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.

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.

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.

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.

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.

Potassium intake: the Cinderella electrolyte.

Dietary guidelines recommend intake targets for some essential minerals, based on observational and experimental evidence relating mineral intake levels to health outcomes. For prevention of cardiovascular disease, reducing sodium intake and increasing potassium intake are the principal tools. While reducing sodium intake has received greatest public health priority, emerging evidence suggests that increasing potassium intake may be a more important target for cardiovascular prevention. Increased potassium intake reduces blood pressure and mitigates the hypertensive effects of excess sodium intake, and the recent large Phase III SSaSS trial reported that increasing potassium intake (and reducing sodium intake) in populations with low potassium intake and high sodium intake, through salt substitution (25% KCl, 75%NaCl), reduces the risk of stroke in patients at increased cardiovascular risk. As key sources of potassium intake include fruit, vegetables, nuts, and legumes, higher potassium intake may be associated with healthy dietary patterns. The current review makes the case that increasing potassium intake might represent a more advantageous dietary strategy for prevention of cardiovascular disease. Future research should focus on addressing the independent effect of potassium supplementation in populations with low or moderate potassium intake, and determine effective strategies to increase potassium intake from diet.

Diet, cardiovascular disease, and mortality in 80 countries.

AIMS: To develop a healthy diet score that is associated with health outcomes and is globally applicable using data from the Prospective Urban Rural Epidemiology (PURE) study and replicate it in five independent studies on a total of 245 000 people from 80 countries. METHODS AND RESULTS: A healthy diet score was developed in 147 642 people from the general population, from 21 countries in the PURE study, and the consistency of the associations of the score with events was examined in five large independent studies from 70 countries. The healthy diet score was developed based on six foods each of which has been associated with a significantly lower risk of mortality [i.e. fruit, vegetables, nuts, legumes, fish, and dairy (mainly whole-fat); range of scores, 0-6]. The main outcome measures were all-cause mortality and major cardiovascular events [cardiovascular disease (CVD)]. During a median follow-up of 9.3 years in PURE, compared with a diet score of ≤1 points, a diet score of ≥5 points was associated with a lower risk of mortality [hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.63-0.77)], CVD (HR 0.82; 0.75-0.91), myocardial infarction (HR 0.86; 0.75-0.99), and stroke (HR 0.81; 0.71-0.93). In three independent studies in vascular patients, similar results were found, with a higher diet score being associated with lower mortality (HR 0.73; 0.66-0.81), CVD (HR 0.79; 0.72-0.87), myocardial infarction (HR 0.85; 0.71-0.99), and a non-statistically significant lower risk of stroke (HR 0.87; 0.73-1.03). Additionally, in two case-control studies, a higher diet score was associated with lower first myocardial infarction [odds ratio (OR) 0.72; 0.65-0.80] and stroke (OR 0.57; 0.50-0.65). A higher diet score was associated with a significantly lower risk of death or CVD in regions with lower than with higher gross national incomes (P for heterogeneity <0.0001). The PURE score showed slightly stronger associations with death or CVD than several other common diet scores (P < 0.001 for each comparison). CONCLUSION: A diet comprised of higher amounts of fruit, vegetables, nuts, legumes, fish, and whole-fat dairy is associated with lower CVD and mortality in all world regions, especially in countries with lower income where consumption of these foods is low.

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.

Risk Factors for Stroke in the Young (18-45 Years): A Case-Control Analysis of INTERSTROKE Data from 32 Countries.

BACKGROUND: It is not clear whether conventional vascular risk factors are responsible for most strokes in patients younger than 45 years of age. Our objective was to evaluate the association of common risk factors with stroke in individuals under 45 years. METHODS: INTERSTROKE was a case-control study carried out in 32 countries between 2007 and 2015. Patients presenting within 5 days of symptom onset of a first stroke were enrolled as cases. Controls were age and sex matched to cases and had no history of stroke. Cases and controls underwent similar evaluations. Odds ratios (ORs) and population attributable risks (PARs) were calculated to determine the association of various risk factors with all stroke, ischemic stroke, and intracranial hemorrhage, for patients 45 years of age or younger. FINDINGS: 1,582 case-control pairs were included in this analysis. The mean age of this cohort was 38.5 years (SD 6.32). Overall, 71% strokes were ischemic. Cardiac causes {OR: 8.42 (95% confidence interval [CI]: 3.01-23.5)}; binge drinking of alcohol (OR: 5.44 [95% CI: 1.81-16.4]); hypertension (OR: 5.41 [95% CI: 3.40-8.58]); ApoB/ApoA1 ratio (OR: 2.74 [95% CI: 1.69-4.46]); psychosocial stress (OR: 2.33 [95% CI: 1.01-5.41]); smoking (OR: 1.85 [95% CI: 1.17-2.94]); and increased waist-to-hip ratio (OR: 1.69 [95% CI: 1.04-2.75]) were the most important risk factors for ischemic stroke in these young cases. For intracerebral hemorrhage, only hypertension (OR: 9.08 [95% CI: 5.46-15.1]) and binge drinking (OR: 4.06 [95% CI: 1.27-13.0]) were significant risk factors. The strength of association and population attributable risk (PAR) for hypertension increased with age (PAR 23.3% in those <35 years of age, 50.7% in 35-45 years of age). INTERPRETATION: Conventional risk factors such as hypertension, smoking, binge drinking of alcohol, central obesity, cardiac causes, dyslipidemia, and psychosocial stress are important risk factors for stroke in those younger than 45 years of age. Hypertension is the most significant risk factor in all age groups and across all regions and both stroke subtypes. These risk factors should be identified and modified in early adulthood to prevent strokes in young individuals.

Global mean potassium intake: a systematic review and Bayesian meta-analysis.

PURPOSE: Increasing potassium intake, especially in populations with low potassium intake and high sodium intake, has emerged as an important population-level intervention to reduce cardiovascular events. Current guideline recommendations, such as those made by the World Health Organisation, recommend a potassium intake of  > 3.5 g/day. We sought to determine summary estimates for mean potassium intake and sodium/potassium (Na/K) ratio in different regions of the world. METHODS: We performed a systematic review and meta-analysis. We identified 104 studies, that included 98 nationally representative surveys and 6 multi-national studies. To account for missingness and incomparability of data, a Bayesian hierarchical imputation model was applied to estimating summary estimates of mean dietary potassium intake (primary outcome) and sodium/potassium ratio. RESULTS: Overall, 104 studies from 52 countries were included (n = 1,640,664). Mean global potassium intake was 2.25 g/day (57 mmol/day) (95% credible interval (CI) 2.05-2.44 g/day), with highest intakes in Eastern and Western Europe (mean intake 3.53g/day, 95% CI 3.05-4.01 g/day and 3.29 g/day, 95% CI 3.13-3.47 g/day, respectively) and lowest intakes in East Asia (mean intake 1.89 g/day; 95% CI 1.55-2.25 g/day). Approximately 31% (95% CI, 30-41%) of global population included have an estimated potassium intake  > 2.5 g/day, with 14% (95% CI 11-17%) above 3.5 g/day. CONCLUSION: Global mean potassium intake (2.25 g/day) falls below current guideline recommended intake level of  > 3.5 g/day, with only 14% (95% CI 11-17%) of the global population achieving guideline-target mean intake. There was considerable regional variation, with lowest mean potassium intake reported in Asia, and highest intake in Eastern and Western Europe.

Comparing functional and quality of life outcomes in transcatheter aortic valve implantation and surgical aortic valve replacement for aortic stenosis: a systematic review and meta-analysis.

BACKGROUND: To compare functional and health related quality of life outcomes post-transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) in patients with critical aortic stenosis (AS) across low to high-risk surgical candidates. These patient-centred factors will be compared between both groups in the short to medium term time frames and will aid in shared decision making between patients and healthcare workers. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials which compared TAVI with SAVR and reported on quality of life (QoL) and functional scores. The scores used were the Kansas City Cardiomyopathy Questionnaire (KCCQ), Euroqol-5DL (EQ5DL), the short form-36/12 (SF-36/12) and the NYHA. RESULTS: We identified eight trials with a total of 8898 participants. Both groups showed improvements from baseline at one month. At one month there was a statistically significant difference in standardised mean difference (SMD) in favour of TAVI for EQ5DL (SMD 0.37, 95% CI 0.26,0.49), KCCQ (SMD 0.53,95% CI 0.48, 0.58), SF physical summary (SMD 0.55, 95% CI 0.31 - 0.78) and SF mental summary (SMD 0.34, 95% CI 0.27 - 0.40). At one year there was no statistically significant difference between any of these QoL metrics. For NYHA, no significant difference in odds ratio of class III/IV was observed at one month between TAVI and SAVR (OR 0.94, 95% CI 0.83, 1.07), however, TAVI was associated with reduced odds ratio of NYHA class I/II at one year (OR 0.87, 95% CI 0.78, 0.98). CONCLUSION: Both groups were associated with improvements in QoL and functional outcomes with TAVI reporting more significant improvements in QoL at one-month post-procedures. No significant improvements between groups were seen at one year. This is the largest meta-analysis comparing post-operative health-related quality of life outcomes post SAVR and TAVI and has major implications in shared decision making for the treatment of aortic stenosis.

Randomised controlled trials of antihypertensive therapy: does exclusion of orthostatic hypotension alter treatment effect? A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Management of antihypertensive therapy is challenging in patients with symptomatic orthostatic hypotension, a population often excluded from randomised controlled trials of antihypertensive therapy. In this systematic review and meta-analysis, we sought to determine whether the association of antihypertensive therapy and adverse events (e.g. falls, syncope), differed among trials that included or excluded patients with orthostatic hypotension. METHODS: We performed a systematic review and meta-analysis of randomised controlled trials comparing blood pressure lowering medications to placebo, or different blood pressure targets on falls or syncope outcomes and cardiovascular events. A random-effects meta-analysis was used to estimate a pooled treatment-effect overall in subgroups of trials that excluded patients with orthostatic hypotension and trials that did not exclude patients with orthostatic hypotension, and tested P for interaction. The primary outcome was fall events. RESULTS: 46 trials were included, of which 18 trials excluded orthostatic hypotension and 28 trials did not. The incidence of hypotension was significantly lower in trials that excluded participants with orthostatic hypotension (1.3% versus 6.2%, P < 0.001) but not incidences of falls (4.8% versus 8.8%; P = 0.40) or syncope (1.5% versus 1.8%; P = 0.67). Antihypertensive therapy was not associated with an increased risk of falls in trials that excluded (OR 1.00, 95% CI; 0.89-1.13) or included (OR 1.02, 95% CI; 0.88-1.18) participants with orthostatic hypotension (P for interaction = 0.90). CONCLUSIONS: The exclusion of patients with orthostatic hypotension does not appear to affect the relative risk estimates for falls and syncope in antihypertensive trials.

Antiplatelet therapy and incident cognitive impairment or dementia-a systematic review and meta-analysis of randomised clinical trials.

OBJECTIVE: The benefit of antiplatelet therapy in preventing cognitive impairment or dementia is uncertain. We investigated the association between antiplatelet therapy and incident cognitive impairment or dementia in randomised clinical trials. METHODS: We searched PubMed, EMBASE and CENTRAL for randomised clinical trials published from database inception through 1 February 2023. Trials that evaluated the association of antiplatelet therapy with incident cognitive impairment or dementia were included. For single-agent antiplatelet, the control group was placebo. For dual agent antiplatelet therapy, the control group was single-agent monotherapy. A random-effects meta-analysis model was used to report pooled treatment effects and 95% confidence intervals (CIs). The primary outcome was incident cognitive impairment or dementia. Secondary outcomes included change in cognitive test scores. RESULTS: A total of 11 randomised clinical trials were included (109,860 participants). All reported the incidence of cognitive impairment or dementia on follow-up. The mean (SD) age of trial participants was 66.2 (7.9) years. Antiplatelet therapy was not significantly associated with a reduced risk of cognitive impairment or dementia (11 trials; 109,860 participants) (3.49% versus 4.18% of patients over a mean trial follow-up of 5.8 years; odds ratio [OR], 0.94 [95% CI, 0.88-1.00]; absolute risk reduction, 0.2% [95% CI, -0.4% to 0.009%]; I2 = 0.0%). Antiplatelet therapy was not significantly associated with mean change in cognitive test scores. CONCLUSION: In this meta-analysis, antiplatelet therapy was not significantly associated with a lower risk of incident cognitive impairment or dementia, but the CIs around this outcome do not exclude a modest preventative effect.

Anger or emotional upset and heavy physical exertion as triggers of stroke: the INTERSTROKE study.

AIMS: In INTERSTROKE, we explored the association of anger or emotional upset and heavy physical exertion with acute stroke, to determine the importance of triggers in a large, international population. METHODS AND RESULTS: INTERSTROKE was a case-control study of first stroke in 32 countries. Using 13 462 cases of acute stroke we adopted a case-crossover approach to determine whether a trigger within 1 hour of symptom onset (case period), vs. the same time on the previous day (control period), was associated with acute stroke. A total of 9.2% (n = 1233) were angry or emotional upset and 5.3% (n = 708) engaged in heavy physical exertion during the case period. Anger or emotional upset in the case period was associated with increased odds of all stroke [odds ratio (OR) 1.37, 99% confidence interval (CI), 1.15-1.64], ischaemic stroke (OR 1.22, 99% CI, 1.00-1.49), and intracerebral haemorrhage (ICH) (OR 2.05, 99% CI 1.40-2.99). Heavy physical exertion in the case period was associated with increased odds of ICH (OR 1.62, 99% CI 1.03-2.55) but not with all stroke or ischaemic stroke. There was no modifying effect by region, prior cardiovascular disease, risk factors, cardiovascular medications, time, or day of symptom onset. Compared with exposure to neither trigger during the control period, the odds of stroke associated with exposure to both triggers were not additive. CONCLUSION: Acute anger or emotional upset was associated with the onset of all stroke, ischaemic stroke, and ICH, while acute heavy physical exertion was associated with ICH only.

Behavioral Sleep Interventions and Cardiovascular Risk Factors: Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND/OBJECTIVES: Chronic sleep disturbance has been consistently associated with cardiovascular disease. We sought to determine whether behavioral interventions to improve sleep have been associated with improvements in 4 common cardiovascular disease risk factors: hypertension, diabetes mellitus (DM), obesity, and smoking. METHODS: Randomized controlled trials evaluating the prospective effect of behavioral sleep interventions on (a) blood pressure in participants with hypertension/prehypertension, (b) glycemic control in participants with DM/pre-DM, (c) anthropometrics in participants who were overweight/obese, and (d) smoking status in smokers were eligible. Where feasible, we undertook random-effects meta-analyses of standardized mean differences in cardiovascular disease risk factor change. RESULTS: Overall, 3 trials met the inclusion criteria for blood pressure, 4 for glycemic control, 9 for overweight/obesity, and 2 for smoking. On meta-analysis, interventions with sleep as the sole behavioral target were associated with a significant reduction in hemoglobin A1c% (-0.84; 95% confidence interval [CI], -1.34 to -0.34), but not a significant reduction in systolic blood pressure (-0.18; 95% CI, -0.55 to 0.20) versus controls. In addition, any interventions with sleep as a behavioral target were associated with significant reductions in hemoglobin A1c% (-0.71; 95% CI, -1.01 to -0.42) and weight (-0.78; 95% CI, -1.11 to -0.45), but not systolic blood pressure (-0.72; 95% CI, -1.82 to 0.37). Trials evaluating smoking status were not amenable to meta-analysis. CONCLUSION: Behavioral interventions to improve sleep were associated with improved glycemic control in patients with DM. It is also possible that these interventions improve weight in individuals who were overweight/obese. A low number of trials and small sample sizes indicate that further large, well-designed randomized controlled trials of interventions are warranted.

Early Metformin in Gestational Diabetes: A Randomized Clinical Trial.

Importance: Gestational diabetes is a common complication of pregnancy and the optimal management is uncertain. Objective: To test whether early initiation of metformin reduces insulin initiation or improves fasting hyperglycemia at gestation weeks 32 or 38. Design, Setting, and Participants: Double-blind, placebo-controlled trial conducted in 2 centers in Ireland (one tertiary hospital and one smaller regional hospital). Participants were enrolled from June 2017 through September 2022 and followed up until 12 weeks' postpartum. Participants comprised 510 individuals (535 pregnancies) diagnosed with gestational diabetes based on World Health Organization 2013 criteria. Interventions: Randomized 1:1 to either placebo or metformin (maximum dose, 2500 mg) in addition to usual care. Main Outcomes And Measures: The primary outcome was a composite of insulin initiation or a fasting glucose level of 5.1 mmol/L or greater at gestation weeks 32 or 38. Results: Among 510 participants (mean age, 34.3 years), 535 pregnancies were randomized. The primary composite outcome was not significantly different between groups and occurred in 150 pregnancies (56.8%) in the metformin group and 167 pregnancies (63.7%) in the placebo group (between-group difference, -6.9% [95% CI, -15.1% to 1.4%]; relative risk, 0.89 [95% CI, 0.78-1.02]; P = .13). Of 6 prespecified secondary maternal outcomes, 3 favored the metformin group, including time to insulin initiation, self-reported capillary glycemic control, and gestational weight gain. Secondary neonatal outcomes differed by group, with smaller neonates (lower mean birth weights, a lower proportion weighing >4 kg, a lower proportion in the >90% percentile, and smaller crown-heel length) in the metformin group without differences in neonatal intensive care needs, respiratory distress requiring respiratory support, jaundice requiring phototherapy, major congenital anomalies, neonatal hypoglycemia, or proportion with 5-minute Apgar scores less than 7. Conclusion and relevance: Early treatment with metformin was not superior to placebo for the composite primary outcome. Prespecified secondary outcome data support further investigation of metformin in larger clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02980276; EudraCT: 2016-001644-19.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Role of Proxy Respondents in International Stroke Research: Experience of the INTERSTROKE Study.

INTRODUCTION: Measuring patient-reported information in stroke research is challenging. To overcome this, use of proxy respondents is often a necessary strategy. In this study, we report on use and effect of proxy respondents on patient case-mix in a large international epidemiologic stroke study (INTERSTROKE). METHODS: This was a cross-sectional study of 13,458 cases of acute first stroke in 32 countries. A standardized study questionnaire recording behavioural cardiovascular risk factors was administered to the patient, and if unable to communicate adequately, a valid proxy, or both. We used logistic regression to evaluate the association of age, sex, education, occupation, stroke severity, and region with need for proxy respondent, and report odds ratio (OR) with 95% confidence interval (CI). RESULTS: Among 13,458 participants with acute stroke, questionnaires were completed by patients alone in 41.4% (n = 5,573), combination of patient and proxy together in 21.7% (n = 2,918), and proxy alone in 36.9% (n = 4,967). Use of proxy alone was greater in participants with severe stroke (4.7% with modified-Rankin score of 0 vs. 80.5% in those with score 5; OR 187.13; 95% CI: 119.61-308.22), older persons (43.8% of those aged 80 years and over vs. 33.2% of those aged less than 40 years; age per decade OR 1.09; 95% CI: 1.06-1.12), women (40.7% vs. 34.3% of men; OR 1.32 95% CI: 1.22-1.43), and those less educated (58.9% of those never educated vs. 25.7% of those who attended third level education; OR 7.84; 95% CI: 6.78-9.08). CONCLUSION: Use of proxy respondents enhances the generalizability of international research studies of stroke, by increasing representation of women, patients with severe stroke, older age, and lower education.

Does prior use of antiplatelet therapy modify the effect of dual antiplatelet therapy in transient ischaemic attack/minor ischaemic stroke: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: The purpose was to determine whether prior use of antiplatelet therapy modifies the effect of dual antiplatelet therapy in patients with acute minor ischaemic stroke or transient ischaemic attack. METHODS: A systematic review and meta-analysis of randomized controlled trials was performed comparing dual antiplatelet therapy to aspirin that reported subgroup analysis by prior antiplatelet use, adhering to the Cochrane Collaboration Guidelines. A fixed-effects meta-analysis was used to estimate a pooled treatment effect overall in subgroups with prior aspirin therapy and without prior aspirin therapy. Difference in treatment effect was assessed by testing p for interaction. The primary outcome measure was recurrent vascular events. RESULTS: Three eligible randomized controlled trials were identified, including 4831 participants with pre-existing antiplatelet use and 16,236 participants without pre-existing aspirin use. Recurrent vascular events occurred in 7.2% (95% confidence interval [CI] 4.3-10) of those without pre-existing aspirin use versus 7.3% (95% CI 4.1-10) of those receiving prior aspirin therapy. Effect of dual antiplatelet therapy on the primary outcome measure was consistent in participants with no prior aspirin use (odds ratio 0.75, 95% CI 0.66-0.84) compared to those taking aspirin before randomization (odds ratio 0.79, 95% CI 0.63-0.998) (p interaction = 0.66). The number needed to treat in the aspirin-naïve group was 55 (95% CI 37-107) compared to 66 (95% CI 32 to -746) in those on prior aspirin therapy. CONCLUSIONS: It was found that the effectiveness of dual antiplatelet therapy in patients with minor ischaemic stroke or high risk transient ischaemic attack does not significantly differ in patients with prior aspirin exposure; therefore there should be no influence on the decision to use dual antiplatelet therapy.

Are clinical trials randomising households to lifestyle interventions to delay cognitive decline feasible? A pilot study to determine the beliefs, preferences, and deterrents for households impacted by dementia based on semi-structured interviews.

INTRODUCTION: While lifestyle risk factors are implicated in the development and progression of cognitive impairment, interventional trials of individual participants have yielded unconvincing evidence. We sought to explore the development of lifestyle interventions targeting the household-unit. METHODS: Semi-structured interviews were carried out among eight households affected by cognitive impairment (i.e. member of the household had cognitive impairment). Interviews took place online using a secure, web-based video platform recommended for patient clinician interaction. Interview content was analysed, and important themes identified. RESULTS: Eighteen participants were interviewed within households, of which eight (one per household) had cognitive impairment and others were spouses or first-degree relatives living in the same home. Several themes emerged; 1) household members without cognitive impairment were more likely to report poor sleep habits, and sleep was perceived to be the hardest behaviour to change; 2) diet generated most interest as a potential lifestyle intervention target as most participants believed there is a strong link with nutrition and cognition; 3) physical activity is challenging to adapt due to lack of motivation and focus when individuals are cognitively impaired. Barriers to study participation, including risk of harm, complexity of intervention and deviation from routine emerged during discussions. CONCLUSIONS: This study identified beliefs and preferences of households towards lifestyle intervention trials. Findings from this study may be used to inform future clinical trial protocols and future qualitative studies should explore acceptability and feasibility of digital intervention applications.