Clinical trial NCT04508855: Management of Atrial Fibrillation in Patients With Cancer (MAFIC Study)
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
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Cancer
Atrial Fibrillation
Keywords: Cancer
Anticoagulation
Atrial fibrillation
Direct oral anticoagulants
low molecular weight heparin
Lead sponsor: AHEPA University Hospital
Sponsor class: OTHER
Collaborators: name: Theagenio Cancer Hospital
First posted: 2020-08-11
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients with cancer and atrial fibrillation receiving direct oral anticoagulants and antineoplastic therapy

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

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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

Primary outcomes:
measure: Major bleeding
timeFrame: 6 months
measure: Clinical relevant bleeding
timeFrame: 6 months
Secondary outcomes:
measure: Deep vein thrombosis or pulmonary embolism
timeFrame: 6 months
measure: Thromboembolic stroke or systemic embolism
timeFrame: 6 months
Other outcomes:
Locations:
city: Thessaloniki
country: Greece
facility: AHEPA University Hospital
city: Thessaloniki
country: Greece
facility: Theagenio Cancer Hospital
Study officials:
References:
citation: Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012 Nov;33(21):2719-47. doi: 10.1093/eurheartj/ehs253. Epub 2012 Aug 24. No abstract available.
citation: Hu YF, Liu CJ, Chang PM, Tsao HM, Lin YJ, Chang SL, Lo LW, Tuan TC, Li CH, Chao TF, Chung FP, Liao JN, Chen TJ, Chen SA. Incident thromboembolism and heart failure associated with new-onset atrial fibrillation in cancer patients. Int J Cardiol. 2013 May 10;165(2):355-7. doi: 10.1016/j.ijcard.2012.08.036. Epub 2012 Sep 16. No abstract available.
citation: Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. doi: 10.1056/NEJMoa025313.
citation: Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018 Jul 10;36(20):2017-2023. doi: 10.1200/JCO.2018.78.8034. Epub 2018 May 10.
citation: Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Buller HR; Hokusai VTE Cancer Investigators. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. doi: 10.1056/NEJMoa1711948. Epub 2017 Dec 12.