Anticoagulant Treatment in Patients with Atrial Fibrillation and Ischemic Stroke Nicole Scheldon Brunner Frandsen, MD,* Andreas Dammann Andersen, MD,* Hamoun Ashournia, MD,* Ivan Brandslund, MD, MD,† Jens Ole Kjærsgaard, MD,* and Ole Jakob Vilholm, MD, PhD*

Background: Atrial fibrillation (AF) is the most common cardiac dysrhythmia, with a lifetime risk of 25%, and it is a well-known independent risk factor for ischemic stroke. Over the last 15 years, efforts have been made to initiate relevant treatment in patients with AF. A retrospective study was set up to clarify whether this effort has resulted in a decreased proportion of patients with known AF experiencing an ischemic stroke. Methods: Patients admitted to the Department of Neurology, Vejle Hospital, Denmark, with ischemic stroke from January 1997 to December 2012 were included in the study. Results: A total of 4134 patients were included in the study. Overall, the yearly proportion of patients with known AF varied between 9% and 18%. No significant change was observed (P 5 .511). The proportion of patients with known AF treated with anticoagulants at the time of the stroke and the proportion of newly discovered AF were significantly increasing during the study period (P 5 .002 and P 5 .035, respectively). Subgroup analysis of the patients aged 65-75 years showed similar results. Conclusions: No significant reduction in the proportion of patients admitted with ischemic stroke and AF was observed. An explanation could be an increase in the prevalence of AF in the general population, leaving the proportion of patients admitted with ischemic stroke unchanged. Other risk factors have been sought reduced as well with the implementation of national guidelines regarding hypertension, hypercholesterolemia, and diabetes. Key Words: Atrial fibrillation—warfarin—ischemic stroke—prevention. Ó 2015 by National Stroke Association

The most common form of cardiac dysrhythmia is atrial fibrillation (AF), with a lifetime risk of approximately 25%.1 Key risk factors include congestive heart failure, a history of myocardial infarction, hypertension, valvular

From the *Department of Neurology, Lillebaelt Hospital, Vejle; and †Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. Received December 12, 2014; revision received January 19, 2015; accepted March 15, 2015. The authors declare that they have no conflicts of interest. The authors report that they did not receive any funding. Address correspondence to Ole Jakob Vilholm, MD, PhD, Department of Neurology, Lillebaelt Hospital, Vejle, Denmark. E-mail: ole. [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.03.018

heart disease—especially in women—and increasing age.2,3 The prevalence of AF increases with age4; that alone will result in an increasing number of patients with AF because of the increasing elderly population. AF is a well-known independent risk factor for ischemic stroke, with a fivefold increase in the risk of stroke.5 Several types of thrombus formation caused by AF are known; this includes abnormal blood stasis because of poor atrial contraction. However, other factors such as abnormal changes in blood coagulation and inflammation responses have been recognized as well.6 The estimated percentage of strokes caused by AF is increasing alongside the aging population and is as high as 50% in the 80-90 years age-group.7,8 AF is also a strong risk factor for the recurrence and the severity of stroke compared with patients admitted with ischemic stroke without AF.9-12

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2015: pp 1-6

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Warfarin has been the preferred prophylactic treatment for stroke prevention in patients with AF in Denmark. New anticoagulants have now been introduced, but warfarin is still widely used. Analysis has confirmed the stroke-reducing effect of warfarin compared with aspirin; however, the risk of bleeding is elevated.13-15 In this context, CHAD2DS2-VASc and HAS-BLED are empirically validated assessment tools for deciding what type of treatment is preferred, comparing the calculated statistical benefit from treatment with the risk of severe bleeding.16,17 Over the past 15 years, an increasing effort has been made to initiate treatment with anticoagulants for the prevention of ischemic stroke in patients with AF. National guidelines have been developed, and a specific effort by the Danish Health and Medicines Authority to educate the general practitioners in initiating and controlling anticoagulant treatment has been made. By using the CHA2DS2-VASc and HAS-BLED to ensure that warfarin is given to the right group of patients, the proportion of patients with known AF that experience an ischemic event should be significantly reduced. This study aimed at investigating whether the effort to initiate relevant anticoagulant treatment in patients with AF has led to a significant reduction in the proportion of patients with ischemic stroke who had a known AF on admission to the hospital.

Materials and Methods Data were retrospectively collected from all patients admitted to Vejle Hospital, Denmark, with acute cerebral infarction in the period from January 1, 1997, to December 31, 2012.

Patients were identified through an extraction of diagnoses from Vejle Hospital by searching for the diagnoses of cerebral infarction (ICD-10: I63.0-I63.9) and unspecified stroke (ICD-10: I64.9). Data on patients admitted from January 1, 1997, to April 30, 2005, were collected from the patients’ files. Data from patients admitted from May 1, 2005, to December 31, 2012, were collected from the electronic patient files (EPJ, electronic patient journal). All patient files were examined and age on admission, gender, and formerly diagnosed AF were registered. Newly discovered AF was defined as the presence of AF on the electrocardiogram (ECG) on admission in patients not formerly known to have AF, AF registered during the hospital stay, or AF registered in the journal. Anticoagulant treatment, the presence of AF on an ECG on admission, and the results of the neuroradiological examination (ischemic/hemorrhagic stroke or no stroke) were also registered. All patients with hemorrhagic stroke were excluded from the study (Fig 1). Patients with known chronic AF, but no AF on the admission ECG were categorized as having paroxysmal AF. Statistical analysis was performed using the program R Core Team (2014; R, a language and environment for statistical computing; R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org/). The statistical analysis was performed using a chi-squared test for trend in proportion to determine whether there was a significant change in the proportion of AF in patients with ischemic stroke. The chi-squared test for trend is a weighted linear regression of the proportions of the group scores, where the test is for a zero slope. The test statistic follows the chi-squared distribution with 1 of freedom. The Kruskal–Wallis rank sum test was applied to test for

Figure 1.

Study design.

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Table 1. Demographic and clinical characteristics Characteristic Total number of patients 4134 Women 1,815 (44%) Men 2,319 (56%) Average age on admission 71 y Average age of the patients with AF 78 y Average age of the patients without AF 70 y AF in total 522 Paroxysmal AF 99 Chronic AF 423 Anticoagulant treatment in total 221 Paroxysmal AF 20 Chronic AF 154 Other causes 47 Abbreviation: AF, atrial fibrillation. Values are in total number of patients unless stated otherwise.

Figure 2. Variation in mean age over the 15-year study period. Abbreviation: AF, atrial fibrillation. P values according to the Kruskal–Wallis rank sum test.

difference in mean age, and the test of equal proportions was applied to test for difference in gender.

Results A total of 4413 patients were screened. Of these, 4137 met the inclusion criteria and were included in the study. The mean age on admission was 71 years. The mean age was 78 years in the group with AF and 70 years in the group with no AF (Table 1). During the 15-year registration period, a total of 522 (13%) patients had a known AF on admission, 99 (19%) had paroxysmal AF, and 423 (81%) had chronic AF (Table 1). There were 287 (7%) patients who were not formerly known with AF; they were diagnosed with AF during admission to the hospital. Of these, 143 (50%) were women (Table 2). There was no significant change in the age or gender distribution during the 15-year period (Fig 2, Fig 3).

Overall, the yearly proportion of patients with known AF and an ischemic stroke event varied between 9% and 18%. No significant decreasing or increasing tendency was observed over the 15-year period (P 5 .511; Fig 4). In the group with known AF, a total of 174 (33%) patients were treated with anticoagulants on admission. The yearly proportion of patients with known AF with anticoagulants varied between 12.5% and 56%. The proportion of patients with known AF and in relevant anticoagulant treatment at the time of the ischemic event significantly increased over the period of study (P 5 .002). A total of 287 (7%) patients were diagnosed with a not previously known AF, which significantly increased (P 5 .035; Fig 4). Subgroup analysis of the 65to 75-year-olds showed no statistically significant changes (Fig 5).

Table 2. Overall distribution of known AF and the presence of AF on ECG at admission (N 5 4134) AF on ECG No Women Men Yes Women Men No ECG Women Men Total

No known Chronic Paroxysmal AF (n) AF (n) AF (n) Total (n) 3,133 1313 1820 287 143 144 192 76 116 3612

56 25 31 358 201 157 9 3 6 423

62 30 32 32 21 11 5 3 2 99

3,251 1368 1883 677 365 312 206 82 124 4134

Abbreviations: AF, atrial fibrillation; ECG, electrocardiogram.

Figure 3. Variation in gender over the 15-year study period. Abbreviation: AF, atrial fibrillation. P values according to the test of equal proportions.

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Figure 4.

Proportions in the total population (all patients). Abbreviations: AF, atrial fibrillation; AC, anticoagulant.

Discussion AF is a well-known independent risk factor for stroke and stroke recurrence.5-7,9,11,12 Studies have shown that treatment with anticoagulants significantly reduces the risk of ischemic stroke.13-15 However, in this study, the proportion of patients with AF on admission and ischemic stroke shows no significant reduction (P 5 .511), although the proportion of patients with AF in relevant anticoagulant treatment on admission increased significantly over the 15-year period. The incidence of AF is known to increase with age,4 and it could be suspected that the constancy in the proportion is because of an increase in the proportion of elderly patients in our study. However, a subgroup analysis on the 65- to 75-year old patients showed similar results. There are no data available regarding the prevalence of AF in the general population in the local area during the registration period. If the prevalence of AF was increasing in the general population over the 15-year period, the number of patients with ischemic stroke due to AF would increase as well, although the percentage of patients with AF experiencing an ischemic stroke would decrease. This could explain why the proportion of AF in patients with ischemic stroke remained unchanged in the study. It could be considered whether the constancy of the proportion of AF in ischemic stroke over the past 15 years is in part because of the effort that has been made over the same period to reduce other risk factors such as hypertension, hypercholesterolemia, and diabetes.

Hypertension is a well-established independent risk factor for ischemic stroke,18,19 and efforts have been made over the past years to reduce morbidity caused by hypertension, thereby hopefully decreasing the number of patients admitted to the hospital with ischemic stroke caused by hypertension. Hypertension is however also a known risk factor for the development of AF,2,3,20 thereby probably leaving the proportion of patients with known hypertension constant in the 2 groups in our study. When collecting data from patient files in this study, blood pressure on admission was not registered. Patients with diabetes have a significantly increased risk of stroke compared with nondiabetics, especially younger patients,21,22 and effort has been put forth to optimize the treatment of diabetes, thereby reducing the proportion of diabetic patients admitted with ischemic stroke. However, in this study, we do not know whether there is any difference in the proportion of diabetic patients in the group with AF compared with the larger group without AF. Poorly regulated anticoagulant treatment in our group of patients with chronic or paroxysmal AF could be a contributing factor in our results. Studies have shown that well-regulated anticoagulant treatment significantly reduces the risk of stroke, whereas poorly regulated anticoagulant treatment, indicated by the measurement of an international normalized ratio below 2, shows a marked increase in the risk of ischemic stroke.13,14,23,24 Data on international normalized ratio on admission are not

ANTICOAGULANT TREATMENT IN ATRIAL FIBRILLATION

Figure 5.

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Proportions in the group of patients aged 65-75 years. Abbreviations: AF, atrial fibrillation; AC, anticoagulant.

present in this study. It would be relevant to investigate this further in our group of patients with AF. Age is a nonmodifiable risk factor for the occurrence of ischemic stroke.25 In this study, the median age of the patients in the AF group is higher than the median age of the patients in the group without AF (70 years versus 78 years). Several studies have shown a similar age difference.5,6,25 Patients with AF and stroke are generally older than patients without atrial AF and stroke, and the reason for this may be that the prevalence of AF increases successively with age, resulting in a higher median age.4 A large group of risk factors for ischemic stroke besides AF have been identified, both modifiable risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking and nonmodifiable risk factors such as age, gender, race, and genetics.25 But as is the case of both hypertension and diabetes, we do not know whether there is a marked difference in the presence of these risk factors in the 2 groups in our study. The effects of national guidelines and the focused effort to educate the general practitioners are seen in this study through a significant increase in the number of patients in relevant anticoagulant treatment. However, no significant decrease in the proportion of patients with AF admitted with ischemic stroke was seen. Further studies are needed to confirm the results of this study. Acknowledgments: The authors would like to thank Henry Christensen for statistical support.

References 1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation. The Framingham Heart Study. Circulation 2004;110:1042-1046. 2. Ptasy MB, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455-2461. 3. Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart study. JAMA 1994; 271:840-844. 4. Wilke T, Groth A, Mueller S, et al. Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients. Europace 2013;15:486-493. 5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke. The Framingham Heart Study. Stroke 1991;22:983-988. 6. Watsom T, Shantsila E, Lip GY. Mechanisms of the thrombogenesis in atrial fibrillation: Virchow’s triad revisited. Lancet 2009;373:155-166. 7. Friberg L, Rosenquist M, Lindgren A, et al. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke 2014;45:2599-2605. 8. Bj€ orck S, Palaszewski B, Friberg L, et al. Atrial fibrillation, stroke risk, and warfarin therapy revisited. Stroke 2013; 44:3103-3108. 9. Penado S, Cano M, Acha O, et al. Atrial fibrillation as a risk factor for stroke recurrence. Am J Med 2003; 114:206-210. 10. Kamel H, Johnson DR, Hegde M, et al. Detection of atrial fibrillation after stroke and the risk of recurrent stroke. J Stroke Cerebrovasc Dis 2012;21:726-731. 11. Penado S, Cano M, Acha O, et al. Stroke severity in patients with atrial fibrillation. Am J Med 2002;112:572-574.

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6 12. Dulli DA, Stanko H, Levine RL. Atrial fibrillation is associated with severe acute ischemic stroke. Neuroepidemiology 2003;22:118-123. 13. Lip GY, Edwards SJ. Stroke prevention with aspirin, warfarin and ximelagatran in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis. Thromb Res 2006;118:321-333. 14. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Int Med 2007; 146:857-867. 15. Ahmad Y, Lip GY. Stroke prevention in atrial fibrillation: Where are we now. Clin Med Insights Cardiol 2012; 6:65-78. 16. Camm JA, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation. Europace 2010; 12:1360-1420. 17. Pisters R, Lane DA, Nieuwlaat R, et al. A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. The Euro heart survey. Chest 2010;138:1093-1100. 18. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-1913. 19. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention,

20.

21.

22.

23.

24.

25.

detection, evaluation, and treatment of high blood pressure. The JNC 7 report. JAMA 2003;289:2560-2571. Healey JF, Connolly SJ. Atrial fibrillation: hypertension as a causative agent, risk factor for complications, and potential therapeutic target. Am J Cardiol 2003; 91(Suppl):9G-14G. Folson AR, Rasmussen ML, Chambless LE, et al. Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. Diabetes Care 1999;22:1077-1083. Kissela BM, Khoury J, Kleindorfer D, et al. Epidemiology of ischemic stroke in patients with diabetes. The greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 2005;28:355-359. Hylek EM, Skates SJ, Sheenan MA, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;355:540-546. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:546s-592s. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:517-584.

Anticoagulant treatment in patients with atrial fibrillation and ischemic stroke.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia, with a lifetime risk of 25%, and it is a well-known independent risk factor for ische...
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