CLINICAL RESEARCH
Europace (2014) 16, 631–638
doi:10.1093/europace/eut333
Atrial fibrillation
Atrial fibrillation patients do not benefit from
acetylsalicylic acid
Sara Själander 1*, Anders Själander 1, Peter J. Svensson 2, and Leif Friberg 3
1
Department of Public Health and Clinical Medicine, Umeå University, S-90185 Umeå, Sweden; 2Department for Coagulation Disorders, University of Lund, S-20502 Malmö, Sweden; and
Karolinska Institute and Department of Cardiology, Danderyd University Hospital, S-18288 Stockholm, Sweden
3
Received 25 June 2013; accepted after revision 24 September 2013; online publish-ahead-of-print 24 October 2013
Aims
Oral anticoagulation is the recommended treatment for stroke prevention in patients with atrial fibrillation. Notwithstanding, many patients are treated with acetylsalicylic acid (ASA) as monotherapy. Our objective was to investigate if
atrial fibrillation patients benefit from ASA as monotherapy for stroke prevention.
.....................................................................................................................................................................................
Methods
Retrospective study of patients with a clinical diagnosis of atrial fibrillation between 1 July 2005 and 1 January 2009 in the
and results
National Swedish Patient register, matched with data from the National Prescribed Drugs register. Endpoints were ischaemic stroke, thrombo-embolic event, intracranial haemorrhage, and major bleeding. The study population consisted
of 115 185 patients with atrial fibrillation, of whom 58 671 were treated with ASA as monotherapy and 56 514 were
without any antithrombotic treatment at baseline. Mean follow-up was 1.5 years. Treatment with ASA was associated
with higher risk of ischaemic stroke and thrombo-embolic events compared with no antithrombotic treatment.
.....................................................................................................................................................................................
Conclusion
Acetylsalicylic acid as monotherapy in stroke prevention of atrial fibrillation has no discernable protective effect against
stroke, and may even increase the risk of ischaemic stroke in elderly patients. Thus, our data support the new European
guidelines recommendation that ASA as monotherapy should not be used as stroke prevention in atrial fibrillation.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Stroke † Acetylsalicylic acid
Introduction
Methods
Atrial fibrillation (AF) is the most common of all cardiac arrhythmias,
and a major cause of stroke.1,2 Oral anticoagulation is the recom-
In Sweden, every individual has a unique civic registration number, of
which the first six digits denote the date of birth and the ninth digit
denotes the sex of the individual. This number is constant throughout
life and is used in all contacts with the healthcare system. Therefore,
Swedish registers makes it possible to follow individual patients contacts
with the healthcare system, as well as purchases of medication at pharmacies over the years, even if the patient moves out of the region. Access to
information in these registers is strictly regulated to prevent infringement
on individuals personal integrity and personal identities are substituted
for anonymous numbers before access for research is granted. The
present study was approved by the ethical committee of Karolinska Institute (EPN 2008/433-32).
We identified 182 678 patients diagnosed with AF or atrial flutter,
either paroxysmal, persistent, or permanent, between 1 July 2005 and
1 January 2009 in Sweden by means of the National Swedish Patient register. The Patient register has been operating with complete national
coverage since 1987 and contains detailed information about hospital
admissions and open clinic visits, primary and secondary diagnoses
according to the International Classification of Disease, 10th edition
mended prophylactic treatment for most patients on the grounds
that it confers a 64% reduction in stroke risk,3 while acetylsalicylic
acid (ASA) has been an option for low-risk patients or for patients
who cannot take oral anticoagulants. However, the net benefit of
ASA has been questioned in recent years, since the absolute benefit
of oral anticoagulation has been shown to increase, and the benefit
of antiplatelet agents appears to decrease with increasing age.4 At
the same time, the rate of serious bleeding is equal between patients
receiving oral anticoagulation and antiplatelet agents in the elderly
(.80 years of age).4 In clinical practice, however, ASA is still widely
used and often so by the patients who are at the highest risk of
stroke; elderly patients and patients with many stroke risk factors.
The aims of this study were to assess the prevalence and net clinical
benefit of ASA as monotherapy for stroke prevention of AF.
* Corresponding author. Department of Internal Medicine, Sundsvall Hospital, SE-85643 Sundsvall, Sweden. Tel: +46 60 181000; fax: +46 60 181718. E-mail: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected].
632
What’s new?
† Oral anticoagulation is the recommended prophylactic treatment for most patients with atrial fibrillation.
† In clinical practice, acetylsalicylic acid (ASA) is still widely used
for these patients.
† Ischaemic stroke was even more common among patients
with ASA, than among those without antithrombotic treatment of any kind.
† Our results suggests that patients with atrial fibrillation, who
are not suitable for oral anticoagulation may benefit more
from abstaining from ASA, than from using it.
S. Själander et al.
When using HAS-BLED, score points were given for hypertension, renal
failure, liver disease, previous severe bleeding, anaemia, platelet or coagulation defect, age ≥65, alcohol index, and the use of antiplatelet agents
(ASA, clopidogrel, ticlodipine, and low-molecular-weight heparins). We
had no information about usage of non-steroidal anti-inflammatory
drugs, which are often used intermittently and does not necessarily need
a prescription to be collected. Since INR values were unknown, no
points could be given for labile INRs.
Table 1 Definitions of endpoints and comorbidities
by ICD-10 codes
Diagnosis
ICD-10 code
Ischaemic strokea
I63
Stroke, unspecifieda
TIA
I64
G45
Peripheral systemic embolisma
I74
Thrombo-embolic eventa
Pulmonary embolism
I63-64, G45, I74
I26
Intracranial bleedinga
I60-62
Gastric/duodenal bleedinga
Any severe bleedinga
K25-28 (subcodes 0,2,4,6 only)
I60-62, I85.0, I98.3, K25-28
(subcodes 0,2,4,6 only),
K62.5, K92.2, D62.9
Anaemiaa
D50-64
Platelet or coagulation defecta
Myocardial infarction
D65-69
I21, I25.2
Ischaemic heart diseasea
I20-25
PCI procedure
CABG procedure
Z95.5 or procedure code
Z95.1 or procedure code
Peripheral arterial diseasea
I70-73
Vascular disease
Heart failurea
I21, I25.2, I70-73
I50
Valvular diseasea
I05-09, I33-39
Pacemaker/ICDa
Z95.0, Z45.0, or procedure
code
Hypertensiona
Diabetes mellitusa
I10-15
E10-14
Obesitya
E65-66
Renal diseasea
N17-19 or code for renal
transplantation or dialysis
Liver diseasea
K70-77 or code for liver
transplantation or resection
Thyroid diseasea
Thyreotoxicosis
E00-07
E05
COPD/emphysemaa
J43-44
Cancer within 3 yearsa
Alcohol abuse (‘Alcohol index’
defined by the National Board of
Health and Welfare)a
Dementiaa
All C-codes
E24.4, F10, G31.2, G62.1, G72.1,
I42.6, K29.2, K70, K86.0,
O35.4, P04.3, Q86.0, T51,
Y90-91, Z50.2, Z71.4
F00-03
Frequent fallsa
W00-19
................................................................................
(ICD-10), as well as codes for surgical procedures. The register was used
to identify patients with AF and to gain information about concurrent illnesses and risk factors, as well as events that occurred during follow-up.
The Patient register has been validated several times, and it has been considered adequate for epidemiological studies by the National Board of
Health and Welfare.5 Information about primary diagnosis is missing in
0.5 – 0.9% of admissions in somatic care.6
Index date was defined as the first episode of AF in a patient after 1 July
2005. For events during follow-up, the first 2 weeks after the index date
were excluded, since transportation between different clinics and hospitals are common. A new occurrence of a diagnosis of ischaemic stroke or
intracranial haemorrhage within the first days of admission is generally
related to the cause of admission and not to a new event. Consequently,
counting of time at risk starts 14 days after index and diagnoses given
during this 2 weeks period have been considered as comorbidities and
not as events during follow-up.
Actual antithrombotic treatment for each patient was obtained
through the Register of Prescribed Drugs. All pharmacies in Sweden
are obliged to report to this register, in which prescribed purchases
are linked to individual patients. Consequently, information about
dates, dosages, and quantities for every prescription dispensed in
Sweden can be obtained. In Sweden, a prescription is needed for purchases of oral anticoagulants as well as antiplatelet agents (including
low-dose ASA). Baseline medication was defined as a drug collected at
a pharmacy between 100 days before and 2 weeks after index date.
The dose of ASA and the INR stability have not been taken into
account in this analysis.
The risk of ischaemic stroke for each patient was assessed by the
CHA2DS2-VASc scheme.7 Bleeding risk was assessed by the
HAS-BLED scheme.8,9 From the Patient register, we obtained information about the diagnoses included in CHA2DS2-VASc and HAS-BLED
as well as diagnoses for complications (thrombo-embolic events and
bleedings). Information about fatal complications was obtained from
the National Cause of Death register.
Endpoints were ischaemic stroke, thrombo-embolic event (ischaemic stroke, unspecified stroke, transient ischaemic attack (TIA), and
systemic embolism), intracranial haemorrhage, and major bleeding
(intracranial haemorrhage, gastrointestinal bleeding, and anaemia secondary to bleeding). Diagnose codes included in the analysis are
shown in Table 1.
The components in CHA2DS2-VASc were defined as a diagnosis of
heart failure, hypertension, age ≥75 at inclusion, diabetes mellitus,
prior ischaemic stroke (ischaemic stroke, unspecified stroke, TIA, systemic emboli), vascular disease (prior myocardial infarction, peripheral
arterial disease), age 65 – 74 years, and female gender.
a
Covariates included in the propensity score matching analysis.
633
AF patients do not benefit from ASA
Statistical methods
Baseline characteristics were presented descriptively and differences
between the groups were tested with t-tests and x 2 test. Annualized incidence of stroke was calculated as events per 100 years at risk, with the
result expressed as percent. Survival was graphically presented with the
Kaplan– Meier method and analysed using univariable and multivariable
Cox regressions. In the multivariable models, we included comorbidities
and medication with known association with stroke, bleeding, or mortality presented in Table 1.
The propensity score for likelihood of treatment with ASA was estimated using logistic regression, in which the treatment assignment was
used as the outcome variable and the covariates as predictors. The covariates used are listed in Table 1. After estimation of the propensity score, we
performed 1 : 1 nearest neighbour matching of the patients treated with
ASA with the patients without antithrombotic treatment. A caliper of
0.2 was defined. Following the matching procedure, we examined
whether or not balance on the covariates had been achieved through
the matching procedure. In this step, we compared the standardized
mean differences of the covariates; balance was defined as standardized
mean differences of the covariates under 0.25 after matching. In the
matched subsample, we compared annualized incidence of all outcome
events between patients treated with ASA and patients without antithrombotic treatment.
P values ,0.05 were considered as significant. Confidence intervals
(CIs) are 95%.
Results
Of 182 678 patients diagnosed with AF, 115 185 filled our inclusion
criteria (treatment with ASA or no antithrombotic treatment). Baseline characteristics are shown in Table 2. In general, patients treated
with ASA were older, had comorbidities to a greater extent, and consequently had higher CHA2DS2-VASc score than patients without
antithrombotic treatment. Of all 182 678 patients with AF or atrial
flutter, 31% did not use any treatment to prevent stroke, 33% were
treated with oral anticoagulation, and 32% were treated with ASA
as monotherapy (Figure 1).
Unadjusted incidence of outcome events
Patients treated with ASA showed no reduction in ischaemic stroke or
thrombo-embolic event, compared with patients without antithrombotic treatment when related to CHA2DS2-VASc score (Figure 2A
and B, Table 3). There was a trend towards a higher incidence of ischaemic stroke and thrombo-embolic events in patients treated with ASA
compared with no antithrombotic treatment. The rates of intracranial
haemorrhage or major bleeding were similar in patients treated with
ASA and patients without antithrombotic therapy when related to
CHA2DS2-VASc score (Figure 2C and D, Table 3).
Ischaemic stroke and thrombo-embolic
events
On multivariate analysis, hypertension, diabetes mellitus, female
gender, prior intracranial haemorrhage, ischaemic stroke, TIA, and
peripheral systemic embolism were associated with an increased
risk of ischaemic stroke and thrombo-embolic events in both the
study groups. In addition, prior severe bleed, peripheral arterial
disease, and vascular disease were also associated with an increased
risk of thrombo-embolic events.
The risk of ischaemic stroke and thrombo-embolic events was
higher among women than among men irrespective of ASA treatment or no treatment. For example, women had 38% higher risk of
ischaemic stroke than men [hazard ratio (HR) 1.38, CI 1.29–1.48]
when treated with ASA and 46% higher risk of ischaemic stroke
than men (HR 1.46, CI 1.35–1.57) when no antithrombotic treatment was given.
Intracranial haemorrhage and major
bleeding
Factors associated with the risk of major bleeding were similar to
those associated with the risk of intracranial haemorrhage. Previous
intracranial haemorrhage and previous severe bleeding were associated with increased risk of a new intracranial haemorrhage or a
new severe bleeding in both treated and untreated patients.
Other factors that showed significant association with increased
risk of major bleeding in both the study groups were prior gastric
or duodenal bleed, anaemia, alcohol abuse, cancer (≤3 years), liver
disease, renal failure, and heart failure.
The risk of intracranial haemorrhage in conjunction with ASA
treatment was lower in women than in men (HR 0.75, CI 0.62–
0.89). The same trend was also seen in the group without antithrombotic treatment, but without statistical significance (HR 0.86, CI
0.71 –1.03). Female gender was associated with lower risk of the endpoint ‘any bleeding’ in patients treated with ASA. There was also a
trend towards lower risk of ‘any bleeding’ in women without antithrombotic treatment, but without statistical significance.
Age stratification
Still after adjustment for cofactors, the risk for ischaemic stroke and
thrombo-embolic events appeared to be higher in patients treated
with ASA compared with patients without antithrombotic treatment
in all age groups (Figure 3A and B). No significant difference in risk for
intracranial haemorrhage or major bleeding was seen between
patients on and off ASA treatment (Figure 3C and D).
Propensity score matching
To make the groups as similar as possible with regard to comorbidities,
we calculated each patients likelihood of receiving ASA treatment
using all available relevant information. In this propensity score matching, 49 447 patients in each study group were successfully matched.
When comparing the matched individuals in the two groups, we
found that treatment with ASA was associated with higher incidence
of stroke and thrombo-embolic events, compared with no antithrombotic treatment. No association was found between ASA treatment
and intracranial or major bleeding events. (Table 4).
Discussion
In this population consisting of 182 678 AF patients, almost one-third
were treated with ASA as monotherapy. According to the new European guideline recommendations from 2012, ASA as monotherapy is
no longer recommended for stroke prevention in AF, with exception
for patients who refuse any form of oral anticoagulation and cannot
tolerate a combination of ASA and clopidogrel.
634
S. Själander et al.
Table 2 Characteristics of the study population at baseline
No treatment (n 5 56 514)
ASA (n 5 58 671)
P
...............................................................................................................................................................................
Age years, mean + SD
80.34 + 10.07
,0.001
Age ,65 years, n (%)
Age 65–74 years, n (%)
11 379 (20.1)
10 584 (18.7)
75.12 + 13.78
5168 (8.8)
8653 (14.7)
,0.001
,0.001
Age ≥75 years, n (%)
34 551 (61.1)
44 850 (76.4)
,0.001
Age ≥80 years, n (%)
Male sex, n (%)
26 060 (46.1)
29 352 (51.9)
36 687 (62.5)
28 021 (47.8)
,0.001
,0.001
Ischaemic stroke, n (%)
4937 (8.7)
7206 (12.3)
,0.001
Unspecified stroke, n (%)
TIA, n (%)
874 (1.5)
2485 (4.4)
1228 (2.1)
3875 (6.6)
,0.001
,0.001
785 (1.4)
713 (1.2)
0.010
Pulmonary embolism, n (%)
Intracranial bleeding, n (%)
Peripheral systemic emboli, n (%)
1543 (2.7)
1427 (2.5)
1078 (1.8)
1242 (2.1)
,0.001
,0.001
Gastric/duodenal bleeding, n (%)
2944 (5.2)
2286 (3.9)
,0.001
Any severe bleeding, n (%)
Anaemia, n (%)
7251 (12.8)
7845 (13.9)
6673 (11.4)
6923 (11.8)
,0.001
,0.001
534 (0.9)
,0.001
Platelet/coagulation defect, n (%)
Myocardial infarction, n (%)
Ischaemic heart disease, n (%)
1200 (2.1)
8087 (14.3)
11 550 (20.4)
13 011 (22.2)
17 864 (30.4)
,0.001
,0.001
PCI procedure, n (%)
1324 (2.3)
2285 (3.9)
,0.001
CABG procedure, n (%)
Peripheral arterial disease, n (%)
1322 (2.3)
2642 (4.7)
1976 (3.4)
3218 (5.5)
,0.001
,0.001
Vascular disease, n (%)
10 729 (19.0)
16 229 (27.7)
,0.001
Heart failure, n (%)
Valvular disease, n (%)
18 536 (32.8)
2173 (3.8)
21 184 (36.1)
1218 (2.1)
,0.001
,0.001
Pacemaker or ICD, n (%)
4345 (7.7)
4187 (7.1)
,0.001
Hypertension, n (%)
Diabetes mellitus, n (%)
21 038 (37.2)
9019 (16.0)
27 211 (46.4)
11 217 (19.1)
,0.001
,0.001
Renal failure, n (%)
3639 (6.4)
3583 (6.1)
0.024
Liver disease, n (%)
Thyroid disease, n (%)
1038 (1.8)
3481 (6.2)
599 (1.0)
3919 (6.7)
,0.001
,0.001
710 (1.3)
565 (1.0)
,0.001
4789 (8.5)
7253 (12.8)
4705 (8.0)
5802 (9.9)
0.007
,0.001
Thyreotoxicosis, n (%)
COPD/emphysema, n (%)
Cancer ≤3 years, n (%)
Alcohol abuse, n (%)
2038 (3.6)
1469 (2.5)
,0.001
Dementia, n (%)
Frequent falls, n (%)
2595 (4.6)
4937 (8.7)
4214 (7.2)
5599 (9.5)
,0.001
,0.001
CHA2DS2-VASc score, mean + SD
3.33 + 1.95
4.00 + 1.76
,0.001
CHADS2 score, mean + SD
HAS-BLED score, mean + SD
1.87 + 1.45
1.92 + 1.19
2.30 + 1.40
2.92 + 0.98
,0.001
,0.001
5168 (9.1)
5783 (10.2)
1416 (2.4)
3134 (5.3)
,0.001
,0.001
CHA2DS2-VASc score
0p, n (%)
1p, n (%)
2p, n (%)
8077 (14.3)
6829 (11.6)
,0.001
3p, n (%)
4p, n (%)
11 059 (19.6)
10 752 (19.0)
11 458 (19.5)
13 293 (22.7)
0.880
,0.001
5p, n (%)
7768 (13.7)
10 638 (18.1)
,0.001
6p, n (%)
7p, n (%)
4835 (8.6)
2172 (3.8)
7205 (12.3)
3365 (5.7)
,0.001
,0.001
8p, n (%)
900 (1.6)
1333 (2.3)
,0.001
635
AF patients do not benefit from ASA
ASA
ASA and clopidogrel
31%
32%
Clopidogrel
Warfarin
Warfarin combination (with
7%
ASA and/or clopidogrel
3%
26%
1%
No antithrombotic
treatment
Figure 1 Proportion of patients in different treatment strategies (N ¼ 182 678).
A
C 1.8%
18%
1.6%
16%
1.4%
14%
1.2%
12%
1.0%
10%
0.8%
8%
0.6%
6%
0.4%
4%
0.2%
2%
0%
0
1
2
3
4
5
6
7
8
CHA2DS2-VASc
B
0.0%
0
1
2
3
4
0
1
2
3
4
5
6
7
CHA2DS2-VASc
8
D 8%
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
7%
6%
5%
4%
3%
2%
1%
0
1
2
3
4
5
6
7
8
CHA2DS2-VASc
0%
5
6
7
8
CHA2DS2-VASc
Figure 2 Annualized incidence of ischaemic stroke (A), thrombo-embolic event (B), intracranial haemorrhage (C), and major bleeding (D) in relation to CHA2DS2-VASc score. Blue line represents no antithrombotic treatment, red line represents treatment with ASA. Broken lines are 95% CI.
Treatment with ASA was not associated with fewer ischaemic
strokes or thrombo-embolic events than if no prophylactic treatment
was given. On the contrary, ASA treatment was associated with more
ischaemic strokes and thrombo-embolic events than if no antithrombotic treatment was given. This was true for most age groups and
CHA2DS2-VASc strata. The higher risk associated with ASA
636
Table 3 Unadjusted and adjusted incidence and HR for outcome events in patients with and without ASA treatment
Endpoint
Events per 100 years at risk (95% CI)
Univariable
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HR (95% CI)
ASA (n 5 58 671)
No ASA
(n 5 56 514)
Multivariable adjustment for
....................................................................................................................................
Age and sex
HR (95% CI)
CHA2DS2-VASc
HAS-BLED
Full model HR
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (95% CI)
By score sum
HR (95% CI)
By cofactors
HR (95% CI)
By score sum
HR (95% CI)
By cofactors
HR (95% CI)
.............................................................................................................................................................................................................................................
Ischaemia
Stroke
Thromboembolism
Bleeding
Intracranial
5.28 (5.12 –5.45)
3.58 (3.45 –3.71)
1.68 (1.62– 1.75)
1.34 (1.29 –1.40)
1.46 (1.40– 1.52)
1.43 (1.37– 1.49)
1.15 (1.11– 1.20)
1.44 (1.39– 1.51)
1.45 (1.39– 1.51)
7.51 (7.31 –7.71)
5.13 (4.97 –5.28)
1.61 (1.56– 1.67)
1.29 (1.24 –1.33)
1.40 (1.35– 1.45)
1.38 (1.33– 1.43)
1.11 (1.07– 1.15)
1.39 (1.34– 1.44)
1.40 (1.35– 1.45)
0.65 (0.60 –0.72)
0.56 (0.51 –0.61)
1.08 (0.97– 1.20)
0.96 (0.86 –1.07)
1.01 (0.91– 1.12)
0.99 (0.89– 1.10)
0.80 (0.72– 0.90)
0.98 (0.88– 1.09)
1.00 (0.90– 1.11)
Any bleeding
Combined endpoint
2.69 (2.58 –2.81)
2.32 (2.22 –2.43)
1.21 (1.15– 1.28)
1.01 (0.95 –1.07)
1.11 (1.05– 1.17)
1.08 (1.02– 1.14)
0.88 (0.83– 0.93)
1.05 (1.00– 1.11)
1.07 (1.01– 1.13)
Ischaemic stroke,
intracranial
bleeding, or death
Death
30.48 (30.09–30.88)
25.89 (25.55–26.24)
1.54 (1.52– 1.57)
1.11 (1.09 –1.13)
1.36 (1.33– 1.38)
1.30 (1.27– 1.32)
1.16 (1.14– 1.18)
1.28 (1.26– 1.30)
1.25 (1.23– 1.27)
26.63 (26.27–27.00)
23.09 (22.77–23.41)
1.53 (1.51– 1.56)
1.08 (1.06 –1.10)
1.35 (1.32– 1.37)
1.28 (1.26– 1.30)
1.17 (1.14– 1.19)
1.26 (1.24– 1.28)
1.23 (1.21– 1.26)
S. Själander et al.
637
AF patients do not benefit from ASA
A
C 2
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
51–60
61–70
71–80
81–90
91–100
0
Age
B
51–60
61–70
71–80
81–90
91–100
51–60
61–70
71–80
81–90
91–100
Age
D
1.8
1.8
1.6
1.6
1.4
1.4
1.2
1.2
1
1
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0
51–60
61–70
71–80
81–90
91–100
Age
0
Age
Figure 3 Hazard ratio for ischaemic stroke (A), thrombo-embolic event (B), intracranial haemorrhage (C), and major bleeding (D) in patients
treated with ASA compared with patients without antithrombotic treatment in relation to age (adjusted for all comorbidities presented in Table 1).
Table 4 Annualized incidence (95% CI) of outcome events in relation to treatement strategy, according to propensity
score matching
ASA
No antithrombotic treatment
P
...............................................................................................................................................................................
7.37% (7.11– 7.63)
6.61% (6.37–6.86)
,0.001
Thrombo-embolic event
10.60% (10.29–10.92)
9.53% (9.24–9.83)
,0.001
Intracranial haemorrhage
Major bleeding
0.95% (0.87– 1.05)
3.85% (3.67– 4.03)
1.00% (0.91–1.10)
4.06% (3.87–4.25)
0.46
0.12
Ischaemic stroke
treatment compared with no treatment remained after adjustment
for comorbidities and propensity score matching.
The use of ASA for stroke prophylaxis in AF was founded on
seven placebo-controlled studies performed from 1989 to
2006.3,10 – 16 Of these, there was just one that showed a statistically
significant, but modest protective effect.11 A meta-analysis based
on these seven trials showed that there was a 22% (CI 6– 35%)
relative risk reduction with ASA compared with placebo.3
However, the reduction mainly concerned TIAs and minor
strokes. When only ‘disabling strokes’ were counted,10,11,13,14
the protective effect was reduced to a barely clinically relevant
13% (CI 218 –36%). The latest trial performed in 2006 was terminated early since ASA was unlikely to reach superiority compared
with no treatment. The effect of ASA was insignificantly negative
regarding cardiovascular death, symptomatic ischaemic stroke,
and TIA.
Recently, data from 12 placebo-controlled studies in the Atrial Fibrillation Investigators database, were reanalysed with the objective to
determine the effect of age on the relative efficacy of oral anticoagulants
and ASA.4 This study showed that efficacy of ASA for protection against
AF-related ischaemic stroke decreased with age and that the protective
effect was none by the age of 75 and became insignificantly negative
638
above that age. Considering that the mean age of the Swedish AF population is 76 years, our findings, although they may seem provocative, are
actually in line with the findings in the placebo-controlled trials that
once formed the basis for treatment for a majority of all AF patients.
Not only does ASA appear to be almost worthless for protection
of ischaemic stroke, it has side effects in the form of increased bleeding risk. A meta-analysis has shown an association between treatment
with ASA and increased incidence of gastrointestinal bleedings, major
bleedings, and intracranial bleedings.17 In this study, we could not
confirm any association between ASA treatment and an increased incidence of bleeding events.
Our study confirms previous observations that women have
higher risk for AF-related stroke than men.7 We also could confirm
findings of lower bleeding risk among women, than among
men.18,19 Since women with AF have higher risk of stroke than
men, and lower risk of bleeding, women may possibly benefit more
from oral anticoagulation treatment than men.
Our results suggest that patients with AF, who are not suitable for
oral anticoagulation, may benefit more from abstaining from ASA,
than from using it.
Limitations
The patients in our study had not been randomized to either receive
ASA or to have no prophylactic treatment at all. In spite of our efforts
to adjust cofactors by means of propensity score matching and multivariable regression, we admit that it is unlikely that we have succeeded in adjusting for everything that may have affected the
outcome. A randomized placebo-controlled study that could give
an unambiguous answer to this very important question will
however never be conducted given the proven efficacy of oral anticoagulants for patients with risk of AF-related stroke.
Use of registry data has limitations since it is dependent on the accuracy of diagnose registration. Validation studies of the Patient register have shown that most diagnoses have a high positive-predictive
value.6 The extent of under diagnosis is not known, and would
require population screening to be determined. It is likely that
some comorbidities have not received a diagnostic code in the registers. Therefore, patients may have received lower risk scores than
they should have had if all circumstances were known.
Since age is not a continuous variable in age stratification as well as
in risk score systems, and since patients treated with ASA in general
are older than patients not on antithrombotic treatment, patients
treated with ASA are expected to be older inside each age strata.
Consequently, age stratification and stratification according to risk
score systems cannot completely compensate for age differences
between the two different treatment strategies. However, the
results were similar after propensity score matching where age was
used as a continuous variable.
Conclusion
Acetylsalicylic acid as monotherapy in stroke prevention of AF has no
discernable protective effect against stroke, and may even increase
the risk of ischaemic stroke in elderly patients. Thus, our data
support the new European guidelines recommendation that ASA
as monotherapy should not be used as stroke prevention in AF
unless there is no alternative.20
S. Själander et al.
Conflict of interest: none declared.
Funding sources
This work was supported by Department of Public Health and Clinical Medicine, Umeå University and the Department of Research and
Development, County Council of Vasternorrland (LVNFOU216571
to A.S. and LVNFOU260131 to S.S.).
References
1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for
stroke: the Framingham Study. Stroke 1991;22:983–8.
2. Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of
antithrombotic therapy. Circulation 1991;84:469 –81.
3. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent
stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;
146:857 – 67.
4. van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD et al. Effect of age
on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation
investigators. Stroke 2009;40:1410 –6.
5. Serdén L. Kodningskvalitet i patientregistret—slutenvård 2008 (available in Swedish
only; Validity of the National Hospital Discharge Registry in Sweden). June 2010.
Avaliable online at http://www.socialstyrelsen.se/publikationer2010/2010-6-27.
6. Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C et al. External review and validation of the Swedish national inpatient register. BMC Public Health
2011;11:450.
7. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification
for predicting stroke and thromboembolism in atrial fibrillation using a novel risk
factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest 2010;
137:263 – 72.
8. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly
score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093 – 100.
9. Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score
for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the
HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding
History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly)
score. J Am Coll Cardiol 2011;57:173 –80.
10. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebocontrolled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK
study. Lancet 1989;1:175 –9.
11. No authors listed. Stroke prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527 –39.
12. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention on
non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
Lancet 1993;342:1255 –62.
13. Diener HC, Lowenthal A. Antiplatelet therapy to prevent stroke: risk of brain hemorrhage and efficacy in atrial fibrillation. J Neurol Sci 1997;153:112.
14. Posada IS, Barriales V. Alternate-day dosing of aspirin in atrial fibrillation. LASAF Pilot
Study Group. Am Heart J 1999;138(Pt 1):137 –43.
15. Benavente O, Hart R, Koudstaal P, Laupacis A, McBride R. Antiplatelet therapy for
preventing stroke in patients with atrial fibrillation and no previous history of
stroke or transient ischemic attacks. Cochrane Database Syst Rev 2000;(2):CD001925.
16. Sato H, Ishikawa K, Kitabatake A, Ogawa S, Maruyama Y, Yokota Y et al. Low-dose
aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan
atrial fibrillation stroke trial. Stroke 2006;37:447 –51.
17. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of
low-dose aspirin and clopidogrel in randomized controlled trials. Am J Med 2006;
119:624 – 38.
18. Poli D, Antonucci E, Testa S, Ageno W, Palareti G; on the behalf of FCSA (Italian Federation of Anticoagulation Clinics). Gender differences of bleeding and stroke risk in
very old atrial fibrillation patients on VKA treatment: results of the EPICA study on
the behalf of FCSA (Italian Federation of Anticoagulation Clinics). Thromb Res 2013;
131:12 –6.
19. Fang MC, Singer DE, Chang Y, Hylek EM, Henault LE, Jensvold NG et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation,
the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation
2005;112:1687 –91.
20. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH et al. 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. Europace
2012;14:1385 –413.