Activity limitations, use of assistive devices, and mortality and clinical events in 25 high-income, middle-income, and low-income countries: an analysis of the PURE study.

BACKGROUND: The focus of most epidemiological studies has been mortality or clinical events, with less information on activity limitations related to basic daily functions and their consequences. Standardised data from multiple countries at different economic levels in different regions of the world on activity limitations and their associations with clinical outcomes are sparse. We aimed to quantify the prevalence of activity limitations and use of assistive devices and the association of limitations with adverse outcomes in 25 countries grouped by different economic levels. METHODS: In this analysis, we obtained data from individuals in 25 high-income, middle-income, and low-income countries from the Prospective Urban Rural Epidemiological (PURE) study (175 660 participants). In the PURE study, individuals aged 35-70 years who intended to continue living in their current home for a further 4 years were invited to complete a questionnaire on activity limitations. Participant follow-up was planned once every 3 years either by telephone or in person. The activity limitation screen consisted of questions on self-reported difficulty with walking, grasping, bending, seeing close, seeing far, speaking, hearing, and use of assistive devices (gait, vision, and hearing aids). We estimated crude prevalence of self-reported activity limitations and use of assistive devices, and prevalence standardised by age and sex. We used logistic regression to additionally adjust prevalence for education and socioeconomic factors and to estimate the probability of activity limitations and assistive devices by age, sex, and country income. We used Cox frailty models to evaluate the association between each activity limitation with mortality and clinical events (cardiovascular disease, heart failure, pneumonia, falls, and cancer). The PURE study is registered with ClinicalTrials.gov, NCT03225586. FINDINGS: Between Jan 12, 2001, and May 6, 2019, 175 584 individuals completed at least one question on the activity limitation questionnaire (mean age 50·6 years [SD 9·8]; 103 625 [59%] women). Of the individuals who completed all questions, mean follow-up was 10·7 years (SD 4·4). The most common self-reported activity limitations were difficulty with bending (23 921 [13·6%] of 175 515 participants), seeing close (22 532 [13·4%] of 167 801 participants), and walking (22 805 [13·0%] of 175 554 participants); prevalence of limitations was higher with older age and among women. The prevalence of all limitations standardised by age and sex, with the exception of hearing, was highest in low-income countries and middle-income countries, and this remained consistent after adjustment for socioeconomic factors. The use of gait, visual, and hearing aids was lowest in low-income countries and middle-income countries, particularly among women. The prevalence of seeing close limitation was four times higher (6257 [16·5%] of 37 926 participants vs 717 [4·0%] of 18 039 participants) and the prevalence of seeing far limitation was five times higher (4003 [10·6%] of 37 923 participants vs 391 [2·2%] of 18 038 participants) in low-income countries than in high-income countries, but the prevalence of glasses use in low-income countries was half that in high-income countries. Walking limitation was most strongly associated with mortality (adjusted hazard ratio 1·32 [95% CI 1·25-1·39]) and most consistently associated with other clinical events, with other notable associations observed between seeing far limitation and mortality, grasping limitation and cardiovascular disease, bending limitation and falls, and between speaking limitation and stroke. INTERPRETATION: The global prevalence of activity limitations is substantially higher in women than men and in low-income countries and middle-income countries compared with high-income countries, coupled with a much lower use of gait, visual, and hearing aids. Strategies are needed to prevent and mitigate activity limitations globally, with particular emphasis on low-income countries and women. FUNDING: Funding sources are listed at the end of the Article.

The impact of hospital presentation time on stroke outcomes: A nationally representative Irish cohort study.

OBJECTIVES: There is conflicting evidence regarding the outcomes of acute stroke patients who present to hospital within normal working hours ('in-hours') compared with the 'out-of-hours' period. This study aimed to assess the effect of time of stroke presentation on outcomes within the Irish context, to inform national stroke service delivery. MATERIALS AND METHODS: A secondary analysis of data from the Irish National Audit of Stroke (INAS) from Jan 2016 to Dec 2019 was carried out. Patient and process outcomes were assessed for patients presenting 'in-hours' (8:00-17:00 Monday-Friday) compared with 'out-of-hours' (all other times). RESULTS: Data on arrival time were available for 13,996 patients (male 56.2%; mean age 72.5 years), of which 55.7% presented 'out-of-hours'. In hospital mortality was significantly lower among those admitted 'in-hours' (11.3%, n = 534) compared with 'out-of-hours' (12.8%, n = 749); (adjusted Odds Ratio (OR) 0.82; 95% Confidence Interval CI [95% CI] 0.72-0.89). Poor functional outcome at discharge (Modified Rankin Scale ≥ 3) was also significantly lower in those presenting 'in-hours' (adjusted OR 0.79; 95% CI 0.68-0.91). In patients receiving thrombolysis, mean door to needle time was shorter for 'in-hours' presentation at 55.8 mins (n = 562; SD 35.43 mins), compared with 'out-of-hours' presentation at 80.5 mins (n = 736; SD 38.55 mins, p < .001). CONCLUSION: More than half of stroke patients in Ireland present 'out-of-hours' and these presentations are associated with a higher mortality and a lower odds of functional independence at discharge. It is imperative that stroke pathways consider the 24 hour period to ensure the delivery of effective stroke care, and modification of 'out-of-hours' stroke care is required to improve overall outcomes.

Corrigendum: Bleeding Risk Prediction in Patients Treated with Antithrombotic Drugs According to the Anatomic Site of Bleeding, Indication for Treatment, and Time Since Treatment Initiation.

[This corrects the article DOI: 10.1055/a-2259-1134.].

Tea and coffee consumption and risk of acute stroke: The INTERSTROKE Study.

BACKGROUND: Stroke is a leading global cause of death and disability. Daily tea/coffee intake is consumed by > 50% of populations and may represent an important population-level exposure. Therefore, it is first essential that we better understand the associations between the tea/coffee intake and stroke. AIMS: This research aims to generate hypotheses about the global associations between tea and coffee intake and stroke. These insights will identify interventions for stroke prevention that can be further explored using alternative study designs. METHODS: INTERSTROKE is a large international matched case-control study of first stroke from 32 countries. Participants were asked "how many cups do you drink each day?" of coffee, green tea, black tea, and other tea. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between intake and stroke. RESULTS: We included 13,462 cases and 13,488 controls from INTERSTROKE; mean age was 61.7 (13.4) years and 59.6% (n = 16,010) were male. Overall, 19.4% (n = 5239) did not consume tea/coffee, 47.0% (n = 12,666) consumed tea only, 14.9% (n = 4024) consumed coffee alone, and 18.6% (n = 5021) consumed both, with significant regional variations. After multivariable adjustment, there was no association between low/moderate coffee intake and stroke, but high consumption (> 4/day) was associated with higher odds of all stroke (OR = 1.37 (95% CI = 1.06-1.77)) or ischemic stroke (OR = 1.32 (95% CI = 1.00-1.74)). Tea consumption was associated with lower odds of all (OR = 0.81 (95% CI = 0.69-0.94) for highest intake) or ischemic stroke (OR = 0.81 (95% CI = 0.68-0.98) for highest intake). CONCLUSIONS: High coffee consumption was associated with higher odds of all or ischemic stroke; low-moderate coffee had no association with stroke. In contrast, tea consumption was associated with lower odds of stroke. These associations suggest that individuals consider avoiding high coffee consumption (⩾ five cups/day) to impact future stroke risk. DATA ACCESS STATEMENT: The design and rationale of INTERSTROKE was published previously. Individual participant data, or other documents are not available.

Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses.

Decline in cognitive function is the most feared aspect of ageing. Poorer midlife cognitive function is associated with increased dementia and stroke risk. The mechanisms underlying variation in cognitive function are uncertain. Here, we assessed associations between 1160 proteins' plasma levels and two measures of cognitive function, the digit symbol substitution test (DSST) and the Montreal Cognitive Assessment in 1198 PURE-MIND participants. We identified five DSST performance-associated proteins (NCAN, BCAN, CA14, MOG, CDCP1), with NCAN and CDCP1 showing replicated association in an independent cohort, GS (N = 1053). MRI-assessed structural brain phenotypes partially mediated (8-19%) associations between NCAN, BCAN, and MOG, and DSST performance. Mendelian randomisation analyses suggested higher CA14 levels might cause larger hippocampal volume and increased stroke risk, whilst higher CDCP1 levels might increase intracranial aneurysm risk. Our findings highlight candidates for further study and the potential for drug repurposing to reduce the risk of stroke and cognitive decline.

Blood pressure variability in acute stroke: Risk factors and association with functional outcomes at 1 month.

BACKGROUND AND PURPOSE: Blood pressure variability, in acute stroke, may be an important modifiable determinant of functional outcome after stroke. In a large international cohort of participants with acute stroke, it was sought to determine the association of blood pressure variability (in the early period of admission) and functional outcomes, and to explore risk factors for increased blood pressure variability. PATIENTS AND METHODS: INTERSTROKE is an international case-control study of risk factors for first acute stroke. Blood pressure was recorded at the time of admission, the morning after admission and the time of interview in cases (median time from admission 36.7 h). Multivariable ordinal regression analysis was employed to determine the association of blood pressure variability (standard deviation [SD] and coefficient of variance) with modified Rankin score at 1-month follow-up, and logistic regression was used to identify risk factors for blood pressure variability. RESULTS: Amongst 13,206 participants, the mean age was 62.19 ± 13.58 years. When measured by SD, both systolic blood pressure variability (odds ratio 1.13; 95% confidence interval 1.03-1.24 for SD ≥20 mmHg) and diastolic blood pressure variability (odds ratio 1.15; 95% confidence interval 1.04-1.26 for SD ≥10 mmHg) were associated with a significant increase in the odds of poor functional outcome. The highest coefficient of variance category was not associated with a significant increase in risk of higher modified Rankin score at 1 month. Increasing age, female sex, high body mass index, history of hypertension, alcohol use, and high urinary potassium and low urinary sodium excretion were associated with increased blood pressure variability. CONCLUSION: Increased blood pressure variability in acute stroke, measured by SD, is associated with an increased risk of poor functional outcome at 1 month. Potentially modifiable risk factors for increased blood pressure variability include low urinary sodium excretion.

Markers of periodontal disease and risk of stroke: INTERSTROKE case-control study.

BACKGROUND: Periodontal disease may be an important modifiable risk factor for stroke. AIMS: To determine the contribution of markers of periodontal disease to stroke risk globally, within subpopulations, and by stroke subtypes. METHODS: INTERSTROKE is the largest international case-control study of risk factors for first acute stroke. All participants were asked a standardised set of questions about the presence or absence of painful teeth, painful gums or lost teeth, as markers of periodontal disease, within the previous year. The total number of reported variables was calculated per participant. Multivariable conditional logistic regression examined the association of these variables with acute stroke. RESULTS: In 26901 participants, across 32 countries, there was a significant multivariable association between lost teeth and stroke (OR 1.11, 95 % CI 1.01 - 1.22), but not painful teeth (OR 1.00, 95 % CI 0.91-1.10) or painful gums (OR 1.01, 95 % CI 0.89 - 1.14). When these symptoms were considered together there was a graded increased odds of stroke, with the largest magnitude of association seen if a patient reported all three of painful teeth, painful gums and lost teeth (OR 1.34, 95 % CI 1.00 - 1.79). CONCLUSIONS: Our findings suggest that features of severe periodontal disease are a risk factor for acute stroke. Periodontal disease should be considered as a potentially modifiable risk factor for stroke.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Bleeding Risk Prediction in Patients Treated with Antithrombotic Drugs According to the Anatomic Site of Bleeding, Indication for Treatment, and Time Since Treatment Initiation.

Background Reasons for the relatively poor performance of bleeding prediction models are not well understood but may relate to differences in predictors for various anatomical sites of bleeding. Methods We pooled individual participant data from four randomized controlled trials of antithrombotic therapy in patients with coronary and peripheral artery diseases, embolic stroke of undetermined source (ESUS), or atrial fibrillation. We examined discrimination and calibration of models for any major bleeding, major gastrointestinal (GI) bleeding, and intracranial hemorrhage (ICH), according to the time since initiation of antithrombotic therapy, and indication for antithrombotic therapy. Results Of 57,813 patients included, 1,948 (3.37%) experienced major bleeding, including 717 (1.24%) major GI bleeding and 274 (0.47%) ICH. The model derived to predict major bleeding at 1 year from any site (c-index, 0.69, 95% confidence interval [CI], 0.68-0.71) performed similarly when applied to predict major GI bleeding (0.71, 0.69-0.74), but less well to predict ICH (0.64, 0.61-0.69). Models derived to predict GI bleeding (0.75, 0.74-0.78) and ICH (0.72, 0.70-0.79) performed better than the general major bleeding model. Discrimination declined over time since the initiation of antithrombotic treatment, stabilizing at approximately 2 years for any major bleeding and major GI bleeding and 1 year for ICH. Discrimination was best for the model predicting ICH in the ESUS population (0.82, 0.78-0.92) and worst for the model predicting any major bleeding in the coronary and peripheral artery disease population (0.66, 0.65-0.69). Conclusion Performance of risk prediction models for major bleeding is affected by site of bleeding, time since initiation of antithrombotic therapy, and indication for antithrombotic therapy.

Pre-morbid sleep disturbance and its association with stroke severity: results from the international INTERSTROKE study.

BACKGROUND AND PURPOSE: Whilst sleep disturbances are associated with stroke, their association with stroke severity is less certain. In the INTERSTROKE study, the association of pre-morbid sleep disturbance with stroke severity and functional outcome following stroke was evaluated. METHODS: INTERSTROKE is an international case-control study of first acute stroke. This analysis included cases who completed a standardized questionnaire concerning nine symptoms of sleep disturbance (sleep onset latency, duration, quality, nocturnal awakening, napping duration, whether a nap was planned, snoring, snorting and breathing cessation) in the month prior to stroke (n = 2361). Two indices were derived representing sleep disturbance (range 0-9) and obstructive sleep apnoea (range 0-3) symptoms. Logistic regression was used to estimate the magnitude of association between symptoms and stroke severity defined by the modified Rankin Score. RESULTS: The mean age of participants was 62.9 years, and 42% were female. On multivariable analysis, there was a graded association between increasing number of sleep disturbance symptoms and initially severe stroke (2-3, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07-1.94; 4-5, OR 1.66, 95% CI 1.23-2.25; >5, OR 2.58, 95% CI 1.83-3.66). Having >5 sleep disturbance symptoms was associated with significantly increased odds of functional deterioration at 1 month (OR 1.54, 95% CI 1.01-2.34). A higher obstructive sleep apnoea score was also associated with significantly increased odds of initially severe stroke (2-3, OR 1.48; 95% CI 1.20-1.83) but not functional deterioration at 1 month (OR 1.19, 95% CI 0.93-1.52). CONCLUSIONS: Sleep disturbance symptoms were common and associated with an increased odds of severe stroke and functional deterioration. Interventions to modify sleep disturbance may help prevent disabling stroke/improve functional outcomes and should be the subject of future research.

Bias assessment and correction for Levin's population attributable fraction in the presence of confounding.

In 1953, Morton Levin introduced a simple approach to estimating population attributable fractions (PAF) depending only on risk factor prevalence and relative risk. This formula and its extensions are still in widespread use today, particularly to estimate PAF in populations where individual data is unavailable. Unfortunately, Levin's approach is known to be asymptotically biased for the PAF when the risk factor-disease relationship is confounded even if relative risks that are correctly adjusted for confounding are used in the estimator. Here we describe a simple re-expression of Miettinen's estimand that depends on the causal relative risk, the unadjusted relative risk and the population risk factor prevalence. While this re-expression is not new, it has been underappreciated in the literature, and the associated estimator may be useful in estimating PAF in populations when individual data is unavailable provided estimated adjusted and unadjusted relative risks can be transported to the population of interest. Using the re-expressed estimand, we develop novel analytic formulae for the relative and absolute asymptotic bias in Levin's formula, solidifying earlier work by Darrow and Steenland that used simulations to investigate this bias. We extend all results to settings with non-binary valued risk factors and continuous exposures and discuss the utility of these results in estimating PAF in practice.

Variations in the prevalence of atrial fibrillation, and in the strength of its association with ischemic stroke, in countries with different income levels: INTERSTROKE case-control study.

BACKGROUND: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level. AIMS: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level. METHODS: In the INTERSTROKE case-control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups-UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke. RESULTS: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29-0.41) and LMIC (aOR 0.50, 95% CI 0.41-0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7-17.8) in HIC, 14.6% (95% CI 12.3-17.1) in UMIC-1, 5.7% (95% CI 4.9-6.7) in UMIC-2, and 6.3% (95% CI 5.3-7.3) in LMIC. CONCLUSION: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio.