Keywords
atrial fibrillation - stroke prevention - cancer
Introduction
Patients with cancer have increased risk of bleeding, which can be a problem when
considering oral anticoagulants (OACs) for stroke prevention in patients with atrial
fibrillation (AF).[1] Current AF guidelines do not specifically address OAC treatment among cancer patients[2]
[3]; however, previous studies indicate that cancer patients with AF benefit from being
treated with OACs.[4]
[5]
The main goal with OAC treatment in patients with AF is to prevent ischemic stroke,
balancing the increased risk of bleedings, especially intracranial, which has high
mortality and the potential to cause impairment of function and life quality, as well
as rising health and social care costs.[6]
[7]
In a previous study of AF patients, we found net cerebrovascular benefit (defined
as reduced risk of ischemic stroke as well as intracranial bleeding) with OAC treatment
compared with no OAC treatment among both cancer and noncancer patients analyzed separately.
In the present study, our aim was to study how active cancer influences the net cerebrovascular
benefit and bleedings after initiation of OAC treatment in patients with AF.
Methods
Study Design and Data Source
In this retrospective cohort study, cross-linking Swedish health registers, all individuals
with a diagnosis of AF between January 1, 2006 and December 31, 2017 were identified
from the National Swedish Patient Register. Patients aged <18 or >100 years and patients
with an absolute indication for OAC due to diagnosis of mitral stenosis or mechanical
heart valve were excluded.
Registers
The National Swedish Patient Register has shown positive predictive values for AF
and stroke of 97 and 88%, respectively, and of 85 to 95% for other diagnoses including
bleedings.[8]
[9]
[10]
[11] The Cancer Register is prospective, has a completeness of 96%, and holds information
on, e.g., tumor site.[12] The Drug Register provides information on all dispensed prescription drugs in Sweden
since 2005.[13] The Cause of Death Register contains details about all deaths which have occurred
in the country, and its completeness is high.[14]
Definitions
AF-related OAC initiation was defined by the first dispensing of OAC adjacent to the
first registered AF diagnosis during the study period: at the earliest 6 months before
the AF diagnosis and at the latest December 30, 2017. OACs were subgrouped into warfarin
(the only registered vitamin K antagonist in Sweden) and nonvitamin K OACs (NOACs).
Information on drug dispensation was collected from the Drug Register. Treatment was
defined as at least one dispensed OAC prescription.
Information on comorbidity at OAC initiation was collected from the Patient Register
using information from 1997 onwards, when the International Classification of Diseases
10th Revision was implemented in Sweden ([Supplementary Table S1], available online only).
Patients with cancer were restricted to those with active cancer defined as a new
cancer diagnosis other than basalioma registered within 1 year prior to OAC initiation
in either the Patient or the Cancer Register, not preceded by any cancer diagnoses
during the 5 years before OAC initiation. Noncancer patients were defined as individuals
without any cancer diagnosis in the previous 5 years. The presence of alcohol-related
disease was assessed with a composite of codes used by the Swedish Board of Health
and Welfare for estimating alcohol-related deaths. The stroke risk score CHA2DS2-VASc[15] was used without counting points for female sex, and the bleeding risk score HAS-BLED[16] without counting points for labile prothrombin time or international normalized
ratio.
Time at risk was calculated as within 1 year from OAC initiation to first event of
interest, emigration, death, or end of follow-up (December 31, 2017). The composite
endpoint cerebrovascular events comprised ischemic stroke and intracranial bleedings.
Bleeding was defined as an admission to a hospital with a major or nonmajor clinically
relevant bleeding diagnosis as described in [Supplementary Table S1], available online only. For ischemic strokes, only the primary or secondary diagnosis
code position was considered, whereas for bleedings, any position was considered.[11]
Statistical Methods
Descriptive data are presented as means or proportions. Differences between groups
are described with standardized differences, and incidence rates as events per 100
patient-years.
In multivariable Cox regression analyses, we included heart failure, hypertension,
age, diabetes, the composite prior ischemic stroke/transient ischemic attack/peripheral
arterial emboli, vascular disease, sex, year of OAC initiation, NOAC (instead of warfarin)
treatment, prior intracerebral bleeding, impaired kidney function, frequent falls,
anemia, prior major bleedings, liver disease, and alcohol-related disease, depending
on the outcome event of interest. All analyses were conducted taking the competing
risk of death before an endpoint event into account: cumulative incidences were estimated
with the Aalen–Johansen nonparametric method,[17] and multivariable subhazard ratios (sHRs) were computed according to the method
of Fine and Gray.[18] Tests were two-sided and used 95% confidence intervals (CIs). p-Values <0.05 and standardized differences >10% were considered significant.
Analyses were performed using Stata version 15.1 (StataCorp, College Station, Texas,
United States).
Ethics
The study conforms to the Declaration of Helsinki and was approved by the regional
ethics committee (EPN 2018/1252–31). Individual patient consent was not required or
obtained.
Results
Patient Characteristics
As presented in [Table 1], the study population of AF patients consisted of 8,228 patients with active cancer
and 323,394 patients without cancer, all of whom had been started on OAC treatment.
The proportions of warfarin and NOAC users did not differ significantly between cancer
and noncancer patients. Cancer patients were more often male, older, and had higher
CHA2DS2-VASc and HAS-BLED scores. They also more often had a history of anemia, gastrointestinal
bleedings, and venous thromboembolism. The most common cancer type was urological
cancer, followed by gastrointestinal, hematological, breast, lung, gynecological,
and intracranial cancers.
Table 1
Patients with atrial fibrillation, cancer versus noncancer: baseline data at OAC initiation
|
At OAC initiation
|
|
Cancer
|
Noncancer
|
Standardized difference
|
|
N (%)
|
8,228 (2.5%)
|
323,394 (97.5%)
|
|
|
Female
|
36.5%
|
43.3%
|
0.139
|
|
Age (mean)
|
75.1
|
73.1
|
−0.211
|
|
Age distribution
|
|
< 65 y
|
10.3%
|
19.5%
|
0.266
|
|
65–74 y
|
35.3%
|
32.1%
|
|
|
75–84 y
|
41.6%
|
35.5%
|
|
|
> 84 years
|
12.7%
|
12.9%
|
|
|
Year of OAC initiation
|
|
2005–2011
|
46.6%
|
52.8%
|
0.123
|
|
2012–2017
|
53.4%
|
47.2%
|
|
|
Risk scores at OAC initiation
|
|
CHADS2-VASc (mean)
|
3.0
|
2.8
|
−0.129
|
|
Low (0 points)
|
3.9%
|
8.5%
|
−0.211
|
|
Intermediate (1 point)
|
14.3%
|
16.0%
|
|
|
High (2–8 points)
|
81.9%
|
75.5%
|
|
|
HAS-BLED (mean)
|
2.3
|
2.0
|
0.188
|
|
Low (0–1 points)
|
28.2%
|
36.4%
|
0.189
|
|
Intermediate (2 points)
|
30.7%
|
29.6%
|
|
|
High (3–5 points)
|
40.7%
|
33.6%
|
|
|
Very high (>5 points)
|
0.5%
|
0.3%
|
|
|
Comorbidity at OAC initiation
|
|
Heart failure
|
24.0%
|
22.7%
|
0.031
|
|
Hypertension
|
55.3%
|
49.7%
|
0.113
|
|
Ischemic heart disease
|
26.4%
|
26.5%
|
0.003
|
|
Prior PCI
|
7.8%
|
7.9%
|
0.005
|
|
Diabetes
|
17.2%
|
15.6%
|
0.042
|
|
Impaired kidney function
|
5.4%
|
3.6%
|
0.086
|
|
End renal stage/dialysis
|
0.4%
|
0.3%
|
0.018
|
|
Prior ischemic stroke
|
11.9%
|
13.0%
|
0.033
|
|
Prior TIA
|
6.0%
|
6.5%
|
0.020
|
|
Prior intracerebral bleeding
|
0.6%
|
0.6%
|
0.001
|
|
Prior anemia
|
17.6%
|
8.0%
|
0.290
|
|
Prior major bleed
|
7.0%
|
4.9%
|
0.089
|
|
Prior GI bleed
|
6.7%
|
4.2%
|
0.108
|
|
COPD
|
7.9%
|
5.9%
|
0.081
|
|
Dementia
|
1.2%
|
1.3%
|
0.015
|
|
Frequent faller
|
3.3%
|
3.5%
|
0.007
|
|
Alcohol-related disease
|
2.3%
|
2.4%
|
0.005
|
|
Obesity
|
3.8%
|
3.6%
|
0.014
|
|
Thyroid disease
|
6.7%
|
6.3%
|
0.014
|
|
Liver disease
|
1.6%
|
1.0%
|
0.052
|
|
Venous thromboembolism < 6 mo
|
9.6%
|
4.3%
|
0.211
|
|
Platelet or coagulation disorders
|
1.9%
|
1.0%
|
0.074
|
|
Antithrombotic medication at OAC initiation
|
|
NOAC
|
30.4%
|
26.8%
|
0.079
|
|
Previous platelet inhibitor
|
37.3%
|
39.3%
|
0.041
|
|
Cancer site
|
|
Gastrointestinal
|
19.1%
|
|
|
|
Pancreatic
|
1.0%
|
|
|
|
Lung
|
6.8%
|
|
|
|
Breast
|
9.1%
|
|
|
|
Gynecological
|
4.9%
|
|
|
|
Urological
|
35.6%
|
|
|
|
Prostate
|
27.2%
|
|
|
|
Intracranial
|
1.3%
|
|
|
|
Hematological
|
10.7%
|
|
|
|
Other
|
14.4%
|
|
|
|
Metastasized[a]
|
9.2%
|
|
|
|
Previous cancer treatment at OAC initiation
|
|
Chemotherapy in hospital
|
3.0%
|
|
|
|
Antitumoral drugs dispensed
|
13.5%
|
|
|
|
Radiotherapy
|
5.1%
|
|
|
Abbreviations: COPD, chronic obstructive pulmonary disease; GI, gastrointestinal;
NOAC, nonvitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; PCI, percutaneous
coronary intervention; TIA, transient ischemic attack.
a Missing data on cancer stage: 43.1%. Standardized difference >10% in bold.
Outcomes
During 1 year after OAC initiation and 308,505 contributed patient-years, 7,299 patients,
of whom 2.8% had active cancer, suffered either an ischemic stroke or an intracranial
bleeding. A total of 14,167 patients (4.8% with cancer) had bleedings, of which 25.8%
were gastrointestinal, and 16.0% intracranial ([Supplementary Table S2], available online only). The death rate was more than doubled in cancer patients,
with 11.66 deaths per 100 patient-years (CI: 10.90–12.46), compared with noncancer
patients (4.74 per 100 patient-years, CI: 4.66–4.81).
Cerebrovascular Events
The cumulative incidences of patients with cerebrovascular events within the first
year after OAC initiation were comparable between cancer patients (2.7%, CI: 2.3–3.0%)
and noncancer patients (2.3%, CI: 2.2–2.3%) ([Fig. 1]).
Fig. 1 OAC-treated patients with atrial fibrillation, cancer versus noncancer patients:
unadjusted cumulative incidences of cerebrovascular events and all bleedings during
first year after OAC initiation, accounting for the competing risk of death. OAC,
oral anticoagulant.
Active cancer was not associated with a statistically significant higher risk for
cerebrovascular events. Subgroup analyses showed higher risks only for patients with
intracranial cancer and breast cancer ([Fig. 2]). Breast cancer was, however, not associated with increased risk for ischemic stroke
compared with no cancer (sHR: 1.30, CI: 0.81–2.09).
Fig. 2 Adjusted risks for cerebrovascular events during the year following OAC initiation
in patients with AF: cancer versus noncancer patients, accounting for the competing
risk of death. AF, atrial fibrillation; OAC, oral anticoagulant.
Predictors of Cerebrovascular Events
In addition to higher age, the composite prior ischemic stroke/transient ischemic
attack/peripheral arterial emboli (sHR: 2.26, CI: 2.15–2.37) and prior intracerebral
bleeding (sHR: 2.11, CI: 1.77–2.52) were the cofactors which showed the strongest
associations with future cerebrovascular events among all studied patients. Other
predictors were impaired kidney function, diabetes, hypertension, frequent falls,
vascular disease, and more recent year of OAC initiation. Treatment with NOACs instead
of warfarin was associated with a lower risk of cerebrovascular events (sHR: 0.78,
CI: 0.73–0.83) ([Supplementary Table S3]).
Bleedings after OAC Initiation
The cumulative incidence of patients with bleedings after OAC initiation was higher
among cancer patients (8.6%, CI: 8.0–9.2%) than among noncancer patients (4.3%, CI:
4.2–4.4%) ([Fig. 1]). Cancer patients regardless of cancer location had higher risk of bleedings than
noncancer patients ([Fig. 3]). Specifically, gastrointestinal bleedings were more common not only among patients
with gastrointestinal cancer, but also among those with urological and hematological
cancers, compared with noncancer patients. The overall increased risk for intracranial
bleedings among cancer patients compared with noncancer patients was driven by individuals
with intracranial or breast cancer ([Supplementary Table S7], available online only).
Fig. 3 Adjusted risks for all bleedings during the year following OAC initiation in patients
with AF: cancer versus noncancer patients, accounting for the competing risk of death.
AF, atrial fibrillation; OAC, oral anticoagulant.
Despite the higher risk of bleedings, active cancer was not associated with fatal
hospital-treated bleedings overall (sHR: 1.17, CI: 0.80–1.70), neither with fatal
intracranial bleedings (sHR: 1.13, CI: 0.71–1.82), accounting for the competing risk
of death owing to other causes.
Besides active cancer, other factors independently associated with bleedings after
OAC initiation were anemia, alcohol-related disease, prior major bleedings, liver
disease, and heart failure. Others were shared with the primary outcome of cerebrovascular
events; higher age, impaired kidney function, frequent falls, vascular disease, hypertension,
diabetes, prior ischemic stroke/transient ischemic attack/peripheral arterial emboli,
and later year of OAC initiation were associated with increased risk; NOAC treatment
was associated with lower risk regarding all studied bleeding endpoints than warfarin
([Supplementary Tables S3–S6], available online only). Exclusion of patients with CHA2DS2-VASc score 0 did not change results.
Discussion
We have previously shown that AF patients both with and without cancer benefit from
OACs, compared with no treatment.[4] In the present study, again using nationwide register data covering all individuals
with AF and cancer, we aimed to compare OAC-treated AF patients with and without cancer.
Related to our previous observations, the main finding was that the net cerebrovascular
benefit was similar among patients with and without active cancer although the overall
bleeding risk was higher among those with cancer.
Cancer patients had a higher comorbidity burden, including cardiovascular and bleeding
risk factors, and additionally doubled mortality. After adjustment for cofactors,
and for the competing risk of death, our analyses showed that the risk for cerebrovascular
events was similar for patients with and without cancer. Patients with brain tumors
did not appear to benefit from OAC owing to higher risk for intracranial bleedings.
A similar lack of net benefit was found for patients with breast cancer. The reason
for this is unclear, but may be due to an increased propensity for bleeding brought
about by an interaction between vitamin K antagonists and selective estrogen receptor
modulators used to inhibit tumor growth[19] or generally more intense antitumoral treatment which we could not adjust for. In
previous studies of OAC-treated AF patients with breast cancer, the bleeding risk
did not differ compared with OAC-treated AF patients without cancer.[20]
[21] However, in contrast to these studies, we recorded more events and studied only
active cancers, making direct comparisons with these studies difficult.
Patients with gastrointestinal, urological, and hematological cancers had an increased
risk for gastrointestinal bleedings. Several cancer types have been previously described
as prone to gastrointestinal bleedings when treated with anticoagulants, mostly due
to local barrier disruption of the gastrointestinal tract, thrombocytopenia, and invasive
procedures or treatments,[22] and our data thus corroborate these findings.
Our findings are largely consistent with the posthoc analyses of the ENGAGE AF-TIMI
48 trial on OAC-treated patients with AF, in which cancer was not associated with
all-cause stroke, but with major bleedings.[23] In the posthoc analyses of the of ROCKET AF trial, results were overall similar,
with the exception that the bleeding risk of cancer patients was not seen for the
specific endpoints: increased bleedings in critical organs and bleedings requiring
blood transfusions.[24] This discrepancy in results may be attributed to the relatively low number of outcome
events, the exclusion of patients with a life expectancy under 2 years, and less precise
definitions of active cancer than in the present study which includes patients who
are often not regarded eligible for drug trials.
Regardless of cancer status, NOAC use instead of warfarin use appeared to be safer
regarding all studied endpoints. The greater safety for NOACs over warfarin regarding
intracranial bleedings is in line with a large meta-analysis by Cavallari et al, including
the posthoc studies mentioned.[5]
Our study has several limitations. First, selection bias could be introduced since
patients eligible for OAC treatment are likely to be healthier and have longer life
expectancy than patients not offered OAC treatment, but also because hospital-based
data tend to select toward individuals with heavier comorbidity. The proportion of
cancer patients with metastases or antitumoral treatment was rather low, indicating
that patients included in the present study had a possibly better prognosis than the
total population of cancer patients with AF. Due to high proportions of missing data
on cancer stage, and lacking validation of the registration of antitumoral treatment,
these factors were not used in the analyses. This could introduce both treatment bias
and missed associations between drug–drug interactions and outcome events. However,
we assumed a greater impact of cancer type than stage, and by making all comparisons
between patients eligible for OAC treatment, the effects of confounding by indication
were minimized.
The main goal with OAC treatment in patients with AF is to prevent ischemic stroke,
which has high mortality and the potential to cause impairment of function and life
quality as well as rising health and social care costs, balancing the increased risk
of bleedings, especially intracranial.[6]
[7]
Third, as some of the analyses were conducted for every subgroup, this resulted in
fewer events and the risk of low power to detect significant differences. However,
a statistically significant increased risk of cerebrovascular events was seen among
patients with intracranial cancer, which constituted the smallest of the subgroups
studied.
Fourth, restricting follow-up time could influence generalizability beyond 1 year
of OAC treatment. On the other hand, it minimizes possible bias introduced by an intention-to-treat-like
approach which could underestimate associations with treatment due to crossover, and
diverging prognoses over time among individuals with cancer.
Fifth, although we found that active cancer was associated with an increased risk
for hospital-treated bleedings in general, no association was seen with fatal bleedings,
with the reservation that an underestimation of fatal bleedings could occur since
only hospital-associated events were studied.
Finally, being an observational study without randomization or individual assessment
of endpoints, we can only report associations and do not claim that our findings represent
causal relationships. However, this nationwide real-world register-based data add
important information to the still developing field of OAC treatment among AF patients
with cancer.
Conclusion
Related to our previous findings, this study shows that among AF patients started
on OAC treatment, no significant difference in net cerebrovascular benefit was found
between noncancer patients and cancer patients, except for those with intracranial
or breast cancer. Awaiting interventional studies with special focus on AF patients
with cancer, our study supports current AF guidelines on OAC treatment originally
aimed for the general AF population. As to the risk of all bleedings including intracranial
bleedings, NOACs seem to be a safer alternative than warfarin.
What Is Known about This Topic?
-
Current guidelines on atrial fibrillation do not address stroke prevention with oral
anticoagulants in the presence of active cancer. Increased risk of bleeding among
cancer patients makes clinical decisions about oral anticoagulants challenging.
-
Atrial fibrillation patients with cancer benefit from oral anticoagulant treatment
with reduced risk of ischemic stroke and lower mortality compared with no treatment.
What Does This Paper Add?
-
In this nationwide cohort study of all patients with atrial fibrillation (2006–2017),
patients with active cancer appeared to have similar net cerebrovascular benefit of
oral anticoagulants to patients without cancer, despite an increased overall risk
of nonfatal bleedings.
-
In the setting of atrial fibrillation, nonvitamin K antagonists seem to be a safer
alternative than warfarin regardless of cancer status.
