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.

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.

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.

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.

Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy.

BACKGROUND: The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven. METHODS: We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event. RESULTS: The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons). The effect of treatment on PCR conversion varied according to geographic region: in Brazil, the odds ratio for PCR conversion was 3.03 (95% CI, 2.12 to 4.34) at 2 years and 1.87 (95% CI, 1.33 to 2.63) at 5 or more years; in Colombia and El Salvador, the odds ratio was 1.33 (95% CI, 0.90 to 1.98) at 2 years and 0.96 (95% CI, 0.63 to 1.45) at 5 or more years; and in Argentina and Bolivia, the odds ratio was 2.63 (95% CI, 1.89 to 3.66) at 2 years and 2.79 (95% CI, 1.99 to 3.92) at 5 or more years (P<0.001 for interaction). However, the rates of PCR conversion did not correspond to effects on clinical outcome (P=0.16 for interaction). CONCLUSIONS: Trypanocidal therapy with benznidazole in patients with established Chagas' cardiomyopathy significantly reduced serum parasite detection but did not significantly reduce cardiac clinical deterioration through 5 years of follow-up. (Funded by the Population Health Research Institute and others; ClinicalTrials.gov number, NCT00123916; Current Controlled Trials number, ISRCTN13967269.).

Age Does Not Affect Metoprolol's Effect on Perioperative Outcomes (From the POISE Database).

BACKGROUND: Perioperative ß-blockade reduces the incidence of myocardial infarction but increases that of death, stroke, and hypotension. The elderly may experience few benefits but more harms associated with ß-blockade due to a normal effect of aging, that of a reduced resting heart rate. The tested hypothesis was that the effect of perioperative ß-blockade is more significant with increasing age. METHODS: To determine whether the effect of perioperative ß-blockade on the primary composite event, clinically significant hypotension, myocardial infarction, stroke, and death varies with age, we interrogated data from the perioperative ischemia evaluation (POISE) study. The POISE study randomly assigned 8351 patients, aged ≥45 years, in 23 countries, undergoing major noncardiac surgery to either 200 mg metoprolol CR daily or placebo for 30 days. Odds ratios or hazard ratios for time to events, when available, for each of the adverse effects were measured according to decile of age, and interaction term between age and treatment was calculated. No adjustment was made for multiple outcomes. RESULTS: Age was associated with higher incidences of the major outcomes of clinically significant hypotension, myocardial infarction, and death. Age was associated with a minimal reduction in resting heart rate from 84.2 (standard error, 0.63; ages 45-54 years) to 80.9 (standard error, 0.70; ages >85 years; P < .0001). We found no evidence of any interaction between age and study group regarding any of the major outcomes, although the limited sample size does not exclude any but large interactions. CONCLUSIONS: The effect of perioperative ß-blockade on the major outcomes studied did not vary with age. Resting heart rate decreases slightly with age. Our data do not support a recommendation for the use of perioperative ß-blockade in any age subgroup to achieve benefits but avoid harms. Therefore, current recommendations against the use of ß-blockers in high-risk patients undergoing noncardiac surgery apply across all age groups.

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.

BACKGROUND: Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. METHODS: We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. FINDINGS: Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). INTERPRETATION: Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.

Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study.

BACKGROUND: Despite the frequency of new clinically important atrial fibrillation (AF) after noncardiac surgery and its increased association with the risk of stroke at 30 days, there are limited data informing their prediction, association with outcomes, and management. METHODS: We used the data from the PeriOperative ISchemic Evaluation trial to determine, in patients undergoing noncardiac surgery, the association of new clinically important AF with 30-day outcomes, and to assess management of these patients. We also aimed to derive a clinical prediction rule for new clinically important AF in this population. We defined new clinically important AF as new AF that resulted in symptoms or required treatment. We recorded an electrocardiogram 6 to 12 hours postoperatively and on the 1st, 2nd, and 30th days after surgery. RESULTS: A total of 211 (2.5% [8351 patients]; 95% confidence interval, 2.2%-2.9%) patients developed new clinically important AF within 30 days of randomization (8140 did not develop new AF). AF was independently associated with an increased length of hospital stay by 6.0 days (95% confidence interval, 3.5-8.5 days) and vascular complications (eg, stroke or congestive heart failure). The usage of an oral anticoagulant at the time of hospital discharge among patients with new AF and a CHADS2 score of 0, 1, 2, 3, and ≥4 was 6.9%, 10.2%, 23.0%, 9.4%, and 33.3%, respectively. Two independent predictors of patients developing new clinically important AF were identified (ie, age and surgery). The prediction rule included the following factors and assigned weights: age ≥85 years (4 points), age 75 to 84 years (3 points), age 65 to 74 years (2 points), intrathoracic surgery (3 points), major vascular surgery (2 points), and intra-abdominal surgery (1 point). The incidence of new AF based on scores of 0 to 1, 2, 3 to 4, and 5 to 6 was 0.5%, 1.0%, 3.1%, and 5.3%, respectively. CONCLUSIONS: Age and surgery are independent predictors of new clinically important AF in the perioperative setting. A minority of patients developing new clinically important AF with high CHADS2 scores are discharged on an oral anticoagulant. There is a need to develop effective and safe interventions to prevent this outcome and to optimize the management of this event when it occurs.

Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial.

BACKGROUND: Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. METHODS: Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase-myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. RESULTS: We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] -0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI -0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). INTERPRETATION: Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01071265.

Cluster randomized controlled trial of Delayed Educational Reminders for Long-term Medication Adherence in ST-Elevation Myocardial Infarction (DERLA-STEMI).

BACKGROUND: Discontinuation of guideline-recommended cardiac medications post-ST-elevation myocardial infarction (STEMI) is common and associated with increased mortality. DERLA-STEMI tested an intervention to improve long-term adherence to cardiac medications post-STEMI. METHODS AND RESULTS: Between September 2011 and December 2012, STEMI patients from one health region in Ontario, who underwent an angiogram during their admission and survived to discharge, were cluster randomized (by primary care provider) to intervention or control. The intervention was an automated system of personalized, educational-reminders sent to the patient and their family physician, urging long-term use of secondary-prevention medications. Interventions were mailed at 1, 2, 5, 8, and 11 months after discharge. A total of 852 eligible participants were randomized to intervention (n = 424, 287 clusters) and control (n = 428, 295 clusters); 87% completed a 12-month follow-up. The primary outcome, defined as the proportion of participants taking (persistence) all 4-cardiovascular medication classes (acetylsalicylic acid, angiotensin blockers, statin, and ß-blocker) at 12 months, was 58.4% (intervention) and 58.9% (control; adjusted odds ratio 1.03, 95% CI 0.77-1.36). Medication adherence, as assessed by the Morisky Medication Adherence Score, was statistically significantly better in the intervention group as compared with control (65.3% vs 58.0%, adjusted odds ratio 1.35, 95% CI 1.01-1.81). CONCLUSION: The results suggest suboptimal use of 4 of 4 cardiac medication classes at 12 months. There was no significant difference compared with usual care in the persistence to guideline-recommended medications post-STEMI when participants (and their family physicians) receive repeated postal reminders.

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.

Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study.

BACKGROUND: Each year, millions of patients worldwide have a perioperative myocardial infarction (MI) after noncardiac surgery. OBJECTIVE: To examine the characteristics and short-term outcome of perioperative MI. DESIGN: Cohort study. (ClinicalTrials.gov registration number: NCT00182039) SETTING: 190 centers in 23 countries. PATIENTS: 8351 patients included in the POISE (PeriOperative ISchemic Evaluation) trial. MEASUREMENTS: Four cardiac biomarker or enzyme assays were measured within 3 days of surgery. The definition of perioperative MI included either autopsy findings of acute MI or an elevated level of a cardiac biomarker or enzyme and at least 1 of the following defining features: ischemic symptoms, development of pathologic Q waves, ischemic changes on electrocardiography, coronary artery intervention, or cardiac imaging evidence of MI. RESULTS: Within 30 days of random assignment, 415 patients (5.0%) had a perioperative MI. Most MIs (74.1%) occurred within 48 hours of surgery; 65.3% of patients did not experience ischemic symptoms. The 30-day mortality rate was 11.6% (48 of 415 patients) among patients who had a perioperative MI and 2.2% (178 of 7936 patients) among those who did not (P < 0.001). Among patients with a perioperative MI, mortality rates were elevated and similar between those with (9.7%; adjusted odds ratio, 4.76 [95% CI, 2.68 to 8.43]) and without (12.5%; adjusted odds ratio, 4.00 [CI, 2.65 to 6.06]) ischemic symptoms. LIMITATION: Cardiac markers were measured only until day 3 after surgery, and additional asymptomatic MIs may have been missed. CONCLUSION: Most patients with a perioperative MI will not experience ischemic symptoms. Data suggest that routine monitoring of troponin levels in at-risk patients is needed after surgery to detect most MIs, which have an equally poor prognosis regardless of whether they are symptomatic or asymptomatic.

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.

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.

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.

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.

Association of diet, exercise, and smoking modification with risk of early cardiovascular events after acute coronary syndromes.

BACKGROUND: Although preventive drug therapy is a priority after acute coronary syndrome, less is known about adherence to behavioral recommendations. The aim of this study was to examine the influence of adherence to behavioral recommendations in the short term on risk of cardiovascular events. METHODS AND RESULTS: The study population included 18 809 patients from 41 countries enrolled in the Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS) 5 randomized clinical trial. At the 30-day follow-up, patients reported adherence to diet, physical activity, and smoking cessation. Cardiovascular events (myocardial infarction, stroke, cardiovascular death) and all-cause mortality were documented to 6 months. About one third of smokers persisted in smoking. Adherence to neither diet nor exercise recommendations was reported by 28.5%, adherence to either diet or exercise by 41.6%, and adherence to both by 29.9%. In contrast, 96.1% of subjects reported antiplatelet use, 78.9% reported statin use, and 72.4% reported angiotensin-converting enzyme/angiotensin receptor blocker use. Quitting smoking was associated with a decreased risk of myocardial infarction compared with persistent smoking (odds ratio, 0.57; 95% confidence interval, 0.36 to 0.89). Diet and exercise adherence was associated with a decreased risk of myocardial infarction compared with nonadherence (odds ratio, 0.52; 95% confidence interval, 0.4 to 0.69). Patients who reported persistent smoking and nonadherence to diet and exercise had a 3.8-fold (95% confidence interval, 2.5 to 5.9) increased risk of myocardial infarction/stroke/death compared with never smokers who modified diet and exercise. CONCLUSIONS: Adherence to behavioral advice (diet, exercise, and smoking cessation) after acute coronary syndrome was associated with a substantially lower risk of recurrent cardiovascular events. These findings suggest that behavioral modification should be given priority similar to other preventive medications immediately after acute coronary syndrome. Clinical Trial Registration Information- URL: http://clinicaltrials.gov/ct2/show/NCT00139815. Unique identifier: NCT00139815.

Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.

BACKGROUND: The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction. METHODS: We undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors. FINDINGS: In the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2.64, 99% CI 2.26-3.08; PAR 34.6%, 99% CI 30.4-39.1); current smoking (2.09, 1.75-2.51; 18.9%, 15.3-23.1); waist-to-hip ratio (1.65, 1.36-1.99 for highest vs lowest tertile; 26.5%, 18.8-36.0); diet risk score (1.35, 1.11-1.64 for highest vs lowest tertile; 18.8%, 11.2-29.7); regular physical activity (0.69, 0.53-0.90; 28.5%, 14.5-48.5); diabetes mellitus (1.36, 1.10-1.68; 5.0%, 2.6-9.5); alcohol intake (1.51, 1.18-1.92 for more than 30 drinks per month or binge drinking; 3.8%, 0.9-14.4); psychosocial stress (1.30, 1.06-1.60; 4.6%, 2.1-9.6) and depression (1.35, 1.10-1.66; 5.2%, 2.7-9.8); cardiac causes (2.38, 1.77-3.20; 6.7%, 4.8-9.1); and ratio of apolipoproteins B to A1 (1.89, 1.49-2.40 for highest vs lowest tertile; 24.9%, 15.7-37.1). Collectively, these risk factors accounted for 88.1% (99% CI 82.3-92.2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90.3% (85.3-93.7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke. INTERPRETATION: Our findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.

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.