Bleeding risk, cancer, and atrial fibrillation. Waiting for ICTHIC 2022

Cancer and atrial fibrillation

A connection exists between cancer and atrial fibrillation (AF) as cancer is statistically associated with AF within the first 3 months after cancer diagnosis [1]. A review and metanalysis highlighted that people with newly diagnosed cancer had a significantly increased risk of AF during subsequent follow-up, within the first 90 days after cancer diagnosis [1].

Systemic inflammation and autonomic dysfunction seem to be the cause of this association. Clinical studies have demonstrated increased pro-inflammatory markers in AF and cancers [1]. An imbalance between the sympathetic and the parasympathetic system might be at the basis of the autonomic dysfunction typical of cancer and AF [1].

In addition, emotional distress may contribute to the increased risk of AF within 90 days after a cancer diagnosis; pain and emotional stress associated with cancer diagnosis results in increased sympathetic activity, which predisposes to AF [1].

A study showed an association of AF with all tumor subtypes analyzed, particularly lung cancer and multiple myeloma (MM). The association between AF and cancer was influenced by age. For example, the odds ratio of lung cancer and MM in patients aged 65–80 years was lower than in those <65 years, which shows that age impacts the development of AF [2].

A diagnosis of AF carries a risk of a cancer diagnosis as well. A cohort study using Danish registry data showed that patients with AF had a markedly increased probability of a cancer diagnosis within 3 months after the AF diagnosis. Moreover, AF was strongly associated with metastatic cancer [3]. Another study showed that women with new-onset AF had an elevated cancer risk beyond 1 year of AF diagnosis [4].

Cancer and bleeding risk

Patients with cancer also have an increased risk of developing venous thromboembolism (VTE) and major bleeding, especially when they begin anticoagulation therapy. While specific scores are available to evaluate VTE risk in cancer patients, the standardized risk models available for AF (CHA₂DS₂-VASC and HAS-BLED score) do not consider the presence of malignancy [5].

Factors increasing the risk of bleeding include the direct erosion and invasion of adjacent blood vessels, mucositis, tissue injury due to cancer-related surgery and radiation treatment, as well as the hypervascularity of tumors. In addition, thrombocytopenia and other disorders (often observed in hematological malignancies or the presence of hepatic metastases, paraneoplastic phenomena, or certain chemotherapies) can further contribute to increased risk of bleeding [5].

Cancer, AF, and bleeding risk

Data from three large trials confirm that AF patients with a history of cancer are at higher risk of major bleeding [6-8].

This risk correlation was not confirmed by a post-hoc analysis of data from the ARISTOTLE trial, which showed a nonsignificant association between cancer (active/remote) and major bleeding [9]. However, a subgroup analysis of a large population-based study in Denmark indicated an association between specific cancer types (such as lung cancer or pleura or urological cancer) and a significantly increased risk of major bleeding [10].

A cohort study that used the Danish population-based healthcare databases showed that patients with AF and cancer had more major bleeding and thromboembolic risk than those without cancer. The highest bleeding risk was observed for intracranial and respiratory cancer and increased with the number of antithrombotic drugs [11].

Bleeding is frequent in patients with AF treated with oral anticoagulant therapy and may be the first manifestation of underlying cancer.

Using data from an unselected real-world cohort, a study investigated the absolute and relative risks of cancer in patients with AF receiving oral anticoagulant (OAC) therapy who presented bleeding complications [12]. Results showed that among patients with AF treated with OAC therapy, gastrointestinal, genitourinary, and bronchopulmonary bleeding are strongly and relatively specifically associated with a new cancer diagnosis within the respective organ systems. Furthermore, the strength of this association increases with the severity of bleeding, with most cancers identified within the first 6 months after the bleeding event [12].

Which anticoagulation therapy should be used?

There are no guidelines specific for people with cancer and AF.

A study performed a cross-sectional survey among European and non-European physicians who had experience treating patients with AF and cancer. The survey aimed to understand beliefs, perceptions, and attitudes in the prescription of anticoagulants for the management of AF in cancer patients [13].

The results highlighted a substantial heterogeneity in therapeutic choices. Overall, direct oral anticoagulants (DOACs) are the preferred choice in AF patients with active cancer, followed by low-molecular-weight heparin (LMWH) and warfarin. In particular, most of the respondents indicated that in patients with active cancer, AF, and a CHA₂Ds₂-VASC score ≥2, oral anticoagulation with DOACs is the preferred choice in the absence of cerebral metastases [13].

DOACs are not the first choice in patients with inoperable gastrointestinal cancers, which predispose them to a high risk of bleeding [13].

In summary

There is a connection between AF and cancer:

• Cancer was statistically associated with AF within the first 3-month period after a cancer diagnosis
• Patients with AF had a markedly increased probability of a cancer diagnosis within 3 months after the AF diagnosis.

Bleeding is frequent in patients with AF treated with oral anticoagulant therapy and may be the first manifestation of underlying cancer. A prompt evaluation of bleeding could be useful for enabling early detection of cancer, especially gastrointestinal, genitourinary, and bronchopulmonary cancers.

Since no guidelines specific for people with cancer and AF exist, specific clinical trials comparing the available anticoagulant strategies and bleeding risks are needed in the setting of AF and cancer.

Keep reading “Use of direct oral anticoagulants in patients with atrial fibrillation and concomitant active cancer.”

References

1. Yuan M, Zhang Z, Tse G, et al. Association of Cancer and the Risk of Developing Atrial Fibrillation: A Systematic Review and Meta-Analysis. Cardiol Res Pract. 2019;2019:8985273.
2. Zubair Khan M, Gupta A, Patel K, et al. Association of atrial fibrillation and various cancer subtypes. J Arrhythm. 2021;37(5):1205-1214.
3. Ostenfeld EB, Erichsen R, Pedersen L, Farkas DK, Weiss NS, Sørensen HT. Atrial fibrillation as a marker of occult cancer. PLoS One. 2014;9(8):e102861.
4. Conen D, Wong JA, Sandhu RK, et al. Risk of Malignant Cancer Among Women With New-Onset Atrial Fibrillation. JAMA Cardiol. 2016;1(4):389-396.
5. Chu G, Versteeg HH, Verschoor AJ, et al. Atrial fibrillation and cancer – An unexplored field in cardiovascular oncology. Blood Rev. 2019;35:59-67.
6. Melloni C, Shrader P, Carver J, et al. Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry. Eur Heart J Qual Care Clin Outcomes. 2017;3(3):192-197.
7. Chen ST, Hellkamp AS, Becker RC, et al. Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKET AF. Eur Heart J Qual Care Clin Outcomes. 2019;5(2):145-152.
8. Fanola CL, Ruff CT, Murphy SA, et al. Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF – TIMI 48 Trial. J Am Heart Assoc. 2018;7(16):e008987.
9. Melloni C, Dunning A, Granger CB, et al. Efficacy and Safety of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and a History of Cancer: Insights from the ARISTOTLE Trial. Am J Med. 2017;130(12):1440-1448.e1.
10. Ording AG, Horváth-Puhó E, Adelborg K, Pedersen L, Prandoni P, Sørensen HT. Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study. Cancer Med. 2017;6(6):1165-1172.
11. G Chu, N Van Rein, M V Huisman, L Pedersen, S C Cannegieter, F A Klok, H T Sorensen, Antithrombotic therapy and bleeding complications in patients with atrial fibrillation and active cancer, European Heart Journal 2021,42(1):ehab724.2869
12. Raposeiras Roubín S, Abu Assi E, Barreiro Pardal C, et al. New Cancer Diagnosis After Bleeding in Anticoagulated Patients With Atrial Fibrillation. J Am Heart Assoc. 2020;9(22):e016836.
13. Boriani G, Lee G, Parrini I, et al. Anticoagulation in patients with atrial fibrillation and active cancer: an international survey on patient management. Eur J Prev Cardiol. 2021;28(6):611-621.