Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study.

BACKGROUND: Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown. METHODS: In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0-3) per current guidelines. DD was considered negative (DD-) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD- or ADD-RS ≤1/DD-. RESULTS: A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6-98.6) and a specificity of 64% (95% CI, 61.6-66.4) for the diagnosis of AAS; 8 patients with AAS had DD-. In 294 patients with ADD-RS=0/DD-, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1.9) and an efficiency of 15.9% (95% CI, 14.3-17.6) for the ADD-RS=0/DD- strategy. In 924 patients with ADD-RS ≤1/DD-, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1) and an efficiency of 49.9% (95% CI, 47.7-52.2) for the ADD-RS ≤1/DD- strategy. CONCLUSIONS: Integration of ADD-RS (either ADD-RS=0 or ADD-RS ≤1) with DD may be considered to standardize diagnostic rule out of AAS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02086136.

Combining High-Sensitivity Cardiac Troponin I and Cardiac Troponin T in the Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Combining 2 signals of cardiomyocyte injury, cardiac troponin I (cTnI) and T (cTnT), might overcome some individual pathophysiological and analytical limitations and thereby increase diagnostic accuracy for acute myocardial infarction with a single blood draw. We aimed to evaluate the diagnostic performance of combinations of high-sensitivity (hs) cTnI and hs-cTnT for the early diagnosis of acute myocardial infarction. METHODS: The diagnostic performance of combining hs-cTnI (Architect, Abbott) and hs-cTnT (Elecsys, Roche) concentrations (sum, product, ratio, and a combination algorithm) obtained at the time of presentation was evaluated in a large multicenter diagnostic study of patients with suspected acute myocardial infarction. The optimal rule-out and rule-in thresholds were externally validated in a second large multicenter diagnostic study. The proportion of patients eligible for early rule-out was compared with the European Society of Cardiology 0/1 and 0/3 hour algorithms. RESULTS: Combining hs-cTnI and hs-cTnT concentrations did not consistently increase overall diagnostic accuracy as compared with the individual isoforms. However, the combination improved the proportion of patients meeting criteria for very early rule-out. With the European Society of Cardiology 2015 guideline recommended algorithms and cut-offs, the proportion meeting rule-out criteria after the baseline blood sampling was limited (6% to 24%) and assay dependent. Application of optimized cut-off values using the sum (9 ng/L) and product (18 ng2/L2) of hs-cTnI and hs-cTnT concentrations led to an increase in the proportion ruled-out after a single blood draw to 34% to 41% in the original (sum: negative predictive value [NPV] 100% [95% confidence interval (CI), 99.5% to 100%]; product: NPV 100% [95% CI, 99.5% to 100%]) and in the validation cohort (sum: NPV 99.6% [95% CI, 99.0-99.9%]; product: NPV 99.4% [95% CI, 98.8-99.8%]). The use of a combination algorithm (hs-cTnI <4 ng/L and hs-cTnT <9 ng/L) showed comparable results for rule-out (40% to 43% ruled out; NPV original cohort 99.9% [95% CI, 99.2-100%]; NPV validation cohort 99.5% [95% CI, 98.9-99.8%]) and rule-in (positive predictive value [PPV] original cohort 74.4% [95% Cl, 69.6-78.8%]; PPV validation cohort 84.0% [95% Cl, 79.7-87.6%]). CONCLUSIONS: New strategies combining hs-cTnI and hs-cTnT concentrations may significantly increase the number of patients eligible for very early and safe rule-out, but do not seem helpful for the rule-in of acute myocardial infarction. CLINICAL TRIAL REGISTRATION: URL (APACE): https://www.clinicaltrial.gov . Unique identifier: NCT00470587. URL (ADAPT): www.anzctr.org.au . Unique identifier: ACTRN12611001069943.

Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI. METHODS: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality. RESULTS: Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L, P<0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 (P<0.0001) and 0.926 (P=0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI (P<0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both P<0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI (P<0.05 for both) and similar to hs-cTnT at predicting death at 3 years. CONCLUSIONS: cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I.

BACKGROUND: Four strategies for very early rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I (hs-cTnI) have been identified. It remains unclear which strategy is most attractive for clinical application. METHODS: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnI levels were measured at presentation and after 1 hour in a blinded fashion. We directly compared all 4 hs-cTnI-based rule-out strategies: limit of detection (LOD, hs-cTnI<2 ng/L), single cutoff (hs-cTnI<5 ng/L), 1-hour algorithm (hs-cTnI<5 ng/L and 1-hour change<2 ng/L), and the 0/1-hour algorithm recommended in the European Society of Cardiology guideline combining LOD and 1-hour algorithm. RESULTS: Among 2828 enrolled patients, acute myocardial infarction was the final diagnosis in 451 (16%) patients. The LOD approach ruled out 453 patients (16%) with a sensitivity of 100% (95% confidence interval [CI], 99.2%-100%), the single cutoff 1516 patients (54%) with a sensitivity of 97.1% (95% CI, 95.1%-98.3%), the 1-hour algorithm 1459 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%), and the 0/1-hour algorithm 1463 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%). Predefined subgroup analysis in early presenters (≤2 hours) revealed significantly lower sensitivity (94.2%, interaction P=0.03) of the single cutoff, but not the other strategies. Two-year survival was 100% with LOD and 98.1% with the other strategies (P<0.01 for LOD versus each of the other strategies). CONCLUSIONS: All 4 rule-out strategies balance effectiveness and safety equally well. The single cutoff should not be applied in early presenters, whereas the 3 other strategies seem to perform well in this challenging subgroup. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Diagnostic value of the cardiac electrical biomarker, a novel ECG marker indicating myocardial injury, in patients with symptoms suggestive of non-ST-elevation myocardial infarction.

BACKGROUND: The cardiac electrical biomarker (CEB) is a novel electrocardiographic (ECG) marker quantifying the dipolar activity of the heart with higher levels indicating myocardial injury. METHODS: We prospectively enrolled 1097 patients presenting with suspected non-ST-elevation myocardial infarction (NSTEMI) to the emergency department (ED). Digital 12-lead ECGs were recorded at presentation and the CEB values were calculated in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 2 years of follow-up. RESULTS: NSTEMI was the final diagnosis in 14% of patients. CEB levels were higher in patients with NSTEMI compared to other causes of chest pain (median 44 (IQR 21-98) vs. 30 (IQR 16-61), p < .001). A weak but significant correlation between levels of high-sensitivity cardiac troponin T (hs-cTnT) at admission to the ED and the CEB was found (r = .23, p < .001). The use of the CEB in addition to conventional ECG criteria improved the diagnostic accuracy for the diagnosis of NSTEMI as quantified by the area under the receiver operating characteristics curve from 0.66 to 0.71 (p < .001) and the sensitivity improved from 43% to 79% (p < .001). CONCLUSION: In conclusion, the CEB, an ECG marker of myocardial injury, significantly improves the accuracy and sensitivity of the ECG for the diagnosis of NSTEMI.

Direct Comparison of 2 Rule-Out Strategies for Acute Myocardial Infarction: 2-h Accelerated Diagnostic Protocol vs 2-h Algorithm.

BACKGROUND: We compared 2 high-sensitivity cardiac troponin (hs-cTn)-based 2-h strategies in patients presenting with suspected acute myocardial infarction (AMI) to the emergency department (ED): the 2-h accelerated diagnostic protocol (2h-ADP) combining hs-cTn, electrocardiogram, and a risk score, and the 2-h algorithm exclusively based on hs-cTn concentrations and their absolute changes. METHODS: Analyses were performed in 2 independent diagnostic cohorts [European Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) study, Australian-New Zealand 2-h Accelerated Diagnostic Protocol to Assess patients with chest Pain symptoms using contemporary Troponins as the only biomarker (ADAPT) study] employing hs-cTnT (Elecsys) and hs-cTnI (Architect). The final diagnosis was adjudicated by 2 independent cardiologists. RESULTS: AMI was the final diagnosis in 16.5% (95% CI, 14.6%-18.6%) of the 1372 patients in APACE, and 12.6% (95% CI, 10.7%-14.7%) of 1153 patients in ADAPT. The negative predictive value (NPV) and sensitivity for AMI were very high and comparable with both strategies using either hs-cTnT or hs-cTnI in both cohorts (all statistical comparisons nonsignificant). The percentage of patients triaged toward rule-out was significantly lower with the 2h-ADP (36%-43%) vs the 2-h algorithm (55%-68%) with both assays and in both cohorts (P < 0.001). The sensitivity of the 2h-ADP was higher for 30-day major adverse cardiovascular events. CONCLUSIONS: Both algorithms provided very high and comparable safety as quantified by the NPV and sensitivity for AMI and major adverse cardiac events (MACE) at 30 days in patients triaged toward rule-out, although sensitivity for MACE at 30 days was lower with both algorithms in cohort 2. Although the 2-h algorithm was more efficacious, not all patients ruled out for AMI by this algorithm were appropriate candidates for early discharge. The 2h-ADP seems superior in the selection of patients for early discharge from the ED. CLINICAL TRIAL REGISTRATION: APACE: http://clinicaltrials.gov/show/NCT00470587ADAPT: Australia-New Zealand Clinical Trials Registry ACTRN12611001069943.

Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction.

AIMS: High-sensitivity cardiac troponin (hs-cTn) assays provide higher diagnostic accuracy for acute myocardial infarction (AMI) when compared with conventional assays, but may result in increased use of unnecessary coronary angiographies due to their increased detection of cardiomyocyte injury in conditions other than AMI. METHODS AND RESULTS: We evaluated the impact of the clinical introduction of high-sensitivity cardiac troponin T (hs-cTnT) on the use of coronary angiography, stress testing, and time to discharge in 2544 patients presenting with symptoms suggestive of AMI to the emergency department (ED) within a multicentre study either before (1455 patients) or after (1089 patients) hs-cTnT introduction. Acute myocardial infarction was more often the clinical discharge diagnosis after hs-cTnT introduction (10 vs. 14%, P < 0.001), while unstable angina less often the clinical discharge diagnosis (14 vs. 9%, P = 0.007). The rate of coronary angiography was similar before and after the introduction of hs-cTnT (23 vs. 23%, P = 0.092), as was the percentage of coronary angiographies showing no stenosis (11 vs. 7%, P = 0.361). In contrast, the use of stress testing was substantially reduced from 29 to 19% (P < 0.001). In outpatients, median time to discharge from the ED decreased by 79 min (P < 0.001). Mean total costs decreased by 20% in outpatients after the introduction of hs-cTnT (P = 0.002). CONCLUSION: The clinical introduction of hs-cTn does not lead to an increased or inappropriate use of coronary angiography. Introduction of hs-cTn is associated with an improved rule-out process and thereby reduces the need for stress testing and time to discharge. CLINICAL TRIAL REGISTRATION INFORMATION: www.clinicaltrials.gov. Identifier, NCT00470587.

One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I.

UNLABELLED: We aimed to prospectively derive and validate a novel 0-/1-hour algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for the early "rule-out" and "rule-in" of acute myocardial infarction (AMI). METHODS: In a prospective multicenter diagnostic study, we enrolled 1,500 patients presenting with suspected AMI to the emergency department. The final diagnosis was centrally adjudicated by 2 independent cardiologists blinded to hs-cTnI concentrations. The hs-cTnI (Siemens Vista) 0-/1-hour algorithm incorporated measurements performed at baseline and absolute changes within 1 hour, was derived in the first 750 patients (derivation cohort), and then validated in the second 750 (validation cohort). RESULTS: Overall, AMI was the final diagnosis in 16% of patients. Applying the hs-cTnI 0-/1-hour algorithm developed in the derivation cohort to the validation cohort, 57% of patients could be classified as "rule-out"; 10%, as "rule-in"; and 33%, as "observe." In the validation cohort, the sensitivity and the negative predictive value for AMI in the "rule-out" zone were 100% (95% CI 96%-100%) and 100% (95% CI 99%-100%), respectively. The specificity and the positive predictive value (PPV) for AMI in the "rule-in" zone were 96% (95% CI 94%-97%) and 70% (95% CI 60%-79%), respectively. Negative predictive value and positive predictive value of the 0-/1-hour algorithm were higher compared to the standard of care combining hs-cTnI with the electrocardiogram (both P < .001). CONCLUSION: The hs-cTnI 0-/1-hour algorithm performs very well for early rule-out as well as rule-in of AMI. The clinical implications are that used in conjunction with all other clinical information, the 0-/1-hour algorithm will be a safe and effective approach to substantially reduce time to diagnosis.

Two-Hour Algorithm for Triage toward Rule-Out and Rule-In of Acute Myocardial Infarction by Use of High-Sensitivity Cardiac Troponin I.

BACKGROUND: The early triage of patients toward rule-out and rule-in of acute myocardial infarction (AMI) is challenging. Therefore, we aimed to develop a 2-h algorithm that uses high-sensitivity cardiac troponin I (hs-cTnI). METHODS: We prospectively enrolled 1435 (derivation cohort) and 1194 (external validation cohort) patients presenting with suspected AMI to the emergency department. The final diagnosis was adjudicated by 2 independent cardiologists. hs-cTnI was measured at presentation and after 2 h in a blinded fashion. We derived and validated a diagnostic algorithm incorporating hs-cTnI values at presentation and absolute changes within the first 2 h. RESULTS: AMI was the final diagnosis in 17% of patients in the derivation and 13% in the validation cohort. The 2-h algorithm developed in the derivation cohort classified 56% of patients as rule-out, 17% as rule-in, and 27% as observation. Resulting diagnostic sensitivity and negative predictive value (NPV) were 99.2% and 99.8% for rule-out; specificity and positive predictive value (PPV) were 95.2% and 75.8% for rule-in. Applying the 2-h algorithm in the external validation cohort, 60% of patients were classified as rule-out, 13% as rule-in, and 27% as observation. Diagnostic sensitivity and NPV were 98.7% and 99.7% for rule-out; specificity and PPV were 97.4% and 82.2% for rule-in. Thirty-day survival was 100% for rule-out patients in both cohorts. CONCLUSIONS: A simple algorithm incorporating hs-cTnI baseline values and absolute 2-h changes allowed a triage toward safe rule-out or accurate rule-in of AMI in the majority of patients.

Diurnal Rhythm of Cardiac Troponin: Consequences for the Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept. METHODS: Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain. RESULTS: In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters. CONCLUSIONS: Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes. CLINICAL TRIAL REGISTRATION: 1. Circadian Variation of Cardiac Troponin, NCT02091427, www.clinicaltrials.gov/ct2/show/NCT02091427. 2. Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) Study, NCT00470587, www.clinicaltrials.gov/ct2/show/NCT00470587.

Diagnostic and prognostic value of ST-segment deviation scores in suspected acute myocardial infarction.

BACKGROUND: Recent advances in digital electrocardiography technology allow evaluating ST-segment deviations in all 12 leads as quantitative variables and calculating summed ST-segment deviation scores. The diagnostic and prognostic utility of summed ST-segment deviation scores is largely unknown. METHODS: We aimed to explore the diagnostic and prognostic utility of the conventional and the modified ST-segment deviation score (Better Analysis of ST-segment Elevations and Depressions in a 12- Lead-ECG-Score (BASEL-Score): sum of elevations in the augmented voltage right - lead (aVR) plus absolute, unsigned ST-segment depressions in the remaining leads) in patients presenting with suspected non-ST-segment elevation myocardial infarction. The diagnostic endpoint was non-ST-segment elevation myocardial infarction, adjudicated by two independent cardiologists. Prognostic endpoint was mortality during two-year follow up. RESULTS: Among 1330 patients, non-ST-segment elevation myocardial infarction was present in 200 (15%) patients. Diagnostic accuracy for non-ST-segment elevation myocardial infarction as quantified by the area under the receiver-operating-characteristics curve was significantly higher for the BASEL-Score (0.73; 95% confidence interval 0.69-0.77) as compared to the conventional ST-segment deviation score (0.53; 95% confidence interval 0.49-0.57, p<0.001). The BASEL-Score provided additional independent diagnostic value to dichotomous electrocardiogram variables (ST-segment depression, T-inversion, both p<0.001) and to high-sensitivity cardiac troponin (p<0.001) as well as clinical judgment at 90 min (p<0.001). Similarly, only the BASEL-Score proved to be an independent predictor of two year mortality. CONCLUSIONS: The modified ST-segment deviation score BASEL-Score focusing on ST-segment elevation in aVR and ST-segment depressions in the remaining leads provides incremental diagnostic and prognostic information.

Gender-specific uncertainties in the diagnosis of acute coronary syndrome.

BACKGROUND: It is unknown whether higher rates of delayed diagnosis and misdiagnosis of acute coronary syndrome (ACS) in women might have contributed to the poorer outcome of women. METHODS: In a prospective diagnostic multicenter study, we recruited patients presenting to the emergency department (ED) with any kind of chest discomfort/chest pain with onset or peak within the last 12 h. We quantified early diagnostic uncertainty for the presence of ACS among treating physicians at the ED after 90 min, possibly responsible for delayed diagnosis, using a visual analogue scale. Late diagnostic uncertainty, possibly responsible for misdiagnosis, was defined as disagreement among two independent cardiologists' adjudication of the final diagnosis after complete work-up. RESULTS: Among 2795 patients (897 women and 1898 men), ACS was the adjudicated final diagnosis in 24 % of women and 35 % of men. Early diagnostic accuracy of clinical judgment of the ED physician for ACS as quantified by the area under the receiver-operating characteristics curve was 0.89 (95 % CI 0.87-0.92) in women and 0.86 (95 % CI 0.85-0.88) in men (p = 0.046). Late diagnostic uncertainty regarding the diagnosis of ACS was 5 % in women and 7 % in men (p = 0.069). CONCLUSION: Diagnostic uncertainty for the presence of ACS in women is not more common as compared to men and does, therefore, not explain the poorer outcome observed in women with ACS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00470587.

Diagnostic and prognostic values of the V-index, a novel ECG marker quantifying spatial heterogeneity of ventricular repolarization, in patients with symptoms suggestive of non-ST-elevation myocardial infarction.

BACKGROUND: The V-index is an ECG marker quantifying spatial heterogeneity of ventricular repolarization. We prospectively assessed the diagnostic and prognostic values of the V-index in patients with suspected non-ST-elevation myocardial infarction (NSTEMI). METHODS: We prospectively enrolled 497 patients presenting with suspected NSTEMI to the emergency department (ED). Digital 12-lead ECGs of five-minute duration were recorded at presentation. The V-index was automatically calculated in a blinded fashion. Patients with a QRS duration >120ms were ruled out from analysis. The final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 24months of follow-up. RESULTS: NSTEMI was the final diagnosis in 14% of patients. V-index levels were higher in patients with AMI compared to other causes of chest pain (median 23ms vs. 18ms, p<0.001). The use of the V-index in addition to conventional ECG-criteria improved the diagnostic accuracy for the diagnosis of NSTEMI as quantified by area under the ROC curve from 0.66 to 0.73 (p=0.001) and the sensitivity of the ECG for AMI from 41% to 86% (p<0.001). Cumulative 24-month mortality rates were 99.4%, 98.4% and 88.3% according to tertiles of the V-index (p<0.001). After adjustment for age and important ECG and clinical parameters, the V-index remained an independent predictor of death. CONCLUSIONS: The V-index, an ECG marker quantifying spatial heterogeneity of ventricular repolarization, significantly improves the accuracy and sensitivity of the ECG for the diagnosis of NSTEMI and independently predicts mortality during follow-up.

Early diagnosis of acute myocardial infarction in patients with mild elevations of cardiac troponin.

BACKGROUND: The early diagnosis of acute myocardial infarction (AMI) in patients with mild elevations of high-sensitivity cardiac troponin (hs-cTn) is a challenge. It is unclear whether copeptin, a marker of endogenous stress, or 1h-hs-cTn changes are better suited to address this important unmet clinical need. METHODS: We prospectively enrolled patients presenting with symptoms suggestive of AMI to the emergency department (ED). Two independent cardiologists adjudicated the final diagnosis. Mild hs-cTn elevations were defined as 26.2 ng/L (99th percentile) to 75 ng/L for hs-cTnI, and 14 ng/L (99th percentile) to 50 ng/L (biological-equivalent to 75 ng/L for hs-cTnI) for hs-cTnT. RESULTS: Among 1356 patients, 80 (6%) had mild hs-cTnI elevations at presentation. Within this group, AMI was the final diagnosis in 39 patients (49%). The diagnostic accuracy for the diagnosis of AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0.51 (95% CI 0.39-0.64) for hs-cTnI at presentation, 0.58 (95% CI 0.45-0.71) for copeptin at presentation, and 0.78 (95% CI 0.68-0.88) for 1h-hs-cTnI changes, which was significantly higher as compared to copeptin (p = 0.02) or hs-cTnI alone (p < 0.001). The additional use of 1h-hs-cTnI changes, but not of copeptin, improved diagnostic accuracy of hs-cTnI at presentation (AUC 0.80, 95% CI 0.70-0.90; p = 0.002 for comparison). Similar findings regarding copeptin and 1h-hs-cTnT/I changes were obtained for mild hs-cTnT elevations. CONCLUSIONS: About 6-22% of patients presenting with suggestive AMI to the ED have mild hs-cTnT/I elevations at presentation. In contrast to copeptin, the addition of 1h-hs-cTn changes substantially improves the early diagnosis of AMI.

Clinical impact of the 2010-2012 low-end shift of high-sensitivity cardiac troponin T.

BACKGROUND: The clinical implications of the 2010-2012 low-end shift of high-sensitivity cardiac troponin T (hs-cTnT) regarding possible misdiagnosis of acute myocardial infarction are largely unknown. METHODS: We aimed to quantify the impact of the 2010-2012 low-end shift and adjustment issue in 857 patients presenting to the emergency department with suspected acute myocardial infarction by comparing measurements performed with affected 2010-2012 lots with recalculated 2010-2012 values using a linear regression formula (provided by the manufacturer) and the corrected assay (re-measured in 2013). The final diagnosis was adjudicated by two independent cardiologists using all information including coronary angiography, echocardiography and serial hs-cTnT levels (with the corrected 2013 assay). RESULTS: Acute myocardial infarction was the adjudicated diagnosis in 195 patients (22.7%). Median hs-TnT values were 8.5 ng/l for affected lots, 11.1 ng/l with recalculated and 10 ng/l with the corrected assay (P<0.001 for all comparisons). Spearman correlation coefficient was 0.937 (<0.001) for correct and affected respective correct and recalculated values. The Cusum test indicated significant deviation from linearity (P<0.01) for both correlations. Deviations nearly exclusively affected hs-cTnT levels below the 99th percentile (14 ng/L). Among the 195 patients with an adjudicated diagnosis of acute myocardial infarction, no patient was misclassified using affected lots if using conventional serial sampling. In contrast, misdiagnosis of acute myocardial infarction was significantly increased by affected lots if applying the novel ESC 0 h/1 h algorithm for the early rule-out of acute myocardial infarction (negative predictive value with affected lots 97.7% versus 99.7% with corrected lots). CONCLUSION: The 2010-2012 hs-cTnT low-end shift affected nearly exclusively levels below the 99th percentile cut-off. While it did not affect the diagnosis of acute myocardial infarction when using conventional serial sampling as done in 2010-2012, it would impact on new early rule-out strategies using very low levels of hs-cTnT such as the ESC 0 h/1 h algorithm. CLINICAL TRIALS REGISTRATION: NCT0047058, NCT00470587.

Characterization of the observe zone of the ESC 2015 high-sensitivity cardiac troponin 0h/1h-algorithm for the early diagnosis of acute myocardial infarction.

OBJECTIVE: The novel high-sensitivity cardiac troponin (hs-cTn) 0h/1h-algorithm substantially improves the early triage of patient's assigned "rule-out" or "rule-in" of acute myocardial infarction (AMI), while diagnostic uncertainty remains in that 25-30% of patients assigned to "observe". We aimed to better characterize these patients. METHODS: In a prospective multicenter diagnostic study, we applied the hs-cTnT 0h/1h-algorithm in 2213 unselected patients presenting with symptoms suggestive of AMI to the emergency department. The final diagnosis was adjudicated by two independent cardiologists using all available information. Survival at 720-days was the prognostic endpoint. Findings were validated using a hs-cTnI 0h/1h-algorithm. RESULTS: Twenty-four percent (n=523) of patients were assigned to "observe" by the hs-cTnT 0h/1h-algorithm. These patients differed significantly in multiple characteristics from "rule-out" and "rule-in" patients: they were older, in 75% male, and very often (57%) had pre-existing coronary artery disease (CAD). Diagnostic uncertainty for the presence of an AMI/UA was high. Only 39% of patients were suitable for coronary computed tomography angiography (CCTA). The most common final adjudicated diagnoses were non-cardiac disease (38%), non-coronary cardiac disease (24%), unstable angina (UA, 21%), and AMI (15%). Absolute hs-cTnT-changes within 3h had the highest diagnostic accuracy for AMI (AUC 0.86). Cumulative 720-day survival rate was 86%, which was significantly lower as compared to "rule-out" (p<0.001) and comparable to "rule-in" (p=ns). Findings were similar for the hs-cTnI "observe" zone. CONCLUSION: "Observe" patients are typically elderly men with pre-existing CAD and high long-term mortality. Absolute hs-cTn-changes within 3h, functional stress imaging and coronary angiography are the key diagnostic modalities.

Clinical Effect of Sex-Specific Cutoff Values of High-Sensitivity Cardiac Troponin T in Suspected Myocardial Infarction.

Importance: It is currently unknown whether the uniform (universal clinical practice for more than 2 decades) or 2 sex-specific cutoff levels are preferable when using high-sensitivity cardiac troponin T (hs-cTnT) levels in the diagnosis of acute myocardial infarction (AMI). Objective: To improve the management of suspected AMI in women by exploring sex-specific vs uniform cutoff levels for hs-cTnT. Design, Setting, and Participants: In an ongoing prospective, diagnostic, multicenter study conducted at 9 emergency departments, the present study evaluated patients enrolled from April 21, 2006, through June 5, 2013. The participants included 2734 adults presenting with suspected AMI. Duration of follow-up was 2 years, and data analysis occurred from June 5 to December 21, 2015. Interventions: The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including measurements of serial hs-cTnT blood concentrations twice: once using the uniform 99th percentile cutoff value level of 14 ng/L and once using sex-specific 99th percentile levels of hs-cTnT (women, 9 ng/L; men, 15.5 ng/L). Main Outcomes and Measures: Diagnostic reclassification in women and men using sex-specific vs the uniform cutoff level in the diagnosis of AMI. Results: Of the 2734 participants, 876 women (32%) and 1858 men (68%) were included. Median (interquartile range) age was 68 (55-77) and 59 (48-71) years, respectively. With the use of the uniform cutoff value, 127 women (14.5%) and 345 men (18.6%) received a final diagnosis of AMI. Among these, at emergency department presentation, levels of hs-cTnT were already above the uniform cutoff value in 427 patients (sensitivity, 91.3% [95% CI, 85%-95.6%] in women vs 90.7% [95% CI, 87.1%-93.5% in men]; specificity, 79.2% [95% CI, 76.1%-82.1%] in women vs 78.5% [95% CI, 76.4%-80.6%] in men). After readjudication using sex-specific 99th percentile levels, diagnostic reclassification regarding AMI occurred in only 3 patients: 0.11% (95% CI, 0.02-0.32) of all patients and 0.6% (95% CI, 0.13-1.85) of patients with AMI. The diagnosis in 2 women was upgraded from unstable angina to AMI, and the diagnosis in 1 man was downgraded from AMI to unstable angina. These diagnostic results were confirmed when using 2 alternative pairs of uniform and sex-specific cutoff values. Conclusions and Relevance: The uniform 99th percentile should remain the standard of care when using hs-cTnT levels for the diagnosis of AMI.