A feasibility study for CODE-MI: High-sensitivity cardiac troponin-Optimizing the diagnosis of acute myocardial infarction/injury in women.

BACKGROUND: CODE-MI is a pan-Canadian, multicentre, stepped-wedge, cluster randomized trial that evaluates the impact of using the female-specific 99th percentile threshold for high-sensitivity cardiac troponin (hs-cTn) on the diagnosis, treatment and outcomes of women presenting to the emergency department (ED) with symptoms suggestive for myocardial ischemia. A feasibility study was conducted to estimate the number of eligible patients, the rate of the study's primary outcome under control conditions, and the statistical power to detect a clinically important difference in the primary outcome. METHODS: Using linked administrative data from 11 hospitals in Ontario, Canada, from October 2014 to September 2017, the following estimates were obtained: number of women presenting to the ED with symptoms suggestive of myocardial ischemia and a 24-hour peak hs-cTn value within the female-specific and overall thresholds (ie, primary cohort); the rate of the 1-year composite outcome of all-cause mortality, re-admission for nonfatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization. Study power was evaluated via simulations. RESULTS: Overall, 2,073,849 ED visits were assessed. Among women, chest pain (with or without cardiac features) and shortness of breath were the most common complaints associated with a diagnosis of acute coronary syndrome. An estimated 7.7% of women with these complaints are eligible for inclusion in the primary cohort. The rate of the 1-year outcome in the primary cohort varied significantly across hospitals with a median rate of 12.2% (95%CI: 7.9%-17.7%). With 30 hospitals, randomized at 5-month intervals in 5 steps, approximately 19,600 women are expected to be included in CODE-MI, resulting in >82% power to detect a 20% decrease in the odds of the primary outcome at a 0.05 significance level. CONCLUSIONS: This feasibility study greatly enhanced the design of CODE-MI, allowed accurate evaluation of the study power, and demonstrated the strength of using linked administrative health data to guide the design of pragmatic clinical trials.

High-Sensitivity Cardiac Troponin-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women (CODE-MI): Rationale and design for a multicenter, stepped-wedge, cluster-randomized trial.

Despite evidence that high-sensitivity cardiac troponin (hs-cTn) levels in women are lower than in men, a single threshold based on the 99th percentile upper reference limit of the overall reference population is commonly used to diagnose myocardial infarction in clinical practice. This trial aims to determine whether the use of a lower female-specific hs-cTn threshold would improve the diagnosis, treatment, and outcomes of women presenting to the emergency department with symptoms suggestive of myocardial ischemia. METHODS/DESIGN: CODE-MI (hs-cTn-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women) is a multicenter, stepped-wedge, cluster-randomized trial of 30 secondary and tertiary care hospitals across 8 Canadian provinces, with the unit of randomization being the hospital. All adults (≥20 years of age) presenting to the emergency department with symptoms suggestive of myocardial ischemia and at least 1 hs-cTn test are eligible for inclusion. Over five, 5-month intervals, hospitals will be randomized to implement lower female hs-cTn thresholds according to the assay being used at each site. Men will continue to be assessed using the overall thresholds throughout. Women with a peak hs-cTn value between the female-specific and the overall thresholds will form our primary cohort. The primary outcome, a 1-year composite of all-cause mortality or readmission for nonfatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization, will be compared before and after the implementation of female thresholds using mixed-effects logistic regression models. The cohort and outcomes will be obtained from routinely collected administrative data. The trial is designed to detect a 20% relative risk difference in the primary outcome, or a 2.2% absolute difference, with 82% power. CONCLUSIONS: This pragmatic trial will assess whether adopting lower female hs-cTn thresholds leads to appropriate assessment of women with symptoms suggestive of myocardial infarction, thereby improving treatment and outcomes.

Long-term Mortality, Readmission, and Resource Utilization Among Hospital Survivors of Out-of-Hospital Cardiac Arrest.

BACKGROUND: Among patients with out-of-hospital cardiac arrest (OHCA), the influence of pre- and in-hospital factors on long-term survival, readmission, and resource utilization is ill-defined, mainly related to challenges combining disparate data sources. METHODS: Adult nontraumatic OHCA from the British Columbia Cardiac Arrest Registry (January 2009 to December 2016) were linked to provincial datasets comprising comorbidities, medications, cardiac procedures, mortality, and hospital admission and discharge. Among hospital-discharge survivors, the 3-year end point of mortality or mortality and all-cause readmission was examined with the use of the Kaplan-Meier method and multivariable Cox regression model for predictors. The use of publicly funded home care and community services within 1 year after discharge also was evaluated. RESULTS: Of the 10,674 linked, emergency medical services-treated adult OHCAs, 3230 were admitted to hospital and 1325 survived to hospital discharge. At 3 years after discharge, the estimated Kaplan-Meier survival rate was 84.1% (95% CI 81.7%-86.1%) and freedom from death or all-cause readmission was 31.8% (29.0%-34.7%). After exclusions, 26.6% (n = 315/1186) accessed residential or home care services within 1 year. Independent predictors of long-term outcomes included age and comorbidities, but also favourable arrest characteristics and in-hospital factors such as revascularization or receipt of an intracardiac defibrillator before discharge. CONCLUSIONS: Among OHCA hospital survivors, the long-term death or readmission risk persists and is modulated by both pre- and in-hospital factors. However, only 1 in 4 survivors required residential or home care after discharge. These results support efforts to improve care processes to increase survival to hospital discharge.

Anticoagulation for Patients With Atrial Fibrillation and End-Stage Renal Disease on Dialysis: A National Survey.

Patients with atrial fibrillation (AF) have a significant increased risk of embolic stroke. Patients with end-stage renal disease who are on dialysis have an increased risk of both embolic stroke and bleeding. Stroke-prevention studies with the use of anticoagulation for AF patients have excluded patients on dialysis, so there remains no consensus on their management. We developed and implemented a pan-Canadian multidisciplinary survey to explore the current beliefs and practices concerning patients with AF on dialysis. We developed an online investigator-designed survey with both quantitative and qualitative responses with the use of a secure university-affiliated electronic service. The survey was distributed to physicians via the QxMD platform and directly to internal medicine, cardiology, and nephrology residency program directors for distribution to faculty members. 130 participants responded, including 46 cardiologists, 45 nephrologists, 30 general internists, and 9 other physicians. The preferred anticoagulant was warfarin. The CHADS2 score used to initiate anticoagulation was highly variable, with specialties differing in use of a CHADS2 threshold of ≥ 1 (P < 0.001) and the impact of previous transient ischemic attack/stroke (P = 0.02). Calciphylaxis history affected the decision to prescribe anticoagulation. Specialties differed in thresholds used to consider direct oral anticoagulants for dialysis patients, with nephrologists more likely to prescribe anticoagulation at higher CHADS2 scores. Our survey demonstrated significant heterogeneity of anticoagulation use for stroke prevention in patients with AF on dialysis. Physician specialty and patient risk profiles contributed to the observed variability. This study reemphasises the need for clinical trials, large observational studies, and consensus guidelines to address evident equipoise.

Prophylactic intravenous magnesium sulphate in addition to oral {beta}-blockade does not prevent atrial arrhythmias after coronary artery or valvular heart surgery: a randomized, controlled trial.

BACKGROUND: Atrial arrhythmias (AA) are an important cause of morbidity after cardiac surgery. Efforts at prevention of postoperative AA have been suboptimal. Perioperative beta-blocker administration is the standard of care at many centers. Although prophylactic administration of magnesium sulfate (MgSO(4)) has been recommended, review of all previously published trials of MgSO(4) reveals conflicting results. This study was designed to address methodological shortcomings from previous studies and is the largest randomized, placebo-controlled trial of intravenous (IV) MgSO(4) for the prevention of AA after coronary artery bypass grafting or cardiac valvular surgery. METHODS AND RESULTS: A total of 927 nonemergent cardiac surgery patients were stratified into 2 groups: isolated coronary artery bypass grafting (n=694), or valve surgery with or without coronary artery bypass grafting (n=233), and randomized to receive either 5g IV MgSO(4) or placebo on removal of the cross-clamp, followed by daily 4-hour infusions, from postoperative day 1 until postoperative day 4. All patients were treated according to an established oral beta-blocker protocol. Postoperative serum Mg levels were checked and standard of care was to administer IV MgSO(4) for low serum levels. The primary end point was AA lasting > or =30 minutes or requiring treatment for hemodynamic compromise. There were no differences in the incidence of AA between patients who received IV MgSO(4) or placebo (26.4% versus 24.3%, respectively). The results were similar when broken down according to stratified groups. CONCLUSIONS: In patients treated with a protocol for postoperative oral beta-blocker after nonemergent cardiac surgery, the addition of prophylactic IV MgSO(4) did not reduce the incidence of AA.

Sex Differences in Diagnoses, Treatment, and Outcomes for Emergency Department Patients With Chest Pain and Elevated Cardiac Troponin.

OBJECTIVE: While sex differences in the treatment and outcomes of subjects with acute coronary syndromes are well documented, little is known about the impact of cardiac troponin (cTn) levels obtained in the emergency department (ED) on the observed sex differences. We sought to determine whether cTn levels by chest pain features modify sex differences in diagnosis, treatment, and outcomes in patients presenting with chest pain suggestive of ischemia. METHODS: All adults presenting to two hospitals in Vancouver, Canada, between May 2008 and March 2013 with ischemic chest pain and with cTn testing were included in the study. Outcomes were obtained through data linkage with population-based administrative data sets, including Vital Statistics (death), Discharge Abstract Database (hospitalizations), and PharmaNet (medications). Cumulative event rates for the composite major adverse cardiac event (MACE) endpoint (death, myocardial infarction [MI], incident admission for heart failure or for angina requiring diagnostic catheterization or revascularization) were estimated for each sex and cTn level using the Kaplan-Meier method; Cox models were used to estimate hazard ratios and 95% confidence interval (CIs) for 1-year MACE and 7-day catheterization. Logistic models were used to estimate odds ratios (ORs) and 95% CI for 90-day medication use. RESULTS: Over the 5-year study period, 25,539 patients presented to the ED with chest pain of which 7,272 (2,933 females and 4,339 males) met the inclusion criteria. Among patients with chest pain with cardiac features/history and cTn > 99th percentile, females were less likely to be diagnosed with MI (46.4% vs. 57.5%). Females in the cTnI > 99th percentile group had the worst outcomes with a 1-year MACE rate of 22.7% (95% CI = 18.5-27.7) versus 18.8% (95% CI = 16.2-21.6), although this difference was attenuated and not statistically significant after adjustment for baseline differences. Overall, females underwent fewer diagnostic catheterizations than males within 7 days of admission to the ED. Even when cTn was above the 99th percentile and the chest pain was cardiac in nature, 48.4% of females underwent a diagnostic catheterization compared to 64.3% of males (p < 0.001). Within 90 days of discharge, females were less likely to use the evidence-based cardiac medications. The most striking sex differences were noted when cTnI levels were > 99th percentile and when the chest pain was cardiac in nature; males filled 25% more prescriptions for statins than their female counterparts. Adjustment for baseline differences did not attenuate this difference. CONCLUSIONS: Sex differences in diagnosis and treatment after presentation to the ED with chest pain are not explained by differences in chest pain features or levels of cTn. Even when females have cardiac chest pain and cTn levels > 99th percentile, they are less likely to be diagnosed with MI, less likely to undergo diagnostic cardiac catheterization within 7 days, and less likely to use evidence-based cardiac medications, but they have the highest 1-year MACE rate. The higher MACE rate appears to be driven by the higher burden of comorbid conditions.

Sex Differences in Cardiac Troponin Testing in Patients Presenting to the Emergency Department with Chest Pain.

BACKGROUND: Elevated cardiac troponin (cTn), with signs/symptoms of ischemia, is a key element in a diagnosis of myocardial infarction (MI). Underdiagnosis of MI in women has been attributed to atypical symptoms, inconsistent ECG findings, and less diagnostic testing. We sought to determine if there are sex differences in cTn testing following presentation to the emergency department (ED) with a chief complaint of ischemic chest pain (CP) and if presentation affects diagnostic assessment. METHODS: All adults presenting to six hospital EDs in the Vancouver, Canada with a chief complaint of ischemic CP from 2009 to 2013 were included. The highest cTn level within 24 hours of ED presentation was used. CP was classified into cardiac- or respiratory dominant based on standard Canadian Emergency Department Triage and Acuity Scale coding. Chi-square testing was used to test for sex differences in CP categories and cTn testing within 24 hours. Logistic regression models were used to examine the association between sex, cTn testing, and CP categories. RESULTS: Of 27,063 patients with ischemic CP, cardiac presentation was more common in men than women, irrespective of age. Among cardiac CP, 24.7% of men were <50 years compared to 18.2% of women; however, more women (19.9%) than men (11.6%) were >80 years. Overall, women were 1.8% less likely to have cTn testing; in patients <50 years, testing was markedly lower in women compared to men [odds ratio, OR (95% confidence intervals, CI) 0.78 (0.70-0.87)]. The odds of cardiac catheterization within 90 days of ED presentation were lower in women [OR, (95% CI) 0.52 (0.44-0.63)]. Even with cardiac CP, 17.7% of women versus 32.7% of men had cardiac catheterization. CONCLUSIONS: In men and women presenting to the ED with ischemic CP, cTn testing overall is similar except among young women under 50 years old, where it is markedly lower. Women undergo less cardiac catheterization, irrespective of CP type.

Sex and Ethnic Differences in Outcomes of Acute Coronary Syndrome and Stable Angina Patients With Obstructive Coronary Artery Disease.

BACKGROUND: The joint contribution of sex, ethnicity, and initial clinical presentation to the long-term outcomes of patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina, in whom there is angiographic evidence for obstructive coronary artery disease, remains unknown. METHODS AND RESULTS: We conducted a population-based cohort study on 49 556 adult ACS or stable angina patients with angiographic evidence of obstructive coronary artery disease (≥ 50% stenosis) in British Columbia. The 2-year composite outcome was all-cause death and hospital readmissions for myocardial infarction, heart failure, cerebrovascular accident, or angina after the index angiography. Sex and ethnic differences in the composite outcome were examined by clinical presentation using the Cox proportional-hazards and logistic regression models. Overall, 25.6% were women, 9.5% were South Asians, 3.0% were Chinese, and 65.9% presented with ACS. Regardless of ethnicity, women were more likely than men to have adverse outcomes, but the magnitude of the sex difference was greater in the ACS patients (P(interaction) for sex and clinical presentation=0.03). Angina readmission accounted for 45% of the composite outcome and was the main component for all groups with the exception of Chinese women with ACS. Furthermore, women were more likely than men to be readmitted for angina (odds ratio [95% confidence interval], 1.13 [1.04-1.22]). CONCLUSIONS: Higher rates of adverse events among women with obstructive coronary artery disease, regardless of ethnicity, as well as high rates of angina readmission, highlight the need for more targeted interventions to reduce the burden of angina because this presentation is clearly not benign.

Long-term outcomes after thoracic aortic surgery: a population-based study.

OBJECTIVE: Long-term survival after aortic surgery has remained largely unexplored, despite suggestions of superior durability compared with endovascular techniques. The objective of the present study was to determine the long-term survival after open thoracic aortic surgery and to identify the predictors of mortality. METHODS: The provincial database was accessed to identify all adult patients who had undergone primary open thoracic aortic surgery in British Columbia since 1993. Kaplan-Meier survival analyses were performed for the entire group and by year of surgery, urgency of surgery, and aortic segment requiring surgery. Multivariate analyses were performed to identify the predictors of mortality. RESULTS: From January 1993 to June 2010, 1960 patients underwent primary open thoracic aortic surgery at 4 hospitals in British Columbia. Overall, the 30-day mortality was 9.1%, with a perioperative stroke rate of 5.8%. Long-term survival was 77.7%, 59.6%, and 44.7% at 5, 10, and 15 years, respectively. Subanalyses demonstrated improved long-term survival in the modern era; among patients undergoing elective aortic surgery; and among patients undergoing surgery on the ascending aorta or aortic root (P < .0001). The preoperative characteristics associated with decreased long-term survival included age older than 65 years, acute renal failure, dialysis, cerebrovascular accident, chronic obstructive pulmonary disease, peripheral vascular disease, and descending or thoracoabdominal aorta surgery. CONCLUSIONS: Long-term survival after elective thoracic aortic surgery is excellent, with improved outcomes in the modern era. Several preoperative risk factors associated with decreased survival were identified, which could assist in risk stratification and patient selection. Finally, the long-term survival rates identified in the present study should serve as a benchmark to which new aortic interventions should be compared.

Do younger women fare worse? Sex differences in acute myocardial infarction hospitalization and early mortality rates over ten years.

BACKGROUND: Recent research has identified younger women as an "at-risk" population with rising prevalence of cardiac risk factors and excess mortality risk following acute myocardial infarction (AMI). However, population-based data on trends in AMI hospitalization and early mortality post AMI among younger adults is scarce. We, therefore, aimed to provide a 10-year, descriptive analysis of these trends in a Canadian setting. METHODS AND RESULTS: We assessed trends and sex differences in AMI hospitalization and 30-day mortality rates using negative binomial and logistic regression, respectively. From 2000 to 2009, there were 70,628 AMI hospitalizations in adults aged ≥20 years, in British Columbia, Canada, with 17.1% of cohort being younger adults ≤55 years. Overall, age-standardized AMI rates (per 100,000 population) declined similarly in men (295.8 to 247.7) and women (152.1 to 128.8) [sex-year interaction p=0.81]. However, these trends differed according to age (age-sex-year interaction p=0.02) with increased rates observed only in younger women (+1.7% per year; p=0.04). The 30-day mortality rates declined similarly for women (19.4% to 13.9%) and men (13.0% to 9.3%) (sex-year interaction p=0.33). Yet, younger women continued to have excess mortality risk, compared with younger men, even in the most recent period [odds ratio: (2008-09)=1.61 (95% onfidence interval: 1.25, 2.08)]. CONCLUSION: While the overall AMI hospitalization and 30-day mortality rates significantly declined in women and men, hospitalization rates in women ≤55 years increased and their excess risk of 30-day mortality persisted. These findings highlight the need to intensify strategies to reduce the incidence of AMI and improve outcomes after AMI in younger women.

High mortality in adults hospitalized for active tuberculosis in a low HIV prevalence setting.

BACKGROUND: This study aims to evaluate the outcomes of adults hospitalized for tuberculosis in a higher-income region with low HIV prevalence. METHODS: A retrospective cohort study was conducted on all adults hospitalized for pulmonary and/or extrapulmonary tuberculosis in an acute-care hospital in Hong Kong during a two-year period. Microscopy and solid-medium culture were routinely performed. The diagnosis of tuberculosis was made by: (1) positive culture of M. tuberculosis, (2) positive M. tuberculosis PCR result, (3) histology findings of tuberculosis infection, and/or (4) typical clinico-radiological manifestations of tuberculosis which resolved after anti-TB treatment, in the absence of alternative diagnoses. Time to treatment ('early', started during initial admission; 'late', subsequent periods), reasons for delay, and short- and long-term survival were analyzed. RESULTS: Altogether 349 patients were studied [median(IQR) age 62(48-77) years; non-HIV immunocompromised conditions 36.7%; HIV/AIDS 2.0%]. 57.9%, 16.3%, and 25.8% had pulmonary, extrapulmonary, and pulmonary-extrapulmonary tuberculosis respectively. 58.2% was smear-negative; 0.6% multidrug-resistant. 43.4% developed hypoxemia. Crude 90-day and 1-year all-cause mortality was 13.8% and 24.1% respectively. 57.6% and 35.8% received 'early' and 'late' treatment respectively, latter mostly culture-guided [median(IQR) intervals, 5(3-9) vs. 43(25-61) days]. Diagnosis was unknown before death in 6.6%. Smear-negativity, malignancy, chronic lung diseases, and prior exposure to fluoroquinolones (adjusted-OR 10.6, 95%CI 1.3-85.2) delayed diagnosis of tuberculosis. Failure to receive 'early' treatment independently predicted higher mortality (Cox-model, adjusted-HR 1.8, 95%CI 1.1-3.0). CONCLUSIONS: Mortality of hospitalized tuberculosis patients is high. Newer approaches incorporating methods for rapid diagnosis and initiation of anti-tuberculous treatment are urgently required to improve outcomes.

A "pre-seasonal" hospital outbreak of influenza pneumonia caused by the drift variant A/Victoria/361/2011-like H3N2 viruses, Hong Kong, 2011.

BACKGROUND: Beginning from late 2011 and early 2012, increasing circulation of antigenically drifted influenza A/Victoria/361/2011-like H3N2 viruses within genotype 3 of the A/Victoria/208/2009 clade have been reported in multiple European countries and elsewhere. Whether these emerging viruses are associated with increased disease severity is unclear. OBJECTIVES: To report the clinical and virological findings of a moderately severe hospital outbreak of A/Victoria/361/2011-like viruses that occurred in November 2011 in Hong Kong. STUDY DESIGN: Clinical and virological hospital outbreak investigation. RESULTS: The outbreak occurred in an adult psychiatric ward in November 2011, a time well before the usual local seasonal influenza winter peak. Altogether, 7 patients and 1 healthcare-worker were affected (mean age, 47 [range, 34-61] years). The attack rates among patients and healthcare-workers were 33% (7/21) and 7% (1/15), respectively. Pneumonia developed in 38% (3/8) of cases; none had underlying immunocompromised conditions. High nasopharyngeal viral loads were detected. All cases responded to antiviral treatment. Multiple amino acid mutations with reference to earlier A(H3N2) vaccine strains were mapped to key antigenic sites on hemagglutinin; however, no critical mutations on receptor binding sites were detected. Viral sequence variations jeopardized the performance of molecular diagnostic assays. CONCLUSIONS: Severe disease and pneumonia occurred in a substantial proportion of non-immunocompromised adults in a hospital outbreak attributed to the emerging antigenically drifted A/Victoria/361/2011-like H3N2 viruses. Close monitoring of the transmission of this drift variant is required. Further studies are also necessary to determine virus virulence.

Sex differences in mortality after transcatheter aortic valve replacement for severe aortic stenosis.

OBJECTIVES: The aim of this study was to examine sex differences in outcome after transcatheter aortic valve replacement (TAVR) with real-world data from 2 large centers in Canada. BACKGROUND: Transcatheter aortic valve replacement is an effective alternative to surgical valve replacement in symptomatic patients with severe aortic stenosis, but the impact of sex on outcomes remains unclear. The PARTNER (Placement of Aortic Transcatheter Valves) 1A trial demonstrated greater benefit of TAVR over surgery in women, but whether this was due to the poorer surgical outcome of women or better TAVR outcome, compared with men, is unknown. METHODS: Consecutive patients (n = 641) undergoing TAVR in Vancouver and Quebec City, Canada, were evaluated. Differences in all-cause mortality were examined with Kaplan-Meier estimates, adjusted logistic regression, and proportional hazards models. RESULTS: Women comprised 51.3% of the cohort. Balloon-expandable valves were used in 97% of cases, with transapical approach in 51.7 % women and 38.1% men. Women had more major vascular complications (12.4% vs. 5.4%, p = 0.003) and borderline significantly more major/life-threatening bleeds (21.6% vs. 15.8%, p = 0.08). At baseline, women had higher aortic gradients and worse renal function but better ejection fractions. Men had more comorbidities: prior myocardial infarction, prior revascularization, and chronic obstructive pulmonary disease. The adjusted odds ratio for 30-day all-cause mortality favored women, 0.39 (95% confidence interval: 0.19 to 0.80; p = 0.01), and this benefit persisted for 2 years, hazard ratio 0.60 (95% confidence interval: 0.41 to 0.88; p = 0.008). CONCLUSIONS: Female sex is associated with better short- and long-term survival after TAVR. Added to the PARTNER 1A findings, these results suggest TAVR might be the preferred treatment option for elderly women with symptomatic severe aortic stenosis.