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ONCOLOGY LETTERS 23: 124, 2022
Anticoagulation for atrial fibrillation in active cancer (Review)
DIMITRIOS FARMAKIS1, PAVLOS PAPAKOTOULAS2, ELENI ANGELOPOULOU3, THEODOROS BISCHINIOTIS4,
GEORGE GIANNAKOULAS5, PANAGIOTIS KLIRIDIS6, DIMITRIOS RICHTER7 and IOANNIS PARASKEVAIDIS8
1
Department of Physiology, University of Cyprus Medical School, Nicosia 2029, Cyprus;
First Department of Clinical Oncology, ‘Theagenio’ Anticancer Hospital, Thessaloniki 546 39;
3
Department of Cardiology, ‘Agioi Anargyroi’ General Oncology Hospital, Athens 145 64; 4Department of Cardiology,
‘Theagenio’ Anticancer Hospital, Thessaloniki 546 39; 5Department of Cardiology, AHEPA General Hospital,
Aristotle University of Thessaloniki, Thessaloniki 546 21; 6Department of Cardiology, ‘Agios Savvas’
General Anti‑Cancer Hospital, Athens 115 22; 7Department of Cardiology, Athens Euroclinic, Athens 115 21;
8
Department of Therapeutics, ‘Alexandra’ General Hospital,
National and Kapodistrian University of Athens Medical School, Athens 115 28, Greece
2
Received November 9, 2021; Accepted February 2, 2022
DOI: 10.3892/ol.2022.13244
Abstract. Atrial fibrillation (AF) may often pre‑exist
in patients with newly diagnosed cancer or occur with
increased frequency shortly after cancer diagnosis. Patients
with active cancer and AF have a particularly high risk of
thromboembolic complications, as both conditions carry
a risk of thrombosis. Thromboembolic risk is determined
by several factors, including advanced age, sex (females),
cancer histology (adenocarcinomas), location (e.g., pancreas,
stomach), advanced stage, anticancer regimens (e.g., platinum
compounds, anti‑angiogenic therapies, immune modulators),
comorbidities (e.g., obesity, kidney disease) and concurrent
therapies (e.g., surgery, central catheters). Physicians are often
reluctant to prescribe anticoagulants to patients with active
cancer and AF, mainly due to fear of bleeding complications,
which is partly related to the paucity of evidence in the field.
Decision making regarding anticoagulation for the prevention
of ischemic stroke and systemic embolism in patients with
active cancer and AF may be challenging and should not
simply rely on the risk prediction scores used in the general
AF population. By contrast, the administration and choice of
anticoagulants should be based on the comprehensive, indi‑
vidualized and periodic evaluation of thromboembolic and
bleeding risk, drug‑drug interactions, patient preferences and
access to therapies.
Correspondence to: Professor Dimitrios Farmakis, Department
of Physiology, University of Cyprus Medical School, Shakolas
Educational Center for Clinical Medicine, Palaios Dromos Lefkosias
Lemesou 215/6, Aglantzia, Nicosia 2029, Cyprus
E‑mail: farmakis.dimitrios@ucy.ac.cy; dimitrios_farmakis@yahoo.com
Key words: cancer, atrial fibrillation, anticoagulation, low molecular
weight heparins, direct oral anticoagulants
Contents
1. Introduction
2. Thrombosis in active cancer: An overview
3. Atrial fibrillation in cancer
4. Anticoagulation strategies for atrial fibrillation in cancer
5. Conclusions
1. Introduction
Cancer‑associated thrombosis (CAT), including venous and
arterial thromboembolic events, is a frequent complication in
cancer that has a significant impact on patients’ morbidity and
mortality and often renders their management challenging (1).
The risk of CAT is increased in patients with active cancer, in
whom the bleeding complications of anticoagulation therapy
may also be frequent (2). Cancer is further associated with
atrial fibrillation (AF) (3). Some cancer patients, particularly
elderly ones, have prevalent AF at the time of cancer diagnosis,
while others will develop AF in the course of the malignancy,
partly because of cancer and its therapy. AF carries per se
a 5‑fold risk of stroke and systemic thromboembolism (4).
Consequently, it has been shown that the coexistence of
AF increases the risk of thromboembolism in patients with
cancer (5).
The present report, derived by a meeting of an inter‑
disciplinary panel of experts held in September 2020 in
Athens, Greece, addresses the issue of anticoagulation for
cancer‑associated AF. Focusing on patients with active
malignancies, the paper describes the difficulties in decision
making that result from the particular features of cancer
patients and the relative paucity of evidence and proposes
an approach to anticoagulation based on the existing data,
where available, the current practice concerning anticoagu‑
lation for cancer‑associated venous thromboembolism and
the limitations of different anticoagulants in the setting of
active cancer.
2
FARMAKIS et al: ATRIAL FIBRILLATION IN ACTIVE CANCER
2. Thrombosis in active cancer: An overview
Active cancer. There is not a widely accepted definition of
active cancer. The term is generally used to describe patients
with recent cancer diagnosis (i.e., within 6 months), those
being currently or having been recently treated with anti‑
cancer therapies and those with metastatic, locally advanced,
recurrent, inoperable or end‑stage disease (6,7). Patients with
active cancer are more prone to disease‑related complica‑
tions, including a high risk of thromboembolic and bleeding
complications (2,6,8). As a result, decision making for antico‑
agulation treatment and prophylaxis in these patients may be
challenging.
Epidemiology. Cancer‑associated thrombosis (CAT) is the
second‑leading cause of death in patients with malignancies,
after cancer progression, accounting for 9% of deaths in a
cohort of 4,466 patients (9). In addition to increased morbidity
and mortality, CAT further affects ongoing anticancer thera‑
pies, escalates patients’ psychological burden and distress and
increases healthcare costs (10‑14).
Cancer‑associated venous thromboembolism (VTE),
including deep vein thrombosis and pulmonary embolism,
represents 30% of all VTE cases, while cancer increases the
age‑ and sex‑adjusted risk of VTE by 5‑fold (9,15,16). VTE, in
turn, confers a 4‑fold risk of death in patients with cancer (17).
Although the term CAT has previously been used to describe
VTE, thromboembolic complications in cancer also arise in
arterial sites, including myocardial infarction, ischemic stroke
and peripheral arterial embolism (18). A new cancer diagnosis
carries a 2‑fold risk of arterial events. In a large dataset of
279,719 pairs of cancer patients and matched controls, the
cumulative incidence of arterial thromboembolism within
6 months from cancer diagnosis was 4.7% compared to
2.2% in controls (19).
Pathophysiology. The pathophysiology of CAT is defined by
the interaction among three main factors, the thrombogenic
effects of cancer, the procoagulant properties of anticancer
treatment and patient‑related factors. More specifically,
cancer cells may directly activate coagulation by the expres‑
sion of tissue factor (TF) and the release of TF‑expressing
microparticles and cancer procoagulant factor (20). At the
same time, cancer may lead to indirect activation of the
coagulation cascade and platelets and inhibition of antico‑
agulant pathways and fibrinolysis through the induction of a
systemic inflammatory reaction (20). The risk of thrombosis
is diverse in different cancer types; pancreatic and stomach
adenocarcinomas are associated with the highest risk, while
haematological malignancies and lung, gynaecological, brain,
renal and bladder cancer also confer an increased risk (21).
Certain anticancer therapies also bear procoagulant properties
resulting from endothelial cell injury or systemic inflam‑
mation (21). Anticancer drugs with increased risk of venous
or arterial thromboembolism include platinum compounds
(cisplatin), anti‑angiogenic agents (e.g., bevacizumab, sunitinib,
pazopanib), BCR‑ABL inhibitors (e.g., nilotinib, ponatinib),
immune modulators (e.g., thalidomide, lenalidomide),
proteasome inhibitors (e.g., carfilzomib), antimetabolites
(e.g., 5‑fluorouracil) and hormonal agents (e.g., tamoxifen and
aromatase inhibitors) (22). Besides specific anticancer agents,
surgery, central venous catheters and supportive therapies
such as blood transfusions and erythropoietin‑stimulating
agents are also associated with increased thromboembolic
risk (21). Patient‑related risk factors for thromboembolism
include female sex, advanced age, obesity, previous history
of arterial or venous thromboembolism, comorbidities such
as infection, renal or pulmonary disease, prolonged bed
rest, poor performance status and hereditary prothrombotic
defects (e.g., factor V Leiden) (23). A number of biomarkers
have further been associated with an increased risk of CAT,
including general haematological or biochemical markers
such as white blood cell and platelet counts and C‑reactive
protein, thrombosis‑related markers such as D‑dimers and
tissue factor (activity or antigen) and adhesion molecules such
as P‑selectin (23). As previously brought out, AF may often be
encountered in patients with active cancer, hence increasing
further the risk of stroke and systemic thromboembolic
events (3). The risk factors for CAT are summarized in Fig. 1.
3. Atrial fibrillation in cancer
Atrial fibrillation (AF). AF is defined as ‘a supraventricular
tachyarrhythmia with uncoordinated atrial electrical activation and consequently ineffective atrial contraction’ (24). The
electrocardiographic characteristics of AF include i) irregu‑
larly irregular R‑R intervals (when atrioventricular conduction
is not impaired); ii) absence of distinct repeating P waves;
iii) irregular atrial activations (24). AF is the most common
sustained arrhythmia posing a significant burden to patients
and healthcare systems worldwide.
Epidemiology. The coexistence of AF and cancer has lately
attracted the attention of clinicians treating patients with
malignancies (3,25). In a large cohort of 833,520 patients from
26 major healthcare systems in US, a new cancer diagnosis
was followed by a 4.4‑fold age‑adjusted risk of incident AF
within the first year (26). The risk ratio fell significantly to
1.22‑1.30 beyond the first year of cancer diagnosis, indicating
a stronger association of AF with active cancer. A particularly
common form of AF in patients with cancer is peri‑operative
AF (3). In a cohort of 13,906 patients undergoing pulmonary
resection for lung cancer, perioperative AF occurred in
12.6% of patients (27). Peri‑operative AF seems to occur more
frequently in patients with advanced age and cancer stage and
coexistence of cardiovascular comorbidities and in association
with prolonged operation and extensive tissue resection (3).
It has further been suggested that there is a reciprocal
relationship between AF and cancer. This is supported by
evidence showing an increased incidence of cancer diagnosis
in patients with prevalent AF of recent onset, indicating that
AF might be a potential marker of occult cancer. In a large
cohort of 269,742 individuals, there was a 5‑fold standardized
risk for cancer within the first 3 months of AF diagnosis (28)
further confirmed by other studies (26,29,30). Although
causality cannot be supported by such epidemiological data,
this reverse relationship stresses at least the common risk
factors that the two entities share, such as ageing, obesity or
smoking, on a background of a systemic low‑level inflamma‑
tion (31). A recent systematic review and meta‑analysis showed
ONCOLOGY LETTERS 23: 124, 2022
3
Figure 1. Risk factors for thrombosis in patients with cancer (content modified from ref. 23).
that bleeding under a direct oral anticoagulants (DOAC), was
associated with 6‑fold risk of cancer detection, while bleeding
under a vitamin K antagonist (VKA) with a 15‑fold risk (32).
Similarly to non‑cancer patients, prevalent or new‑onset AF
increases the risk of thromboembolic events in patients with
a malignancy. In a retrospective cohort of 24,125 patients
with newly diagnosed malignant disease, 2.4% of patients had
prevalent AF at the time of cancer diagnosis, while another
1.8% developed AF after cancer diagnosis; both baseline and
new‑onset AF were associated with a significantly higher inci‑
dence of thromboembolism compared to the absence of AF,
even after adjustment for age, sex and comorbidities (5).
Pathophysiology. Several mechanisms have been proposed
for the pathogenesis of AF in patients with malignancies (33).
Cancer may induce AF directly through the invasion of the
heart by primary or metastatic cardiac tumours or tumours
of adjacent or remote organs. More commonly, cancer may
indirectly cause AF through a series of potential mechanisms
such as fluid imbalance, hypoxia, electrolyte and metabolic
abnormalities, infection, anaemia, autonomic nervous system
dysregulation and paraneoplastic manifestations.
Anticancer drugs and other supportive therapies have
further been associated with AF. An analysis of the World
Health Organization’s pharmacovigilance database VigiBase
identified a long list of systemic anticancer therapies associ‑
ated with AF including alkylating agents (e.g., cisplatin,
dacarbazine), anthracyclines (e.g., doxorubicin, idarubicin,
daunorubicin), antimetabolites (e.g., gemcitabine, clofara‑
bine), taxanes (e.g., docetaxel), bruton kinase inhibitors
(e.g., ibrutinib), BCR‑Abl inhibitors (e.g., nilotinib, ponatinib),
proteasome inhibitors (e.g., bortezomib), immune checkpoint
inhibitors (e.g., ipilimumab), immunomodulatory agents
(e.g., aldesleukin, pomalidomide, lenalidomide), monoclonal
antibodies (e.g., rituximab) and androgen deprivation agents
(e.g., abiraterone) (34,35). Anticancer drug‑induced AF may
manifest during or shorty (within 24 h) after drug adminis‑
tration, as in the case of cisplatin or gemcitabine, or develop
several days or even months later, as, for example, with ibru‑
tinib (36).
In addition, surgery, particularly pulmonary resection or
other extensive operations are often followed by peri‑operative
AF (3).
Besides cancer and anticancer therapies, more importantly,
as previously implied, cancer and AF share common risk
factors that could pave the way simultaneously to the two
conditions.
As in the case of VTE, AF‑associated thrombosis can be
explained by the Virchow’s triad. AF is associated with stasis
due to stagnant blood flow in the atria, wall changes due to
atrial remodelling and endothelial injury, and hypercoagula‑
bility due to the activation of platelets and coagulation factors
and inflammation (33,37). The interaction among cancer,
anticancer therapy and AF is outlined in Fig. 2.
Inflammation seems to be a common denominator
underlying cancer, AF and thrombosis. It seems to play an
important role in tumour survival, proliferation, angiogenesis
and metastasis (38). As previously stated, inflammation is
believed to be involved in CAT (39,40), while there is evidence
for a pathogenic role of blood coagulation in tumour growth
and metastasis (41,42). An intrinsic pathway of inflamma‑
tion (driven in tumour cells), as well as an extrinsic pathway
4
FARMAKIS et al: ATRIAL FIBRILLATION IN ACTIVE CANCER
Figure 2. The complex interplay among cancer, anticancer therapy and AF. Cancer and its therapy may lead to AF. At the same time, cancer and AF share
common risk factors, including aging, cardiometabolic comorbidities such as hypertension, diabetes mellitus and obesity, and genetic predisposition. All the
above, cancer, anticancer therapy, AF and their common patient‑related risk factors, are predisposing factors for thromboembolic complications including
stroke. AF, atrial fibrillation.
(in tumour‑infiltrating leukocytes) both seem to contribute to
tumour progression (43). Inflammation, activated by cardio‑
metabolic risk factors and comorbidities is further believed to
hold a key role in the pathogenesis of atrial disease, a constel‑
lation of structural, electrical and functional atrial changes
that underlies the development of AF (44). The production
of reactive oxygen species (ROS), which are by‑products of
cellular metabolism and oxygen use and have been associated
with an increased risk of cancer development via DNA damage
and genetic destabilization (43,44), seems to be an important
player in the association between inflammation on one hand
and AF and cancer on the other (45). An increase in inflam‑
matory markers such as C‑reactive protein, tumour necrosis
factor‑a and interleukins 2, 6, and 8 has actually been found
in patients with AF (3). Additionally, inflammation can be
both a cause as well as a consequence of VTE. VTE‑induced
inflammation leads to the impaired thrombus recovery and
the increased risk of VTE‑related complications (46). VTE
and AF share many common risk factors, including old age,
obesity, heart failure, and inflammatory states. Moreover, VTE
and more specifically pulmonary embolism (PE) may lead to
AF through right‑sided pressure overload. Epidemiological
studies indicate that AF can be seen as a presenting sign,
during the early phase of PE, or develop later in the course of
recovery from PE (47).
4. Anticoagulation strategies for atrial fibrillation in cancer
The management of AF in patients with malignancies in terms
of rhythm and rate control follows the strategies that apply to
the general AF population, taking under consideration cancer
prognosis and the potential interactions of cardioactive medi‑
cations with anticancer agents and supportive therapies (4).
Challenges. There are important challenges in decision
making regarding anticoagulation therapy for stroke and
systemic embolism prevention in AF patients with malignan‑
cies. Patients with AF and active cancer may have a higher
thrombotic risk compared to those with AF due to specific
cancer histology and location and specific anticancer therapies,
as previously noticed. On the other hand, patients with active
cancer may also have a higher risk of bleeding, also associ‑
ated with cancer or anticancer therapies (2,8,48). Patients with
increased risk of bleeding include those with intracranial
tumours, gastrointestinal or genitourinary cancer or haema‑
tological malignancies, and those having thrombocytopenia
either due to bone marrow invasion or due to myelotoxicity
from systemic anticancer therapy or irradiation. In a prospec‑
tive cohort study on 2,288 patients with AF treated with DOAC,
the risk of both thromboembolic events and major bleeding
was 4‑fold higher in patients with active cancer compared to
those without cancer or those with non‑active cancer [adjusted
hazard ration (HR) of thromboembolism, 4.03 (1.35‑12.03);
adjusted HR for major bleeding, 3.87, 95% CI, 2.16‑6.94)].
It has been previously highlighted that patients with
prevalent AF may have an increased probability of being diag‑
nosed with cancer, particularly during the first months of AF
diagnosis. Furthermore, because of advancing age and accu‑
mulation of other comorbid conditions, the incidence of cancer
is steadily increasing with time after AF diagnosis. In a Danish
population cohort of 55,100 individuals, up to one fourth of
individuals who developed AF were subsequently diagnosed
ONCOLOGY LETTERS 23: 124, 2022
with cancer over a 12‑year period following AF diagnosis (29).
In these patients, the decision to continue or modify their
previous anticoagulation regimen before the initiation of anti‑
cancer therapy and during the active phase of cancer may pose
an additional challenge.
Scores that are widely recommended and used for the
prediction of thromboembolic or haemorrhagic risk in the
general AF population have not been sufficiently validated
in patients with cancer, including the CHA 2DS2VASc score
(Congestive heart failure, Hypertension, Age ≥75 years,
Diabetes mellitus, prior Stroke or transient ischemic attack
or thromboembolism, Vascular disease, Age 65-74, Sex
category). Similarly, the HAS‑BLED score (Hypertension,
Abnormal renal or liver function, Stroke, Bleeding history or
predisposition, Labile INR, Elderly, Drugs or alcohol), used
for the estimation of bleeding risk in the general AF popula‑
tion, seems to underestimate this risk in patients with AF and
concomitant cancer, according to a large cohort study (49).
At the same time, anticoagulants may interact with anti‑
cancer medications and other supportive therapies prescribed
in patients with cancer that may either attenuate or intensify the
anticoagulant effect, thus increasing the risk of thromboem‑
bolic or bleeding complications, respectively (50). Drug‑drug
interactions (DDI) are a growing concern in patients with
cancer (51). It has been reported that at least 46% of cancer
patients were exposed to at least one DDI (52); 84% of these
DDIs were associated with a deterioration of patients’ status
and required treatment while 14% were even life‑threatening
or exposed patients to permanent damage. The risk of DDI is
even more pronounced in elderly patients (53). On the other
hand, among 115,362 patients with AF or VTE who were
newly prescribed DOACs, one third of patients presented one
potential DDI and 12.6% had at least 2 DDIs (54); patients
with bleeding had an 85% higher occurrence of DDIs when
compared to those without. It appears that a regular assess‑
ment of potential DDI should be implemented, and therapies
need to be adequately adjusted.
Finally, cancer patients are often elderly and fragile indi‑
viduals, suffering from additional conditions and receiving
additional medications. Frailty, comorbidities and polyphar‑
macy may impair drug tolerance and safety and complicate
DDI. As previously spotlighted, AF may be prevalent at the
time of cancer diagnosis and these patients may have already
been prescribed a certain anticoagulation regimen that might
not be appropriate for a given cancer type or anticancer therapy
plan (29).
In this context, oncology clinicians need to monitor the
anticoagulant effect and make dose adjustments. Though,
clinical studies are conducted with a fixed dose of DOACs and
do not assess clinical outcomes based on DDI or coagulation
assays. Therefore, no evidence based recommendation for
drug concentration measurements, coagulation tests, assay
standardization, or target therapeutic ranges has been clearly
established for DOAC (55).
According to an international questionnaire‑based survey
addressing the concerns and prescribing preferences of
960 cardiologists regarding AF in cancer, the most important
limitations in the prescription of anticoagulants for stroke and
systemic embolism prevention included the lack of dedicated
clinical trials (34%), DDI with anticancer agents (32%) and the
5
need to monitor the anticoagulant effect and make dose adjust‑
ments (19%) (56). In accordance to these findings, there seems
to be a gap in the treatment of AF in cancer patients, with
low usage of thromboembolic therapy that is not prescribed
in 44% of patients despite a high thromboembolic risk and an
acceptable bleeding risk (57).
Advantages and disadvantages of available anticoagulants
Vitamin K antagonists. Vitamin K antagonists [VKA] bear
many disadvantages in the setting of cancer. They have
multiple interactions with numerous anticancer agents (58)
and a narrow therapeutic window with a low likelihood to
achieve optimal TTR due to gastrointestinal complication
such as vomiting, malnutrition and hepatic dysfunction (59).
In a study of patients with prevalent AF and newly diagnosed
cancer, there was no benefit from VKA therapy mainly due
to suboptimal INR control, as only 12% of patients were in
optimal INR range (60). VKA has also been associated with a
6‑fold higher risk of bleeding in patients with cancer compared
to those without (61). These drugs are also difficult to handle
peri‑operatively. However, VKA remain the only anticoagu‑
lants currently indicated for valvular AF, including patients
with moderate or severe mitral valve stenosis and those with
mechanical valve prosthesis (4).
Low molecular weight heparins. Low molecular weight
heparins [LMWH] have long been the preferred agents for
the primary and secondary prevention of VTE in patients
with cancer and there is considerable accumulated experi‑
ence with their use in this setting (62,63). LMWH further
lack notable interactions with anticancer drugs and they are
administered parenterally and therefore their absorption is not
affected by gastrointestinal complications such as vomiting.
It has also been suggested that LMWH may bear anti‑tumour
properties, including anti‑proliferative, anti‑angiogenic and
anti‑metastatic actions along with favourable effects on cellular
adhesion, epithelial‑mesenchymal transition [EMT], extracel‑
lular matrix heparinase and metalloproteinases, cancer‑drug
resistance and tumour micro‑environment (64‑66). The poten‑
tial anti‑inflammatory effects of LMWH may also be relevant,
given the key pathogenetic role of inflammation in cancer,
AF and thrombosis (67). These additional properties may be
related to the survival advantage associated with LMWH in
cancer patients without thromboembolic events in a small
clinical study (68).
There is no clear evidence on the effectiveness of LMWH in
stroke or systemic embolism prevention in AF, although these
drugs are often used as alternatives to oral anticoagulants in AF
patients in different settings including peri‑procedural bridging
and transoesophageal echocardiography‑guided cardiover‑
sion (69‑71). The parenteral route of administration may impair
patients’ compliance, although evidence suggests that LMWH
are acceptable by patients in the context of cancer (72).
Direct oral anticoagulants. Direct oral anticoagulants [DOAC]
are currently indicated as first‑line agents for stroke or systemic
embolism prevention in the general AF population (4). DOAC
have a lower risk of intracranial bleeding compared to VKA,
while there is also the possibility of a reversal agent, currently
for dabigatran and soon for the rest of DOAC. In patients with
6
FARMAKIS et al: ATRIAL FIBRILLATION IN ACTIVE CANCER
cancer, recent evidence from randomized controlled trials
have shown that DOAC are viable alternatives to LMWH for
VTE with a higher efficacy in preventing VTE recurrence but
with worse safety in terms of bleeding complications (73‑77).
Concerning AF in cancer, evidence derived by secondary
analyses of randomized trials or observational studies shows
that DOAC, and more specifically rivaroxaban, apixaban and
edoxaban, seem to have preserved efficacy and safety over
VKA for stroke and systemic embolism prevention in patients
with AF and cancer (78‑82). In addition, two meta‑analyses
including the above secondary analyses along with observa‑
tional retrospective studies have further advocated for better
outcomes in terms of thromboembolic and bleeding risks
with DOAC vs. VKA in patients with AF and cancer (83,84).
However, patients with cancer, particularly those with an active
malignancy, were considerably underrepresented in these
trials. In ROCKET‑AF that assessed the efficacy and safety
of rivaroxaban vs. warfarin in AF, any history of cancer was
present in 4.5% of patients, while metastatic cancer was present
in less than 0.1% of cases (78). Similarly, in ARISTOTLE on
apixaban, 6.6% of patients enrolled had a history of cancer,
while only 0.7% had an active malignancy (79). Finally, in
ENGAGE‑AF on edoxaban, patients with cancer were gener‑
ally excluded, yet a 5.5% of the study population developed
active cancer in the course of the trial after a variable time
period from study onset (80). Furthermore, cancer populations
across studies included in the meta‑analyses were heteroge‑
neous, which might have led to uncontrolled confounding.
All four licensed DOAC are substrates for P‑glycoprotein
and therefore should be avoided with drugs that are potent
inhibitors or inducers of P‑glycoprotein (50). In addition,
rivaroxaban and apixaban are also metabolized by cytochrome
P450 (CYP3A4) and should be used with extreme caution with
other inducers or inhibitors of CYP3A4 (85). DOAC may
therefore have significant interactions with anticancer agents,
other supportive therapies prescribed in patients with cancer,
but also food, herbs and over‑the‑counter [OTC] drugs. In a
recent report, 33% of patients receiving apixaban had at least
one OTC product with potentially serious apixaban interac‑
tions daily or most of the days (86). The different DOAC have
variable degrees of renal clearance and their activity can be
affected in patients with cancer and chronic kidney disease
or worsening renal function (44). Due to their oral route of
administration, DOAC have an unpredictable absorption in the
case of gastrointestinal complications such as vomiting.
Current practice and recommendations. The available
guidelines, position statements or other documents on anti‑
coagulation for AF in cancer recommend the use of general
scores such as CHA2DS2VASc and HAS‑BLED (hypertension,
abnormal renal or liver function, stroke, bleeding, labile inter‑
national normalized ratio, elderly, drugs or alcohol) (3,87,88).
In addition to these scores, it is, however, reinforced that
supplementary parameters should be taken under consid‑
eration, mainly for safety reasons, such as platelet count or
tumour location (3,87,88).
Patients with cancer are often elderly with multiple
comorbidities and therefore are classified as individuals with
increased risk of thromboembolism by the general predic‑
tion scores. In a recent retrospective analysis on 472 cancer
patients with AF or atrial flutter, the mean CHA 2DS2‑VASc
was 2.8 (89); 44% did not receive anticoagulation, despite
the fact that only 18% had platelet counts 60 ms from baseline) in clinical trials.42 The
HDAC inhibitors romidepsin, panobinostat, and
vorinostat are also associated with substantial
QT prolongation.41 Finally, hormonal therapies,
such as selective estrogen receptor modifying
(SERM) agents and androgen deprivation therapy,
have been shown to have QT-prolonging effects.43
The clinical relevance of QTc prolongation has
yet to be specifically determined for many cancer
therapeutics. In one retrospective study of 113 patients treated with ATO, only 1 patient developed
torsade’s de pointes (in the setting of marked hypokalemia and hypomagnesemia) despite 65%
having a Bazett corrected QT interval of greater
than 500 ms.39 Nevertheless, there is still need
for caution when initiating these medications or
adjusting their dose. Frequent ECG monitoring is
a mainstay of safe administration, along with careful monitoring and repletion of electrolytes. During
induction chemotherapy, many patients require
the use of antiemetics and antibiotics, and careful
attention should be made in selecting agents that
do not further lengthen the QT interval. There is a
largely additive, if not synergistic effect, of
combining QT-prolonging agents as part of a
chemotherapy regimen.24,44 Adjustment and or
cessation of noncancer agents with QTprolonging potential should be prioritized over
altering the cancer treatment. Should TdP
develop, prompt administration of magnesium sulfate is essential. In addition, the heart rate should
be maintained at greater than 100 bpm with either
isoproterenol or transvenous pacing.45
Ventricular Arrhythmias
Most cases of VT/VF in cancer are directly attributed to the physiologic burden of the disease itself,
as VT/VF are more common in patients with widely
metastatic disease. Metastasis to the heart itself,
although rare, has also been implicated in the
development of VAs.46 Ventricular arrhythmias in
the setting of cancer treatment are most
commonly due to QT-prolonging effects as discussed above, or secondary to another primary
cardiotoxicity (such as ischemia or LV dysfunction), though the BTK inhibitor ibrutinib likely has
a direct arrhythmogenic effect with ventricular arrhythmias identified rare yet lethal side effect of
this class of drugs.47–49 The arrhythmogenic complications of antimetabolites such as 5-fluorouracil
can be readily ascribed to ischemia from vasospasm,50,51 while anthracyclines and anti-HER2targeted therapies such as trastuzumab are known
to induce cardiomyopathies from which ventricular
arrhythmias can sometimes arise. Myocarditis is
estimated to occur in 1.14% of all patients
receiving immune checkpoint inhibitor therapy,
with greater prevalence among anti-CTLA4 therapies over anti-PD1/PDL1. Ventricular arrhythmias
frequently occur in the setting of fulminant
disease.52
There are few studies that have specifically
addressed the management of ventricular arrhythmias due to chemotherapy. Current guidelines are
more general, recommending implantable
cardioverter-defibrillator in patients with LVEF
less than 35% refractory to guideline-directed
medical therapy, NYHA class II–III symptoms,
and life expectancy great
