Atrial Fibrillation Patients Do Not Benefit From Acetylsalicylic Acid

Sara Själander; Anders Själander; Peter J. Svensson; Leif Friberg

Europace. 2014;16(5):631-638. 

Abstract and Introduction

Abstract

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 and Results Retrospective study of patients with a clinical diagnosis of atrial fibrillation between 1 July 2005 and 1 January 2009 in the 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.

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 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 (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.  Definitions of endpoints and comorbidities by ICD-10 codes

Diagnosis ICD-10 code
Ischaemic strokea I63
Stroke, unspecifieda I64
TIA G45
Peripheral systemic embolisma I74
Thrombo-embolic eventa I63–64, G45, I74
Pulmonary embolism I26
Intracranial bleedinga I60–62
Gastric/duodenal bleedinga K25–28 (subcodes 0,2,4,6 only)
Any severe bleedinga 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 D65–69
Myocardial infarction I21, I25.2
Ischaemic heart diseasea I20–25
PCI procedure Z95.5 or procedure code
CABG procedure Z95.1 or procedure code
Peripheral arterial diseasea I70–73
Vascular disease I21, I25.2, I70–73
Heart failurea I50
Valvular diseasea I05–09, I33–39
Pacemaker/ICDa Z95.0, Z45.0, or procedure code
Hypertensiona I10–15
Diabetes mellitusa 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 E00–07
Thyreotoxicosis E05
COPD/emphysemaa J43–44
Cancer within 3 yearsa All C-codes
Alcohol abuse ('Alcohol index' defined by the National Board of Health and Welfare)a 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
Dementiaa F00–03
Frequent fallsa W00–19

aCovariates included in the propensity score matching analysis

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.

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.

Statistical Methods

Baseline characteristics were presented descriptively and differences between the groups were tested with t-tests and χ 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.  Definitions of endpoints and comorbidities by ICD-10 codes

Diagnosis ICD-10 code
Ischaemic strokea I63
Stroke, unspecifieda I64
TIA G45
Peripheral systemic embolisma I74
Thrombo-embolic eventa I63–64, G45, I74
Pulmonary embolism I26
Intracranial bleedinga I60–62
Gastric/duodenal bleedinga K25–28 (subcodes 0,2,4,6 only)
Any severe bleedinga 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 D65–69
Myocardial infarction I21, I25.2
Ischaemic heart diseasea I20–25
PCI procedure Z95.5 or procedure code
CABG procedure Z95.1 or procedure code
Peripheral arterial diseasea I70–73
Vascular disease I21, I25.2, I70–73
Heart failurea I50
Valvular diseasea I05–09, I33–39
Pacemaker/ICDa Z95.0, Z45.0, or procedure code
Hypertensiona I10–15
Diabetes mellitusa 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 E00–07
Thyreotoxicosis E05
COPD/emphysemaa J43–44
Cancer within 3 yearsa All C-codes
Alcohol abuse ('Alcohol index' defined by the National Board of Health and Welfare)a 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
Dementiaa F00–03
Frequent fallsa W00–19

aCovariates included in the propensity score matching analysis

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 . 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.

Table 1.  Definitions of endpoints and comorbidities by ICD-10 codes

Diagnosis ICD-10 code
Ischaemic strokea I63
Stroke, unspecifieda I64
TIA G45
Peripheral systemic embolisma I74
Thrombo-embolic eventa I63–64, G45, I74
Pulmonary embolism I26
Intracranial bleedinga I60–62
Gastric/duodenal bleedinga K25–28 (subcodes 0,2,4,6 only)
Any severe bleedinga 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 D65–69
Myocardial infarction I21, I25.2
Ischaemic heart diseasea I20–25
PCI procedure Z95.5 or procedure code
CABG procedure Z95.1 or procedure code
Peripheral arterial diseasea I70–73
Vascular disease I21, I25.2, I70–73
Heart failurea I50
Valvular diseasea I05–09, I33–39
Pacemaker/ICDa Z95.0, Z45.0, or procedure code
Hypertensiona I10–15
Diabetes mellitusa 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 E00–07
Thyreotoxicosis E05
COPD/emphysemaa J43–44
Cancer within 3 yearsa All C-codes
Alcohol abuse ('Alcohol index' defined by the National Board of Health and Welfare)a 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
Dementiaa F00–03
Frequent fallsa W00–19

aCovariates included in the propensity score matching analysis

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 . 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).

Table 2.  Characteristics of the study population at baseline

  No treatment (n = 56 514) ASA (n = 58 671) P
Age years, mean ± SD 75.12 ± 13.78 80.34 ± 10.07 <0.001
Age <65 years, n (%) 11 379 (20.1) 5168 (8.8) <0.001
Age 65–74 years, n (%) 10 584 (18.7) 8653 (14.7) <0.001
Age ≥75 years, n (%) 34 551 (61.1) 44 850 (76.4) <0.001
Age ≥80 years, n (%) 26 060 (46.1) 36 687 (62.5) <0.001
Male sex, n (%) 29 352 (51.9) 28 021 (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) 0.010
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) 13 011 (22.2) <0.001
Ischaemic heart disease, n (%) 11 550 (20.4) 17 864 (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 (%) 10 729 (19.0) 16 229 (27.7) <0.001
Heart failure, n (%) 18 536 (32.8) 21 184 (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 (%) 21 038 (37.2) 27 211 (46.4) <0.001
Diabetes mellitus, n (%) 9019 (16.0) 11 217 (19.1) <0.001
Renal failure, n (%) 3639 (6.4) 3583 (6.1) 0.024
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) 0.007
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
CHA2DS2-VASc score, mean ± SD 3.33 ± 1.95 4.00 ± 1.76 <0.001
CHADS2 score, mean ± SD 1.87 ± 1.45 2.30 ± 1.40 <0.001
HAS-BLED score, mean ± SD 1.92 ± 1.19 2.92 ± 0.98 <0.001
CHA2DS2-VASc score
   0p, n (%) 5168 (9.1) 1416 (2.4) <0.001
   1p, n (%) 5783 (10.2) 3134 (5.3) <0.001
   2p, n (%) 8077 (14.3) 6829 (11.6) <0.001
   3p, n (%) 11 059 (19.6) 11 458 (19.5) 0.880
   4p, n (%) 10 752 (19.0) 13 293 (22.7) <0.001
   5p, n (%) 7768 (13.7) 10 638 (18.1) <0.001
   6p, n (%) 4835 (8.6) 7205 (12.3) <0.001
   7p, n (%) 2172 (3.8) 3365 (5.7) <0.001
   8p, n (%) 900 (1.6) 1333 (2.3) <0.001

Figure 1.

 

Proportion of patients in different treatment strategies (N = 182 678).

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, ). 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.  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) Multivariable adjustment for
ASA (n = 58 671) No ASA (n = 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 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)
   Thromboembolism 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)
Bleeding
   Intracranial 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 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)
Combined endpoint
   Ischaemic stroke, intracranial bleeding, or 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)
Death 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)

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) Multivariable adjustment for
ASA (n = 58 671) No ASA (n = 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 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)
   Thromboembolism 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)
Bleeding
   Intracranial 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 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)
Combined endpoint
   Ischaemic stroke, intracranial bleeding, or 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)
Death 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)

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.

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).

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).

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.  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% (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 0.95% (0.87–1.05) 1.00% (0.91–1.10) 0.46
Major bleeding 3.85% (3.67–4.03) 4.06% (3.87–4.25) 0.12

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.

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 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 −18–36%). 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 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]

Sidebar

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.

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