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.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case­control 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 case­control 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 1.46­1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61­2.11) than ICH (OR 1.19 95% CI 1.00­1.41). 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 2.24­4.10) and PAR (18.6%, 15.1­22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63­2.87) and undetermined cause (OR 1.97, 95% CI 1.55­2.50). Both filtered (OR 1.73, 95% CI 1.50­1.99) and non-filtered (OR 2.59, 95% CI 1.79­3.77) 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 1.69­2.27), ischemic stroke (OR 1.89, 95% CI 1.59­2.24) and ICH (OR 2.00, 95% CI 1.60­2.50). 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.

Gender differences in cardiovascular risk, treatment, and outcomes: a post hoc analysis from the REWIND trial.

Objectives. To assess whether the use of cardioprotective therapies for type 2 diabetes varies by gender and whether the risk of cardiovascular events is higher in women versus men in the REWIND trial, including an international type 2 diabetes patient population with a wide range of baseline risk. Design. Gender differences in baseline characteristics, cardioprotective therapy, and the achieved clinical targets at baseline and two years were analyzed. Hazards for cardiovascular outcomes (fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, cardiovascular death, all-cause mortality, and heart failure hospitalization), in women versus men were analyzed using two Cox proportional hazard models, adjusted for randomized treatment and key baseline characteristics respectively. Time-to-event analyses were performed in subgroups with or without history of cardiovascular disease using Cox proportional hazards models that included gender, subgroup, randomized treatment, and gender-by-subgroup interactions. Results. Of 9901 participants, 46.3% were women. Significantly fewer women than men had a cardiovascular disease history. Although most women met treatment targets for blood pressure (96.7%) and lipids (72.8%), fewer women than men met the target for cardioprotective therapies at baseline and after two years, particularly those with prior cardiovascular disease, who used less renin-angiotensin-aldosterone system inhibitors, statins, and aspirin than men. Despite these differences, women had lower hazards than men for all outcomes except stroke. No significant gender and cardiovascular disease history interactions were identified for cardiovascular outcomes. Conclusions. In REWIND, most women met clinically relevant treatment targets, but in lower proportions than men. Women had a lower risk for all cardiovascular outcomes except stroke. Clinical trials.gov registration number: NCT01394952.

Influenza vaccine to reduce adverse vascular events in patients with heart failure: a multinational randomised, double-blind, placebo-controlled trial.

BACKGROUND: Influenza increases the risk of cardiovascular events and deaths. We aimed to see whether influenza vaccination reduces death and vascular events in patients with heart failure. METHODS: We did a pragmatic, randomised, double-blind, placebo-controlled trial in 30 centres (mostly hospitals affliated with universities or a research institute) in ten countries in Asia, the Middle East, and Africa (7 in India, 4 in Philippines, 4 in Nigeria, 6 in China, 1 in Zambia, 2 in Mozambique, 3 in Saudi Arabia, 1 in Kenya, 1 in Uganda, and 1 in Zambia). Participants (aged ≥18 years; 52·1% female; not disaggregated by race or ethnicity) with heart failure (New York Heart Association class II, III, or IV) were randomly assigned (1:1) by a centralised web-based system with block randomisation stratified by site, to receive 0·5 ml intramuscularly once a year for up to 3 years of either inactivated standard dose influenza vaccine or placebo (saline). We excluded people who had received influenza vaccine in 2 of the previous 3 years, and those likely to require valve repair or replacement. Those who administered assigned treatments were not masked and had no further role in the study. Investigators, study coordinators, outcome adjudicators, and participants were masked to group assignment. The first of two co-primary outcomes was a first-event composite for cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, and the second was a recurrent-events composite for cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. Outcomes were assessed every 6 months in the intention-to-treat population. Secondary outcomes were all-cause death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, all-cause hospitalisation, hospitalisation for heart failure, and pneumonia, both overall and during periods of peak influenza exposure. This study is registered with ClinicalTrials.gov, NCT02762851. FINDINGS: Between June 2, 2015, and Nov 21, 2021, we enrolled 5129 participants and randomly assigned (1:1) 2560 (50·0%) to influenza vaccine and 2569 (50·0%) to placebo. The first co-primary outcome occurred in 380 (14·8%) of 2560 participants in the vaccine group and 410 (16·0%) of 2569 participants in the placebo group (hazard ratio [HR] 0·93 [95% CI 0·81-1·07]; p=0·30). The second co-primary outcome occurred in 754 (29·5%) of 2560 participants in the vaccine group and 819 (31·9%) of 2569 participants in the placebo group; HR 0·92 [95% CI 0·84-1·02]; p=0·12). The secondary outcomes of all-cause hospitalisations (HR 0·84 [95% CI 0·74-0·97]; p=0·013) and pneumonia (HR 0·58 [0·42-0·80]; p=0·0006) were significantly reduced in the vaccine group compared with in the placebo group but there was no significant difference between groups for all-cause death, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. In a prespecified analysis, in which events were limited to periods of peak influenza circulation, the first co-primary outcome, and the secondary outcomes of all-cause death, cardiovasular death, and pneumonia were significantly lower in the vaccinated group than in the placebo group, whereas the second co-primary outcome and the secondary outcomes of non-fatal myocardial infarction, non-fatal stroke, all-cause hospitalisation, and hospitalisation for heart failure were not significantly lower. INTERPRETATION: Although the prespecified co-primary outcomes during the entire period of observation were not statistically significant, the reduction during the peak influenza circulating period suggests that there is likely to be a clinical benefit of giving influenza vaccine, given the clear reduction in pneumonia, a moderate reduction in hospitalisations, and a reduction in cardiovascular events and deaths during periods of peak circulation of influenza. Taken in conjunction with previous trials and the observational studies, the collective data suggest benefit. FUNDING: UK Joint Global Health Trials Scheme and Canadian Institutes for Health Research Foundation.

Association of Lipids, Lipoproteins, and Apolipoproteins with Stroke Subtypes in an International Case Control Study (INTERSTROKE).

BACKGROUND AND PURPOSE: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes. METHODS: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH). RESULTS: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001). CONCLUSIONS: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Novel Indices of Cognitive Impairment and Incident Cardiovascular Outcomes in the REWIND Trial.

CONTEXT: Low cognitive scores are risk factors for cardiovascular outcomes. Whether this relationship is stronger using novel cognitive indices is unknown. METHODS: Participants in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial who completed both the Montreal Cognitive Assessment (MoCA) score and Digit Substitution Test (DSST) at baseline (N = 8772) were included. These scores were used to identify participants with baseline substantive cognitive impairment (SCI), defined as a baseline score on either the MoCA or DSST ≥ 1.5 SD below either score's country-specific mean, or SCI-GM, which was based on a composite index of both scores calculated as their geometric mean (GM), and defined as a score that was ≥ 1.5 SD below their country's average GM. Relationships between these measures and incident major adverse cardiovascular events (MACE), and either stroke or death were analyzed. RESULTS: Compared with 7867 (89.7%) unaffected participants, the 905 (10.3%) participants with baseline SCI had a higher incidence of MACE (unadjusted hazard ratio [HR] 1.34; 95% CI 1.11, 1.62; P = 0.003), and stroke or death (unadjusted HR 1.60; 95% CI 1.33, 1.91; P < 0.001). Stronger relationships were noted for SCI-GM and MACE (unadjusted HR 1.61; 95% CI 1.28, 2.01; P < 0.001), and stroke or death (unadjusted HR 1.85; 95% CI 1.50, 2.30; P < 0.001). For SCI-GM but not SCI, all these relationships remained significant in models that adjusted for up to 10 SCI risk factors. CONCLUSION: Country-standardized SCI-GM was a strong independent predictor of cardiovascular events in people with type 2 diabetes in the REWIND trial.

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study.

Importance: Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. Objective: To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. Design, Setting, and Participants: This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. Main Outcomes and Measures: Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). Results: The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). Conclusions and Relevance: In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

Dulaglutide and incident atrial fibrillation or flutter in patients with type 2 diabetes: A post hoc analysis from the REWIND randomized trial.

AIM: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once-weekly subcutaneous dulaglutide versus placebo. MATERIALS AND METHODS: Patients without electrocardiographic (ECG)-confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. RESULTS: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow-up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person-years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person-years (P = .59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. CONCLUSION: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at-risk group of patients with type 2 diabetes.

Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial.

BACKGROUND: Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes. METHODS: The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85-0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18-1·05, p=0·006). INTERPRETATION: Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes. FUNDING: Eli Lilly and Company.

High-Sensitivity Estimate of the Incidence of New-Onset Atrial Fibrillation in Critically Ill Patients.

To estimate the incidence of new-onset atrial fibrillation in critically ill patients. DESIGN: Prospective cohort. SETTING: Medical-surgical ICU. SUBJECTS: Consecutive patients without a history of atrial fibrillation but with atrial fibrillation risk factors. INTERVENTIONS: Electrocardiogram patch monitor until discharge from hospital or up to 14 days. MEASUREMENTS AND MAIN RESULTS: A total of 249 participants (median age of 71 yr [interquartile range] 64-78 yr; 35% female) completed the study protocol of which 158 (64%) were admitted to ICU for medical illness, 78 (31%) following noncardiac surgery, and 13 (5%) with trauma. Median Acute Physiology and Chronic Health Evaluation II score was 16 (interquartile range, 12-22). Median duration of patch electrocardiogram monitoring, ICU, and hospital lengths of stay were 6 (interquartile range, 3-12), 4 (interquartile range, 2-8), and 11 days (interquartile range, 5-23 d), respectively.Atrial fibrillation ≥ 30 seconds was detected by the patch in 44 participants (17.7%), and three participants (1.2%) had atrial fibrillation detected clinically after patch removal, resulting in an overall atrial fibrillation incidence of 18.9% (95% CI, 14.2-24.3%).Total duration of atrial fibrillation ranged from 53 seconds to the entire monitoring time. The proportion of participants with ≥1 episode(s) of ≥6 minute, ≥1 hour, ≥12 hour and ≥24 hour duration was 14.8%, 13.2%, 7.0%, and 5.3%, respectively. The clinical team recognized only 70% of atrial fibrillation cases that were detected by the electrocardiogram patch. CONCLUSIONS: Among patients admitted to an ICU, the incidence of new-onset atrial fibrillation is approximately one in five, although approximately one-third of cases are not recognized by the clinical team.

Urinary Sodium and Potassium, and Risk of Ischemic and Hemorrhagic Stroke (INTERSTROKE): A Case-Control Study.

BACKGROUND: Although low sodium intake (<2 g/day) and high potassium intake (>3.5 g/day) are proposed as public health interventions to reduce stroke risk, there is uncertainty about the benefit and feasibility of this combined recommendation on prevention of stroke. METHODS: We obtained random urine samples from 9,275 cases of acute first stroke and 9,726 matched controls from 27 countries and estimated the 24-hour sodium and potassium excretion, a surrogate for intake, using the Tanaka formula. Using multivariable conditional logistic regression, we determined the associations of estimated 24-hour urinary sodium and potassium excretion with stroke and its subtypes. RESULTS: Compared with an estimated urinary sodium excretion of 2.8-3.5 g/day (reference), higher (>4.26 g/day) (odds ratio [OR] 1.81; 95% confidence interval [CI], 1.65-2.00) and lower (<2.8 g/day) sodium excretion (OR 1.39; 95% CI, 1.26-1.53) were significantly associated with increased risk of stroke. The stroke risk associated with the highest quartile of sodium intake (sodium excretion >4.26 g/day) was significantly greater (P < 0.001) for intracerebral hemorrhage (ICH) (OR 2.38; 95% CI, 1.93-2.92) than for ischemic stroke (OR 1.67; 95% CI, 1.50-1.87). Urinary potassium was inversely and linearly associated with risk of stroke, and stronger for ischemic stroke than ICH (P = 0.026). In an analysis of combined sodium and potassium excretion, the combination of high potassium intake (>1.58 g/day) and moderate sodium intake (2.8-3.5 g/day) was associated with the lowest risk of stroke. CONCLUSIONS: The association of sodium intake and stroke is J-shaped, with high sodium intake a stronger risk factor for ICH than ischemic stroke. Our data suggest that moderate sodium intake-rather than low sodium intake-combined with high potassium intake may be associated with the lowest risk of stroke and expected to be a more feasible combined dietary target.

Variations in knowledge, awareness and treatment of hypertension and stroke risk by country income level.

OBJECTIVE: Hypertension is the most important modifiable risk factor for stroke globally. We hypothesised that country-income level variations in knowledge, detection and treatment of hypertension may contribute to variations in the association of blood pressure with stroke. METHODS: We undertook a standardised case-control study in 32 countries (INTERSTROKE). Cases were patients with acute first stroke (n=13 462) who were matched by age, sex and site to controls (n=13 483). We evaluated the associations of knowledge, awareness and treatment of hypertension with risk of stroke and its subtypes and whether this varied by gross national income (GNI) of country. We estimated OR and population attributable risk (PAR) associated with treated and untreated hypertension. RESULTS: Hypertension was associated with a graded increase in OR by reducing GNI, ranging from OR 1.92 (99% CI 1.48 to 2.49) to OR 3.27 (2.72 to 3.93) for highest to lowest country-level GNI (p-heterogeneity<0.0001). Untreated hypertension was associated with a higher OR for stroke (OR 5.25; 4.53 to 6.10) than treated hypertension (OR 2.60; 2.32 to 2.91) and younger age of first stroke (61.4 vs 65.4 years; p<0.01). Untreated hypertension was associated with a greater risk of intracerebral haemorrhage (OR 6.95; 5.61 to 8.60) than ischaemic stroke (OR 4.76; 3.99 to 5.68). The PAR associated with untreated hypertension was higher in lower-income regions, PAR 36.3%, 26.3%, 19.8% to 10.4% by increasing GNI of countries. Lifetime non-measurement of blood pressure was associated with stroke (OR 1.80; 1.32 to 2.46). CONCLUSIONS: Deficits in knowledge, detection and treatment of hypertension contribute to higher risk of stroke, younger age of onset and larger proportion of intracerebral haemorrhage in lower-income countries.

Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial.

BACKGROUND: Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. METHODS: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018). INTERPRETATION: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated. FUNDING: Eli Lilly and Company.

Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

SUPERIOR SVG: no touch saphenous harvesting to improve patency following coronary bypass grafting (a multi-Centre randomized control trial, NCT01047449).

BACKGROUND: Single centre studies support No Touch (NT) saphenous vein graft (SVG) harvesting technique. The primary objective of the SUPERIOR SVG study was to determine whether NT versus conventional (CON) SVG harvesting was associated with improved SVG patency 1 year after coronary artery bypass grafting surgery (CABG). METHODS: Adults undergoing isolated CABG with at least 1 SVG were eligible. CT angiography was performed 1-year post CABG. Leg adverse events were assessed with a questionnaire. A systematic review was performed for published NT graft patency studies and results aggregated including the SUPERIOR study results. RESULTS: Two hundred and-fifty patients were randomized across 12-centres (NT 127 versus CON 123 patients). The primary outcome (study SVG occlusion or cardiovascular (CV) death) was not significantly different in NT versus CON (NT: 7/127 (5.5%), CON 13/123 (10.6%), p = 0.15). Similarly, the proportion of study SVGs with significant stenosis or total occlusion was not significantly different between groups (NT: 8/102 (7.8%), CON: 16/107 (15.0%), p = 0.11). Vein harvest site infection was more common in the NT patients 1 month postoperatively (23.3% vs 9.5%, p < 0.01). Including this study's results, in a meta-analysis, NT was associated with a significant reduction in SVG occlusion, Odds Ratio 0.49, 95% Confidence Interval 0.29-0.82, p = 0.007 in 3 randomized and 1 observational study at 1 year postoperatively. CONCLUSIONS: The NT technique was not associated with improved patency of SVGs at 1-year following CABG while early vein harvest infection was increased. The aggregated data is supportive of an important reduction of SVG occlusion at 1 year with NT harvesting. TRIAL REGISTRATION: NCT01047449 .

Perioperative Pregabalin and Intraoperative Lidocaine Infusion to Reduce Persistent Neuropathic Pain After Breast Cancer Surgery: A Multicenter, Factorial, Randomized, Controlled Pilot Trial.

Persistent postsurgical pain is defined as pain localized to the area of surgery of a duration of ≥2 months and is, unfortunately, a common complication after breast cancer surgery. Although there is insufficient evidence to support any preventative strategy, prior literature suggests the possible efficacy of intravenous lidocaine and perioperative pregabalin in preventing persistent pain after surgery. To determine feasibility of conducting a larger definitive trial, we conducted a multicenter 2 × 2 factorial, randomized, placebo-controlled pilot trial of 100 female patients undergoing breast cancer surgery. Patients were randomized to receive an intraoperative lidocaine infusion (1.5 mg/kg bolus followed by 2 mg/kg/h) or placebo and perioperative pregabalin (300 mg preoperatively, 75 mg twice daily for 9 days) or placebo. All feasibility criteria were surpassed; recruitment of 100 patients was accomplished within 42 weeks, with a follow-up rate of 100% and study drug compliance of ≥80%. At 3 months, 53% of patients reported persistent neuropathic pain. Although there was no interaction between lidocaine and pregabalin, lidocaine decreased the development of persistent neuropathic pain (43.1% vs 63.3%; relative risk = .68; 95% confidence interval = .47-1.0). Pregabalin did not reduce persistent pain (60% vs 46%; relative risk = 1.3; 95% confidence interval = .90-1.90) and neither pregabalin nor lidocaine impacted acute postoperative pain, opioid consumption, pain interference, or quality of life. Our pilot trial successfully demonstrated feasibility and provided promising data for conducting further trials of intraoperative lidocaine infusions during breast cancer surgeries. Clinical trial number: NCT02240199 PERSPECTIVE: This article reports the findings of a pilot randomized, controlled trial evaluating the effects of perioperative pregabalin and intraoperative lidocaine infusions in patients undergoing breast cancer surgery. This trial demonstrated the feasibility of conducting a larger trial and provided promising data that these interventions may decrease the development of persistent pain.

Effects of trypanocidal treatment on echocardiographic parameters in chagas cardiomyopathy and prognostic value of wall motion score index: A BENEFIT trial echocardiographic substudy

Serial echocardiographic studies in chronic Chagas cardiomyopathy are scarce. The aims of this study were to evaluate whether therapy with benznidazole modifies the progression of cardiac impairment and to identify baseline echocardiographic parameters related to prognosis. METHODS: A prospective sub study was conducted in 1,508 patients with chronic Chagas cardiomyopathy randomized to benznidazole or placebo, who underwent two-dimensional echocardiography at enrollment, 2 years, and final follow-up (5.4 years). Left ventricular (LV) ejection fraction, LV wall motion score index (WMSI), indexed left atrial volume, and chamber dimensions were collected and correlated to all-cause death and a composite hard outcome using univariate and multivariate analyses. RESULTS: At enrollment, most patients had normal chamber dimensions, and 70.5% had preserved LV ejection fractions. During follow-up, all chamber dimensions increased similarly in both treatment arms. LV ejection fraction was comparably reduced (55.7 ± 12.7% to 52.1 ± 14.6% vs 56.3 ± 12.7% to 52.8 ± 14.1%) and LV WMSI similarly increased (1.31 ± 0.41 to 1.49 ± 0.03 and 1.27 ± 0.38 to 1.51 ± 0.03) for the benznidazole and placebo groups, respectively (P > .05). A higher baseline LV WMSI was identified in subjects who died compared with those alive at final echocardiography (1.76 ± 0.517 vs 1.271 ± 0.393, P < .0001). There was a significant (P < .0001) graded increase in the risk for the composite outcome with worsening LV WMSI (hazard ratios, 2.27 [95% CI, 1.69-3.06] and 6.42 [95% CI, 4.94-8.33]) and also of death (hazard ratios, 2.45 [95% CI, 1.62-3.71] and 8.99 [95% CI, 6.3-12.82]) for 1 < LV WMSI < 1.5 and LV WMSI > 1.5, respectively. Both LV WMSI and indexed left atrial volume remained independent predictors in multivariate analysis. CONCLUSIONS: Trypanocidal treatment had no effect on echocardiographic progression of chronic Chagas cardiomyopathy over 5.4 years. Despite normal global LV systolic function, regional wall motion abnormalities and indexed left atrial volume identified patients at higher risk for hard adverse clinical outcomes. Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved. KEYWORDS: Chagas cardiomyopathy; Echocardiography; Prognosis; Trypanocidal therapy. (AU)

Effects of Trypanocidal Treatment on Echocardiographic Parameters in Chagas Cardiomyopathy and Prognostic Value of Wall Motion Score Index: A BENEFIT Trial Echocardiographic Substudy.

BACKGROUND: Serial echocardiographic studies in chronic Chagas cardiomyopathy are scarce. The aims of this study were to evaluate whether therapy with benznidazole modifies the progression of cardiac impairment and to identify baseline echocardiographic parameters related to prognosis. METHODS: A prospective substudy was conducted in 1,508 patients with chronic Chagas cardiomyopathy randomized to benznidazole or placebo, who underwent two-dimensional echocardiography at enrollment, 2 years, and final follow-up (5.4 years). Left ventricular (LV) ejection fraction, LV wall motion score index (WMSI), indexed left atrial volume, and chamber dimensions were collected and correlated to all-cause death and a composite hard outcome using univariate and multivariate analyses. RESULTS: At enrollment, most patients had normal chamber dimensions, and 70.5% had preserved LV ejection fractions. During follow-up, all chamber dimensions increased similarly in both treatment arms. LV ejection fraction was comparably reduced (55.7 ± 12.7% to 52.1 ± 14.6% vs 56.3 ± 12.7% to 52.8 ± 14.1%) and LV WMSI similarly increased (1.31 ± 0.41 to 1.49 ± 0.03 and 1.27 ± 0.38 to 1.51 ± 0.03) for the benznidazole and placebo groups, respectively (P > .05). A higher baseline LV WMSI was identified in subjects who died compared with those alive at final echocardiography (1.76 ± 0.517 vs 1.271 ± 0.393, P < .0001). There was a significant (P < .0001) graded increase in the risk for the composite outcome with worsening LV WMSI (hazard ratios, 2.27 [95% CI, 1.69-3.06] and 6.42 [95% CI, 4.94-8.33]) and also of death (hazard ratios, 2.45 [95% CI, 1.62-3.71] and 8.99 [95% CI, 6.3-12.82]) for 1 < LV WMSI < 1.5 and LV WMSI > 1.5, respectively. Both LV WMSI and indexed left atrial volume remained independent predictors in multivariate analysis. CONCLUSIONS: Trypanocidal treatment had no effect on echocardiographic progression of chronic Chagas cardiomyopathy over 5.4 years. Despite normal global LV systolic function, regional wall motion abnormalities and indexed left atrial volume identified patients at higher risk for hard adverse clinical outcomes.

Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. METHODS: In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. FINDINGS: Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55-0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55-1·53; p=0·76). INTERPRETATION: Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication [corrected]. FUNDING: Boehringer Ingelheim and Canadian Institutes of Health Research.