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.

External validation of the 0/1h-algorithm and derivation of a 0/2h-algorithm using a new point-of-care Hs-cTnI assay.

BACKGROUND: The high-sensitivity cardiac troponin (hs-cTn) I point-of-care (POC) hs-cTnI-PATHFAST assay has recently become clinically available. METHODS: We aimed to externally validate the hs-cTnI-PATHFAST 0/1h-algorithm recently developed for the early diagnosis of non-ST-segment-elevation myocardial infarction (NSTEMI) and derive and validate a 0/2-algorithm in patients presenting to the emergency department with acute chest discomfort included in a multicenter diagnostic study. Two independent cardiologists centrally adjudicated the final diagnoses using all the clinical and study-specific information available including serial measurements of hs-cTnI-Architect. RESULTS: Among 1,532 patients (median age 60 years, 33% [n = 501] women), NSTEMI was the final diagnosis in 13%. External validation of the hs-cTnI-PATHFAST 0/1h-algorithm showed very high negative predictive value (NPV; 100% [95%CI, 99.5%-100%]) and sensitivity 100% (95%CI, 98.2%-100%) for rule-out of NSTEMI. Positive predictive value (PPV) and specificity for rule-in of NSTEMI were high (74.9% [95%CI, 68.3%-80.5%] and 96.4% [95%CI, 95.2%-97.3%], respectively). Among 1,207 patients (median age 61 years, 32% [n = 391] women) available for the derivation (n = 848) and validation (n = 359) of the hs-cTnI-PATHFAST 0/2h-algorithm, a 0h-concentration <3 ng/L or a 0h-concentration <4 ng/L with a 2h-delta <4ng/L ruled-out NSTEMI in 52% of patients with a NPV of 100% (95%CI, 98-100) and sensitivity of 100% (95%CI, 92.9%-100%) in the validation cohort. A 0h-concentration ≥90ng/L or a 2h-delta ≥ 55ng/L ruled-in 38 patients (11%): PPV 81.6% (95%CI, 66.6-90.8), specificity 97.7% (95%CI, 95.4-98.9%). CONCLUSIONS: The POC hs-cTnI-PATHFAST assay allows rapid and effective rule-out and rule-in of NSTEMI using both a 0/1h- and a 0/2h-algorithm with high NPV/sensitivity for rule-out and high PPV/specificity for rule-in. CLINICAL TRIAL REGISTRATION: 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 <9ng/L at presentation (if chest pain onset >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.

Hyperacute T Wave in the Early Diagnosis of Acute Myocardial Infarction.

STUDY OBJECTIVE: The diagnostic performance of T-wave amplitudes for the detection of myocardial infarction is largely unknown. We aimed to address this knowledge gap. METHODS: T-wave amplitudes were automatically measured in 12-lead ECGs of patients presenting with acute chest discomfort to the emergency department within a prospective diagnostic multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists. Patients with left ventricular hypertrophy, complete left bundle branch block, or paced ventricular depolarization were excluded. The performance for lead-specific 95th-percentile thresholds were reported as likelihood ratios (lr), specificity, and sensitivity. RESULTS: Myocardial infarction was the final diagnosis in 445 (18%) of 2457 patients. In most leads, T-wave amplitudes tended to be greater in patients without myocardial infarction than those with myocardial infarction, and T-wave amplitude exceeding the 95th percentile had positive and negative lr close to 1 or with confidence intervals (CIs) crossing 1. The exceptions were leads III, aVR, and V1, which had positive lrs of 3.8 (95% CI, 2.7 to 5.3), 4.3 (95% CI, 3.1 to 6.0) and 2.0 (95% CI, 1.4 to 2.9), respectively. These leads normally have inverted T waves, so T-wave amplitude exceeding the 95th percentile reflects upright rather than increased-amplitude hyperacute T waves. CONCLUSION: Hyperacute T waves, when defined as increased T-wave amplitude exceeding the 95th percentile, did not provide useful information in diagnosing myocardial infarction in this sample.

International Validation of the Canadian Syncope Risk Score : A Cohort Study.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes not evident during emergency department (ED) evaluation. OBJECTIVE: To externally validate the CSRS and compare it with another validated score, the Osservatorio Epidemiologico della Sincope nel Lazio (OESIL) score. DESIGN: Prospective cohort study. SETTING: Large, international, multicenter study recruiting patients in EDs in 8 countries on 3 continents. PARTICIPANTS: Patients with syncope aged 40 years or older presenting to the ED within 12 hours of syncope. MEASUREMENTS: Composite outcome of serious clinical plus procedural events (primary outcome) and the primary composite outcome excluding procedural interventions (secondary outcome). RESULTS: Among 2283 patients with a mean age of 68 years, the primary composite outcome occurred in 7.2%, and the composite outcome excluding procedural interventions occurred in 3.1% at 30 days. Prognostic performance of the CSRS was good for both 30-day composite outcomes and better compared with the OESIL score (area under the receiver-operating characteristic curve [AUC], 0.85 [95% CI, 0.83 to 0.88] vs. 0.74 [CI, 0.71 to 0.78] and 0.80 [CI, 0.75 to 0.84] vs. 0.69 [CI, 0.64 to 0.75], respectively). Safety of triage, as measured by the frequency of the primary composite outcome in the low-risk group, was higher using the CSRS (19 of 1388 [0.6%]) versus the OESIL score (17 of 1104 [1.5%]). A simplified model including only the clinician classification of syncope (cardiac syncope, vasovagal syncope, or other) variable at ED discharge-a component of the CSRS-achieved similar discrimination as the CSRS (AUC, 0.83 [CI, 0.80 to 0.87] for the primary composite outcome). LIMITATION: Unable to disentangle the influence of other CSRS components on clinician classification of syncope at ED discharge. CONCLUSION: This international external validation of the CSRS showed good performance in identifying patients at low risk for serious outcomes outside of Canada and superior performance compared with the OESIL score. However, clinician classification of syncope at ED discharge seems to explain much of the performance of the CSRS in this study. The clinical utility of the CSRS remains uncertain. PRIMARY FUNDING SOURCE: Swiss National Science Foundation & Swiss Heart Foundation.

Performance of the ESC 0/2h-algorithm using high-sensitivity cardiac troponin I in the early diagnosis of myocardial infarction.

The 2020 guidelines of the European Society of Cardiology (ESC) recommend a novel ESC 0/2h-algorithm as the preferred alternative to the ESC 0/1h-algorithm in the early triage for rule-out and/or rule-in of Non-ST-segment-elevation myocardial infarction (NSTEMI). The aim was to prospectively validate the performance of the ESC 0/2h-algorithm using the high-sensitivity cardiac troponin I (hs-cTnI) assay (ARCHITECT) in an international, multicenter diagnostic study enrolling patients presenting with acute chest discomfort to the emergency department.

Socio-Demographic Health Determinants Are Associated with Poor Prognosis in Spanish Patients Hospitalized with COVID-19.

INTRODUCTION: Social vulnerability is a known determinant of health in respiratory diseases. Our aim was to identify whether there are socio-demographic factors among COVID-19 patients hospitalized in Spain and their potential impact on health outcomes during the hospitalization. METHODS: A multicentric retrospective case series study based on administrative databases that included all COVID-19 cases admitted in 19 Spanish hospitals from 1 March to 15 April 2020. Socio-demographic data were collected. Outcomes were critical care admission and in-hospital mortality. RESULTS: We included 10,110 COVID-19 patients admitted to 18 Spanish hospitals (median age 68 (IQR 54-80) years old; 44.5% female; 14.8% were not born in Spain). Among these, 779 (7.7%) cases were admitted to critical care units and 1678 (16.6%) patients died during the hospitalization. Age, male gender, being immigrant, and low hospital saturation were independently associated with being admitted to an intensive care unit. Age, male gender, being immigrant, percentile of average per capita income, and hospital experience were independently associated with in-hospital mortality. CONCLUSIONS: Social determinants such as residence in low-income areas and being born in Latin American countries were associated with increased odds of being admitted to an intensive care unit and of in-hospital mortality. There was considerable variation in outcomes between different Spanish centers.

Incidence, characteristics, determinants, and prognostic impact of recurrent syncope.

AIMS: The aim of this study is to characterize recurrent syncope, including sex-specific aspects, and its impact on death and major adverse cardiovascular events (MACE). METHODS AND RESULTS: We characterized recurrent syncope in a large international multicentre study, enrolling patients ≥40 years presenting to the emergency department (ED) with a syncopal event within the last 12 h. Syncope aetiology was centrally adjudicated by two independent cardiologists using all information becoming available during syncope work-up and long-term follow-up. Overall, 1790 patients were eligible for this analysis. Incidence of recurrent syncope was 20% [95% confidence interval (CI) 18-22%] within the first 24 months. Patients with an adjudicated final diagnosis of cardiac syncope (hazard ratio (HR) 1.50, 95% CI 1.11-2.01) or syncope with an unknown aetiology even after central adjudication (HR 2.11, 95% CI 1.54-2.89) had an increased risk for syncope recurrence. Least Absolute Shrinkage and Selection Operator regression fit on all patient information available early in the ED identified >3 previous episodes of syncope as the only independent predictor for recurrent syncope (HR 2.13, 95% CI 1.64-2.75). Recurrent syncope carried an increased risk for death (HR 1.87, 95% CI 1.26-2.77) and MACE (HR 2.69, 95% CI 2.02-3.59) over 24 months of follow-up, however, with a time-dependent effect. These findings were confirmed in a sensitivity analysis excluding patients with syncope recurrence or MACE before or during ED evaluation. CONCLUSION: Recurrence rates of syncope are substantial and vary depending on syncope aetiology. Importantly, recurrent syncope carries a time-dependent increased risk for death and MACE. TRIAL REGISTRATION: BAsel Syncope EvaLuation (BASEL IX, ClinicalTrials.gov registry number NCT01548352).

0/1-Hour Triage Algorithm for Myocardial Infarction in Patients With Renal Dysfunction.

BACKGROUND: The European Society of Cardiology recommends a 0/1-hour algorithm for rapid rule-out and rule-in of non-ST-segment elevation myocardial infarction using high-sensitivity cardiac troponin (hs-cTn) concentrations irrespective of renal function. Because patients with renal dysfunction (RD) frequently present with increased hs-cTn concentrations even in the absence of non-ST-segment elevation myocardial infarction, concern has been raised regarding the performance of the 0/1-hour algorithm in RD. METHODS: In a prospective multicenter diagnostic study enrolling unselected patients presenting with suspected non-ST-segment elevation myocardial infarction to the emergency department, we assessed the diagnostic performance of the European Society of Cardiology 0/1-hour algorithm using hs-cTnT and hs-cTnI in patients with RD, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2, and compared it to patients with normal renal function. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including cardiac imaging. Safety was quantified as sensitivity in the rule-out zone, accuracy as the specificity in the rule-in zone, and efficacy as the proportion of the overall cohort assigned to either rule-out or rule-in based on the 0- and 1-hour sample. RESULTS: Among 3254 patients, RD was present in 487 patients (15%). The prevalence of non-ST-segment elevation myocardial infarction was substantially higher in patients with RD compared with patients with normal renal function (31% versus 13%, P<0.001). Using hs-cTnT, patients with RD had comparable sensitivity of rule-out (100.0% [95% confidence interval {CI}, 97.6-100.0] versus 99.2% [95% CI, 97.6-99.8]; P=0.559), lower specificity of rule-in (88.7% [95% CI, 84.8-91.9] versus 96.5% [95% CI, 95.7-97.2]; P<0.001), and lower overall efficacy (51% versus 81%, P<0.001), mainly driven by a much lower percentage of patients eligible for rule-out (18% versus 68%, P<0.001) compared with patients with normal renal function. Using hs-cTnI, patients with RD had comparable sensitivity of rule-out (98.6% [95% CI, 95.0-99.8] versus 98.5% [95% CI, 96.5-99.5]; P=1.0), lower specificity of rule-in (84.4% [95% CI, 79.9-88.3] versus 91.7% [95% CI, 90.5-92.9]; P<0.001), and lower overall efficacy (54% versus 76%, P<0.001; proportion ruled out, 18% versus 58%, P<0.001) compared with patients with normal renal function. CONCLUSIONS: In patients with RD, the safety of the European Society of Cardiology 0/1-hour algorithm is high, but specificity of rule-in and overall efficacy are decreased. Modifications of the rule-in and rule-out thresholds did not improve the safety or overall efficacy of the 0/1-hour algorithm. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Clinical Use of a New High-Sensitivity Cardiac Troponin I Assay in Patients with Suspected Myocardial Infarction.

BACKGROUND: We aimed to validate the clinical performance of the high-sensitivity cardiac troponin I [VITROS® Immunodiagnostic Products hs Troponin I (hs-cTnI-VITROS)] assay. METHODS: We enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by 2 independent cardiologists considering all clinical information, including cardiac imaging: first, using serial hs-cTnT-Elecsys (primary analysis) and, second, using hs-cTnI-Architect (secondary analysis) measurements in addition to the clinically used (hs)-cTn. hs-cTnI-VITROS was measured at presentation and at 1 h in a blinded fashion. The primary objective was direct comparison of diagnostic accuracy as quantified by the area under the ROC curve (AUC) of hs-cTnI-VITROS vs hs-cTnT-Elecsys and hs-cTnI-Architect, and in a subgroup also hs-cTnI-Centaur and hs-cTnI-Access. Secondary objectives included the derivation and validation of an hs-cTnI-VITROS-0/1-h algorithm. RESULTS: AMI was the adjudicated final diagnosis in 158 of 1231 (13%) patients. At presentation, the AUC for hs-cTnI-VITROS was 0.95 (95% CI, 0.93-0.96); for hs-cTnT-Elecsys, 0.94 (95% CI, 0.92-0.95); and for hs-cTnI-Architect, 0.92 (95% CI, 0.90-0.94). AUCs for hs-cTnI-Centaur and hs-cTnI-Access were 0.95 (95% CI, 0.94-0.97). Applying the derived hs-cTnI-VITROS-0/1-h algorithm (derivation cohort n = 519) to the validation cohort (n = 520), 53% of patients were ruled out [sensitivity, 100% (95% CI, 94.1-100)] and 14% of patients were ruled in [specificity, 95.6% (95% CI, 93.4-97.2)]. Patients ruled out by the 0/1-h algorithm had a survival rate of 99.8% at 30 days. Findings were confirmed in the secondary analyses using the adjudication including serial measurements of hs-cTnI-Architect. CONCLUSIONS: The hs-cTnI-VITROS assay has at least comparable diagnostic accuracy with the currently best validated hs-cTnT and hs-cTnI assays. CLINICALTRIALSGOV IDENTIFIER: NCT00470587.

High-Sensitivity Cardiac Troponin I Assay for Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: The aim of this study was to validate the clinical performance of the Beckman Access high-sensitivity cardiac troponin I (hs-cTnI) assay. METHODS: We enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by 2 independent cardiologists with all clinical information including cardiac imaging twice: first, using serial hs-cTnT (Elecsys, primary analysis), and second, using hs-cTnI (Architect, secondary analysis) measurements in addition to the clinically used hs-cTn. hs-cTnI Access was measured at presentation and at 1 h. The primary objective was a direct comparison of diagnostic accuracy as quantified by the area under the ROC curve (AUC) of hs-cTnI Access vs the hs-cTnT Elecsys and hs-cTnI Architect assays. Secondary objectives included the derivation and validation of an hs-cTnI Access-specific 0/1-h algorithm. RESULTS: AMI was the adjudicated final diagnosis in 243 of 1579 (15.4%) patients. The AUC at presentation for hs-cTnI Access was 0.95 (95% CI, 0.94-0.96), higher than hs-cTnI Architect [0.92 (95% CI, 0.91-0.94; P < 0.001)] and comparable to hs-cTnT Elecsys [0.94 (95% CI, 0.93-0.95; P = 0.12)]. Applying the derived hs-cTnI Access 0/1-h algorithm (derivation cohort n = 686) to the validation cohort (n = 680), 60% of patients were ruled out [sensitivity, 98.9% (95% CI, 94.3-99.8)], and 15% of patients were ruled in [specificity, 95.9% (95% CI, 94.0-97.2)]. Patients ruled out by the 0/1-h algorithm had a survival rate of 100% at 30 days. Findings were confirmed in the secondary analyses by the adjudication including serial measurements of Architect hs-cTnI. CONCLUSIONS: Diagnostic accuracy and clinical utility of the Beckman hs-cTnI Access assay are very high and at least comparable to Roche hs-cTnT and Abbott hs-cTnI assays. ClinicalTrials.gov Identifier: NCT00470587.

Predicting Acute Myocardial Infarction with a Single Blood Draw.

BACKGROUND: We desired to determine cardiac troponin (cTn) concentrations necessary to achieve a positive predictive value (PPV) of ≥75% for acute myocardial infarction (AMI) to justify immediate admission of patients to a monitored unit and, in general, early coronary angiography. METHODS: In a prospective multicenter diagnostic study enrolling patients presenting to the emergency department with symptoms suggestive of AMI, final diagnoses were adjudicated by 2 independent cardiologists based on clinical information including cardiac imaging. cTn concentrations were measured using 5 different sensitive and high-sensitivity cTn (hs-cTn) assays in a blinded fashion at presentation and serially thereafter. The diagnostic end point was PPV for rule-in of AMI of initial cTn concentrations alone and in combination with early changes. RESULTS: Among 3828 patients, 616 (16%) had an AMI. At presentation, 7% to 14% of patients had cTnT/I concentrations associated with a PPV of ≥75%. Adding absolute or relative changes did not significantly further increase the PPV. PPVs increased from 46.5% (95% CI, 43.6-49.4) for hs-cTnT at presentation >14 ng/L to 78.9% (95% CI, 74.7-82.5) for >52 ng/L (P < 0.001), whereas PPVs in higher hs-cTnT strata remained largely unchanged [e.g., 82.4% (95% CI, 77.5-86.7) for >80 ng/L vs 83.9% (95% CI, 76.0-90.1) for >200 ng/L (P = 0.72)]. The addition of early changes in hs-cTnT further increased the PPV up to 60 ng/L, but not for higher concentrations. CONCLUSIONS: Serial sampling does not seem necessary for predicting AMI and concurrent decision-making in about 10% of patients, as it only marginally increases the PPV for AMI and not in a statistically or clinically significant way. CLINICALTRIALSGOV IDENTIFIER: NCT00470587.

Circadian, weekly, seasonal, and temperature-dependent patterns of syncope aetiology in patients at increased risk of cardiac syncope.

AIMS: It is unknown whether cardiac syncope, and possibly also other syncope aetiologies exhibit circadian, weekly, seasonal, and temperature-dependent patterns. METHODS AND RESULTS: We prospectively recorded the exact time, date, and outside temperature of syncope of patients >40 years old presenting with syncope to the emergency department in a diagnostic multicentre study. Two independent cardiologists/emergency physicians adjudicated the final diagnosis based on all information becoming available during clinical work-up including 1-year follow-up. Among 1230 patients, the adjudicated aetiology was cardiac in 14.6%, reflex in 39.2%, orthostatic in 25.7%, other non-cardiac in 9.7%, and unknown in 10.8% of patients. All syncope aetiologies occurred much more frequently during the day when compared with the night (P < 0.01). While reflex and orthostatic syncope showed a broad peak of prevalence with 80.9% of these events occurring between 4 am and 4 pm, cardiac syncope showed a narrow peak of prevalence with 70.1% of all events occurring between 8 am and 2 pm. A weekly pattern was present for most syncope aetiologies, with events occurring mainly from Monday to Friday (P < 0.01). Reflex syncope displayed a seasonal rhythm and was more common in winter (P < 0.01), while cardiac syncope stayed constant over the year. Syncope occurred most often when the outside temperature was coldest. Overall the patterns observed for cardiac syncope were similar to the patterns observed for its differential diagnosis. CONCLUSION: Syncope aetiologies in patients >40 years old display circadian, weekly, seasonal, and temperature-dependent patterns. Unfortunately, these patterns do not allow to reliably differentiate cardiac syncope from other aetiologies.

Indications and practical approach to non-invasive ventilation in acute heart failure.

In acute heart failure (AHF) syndromes significant respiratory failure (RF) is essentially seen in patients with acute cardiogenic pulmonary oedema (ACPE) or cardiogenic shock (CS). Non-invasive ventilation (NIV), the application of positive intrathoracic pressure through an interface, has shown to be useful in the treatment of moderate to severe RF in several scenarios. There are two main modalities of NIV: continuous positive airway pressure (CPAP) and pressure support ventilation (NIPSV) with positive end expiratory pressure. Appropriate equipment and experience is needed for NIPSV, whereas CPAP may be administered without a ventilator, not requiring special training. Both modalities have shown to be effective in ACPE, by a reduction of respiratory distress and the endotracheal intubation rate compared to conventional oxygen therapy, but the impact on mortality is less conclusive. Non-invasive ventilation is also indicated in patients with AHF associated to pulmonary disease and may be considered, after haemodynamic stabilization, in some patients with CS. There are no differences in the outcomes in the studies comparing both techniques, but CPAP is a simpler technique that may be preferred in low-equipped areas like the pre-hospital setting, while NIPSV may be preferable in patients with significant hypercapnia. The new modality 'high-flow nasal cannula' seems promising in cases of AHF with less severe RF. The correct selection of patients and interfaces, early application of the technique, the achievement of a good synchrony between patients and the ventilator avoiding excessive leakage, close monitoring, proactive management, and in some cases mild sedation, may warrant the success of the technique.

Impact of age on the performance of the ESC 0/1h-algorithms for early diagnosis of myocardial infarction.

Aims: We aimed to evaluate the impact of age on the performance of the European Society of Cardiology (ESC) 0/1h-algorithms and to derive and externally validate alternative cut-offs specific to older patients. Methods and results: We prospectively enrolled patients presenting to the emergency department (ED) with symptoms suggestive of acute myocardial infarction in three large diagnostic studies. Final diagnoses were adjudicated by two independent cardiologists. High-sensitivity cardiac troponin (hs-cTn) T and I concentrations were measured at presentation and after 1 h. Patients were stratified according to age [<55 years (young), ≥55 to <70 years (middle-age), ≥70 years (old)]. Rule-out safety of the ESC hs-cTnT 0/1h-algorithm was very high in all age-strata: sensitivity 100% [95% confidence interval (95% CI) 94.9-100] in young, 99.3% (95% CI 96.0-99.9) in middle-age, and 99.3% (95% CI 97.5-99.8) in old patients. Accuracy of rule-in decreased with age: specificity 97.0% (95% CI 95.8-97.9) in young, 96.1% (95% CI 94.5-97.2) in middle-age, and 92.7% (95% CI 90.7-94.3) in older patients. Triage efficacy decreased with increasing age (young 93%, middle-age 80%, old 55%, P < 0.001). Similar results were found for the ESC hs-cTnT 0/1h-algorithm. Alternative, slightly higher cut-off concentrations optimized for older patients maintained very high safety of rule-out, increased specificity of rule-in (P < 0.01), reduced overall efficacy for hs-cTnT (P < 0.01), while maintaining efficacy for hs-cTnI. Findings were confirmed in two validation cohorts (n = 2767). Conclusion: While safety of the ESC 0/1h-algorithms remained very high, increasing age significantly reduced overall efficacy and the accuracy of rule-in. Alternative slightly higher cut-off concentrations may be considered for older patients, particularly if using hs-cTnI. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587 and NCT02355457 (BACC).

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.

Effect of Acute Coronary Syndrome Probability on Diagnostic and Prognostic Performance of High-Sensitivity Cardiac Troponin.

BACKGROUND: There is concern that high-sensitivity cardiac troponin (hs-cTn) may have low diagnostic accuracy in patients with low acute coronary syndrome (ACS) probability. METHODS: We prospectively stratified patients presenting with acute chest discomfort to the emergency department (ED) into 3 groups according to their probability for ACS as assessed by the treating ED physician using a visual analog scale: ≤10%, 11% to 79%, and ≥80%, reviewing all information available at 90 min. hs-cTnT and hs-cTnI concentrations were determined in a blinded fashion. Two independent cardiologists adjudicated the final diagnosis. RESULTS: Among 3828 patients eligible for analysis, 1189 patients had low (≤10%) probability for ACS. The incidence of non-ST-segment elevation myocardial infarction (NSTEMI) increased from 1.3% to 12.2% and 54.8% in patients with low, intermediate, and high ACS probability, respectively. The positive predictive value of hs-cTnT and hs-cTnI was low in patients with low ACS probability and increased with the incidence of NSTEMI, whereas the diagnostic accuracy of hs-cTnT and hs-cTnI for NSTEMI as quantified by the area under the curve (AUC) was very high and comparable among all 3 strata, e.g., AUC hs-cTnI, 0.96 (95% CI, 0.94-0.97); 0.87 (95% CI, 0.85-0.89); and 0.89 (95% CI, 0.87-0.92), respectively. Findings were validated using bootstrap analysis as an alternative methodology to define ACS probability. Similarly, higher hs-cTnT/I concentrations independently predicted all-cause mortality within 2 years (e.g., hs-cTnT hazard ratio, 1.39; 95% CI, 1.27-1.52), irrespective of ACS probability. CONCLUSIONS: Diagnostic and prognostic accuracy and utility of hs-cTnT and hs-cTnI remain high in patients with acute chest discomfort and low ACS probability.ClinicalTrials.gov Identifier: NCT00470587.

Clinical Validation of a Novel High-Sensitivity Cardiac Troponin I Assay for Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Clinical performance of the novel high-sensitivity cardiac troponin I (Siemens-hs-cTnI-Centaur) assay is unknown. We aimed to clinically validate the Siemens-hs-cTnI-Centaur assay and develop 0/1-h and 0/2-h algorithms. METHODS: We enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by 2 independent cardiologists including all clinical information twice: first, using serial hs-cTnT (Roche-Elecsys, primary analysis); second, using hs-cTnI (Abbott-Architect, secondary analysis) measurements in addition to the clinically applied (hs)-cTn. Siemens-hs-cTnI-Centaur was measured at presentation, 1 h, and 2 h. The primary objective was a direct comparison of diagnostic accuracy, quantified by the area under the ROC curve (AUC), of Siemens-hs-cTnI-Centaur vs the 2 established hs-cTn assays (Roche-hs-cTnT-Elecsys, Abbott-hs-cTnI-Architect). Secondary objectives included the development of Siemens-hs-cTnI-Centaur-specific 0/1-h and 0/2-h algorithms. RESULTS: AMI was the final diagnosis in 318 of 1755 (18%) patients (using Roche-hs-cTnT-Elecsys for adjudication). The AUC at presentation for Siemens-hs-cTnI-Centaur was 0.94 (95% CI, 0.92-0.96) and comparable with 0.95 (95% CI, 0.93-0.97) for Roche-hs-cTnT-Elecsys and 0.93 (95% CI, 0.90-0.96) for Abbott-hs-cTnI-Architect. Applying the derived Siemens-hs-cTnI-Centaur 0/1-h algorithm to the validation cohort, 46% of patients were ruled out (sensitivity, 99.1%; 95% CI, 95.3-100), and 18% of patients were ruled in (specificity, 94.1%; 95% CI, 91.8-95.9). The Siemens-hs-cTnI-Centaur 0/2-h algorithm ruled out 55% of patients (sensitivity, 100%; 95% CI, 94.1-100), and ruled in 18% of patients (specificity, 96.0%; 95% CI, 93.1-97.9). Findings were confirmed in the secondary analyses using serial measurements of Abbott-hs-cTnI-Architect for adjudication. CONCLUSIONS: Diagnostic accuracy and clinical utility of the novel Siemens-hs-cTnI-Centaur assay are high and comparable with the established hs-cTn assays. ClinicalTrials.gov Identifier: NCT00470587.