Atrial fibrillation patients do not benefit from acetylsalicylic acid

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1 Europace (2014) 16, doi: /europace/eut333 CLINICAL RESEARCH 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 Umeå, Sweden; 2 Department for Coagulation Disorders, University of Lund, S Malmö, Sweden; and 3 Karolinska Institute and Department of Cardiology, Danderyd University Hospital, S Stockholm, Sweden 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 patients with atrial fibrillation, of whom were treated with ASA as monotherapy and 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 Atrial fibrillation (AF) is the most common of all cardiac arrhythmias, and a major cause of stroke. 1,2 Oral anticoagulation is the recommended 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. Methods 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 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 * Corresponding author. Department of Internal Medicine, Sundsvall Hospital, SE Sundsvall, Sweden. Tel: ; fax: sara.sjalander@lvn.se Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 632 S. Själander et al. 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. (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 % of admissions in somatic care. 6 Index date was defined as the first episode of AF in a patient after 1 July 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 CHA 2 DS 2 -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 CHA 2 DS 2 -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 CHA 2 DS 2 -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 years, and female gender. 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 stroke a I63 Stroke, unspecified a I64 TIA G45 Peripheral systemic embolism a I74 Thrombo-embolic event a I63-64, G45, I74 Pulmonary embolism I26 Intracranial bleeding a I60-62 Gastric/duodenal bleeding a K25-28 (subcodes 0,2,4,6 only) Any severe bleeding a I60-62, I85.0, I98.3, K25-28 (subcodes 0,2,4,6 only), K62.5, K92.2, D62.9 Anaemia a D50-64 Platelet or coagulation defect a D65-69 Myocardial infarction I21, I25.2 Ischaemic heart disease a I20-25 PCI procedure Z95.5 or procedure code CABG procedure Z95.1 or procedure code Peripheral arterial disease a I70-73 Vascular disease I21, I25.2, I70-73 Heart failure a I50 Valvular disease a I05-09, I33-39 Pacemaker/ICD a Z95.0, Z45.0, or procedure code Hypertension a I10-15 Diabetes mellitus a E10-14 Obesity a E65-66 Renal disease a N17-19 or code for renal transplantation or dialysis Liver disease a K70-77 or code for liver transplantation or resection Thyroid disease a E00-07 Thyreotoxicosis E05 COPD/emphysema a J43-44 Cancer within 3 years a All C-codes Alcohol abuse ( Alcohol index defined by the National Board of Health and Welfare) a Dementia a F00-03 Frequent falls a W00-19 a Covariates included in the propensity score matching analysis. 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

3 AF patients do not benefit from ASA 633 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 andpatients without antithrombotic treatment. P values,0.05 were considered as significant. Confidence intervals (CIs) are 95%. Results Of patients diagnosed with AF, 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 CHA 2 DS 2 -VASc score than patients without antithrombotic treatment. Of all 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 CHA 2 DS 2 -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 CHA 2 DS 2 -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 ] when treated with ASA and 46% higher risk of ischaemic stroke than men (HR 1.46, CI ) 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 ). The same trend was also seen in the group without antithrombotic treatment, but without statistical significance (HR 0.86, CI ). 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, 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 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.

4 634 S. Själander et al. Table 2 Characteristics of the study population at baseline No treatment (n ) ASA (n ) P... Age years, mean + SD ,0.001 Age,65 years, n (%) (20.1) 5168 (8.8),0.001 Age years, n (%) (18.7) 8653 (14.7),0.001 Age 75 years, n (%) (61.1) (76.4),0.001 Age 80 years, n (%) (46.1) (62.5),0.001 Male sex, n (%) (51.9) (47.8),0.001 Ischaemic stroke, n (%) 4937 (8.7) 7206 (12.3),0.001 Unspecified stroke, n (%) 874 (1.5) 1228 (2.1),0.001 TIA, n (%) 2485 (4.4) 3875 (6.6),0.001 Peripheral systemic emboli, n (%) 785 (1.4) 713 (1.2) Pulmonary embolism, n (%) 1543 (2.7) 1078 (1.8),0.001 Intracranial bleeding, n (%) 1427 (2.5) 1242 (2.1),0.001 Gastric/duodenal bleeding, n (%) 2944 (5.2) 2286 (3.9),0.001 Any severe bleeding, n (%) 7251 (12.8) 6673 (11.4),0.001 Anaemia, n (%) 7845 (13.9) 6923 (11.8),0.001 Platelet/coagulation defect, n (%) 1200 (2.1) 534 (0.9),0.001 Myocardial infarction, n (%) 8087 (14.3) (22.2),0.001 Ischaemic heart disease, n (%) (20.4) (30.4),0.001 PCI procedure, n (%) 1324 (2.3) 2285 (3.9),0.001 CABG procedure, n (%) 1322 (2.3) 1976 (3.4),0.001 Peripheral arterial disease, n (%) 2642 (4.7) 3218 (5.5),0.001 Vascular disease, n (%) (19.0) (27.7),0.001 Heart failure, n (%) (32.8) (36.1),0.001 Valvular disease, n (%) 2173 (3.8) 1218 (2.1),0.001 Pacemaker or ICD, n (%) 4345 (7.7) 4187 (7.1),0.001 Hypertension, n (%) (37.2) (46.4),0.001 Diabetes mellitus, n (%) 9019 (16.0) (19.1),0.001 Renal failure, n (%) 3639 (6.4) 3583 (6.1) Liver disease, n (%) 1038 (1.8) 599 (1.0),0.001 Thyroid disease, n (%) 3481 (6.2) 3919 (6.7),0.001 Thyreotoxicosis, n (%) 710 (1.3) 565 (1.0),0.001 COPD/emphysema, n (%) 4789 (8.5) 4705 (8.0) Cancer 3 years, n (%) 7253 (12.8) 5802 (9.9),0.001 Alcohol abuse, n (%) 2038 (3.6) 1469 (2.5),0.001 Dementia, n (%) 2595 (4.6) 4214 (7.2),0.001 Frequent falls, n (%) 4937 (8.7) 5599 (9.5),0.001 CHA 2 DS 2 -VASc score, mean + SD ,0.001 CHADS 2 score, mean + SD ,0.001 HAS-BLED score, mean + SD ,0.001 CHA 2 DS 2 -VASc score 0p, n (%) 5168 (9.1) 1416 (2.4), p, n (%) 5783 (10.2) 3134 (5.3), p, n (%) 8077 (14.3) 6829 (11.6), p, n (%) (19.6) (19.5) p, n (%) (19.0) (22.7), p, n (%) 7768 (13.7) (18.1), p, n (%) 4835 (8.6) 7205 (12.3), p, n (%) 2172 (3.8) 3365 (5.7), p, n (%) 900 (1.6) 1333 (2.3),0.001

5 AF patients do not benefit from ASA 635 ASA 31% 32% ASA and clopidogrel Clopidogrel 7% 26% 3% 1% Figure 1 Proportion of patients in different treatment strategies (N ¼ ). A 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% B 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% CHA 2 DS 2 -VASc CHA 2 DS 2 -VASc C D 1.8% 1.6% 1.4% 1.2% 1.0% 0.8% 0.6% 0.4% 0.2% 0.0% 8% 7% 6% 5% 4% 3% 2% 1% 0% Warfarin Warfarin combination (with ASA and/or clopidogrel No antithrombotic treatment CHA 2 DS 2 -VASc CHA 2 DS 2 -VASc Figure 2 Annualized incidence of ischaemic stroke (A), thrombo-embolic event (B), intracranial haemorrhage (C), and major bleeding (D) in relation to CHA 2 DS 2 -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 eventsthan 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 CHA 2 DS 2 -VASc strata. The higher risk associated with ASA

6 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 ) No ASA Age and sex CHA 2 DS 2 -VASc HAS-BLED Full model HR (n ) HR (95% CI) (95% CI) By score sum By cofactors By score sum By cofactors HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)... Ischaemia Stroke 5.28 ( ) 3.58 ( ) 1.68 ( ) 1.34 ( ) 1.46 ( ) 1.43 ( ) 1.15 ( ) 1.44 ( ) 1.45 ( ) Thromboembolism 7.51 ( ) 5.13 ( ) 1.61 ( ) 1.29 ( ) 1.40 ( ) 1.38 ( ) 1.11 ( ) 1.39 ( ) 1.40 ( ) Bleeding Intracranial 0.65 ( ) 0.56 ( ) 1.08 ( ) 0.96 ( ) 1.01 ( ) 0.99 ( ) 0.80 ( ) 0.98 ( ) 1.00 ( ) Any bleeding 2.69 ( ) 2.32 ( ) 1.21 ( ) 1.01 ( ) 1.11 ( ) 1.08 ( ) 0.88 ( ) 1.05 ( ) 1.07 ( ) Combined endpoint Ischaemic stroke, ( ) ( ) 1.54 ( ) 1.11 ( ) 1.36 ( ) 1.30 ( ) 1.16 ( ) 1.28 ( ) 1.25 ( ) intracranial bleeding, or death Death ( ) ( ) 1.53 ( ) 1.08 ( ) 1.35 ( ) 1.28 ( ) 1.17 ( ) 1.26 ( ) 1.23 ( ) nloaded from by guest on 09 November S. Själander et al.

7 AF patients do not benefit from ASA 637 A B Age Age 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 ,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 C D 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... Ischaemic stroke 7.37% ( ) 6.61% ( ),0.001 Thrombo-embolic event 10.60% ( ) 9.53% ( ),0.001 Intracranial haemorrhage 0.95% ( ) 1.00% ( ) 0.46 Major bleeding 3.85% ( ) 4.06% ( ) 0.12 Age Age 13% (CI %). 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 effectof ageon the relative efficacyof oralanticoagulants and ASA. 4 Thisstudyshowed that efficacyofasaforprotectionagainst AF-related ischaemic stroke decreased with age and that the protective effect was none by the age of 75 and became insignificantly negative

8 638 S. Själander et al. 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 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 (LVNFOU to A.S. and LVNFOU 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: Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991;84: 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: van WalravenC, Hart RG, Connolly S, AustinPC, MantJ, Hobbs FD et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke 2009;40: Serdén L. 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