Rates of Ischemic Stroke During Warfarin Treatment for Atrial Fibrillation Jennifer M. Tung, PharmD; Muhammad M. Mamdani, PharmD; David N. Juurlink, PhD; J. Michael Paterson, MSc; Moira K. Kapral, MD; Tara Gomes, MHSc Background and Purpose—Recent evidence suggests that there may be an increased risk of ischemic stroke immediately after warfarin initiation. We examined the rate of ischemic stroke among patients with atrial fibrillation newly started on warfarin therapy. Methods—We conducted a population-based cohort study among Ontario residents aged ≥66 years with atrial fibrillation who received warfarin between April 1, 1997, and March 31, 2010. Each patient was followed up for ≤5 years in 30-day intervals. For each interval, we determined the rate of ischemic stroke. Results—After 5 years, the cumulative incidence of ischemic stroke among new users of warfarin (n=148 446) was 4.0% (n=6006). The risk was highest during the first 30 days after initiation (6.0% per person-year; 95% confidence interval, 5.5%–6.4%) compared with the remainder of follow-up (1.6% per person-year; 95% confidence interval, 1.5%–1.6%), and increased with higher baseline CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke) scores. Less frequent monitoring may have contributed. Conclusions—In a large cohort of older patients with atrial fibrillation, we observed the highest rate of ischemic stroke in the first 30 days after warfarin initiation. Although causation cannot be established given the observational nature of this study, our findings highlight the need for future research in this population. (Stroke. 2015;46:1120-1122. DOI: 10.1161/ STROKEAHA.114.007852.) Key Words: anticoagulants ◼ epidemiology
W
arfarin is effective for the prevention of ischemic stroke and systemic embolism in patients with atrial fibrillation.1 However, the inconvenience of laboratory monitoring and risk of hemorrhage can complicate therapy. The risk of major hemorrhage is greatest within the first 30 days of therapy,2 and a recent case–control study in atrial fibrillation patients found a 71% increased risk of ischemic stroke in the first 30 days of warfarin therapy.3 Remaining unclear is the absolute risk of ischemic stroke throughout the course of warfarin therapy and whether it is influenced by patient characteristics. The objective of this study was to examine whether an acute risk of ischemic stroke exists among patients with atrial fibrillation newly initiated on warfarin.
assessed various baseline characteristics (Table 1; Table I in the online-only Data Supplement) and followed up each patient from warfarin initiation until the first of ischemic stroke, death, warfarin discontinuation, end of the maximum 5-year follow-up, or the end of the study period (March 31, 2012; online-only Data Supplement). The Research Ethics Board of Sunnybrook Health Sciences Center, Toronto approved this study. Crude rates were calculated in 30-day intervals as the total number of participants with a hospital visit for ischemic stroke divided by the number of event-free warfarin users at the beginning of each interval and expressed as percentage per person-year (PPY). We stratified all analyses by CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke) score and stroke history,4 and used the Cochrane–Armitage test for trend and χ2 tests to identify differences in crude stroke rates. We performed a sensitivity analysis for timing of atrial fibrillation diagnosis.
Methods
Results
We conducted a population-based cohort study of Ontario residents aged ≥66 years who received warfarin between April 1, 1997, and March 31, 2010. The primary outcome was a hospital visit (inpatient or emergency department admission) for ischemic stroke. We
We identified 148 446 patients aged ≥66 years with atrial fibrillation who began warfarin therapy over the study period, and of these patients, 6006 experienced an ischemic stroke. Of
Received October 18, 2014; final revision received January 25, 2015; accepted January 28, 2015. From the Institute for Clinical Evaluative Sciences (M.M.M., D.N.J., J.M.P., M.K.K., T.G.), Sunnybrook Research Institute (D.N.J.), Department of Medicine (M.K.K.), Institute of Health Policy, Management, and Evaluation (M.M.M., D.N.J., J.M.P., M.K.K., T.G.), and Leslie Dan Faculty of Pharmacy (J.M.T., M.M.M., T.G.), University of Toronto, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada (M.M.M., T.G.); Division of General Internal Medicine and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.K.K.); and Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada (J.M.P.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114. 007852/-/DC1. Correspondence to Tara Gomes, MHSc, 30 Bond St, Toronto, Ontario, Canada. E-mail [email protected] © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007852
1120
Tung et al Warfarin Initiation and Ischemic Stroke 1121 Table 1. Baseline Characteristics
(n=2,917) after 1 year, 2.7% (n=4067) after 2 years, and 4.0% (n=6006) after 5 years. The risk was highest during the first 30 days of warfarin therapy: 6.0% PPY (95% confidence interval, 5.5%–6.4%) versus 1.6% PPY (95% confidence interval, 1.5%–1.6%) during the remainder of the 5-year follow-up (Table 2; Figure). Crude 5-year rates of ischemic stroke increased significantly as CHADS2 scores increased (P30
76 061 (51.2)
5.8 (5.3–6.5)
1.6 (1.6–1.7)
1.8 (1.8–1.9)
CHADS2 indicates score comprised of congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke; and CI, confidence interval.
1122 Stroke April 2015
Figure. Rate of ischemic stroke among new warfarin users with atrial fibrillation.
analysis stratifying patients by timing of warfarin initiation after atrial fibrillation diagnosis found similar stroke rates in both groups. This suggests our findings are not simply influenced by elevated rates of stroke after atrial fibrillation diagnosis, as has been previously reported.8 Moreover, few patients received heparins or antiplatelet agents before initiating warfarin. Studies are needed to determine whether bridging therapy, antiplatelet therapy, or use of direct-acting anticoagulants mitigate this early increased stroke risk. Strengths of this study include its large, populationbased sample and long follow-up. Limitations include our inability to assess the quality of anticoagulation. We also could not capture stroke events that did not result in hospitalization or some important risk factors for stroke, such as hypertension.
Conclusions In this large, population-based cohort study of older patients with atrial fibrillation, we observed the highest rate of ischemic stroke in the first 30 days after warfarin initiation. Although this does not provide evidence of a causal link between warfarin initiation and stroke, the persistence of thromboembolic risk despite anticoagulation highlights the need for future research in this area.
Acknowledgments We thank Brogan Inc, Ottawa for use of their Drug Product and Therapeutic Class Database.
Sources of Funding This study was supported by the Ontario Drug Policy Research Network which is funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC), and supported by the Institute for Clinical Evaluative Sciences (ICES). Opinions, results, and conclusions reported are those of the authors and independent from funding sources. No endorsement by ICES or the MOHLTC is
intended or should be inferred. Dr Kapral holds a career investigator award from the Heart and Stroke Foundation of Ontario.
Disclosures T. Gomes, M.M. Mamdani, J.M. Paterson, and D.N. Juurlink have received grant funding from the Ontario Ministry of Health and LongTerm Care (MOHLTC). J.M. Paterson is an employee of Institute for Clinical Evaluative Sciences, which is funded by the MOHLTC. M.M. Mamdani is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Novo Nordisk and Pfizer. The other authors report no conflicts.
References 1. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA. 2003;290:2685–2692. doi: 10.1001/jama.290.20.2685. 2. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185:E121–E127. doi: 10.1503/cmaj.121218. 3. Azoulay L, Dell’Aniello S, Simon TA, Renoux C, Suissa S. Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. Eur Heart J. 2014;35:1881–1887. doi: 10.1093/eurheartj/eht499. 4. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864–2870. 5. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med. 2012;172:623–631, discussion 631. doi: 10.1001/archinternmed.2012.121. 6. Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med. 2007;167:2417–2422. doi: 10.1001/ archinte.167.22.2417. 7. Viganò S, Mannucci PM, Solinas S, Bottasso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol. 1984;57:213–220. 8. Lehto M, Snapinn S, Dickstein K, Swedberg K, Nieminen MS; OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur Heart J. 2005;26:350–356. doi: 10.1093/ eurheartj/ehi064.
W
arfarin is effective for the prevention of ischemic stroke and systemic embolism in patients with atrial fibrillation.1 However, the inconvenience of laboratory monitoring and risk of hemorrhage can complicate therapy. The risk of major hemorrhage is greatest within the first 30 days of therapy,2 and a recent case–control study in atrial fibrillation patients found a 71% increased risk of ischemic stroke in the first 30 days of warfarin therapy.3 Remaining unclear is the absolute risk of ischemic stroke throughout the course of warfarin therapy and whether it is influenced by patient characteristics. The objective of this study was to examine whether an acute risk of ischemic stroke exists among patients with atrial fibrillation newly initiated on warfarin.
assessed various baseline characteristics (Table 1; Table I in the online-only Data Supplement) and followed up each patient from warfarin initiation until the first of ischemic stroke, death, warfarin discontinuation, end of the maximum 5-year follow-up, or the end of the study period (March 31, 2012; online-only Data Supplement). The Research Ethics Board of Sunnybrook Health Sciences Center, Toronto approved this study. Crude rates were calculated in 30-day intervals as the total number of participants with a hospital visit for ischemic stroke divided by the number of event-free warfarin users at the beginning of each interval and expressed as percentage per person-year (PPY). We stratified all analyses by CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke) score and stroke history,4 and used the Cochrane–Armitage test for trend and χ2 tests to identify differences in crude stroke rates. We performed a sensitivity analysis for timing of atrial fibrillation diagnosis.
Methods
Results
We conducted a population-based cohort study of Ontario residents aged ≥66 years who received warfarin between April 1, 1997, and March 31, 2010. The primary outcome was a hospital visit (inpatient or emergency department admission) for ischemic stroke. We
We identified 148 446 patients aged ≥66 years with atrial fibrillation who began warfarin therapy over the study period, and of these patients, 6006 experienced an ischemic stroke. Of
Received October 18, 2014; final revision received January 25, 2015; accepted January 28, 2015. From the Institute for Clinical Evaluative Sciences (M.M.M., D.N.J., J.M.P., M.K.K., T.G.), Sunnybrook Research Institute (D.N.J.), Department of Medicine (M.K.K.), Institute of Health Policy, Management, and Evaluation (M.M.M., D.N.J., J.M.P., M.K.K., T.G.), and Leslie Dan Faculty of Pharmacy (J.M.T., M.M.M., T.G.), University of Toronto, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada (M.M.M., T.G.); Division of General Internal Medicine and Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada (M.K.K.); and Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada (J.M.P.). The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114. 007852/-/DC1. Correspondence to Tara Gomes, MHSc, 30 Bond St, Toronto, Ontario, Canada. E-mail [email protected] © 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.114.007852
1120
Tung et al Warfarin Initiation and Ischemic Stroke 1121 Table 1. Baseline Characteristics
(n=2,917) after 1 year, 2.7% (n=4067) after 2 years, and 4.0% (n=6006) after 5 years. The risk was highest during the first 30 days of warfarin therapy: 6.0% PPY (95% confidence interval, 5.5%–6.4%) versus 1.6% PPY (95% confidence interval, 1.5%–1.6%) during the remainder of the 5-year follow-up (Table 2; Figure). Crude 5-year rates of ischemic stroke increased significantly as CHADS2 scores increased (P30
76 061 (51.2)
5.8 (5.3–6.5)
1.6 (1.6–1.7)
1.8 (1.8–1.9)
CHADS2 indicates score comprised of congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke; and CI, confidence interval.
1122 Stroke April 2015
Figure. Rate of ischemic stroke among new warfarin users with atrial fibrillation.
analysis stratifying patients by timing of warfarin initiation after atrial fibrillation diagnosis found similar stroke rates in both groups. This suggests our findings are not simply influenced by elevated rates of stroke after atrial fibrillation diagnosis, as has been previously reported.8 Moreover, few patients received heparins or antiplatelet agents before initiating warfarin. Studies are needed to determine whether bridging therapy, antiplatelet therapy, or use of direct-acting anticoagulants mitigate this early increased stroke risk. Strengths of this study include its large, populationbased sample and long follow-up. Limitations include our inability to assess the quality of anticoagulation. We also could not capture stroke events that did not result in hospitalization or some important risk factors for stroke, such as hypertension.
Conclusions In this large, population-based cohort study of older patients with atrial fibrillation, we observed the highest rate of ischemic stroke in the first 30 days after warfarin initiation. Although this does not provide evidence of a causal link between warfarin initiation and stroke, the persistence of thromboembolic risk despite anticoagulation highlights the need for future research in this area.
Acknowledgments We thank Brogan Inc, Ottawa for use of their Drug Product and Therapeutic Class Database.
Sources of Funding This study was supported by the Ontario Drug Policy Research Network which is funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC), and supported by the Institute for Clinical Evaluative Sciences (ICES). Opinions, results, and conclusions reported are those of the authors and independent from funding sources. No endorsement by ICES or the MOHLTC is
intended or should be inferred. Dr Kapral holds a career investigator award from the Heart and Stroke Foundation of Ontario.
Disclosures T. Gomes, M.M. Mamdani, J.M. Paterson, and D.N. Juurlink have received grant funding from the Ontario Ministry of Health and LongTerm Care (MOHLTC). J.M. Paterson is an employee of Institute for Clinical Evaluative Sciences, which is funded by the MOHLTC. M.M. Mamdani is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Novo Nordisk and Pfizer. The other authors report no conflicts.
References 1. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA. 2003;290:2685–2692. doi: 10.1001/jama.290.20.2685. 2. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185:E121–E127. doi: 10.1503/cmaj.121218. 3. Azoulay L, Dell’Aniello S, Simon TA, Renoux C, Suissa S. Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. Eur Heart J. 2014;35:1881–1887. doi: 10.1093/eurheartj/eht499. 4. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864–2870. 5. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med. 2012;172:623–631, discussion 631. doi: 10.1001/archinternmed.2012.121. 6. Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med. 2007;167:2417–2422. doi: 10.1001/ archinte.167.22.2417. 7. Viganò S, Mannucci PM, Solinas S, Bottasso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol. 1984;57:213–220. 8. Lehto M, Snapinn S, Dickstein K, Swedberg K, Nieminen MS; OPTIMAAL investigators. Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience. Eur Heart J. 2005;26:350–356. doi: 10.1093/ eurheartj/ehi064.
