin 115 IU/kg once daily; <50kg, 5000IU, 50-70kg, 7.500 IU, >70kg, 10000IU Nadroparin: Patients weighing 40 to 100 kg: SC, 171 anti-factor Xa IU per kg of body weight once a day; patients weighing over 100 kg will not receive nadroparin because a treatment dosage has not been established; Dalteparin: 200 units IU/kg SC daily for 30 days, then 150 units IU/Kg SC daily Dose adjustments will occur only in case of renal insufficiency according to the medicine's SPC The treatment with the LMWH will last at least during the period of active antineoplastic therapy of cancer patients	Drug: Low molecular weight heparin Switch from direct oral anticoagulants to low molecular weight heparin

Arm

Intervention/Treatment

Cancer patients with atrial fibrillation

All patients will be assigned to receive subcutaneous LMWH in therapeutic doses More specifically the regimens will be as follows: Tinzaparin 175 units/Kg once daily; Enoxaparin 1unit/kg twice daily; Fondaparinux <50 kg, 5 mg SC once daily, 50-100 kg, 7.5 mg SC once daily, >100 kg, 10 mg SC once daily; Bemiparin 115 IU/kg once daily; <50kg, 5000IU, 50-70kg, 7.500 IU, >70kg, 10000IU Nadroparin: Patients weighing 40 to 100 kg: SC, 171 anti-factor Xa IU per kg of body weight once a day; patients weighing over 100 kg will not receive nadroparin because a treatment dosage has not been established; Dalteparin: 200 units IU/kg SC daily for 30 days, then 150 units IU/Kg SC daily Dose adjustments will occur only in case of renal insufficiency according to the medicine's SPC The treatment with the LMWH will last at least during the period of active antineoplastic therapy of cancer patients

Drug: Low molecular weight heparin

Switch from direct oral anticoagulants to low molecular weight heparin

Outcome Measures

Primary Outcome Measures

Major bleeding [6 months]
Death or a decrease in hemoglobin level of ≥ 2 g/dL over 24 hours or the need for transfusion of ≥ 2 units of packed red cells or clinically overt bleeding at critical site (eg, intracranial, retroperitoneal)
Clinical relevant bleeding [6 months]
Bleeding that does not meet the criteria for major bleeding, however, it requires medical treatment or it affects the patient's daily activity

Secondary Outcome Measures

Deep vein thrombosis or pulmonary embolism [6 months]
t The first episode of symptomatic, documented deep vein thrombosis or pulmonary embolism
Thromboembolic stroke or systemic embolism [6 months]
The first episode of symptomatic, documented thromboembolic stroke or systemic embolism

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects diagnosed with cancer other than basal-cell or squamous-cell skin cancer which was objectively confirmed and are programmed for antineoplastic treatment
Subjects between 18 to 75 years of age at inclusion
Subjects must weigh at least 40 kg at inclusion
Subjects receiving direct oral anticoagulant treatment (rivaroxaban, dabigatran, apixaban, edoxaban) for prevention of stroke and systemic embolism in non-valvular atrial fibrillation

Exclusion Criteria:

Patients that have active or serious bleeding within the previous two weeks
Patients that have conditions associated with high bleeding risk (active peptic ulcer, recent neurosurgery
Patients with platelet count below 50000 per cubic millimeter
Patients who have contraindications to heparin (heparin-induced thrombocytopenia)
Patients with calculated creatinine clearance < 30 ml/min using the Cockcroft-Gault formula
Women who are pregnant
Life expectancy less than 6 months
Anticoagulation contraindications
Recent brain surgery within 6 months
Vascular surgery within 6 months