Long-term risk of major adverse cardiovascular events following ischemic stroke or TIA

Data are scarce on long-term outcomes after ischemic stroke (IS) or transient ischemic attack (TIA). In this prospective cohort study, we examined the cumulative incidence of major adverse cardiovascular events (MACE) after IS and TIA using a competing risk model and factors associated with new events using a Cox-proportional hazard regression model. All patients discharged alive from Östersund Hospital with IS or TIA between 2010 and 2013 (n = 1535) were followed until 31 December 2017. The primary endpoint was a composite of IS, type 1 acute myocardial infarction (AMI), and cardiovascular (CV) death. Secondary endpoints were the individual components of the primary endpoint, in all patients and separated in IS and TIA subgroups. The cumulative incidence of MACE (median follow-up: 4.4 years) was 12.8% (95% CI: 11.2–14.6) within 1 year after discharge and 35.6% (95% CI: 31.8–39.4) by the end of follow-up. The risk of MACE and CV death was significantly increased in IS compared to TIA (p-values < 0.05), but not the risk of IS or type 1 AMI. Age, kidney failure, prior IS, prior AMI, congestive heart failure, atrial fibrillation, and impaired functional status, were associated with an increased risk of MACE. The risk of recurring events after IS and TIA is high. IS patients have a higher risk of MACE and CV death than TIA patients.

Supplemental Table S2. Number of contributing events in the MACE composite presented in Table  2. Except for death and revascularisation, outcome events were identified based on a review of medical discharge records and registered discharge diagnoses. Consequently, potential events of myocardial infarction, stroke, or TIA required the patient to be admitted to hospital and hospitalised to be included as outcome events. Identification of revascularisation events was based on registry data, which included both in-patient and outpatient procedures performed at Östersund Hospital or the University Hospital of Northern Sweden. The patient medical record is electronic and connected with the National Civil Register. When a patient died within the national boarders of Sweden, this information, including the date of death, was usually available within 24 hours. All care givers within Jämtland-Härjedalen used the same electronic medical record. Thus, for events of death occurring within the county, all medical documentation except for forensic protocols was available to the reviewers. In a few cases (n=14), the underlying cause of death could not be classified as cardiovascular or noncardiovascular due to absent or insufficient documentation.

Death
Classified as cardiovascular, non-cardiovascular, or undetermined.
A. Cardiovascular death Includes death due to any of the following conditions: A. Acute myocardial infarction As defined below or verified by autopsy. Includes death by any cardiovascular mechanism (arrhythmia, sudden cardiac death, congestive heart failure, stroke, pulmonary embolism, peripheral artery disease, invasive revascularisation procedure) within 30 days of an acute myocardial infarction.
B. Sudden cardiac death Unexpected death, not caused by acute myocardial infarction. Includes death according to any of the following scenarios: i. Witnessed and occurring without new or worsening symptoms; ii.
Witnessed within 60 minutes after onset or worsening of cardiac symptoms; iii.
Witnessed or unwitnessed with arrhythmia identified by ECG recording, defibrillator monitoring, or implantable device such as cardioverter defibrillator or loop recorder; iv.
Death after unsuccessful resuscitation from cardiac arrest; v.
Death after successful resuscitation from cardiac arrest without identification of a specific cardiac or non-cardiac aetiology; vi.
Patients found dead within 24 hours of last being seen well and stable and without signs of a specific non-cardiovascular cause.
C. Congestive heart failure Death in association with clinical worsening of symptoms of congestive heart failure regardless of aetiology (ischaemic heart disease, non-ischaemic cardiomyopathy, valvular disease).

D. Stroke
Death as a direct consequence of stroke or indirectly due to a related complication.
E. Cardiovascular procedure Death caused by immediate complication of a cardiac procedure.
F. Cardiovascular bleeding Death due to any of the following: i. Non-stroke intracerebral haemorrhage; ii.
G. Other Death due to other cardiovascular conditions, such as pulmonary embolism or peripheral artery disease.
B. Non-cardiovascular death Documentation supporting death due to a specific, non-cardiovascular cause, such as: i. Pulmonary; ii.
C. Undetermined cause of death Death cannot be classified as cardiovascular or non-cardiovascular due to absent documentation.

Acute myocardial infarction
Based on 2012 Third Universal Definition of Myocardial Infarction. Acute myocardial infarction should be used when there is evidence of myocardial necrosis in the clinical setting of myocardial ischaemia, i.e., any of the following should apply: i. Rise and/or fall of cardiac biomarkers with at least one measurement above the 99 th percentile of the upper reference limit (URL) in combination with at least one of the following: a. Ischaemic symptoms; b. New or presumed new ECG changes (described in further detail below): STelevation, ST-depression, T-wave inversion, or LBBB; c. Development of pathological Q-wave (described in further detail below); d. Evidence by imaging of loss of viable myocardium or new regional wall motion abnormality; e. Intracoronary thrombus identified by coronary angiography or autopsy. ii.
Sudden cardiac death preceded by clinical symptoms of cardiac ischaemia and new onset ischaemic ECG changes in a patient in whom death occurred before cardiac biomarkers were obtained or would be increased. iii.
Percutaneous coronary intervention (PCI)-related MI: elevation of cardiac biomarkers >5 times the URL (or increased >20% in a patient with stable elevation or falling values) and at least one of the following: a. Ischaemic symptoms; b. Ischaemic ECG changes; c. Angiographic evidence of procedural complication; d. Evidence by imaging of loss of viable myocardium or new regional wall motion abnormality. iv.
Stent thrombosis detected by coronary angiography or autopsy in combination with ischaemic symptoms and a rise/fall of cardiac biomarkers with at least one value above the 99 th percentile of the URL. v.
Coronary artery bypass grafting (CABG)-related MI: elevation of cardiac biomarkers (>10 times the URL) in a patient with normal baseline levels in combination with any of the following: a. New Q-wave or LBBB; b. Angiographic evidence of occlusion of a new graft or a native coronary artery; c. Evidence by imaging of loss of viable myocardium or new regional wall motion abnormality.

Subclassification of myocardial infarction:
Type 1: Spontaneous myocardial infarction Plaque rupture, ulceration, fissuring, erosion or dissection resulting in intraluminal thrombus and decreased myocardial blood flow.

Type 2: Myocardial infarction secondary to an ischaemic imbalance
A condition other than coronary artery disease contributes to an imbalance between myocardial oxygen demand and supply, resulting in myocardial necrosis.

Type 3: Myocardial infarction resulting in death when biomarker values are unavailable
Type 4a: Myocardial infarction related to PCI Type 4b: Myocardial infarction related to stent thrombosis

Criteria for ECG changes suggestive of ischaemia:
STEMI: ST-elevation in two contiguous leads with cut-points: 1 mV in all leads other than lead V2-V3 where the following cut points apply: 2 mV for men ≥40 years; 2·5 mV for men <40 years; 1·5 mm for women.

Revascularisation
Invasive revascularisation regardless of indication. i. PCI with balloon or stent; ii. CABG.

TIA and stroke
The distinction between a TIA and an ischaemic stroke is the presence of infarction. Duration of symptoms for 24 h is interpreted as presence of infarction, even when evidence is absent on imaging.
i. TIA Transient ischaemic attack is defined as a transient (within 24 h) episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischaemia without acute infarction.
ii. Ischaemic stroke Ischaemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central neurons system. iii.
Haemorrhagic stroke Acute episode of focal or global cerebral or spinal dysfunction caused by spontaneous intracerebral haemorrhage (excluding subarachnoid haemorrhage).
iv. Undetermined Acute episode of focal or global cerebral, spinal, or retinal dysfunction caused by presumed infarction or haemorrhage, but with insufficient information to allow categorisation (i.e., imaging not performed). Introduction

Study design 4
Present key elements of study design early in the paper 2-4 Methods

Setting 5
Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection 2-4 Study population, data collection Participants 6 (a) Cohort study-Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study-Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study-Give the eligibility criteria, and the sources and methods of selection of participants 2-4 Methods (b) Cohort study-For matched studies, give matching criteria and number of exposed and unexposed

Results
Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed  Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses 5-6 Results Source of funding *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.

Discussion
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.