Stroke. Long-Term Effects of Secondary Prevention on Cognitive Function in Stroke Patients

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1 Stroke Long-Term Effects of Secondary Prevention on Cognitive Function in Stroke Patients Abdel Douiri, PhD; Christopher McKevitt, PhD; Eva S. Emmett, MD; Anthony G. Rudd, MD, FRCP; Charles D.A. Wolfe, MD, FFPH Background Limited long-term follow-up data exist on the impact of appropriate secondary prevention therapies on cognitive function in patients after first-ever stroke. The aim of this study is to determine the effect of secondary prevention of vascular events on cognitive function after stroke. Methods and Results Data were collected between 1995 and 2011 (n=4413) from the community-based South London Stroke Register covering an inner-city multiethnic source population of inhabitants. Modified Poisson regression models were constructed to adjust for cognitive function status at 3 months, demographic and socioeconomic characteristics, case mix, stroke subtype, vascular risk factors, disability, and stroke recurrence. In patients with ischemic strokes without a history of atrial fibrillation (AF), there was a reduced risk of cognitive impairment associated with the use of different prevention treatments: (1) antihypertensives (relative risk, 0.7 [95% confidence interval, ] for diuretics; relative risk, 0.8 [95% confidence interval, ] for angiotensin-converting enzyme inhibitors; and relative risk, 0.7 [95% confidence interval, ] for their combination), (2) a combination of aspirin and dipyridamole (relative risk, 0.8 [95% confidence interval, ]), and (3) statin (relative risk, 0.9 [95% confidence interval, ]) when clinically indicated. Protective effects against cognitive impairment were also observed in patients on the combination of antihypertensives, antithrombotic agents, and lipid-lowering drugs (relative risk, 0.55 [95% confidence interval, ]). No significant associations were noted between poststroke cognitive impairment and antihypertensives among hemorrhagic stroke patients. Conclusions Appropriate vascular risk management was associated with a long-term reduced risk of cognitive impairment. Focus on optimal preventive drug therapy of vascular risk factors and management should be supported. (Circulation. 2013;128: ) Key Words: drug therapy mild cognitive impairment prevention & control stroke vascular dementia Cognitive impairment is recognized as one of the major long-term effects of stroke. 1 5 In a study of patients with first-ever stroke from the community-based, prospective South London Stroke Register (SLSR) between 1995 and 2010, the overall age-standardized prevalence of cognitive impairment remained persistently high over time at 22% up to 15 years after stroke. Similar prevalence rates have also been observed in short follow-up studies. 6 Nevertheless, there are limitations in many follow-up studies trying to identify and investigate the potential mechanisms of the association of cognitive impairment with underlying risk factors. 7,8 Clinical Perspective on p 1348 Vascular risk factors are common among stroke patients, 8 and controlling these underlying vascular risk factors is central to secondary prevention initiatives, not only for reducing the risk of recurrent stroke but potentially also for reducing the risk of other vascular consequences such as cognitive impairment. Evidence-based pharmacotherapy for secondary stroke prevention, as recommended by guidelines, 9 15 focuses on the modulation of vascular risk factors, including antithrombotic treatments and control of blood pressure and lipid levels, for a wide spectrum of stroke patients. In a multicenter, randomized clinical trial with >4 years of follow-up and including 6105 stroke or transient ischemic attack subjects with a mean blood pressure at enrollment of 147/86 mm Hg, 16 patients who were given combined antihypertensive treatments of an angiotensin-converting enzyme inhibitor (ACEI) and a diuretic (perindopril and indapamide) to control blood pressure had a reduced risk of 19% (95% confidence interval [CI], 4 32) of cognitive deterioration (a decline of 3 points in the Mini-Mental State Examination score). However, preliminary results from another multicenter, randomized clinical trial involving patients with a recent ischemic stroke and with a mean blood pressure at randomization of 144/84 mm Hg did not replicate these findings either Received February 24, 2013; accepted July 31, From the Division of Health and Social Care, King s College London, London, UK; and National Institute for Health Research Biomedical Research Centre, Guy s and St. Thomas NHS Trust and King s College London, London, UK. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Abdel Douiri, PhD, King s College London, Division of Health and Social Care Research, Capital House, 42 Weston St, London SE1 3QD, UK. abdel.douiri@kcl.ac.uk 2013 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 1342 Circulation September 17, 2013 with angiotensin receptor blockers (telmisartan) or with the two antiplatelet regimens (extended-release dipyridamole plus aspirin, or clopidogrel monotherapy). 17 Consequently, there is still no clear evidence on the effect of secondary prevention strategies of vascular risk on long-term cognitive impairment. The aim of this study is to investigate the relationship between the use of secondary prevention drug therapies to control vascular risk in stroke patients and long-term cognitive impairment in patients after first-ever stroke and up to 10 years later in a population sample, the SLSR ( ). Methods Study Population The SLSR is a prospective population-based stroke register that was set up in January 1995 and records all first-ever strokes in patients of all ages for an inner area of South London, including 22 electoral wards in Lambeth and Southwark. Data collected between 1995 and 2010 were used in this analysis. The total source population of the SLSR area was individuals; their self-reported race was as follows in the 2001 Census: 63% white, 28% black (9% black Caribbean, 15% black African, and 4% black other), and 9% other. 18 Case Ascertainment Standardized criteria were applied to ensure completeness of case ascertainment, including multiple overlapping sources of notification. All patients with a suspected diagnosis of stroke or transient ischemic attack documented in different hospital- and community-based information sources were investigated for study eligibility. Completeness of case ascertainment has been estimated at 88% by a multinomial-logit capture-recapture model using the methods described elsewhere. 18,19 Data Collection Specially trained study nurses and field workers collected all data prospectively whenever feasible. A study doctor verified the diagnosis of stroke. Patients were examined within 48 hours of referral to SLSR when possible. The following sociodemographic characteristic was collected at initial assessment: self-definition of race (Census question), stratified into white, black (black Caribbean, black African, and black other), and other ethnic group. Socioeconomic status was based on the 2007 Index of Multiple Deprivation, a UK government statistic that combines a set of indicators (in 7 domains: income, employment, health, education, barriers to housing and services, living environment, and crime) chosen to cover a range of economic, social, and housing issues in a single score for each small area in England. 20 The Index of Multiple Deprivation scores range from 1 to 100 (categorized into quintiles in the analyses); higher scores indicate more deprived areas. Stroke was defined according to World Health Organization criteria. Pathological stroke subtypes were classified using neuroradiology or necropsy results into ischemic stroke, primary intracerebral hemorrhage, or subarachnoid hemorrhage. Ischemic strokes were further investigated according to 2 stroke subtypes: the Oxfordshire Community Stroke Project (OCSP) 21 classification and the modified Trial of Org in Acute Stroke Treatment (TOAST) classification. The OCSP classification contains 4 subtypes according to clinical features: lacunar infarcts, total anterior circulation infarcts, partial anterior circulation infarcts, and posterior circulation infarcts. Modified TOAST classification denotes 5 etiologic subtypes: largeartery atherosclerosis (LAA), cardioembolism, small-vessel occlusion, other determined type, and no type identified. Data with modified TOAST classification were collected only after The definition of stroke recurrence was the same as for the index stroke. Only recurrences 21 days after the initial event or, if earlier, clearly in a different vascular territory were included. Vascular risk factors for stroke (either self-reported or from medical notes), before and after stroke at each time point, were collected, including smoking, hypertension, diabetes mellitus, AF, ischemic heart disease (IHD; angina pectoris or myocardial infarction), and transient ischemic attack. Pharmacotherapy for appropriate secondary stroke prevention data was also collected, from the prescribed drugs, at each time point after stroke, including antihypertensives (diuretics, ACEIs, β-blockers, calcium channel blockers, or angiotensin II receptor antagonists), anticoagulants (warfarin or heparin), antiplatelet agents (aspirin, dipyridamole, or clopidogrel), diabetes mellitus control treatments (oral treatment or insulin), and lipid-lowering drugs (statins, cholesterol absorption inhibitors, or fibrates). Because stroke patients often have systemic vascular arteriosclerosis, recommended optimal drug regimen was defined as a combination of appropriate antithrombotic treatments with blood pressure and lipid lowering for ischemic strokes and of antihypertensives for hemorrhagic strokes. Glasgow Coma Score 22 dichotomized to <13 or 13 was used to measure stroke severity at onset, and the Barthel Index 23 scores at annual follow-up with a cutoff of 15 was used to identify patients with moderate (Barthel Index=10 14) to severe disability (Barthel Index < 9). Other case-mix indicators used for initial functional neurological deficit included sensory or motor deficits (face, arm, hand, or leg), speech deficit (dysarthria, aphasia, or dysphasia), and visual deficit (visual field defects or visuospatial neglect). Before January 1, 2000, cognitive state was assessed with the Mini- Mental State Examination 24 in the acute phase and at follow-up; after that date, the Abbreviated Mental Test 25 was used for all assessments. Subjects were defined as cognitively impaired according to predefined cutoff points (Mini-Mental State Examination <24 or Abbreviated Mental Test <8). 18 Patients were assessed at the onset of stroke, at 3 months, and annually after stroke. All follow-up assessments included in the present study were completed by August 31, Statistical Analysis Descriptive analyses were performed at 3 months after stroke. Proportions and relative risks (RRs) of baseline characteristics were compared between patients with and without cognitive impairment at 3 months. Multivariate analyses, with and without interaction with vascular risk factors, were used to determine the baseline RRs of cognitive impairment in patients with vascular risk factors. Adjusted RR estimates were conducted with multivariate generalized modified Poisson regression analyses with robust standard error. To investigate the association between short- and long-term cognitive impairment and vascular risk factors, longitudinal generalized estimating equation log-linear Poisson models with robust standard errors and an exchangeable correlation matrix to account for repeated measures within individuals were used with 1, 5, and 10 years of follow-up after stroke. The interactions between each vascular risk factor with secondary prevention drugs for the risk of cognitive impairment were investigated. Analyses of major stroke subgroups (hemorrhagic stroke, ischemic stroke with AF, and ischemic stroke without AF) were conducted according to the drug regimen (single or combination drug therapy) and according to vascular risk factors (AF, IHD, diabetes mellitus, hypercholesterolemia) and TOAST stroke subtypes (LAA, cardioembolism, small-vessel occlusion). Multivariate models were adjusted for cognitive function status at 3 months, sociodemographic status, case-mix, stroke subtype, and the time-varying covariates of disability, stroke recurrence, and vascular risk factors. To assess the robustness of the results, we performed additional analyses using multiple imputation of missing data based on inverse probability weights. The probability of response was estimated with multivariable logistic regression including factors associated with dropping out (cognitive score at previous visits, age, socioeconomic status, and race). This approach had little effect on the estimates. The observed data analysis was therefore used for the present study. Statistical analyses were performed with Stata (2012, StataCorp LP, College Station, TX). Ethics All patients or their relatives gave written informed consent to participate in the study, and over the study period, very few patients have declined to be registered. The design of the study was approved

3 Douiri et al Stroke Secondary Prevention and Cognitive Function 1343 by the ethics committees of Guy s and St. Thomas National Health Service Foundation Trust, King s College Hospital Foundation Trust, St. George s University Hospital, National Hospital for Nervous Diseases, and Westminster Hospital. Results A total of 4413 patients with their first-ever stroke between January 1, 1995, and December 31, 2011, were registered, of whom 1137 (26%) were dead within 3 months, 689 (16%) were not eligible because of late registration or because their date of follow-up was not reached, and 575 (13%) were unable to undergo a cognitive assessment because of a severe verbal, visual, or hearing impairment. Of the 2012 remaining subjects, 1682 stroke survivors were able to undergo a cognitive assessment at 3 months, 1448 at 1 year, 684 at 5 years, and 200 at 10 years. The characteristics of the patients at each time point of follow-up, including year of stroke, are presented in Table I in the online-only Data Supplement. The characteristics of these patients 3 months after stroke, including sociodemographic factors, past medical history, case mix, and stroke subtypes, are presented in Table 1. The crude prevalence of cognitive impairment at this time point was 31% (95% CI, ). The average age of those patients with cognitive impairment was 73 years (standard deviation, 12.7 years), and 50% were female. Most patients were white (72%), followed by black (22%; 13% black Caribbean, 8% black African, and 1% black other); other race was recorded in 6%, and race was unknown in 2.5%. Of the total cohort, 81% had ischemic strokes, 14% had primary intracerebral hemorrhage, and 5% had subarachnoid hemorrhage. Partial circulation infarcts and lacunar infarcts were the most predominant ischemic stroke subtypes in the OCSP classification of stroke subtype (33% and 34%, respectively), and small-vessel occlusion and cardioembolic subtypes were the most predominant ischemic stroke subtypes in the modified TOAST classifications (25% and 26%, respectively). Before stroke, 60% (95% CI, ) of the survivors at 3 months were on 1 primary stroke preventive medications, including 52% (95% CI, ) on antihypertensive drugs, 20% (95% CI, ) on lipid-lowering treatments, and 34% (95% CI, ) on antithrombotic agents (antiplatelets or anticoagulants). Among ischemic stroke patients, antihypertensives were prescribed to 69% (95% CI, ), lipid-lowering drugs to 46% (95% CI, ), and antithrombotic agents to 91% (95% CI, ), and 37% (95% CI, ) were on an optimal medication therapy, defined as a combination of the 3 therapies. Antihypertensives were prescribed to 65% (95% CI, ) of the hemorrhage stroke patients. Table 2 shows the percentage of patients on secondary prevention medications (antihypertensives, antiplatelets, anticoagulants, or lipid-lowering agents) by cognitive status at 3 months and their RRs. Among antihypertensive treatments, monotherapy drugs were the most frequently prescribed (48%; 95% CI, ), followed by ACEIs combined with other antihypertensive drugs (25%; 95% CI, ). Antiplatelet agents, aspirin, or dipyridamole or clopidogrel were prescribed to 77% (95% CI, ) of patients with ischemic strokes, and of these, 75% (95% CI, ) were on aspirin alone and 18% (95% CI, ) were on combination antiplatelet therapy, with 74% (95% CI, ) on aspirin and dipyridamole. In a multivariate analysis controlling for sociodemographic factors, prestroke vascular risk factors, case mix, stroke recurrence, and stroke subtypes, stroke survivors at 3 months experienced a 55% (95% CI, ) increased risk of cognitive impairment if they had diabetes mellitus and 30% (95% CI, ) increased risk if they had AF. Lower risk of cognitive impairment was observed among patients with a medical history of hypercholesterolemia (RR, 0.76; 95% CI, ). An additional analysis was conducted to investigate the interaction between different prestroke vascular comorbidities. Patients with a history of AF and IHD were at increased risk of cognitive deficit at 3 months after stroke (RR, 1.6; 95% CI, ); however, lower risks were observed among stroke survivors with hypercholesterolemia and IHD (RR, 0.6; 95% CI, ). In the longitudinal analysis adjusting for 3-month cognitive status, sociodemographic factors, vascular risk factors, case mix, disability, stroke recurrence, and stroke subtypes, lipidlowering drug use was associated with decreased risk of cognitive impairment at any time after stroke. However, optimal therapy that included anticoagulant, antiplatelet, and antihypertensive drugs was related to a protective effect of cognitive impairment after 2, 3, 5, and 7 years of treatment after stroke. Patients with hypertension were at higher risk of long-term cognitive impairment among stroke survivors up to 10 years after stroke (RR, 1.2; 95% CI, ). Figure 1 illustrates the adjusted RR reduction of secondary prevention drugs with 1-, 5-, and 10-year treatments after stroke. The interaction-terms analyses with vascular risk factors showed additional protection from cognitive impairment when combined antiplatelet therapies or anticoagulants were prescribed to patients with IHD (RR, 0.7; 95% CI, ; and RR, 0.7; 95% CI, , respectively). Furthermore, a protective effect against cognitive impairment was also observed when combined antihypertensive therapies were prescribed to patients with LAA strokes (RR, 0.7; 95% CI, ). However, a causal association of cognitive impairment was observed only when antihypertensive monotherapies were prescribed to patients with AF (RR, 1.3; 95% CI, ). Adjusted RRs of the interaction of secondary prevention drugs with IHD and AF are presented in Table II in the online-only Data Supplement. Adjusted longitudinal subgroup analyses up to 10 years after stroke were also conducted in hemorrhagic stroke patients and in each group of ischemic stroke patients with and without AF according to drug regimen (single or combination drug therapy and optimal medication therapy) to examine the long-term effect of secondary prevention on cognitive impairment. Figure 2 summarizes the main results from this analysis. Subgroup analysis in different TOAST ischemic subtypes (LAA, cardioembolism, small-vessel occlusion) was also conducted. Among LAA strokes, combined antihypertensives were strongly related to a reduction in risk of cognitive impairment (RR, 0.3; 95% CI, ), and among smallvessel occlusion strokes, both monotherapy and combined antihypertensive drugs were related to strong protective effects

4 1344 Circulation September 17, 2013 Table 1. Baseline Characteristics of SLSR Patients ( ) at 3 Months Cognitive Deficit (n=529) No Cognitive Deficit (n=1153) Univariate Comparisons* 95% CI n % n % RR Lower Upper Age group, y Sex Male Female Race White Black Socioeconomic status (Index of Multiple Deprivation) 20% least deprived % most deprived Prestroke vascular risk factors Hypertension Hypercholesterolemia Diabetes mellitus IHD AF TIA Smoking Functional neurological deficit at onset Coma Sensory/motor deficits Absent Sensory or motor Sensory and motor Speech deficit Visual deficit Stroke subtypes Ischemic stroke PICH SAH TOAST subtypes (data collected after 1999 but dominator all data set) LAA CE SVO OTH/UND AF indicates atrial fibrillation; CE, cardioembolism; CI, confidence interval; IHD, ischemic heart disease; LAA, large-artery atherosclerosis; OTH/UND, other determined or undefined type; PICH, primary intracerebral hemorrhage stroke; RR, relative risk; SAH, subarachnoid hemorrhage stroke; SLSR, South London Stroke Register; SVO, small-vessel occlusion; TIA, transient ischemic attack; and TOAST, Trial of Org in Acute Stroke Treatment. *Univariate comparisons: cognitive deficit versus no cognitive deficit. (RR, 0.8; 95% CI, ; RR, 0.8; 95% CI, ; and RR, 0.7; 95% CI, , respectively). Optimal therapy was strongly associated with a protective effect of cognitive deficit in LAA strokes (RR, 0.1; 95% CI, ). A further specific adjusted longitudinal subgroup analysis was also conducted according to drug type and regimen (single

5 Douiri et al Stroke Secondary Prevention and Cognitive Function 1345 Table 2. Prescribed Drugs of SLSR Patients by Cognitive Function Status at 3 Months Drugs Cognitive Deficit No Cognitive Deficit Total Univariate Comparisons 95% CI n % n % n % RR Lower Upper Antihypertensive Monotherapy Polytherapy β-blocker ACEI Other Antiplatelet Monotherapy Polytherapy Aspirin/dipyridamole Other Anticoagulant Lipid lowering ACEI+ indicates angiotensin-converting enzyme inhibitor based combination; β-blocker+, β-blocker based combination; CI, confidence interval; Other+, other combination; RR, relative risk; and SLSR, South London Stroke Register. drug therapy for statin, warfarin, aspirin, diuretic, ACEI, and β-blocker; combination drug therapy of aspirin and dipyridamole, β-blocker and diuretic, and ACEI and diuretic) to examine the long-term effect of cognitive impairment on stroke survivors up to 10 years after stroke. Figure 3 shows all the findings from this analysis. Discussion This study investigated the effect of the secondary prevention of stroke (antiplatelet agents, antihypertensive drugs, lipidlowering drugs, and anticoagulants) on long-term cognitive impairment after stroke. To the best of our knowledge, this is the first population-based study to assess the relationship between cognitive impairment and vascular secondary prevention up to 10 years after stroke 26 with different drug regimens. 8 Findings from this study not only provided indicators of potential association between secondary prevention and cognitive impairment but also helped to improve our understanding of which pharmacotherapies effectively help to treat vascular risk factors and to alter or slow the progression of cognitive decline after a stroke. The most important observation in our study was that appropriate management of vascular risk factors was associated Figure 1. Short- and long-term relative risk (RR) reduction of secondary prevention drugs in all SLSR patients. CI indicates confidence interval.

6 1346 Circulation September 17, 2013 Figure 2. Adjusted longitudinal analysis of effect of treatment on the relative risk (RR) of cognitive impairment in patients with hemorrhagic and ischemic stroke by drug type. AF indicates atrial fibrillation; and CI, confidence interval. with improved protective effect of long-term cognitive outcome among stroke patients. Several trials have assessed the effect of stroke secondary prevention drugs on recurrent stroke and survival 27 ; however, the question of whether such drugs prevent or delay cognitive decline is still relatively unexplored. 8 In this study, lipid management after stroke was found to be independently associated with a reduced risk of cognitive impairment in most patients regardless of age. This association was observed in short- and long-term follow-up with lower risks at 3 months observed among stroke survivors with hypercholesterolemia, which supports the hypothesis that lipid control therapy may have only prevented the incidence of cognitive impairment in cognitively healthy individuals rather than affecting the progression of cognitive decline. Moreover, the lower risks of cognitive impairment at 3 months among stroke survivors with hypercholesterolemia could be explained by a carryover effect of lipid-lowering drugs in the primary stroke prevention strategies. These findings support and confirm that continuation of lipid-lowering intake after stroke may help to prevent the development of cognitive impairment. Antihypertensive therapies and optimal medication therapy were strongly associated with beneficial long-term cognitive function in patients with ischemic stroke without a history of AF. However, antiplatelet monotherapy use alone was borderline associated with a reduction in risk of cognitive impairment. These differences in drug regimens suggest that optimal combinations of antithrombotic agents, antihypertensive therapies, and lipid-lowering agents appear to protect patients with ischemic stroke from cognitive impairment. Dual antiplatelet therapies and anticoagulants were both associated with a long-term protective effect against cognitive impairment. This finding was also observed in subgroup analyses in ischemic stroke, which supports that the prescription of dual antiplatelet therapies with close monitoring for patients who do not tolerate anticoagulant therapy with warfarin could help to prevent cognitive impairment. On the other hand, there is no evidence from this population sample that antihypertensive drugs are associated with reduced cognitive deficit in patients with hemorrhagic stroke and ischemic strokes with AF. Of all combination drug therapies investigated in this study, those associated with a reduction in risk of cognitive impairment were statins, warfarin, a combination of aspirin and dipyridamole, and diuretics or ACEIs or the combination of a diuretic and an ACEI. Although the choice of specific drugs should be individualized to include consideration of specific patient characteristics, this investigation has provided valuable information on the associated effect of different combinations on the long-term cognitive impairment in a broad spectrum of stroke patients. There are some limitations to this study. This prospective, population-based study has produced estimates of cognitive status in stroke survivors but with no comparison with the nonstroke population. Data were based mainly on prescribed drugs without taking into account patients systolic blood pressure or lipid profile target levels, and we have no information on patients adherence to drugs, which may attenuate the effect of treatments, particularly in the interaction analyses between different drugs. In addition, data on lifestyle changes such as diet and exercise, which may provide added cognitive benefits, were not included in this study. It was not possible to examine the influence of educational status on cognitive function in this register of stroke survivors because of missing or

7 Douiri et al Stroke Secondary Prevention and Cognitive Function 1347 Figure 3. Adjusted longitudinal analysis of effect of treatment on the relative risk (RR) of cognitive impairment in patients with hemorrhagic and ischemic stroke by drug class. AF indicates atrial fibrillation; and CI, confidence interval. unstated education level data. However, we included socioeconomic status of the SLSR patients using the Index of Multiple Deprivation, which could serve as a surrogate for educational status because individuals in high socioeconomic levels usually tend to have higher educational levels. Furthermore, the psychometric screening tools used in this study may underestimate the incidence of cognitive impairment, particularly mild cognitive impairment. It has been shown that the Mini-Mental State Examination and Abbreviated Mental Test are insensitive to mild cognitive impairment and executive function Despite these limitations in detecting mild cases, this study has shown a protective association with optimal secondary prevention drugs. Similar large, long-term studies of poststroke cognitive function using sensitive tools to detect mild cognitive impairment and executive function such as the Montreal Cognitive Assessment 28,32 would be of benefit to confirm our finding that optimal poststroke pharmacotherapy for secondary prevention could influence the process of cognitive impairment. Conclusions Controlling vascular risk factors is an important preventive treatment strategy to decrease the risk of stroke recurrence and cognitive impairment. Effective poststroke secondary prevention could help to prevent or delay the onset of severe global cognitive impairment. Differences in and overlaps of vascular risk factors are common among stroke patients, and personalized preventive strategies are critical for altering severe cognitive deficit. Given the high risk of cognitive impairment after stroke, this study shows that optimal preventive intervention and strategic planning are needed for health systems to avert or delay the incidence of cognitive decline progression among stroke survivors. Acknowledgments We thank all the patients, their families, and the healthcare professionals involved. Particular thanks go to all the fieldworkers and the whole team who have collected data since 1995 for the SLSR. Sources of Funding The study was funded by the Northern & Yorkshire NHS R&D Program in Cardiovascular Disease and Stroke, Guy s and St. Thomas Hospital Charity, Stanley Thomas Johnson Foundation, the Stroke Association, Department of Health Healthcare Quality Improvement Partnership grant, and National Institute for Health Research Program grant (RP-PG ). Drs Douiri, McKevitt, and Professor Wolfe acknowledge financial support from the National Institute for Health Research (NIHR) Biomedical Research Center (BRC) based at Guy s and St. Thomas NHS Foundation Trust and King s College London. The views expressed in this article are those of the authors and not necessarily those of the BRC, the NHS, the NIHR, or the Department of Health. None. Disclosures References 1. Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol. 2005;4: Mackay J, Mensah GA. The Atlas of Heart Disease and Stroke. Geneva, Switzerland: World Health Organization; Langa KM, Chernew ME, Kabeto MU, Herzog AR, Ofstedal MB, Willis RJ, Wallace RB, Mucha LM, Straus WL, Fendrick AM. National estimates of the quantity and cost of informal caregiving for the elderly with dementia. J Gen Intern Med. 2001;16:

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Framingham stroke risk profile and lowered cognitive performance. Stroke. 2004;35: Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzman DM, Rosenberg GA, Wallin A, Dichgans M, Marler JR, Leblanc GG. National Institute of Neurological Disorders and Stroke--Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke. 2006;37: Clinical Perspective The prevalence of cognitive impairment in patients with previous stroke is high, with up to a quarter of patients affected. The cognitive impairment is due at least in part to progressive ischemic damage occurring after the index event, so it seems logical that secondary prevention measures will reduce not only the risk of recurrent ischemic episodes but also the risk of global cognitive decline. This study shows that treating with antihypertensive medication or a combination of aspirin and dipyridamole significantly protects against cognitive decline. The combination of antihypertensives, antithrombotics, and lipid-lowering drugs reduces the risk of cognitive impairment by about half. The protective effect was not seen in hemorrhagic stroke patients or in patients whose stroke was associated with atrial fibrillation.