Quantifying the risk of heart disease following acute ischaemic stroke: a comprehensive meta-analysis of over 50,000 subjects For peer review only

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1 Quantifying the risk of heart disease following acute ischaemic stroke: a comprehensive meta-analysis of over 0,000 subjects Journal: BMJ Open Manuscript ID: bmjopen-0-00 Article Type: Research Date Submitted by the Author: -Jul-0 Complete List of Authors: Gunnoo, Trishna; Imperial College London, Hasan, Nazeeha; Imperial College London, khan, Muhammod; Royal Holloway college, University of London, Slark, Julia; University of Auckland, Bentley, Paul; Imperial College London, Sharma, Pankaj; University of London, <b>primary Subject Heading</b>: Cardiovascular medicine Secondary Subject Heading: Neurology, Cardiovascular medicine Keywords: Stroke < NEUROLOGY, Audit < CARDIOLOGY, Ischaemic heart disease < CARDIOLOGY, Myocardial infarction < CARDIOLOGY BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

2 Page of 0 BMJ Open Quantifying the risk of heart disease following acute ischaemic stroke: a comprehensive metaanalysis of over 0,000 subjects Trishna Gunnoo, MBBS BSc ; Nazeeha Hasan, PhD ; Muhammad Saleem Khan, MSc, Julia Slark, PhD ; Paul Bentley, MRCP PhD ; Pankaj Sharma, MD PhD FRCP () Institute of Cardiovascular Research, Royal Holloway University of London (ICRUL), London UK () Department of Medicine, Imperial College London, UK () Faculty of Medical & Health Sciences, University of Auckland, New Zealand Correspondence: pankaj.sharma@rhul.ac.uk Key words: ischaemic stroke, asymptomatic coronary artery disease, myocardial infarction, prevalence, risk, meta-analysis, systematic review Word count: 0 (excluding references, title page and abstract) BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

3 Page of Abstract Objective: Following acute stroke there is a high risk of recurrence. However, the leading cause of its mortality is due to coronary artery disease (CAD) and myocardial infarction (MI) but that risk has not been robustly quantified. We sought to reliably quantify the risk of ischaemic heart disease (IHD) in patients presenting with acute ischaemic stroke in the absence of a known cardiac history. Setting: A meta-analysis study. PubMed, MEDLINE, EMBASE and Google Scholar were searched for potential studies. Included studies reported an acute cerebral ischaemic event in patients without known IHD and follow-up for CAD or MI within one year. Using arcsine transformed proportions for meta-analysis, studies were combined using a generic inverse variance random-effects model to calculate pooled standardised mean difference and % confidence intervals. These were interpreted as percentage prevalence or incidence of CAD in acute ischaemic stroke. Results: Sixteen studies with acute ischaemic stroke patients demonstrated a mean average of asymptomatic CAD in %. Anatomical methods of CAD detection revealed a prevalence of asymptomatic 0% coronary stenosis in % (% CI -%; p<0.0000). Eight studies with ischaemic stroke patients revealed an overall risk of MI in the year following stroke of % (% CI - %; p<0.0000) despite the absence of any cardiac history. Conclusions: One-third of ischaemic stroke patients with no previous cardiac history have more than 0% coronary stenosis and % are at risk of developing MI within a year. Our findings provide a reliable quantitative measure of the risk of IHD following ischaemic stroke in patients with no previous cardiac history. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

4 Page of 0 BMJ Open What is already known about the subject? Most stroke patients do not die of stroke but rather heart disease. As stroke is largely and atherosclerotic disease, it is likely that other non-cerebral vessels are likely affected including cardiac vessels. However, robust assessment of the extent of coronary vessel involvement in stroke patients in the absence of previous cardiac history is debated. What does this study add? We have robustly quantified the risk of cardiac disease following a stroke in patients with no previous cardiac history. One-third of stroke patients have greater than 0% coronary stenosis. To the best of our knowledge this is the largest such study carried out to-date. How might this impact on clinical practice? This work has important implications for managing cardiac sub-clinical disease in stroke patient and providing an accurate risk profile to these high-risk patients. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

5 Page of Introduction Cardiovascular disease is the single leading cause of mortality worldwide [], costing the UK economy billion every year []. Given our ageing population and global increase in noncommunicable diseases, the burden of heart disease and stroke are becoming an ever increasing public health issue []. Atherosclerosis as a systemic disease process; common risk factors and pathophysiology exists between ischaemic stroke, coronary artery disease (CAD) and myocardial infarction (MI) []. Any acute atherosclerotic event increases the risk for another in the same or different vascular bed []. Following an acute ischaemic stroke there is a high short-term risk of recurrence; however, the leading cause of mortality in these patients is MI []. A number of studies have evaluated the relationship between stroke and MI yet show varying results on the rate of subsequent cardiovascular events [ ] with wide discrepancy in the observed prevalence of asymptomatic CAD ranging reported from -0% [0 ] following an ischaemic stroke. While it is probable that those with an established history of IHD will account for the majority of subsequent coronary events following stroke, the true risk of CAD and MI in stroke patients in the absence of previous cardiac history is unclear. In an attempt to provide clarity and quantification on this issue, we conducted a comprehensive systematic review and meta-analysis to determine the prevalence of asymptomatic CAD and incidence of MI in acute ischaemic stroke patients in the absence of previous cardiac disease. To the best of our knowledge, this is the largest such study conducted to date. Methods Data Sources A comprehensive search was performed using electronic databases PubMed, MEDLINE, EMBASE and Google Scholar, to identify all relevant published studies up to April 0. The search strategy included keywords with synonyms and MeSH terms: stroke, cerebrovascular accident, brain/cerebral infarction, transient ischaemic attack/tia, asymptomatic coronary artery disease/cad, silent ischaemic heart disease, silent myocardial infarction, silent myocardial ischaemia with and/or as the BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

6 Page of 0 BMJ Open Boolean operator (Supplement S). Foreign language literature was included and papers translated where necessary. Manual searches identified additional studies from the references of electronically identified studies. Study Selection Studies were selected if they fulfilled the following inclusion criteria: ) acute onset of stroke or TIA; ) lesion confirmed by brain imaging (CT/MRI) or at autopsy; ) investigations for CAD with acceptable levels of sensitivity and specificity []; ) diagnosis of MI according to criteria from joint definition proposed by the European Society of Cardiology and the American College of Cardiology [], and; ) follow-up data for CAD or MI up to one year from stroke onset. Studies were excluded if: ) age < years; ) haemorrhagic stroke; and ) previous history of IHD (CAD or MI), unless subgroup data was presented for extraction. Due to the low specificity of ECG to detect ischemia, investigations using ECG or exercise ECG alone were excluded, except when in conjunction with another modality of testing such as troponin []. Where duplicate studies were identified, data from the latest dataset was used. To ensure inclusion of high quality studies, only studies including more than 0 participants were included for final analysis. Study quality was assessed using STROBE [] and MOOSE [] criteria for meta-analyses of observational studies and PRISMA guidelines were followed []. Data Extraction Data extraction was undertaken independently by two investigators (TG and JS) and any disagreements were resolved by consensus or by the opinion of a third reviewer. For each selected study, the total population of ischaemic stroke patients without a history of IHD and the proportion with asymptomatic CAD or MI were extracted. Additional information on study design, method of CAD/MI diagnosis, as well as baseline characteristics such as mean age, sex, ethnicity and the presence of risk factors for cardiovascular disease was documented. Statistical Analysis As this was a one-sided investigation without a comparison group, a double arcsine transformation was used for proportion meta-analysis []. For each study, the proportion of stroke patients who were positive for asymptomatic CAD or silent MI from the total population of patients was recorded. The standardised mean difference (SMD) and standard error for each proportion was then calculated and the results were combined using a generic inverse variance random-effects model to calculate BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

7 Page of weighted pooled SMD and % CIs using Review Manager [0]. The concluding result was interpreted as percentage prevalence of CAD or incidence of MI. To accurately determine the prevalence of asymptomatic CAD, meta-analysis was restricted to studies reporting more sensitive methods of CAD investigation and significant coronary artery occlusion ( 0% stenosis). Tests for heterogeneity and sensitivity analysis were performed by systematically and iteratively by removing one study at a time and re-running the model to determine the overall effect size. Based on the statistical method used, it was not possible or appropriate to assess for publication bias in this study []. Results 0 records were identified through comprehensive searching and following screening and exclusions a total of studies met our inclusion criteria (Supplementary Figure ). Sixteen studies with acute ischaemic stroke/tia patients investigated for asymptomatic CAD and eight studies with patients demonstrated risk of MI following ischaemic stroke in those without a prior cardiac history (Table). All studies recruited patients prospectively. Prevalence of Asymptomatic CAD There were a similar proportion of males to females in each of the included studies, with average of % male and mean age of years. With the exception of a single autopsy study [], where the median time between stroke and death was days (interquartile range, - days), all studies recruited stroke patients within 0 days. Whilst most studies consisted of ischaemic stroke of atherosclerotic aetiology, studies excluded cardioembolic stroke [ 0 ] and only one study included those with suspected cardioembolism []. Three studies looked exclusively at first ischaemic stroke [ ]. There was limited data available for the risk factors present in patients found to have asymptomatic CAD; where evaluated, there were varying levels of all risk factors, except hypertension which coexisted in -% of stroke patients and as high as % in one study []. Due to the variety of methods of investigation with varying levels of sensitivity, and wide range of results, it was not appropriate to perform meta-analysis on all studies but the mean average of asymptomatic CAD was %. Meta-analysis was performed on 0 studies using coronary angiography, CTCA (Computed Tomography Coronary Angiography) and autopsy as more sensitive investigations for asymptomatic BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

8 Page of 0 BMJ Open CAD in stroke patients. This revealed for any degree of coronary plaque a pooled SMD of.0 (%.-.; T²=0.0; I²=%; p<0.0000) equivalent to a prevalence of % (% CI -%). A pooled SMD of. (% CI 0.-., T²=0.; I²=%; p<0.0000) was observed (Supplementary Figure ) equivalent to a prevalence for 0% asymptomatic coronary stenosis of % (% CI -%). Significant heterogeneity was observed, which was unchanged following iterative analysis, removal of patients with TIA [ ] and a unique autopsy study conducted prior to the year 000 []. Prevalence of any degree of coronary artery stenosis was not statistically significant, most likely due to high variance in the studies analysed. However, removal of non-caucasian populations [ - -] yielded a statistically significant pooled SMD of.0 (% CI 0.-.; p=0.0; T²=0.0; I²=%), equivalent to an asymptomatic CAD prevalence of % (% CI -0%). Incidence of Myocardial Infarction With the exception of one study [0], all eight studies prospectively recruited stroke patients. The majority of studies were based in predominately Caucasian populations from across Europe, Canada and the USA. The largest observational study included a total of participants from multiple stroke centres across Austria []. For each study there were similar demographics including a balanced proportion of males to females, with an average of % males, and a mean age of 0 years old. There were limited data evaluating risk factors in those patients with MI which was diagnosed within months of the acute ischaemic stroke and, in most studies in-hospital. A pooled SMD of 0. (% CI 0.-0.; T²=0.0; I²=%; p<0.0000) equivalent to a total MI incidence of % (% CI -%) in stroke patients with no previous cardiac history (Supplementary Figure ). Discussion This study which quantities the risk of IHD following ischaemic stroke revealed that over half of such stroke patients have evidence of asymptomatic coronary plaque and one in three patients has an occlusion of clinical significance (>0% stenosis). Given the strong evidence linking coronary artery stenosis >0% to the high risk of acute MI [ ], and our findings that % of ischaemic stroke patients suffer from MI within one year, it is clear that many more individuals with no prior history of IHD may be at risk of MI than previously appreciated. Our results are supported by previously published data that demonstrate a high burden of coronary plaque even when there is no previous evidence of systemic disease. The Asymptomatic Myocardial BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

9 Page of Ischemia in Stroke and Atherosclerotic Disease (AMISTAD) study set out to determine whether asymptomatic coronary atherosclerosis predicts a higher risk of major vascular event on stroke patients, and found that from baseline diagnosis of asymptomatic CAD, the two year Hazard Ratio of stroke patients developing vessel disease (coronary stenosis >0%) was. (% CI.-. []. In the Multiple Atherosclerosis Site in Stroke (MASS) study, stroke patients with no atherosclerotic plaque in the cerebral arteries demonstrated prevalence of coronary plaque as high as % []. Thus, despite the limitations in predicting the presence of asymptomatic CAD based on the detection of extra-cardiac atherosclerosis, an association exists and there is a significant global vascular burden in patients with stroke. Following stroke/tia patients with no known IHD history, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated not only the high risk of cardiac events, but also supports the benefits of statin therapy in the treatment of stroke when considering this ischaemic event as a coronary risk equivalent [ ]. In determining the beneficial effects of blood pressure reduction, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) found that.% of ischemic stroke patients went on to have non-fatal MI or death accountable to CHD, concluding that secondary prevention should target not only the cause of the original event but also mixed vascular risk factors []. The results from an older meta-analysis [], calculated a.% annual risk of MI after ischaemic stroke/tia, although it failed to estimate the risk of MI according to previous cardiac history. Our results support proposals of the American Heart Association and American Stroke Association in recommending that stroke patients be considered for further cardiac evaluation based on their individual cardiovascular risk factor profile [-]. Despite our efforts, no meta-analysis is free from publication bias. A considerable level of heterogeneity in our analyses reflects clinical differences between the studies with inclusion of different subtypes of ischaemic event partly accounting for some of the observed variation. To limit the effect of major differences in clinical cardiovascular care occurring studies prior to year 000 were removed. Quality control was improved by incorporating studies with at least 0 subjects. Study populations located worldwide demonstrated the global burden of asymptomatic disease; however, our results should be extrapolated to certain ancestral populations with caution. We demonstrate up to a third of ischaemic stroke patients with no previous cardiac history have more than 0% coronary stenosis and % are at risk of developing MI within a year even in the BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

10 Page of 0 BMJ Open absence of any previous cardiac symptoms. Thus, cardiac risk posed to ischaemic stroke patients is substantial even in the absence of a prior IHD history. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

11 Page 0 of Author contributions: PS conceived the idea. TG and JS undertook the preliminary searches and designed the search criteria. NH, PB and MS undertook statistical revision. All authors contributed intellectually to the final manuscript. Competing interests: None. Funding: PS was, and PB is, funded by Department of Health (UK) Senior Fellowships. NZ is funded by the MRC Data sharing statement: All data will be uploaded to the BMJ Open resource. 0 BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

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15 Page of SUPPLEMENTARY MATERIAL Figure : Flow diagram of search strategy BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

16 Page of 0 BMJ Open Table: Table of study characteristics Study Gongora-Rivera 00 MASS [] Amarenco 0 AMISTAD [] Location France Male (%) Median Age 0 Ischaemic Event Method of Investigation N Asymptomatic CAD MI fatal stroke Autopsy/pathology: plaques, ischaemia, MI necrosis/fibrosis >cm n % >0% stenosis n % 0 % France stroke coronary angiography % - - Ahn 0 [] Korea stroke/tia CTCA % Calvet 00 PRECORIS [] France 0 stroke/tia CTCA % - - Cha 0 [] Korea stroke/tia CTCA 0 0 % Cho 0 [] Korea 0 st stroke CTCA % - - Hoshino 00 [ ] Japan st stroke CTCA 00 % - - Kim 0 [] Korea 0 stroke CTCA 00 % - - Seo 00 [] Korea stroke CTCA % - - Yoon 00 [] Korea 0 stroke/tia CTCA 0 0 % - - Arauz 00 [] Mexico st stroke stress SPECT Chimowitz [0] Di Pasquale [] Urbinati [ ] Nighoghossian 00 [0] Leys 00 DETECT [] Gattringer 0 [ ] Jensen 00 [] USA stroke/tia Italy Italy stroke/tia of carotid system stroke/tia of carotid system stress thallium myocardial scintigraphy exercise thallium myocardial imaging exercise thallium myocardial scintigraphy France 0 stroke stress echo France stroke ECG + echo Austria stroke/tia Troponin + ECG Denmark stroke Troponin + ECG Lee 00 [0] Korea stroke Troponin + ECG Liao 00 [] Canada stroke Troponin + ECG Mathias 0 [ ] Prosser 00 VISTA [] USA stroke Troponin + ECG + echo Canada Germany Sweden UK, US stroke cardiac mortality & serious cardiac adverse events Song 00 [] Korea stroke Troponin + ECG BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

17 Page of Figure : Meta-analysis and forest plot for prevalence of asymptomatic coronary stenosis 0% in acute ischaemic stroke/transient ischaemic attack (TIA) BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

18 Page of 0 BMJ Open Figure : Meta-analysis and forest plot illustrating the prevalence of MI in acute ischaemic stroke patients with no known IHD Std. Mean Difference = Standardised Mean Difference IV = Inverse Variance Method; % CI = % Confidence Intervals + Total = number of patients positive for asymptomatic coronary artery disease N Total = total number of acute ischaemic stroke/tia patients with no known ischaemic heart disease BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

19 Page of SUPPLEMENTARY MATERIAL S: Search strategy terms. stroke. cerebrovascular accident OR CVA. brain OR cerebral infarction. transient ischaemic attack OR transient ischemic attack OR TIA. Cerebral Infarction/ or Stroke/ or Brain Ischemia/ or Ischemic Attack, Transient/. OR OR OR OR. asymptomatic coronary artery disease OR asymptomatic CAD. asymptomatic coronary heart disease OR asymptomatic CHD. subclinical ischaemic heart disease 0. silent myocardial infarction OR silent MI. silent myocardial ischaemia. OR OR OR 0 OR. AND. limit to humans S: Arcsine transformation formulae & methodology n = number of stroke patients without known ischaemic heart disease Calculate: Proportion (P) = number of positive events / n Transform data: Standardised Mean Difference (SMD) = x arcsin ( P) Standard Error (SE) = / n Enter SMD and SE into Review Manager using Generic Inverse Variance data type and statistical method, with random-effects analysis model (DerSimonian and Laird) to produce pooled effect measure SMD = (A) Transform data back to original scale to give pooled percentage prevalence % Prevalence = (Sin x ( A / ) ) x 00 BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

20 Page of 0 BMJ Open Section/topic TITLE PRISMA 00 Checklist # Checklist item Title Identify the report as a systematic review, meta-analysis, or both. 0 ABSTRACT Structured summary Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale Describe the rationale for the review in the context of what is already known. Objectives Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, 0 outcomes, and study design (PICOS). METHODS Protocol and registration Eligibility criteria Information sources 0 Search Study selection Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 0 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. Data items List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 0 Risk of bias in individual Describe methods used for assessing risk of bias of individual studies (including specification of whether this was studies done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures State the principal summary measures (e.g., risk ratio, difference in means). Synthesis of results Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I ) for each meta-analysis. on December 0 by guest. Protected by copyright. Reported on page # BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from

21 Page 0 of 0 Section/topic 0 Additional analyses PRISMA 00 Checklist Risk of bias across studies # Checklist item Page of Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. RESULTS Study selection Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. - Study characteristics For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and - provide the citations. 0 Risk of bias within studies Present data on risk of bias of each study and, if available, any outcome level assessment (see item ). - Results of individual studies 0 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each - intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results Present results of each meta-analysis done, including confidence intervals and measures of consistency. - Risk of bias across studies Present results of any assessment of risk of bias across studies (see Item ). - Additional analysis Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item ]). - DISCUSSION 0 Summary of evidence Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 0 identified research, reporting bias). Conclusions Provide a general interpretation of the results in the context of other evidence, and implications for future research. 0 FUNDING Funding Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. Page of Reported on page # 0 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (00). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med (): e0000. doi:0./journal.pmed0000 For more information, visit: on December 0 by guest. Protected by copyright. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from -

22 Quantifying the risk of heart disease following acute ischaemic stroke: a meta-analysis of over 0,000 subjects Journal: BMJ Open Manuscript ID bmjopen-0-00.r Article Type: Research Date Submitted by the Author: -Oct-0 Complete List of Authors: Gunnoo, Trishna; Imperial College London, Hasan, Nazeeha; Imperial College London, khan, Muhammod; Royal Holloway college, University of London, Slark, Julia; University of Auckland, Bentley, Paul; Imperial College London, Sharma, Pankaj; University of London, <b>primary Subject Heading</b>: Cardiovascular medicine Secondary Subject Heading: Neurology, Cardiovascular medicine Keywords: Stroke < NEUROLOGY, Audit < CARDIOLOGY, Ischaemic heart disease < CARDIOLOGY, Myocardial infarction < CARDIOLOGY BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

23 Page of BMJ Open Quantifying the risk of heart disease following acute ischaemic stroke: a meta-analysis of over 0,000 subjects Trishna Gunnoo, MBBS BSc ; Nazeeha Hasan, PhD ; Muhammad Saleem Khan, MSc ; Julia Slark, PhD ; Paul Bentley, MRCP PhD ; Pankaj Sharma, MD PhD FRCP () Department of Medicine, Imperial College London, UK () Ashford & St Peters Hospital, Surrey, UK () Faculty of Medical & Health Sciences, University of Auckland, New Zealand () Institute of Cardiovascular Research Royal Holloway University of London (ICRUL), Correspondence: pankaj.sharma@rhul.ac.uk Institute of Cardiovascular Research Royal Holloway University of London (ICRUL) Egham London TW0 0EX Key words: ischaemic stroke, asymptomatic coronary artery disease, myocardial infarction, prevalence, risk, meta-analysis, systematic review Word count: 0 (excluding references, title page, abstract and figures) BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

24 Page of Abstract Objective: Following an acute stroke there is a high risk of recurrence. However, the leading cause of its mortality is due to coronary artery disease (CAD) and myocardial infarction (MI) but that risk has not been robustly quantified. We sought to reliably quantify the risk of ischaemic heart disease (IHD) in patients presenting with acute ischaemic stroke (AIS) in the absence of a known cardiac history. Setting: A meta-analysis study. PubMed, MEDLINE, EMBASE and Google Scholar were searched for potential studies to October 0. Included studies reported an acute cerebral ischaemic event and followed for CAD or MI within one year in patients without known IHD. Using arcsine transformed proportions for meta-analysis, studies were combined using a generic inverse variance randomeffects model to calculate pooled standardised mean difference and % confidence intervals. These were interpreted as percentage prevalence of CAD or incidence of MI following AIS. Results: Seventeen studies with AIS patients demonstrated a mean average of asymptomatic CAD in %. Anatomical methods of CAD detection revealed a prevalence of asymptomatic 0% coronary stenosis in % (% CI -%; p<0.0000). Eight studies with ischaemic stroke patients revealed an overall risk of MI in the year following stroke of % (% CI -%; p<0.0000) despite the absence of any cardiac history. Conclusions: One-third of ischaemic stroke patients with no previous cardiac history have more than 0% coronary stenosis and % are at risk of developing MI within a year. Our findings provide a reliable quantitative measure of the risk of IHD following AIS in patients with no previous cardiac history. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

25 Page of BMJ Open Article summary Strengths and limitations of this study We study the risk of heart disease following a stroke in those patients with no previous cardiac history. This study is the largest of its kind and, by bringing together multiple datasets, robustly quantifies the risk of heart disease following stroke. As with all meta-analyses the main limitation of this work relates to publication bias. Most stroke patients die of heart disease One in three ischaemic stroke patients with no previous cardiac history have more than 0% coronary stenosis % are at risk of developing MI within a year of their stroke Stroke patients need to be screened for silent heart disease and appropriate and aggressive management of total cardiovascular risk factors is required What is already known about the subject? Most stroke patients do not die of stroke but rather heart disease. As stroke is largely an atherosclerotic disease, it is likely that other non-cerebral vessels are likely affected including cardiac vessels. However, robust assessment of the extent of coronary vessel involvement in stroke patients in the absence of previous cardiac history is not available. What does this study add? We have robustly quantified the risk of cardiac disease following a stroke in patients with no previous cardiac history. One-third of stroke patients have a greater than 0% coronary stenosis, and % are at risk of suffering a heart attack within one year following their stroke. To the best of our knowledge this is the largest such study carried out to-date. How might this impact on clinical practice? This work has important implications for managing cardiac sub-clinical disease in stroke patients and provides an accurate risk profile to these high-risk patients. More targeted clinical management decisions for secondary prevention strategies and attention to the patient s overall cardiovascular risk profile are now able to be made. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

26 Page of Introduction Cardiovascular disease is the single leading cause of mortality worldwide, costing the UK economy billion every year, with The National Health Service in England spending around. billion on CVD in 0/0. Given our ageing population and global increase in non-communicable diseases, the burden of heart disease and stroke are becoming an ever increasing public health issue. Atherosclerosis as a systemic disease process; common risk factors and pathophysiology exists between ischaemic stroke, coronary artery disease (CAD) and myocardial infarction (MI). Any acute atherosclerotic event increases the risk for another in the same or different vascular bed. Following an acute ischaemic stroke (AIS) there is a high short-term risk of recurrence; however, the leading cause of mortality in these patients is MI.,, A number of studies have evaluated the relationship between stroke and MI yet show varying results on the rate of subsequent cardiovascular events,, with wide discrepancy in the observed prevalence of asymptomatic CAD ranging -0% following AIS. 0, While it is probable that those with an established history of IHD will account for the majority of subsequent coronary events following AIS, the true risk of CAD and MI in stroke patients in the absence of previous cardiac history is unclear. In an attempt to provide clarity and quantification on this issue, we conducted a systematic review and meta-analysis to determine the prevalence of asymptomatic CAD and incidence of MI in AIS patients in the absence of previous cardiac disease. To the best of our knowledge, this is the largest such study conducted to-date. Methods Data Sources A search was performed using electronic databases PubMed, MEDLINE, EMBASE and Google Scholar, to identify all relevant published studies up to October 0. The search strategy included keywords with synonyms and MeSH terms: [stroke] OR [cerebrovascular accident] OR [CVA brain] OR [cerebral infarction] OR [transient ischaemic attack] OR [transient ischemic attack] OR [TIA] OR [Cerebral Infarction] OR [Stroke] OR [Brain Ischemia] OR [Ischemic Attack] OR [Transient], along with [asymptomatic coronary artery disease] OR [asymptomatic CAD]; [asymptomatic coronary heart disease] OR [asymptomatic CHD], along with [subclinical ischaemic heart disease] OR [silent myocardial infarction] OR [silent MI] OR [silent myocardial ischaemia]. Search criteria were limited to humans. All terms where then subjected to interaction with each other with Boolean operators AND or OR. Foreign language literature was included and papers translated where necessary. Manual searches identified additional studies from the references of electronically identified studies. BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

27 Page of BMJ Open Study Selection Studies were selected if they fulfilled the following inclusion criteria: ) acute onset of stroke or TIA; ) lesion confirmed by brain imaging (CT/MRI) or at autopsy; ) investigations for CAD with acceptable levels of sensitivity and specificity; ) diagnosis of MI according to criteria of the third universal definition proposed by international expert consensus, and; ) follow-up data for CAD or MI up to one year from stroke onset. Studies were excluded if: ) age < years; ) haemorrhagic stroke; and ) previous history of IHD (CAD or MI), unless subgroup data was presented for extraction. Due to the low specificity of ECG to detect ischemia, investigations using ECG or exercise ECG alone were excluded, except when in conjunction with another modality of testing such as troponin. Where duplicate studies were identified, data from the latest dataset was used. In an attempt to enhance the quality of our analyses only studies that recruited a minimum of 0 participants were included for final analysis. We used STROBE and MOOSE criteria for meta-analyses of observational studies and PRISMA guidelines were followed. Data Extraction Data extraction was undertaken independently by two investigators (TG and JS) and any disagreements were resolved by consensus or by the opinion of a third reviewer. For each selected study, the total population of ischaemic stroke patients without a history of IHD and the proportion with asymptomatic CAD or MI were extracted. Additional information on study design, method of CAD/MI diagnosis, as well as baseline characteristics such as mean age, sex, ethnicity and the presence of risk factors for cardiovascular disease was documented. Statistical Analysis As this was a one-sided investigation without a comparison group, a double arcsine transformation was used for proportion meta-analysis., For each study, the proportion of stroke patients who were positive for asymptomatic CAD or silent MI from the total population of patients was recorded. The proportions P within the populations were calculated by dividing the number of positive events by the number of stroke patients without known heart disease. The standardised mean difference (SMD) and standard error for each proportion was then calculated: Standardised Mean Difference (SMD) = x arcsin ( P) and a Standard Error (SE) was generated by / n. The results were combined using a generic inverse variance random-effects model (DerSimonian and Laird) to calculate weighted pooled SMD and % CIs using Review Manager SMD = (A). 0 The concluding result was interpreted as percentage prevalence of CAD or incidence of MI by transforming data back to original scale to give pooled percentage prevalence: % Prevalence = (Sin x (A/)) x 00 ( the_standardized_mean_diffe rence.htm) BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

28 Page of To accurately determine the prevalence of asymptomatic CAD, meta-analysis was restricted to studies reporting more sensitive methods of CAD investigation and significant coronary artery occlusion ( 0% stenosis). Tests for heterogeneity and sensitivity analysis were performed by systematically and iteratively by removing one study at a time and re-running the model to determine the overall effect size. Based on the statistical method used, it was not possible or appropriate to assess for publication bias in this study. Table One: Included studies and their characteristics BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.

29 Page of BMJ Open STUDY Location Gongora-Rivera 00 MASS France Male (%) Mean Age Ischaemic Event Method of Investigation N 0 fatal stroke Autopsy: plaque, ischaemia, MI necrosis/fibrosis >cm Asymptomatic CAD n % >0% stenosis MI n % 0 % Amarenco 0 France stroke Coronary angiography % - - AMISTAD Ahn 0 Korea stroke/tia CTCA % Calvet 00 France 0 stroke/tia CTCA % - - PRECORIS Cha 0 Korea stroke/tia CTCA 0 0 % Cho 0 Korea 0 st stroke CTCA % - - Hoshino 00 Japan st stroke CTCA 00 % - - Iwasaki 0 Japan stroke CCS (calcium score) % - - Kim 0 Korea 0 stroke CTCA 00 % - - Seo 00 Korea stroke CTCA % - - Yoon 00 Korea 0 stroke/tia CTCA 0 0 % - - Arauz 00 0 Mexico st stroke Stress SPECT Chimowitz USA stroke/tia Di Pasquale Italy stroke/tia of carotid system Urbinati Italy stroke/tia of carotid system Stress thallium myocardial scintigraphy Exercise thallium myocardial imaging Exercise thallium myocardial scintigraphy Nighoghossian 0 France 0 stroke Stress echo Leys 00 France stroke ECG + echo DETECT Gattringer 0 Austria stroke/tia Troponin + ECG Jensen 00 Denmark stroke Troponin + ECG Lee 00 Korea stroke Troponin + ECG Liao 00 Canada stroke Troponin + ECG Mathias 0 USA stroke Troponin + ECG + echo Prosser 00 VISTA 0 Canada Germany Sweden UK, US stroke Cardiac mortality & serious cardiac adverse events Song 00 Korea stroke Troponin + ECG BMJ Open: first published as 0./bmjopen-0-00 on 0 January 0. Downloaded from on December 0 by guest. Protected by copyright.