Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction.

BACKGROUND: Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an era before modern biomarker-based diagnosis of myocardial infarction and treatment with percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin-angiotensin-aldosterone system antagonists. METHODS: In a parallel-group, open-label trial performed at 45 centers in Sweden, Estonia, and New Zealand, we randomly assigned patients with an acute myocardial infarction who had undergone coronary angiography and had a left ventricular ejection fraction of at least 50% to receive either long-term treatment with a beta-blocker (metoprolol or bisoprolol) or no beta-blocker treatment. The primary end point was a composite of death from any cause or new myocardial infarction. RESULTS: From September 2017 through May 2023, a total of 5020 patients were enrolled (95.4% of whom were from Sweden). The median follow-up was 3.5 years (interquartile range, 2.2 to 4.7). A primary end-point event occurred in 199 of 2508 patients (7.9%) in the beta-blocker group and in 208 of 2512 patients (8.3%) in the no-beta-blocker group (hazard ratio, 0.96; 95% confidence interval, 0.79 to 1.16; P = 0.64). Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points (death from any cause, 3.9% in the beta-blocker group and 4.1% in the no-beta-blocker group; death from cardiovascular causes, 1.5% and 1.3%, respectively; myocardial infarction, 4.5% and 4.7%; hospitalization for atrial fibrillation, 1.1% and 1.4%; and hospitalization for heart failure, 0.8% and 0.9%). With regard to safety end points, hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker occurred in 3.4% of the patients in the beta-blocker group and in 3.2% of those in the no-beta-blocker group; hospitalization for asthma or chronic obstructive pulmonary disease in 0.6% and 0.6%, respectively; and hospitalization for stroke in 1.4% and 1.8%. CONCLUSIONS: Among patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (≥50%), long-term beta-blocker treatment did not lead to a lower risk of the composite primary end point of death from any cause or new myocardial infarction than no beta-blocker use. (Funded by the Swedish Research Council and others; REDUCE-AMI ClinicalTrials.gov number, NCT03278509.).

Prognostic significance of chronic myocardial injury diagnosed by three different cardiac troponin assays in patients admitted with suspected acute coronary syndrome.

OBJECTIVES: Chronic myocardial injury (CMI) is defined as stable concentrations of cardiac troponin T or I (cTnT or cTnI) above the assay-specific 99th percentile upper reference limit (URL) and signals poor outcome. The clinical implications of diagnosing CMI are unclear. We aimed to assess prevalence and association of CMI with long-term prognosis using three different high-sensitivity cTn (hs-cTn) assays. METHODS: A total of 1,292 hospitalized patients without acute myocardial injury had cTn concentrations quantified by hs-cTn assays by Roche Diagnostics, Abbott Diagnostics and Siemens Healthineers. The median follow-up time was 4.1 years. The prevalence of CMI and hazard ratios for mortality and cardiovascular (CV) events were calculated based on the URL provided by the manufacturers and compared to the prognostic accuracy when lower percentiles of cTn (97.5, 95 or 90), limit of detection or the estimated bioequivalent concentrations between assays were used as cutoff values. RESULTS: There was no major difference in prognostic accuracy between cTnT and cTnI analyzed as continuous variables. The correlation between cTnT and cTnI was high (r=0.724-0.785), but the cTnT assay diagnosed 3.9-4.5 times more patients with having CMI based on the sex-specific URLs (TnT, n=207; TnI Abbott, n=46, TnI Siemens, n=53) and had higher clinical sensitivity and AUC at the URL. CONCLUSIONS: The prevalence of CMI is highly assay-dependent. cTnT and cTnI have similar prognostic accuracy for mortality or CV events when measured as continuous variables. However, a CMI diagnosis according to cTnT has higher prognostic accuracy compared to a CMI diagnosis according to cTnI.

Temporal biomarker concentration patterns during the early course of acute coronary syndrome.

OBJECTIVES: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. METHODS: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. RESULTS: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. CONCLUSIONS: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

Prospective benchmarking of an observational analysis in the SWEDEHEART registry against the REDUCE-AMI randomized trial.

Prospective benchmarking of an observational analysis against a randomized trial increases confidence in the benchmarking process as it relies exclusively on aligning the protocol of the trial and the observational analysis, while the trials findings are unavailable. The Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction (REDUCE-AMI, ClinicalTrials.gov ID: NCT03278509) trial started recruitment in September 2017 and results are expected in 2024. REDUCE-AMI aimed to estimate the effect of long-term use of beta blockers on the risk of death and myocardial following a myocardial infarction with preserved left ventricular systolic ejection fraction. We specified the protocol of a target trial as similar as possible to that of REDUCE-AMI, then emulated the target trial using observational data from Swedish healthcare registries. Had everyone followed the treatment strategy as specified in the target trial protocol, the observational analysis estimated a reduction in the 5-year risk of death or myocardial infarction of 0.8 percentage points for beta blockers compared with no beta blockers; effects ranging from an absolute reduction of 4.5 percentage points to an increase of 2.8 percentage points in the risk of death or myocardial infarction were compatible with our data under conventional statistical criteria. Once results of REDUCE-AMI are published, we will compare the results of our observational analysis against those from the trial. If this prospective benchmarking is successful, it supports the credibility of additional analyses using these observational data, which can rapidly deliver answers to questions that could not be answered by the initial trial. If benchmarking proves unsuccessful, we will conduct a "postmortem" analysis to identify the reasons for the discrepancy. Prospective benchmarking shifts the investigator focus away from an endeavour to use observational data to obtain similar results as a completed randomized trial, to a systematic attempt to align the design and analysis of the trial and the observational analysis.

Biomarkers associated with cardiovascular disease in women with spontaneous preterm birth: A case-control study.

INTRODUCTION: Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up. MATERIAL AND METHODS: Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up. CLINICALTRIALS: gov registration NCT05693285. RESULTS: In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up. CONCLUSIONS: Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease.

Elevated low-density lipoprotein cholesterol: An inverse marker of morbidity and mortality in patients with myocardial infarction.

BACKGROUND: The incidence of atherosclerotic cardiovascular disease increases with levels of low-density lipoprotein cholesterol (LDL-C). Yet, a paradox may exist where lower LDL-C levels at myocardial infarction (MI) are associated with poorer prognoses. OBJECTIVE: To assess the association between LDL-C levels at MI with risk factor burden and cause-specific outcomes. METHODS: Statin-naive patients hospitalized for a first MI and registered in SWEDEHEART were included. Data were linked to Swedish registers. Primary outcomes were all-cause mortality and nonfatal MI. Associations between LDL-C and outcomes were assessed using adjusted proportional hazards models. RESULTS: Among 63,168 patients (median age, 66 years), the median LDL-C level was 3.0 mmol/L (interquartile range 2.4-3.6). Patient age and comorbidities increased as LDL-C decreased. During a median follow-up of 4.5 years, 10,236 patients died, and 4973 had nonfatal MI. Patients with the highest LDL-C had a lower risk of mortality (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.71-0.80). The risk of hospitalization for pneumonia, hip fracture, chronic obstructive pulmonary disease, and new cancer diagnosis was lower with higher LDL-C (HR range, 0.40-0.81). Patients with the highest LDL-C had a greater risk of recurrent MI (HR 1.16; 95% CI 1.07-1.26). CONCLUSIONS: Patients with the highest LDL-C levels at MI had the lowest incidence of mortality and morbidity. This seems to reflect lower age at MI, less underlying morbidities, paired with the modifiability of LDL-C. However, supporting the causal association between LDL-C and ischemic heart disease, elevated LDL-C was simultaneously associated with an increased risk of nonfatal MI.

Statin Treatment Intensity, Discontinuation, and Long-Term Outcome in Patients With Acute Myocardial Infarction and Impaired Kidney Function.

ABSTRACT: Statin dosage in patients with acute myocardial infarction (AMI) and concomitant kidney dysfunction is a clinical dilemma. We studied discontinuation during the first year after an AMI and long-term outcome in patients receiving high versus low-moderate intensity statin treatment, in relation to kidney function. For the intention-to-treat analysis (ITT-A), we included all patients admitted to Swedish coronary care units for a first AMI between 2005 and 2016 that survived in-hospital, had known creatinine, and initiated statin therapy (N = 112,727). High intensity was initiated in 38.7% and low-moderate in 61.3%. In patients with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 , 25% discontinued treatment the first year; however, the discontinuation rate was similar regardless of the statin intensity. After excluding patients who died, changed therapy, or were nonadherent during the first year, 84,705 remained for the on-treatment analysis (OT-A). Patients were followed for 12.6 (median 5.6) years. In patients with eGFR 30-59 mL/min, high-intensity statin was associated with lower risk for the composite death, reinfarction, or stroke both in ITT-A (hazard ratio [HR] 0.93; 95% confidence interval, 0.87-0.99) and OT-A (HR 0.90; 0.83-0.99); the interaction test for OT-A indicated no heterogeneity for the eGFR < 60 mL/min group ( P = 0.46). Similar associations were seen for all-cause mortality. We confirm that high-intensity statin treatment is associated with improved long-term outcome after AMI in patients with reduced kidney function. Most patients with reduced kidney function initiated on high-intensity statins are persistent after 1 year and equally persistent as patients initiated on low-moderate intensity.

Differences between high-sensitivity cardiac troponin T and I in stable populations: underlying causes and clinical implications.

OBJECTIVES: Measurement of high-sensitivity (hs) cardiac troponin (cTn) T and I is widely studied for cardiac assessment of stable populations. Recent data suggest clinical and prognostic discrepancies between both hs-cTn. We aimed at reviewing published studies with respect to underlying causes and clinical implications. CONTENT: We summarized current evidence on release and clearance mechanisms of cTnT and I, and on preanalytical and assay-related issues potentially portending to differences in measured concentrations. We also performed a systematic review of outcome studies comparing both hs-cTn in the general population, patients with congestive heart failure, stable coronary artery disease and atrial fibrillation. SUMMARY AND OUTLOOK: For the interpretation of concentrations of hs-cTnT, stronger association with renal dysfunction compared to hs-cTnI should be considered. Hs-cTnT also appears to be a stronger indicator of general cardiovascular morbidity and all-cause mortality. Hs-cTnI concentrations tend to be more sensitive to coronary artery disease and ischemic outcomes. These findings apparently reflect variations in the mechanisms of cardiac affections resulting in cTn release. Whether these differences are of clinically relevance remains to be elucidated. However, having the option of choosing between either hs-cTn might represent an option for framing individualized cardiac assessment in the future.

Antibody-mediated interferences affecting cardiac troponin assays: recommendations from the IFCC Committee on Clinical Applications of Cardiac Biomarkers.

The International Federation of Clinical Chemistry Committee on Clinical Applications of Cardiac Biomarkers (IFCC C-CB) provides educational documents to facilitate the interpretation and use of cardiac biomarkers in clinical laboratories and practice. Our aim is to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay. Measurements of cardiac troponin (cTn) have a prominent place in the clinical work-up of patients with suspected acute coronary syndrome. It is therefore important that clinical laboratories know how to recognize and assess analytical issues. Two emerging analytical issues resulting in falsely high cTn concentrations, often several fold higher than the upper reference limit (URL), are antibody-mediated assay interference due to long-lived cTn-antibody complexes, called macrotroponin, and crosslinking antibodies that are frequently referred to as heterophilic antibodies. We provide an overview of antibody-mediated cTn assay interference and provide recommendations on how to confirm the interference and interpret the results.

HEART-score can be simplified without loss of discriminatory power in patients with chest pain - Introducing the HET-score.

BACKGROUND: The History, Electrocardiogram (ECG), Age, Risk factors and Troponin, (HEART) score is useful for early risk stratification in chest pain patients. The aim was to validate previous findings that a simplified score using history, ECG and troponin (HET-score) has similar ability to stratify risk. METHODS: Patients presenting with chest pain with duration of ≥10 min and an onset of last episode ≤12 h but without ST-segment elevation on ECG at 6 emergency departments were eligible for inclusion. The HEART-score and the simplified HET-score were calculated. The endpoint was a composite of myocardial infarction (MI) as index diagnosis, readmission due to new MI or death within 30 days. RESULTS: HEART-score identified 32% as low risk (0-2p), 47% as intermediate risk (3-5p), and 20% as high risk (6-10p) patients. The endpoint occurred in 0.5%, 7.3% and 35.7%, respectively. HET-score identified 39%, 42% and 19% as low- (0p), intermediate- (1-2p) and high-risk (3-6p) patients, with the endpoint occurring in 0.6%, 6.2% and 43.2%, respectively. When all variables included in the HEART-score were included in a multivariable logistic regression analysis, only History (OR, CI [95%]): 2.97(2.16-4.09), ECG (1.61[1.14-2.28]) and troponin level (5.21[3.91-6.95]) were significantly associated with cardiovascular events. When HEART- and HET-score were compared in a ROC-analysis, HET-score had a significantly larger AUC (0.887 vs 0.853, p < 0.001). CONCLUSIONS: Compared with HEART-score, HET-score is simpler and appears to have similar ability to discriminate between chest pain patients with and without cardiovascular event.

Entrustable professional activities (EPAs) for undergraduate medical education - development and exploration of social validity.

BACKGROUND: The development of entrustable professional activities (EPAs) as a framework for work-based training and assessment in undergraduate medical education has become popular. EPAs are defined as units of a professional activity requiring adequate knowledge, skills, and attitudes, with a recognized output of professional labor, independently executable within a time frame, observable and measurable in its process and outcome, and reflecting one or more competencies. Before a new framework is implemented in a specific context, it is valuable to explore social validity, that is, the acceptability by relevant stakeholders. AIM: The aim of our work was to define Core EPAs for undergraduate medical education and further explore the social validity of the constructs. METHOD AND MATERIAL: In a nationwide collaboration, EPAs were developed using a modified Delphi procedure and validated according to EQual by a group consisting of teachers nominated from each of the seven Swedish medical schools, two student representatives, and an educational developer (n = 16). In the next step, social validity was explored in a nationwide survey. The survey introduced the suggested EPAs. For each EPA, the importance of the EPA was rated, as was the rater's perception of the present graduates' required level of supervision when performing the activity. Free-text comments were also included and analyzed. RESULTS: Ten Core EPAs were defined and validated. The validation scores for EQual ranged from 4.1 to 4.9. The nationwide survey had 473 responders. All activities were rated as "important" by most responders, ranging from 54 to 96%. When asked how independent current graduates were in performing the ten activities, 6 to 35% reported "independent". The three themes of the free text comments were: 'relevant target areas and content'; 'definition of the activities'; and 'clinical practice and learning'. CONCLUSION: Ten Core EPAs were defined and assessed as relevant for Swedish undergraduate medical education. There was a consistent gap between the perceived importance and the certainty that the students could perform these professional activities independently at the time of graduation. These results indicate that the ten EPAs may have a role in undergraduate education by creating clarity for all stakeholders.

Helicobacter pylori and Pro-Inflammatory Protein Biomarkers in Myocardial Infarction with and without Obstructive Coronary Artery Disease.

Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different populations and may have separate pathophysiological mechanisms, with greater inflammatory activity in MINOCA compared to MI-CAD. Helicobacter pylori (Hp) can cause systemic inflammation and has been associated with cardiovascular disease (CVD). We aimed to investigate whether Hp infection is associated with concentrations of protein biomarkers of inflammation and CVD. In a case-control study, patients with MINOCA (n = 99) in Sweden were included, complemented by matched subjects with MI-CAD (n = 99) and controls (n = 100). Protein biomarkers were measured with a proximity extension assay in plasma samples collected 3 months after MI. The seroprevalence of Hp and cytotoxin-associated gene A (CagA) was determined using ELISA. The associations between protein levels and Hp status were studied with linear regression. The prevalence of Hp was 20.2%, 19.2%, and 16.0% for MINOCA, MI-CAD, and controls, respectively (p = 0.73). Seven proteins were associated with Hp in an adjusted model: tissue plasminogen activator (tPA), interleukin-6 (IL-6), myeloperoxidase (MPO), TNF-related activation-induced cytokine (TRANCE), pappalysin-1 (PAPPA), soluble urokinase plasminogen activator receptor (suPAR), and P-selectin glycoprotein ligand 1 (PSGL-1). Hp infection was present in one in five patients with MI, irrespective of the presence of obstructive CAD. Inflammatory proteins were elevated in Hp-positive subjects, thus not ruling out that Hp may promote an inflammatory response and potentially contribute to the development of CVD.

Novel Criteria for the Observe-Zone of the ESC 0/1h-hs-cTnT Algorithm.

BACKGROUND: The non-ST-segment-elevation myocardial infarction (NSTEMI) guidelines of the European Society of Cardiology (ESC) recommend a 3h cardiac troponin determination in patients triaged to the observe-zone of the ESC 0/1h-algorithm; however, no specific cutoff for further triage is endorsed. Recently, a specific cutoff for 0/3h high-sensitivity cardiac troponin T (hs-cTnT) change (7 ng/L) was proposed, warranting external validation. METHODS: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction, on the basis of complete cardiac workup, cardiac imaging, and serial hs-cTnT. Hs-cTnT concentrations were measured at presentation, after 1 hour, and after 3 hours. The objective was to externally validate the proposed cutoff, and if necessary, derive and internally as well as externally validate novel 0/3h-criteria for the observe-zone of the ESC 0/1h-hs-cTnT-algorithm in an independent multicenter cohort. RESULTS: Among 2076 eligible patients, application of the ESC 0/1h-hs-cTnT-algorithm triaged 1512 patients (72.8%) to either rule out or rule in NSTEMI, leaving 564 patients (27.2%) in the observe-zone (adjudicated NSTEMI prevalence, 120/564 patients, 21.3%). The suggested 0/3h-hs-cTnT-change of <7 ng/L triaged 517 patients (91.7%) toward rule-out, resulting in a sensitivity of 33.3% (95% CI, 25.5-42.2), missing 80 patients with NSTEMI, and ≥7 ng/L triaged 47 patients toward rule-in (8.3%), resulting in a specificity of 98.4% (95% CI, 96.8-99.2). Novel derived 0/3h-criteria for the observe-zone patients ruled out NSTEMI with a 3h hs-cTnT concentration <15 ng/L and a 0/3h-hs-cTnT absolute change <4 ng/L, triaging 138 patients (25%) toward rule-out, resulting in a sensitivity of 99.2% (95% CI, 96.0-99.9), missing 1 patient with NSTEMI. A 0/3h-hs-cTnT absolute change ≥6 ng/L triaged 63 patients (11.2%) toward rule-in, resulting in a specificity of 98% (95% CI, 96.2-98.9) Thereby, the novel 0/3h-criteria reduced the number of patients in the observe zone by 36%s and the number of type 1 myocardial infarction by 50%. Findings were confirmed in both internal and external validation. CONCLUSIONS: A combination of a 3h-hs-cTnT concentration (<15 ng/L) and a 0/3h absolute change (<4 ng/L) is necessary to safely rule out NSTEMI in patients remaining in the observe-zone of the ESC 0/1h-hs-cTnT-algorithm. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT00470587.

Benchmarking Observational Analyses Before Using Them to Address Questions Trials Do Not Answer: An Application to Coronary Thrombus Aspiration.

To increase confidence in the use of observational analyses when addressing effectiveness questions beyond those addressed by randomized trials, one can first benchmark the observational analyses against existing trial results. We used Swedish registry data to emulate a target trial similar to the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) randomized trial, which found no difference in the risk of death or myocardial infarction by 1 year with or without thrombus aspiration among individuals with ST-elevation myocardial infarction. We benchmarked the emulation against the trial at 1 year and then extended the emulation's follow-up to 3 years and estimated effects in subpopulations underrepresented in the trial. As in the TASTE trial, the observational analysis found no differences in risk of outcomes by 1 year between groups (risk difference = 0.7 (confidence interval, -0.7, 2.0) and -0.2 (confidence interval, -1.3, 1.0) for death and myocardial infarction, respectively), so benchmarking was considered successful. We additionally showed no difference in risk of death or myocardial infarction by 3 years, or within subpopulations by 1 year. Benchmarking against an index trial before using observational analyses to answer questions beyond those the trial could address allowed us to explore whether the observational data can be trusted to deliver valid estimates of treatment effects.

Application of High-Sensitivity Troponin in Suspected Myocardial Infarction.

BACKGROUND: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. METHODS: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. RESULTS: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. CONCLUSIONS: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.).

The clinical approach to diagnosing peri-procedural myocardial infarction after percutaneous coronary interventions according to the fourth universal definition of myocardial infarction - from the study group on biomarkers of the European Society of Cardiology (ESC) Association for Acute CardioVascular Care (ACVC).

PURPOSE: This review intends to illustrate basic principles on how to apply the Fourth Universal Definition of Myocardial Infarction (UDMI) for the diagnosis of peri-procedural myocardial infarction (MI) after percutaneous coronary interventions (PCI) in clinical practice. METHODS AND RESULTS: Review of routine case-based events. Increases in cardiac troponin (cTn) concentrations are common after elective PCI in patients with chronic coronary syndrome (CCS). Peri-procedural PCI-related MI (type 4a MI) in CCS patients should be diagnosed in cases of major peri-procedural acute myocardial injury indicated by an increase in cTn concentrations of >5-times the 99th percentile upper reference limit (URL) together with evidence of new peri-procedural myocardial ischaemia as demonstrated by electrocardiography (ECG), imaging, or flow-limiting peri-procedural complications in coronary angiography. Measurement of cTn baseline concentrations before elective PCI is useful. In patients presenting with acute MI undergoing PCI, peri-procedural increases in cTn concentrations are usually due to their index presentation and not PCI-related, apart from obvious major peri-procedural complications, such as persistent occlusion of a large side branch or no-reflow after stent implantation. CONCLUSION: The distinction between type 4a MI, PCI-related acute myocardial injury, and chronic myocardial injury can be challenging in individuals undergoing PCI. Careful integration of all available clinical data is essential for correct classification.

Low-density lipoprotein cholesterol reduction and statin intensity in myocardial infarction patients and major adverse outcomes: a Swedish nationwide cohort study.

AIMS: Clinical trials have demonstrated that a reduction in low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular (CV) events. This has, however, not yet been shown in a real-world setting. We aimed to investigate the association between LDL-C changes and statin intensity with prognosis after a myocardial infarction (MI). METHODS AND RESULTS: Patients admitted with MI were followed for mortality and major CV events. Changes in LDL-C between the MI and a 6- to 10-week follow-up visit were analysed. The associations between quartiles of LDL-C change and statin intensity with outcomes were assessed using adjusted Cox regression analyses. A total of 40 607 patients were followed for a median of 3.78 years. The median change in LDL-C was a 1.20 mmol/L reduction. Patients with larger LDL-C reduction (1.85 mmol/L, 75th percentile) compared with a smaller reduction (0.36 mmol/L, 25th percentile) had lower hazard ratios (HR) for all outcomes (95% confidence interval): composite of CV mortality, MI, and ischaemic stroke 0.77 (0.70-0.84); all-cause mortality 0.71 (0.63-0.80); CV mortality 0.68 (0.57-0.81); MI 0.81 (0.73-0.91); ischaemic stroke 0.76 (0.62-0.93); heart failure hospitalization 0.73 (0.63-0.85), and coronary artery revascularization 0.86 (0.79-0.94). Patients with ≥50% LDL-C reduction using high-intensity statins at discharge had a lower incidence of all outcomes compared with those using a lower intensity statin. CONCLUSIONS: Larger early LDL-C reduction and more intensive statin therapy after MI were associated with a reduced hazard of all CV outcomes and all-cause mortality. This supports clinical trial data suggesting that earlier lowering of LDL-C after an MI confers the greatest benefit.

Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome: Insights From the SWEDEHEART Registry.

BACKGROUND: The comparative efficacy and safety of ticagrelor versus clopidogrel in older patients with myocardial infarction (MI) has received limited study. METHODS: We performed an observational analysis of all patients ≥80 years (n=14 005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI, or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in <80-year-old patients was performed. RESULTS: In patients ≥80 years, the incidence of the primary ischemic outcome (hazard ratio [HR], 0.97 [95% CI, 0.88-1.06]) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (HR, 1.17 [95% CI, 1.03-1.32]) and bleeding (HR, 1.48 [95% CI, 1.25-1.76]), but a lower risk of MI (HR, 0.80 [95% CI, 0.70-0.92]) and stroke (HR, 0.72 [95% CI, 0.56-0.93]). In <80-year-old patients, the incidence of the primary ischemic outcome was 17% (HR, 0.83 [95% CI, 0.77-0.89]) lower with ticagrelor. Ticagrelor was associated with 15% (HR, 0.85 [95% CI, 0.76-0.96]) lower risk of death, 32% higher risk of bleeding (HR, 1.32 [95% CI, 1.18-1.47]), but lower risk of MI (HR, 0.82 [95% CI, 0.75-0.91]) and stroke (HR, 0.82 [95% CI, 0.69-0.98]). CONCLUSIONS: Ticagrelor use among elderly patients with MI was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor versus clopidogrel in the elderly is needed.

Randomized evaluation of beta blocker and ACE-inhibitor/angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and occurs in 6-8% of all patients fulfilling the diagnostic criteria for acute myocardial infarction (AMI). This paper describes the rationale behind the trial 'Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment (ACEI/ARB) of MINOCA patients' (MINOCA-BAT) and the need to improve the secondary preventive treatment of MINOCA patients. METHODS: MINOCA-BAT is a registry-based, randomized, parallel, open-label, multicenter trial with 2:2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce the composite endpoint of death of any cause, readmission because of AMI, ischemic stroke or heart failure in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 3500 patients will be randomized into four groups; e.g. ACEI/ARB and beta blocker, beta blocker only, ACEI/ARB only and neither ACEI/ARB nor beta blocker, and followed for a mean of 4 years. SUMMARY: While patients with MINOCA have an increased risk of serious cardiovascular events and death, whether conventional secondary preventive therapies are beneficial has not been assessed in randomized trials. There is a limited basis for guideline recommendations in MINOCA. Furthermore, studies of routine clinical practice suggest that use of secondary prevention therapies in MINOCA varies considerably. Thus results from this trial may influence future treatment strategies and guidelines specific to MINOCA patients.

Randomized comparison of early supplemental oxygen versus ambient air in patients with confirmed myocardial infarction: Sex-related outcomes from DETO2X-AMI.

BACKGROUND: The purpose of this study is to investigate the impact of oxygen therapy on cardiovascular outcomes in relation to sex in patients with confirmed myocardial infarction (MI). METHODS: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction trial randomized 6,629 patients to oxygen at 6 L/min for 6-12 hours or ambient air. In the present subgroup analysis including 5,010 patients (1,388 women and 3,622 men) with confirmed MI, we report the effect of supplemental oxygen on the composite of all-cause death, rehospitalization with MI, or heart failure at long-term follow-up, stratified according to sex. RESULTS: Event rate for the composite endpoint was 18.1% in women allocated to oxygen, compared to 21.4% in women allocated to ambient air (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.65-1.05). In men, the incidence was 13.6% in patients allocated to oxygen compared to 13.3% in patients allocated to ambient air (HR 1.03, 95% CI 0.86-1.23). No significant interaction in relation to sex was found (P= .16). Irrespective of allocated treatment, the composite endpoint occurred more often in women compared to men (19.7 vs 13.4%, HR 1.51; 95% CI, 1.30-1.75). After adjustment for age alone, there was no difference between the sexes (HR 1.06, 95% CI 0.91-1.24), which remained consistent after multivariate adjustment. CONCLUSION: Oxygen therapy in normoxemic MI patients did not significantly affect all-cause mortality or rehospitalization for MI or heart failure in women or men. The observed worse outcome in women was explained by differences in baseline characteristics, especially age.