CLINICAL RESEARCH
Europace (2014) 16, 631–638 doi:10.1093/europace/eut333
Atrial fibrillation
Atrial fibrillation patients do not benefit from acetylsalicylic acid Sara Sja¨lander 1*, Anders Sja¨lander 1, Peter J. Svensson 2, and Leif Friberg 3 1
Department of Public Health and Clinical Medicine, Umea˚ University, S-90185 Umea˚, Sweden; 2Department for Coagulation Disorders, University of Lund, S-20502 Malmo¨, 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
----------------------------------------------------------------------------------------------------------------------------------------------------------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].
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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.
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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. Sja¨lander 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
................................................................................
a
Covariates included in the propensity score matching analysis.
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(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.
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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%.
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.
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.
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Results
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.
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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
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
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PCI procedure, n (%)
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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).
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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
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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
Multivariable adjustment for
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HR (95% CI)
ASA (n 5 58 671)
....................................................................................................................................
No ASA (n 5 56 514)
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
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. Sja¨lander et al.
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Intracranial
5.28 (5.12 –5.45)
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
1.6
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
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1.8
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
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
Conflict of interest: none declared.
Funding sources This work was supported by Department of Public Health and Clinical Medicine, Umea˚ 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. Serde´n L. Kodningskvalitet i patientregistret—slutenva˚rd 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.
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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.
S. Sja¨lander et al.
Europace (2014) 16, 631–638 doi:10.1093/europace/eut333
Atrial fibrillation
Atrial fibrillation patients do not benefit from acetylsalicylic acid Sara Sja¨lander 1*, Anders Sja¨lander 1, Peter J. Svensson 2, and Leif Friberg 3 1
Department of Public Health and Clinical Medicine, Umea˚ University, S-90185 Umea˚, Sweden; 2Department for Coagulation Disorders, University of Lund, S-20502 Malmo¨, 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
----------------------------------------------------------------------------------------------------------------------------------------------------------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].
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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.
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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. Sja¨lander 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
................................................................................
a
Covariates included in the propensity score matching analysis.
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(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.
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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%.
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.
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.
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Results
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.
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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
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
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PCI procedure, n (%)
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).
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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
Multivariable adjustment for
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HR (95% CI)
ASA (n 5 58 671)
....................................................................................................................................
No ASA (n 5 56 514)
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
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. Sja¨lander et al.
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Intracranial
5.28 (5.12 –5.45)
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
1.6
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
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1.8
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
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
Conflict of interest: none declared.
Funding sources This work was supported by Department of Public Health and Clinical Medicine, Umea˚ University and the Department of Research and Development, County Council of Vasternorrland (LVNFOU216571 to A.S. and LVNFOU260131 to S.S.).
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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.
S. Sja¨lander et al.
