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.

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 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 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.

Sex-specific factors in microvascular angina.

In women presenting for evaluation of suspected ischemic symptoms, a diagnosis of normal coronary arteries is 5 times more common than it is in men. These women are often labelled as having cardiac syndrome X, and a subset of them have microvascular angina caused by microvascular coronary dysfunction (MCD). MCD is not benign and is associated with an annual 2.5% cardiac event rate. Noninvasive testing for MCD remains insensitive, although newer imaging modalities, such as adenosine cardiac magnetic resonance imaging, appear promising. The gold standard for diagnosis of MCD is coronary reactivity testing, an invasive technique that is not available in many countries. With regard to treatment, large-scale trials are lacking. Although research is ongoing, the current platform of therapy consists of antiangina, antiplatelet, and endothelium-modifying agents (primarily angiotensin-converting enzyme inhibitors and statins).

Basis for sex-dependent outcomes in acute coronary syndrome.

This review aims to provide new insights into the basis for sex differences in acute coronary syndrome (ACS). Sex differences in mortality after ACS depend on age and the type of ACS, with the greatest gap being observed among younger adults and patients with ST-segment elevation myocardial infarction (STEMI). The sex gap diminishes with increasing age and does not appear to exist to the same extent among patients with non-STEMI or unstable angina. Although it is clear that younger women with acute myocardial infarction have higher mortality than do men in the short term; whether this difference is present in the long term remains unclear. Furthermore, women with ACS face delays in diagnosis and treatment, undergo less invasive management, have more bleeding complications, and receive less evidence-based medical therapy than do their male counterparts. Finally, women with ACS consistently report lower health-related quality of life than do men. To date, our understanding of the sex differences in ACS remains limited. The impact of biological factors and nonbiological factors (especially gender roles) need to be explored to elucidate the disparities in health outcomes between men and women.

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.

Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease.

BACKGROUND: We comparatively evaluated clinical outcomes in men and women presenting with stable angina with no coronary artery disease (CAD), nonobstructive CAD, and obstructive CAD on coronary angiography. METHODS: We studied all patients ≥20 years with stable angina, undergoing coronary angiography in British Columbia, Canada, from July 1999 to December 2002 (n = 13,695) with maximum follow-up to 3 years. No CAD, nonobstructive CAD, and obstructive CAD were defined as 0%, 1% to 49%, and ≥50% luminal narrowing in any epicardial coronary artery, respectively. Freedom from major adverse cardiac events (MACEs), which included the combined end points of all-cause mortality, nonfatal acute myocardial infarction, nonfatal stroke, and heart failure admissions, was estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% CIs for MACE were estimated up to 3 years postcatheterization and compared between sex and CAD groups. RESULTS: Within the first year, women with nonobstructive CAD had a higher risk of MACE than men with nonobstructive CAD (adjusted HR 2.43, 95% CI 1.08-5.49). Furthermore, women with nonobstructive CAD had a 2.55-fold higher risk of MACE than women with no CAD (95% CI 1.33-4.88). In contrast, men with nonobstructive CAD had a similar risk as men with no CAD (adjusted HR 0.61, 95% CI 0.26-1.45). The differences in MACE according to extent of CAD were not evident in the longer term. CONCLUSIONS: Women with stable angina and nonobstructive CAD are 3 times more likely to experience a cardiac event within the first year of cardiac catheterization than men. A prospective trial to examine the impact of medical therapy on MACE in patients with nonobstructive CAD is warranted.

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.

Trends in wait times for cardiac revascularization.

BACKGROUND: Improving access to care and reducing wait times are perpetual objectives of Canada's provincially administered health care systems. The objective of this study was to investigate wait times for both percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery. METHODS: Clinical registry data for all patients who underwent PCI or isolated CABG between fiscal years 1995-1996 and 2007-2008 in Alberta and between fiscal years 2000-2001 and 2007-2008 in British Columbia was used. The first revascularization procedure was identified and linked to its preceding catheterization procedure. "Time to procedure" was calculated as the number of days between catheterization and revascularization dates. Times to PCI and CABG from catheterization were described by fiscal year. RESULTS: Between April 1, 1995, and March 31, 2008, in Alberta, 50,068 patients received revascularization following their catheterization. Between April 1, 2000, and March 31, 2008, in British Columbia, 52,462 patients received revascularization following their catheterization. Of these, 70.6% and 29.4% received PCI and CABG, respectively, in Alberta, and 74.9% and 25.1% received PCI and CABG, respectively, in British Columbia. For CABG, median waiting times decreased from 31 to 13 days in Alberta and from 17 to 11 days in British Columbia; for PCIs, most now occur on the same day as catheterization. CONCLUSIONS: Both Alberta and British Columbia have experienced remarkable improvements in wait times for coronary revascularization procedures from time of catheterization.

Outcomes after percutaneous coronary interventions in patients with CKD: improved outcome in the stenting era.

BACKGROUND: Percutaneous coronary intervention (PCI) with stenting reduces adverse events in the general population compared with balloon angioplasty. The benefit of stents in high-risk patients normally excluded from clinical trials has not been well studied. Outcomes after PCIs in patients with chronic kidney disease (CKD) before and after widespread use of stents were compared. METHODS: All patients undergoing PCIs at our center within 2 periods selected for high and low stent use were included. Demographic, kidney and cardiac function, and PCI data were collected. Kaplan-Meier curves were constructed, and Cox proportional hazards analysis was used to assess the effect of high stent use on major adverse cardiac event, a composite of cardiac revascularization, myocardial infarction, or death 3 years after PCI. RESULTS: A total of 1,879 patients (780 patients, low stent use; 1,099 patients, high stent use; 18% and 94.1% stent use, respectively) with a mean age of 63 years, 73% men, and 26% of patients with a glomerular filtration rate less than 60 mL/min were included. At baseline, there was a greater prevalence of severe CKD, cardiac risk factors, and cardiovascular disease in the high-stent-use cohort. Major adverse cardiac events were reduced in the contemporary cohort (hazard ratio, 0.61; 95% confidence interval, 0.52 to 0.72); this benefit extended across all stages of kidney function. CONCLUSION: Patients with CKD undergoing PCI in the stenting era show improved outcomes. Additional studies are needed to determine optimal revascularization strategies in patients with CKD.

Cross-provincial use of cardiac services: the importance of data-sharing for clinical registries and outcomes research.

BACKGROUND: The structure of the Canadian health care system lends itself to health services and health outcomes research. It is possible to track hospital admissions and discharges, physician billings and prescriptions using administrative databases. In addition, several provinces have developed registries that provide detailed clinical and procedural information. Using the unique personal health numbers assigned to all Canadian residents, linkage between administrative databases and population-based clinical registries provides important information regarding the use of health services and health outcomes. OBJECTIVE: To determine the extent of cross-border (British Columbia-Alberta border) use of cardiac services by British Columbia residents. METHODS: Population rates of cardiac procedures were calculated using two prospective clinical registries (British Columbia Cardiac Registries and Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease [APPROACH]), as well as administrative databases (the British Columbia Ministry of Health's hospitalization and Medical Services Plan databases). RESULTS: Analyses using only British Columbia data suggest low cardiac procedure rates for patients living in eastern British Columbia. By accessing APPROACH data, it was determined that more than 80% of British Columbia cardiac patients living along the British Columbia-Alberta border access procedural services in Alberta. CONCLUSIONS: While residents of eastern British Columbia appear to have reduced access to cardiac services when data from British Columbia are analyzed in isolation, they are actually accessing care in Alberta. Analyses based solely on single province data sources will underestimate cardiac procedures rates.

Population rates of invasive cardiac procedures in British Columbia, 1995 to 2001.

BACKGROUND: This study examined the rates of coronary angiography (CA), percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) in British Columbia (BC) between 1995 and 2001. METHODS: Data sources were as follows: CABG--BC Cardiac Registries; CA and PCI--BC Medical Services Plan; acute coronary syndromes (ACS)--Hospital Separation database; population data--BC Statistics. All rates were age and sex standardized per 100,000 BC resident adults over 20 years of age. RESULTS: The rate of diagnostic CA increased from 352 per 100,000 in 1995 to 400 per 100,000 in 2001 (P<0.01). The rate of PCI increased from 101 per 100,000 in 1995 to 154 per 100,000 in 2001 (P<0.01). Single stage 'ad hoc' PCI increased from 38% in 1995 to 68% in 2001. The rate of CABG remained stable at between 70 and 79 per 100,000. There was a downward trend in the annual hospitalized incidence of ACS (477 to 430 per 100,000, P=0.04). The incidence of ACS and the rates of CA, PCI and CABG were higher for men in all age groups. PCI was more common than CABG in all groups. CONCLUSIONS: The incidence of ACS in BC is falling. The rates of diagnostic CA and PCI are increasing. The latter finding may reflect an appropriate evidence-based response to data supporting greater application of CA following ACS after publication of several studies supporting a routine invasive approach. The PCI rate is rising compared with the CABG rate, likely reflecting changes in patient selection and improved PCI technology, as well as a limited ability of the system to provide surgical procedures.