Screening, Diagnosis and Management of Atrial Fibrillation in Cancer Patients: Current Evidence and Future Perspectives

Gonçalves-Teixeira, Pedro; Costa, Telma; Fragoso, Isabel; Ferreira, Diogo; Brandão, Mariana; Leite-Moreira, Adelino; Sampaio, Francisco; Ribeiro, José; Fontes-Carvalho, Ricardo

Pedro Gonçalves-Teixeira Correspondência: Pedro Gonçalves-Teixeira • Departamento de Cardiologia – Centro Hospitalar de Vila Nova de Gaia – Rua Conceição Fernandes s.n., 4434-502, Vila Nova de Gaia – Portugal E-mail: pedromgoncalvesteixeira@gmail.com

Departamento de Cardiologia, Vila Nova de Gaia Hospital Center, Gaia – Portugal

Departamento de Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto – Portugal

Clínica Cardio-Oncológica, Centro Hospitalar Vila Nova de Gaia, Gaia – Portugal

http://orcid.org/0000-0001-8837-2746

Telma Costa

Clínica Cardio-Oncológica, Centro Hospitalar Vila Nova de Gaia, Gaia – Portugal

Departamento de Oncologia, Centro Hospitalar Vila Nova de Gaia, Gaia – Portugal

http://orcid.org/0000-0002-9625-1124

Isabel Fragoso

Unidade de Atenção Primária à Saúde Aracetti, Arazede – Portugal

http://orcid.org/0000-0001-5876-2348

Diogo Ferreira

Departamento de Cardiologia, Vila Nova de Gaia Hospital Center, Gaia – Portugal

Departamento de Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto – Portugal

http://orcid.org/0000-0002-2904-8580

Mariana Brandão

Departamento de Cardiologia, Vila Nova de Gaia Hospital Center, Gaia – Portugal

http://orcid.org/0000-0001-9913-0435

Adelino Leite-Moreira

Departamento de Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto – Portugal

Departamento de Cirurgia Cardiotorácica, Hospital Universitário São João, Porto – Portugal

Unidade de Pesquisa Cardiovascular (UnIC), Faculdade de Medicina, Universidade do Porto, Porto – Portugal

http://orcid.org/0000-0001-7808-3596

Francisco Sampaio

Departamento de Cardiologia, Vila Nova de Gaia Hospital Center, Gaia – Portugal

Departamento de Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto – Portugal

José Ribeiro

Departamento de Cardiologia, Vila Nova de Gaia Hospital Center, Gaia – Portugal

Clínica Cardio-Oncológica, Centro Hospitalar Vila Nova de Gaia, Gaia – Portugal

http://orcid.org/0000-0002-2165-7680

Ricardo Fontes-Carvalho

Departamento de Cardiologia, Vila Nova de Gaia Hospital Center, Gaia – Portugal

Departamento de Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto – Portugal

http://orcid.org/0000-0003-2306-8393

Mailing Address: Pedro Gonçalves-Teixeira • Departamento de Cardiologia – Centro Hospitalar de Vila Nova de Gaia – Rua Conceição Fernandes s.n., 4434-502, Vila Nova de Gaia – Portugal E-mail: pedromgoncalvesteixeira@gmail.com

Author Contributions

Conception and design of the research: Gonçalves-Teixeira P, Costa T, Fragoso I, Leite-Moreira A, Sampaio F, Ribeiro J, Fontes-Carvalho R; Acquisition of data: Gonçalves-Teixeira P; Analysis and interpretation of the data: Gonçalves-Teixeira P, Costa T, Fragoso I, Ferreira D, Brandão M; Writing of the manuscript: Gonçalves-Teixeira P, Costa T, Fragoso I; Critical revision of the manuscript for intellectual content: Gonçalves-Teixeira P, Costa T, Fragoso I, Ferreira D, Brandão M, Leite-Moreira A, Sampaio F, Ribeiro J, Fontes-Carvalho R.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Figures (3)
Tables (2)

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Figure 1
The multifactorial, bidirectional, interplay between cancer and atrial fibrillation. See text for further details.

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Figure 2
Several methods are available for outpatient atrial fibrillation screening. BP: blood pressure. CIED: cardiac implantable electronic device. ICM: implantable cardiac monitor

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Figure 3
Cancer patients with AF are at simultaneously high thrombotic and bleeding risk. Patient factors, as well as tumor-specific risks and cancer therapeutics adverse effects pose additional challenges. The indication for anticoagulation in these patients must be individualized, and several factors, not included in classic risk scores, should be considered. (*) Vinca alkaloids, alkylating agents, monoclonal antibodies (aflibercept, bevacizumab, ramucirumab, trastuzumab emtansine), antiestrogens, antimetabolites (pentostatin), anthracyclines, bleomycin, campothecins, carfilzomib, epipodophyllotoxins, ibrutinib, BCR-ABL, BRAF, and VEGF/VEGFR inhibitors, interleukins, L-asparaginase, ruxolitinib, taxanes, temozolomide, cyclophosphamide, ifosfamide, megestrol, tamoxifen. (**) CHA2DS2-VASc score is a strong predictor of thromboembolic events in patients with previously known AF but performed poorly for stroke risk prediction in those with cancer and newly diagnosed AF. See text for further details. (***) Alkylating agents (carboplatin, cyclophosphamide, cisplatin, estramustine, oxaliplatin, temozolomide), gonadotropin-releasing hormone analogs, antiandrogens, monoclonal antibodies (aflibercept, bevacizumab, cetuximab, panitumumab), anthracyclines, antimetabolites (capecitabine, 5-fluorouracil, gemcitabine, methotrexate, pentostatin), immunomodulators (lenalidomide, pomalidomide, thalidomide), aromatase inhibitors, bleomycin, protein kinase inhibitors (axitinib, lenvatinib, pazopanib, sorafenib, sunitinib), mTOR inhibitors, proteosome inhibitors (carfilzomib), irinotecan, taxanes, tasonermin, tretinoin, megestrol, progestogens, raloxifene, tamoxifen, vinflunine, vorinostat, erythropoiesis-stimulating agents and granulocyte colony-stimulating factors.

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Table 1
Reported frequency of cancer therapy-induced atrial fibrillation

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Table 2
NOACs versus Warfarin for stroke prevention in patients with atrial fibrillation

Therapeutic class	Drug agent	Reported frequency of AF
Alkylating agents	Anthracyclines	0.55 – 10.3%
	Melphalan	10.8 – 33%
	Busulfan	6.4%
	Cyclophosphamide	2%
Antimetabolites	5-Fluorouracil	5%
	Capecitabine	0.5 – 1.1%
	Gemcitabine	0-8.1% ^() ()** AF incidence of 0% when used alone, 8% when associated with vinorelbine.
Taxanes	Paclitaxel	0.18 - 1%
IImmunomodulators	Talidomide	4.7%
IImmunomodulators	Lenalidomide	4.6 - 7%
Platinum derivates	Cisplatin	10-32%
Tyrosine kinase inhibitors	Ibrutinib (BTK)	3-16%
	Nilotinib (BCR-ABL1)	0.8%
	Ponatinib (BCR-ABL1)	3-7%
	Vemurafenib (BRAF)	1.5%
	Imatinib (BCR-ABL1)	0.55 – 33%
	Dasatinib (BCR-ABL1)	5.6%
	Sorafenib (VEGFR)	5.1% ^() () The reported prevalence was found in association with 5-FU, in a phase II study. It is noteworthy to recall that this association is not currently used in daily clinical practice.
Proteasome inhibitors	Bortezomib	2.2%
Proteasome inhibitors	Carfilzomib	3.2 – 3.8%
Monoclonal antibodies	Trastuzumab (HER2/ERBB2)	1.2%
	Bevacizumab (VEFG)	2.2%
	Cetuximab (EGFR/HER1)	4.8%
	Alentuzumab (CD52)	1.2%
	Rituximab (CD20)	1%
Other	Interleukin 2	4.3 – 8%
ICIs	Nivolumab (anti-PD1)	13%
	Pembrolizumab (anti-PD1)
	Ipilimumab (anti-CTLA4)
CAR-T cell therapy		2.2%
Hormonotherapy	Degarelix	2%
Hormonotherapy	Abiraterone	1 – 5%
Radiation therapy		0.5 –3.2%

NOAC	Primary Efficacy endpoint vs. Warfarin RR [95% CI]		Primary Safety endpoint ^* * Major bleeding results, unless otherwise specified. vs. Warfarin RR [95% CI]
NOAC	General population ^ Data from landmark RCTs.	Cancer ^* ***** Data from post-hoc subanalysis or observational studies.	General population ^ Data from landmark RCTs.	Cancer ^* ***** Data from post-hoc subanalysis or observational studies.
Dabigatran	0.91 [0.53-0.82] ^† † The results for Dabigatran 150mg dosage are presented.	0.14 [0.03 - 0.57] ^§ § Results from an observational retrospective study, which included 140 patients on Dabigatran, and counted two ischemic strokes and three major bleeding events in this study arm (Kim K, et al. 2018].	0.93 [0.81-1.07] ^† † The results for Dabigatran 150mg dosage are presented.	0.23 [0.07-0.74] ^§ § Results from an observational retrospective study, which included 140 patients on Dabigatran, and counted two ischemic strokes and three major bleeding events in this study arm (Kim K, et al. 2018].
Rivaroxaban	0.79 [0.66-0.96]	0.52 [0.22-1.21]	1.03 [0.96-1.11]	1.09 [0.82-1.44] ^†† †† Major or clinically relevant nonmajor bleeding events.
Apixaban	0.79 [0.66-0.95]	1.09 [0.56-2.26]	0.69 [0.60-0.80]	0.80 [0.56-1.14] ^†† †† Major or clinically relevant nonmajor bleeding events.
Edoxaban	0.79 [0.63-0.99] ^‡ ‡ The results for Edoxaban 60mg dosage are presented.	0.60 [0.31-1.15] ^‡ ‡ The results for Edoxaban 60mg dosage are presented.	0.87 [0.73-1.04] ^‡ ‡ The results for Edoxaban 60mg dosage are presented.	0.98 [0.69–1.40] ^‡ ‡ The results for Edoxaban 60mg dosage are presented.

[1] Mailing Address: Pedro Gonçalves-Teixeira • Departamento de Cardiologia – Centro Hospitalar de Vila Nova de Gaia – Rua Conceição Fernandes s.n., 4434-502, Vila Nova de Gaia – Portugal E-mail: pedromgoncalvesteixeira@gmail.com

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Screening, Diagnosis and Management of Atrial Fibrillation in Cancer Patients: Current Evidence and Future Perspectives

Abstract