Journal of the Neurological Sciences 334 (2013) 139–142
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Ischemic stroke in patients with atrial ﬁbrillation receiving oral anticoagulation Virginia A. Pujol Lereis, Sebastian Ameriso, Guillermo P. Povedano, Sebastián F. Ameriso ⁎ Institute for Neurological Research, FLENI, Buenos Aires, Argentina
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Article history: Received 7 May 2013 Received in revised form 16 July 2013 Accepted 8 August 2013 Available online 15 August 2013 Keywords: Atrial ﬁbrillation Anticoagulants Stroke Prevention Management Arrhythmia Comorbidities
a b s t r a c t Background: Atrial ﬁbrillation is the most common cause of embolic stroke associated to heart disease. Oral anticoagulation with vitamin K antagonists substantially reduces this risk. Aims: We assessed a group of patients with prior diagnosis of atrial ﬁbrillation who sustained an ischemic stroke while receiving an adequate regime of oral anticoagulation. Methods: We evaluated consecutive patients with ischemic stroke and prior diagnosis of atrial ﬁbrillation. We determined demographics, clinical characteristics, TOAST stroke subtypes, CHADS2 scores, and prior or concomitant use of oral anticoagulants. Results: We studied 112 patients. Thirty nine of them (35%) had received an adequate dose of a vitamin K antagonist during the 24-hour period preceding the stroke. There were no differences in demographics, vascular risk factors, CHADS2 scores, nor medications use between patients who were or were not receiving anticoagulation. Other potential etiologies for stroke occurrence were found in 8 (21%) anticoagulated patients, and in 3 (4%) non-anticoagulated subjects (p b 0.01). Anticoagulated patients had a mean international normalized ratio (INR) of 2.3 ± 1.3 (median 2.05), and INR was within therapeutic ranges (i.e., ≥2) in 54% of these subjects. Conclusions: A substantial proportion of patients with atrial ﬁbrillation who have an ischemic stroke are already receiving oral anticoagulation. Sub-optimal levels of anticoagulation and additional etiologies explain, only in part, this failure. Further research is needed to help ﬁnd adequate therapeutic strategies in atrial ﬁbrillation patients who sustain an ischemic stroke while receiving oral anticoagulation. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Despite remaining the second cause of death and the ﬁrst cause of disability worldwide, stroke still represents a therapeutic challenge in its primary and secondary prevention scenarios . Non-valvular atrial ﬁbrillation (AF) is the most common cause of cardioembolic stroke, causing 15–20% of all ischemic strokes. The rate of ischemic stroke among patients with AF averages 5% per year, 2 to 7 times greater than the rate of subjects without AF [2,3]. This risk is not homogeneous and increases cumulatively with the presence of additional stroke risk factors . Stroke in patients with AF is associated with higher mortality, greater disability, longer hospital stays, and lower rates of discharge to home . Several clinical trials and meta-analysis have demonstrated the beneﬁcial effect of vitamin K antagonists (VKA) compared with placebo, aspirin, and aspirin plus clopidogrel in the prevention of thromboembolic events among patients with AF . Oral anticoagulation (OAC) ⁎ Corresponding author at: Department of Neurology, Institute for Neurological Research, FLENI. Montañeses 2325 (C1428AQK), Buenos Aires, Argentina. Tel.: +54 11 5777 3200 (int. 2800); fax: +54 11 5777 3200 (int. 2806). E-mail address: sameriso@ﬂeni.org.ar (S.F. Ameriso). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.08.013
with VKA is a very effective strategy to prevent stroke and other vascular events in patients with AF, reducing stroke risk by about two thirds . Warfarin also demonstrated a signiﬁcant reduction in allcause mortality . Nevertheless, OAC with VKA has several limitations, such as drug–drug interactions, food interactions, slow onset of action, increased bleeding risk, and need for routine anticoagulation monitoring to maintain a therapeutic range. Furthermore, their use is still suboptimal worldwide, and rate of discontinuation is high . A substantial proportion of subjects with AF do not receive OAC based on fears of hemorrhagic complications. Rate of use is even lower in elderly subjects, the population at highest risk of ischemic events [8,9]. Moreover, OAC with VKA does not impede the occurrence of ischemic strokes in certain subjects, despite adequate use . Management strategies in patients who sustained a stroke while receiving anticoagulants are not addressed in most international published guidelines [11,12]. The limitations of VKA provided the rationale for the development of new antithrombotic agents. New OAC with different pharmacological properties appears as a reasonable alternative to VKA . They exert their anticoagulant effects by combining reversibly with either thrombin (i.e., dabigatran) or factor Xa (rivaroxaban and apixaban). Clinical trials have proven that these agents compare favorably with warfarin both in the occurrence of subsequent ischemic events and
V.A. Pujol Lereis et al. / Journal of the Neurological Sciences 334 (2013) 139–142
in the incidence of hemorrhagic complications [14–16]. Regulatory approval of these agents as a therapeutic option for stroke prevention in patients with AF is being obtained worldwide. Nevertheless, costeffectiveness, lack of speciﬁc reversal agents for hemorrhagic complications, and long-term safety concerns may be responsible for the low rate of use and slow transition from VKA to new drugs . The objective of this study was to assess consecutive patients with recent ischemic strokes and previously diagnosed AF. We identiﬁed those who were already receiving an adequate and supervised regime of OAC with VKA and analyzed potential distinct characteristics of this subgroup.
2. Subjects and methods We studied patients admitted to the Institute for Neurological Research (FLENI) in Buenos Aires, Argentina. Stroke was deﬁned as the sudden onset of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, with acute infarction in imaging studies. We assessed consecutive patients with acute ischemic stroke and prior diagnosis of AF. We identiﬁed those subjects who had received a dose of a VKA within 24 hours before the stroke, and compared them with those not receiving anticoagulation. As a practical deﬁnition, we considered those subjects who had received their recommended dose of oral anticoagulant within 24 hours of the stroke, to be following an adequate plan of anticoagulation, without considering actual INR upon admission or total time in range (TTR). We assessed demographic characteristics, vascular risk factors, oral anticoagulation with acenocumarol or warfarin, and other medications used at the time of the stroke. International normalized ratio (INR) upon admission, stroke subtypes according to
TOAST criteria , and CHADS2 scores were also analyzed . Ethical guidelines were followed and the study was approved by the institutional ethics committee. Means, standard deviations (SD), and medians were calculated for continuous variables and frequencies for dichotomous variables. Differences between groups were examined using Student t tests and Yates-corrected χ2 tests. Differences were considered statistically signiﬁcant when p b 0.05 was obtained. 3. Results We studied 112 patients with ischemic stroke and prior diagnosis of AF. Thirty-nine subjects (35%) had received an adequate dose of a VKA during the 24-hour period preceding the stroke, another twelve patients (11%) had discontinued antithrombotic treatment during the 2-week period preceding the stroke (Fig. 1). Characteristics of the patient population are showed in Table 1. There were no signiﬁcant differences in age, gender distribution, or vascular risk factors proﬁle (i.e, hypertension, hypercholesterolemia, diabetes, and coronary artery disease) between patients receiving or not-receiving OAC, except that non-anticoagulated subjects were more likely to be smokers. Medications used at the time of the stroke were similar in both groups, except for higher rate of statins use in anticoagulated patients. CHADS2 scores were similar in patients receiving and not-receiving OAC. In the anticoagulated group, the INR on admission was within therapeutic range (≥2) in 21 (54%) of the subjects. Mean INR was 2.3 ± 1.3 (median 2.05). Eight of 39 anticoagulated patients (21%) met TOAST criteria for “other etiologies” stroke subtypes in addition to AF. Six subjects had large-artery atherosclerotic disease, 1 had a complex aortic arch plaque, and 1 had cancer. Six of these 8 patients had INR within
112 total patients
12 recently discontinued OAC
Reason for discontinuation: •4 unkown •4 minor procedures •2 minor bleeding •1 INR >3 •1history or repetead falls
73 not anticoagulated
61 never received OAC
•Reason for not anticoagulation: •42 unkown •18 unkown AF •4 previous ECV •4 intracranial hemorrhages •3 patients refusal •2 repeated ECG with sinus rhythm •2 pour clinical condition •2 history or repetead falls •1 minor bleeding
ECV: electrical cardioversion, ECG: electrocardiogram Fig. 1. Study population distribution. ECV: electrical cardioversion, ECG: electrocardiogram.
V.A. Pujol Lereis et al. / Journal of the Neurological Sciences 334 (2013) 139–142 Table 1 Demographic and clinical features of study population. All subjects Anticoagulated Non-anticoagulated p n = 112 n = 39 n = 73 Age, mean ± SD (years) Male, n (%) Vascular risk factors, n (%) Hypertension Hypercholesterolemia Diabetes Smoke Coronary artery disease Heart failure Previous stroke/TIA Previous medication, n (%) Antiplatelets Antihypertensive drugs Statins CHADS2 score 0, n (%) 1, n (%) 2, n (%) 3, n (%) 4, n (%)
74 ± 11 64 (57)
73 ± 6 24 (62)
74 ± 12 40 (55)
89 (79) 41 (37) 13 (12) 36 (32) 20 (18) 18 (16) 34 (31)
28 (29) 13 (33) 4 (19) 18 (46) 6 (15) 6 (15) 15 (38)
61 (84) 27 (37) 9 (12) 18 (25) 12 (16) 18 (25) 20 (27)
NS NS NS 0.035 NS NS NS
57 89 26
16 (41) 57 (78) 15 (38)
41 (56) 32 (82) 11 (15)
NS NS 0.009
8 (7) 24 (21) 37 (33) 28 (25) 11 (10)
4 (10) 7 (18) 12 (31) 9 (23) 7 (18)
4 (6) 17 (23) 25 (33) 19 (26) 4 (6)
NS NS NS NS NS
TIA: transient ischemic attack; NS: not signiﬁcant; SD: standard deviation.
therapeutic range. Only 3 of 73 non-anticoagulated subjects (4%) met criteria for “other etiologies” (p b 0.01). All of them had large-artery atherosclerotic disease (Table 2). 4. Discussion This report conﬁrms that a substantial proportion of patients with previously known AF who sustain a stroke are already receiving anticoagulation. Thirty ﬁve percent of our patients were receiving VKA at the time of the stroke. This is similar to values reported previously in the literature [19,20]. When patients who discontinued OAC for medical reasons within 14 days prior to the vascular event were considered, the percentage of prior anticoagulation rose to 46%, similar to literature reports . No demographic or clinical characteristics helped to identify those subjects who had an ischemic stroke while receiving VKA, except for a higher prevalence of other potential etiology for stroke. Interestingly, OAC “failure” rates appear to be similar to aspirin “failure” rates in non-cardioembolic stroke patients . Despite the demonstrated robust beneﬁts of OAC for stroke prevention in AF patients, the use of VKA has plateaued at approximately 50–60% of eligible patients in most countries [13,23,24]. A multicenter survey done in Argentina on 840 patients showed that 49% of the subjects were treated with OAC, although there were contraindications for use in only 17% of them . Most non-anticoagulated patients in our report had CHADS2 scale values equal or higher than 2, without a formal contraindication for VKA use. The relationship between INR control and both embolic and hemorrhagic outcomes is well established . The optimal intensity of oral anticoagulation for stroke prevention in patients with AF appears to be achieved in subjects with an INR of 2.0 to 3.0. Results from several controlled trials suggest that the efﬁcacy of oral anticoagulation declines
signiﬁcantly below an INR of 2.0, and hemorrhagic risk rice with IRN N 3 . A high percentage of AF patients are often found to have subtherapeutic levels of anticoagulation and therefore may be under protected from stroke. The proportion of patients with adequate INR values in our population was similar to values reported in international trials. In our study, INR was between 2 and 3 in 75% of subjects with other potential etiologies. Despite the effectiveness of prevention strategies, our data suggest that their use is still suboptimal and often fails to prevent strokes. Improved management strategies are needed to maximize stroke prevention in this setting. In our study no demographic or clinical characteristics helped to identify those subjects. Clinical trials or guideline recommendations addressing these scenarios are lacking. New OAC as dabigatran, rivaroxaban, and apixaban appears to have a better beneﬁt/risk ratio proﬁle than warfarin and are being approved in several countries for stroke prevention in AF subjects. Updated prevention guidelines recommend these new OACs as alternatives to VKA [11,12]. However, they do not provide advice on the proper strategies for patients who have a stroke while already receiving VKA. Consistent with previous reports, we found that patients who had a stroke while receiving OAC often had other potential etiologies for stroke . Approximately one quarter of patients who present with AF and ischemic stroke have other potential causes of the stroke, especially large artery disease . Thus, it is particularly important to search for additional stroke etiologies in patients with AF who sustain a stroke despite adequate anticoagulation as additional or alternative therapies may be indicated. Moreover, consideration of “VKA failure” without excluding other potential causes of stroke could be associated with initiation of inadequate treatment strategies. Although we measured INR upon admission in every subject, we used a practical “real word” deﬁnition of adequate anticoagulation. This study had the limitation of not evaluated TTR. Thus, we did not assess the history of anticoagulation in these patients. In conclusion, stroke in patients with AF often occurs in subjects already receiving an adequate regime of VKA in the recommended therapeutic range. Although conditions other than AF can explain, only in part, “VKA failure,” they should be investigated thoroughly as ﬁndings may provide an opportunity for improvement in the management of these subjects. Recommendations for the proper management strategies in subjects who have a stroke while taking VKA are needed. In this setting, the availability of new OAC with different pharmacological effects and the development of endovascular devices (i.e. left atrial appendage closure) may provide alternative therapeutic approaches. Grant support No grant support was received for this study. Conﬂicts of interest There are no known conﬂicts of interest associated with this publication.
Table 2 Stroke etiologies by TOAST criteria. Distribution of “other etiologies” between anticoagulated and not-anticoagulated patients. Anticoagulated n = 39
Other etiologiesa, n (%) Large-artery atherosclerotic disease Complex aortic arch plaque Cancer a
Not-anticoagulated n = 73
All anticoagulated n = 39
RIN within therapeutic range n = 21
RIN offside therapeutic range n = 18
8 (21) 6 (15) 1 (3) 1 (3)
6 (29) 4 (19) 1 (5) 1 (5)
2 (11) 2 (11) 0 0
Other etiologies of classical TOAST criteria include other etiologies in addition to atrial ﬁbrillation, more than one etiology.
3 (4) 3 (4) 0 0
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References  Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and Stroke Statistics—2013 Update. A Report From the American Heart Association. Circulation 2013;127: e6-245.  Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial ﬁbrillation in older adults. Circulation 1997;96:2455–61.  Wolf PA, Abbott RD, Kannel WB. Atrial ﬁbrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983–8.  Hughes M, Lip GY. Guideline Development Group, National Clinical Guideline for Management of Atrial Fibrillation in Primary and Secondary Care, National Institute for Health and Clinical Excellence. Stroke and thromboembolism in atrial ﬁbrillation: a systematic review of stroke risk factors, risk stratiﬁcation schema and cost effectiveness data. Thromb Haemost 2008;99:295–304.  Steger C, Pratter A, Martinek-Bregel M, et al. Stroke patients with atrial ﬁbrillation have a worse prognosis than patients without: data from the Austrian Stroke registry. Eur Heart J 2004;25:1734–40.  Hart RG, Pearce LA, Aguliar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial ﬁbrillation. Ann Intern Med 2007;146:857–67.  Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial ﬁbrillation: a meta-analysis. Ann Intern Med 1999;131: 492–501.  Birman-Deych E, Radford MJ, Nilasena DS, et al. Use and effectiveness of warfarin in Medicare beneﬁciaries with atrial ﬁbrillation. Stroke 2006;37:1070–4.  Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the ﬁrst year of therapy among elderly patients with atrial ﬁbrillation. Circulation 2007;115:2689–96.  Connolly SJ, Pogue J, Eikelboom J, et al. Beneﬁt of oral anticoagulant over antiplatelet therapy in atrial ﬁbrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008;118:2029–37.  Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the canadian cardiovascular society atrial ﬁbrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125–36.  Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial ﬁbrillation: a science advisory for healthcare professionals from the American Heart Association/AmericanStroke Association. Stroke 2012;43:3442–53.  Eikelboom AW, Witz JI. New anticoagulants. Circulation 2010;121:1523–32.
 Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial ﬁbrillation. N Engl J Med 2011;365:981–93.  Connolly JS, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139–51.  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365:883–91.  Adams Jr HP, Bendixen BH, Kappelle LJ, et al. Classiﬁcation of subtype of acute ischemic stroke: deﬁnitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35–41.  Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classiﬁcation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70.  Nieuwlaat R, Olsson SB, Lip GY, et al. Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial ﬁbrillation. The Euro Heart Survey on Atrial Fibrillation. Am Heart J 2007;153:1006–12.  Kowey PR, Reiffel JA, Myerburg R, et al. Warfarin and Aspirin Use in Atrial Fibrillation Among Practicing Cardiologist (from the AFFECTS Registry). Am J Cardiol 2010;105: 1130–4.  Labadet C, Liniado C, Ferreiros ER, et al. Resultados del Primer Estudio Nacional, Multicéntrico y Prospectivo de Fibrilación Auricular Crónica en la República Argentina. Rev Argent Cardiol 2001;69:49–67.  Pujol Lereis VA, Ameriso S, Povedano GP, et al. Ischemic Stroke in Patients Receiving Aspirin. J Stroke Cerebrovasc Dis 2011;21:868–72.  Bungard TJ, Ghali WA, Teo KK, et al. Why do patients with atrial ﬁbrillation not receive warfarin? Arch Intern Med 2000;160:41–6.  Connolly SJ, Eikelboom J, O’Donnell M, et al. Challenges of establishing new antithrombotic therapies in atrial ﬁbrillation. Circulation 2007;116:449–55.  Rose MJ, Hylek EM, Ozonoff A. Risk-Adjusted Percent Time in Therapeutic Range as a Quality Indicator for Outpatient Oral Anticoagulation Results of the Veterans Affairs Study To Improve Anticoagulation (VARIA). Circ Cardiovasc Qual Outcomes 2011;4: 22–9.  Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation and outcomes in patients with atrial ﬁbrillation: a systematic review and meta-analysis. Chest 2004;126:1938–45.  Hart RG, Pearce LA, Miller VT, et al. Cardioembolic vs. noncardioembolic strokes in atrial ﬁbrillation: frequency and effect of antithrombotic agents in the stroke prevention in atrial ﬁbrillation studies. Cerebrovasc Dis 2000;10:39–43.  Chang YJ, Ryu SJ, Lin SK. Carotid artery stenosis in ischemic stroke patients with nonvalvular atrial ﬁbrillation. Cerebrovasc Dis 2002;13:16–20.