Could paramedics use the HEART Pathway to identify patients at low-risk of myocardial infarction in the prehospital setting?

In the Emergency Department, patients with suspected myocardial infarction can be risk stratified using the HEART pathway, which has recently been amended for prehospital use and modified for the incorporation of a high-sensitivity cardiac troponin test. In a prospective analysis, the performance of both HEART pathways in the prehospital setting, with a high-sensitivity cardiac troponin test using 3 different thresholds, was evaluated for major adverse cardiac events at 30 days. We found that both low-risk HEART pathways, when using the most conservative cardiac troponin thresholds, approached but did not reach accepted rule-out performance in the Emergency Department.

Application of the Universal Definition of Myocardial Infarction in Clinical Practice in Scotland and Sweden.

Importance: Whether the diagnostic classifications proposed by the universal definition of myocardial infarction (MI) to identify type 1 MI due to atherothrombosis and type 2 MI due to myocardial oxygen supply-demand imbalance have been applied consistently in clinical practice is unknown. Objective: To evaluate the application of the universal definition of MI in consecutive patients with possible MI across 2 health care systems. Design, Setting, and Participants: This cohort study used data from 2 prospective cohorts enrolling consecutive patients with possible MI in Scotland (2013-2016) and Sweden (2011-2014) to assess accuracy of clinical diagnosis of MI recorded in hospital records for patients with an adjudicated diagnosis of type 1 or type 2 MI. Data were analyzed from August 2022 to February 2023. Main Outcomes and Measures: The main outcome was the proportion of patients with a clinical diagnosis of MI recorded in the hospital records who had type 1 or type 2 MI, adjudicated by an independent panel according to the universal definition. Characteristics and risk of subsequent MI or cardiovascular death at 1 year were compared. Results: A total of 50 356 patients were assessed. The cohort from Scotland included 28 783 (15 562 men [54%]; mean [SD] age, 60 [17] years), and the cohort from Sweden included 21 573 (11 110 men [51%]; mean [SD] age, 56 [17] years) patients. In Scotland, a clinical diagnosis of MI was recorded in 2506 of 3187 patients with an adjudicated diagnosis of type 1 MI (79%) and 122 of 716 patients with an adjudicated diagnosis of type 2 MI (17%). Similar findings were observed in Sweden, with 970 of 1111 patients with adjudicated diagnosis of type 1 MI (87%) and 57 of 251 patients with adjudicated diagnosis of type 2 MI (23%) receiving a clinical diagnosis of MI. Patients with an adjudicated diagnosis of type 1 MI without a clinical diagnosis were more likely to be women (eg, 336 women [49%] vs 909 women [36%] in Scotland; P < .001) and older (mean [SD] age, 71 [14] v 67 [14] years in Scotland, P < .001) and, when adjusting for competing risk from noncardiovascular death, were at similar or increased risk of subsequent MI or cardiovascular death compared with patients with a clinical diagnosis of MI (eg, 29% vs 18% in Scotland; P < .001). Conclusions and Relevance: In this cohort study, the universal definition of MI was not consistently applied in clinical practice, with a minority of patients with type 2 MI identified, and type 1 MI underrecognized in women and older persons, suggesting uncertainty remains regarding the diagnostic criteria or value of the classification.

Uniform or Sex-Specific Cardiac Troponin Thresholds to Rule Out Myocardial Infarction at Presentation.

BACKGROUND: Myocardial infarction can be ruled out in patients with a single cardiac troponin measurement. Whether use of a uniform rule-out threshold has resulted in sex differences in care remains unclear. OBJECTIVES: The purpose of this study was to evaluate implementation of a uniform rule-out threshold in females and males with possible myocardial infarction, and to derive and validate sex-specific thresholds. METHODS: The implementation of a uniform rule-out threshold (<5 ng/L) with a high-sensitivity cardiac troponin I assay was evaluated in consecutive patients presenting with possible myocardial infarction. The proportion of low-risk patients discharged from the emergency department and incidence of myocardial infarction or cardiac death at 30 days were determined. Sex-specific thresholds were derived and validated, and proportion of female and male patients were stratified as low-risk compared with uniform threshold. RESULTS: In 16,792 patients (age 58 ± 17 years; 46% female) care was guided using a uniform threshold. This identified more female than male patients as low risk (73% vs 62%), but a similar proportion of low-risk patients were discharged from the emergency department (81% for both) with fewer than 5 (<0.1%) patients having a subsequent myocardial infarction or cardiac death at 30 days. Compared with a uniform threshold of <5 ng/L, use of sex-specific thresholds would increase the proportion of female (61.8% vs 65.9%) and reduce the proportion of male (54.8% vs 47.8%) patients identified as low risk. CONCLUSIONS: Implementation of a uniform rule-out threshold for myocardial infarction was safe and effective in both sexes. Sex-specific rule-out thresholds should be considered, but their impact on effectiveness and safety may be limited.

Machine Learning for Myocardial Infarction Compared With Guideline-Recommended Diagnostic Pathways.

BACKGROUND: Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome (CoDE-ACS) is a validated clinical decision support tool that uses machine learning with or without serial cardiac troponin measurements at a flexible time point to calculate the probability of myocardial infarction (MI). How CoDE-ACS performs at different time points for serial measurement and compares with guideline-recommended diagnostic pathways that rely on fixed thresholds and time points is uncertain. METHODS: Patients with possible MI without ST-segment-elevation were enrolled at 12 sites in 5 countries and underwent serial high-sensitivity cardiac troponin I concentration measurement at 0, 1, and 2 hours. Diagnostic performance of the CoDE-ACS model at each time point was determined for index type 1 MI and the effectiveness of previously validated low- and high-probability scores compared with guideline-recommended European Society of Cardiology (ESC) 0/1-hour, ESC 0/2-hour, and High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome) pathways. RESULTS: In total, 4105 patients (mean age, 61 years [interquartile range, 50-74]; 32% women) were included, among whom 575 (14%) had type 1 MI. At presentation, CoDE-ACS identified 56% of patients as low probability, with a negative predictive value and sensitivity of 99.7% (95% CI, 99.5%-99.9%) and 99.0% (98.6%-99.2%), ruling out more patients than the ESC 0-hour and High-STEACS (25% and 35%) pathways. Incorporating a second cardiac troponin measurement, CoDE-ACS identified 65% or 68% of patients as low probability at 1 or 2 hours, for an identical negative predictive value of 99.7% (99.5%-99.9%); 19% or 18% as high probability, with a positive predictive value of 64.9% (63.5%-66.4%) and 68.8% (67.3%-70.1%); and 16% or 14% as intermediate probability. In comparison, after serial measurements, the ESC 0/1-hour, ESC 0/2-hour, and High-STEACS pathways identified 49%, 53%, and 71% of patients as low risk, with a negative predictive value of 100% (99.9%-100%), 100% (99.9%-100%), and 99.7% (99.5%-99.8%); and 20%, 19%, or 29% as high risk, with a positive predictive value of 61.5% (60.0%-63.0%), 65.8% (64.3%-67.2%), and 48.3% (46.8%-49.8%), resulting in 31%, 28%, or 0%, who require further observation in the emergency department, respectively. CONCLUSIONS: CoDE-ACS performs consistently irrespective of the timing of serial cardiac troponin measurement, identifying more patients as low probability with comparable performance to guideline-recommended pathways for MI. Whether care guided by probabilities can improve the early diagnosis of MI requires prospective evaluation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00470587.

Implementation of a high sensitivity cardiac troponin I assay and risk of myocardial infarction or death at five years: observational analysis of a stepped wedge, cluster randomised controlled trial.

OBJECTIVE: To evaluate the impact of implementing a high sensitivity assay for cardiac troponin I on long term outcomes in patients with suspected acute coronary syndrome. DESIGN: Secondary observational analysis of a stepped wedge, cluster randomised controlled trial. SETTING: 10 secondary and tertiary care centres in Scotland, UK. PARTICIPANTS: 48 282 consecutive patients with suspected acute coronary syndrome. Myocardial injury was defined as any high sensitivity assay result for cardiac troponin I >99th centile of 16 ng/L in women and 34 ng/L in men. INTERVENTION: Hospital sites were randomly allocated to either early (n=5 hospitals) or late (n=5 hospitals) implementation of a high sensitivity cardiac troponin I assay with sex specific diagnostic thresholds. MAIN OUTCOME MEASURE: The main outcome was myocardial infarction or death at five years. RESULTS: 10 360 patients had cardiac troponin concentrations greater than the 99th centile, of whom 1771 (17.1%) were reclassified by the high sensitivity assay. The five year incidence of subsequent myocardial infarction or death before and after implementation of the high sensitivity assay was 29.4% (5588/18 978) v 25.9% (7591/29 304), respectively, in all patients (adjusted hazard ratio 0.97, 95% confidence interval 0.93 to 1.01), and 63.0% (456/720) v 53.9% (567/1051), respectively, in those reclassified by the high sensitivity assay (0.82, 0.72 to 0.94). After implementation of the high sensitivity assay, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischaemic myocardial injury (0.83, 0.75 to 0.91) but not in those with type 1 or type 2 myocardial infarction (0.92, 0.83 to 1.01 and 0.98, 0.84 to 1.14). CONCLUSIONS: Implementation of a high sensitivity cardiac troponin I assay in the assessment of patients with suspected acute coronary syndrome was associated with a reduced risk of subsequent myocardial infarction or death at five years in those reclassified by the high sensitivity assay. Improvements in outcome were greatest in patients with non-ischaemic myocardial injury, suggesting a broader benefit beyond the identification of myocardial infarction. TRIAL REGISTRATION: ClinicalTrials.gov NCT01852123.

Performance of a prehospital HEART score in patients with possible myocardial infarction: a prospective evaluation.

INTRODUCTION: The History, Electrocardiogram (ECG), Age, Risk Factors and Troponin (HEART) score is commonly used to risk stratify patients with possible myocardial infarction as low risk or high risk in the Emergency Department (ED). Whether the HEART score can be used by paramedics to guide care were high-sensitivity cardiac troponin testing available in a prehospital setting is uncertain. METHODS: In a prespecified secondary analysis of a prospective cohort study where paramedics enrolled patients with suspected myocardial infarction, a paramedic Heart, ECG, Age, Risk Factors (HEAR) score was recorded contemporaneously, and a prehospital blood sample was obtained for subsequent cardiac troponin testing. HEART and modified HEART scores were derived using laboratory contemporary and high-sensitivity cardiac troponin I assays. HEART and modified HEART scores of ≤3 and ≥7 were applied to define low-risk and high-risk patients, and performance was evaluated for an outcome of major adverse cardiac events (MACEs) at 30 days. RESULTS: Between November 2014 and April 2018, 1054 patients were recruited, of whom 960 (mean 64 (SD 15) years, 42% women) were eligible for analysis and 255 (26%) experienced a MACE at 30 days. A HEART score of ≤3 identified 279 (29%) as low risk with a negative predictive value of 93.5% (95% CI 90.0% to 95.9%) for the contemporary assay and 91.4% (95% CI 87.5% to 94.2%) for the high-sensitivity assay. A modified HEART score of ≤3 using the limit of detection of the high-sensitivity assay identified 194 (20%) patients as low risk with a negative predictive value of 95.9% (95% CI 92.1% to 97.9%). A HEART score of ≥7 using either assay gave a lower positive predictive value than using the upper reference limit of either cardiac troponin assay alone. CONCLUSIONS: A HEART score derived by paramedics in the prehospital setting, even when modified to harness the precision of a high-sensitivity assay, does not allow safe rule-out of myocardial infarction or enhanced rule-in compared with cardiac troponin testing alone.

Troponin in early presenters to rule out myocardial infarction.

AIMS: Whether a single cardiac troponin measurement can safely rule out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The study aim was to assess the performance of troponin in early presenters. METHODS AND RESULTS: In patients with possible myocardial infarction, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4-12, and >12 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In 41 103 consecutive patients [60 (17) years, 46% women], 12 595 (31%) presented within 3 h, and 3728 (9%) had myocardial infarction. In those presenting ≤3 h, a threshold of 2 ng/L had greater sensitivity and negative predictive value [99.4% (95% confidence interval 99.2%-99.5%) and 99.7% (99.6%-99.8%)] compared with 5 ng/L [96.5% (96.2%-96.8%) and 99.3% (99.1%-99.4%)]. In those presenting ≥3 h, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% (70.6%-72.2%) and 92.5% (92.0%-93.0%), respectively. Findings were consistent in an external validation cohort of 7088 patients. CONCLUSION: In early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of myocardial infarction. The 99th centile should not be used to rule out myocardial infarction at presentation even in those presenting later following symptom onset.

Troponin in acute chest pain to risk stratify and guide effective use of computed tomography coronary angiography (TARGET-CTCA): a randomised controlled trial.

BACKGROUND: The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death. METHODS: TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months. DISCUSSION: This randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03952351. Registered on May 16, 2019.

Machine learning for diagnosis of myocardial infarction using cardiac troponin concentrations.

Although guidelines recommend fixed cardiac troponin thresholds for the diagnosis of myocardial infarction, troponin concentrations are influenced by age, sex, comorbidities and time from symptom onset. To improve diagnosis, we developed machine learning models that integrate cardiac troponin concentrations at presentation or on serial testing with clinical features and compute the Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome (CoDE-ACS) score (0-100) that corresponds to an individual's probability of myocardial infarction. The models were trained on data from 10,038 patients (48% women), and their performance was externally validated using data from 10,286 patients (35% women) from seven cohorts. CoDE-ACS had excellent discrimination for myocardial infarction (area under curve, 0.953; 95% confidence interval, 0.947-0.958), performed well across subgroups and identified more patients at presentation as low probability of having myocardial infarction than fixed cardiac troponin thresholds (61 versus 27%) with a similar negative predictive value and fewer as high probability of having myocardial infarction (10 versus 16%) with a greater positive predictive value. Patients identified as having a low probability of myocardial infarction had a lower rate of cardiac death than those with intermediate or high probability 30 days (0.1 versus 0.5 and 1.8%) and 1 year (0.3 versus 2.8 and 4.2%; P < 0.001 for both) from patient presentation. CoDE-ACS used as a clinical decision support system has the potential to reduce hospital admissions and have major benefits for patients and health care providers.

Personalized diagnosis in suspected myocardial infarction.

BACKGROUND: In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays. METHODS: In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients. RESULTS: Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy. CONCLUSION: We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care. TRIAL REGISTRATION NUMBERS: Data of following cohorts were used for this project: BACC ( www. CLINICALTRIALS: gov ; NCT02355457), stenoCardia ( www. CLINICALTRIALS: gov ; NCT03227159), ADAPT-BSN ( www.australianclinicaltrials.gov.au ; ACTRN12611001069943), IMPACT ( www.australianclinicaltrials.gov.au , ACTRN12611000206921), ADAPT-RCT ( www.anzctr.org.au ; ANZCTR12610000766011), EDACS-RCT ( www.anzctr.org.au ; ANZCTR12613000745741); DROP-ACS ( https://www.umin.ac.jp , UMIN000030668); High-STEACS ( www. CLINICALTRIALS: gov ; NCT01852123), LUND ( www. CLINICALTRIALS: gov ; NCT05484544), RAPID-CPU ( www. CLINICALTRIALS: gov ; NCT03111862), ROMI ( www. CLINICALTRIALS: gov ; NCT01994577), SAMIE ( https://anzctr.org.au ; ACTRN12621000053820), SEIGE and SAFETY ( www. CLINICALTRIALS: gov ; NCT04772157), STOP-CP ( www. CLINICALTRIALS: gov ; NCT02984436), UTROPIA ( www. CLINICALTRIALS: gov ; NCT02060760).

Sex Differences in Oral Anticoagulation Therapy in Patients Hospitalized With Atrial Fibrillation: A Nationwide Cohort Study.

Background Important disparities in the treatment and outcomes of women and men with atrial fibrillation (AF) are well recognized. Whether introduction of direct oral anticoagulants has reduced disparities in treatment is uncertain. Methods and Results All patients who had an incident hospitalization from 2010 to 2019 with nonvalvular AF in Scotland were included in the present cohort study. Community drug dispensing data were used to determine prescribed oral anticoagulation therapy and comorbidity status. Logistic regression modeling was used to evaluate patient factors associated with treatment with vitamin K antagonists and direct oral anticoagulants. A total of 172 989 patients (48% women [82 833 of 172 989]) had an incident hospitalization with nonvalvular AF in Scotland between 2010 and 2019. By 2019, factor Xa inhibitors accounted for 83.6% of all oral anticoagulants prescribed, while treatment with vitamin K antagonists and direct thrombin inhibitors declined to 15.9% and 0.6%, respectively. Women were less likely to be prescribed any oral anticoagulation therapy compared with men (adjusted odds ratio [aOR], 0.68 [95% CI, 0.67-0.70]). This disparity was mainly attributed to vitamin K antagonists (aOR, 0.68 [95% CI, 0.66-0.70]), while there was less disparity in the use of factor Xa inhibitors between women and men (aOR, 0.92 [95% CI, 0.90-0.95]). Conclusions Women with nonvalvular AF were significantly less likely to be prescribed vitamin K antagonists compared with men. Most patients admitted to the hospital in Scotland with incident nonvalvular AF are now treated with factor Xa inhibitors and this is associated with fewer treatment disparities between women and men.

Coronary low-attenuation plaque and high-sensitivity cardiac troponin.

OBJECTIVE: In patients with acute chest pain who have had myocardial infarction excluded, plasma cardiac troponin I concentrations ≥5 ng/L are associated with risk of future adverse cardiovascular events. We aim to evaluate the association between cardiac troponin and coronary plaque composition in such patients. METHODS: In a prespecified secondary analysis of a prospective cohort study, blinded quantitative plaque analysis was performed on 242 CT coronary angiograms of patients with acute chest pain in whom myocardial infarction was excluded. Patients were stratified by peak plasma cardiac troponin I concentration ≥5 ng/L or <5 ng/L. Associations were assessed using univariable and multivariable logistic regression analyses. RESULTS: The cohort was predominantly middle-aged (62±12 years) men (69%). Patients with plasma cardiac troponin I concentration ≥5 ng/L (n=161) had a higher total (median 33% (IQR 0-47) vs 0% (IQR 0-33)), non-calcified (27% (IQR 0-37) vs 0% (IQR 0-28)), calcified (2% (IQR 0-8) vs 0% (IQR 0-3)) and low-attenuation (1% (IQR 0-3) vs 0% (IQR 0-1)) coronary plaque burden compared with those with concentrations <5 ng/L (n=81; p≤0.001 for all). Low-attenuation plaque burden was independently associated with plasma cardiac troponin I concentration ≥5 ng/L after adjustment for clinical characteristics (adjusted OR per doubling 1.62 (95% CI 1.17 to 2.32), p=0.005) or presence of any visible coronary artery disease (adjusted OR per doubling 1.57 (95% CI 1.07 to 2.37), p=0.026). CONCLUSION: In patients with acute chest pain but without myocardial infarction, plasma cardiac troponin I concentrations ≥5 ng/L are associated with greater burden of low-attenuation coronary plaque.

Improving Risk Stratification for Patients With Type 2 Myocardial Infarction.

BACKGROUND: Despite poor cardiovascular outcomes, there are no dedicated, validated risk stratification tools to guide investigation or treatment in type 2 myocardial infarction. OBJECTIVES: The goal of this study was to derive and validate a risk stratification tool for the prediction of death or future myocardial infarction in patients with type 2 myocardial infarction. METHODS: The T2-risk score was developed in a prospective multicenter cohort of consecutive patients with type 2 myocardial infarction. Cox proportional hazards models were constructed for the primary outcome of myocardial infarction or death at 1 year using variables selected a priori based on clinical importance. Discrimination was assessed by area under the receiving-operating characteristic curve (AUC). Calibration was investigated graphically. The tool was validated in a single-center cohort of consecutive patients and in a multicenter cohort study from sites across Europe. RESULTS: There were 1,121, 250, and 253 patients in the derivation, single-center, and multicenter validation cohorts, with the primary outcome occurring in 27% (297 of 1,121), 26% (66 of 250), and 14% (35 of 253) of patients, respectively. The T2-risk score incorporating age, ischemic heart disease, heart failure, diabetes mellitus, myocardial ischemia on electrocardiogram, heart rate, anemia, estimated glomerular filtration rate, and maximal cardiac troponin concentration had good discrimination (AUC: 0.76; 95% CI: 0.73-0.79) for the primary outcome and was well calibrated. Discrimination was similar in the consecutive patient (AUC: 0.83; 95% CI: 0.77-0.88) and multicenter (AUC: 0.74; 95% CI: 0.64-0.83) cohorts. T2-risk provided improved discrimination over the Global Registry of Acute Coronary Events 2.0 risk score in all cohorts. CONCLUSIONS: The T2-risk score performed well in different health care settings and could help clinicians to prognosticate, as well as target investigation and preventative therapies more effectively. (High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome [High-STEACS]; NCT01852123).

Influence of Age on the Diagnosis of Myocardial Infarction.

BACKGROUND: The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction. METHODS: In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups (<50, 50-74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds. RESULTS: In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5-82.9), 80.6% (95% CI, 79.2-82.1), and 81.6% (95% CI, 79.8-83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1-98.5) to 95.5% (95% CI, 95.2-95.8), and 82.6% (95% CI, 81.9-83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%-91.9%] versus 82.6% [95% CI, 81.9%-83.4%]) and positive predictive value (59.3% [57.0%-61.5%] versus 51.5% [49.9%-53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%-57.9%] versus 81.6% [79.8%-83.3%]. CONCLUSIONS: Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population.

Assessment of Cardiac, Vascular, and Pulmonary Pathobiology In Vivo During Acute COVID-19.

Background Acute COVID-19-related myocardial, pulmonary, and vascular pathology and how these relate to each other remain unclear. To our knowledge, no studies have used complementary imaging techniques, including molecular imaging, to elucidate this. We used multimodality imaging and biochemical sampling in vivo to identify the pathobiology of acute COVID-19. Specifically, we investigated the presence of myocardial inflammation and its association with coronary artery disease, systemic vasculitis, and pneumonitis. Methods and Results Consecutive patients presenting with acute COVID-19 were prospectively recruited during hospital admission in this cross-sectional study. Imaging involved computed tomography coronary angiography (identified coronary disease), cardiac 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography (identified vascular, cardiac, and pulmonary inflammatory cell infiltration), and cardiac magnetic resonance (identified myocardial disease) alongside biomarker sampling. Of 33 patients (median age 51 years, 94% men), 24 (73%) had respiratory symptoms, with the remainder having nonspecific viral symptoms. A total of 9 patients (35%, n=9/25) had cardiac magnetic resonance-defined myocarditis. Of these patients, 53% (n=5/8) had myocardial inflammatory cell infiltration. A total of 2 patients (5%) had elevated troponin levels. Cardiac troponin concentrations were not significantly higher in patients with and without myocarditis (8.4 ng/L [interquartile range, IQR: 4.0-55.3] versus 3.5 ng/L [IQR: 2.5-5.5]; P=0.07) or myocardial cell infiltration (4.4 ng/L [IQR: 3.4-8.3] versus 3.5 ng/L [IQR: 2.8-7.2]; P=0.89). No patients had obstructive coronary artery disease or vasculitis. Pulmonary inflammation and consolidation (percentage of total lung volume) was 17% (IQR: 5%-31%) and 11% (IQR: 7%-18%), respectively. Neither were associated with the presence of myocarditis. Conclusions Myocarditis was present in a third patients with acute COVID-19, and the majority had inflammatory cell infiltration. Pneumonitis was ubiquitous, but this inflammation was not associated with myocarditis. The mechanism of cardiac pathology is nonischemic and not attributable to a vasculitic process. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN12154994.

Development and validation of a decision support tool for the diagnosis of acute heart failure: systematic review, meta-analysis, and modelling study.

OBJECTIVES: To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics. DESIGN: Individual patient level data meta-analysis and modelling study. SETTING: Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies. PARTICIPANTS: Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated. MAIN OUTCOME MEASURE: Adjudicated diagnosis of acute heart failure. RESULTS: Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure. CONCLUSIONS: In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach. STUDY REGISTRATION: PROSPERO CRD42019159407.

Cardiovascular risk factors and markers of myocardial injury and inflammation in people living with HIV in Nairobi, Kenya: a pilot cross-sectional study.

OBJECTIVES: To determine the prevalence of cardiovascular disease (CVD) risk factors and explore associations with high-sensitivity cardiac troponin I (hscTnI) and high-sensitivity C-reactive protein (hsCRP) in people living with HIV (PLHIV) in Kenya. DESIGN: Pilot cross-sectional study. SETTING: Data were collected from community HIV clinics across two sites in Nairobi, Kenya, from July 2019 to May 2020. PARTICIPANTS: Convenience sample of 200 PLHIV (≥30 years with no prior history of CVD). OUTCOME MEASURES: Prevalence of cardiovascular risk factors and its association with hsTnI and hsCRP levels. RESULTS: Across 200 PLHIV (median age 46 years, IQR 38-53; 61% women), the prevalence of hypercholesterolaemia (total cholesterol >6.1 mmol/L) and hypertension were 19% (n=30/199) and 30% (n=60/200), respectively. Smoking and diabetes prevalence was 3% (n=5/200) and 4% (n=7/200). HscTnI was below the limit of quantification (<2.5 ng/L) in 65% (n=109/169). High (>3 mg/L), intermediate (1-3 mg/L) and low (<1 mg/L) hsCRP levels were found in 38% (n=75/198), 33% (n=65/198) and 29% (n=58/198), respectively. Framingham laboratory-based risk scores classified 83% of PLHIV at low risk with 12% and 5% at intermediate and high risk, respectively. Older age (adjusted OR (aOR) per year increase 1.05, 95% CI 1.01 to 1.08) and systolic blood pressure (140-159 mm Hg (aOR 2.96; 95% CI 1.09 to 7.90) and >160 mm Hg (aOR 4.68, 95% CI 1.55 to 14) compared with <140 mm Hg) were associated with hscTnI levels. No associations were observed between hsCRP and CVD risk factors. CONCLUSION: The majority of PLHIV-using traditional risk estimation systems-have a low estimated CVD risk likely reflecting a younger aged population predominantly consisting of women. Hypertension and hypercholesterolaemia were common while smoking and diabetes rates remained low. While hscTnI values were associated with increasing age and raised blood pressure, no associations between hsCRP levels and traditional cardiovascular risk factors were observed.

Validation of the myocardial-ischaemic-injury-index machine learning algorithm to guide the diagnosis of myocardial infarction in a heterogenous population: a prespecified exploratory analysis.

BACKGROUND: Diagnostic pathways for myocardial infarction rely on fixed troponin thresholds, which do not recognise that troponin varies by age, sex, and time within individuals. To overcome this limitation, we recently introduced a machine learning algorithm that predicts the likelihood of myocardial infarction. Our aim was to evaluate whether this algorithm performs well in routine clinical practice and predicts subsequent events. METHODS: The myocardial-ischaemic-injury-index (MI3) algorithm was validated in a prespecified exploratory analysis using data from a multi-centre randomised trial done in Scotland, UK that included consecutive patients with suspected acute coronary syndrome undergoing serial high-sensitivity cardiac troponin I measurement. Patients with ST-segment elevation myocardial infarction were excluded. MI3 incorporates age, sex, and two troponin measurements to compute a value (0-100) reflecting an individual's likelihood of myocardial infarction during the index visit and estimates diagnostic performance metrics (including area under the receiver-operating-characteristic curve, and the sensitivity, specificity, negative predictive value, and positive predictive value) at the computed score. Model performance for an index diagnosis of myocardial infarction (type 1 or type 4b), and for subsequent myocardial infarction or cardiovascular death at 1 year was determined using the previously defined low-probability threshold (1·6) and high-probability MI3 threshold (49·7). The trial is registered with ClinicalTrials.gov, NCT01852123. FINDINGS: In total, 20 761 patients (64 years [SD 16], 9597 [46%] women) enrolled between June 10, 2013, and March 3, 2016, were included from the High-STEACS trial cohort, of whom 3272 (15·8%) had myocardial infarction. MI3 had an area under the receiver-operating-characteristic curve of 0·949 (95% CI 0·946-0·952) identifying 12 983 (62·5%) patients as low-probability for myocardial infarction at the pre-specified threshold (MI3 score <1·6; sensitivity 99·3% [95% CI 99·0-99·6], negative predictive value 99·8% [99·8-99·9]), and 2961 (14·3%) as high-probability at the pre-specified threshold (MI3 score ≥49·7; specificity 95·0% [94·6-95·3], positive predictive value 70·4% [68·7-72·0]). At 1 year, subsequent myocardial infarction or cardiovascular death occurred more often in high-probability patients than low-probability patients (520 [17·6%] of 2961 vs 197 [1·5%] of 12 983], p<0·0001). INTERPRETATION: In consecutive patients undergoing serial cardiac troponin measurement for suspected acute coronary syndrome, the MI3 algorithm accurately estimated the likelihood of myocardial infarction and predicted subsequent adverse cardiovascular events. By providing individual probabilities the MI3 algorithm could improve the diagnosis and assessment of risk in patients with suspected acute coronary syndrome. FUNDING: Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSX.

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment.