External validation of the myocardial-ischaemic-injury-index machine learning algorithm for the early diagnosis of myocardial infarction: a multicentre cohort study

Background The myocardial-ischaemic-injury-index (MI$^{3}$) is a novel machine learning algorithm for the early diagnosis of type 1 non-ST-segment elevation myocardial infarction (NSTEMI). The performance of MI$^{3}$, both when using early serial blood draws (eg, at 1 h or 2 h) and in direct comparison with guideline-recommended algorithms, remains unknown. Our aim was to externally validate MI$^{3}$ and compare its performance with that of the European Society of Cardiology (ESC) 0/1h-algorithm. Methods In this secondary analysis of a multicentre international diagnostic cohort study, adult patients (age >18 years) presenting to the emergency department with symptoms suggestive of myocardial infarction were prospectively enrolled from April 21, 2006, to Feb 27, 2019 in 12 centres from five European countries (Switzerland, Spain, Italy, Poland, and Czech Republic). Patients were excluded if they presented with ST-segment-elevation myocardial infarction, did not have at least two serial high-sensitivity cardiac troponin I (hs-cTnI) measurements, or if the final diagnosis remained unclear. The final diagnosis was centrally adjudicated by two independent cardiologists using all available medical records, including serial hs-cTnI measurements and cardiac imaging. The primary outcome was type 1 NSTEMI. The performance of MI$^{3}$ was directly compared with that of the ESC 0/1h-algorithm. Findings Among 6487 patients, (median age 61·0 years [IQR 49·0-73·0]; 2122 [33%] female and 4365 [67%] male), 882 (13·6%) patients had type 1 NSTEMI. The median time difference between the first and second hs-cTnI measurement was 60·0 mins (IQR 57·0-70·0). MI$^{3}$ performance was very good, with an area under the receiver-operating-characteristic curve of 0·961 (95% CI 0·957 to 0·965) and a good overall calibration (intercept -0·09 [-0·2 to 0·02]; slope 1·02 [0·97 to 1·08]). The originally defined MI3 score of less than 1·6 identified 4186 (64·5%) patients as low probability of having a type 1 NSTEMI (sensitivity 99·1% [95% CI 98·2 to 99·5]; negative predictive value [NPV] 99·8% [95% CI 99·6 to 99·9]) and an MI$^{3}$ score of 49·7 or more identified 915 (14·1%) patients as high probability of having a type 1 NSTEMI (specificity 95·0% [94·3 to 95·5]; positive predictive value [PPV] 69·1% [66·0-72·0]). The sensitivity and NPV of the ESC 0/1h-algorithm were higher than that of MI$^{3}$ (difference for sensitivity 0·88% [0·19 to 1·60], p=0·0082; difference for NPV 0·18% [0·05 to 0·32], p=0·016), and the rule-out efficacy was higher for MI3 (11% difference, p<0·0001). Specificity and PPV for MI$^{3}$ were superior (difference for specificity 3·80% [3·24 to 4·36], p<0·0001; difference for PPV 7·84% [5·86 to 9·97], p<0·0001), and the rule-in efficacy was higher for the ESC 0/1h-algorithm (5·4% difference, p<0·0001). Interpretation MI$^{3}$ performs very well in diagnosing type 1 NSTEMI, demonstrating comparability to the ESC 0/1h-algorithm in an emergency department setting when using early serial blood draws. Funding Swiss National Science Foundation, Swiss Heart Foundation, the EU, the University Hospital Basel, the University of Basel, Abbott, Beckman Coulter, Roche, Idorsia, Ortho Clinical Diagnostics, Quidel, Siemens, and Singulex

Lower diagnostic accuracy of hs-cTnI in patients with prior coronary artery bypass grafting

High-sensitivity cardiac troponin T (hs-cTnT) and the ESC 0/1h-hs-cTnT-algorithm have worse performance in the early diagnosis of myocardial infarction (MI) in patients with prior coronary artery bypass grafting (CABG). It is unknown, whether this concern applies also to hs-cTnI, the most widely used analyte worldwide.; In an international multicenter diagnostic study, two cardiologists centrally adjudicated the final diagnosis in patients presenting to the emergency department with symptoms suggestive of MI according to the Third Universal Definition of MI. The objective was to compare the diagnostic accuracy of hs-cTnI assays and their performance within the ESC hs-cTnI 0/1h-algorithms in patients with versus without prior CABG. Findings were externally validated in an U.S. multicenter diagnostic study.; A total of 392/5'200 patients (8%) had prior coronary artery bypass grafting (CABG). Diagnostic accuracy of hs-cTnI as quantified by the area under the receiver-operating characteristics-curve (AUC) in these patients was high, but lower versus patients without prior CABG (e.g. hs-cTnI-Architect 0.91 versus 0.95; p = 0.016). Sensitivity/specificity of rule-out/in by the European Society of Cardiology (ESC) 0/1h-hs-cTnI-algorithms remained very high [e.g. hs-cTnI-Architect 100% and 93.5%], but efficacy was lower (52% versus 74%, p < 0.01). External validation (n = 2113) confirmed these findings in 192 patients with prior CABG using hs-cTnI-Atellica, with 52% versus 36% (p < 0.001) remaining in the observe zone.; Diagnostic accuracy of hs-cTnI and efficacy of the ESC 0/1h-hs-cTnI-algorithms are lower in patients with prior CABG, but sensitivity/specificity remain very high.; https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587

A 0/1h-algorithm using cardiac myosin-binding protein C for early diagnosis of myocardial infarction.

AIMS Cardiac myosin-binding protein C (cMyC) demonstrated high diagnostic accuracy for the early detection of non-ST-elevation myocardial infarction (NSTEMI). Its dynamic release kinetics may enable a 0/1h-decision algorithm that is even more effective than the ESC hs-cTnT/I 0/1 h rule-in/rule-out algorithm. METHODS AND RESULTS In a prospective international diagnostic study enrolling patients presenting with suspected NSTEMI to the emergency department, cMyC was measured at presentation and after 1 h in a blinded fashion. Modelled on the ESC hs-cTnT/I 0/1h-algorithms, we derived a 0/1h-cMyC-algorithm. Final diagnosis of NSTEMI was centrally adjudicated according to the 4th Universal Definition of Myocardial Infarction. Among 1495 patients, the prevalence of NSTEMI was 17%. The optimal derived 0/1h-algorithm ruled-out NSTEMI with cMyC 0 h concentration below 10 ng/L (irrespective of chest pain onset) or 0 h cMyC concentrations below 18 ng/L and 0/1 h increase <4 ng/L. Rule-in occurred with 0 h cMyC concentrations of at least 140 ng/L or 0/1 h increase ≥15 ng/L. In the validation cohort (n = 663), the 0/1h-cMyC-algorithm classified 347 patients (52.3%) as 'rule-out', 122 (18.4%) as 'rule-in', and 194 (29.3%) as 'observe'. Negative predictive value for NSTEMI was 99.6% [95% confidence interval (CI) 98.9-100%]; positive predictive value 71.1% (95% CI 63.1-79%). Direct comparison with the ESC hs-cTnT/I 0/1h-algorithms demonstrated comparable safety and even higher triage efficacy using the 0h-sample alone (48.1% vs. 21.2% for ESC hs-cTnT-0/1 h and 29.9% for ESC hs-cTnI-0/1 h; P < 0.001). CONCLUSION The cMyC 0/1h-algorithm provided excellent safety and identified a greater proportion of patients suitable for direct rule-out or rule-in based on a single measurement than the ESC 0/1h-algorithm using hs-cTnT/I. TRIAL REGISTRATION ClinicalTrials.gov number, NCT00470587

Diagnostic discrimination of a novel high-sensitivity cardiac troponin I assay and derivation/validation of an assay-specific 0/1h-algorithm

BACKGROUND We aimed to assess the diagnostic utility of the Dimension EXL LOCI High-Sensitivity Troponin I (hs-cTnI-EXL) assay. METHODS This multicenter study included patients with chest discomfort presenting to the emergency department. Diagnoses were centrally and independently adjudicated by two cardiologists using all available clinical information. Adjudication was performed twice including serial measurements of high-sensitivity cardiac troponin (hs-cTn) I-Architect (primary analysis) and serial measurements of hs-cTnT-Elecsys (secondary analysis) in addition to the clinically used (hs)-cTn. The primary objective was to assess and compare the discriminatory performance of hs-cTnI-EXL, hs-cTnI-Architect and hs-cTnT-Elecsys for acute myocardial infarction (MI). Furthermore, we derived and validated a hs-cTnI-EXL-specific 0/1h-algorithm. RESULTS Adjudicated MI was the diagnosis in 204/1454 (14%) patients. The area under the receiver operating characteristics curve for hs-cTnI-EXL was 0.94 (95%CI, 0.93-0.96), and comparable to hs-cTnI-Architect (0.95; 95%CI, 0.93-0.96) and hs-cTnT-Elecsys (0.93; 95%CI, 0.91-0.95). In the derivation cohort (n = 813), optimal criteria for rule-out of MI were 3h) or <9ng/L and 0h-1h-change <5ng/L, and for rule-in ≥160ng/L at presentation or 0h-1h-change ≥100ng/L. In the validation cohort (n = 345), these cut-offs ruled-out 56% of patients (negative predictive value 99.5% (95%CI, 97.1-99.9), sensitivity 97.8% (95%CI, 88.7-99.6)), and ruled-in 9% (positive predictive value 83.3% (95%CI, 66.4-92.7), specificity 98.3% (95%CI, 96.1-99.3)). Secondary analyses using adjudication based on hs-cTnT measurements confirmed the findings. CONCLUSIONS The overall performance of the hs-cTnI-EXL was comparable to best-validated hs-cTnT/I assays and an assay-specific 0/1h-algorithm safely rules out and accurately rules in acute MI. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov number, NCT00470587

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

Circadian rhythm of cardiac troponin I and its clinical impact on the diagnostic accuracy for acute myocardial infarction

High-sensitivity cardiac troponin T (hs-cTnT) blood concentrations were shown to exhibit a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime and peak concentrations in the morning. We aimed to investigate whether this also applies to (h)s-cTnI assays and whether it would affect diagnostic accuracy for acute myocardial infarction (AMI).; Blood concentrations of cTnI were measured at presentation and after 1 h using four different cTnI assays: three commonly used sensitive (s-cTnI Architect, Ultra and Accu) and one experimental high-sensitivity assay (hs-cTnI Accu) in a prospective multicenter diagnostic study of patients presenting to the emergency department with suspected AMI. These concentrations and their diagnostic accuracy for AMI (quantified by the area under the curve (AUC)) were compared between morning (11 p.m. to 2 p.m.) and evening (2 p.m. to 11 p.m.) presenters.; Among 2601 patients, AMI was the final diagnosis in 17.6% of patients. Concentrations of (h)s-cTnI as measured using all four assays were comparable in patients presenting in the morning versus patients presenting in the evening. Diagnostic accuracy for AMI of all four (h)s-cTnI assays were high and comparable between patients presenting in the morning versus presenting in the evening (AUC at presentation: 0.90 vs 0.93 for s-cTnI Architect; 0.91 vs 0.94 for s-cTnI Ultra; 0.89 vs 0.94 for s-cTnI Accu; 0.91 vs 0.94 for hs-cTnI Accu).; Cardiac TnI does not seem to express a diurnal rhythm. Diagnostic accuracy for AMI is very high and does not differ with time of presentation.; NCT00470587, http://clinicaltrials.gov/show/NCT00470587