Application of High-Sensitivity Troponin in Suspected Myocardial Infarction.

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

Comparison of four decision aids for the early diagnosis of acute coronary syndromes in the emergency department.

OBJECTIVES: To directly compare the diagnostic accuracy of four decision aids (Troponin-only Manchester Acute Coronary Syndromes (T-MACS), History, ECG, Age, Risk factors and Troponin (HEART), Thrombolysis in Myocardial Infarction (TIMI) and Emergency Department Assessment of Chest Pain (EDACS)) used to expedite the early diagnosis of acute coronary syndromes (ACS) in the ED. METHODS: We prospectively included patients who presented to 14 EDs in England (February 2015 to June 2017) with suspected ACS within 12 hours of symptom onset. Data to enable evaluation of the T-MACS, HEART, TIMI and EDACS decision aids (without recalibration) were prospectively collected, blinded to patient outcome. We tested admission blood samples for high-sensitivity cardiac troponin I (hs-cTnI; Siemens ADVIA Centaur). Patients also underwent serial cardiac troponin testing over 3-12 hours. The target condition was an adjudicated diagnosis of acute myocardial infarction (AMI). We also evaluated the incidence of major adverse cardiac events (including death, AMI or coronary revascularisation) at 30 days. Diagnostic accuracy of each decision aid and hs-cTnI alone (using the limit of quantification cut-off, 3 ng/L) was evaluated by calculating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Of 999 included patients, 132 (13.2%) had AMI. C-statistics were 0.96 for T-MACS, 0.78 for HEART and 0.69 for TIMI. The sensitivities of T-MACS, HEART, TIMI, EDACS and hs-cTnI <3 ng/L for AMI were 99.2% (95% CI 95.7% to 100.0%), 91.8% (85.0% to 96.2%), 97.5% (92.9% to 99.5%), 96.2% (92.2% to 99.4%) and 99.2% (95.9% to 100.0%), respectively. The respective strategies would have ruled out 46.5%, 34.9%, 19.4%, 48.3% and 28.8% patients. PPVs for the decision aids that identify 'high-risk' patients were 80.4% (T-MACS), 51.9% (TIMI) and 37.2% (HEART). CONCLUSIONS: In this study, T-MACS could rule out AMI in 46.5% patients with 99.2% sensitivity. EDACS could rule out AMI in 48.3% patients with lower sensitivity, although the difference was not statistically significant. The HEART and TIMI scores had lower diagnostic accuracy.

Diagnostic accuracy of the Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid with a point-of-care cardiac troponin assay.

OBJECTIVE: Point-of-care (POC) cardiac troponin (cTn) assays have a rapid turnaround time but are generally less sensitive than laboratory-based assays. Previous research found that the Abbott i-Stat cardiac troponin I (cTnI) assay has good diagnostic accuracy when used with the Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid and serial sampling over 3 hours. Accuracy of other assays may differ. We therefore evaluated the diagnostic accuracy of a different POC cTnI assay with serial sampling over 3 hours, both with T-MACS and when used alone. METHODS: In a prospective diagnostic accuracy study at eight EDs in England (July 2015-October 2017), we collected clinical data from consenting adults with suspected ACS at the time of assessment in the ED. Blood samples were drawn on arrival and 3 hours later for POC cTnI (Cardio 3 Triage, Alere). The target condition was an adjudicated diagnosis of acute myocardial infarction (AMI), based on reference standard serial laboratory-based cTn testing. We calculated test characteristics for POC cTnI using the limit of detection (LoD, 0.01 µg/L) and the T-MACS decision aid. RESULTS: Of 347 participants, 59 (14.9%) had AMI. With serial POC cTnI testing over 3 hours, POC cTnI at the LoD cut-off ruled out AMI in 193 (55.6%) patients with 98.1% sensitivity (95% CI 89.9% to 100.0%) and 99.5% negative predictive value (NPV, 95% CI 96.5% to 99.9%). T-MACS ruled out AMI in 117 (33.7%) patients with 98.1% sensitivity (95% CI 89.9% to 100%) and 99.2% NPV (95% CI 94.3% to 99.9%). T-MACS ruled in AMI with 97.9% specificity (95% CI 95.8% to 99.5%) and 83.7% positive predictive value (95% CI 70.6% to 91.7%). CONCLUSIONS: With serial sampling over 3 hours, the Alere Cardio 3 Triage cTnI assay has relatively high NPV for AMI using either the LoD cut-off alone or the T-MACS decision aid. However, wide CIs around the measures of diagnostic accuracy mean that further prospective testing of this strategy is required before clinical implementation. TRIAL REGISTRATION NUMBER: UKCRN 18000.

Diagnostic Accuracy of a High-Sensitivity Cardiac Troponin Assay with a Single Serum Test in the Emergency Department.

OBJECTIVES: We sought to evaluate diagnostic accuracy of a high-sensitivity cardiac troponin I (hs-cTnI) assay for acute coronary syndromes (ACS) in the emergency department (ED). The assay has high precision at low concentrations and can detect cTnI in 96.8% of healthy individuals. METHODS: In successive prospective multicenter studies ("testing" and "validation"), we included ED patients with suspected ACS. We drew blood for hs-cTnI [Singulex Clarity® cTnI; 99th percentile, 8.67 ng/L; limit of detection (LoD), 0.08 ng/L] on arrival. Patients also underwent hs-cTnT (Roche Elecsys) testing over ≥3 h. The primary outcome was an adjudicated diagnosis of ACS, defined as acute myocardial infarction (AMI; prevalent or incident), death, or revascularization within 30 days. RESULTS: The testing and validation studies included 665 and 2470 patients, respectively, of which 94 (14.1%) and 565 (22.9%) had ACS. At a 1.5-ng/L cutoff, hs-cTnI had good sensitivity for AMI in both studies (98.7% and 98.1%, respectively) and would have "ruled out" 40.1% and 48.9% patients. However, sensitivity was lower for ACS (95.7% and 90.6%, respectively). At a 0.8-ng/L cutoff, sensitivity for ACS was higher (97.5% and 97.9%, ruling out 28.6% patients in each cohort). The hs-cTnT assay had similar performance at the LoD (24.6% ruled out; 97.2% sensitivity for ACS). CONCLUSIONS: The hs-cTnI assay could immediately rule out AMI in 40% of patients and ACS in >25%, with similar accuracy to hs-cTnT at the LoD. Because of its high precision at low concentrations, this hs-cTnI assay has favorable characteristics for this clinical application.

Optimising antiplatelet utilisation in the acute care setting: a novel threshold for medical intervention in suspected acute coronary syndromes.

OBJECTIVES: To construct a model to optimise and personalise recommendations for antiplatelet prescription for patients with suspected acute coronary syndrome (ACS). Acknowledging that emergency physicians work with diagnostic uncertainty, we sought to identify the point at which the probability of ACS is sufficiently high that the benefits of antiplatelet treatment outweigh the risks. Second, we evaluated the projected clinical impact of this approach by using a clinical prediction model (Troponin-only Manchester Acute Coronary Syndromes (T-MACS)) to calculate the probability of ACS. METHODS: We conducted three systematic reviews, quantifying the effects of ticagrelor, clopidogrel or aspirin-alone treatment strategies for ACS (November 2017). We extracted data for (a) clinical outcomes and (b) weighted patient preferences (utilities) for each outcome. We then constructed utilitarian models, simulating the probability of clinical outcomes with different treatment strategies. This identified the threshold probability of ACS at which each treatment strategy became superior.We validated this approach in a prospective diagnostic study including patients with suspected ACS that was conducted at two large UK teaching hospitals (St George's Hospital London recruited October 2015 to June 2017 and Manchester Royal Infirmary: February 2015 to August 2017). We calculated the probability of ACS using T-MACS. The diagnosis of ACS was adjudicated based on serial high-sensitivity troponin testing and 30-day follow-up. RESULTS: We constructed three models using data from six studies. Prescribing ticagrelor had greatest overall benefit when the probability of ACS exceeded 8.0%. Below that threshold, aspirin alone yielded greater benefit. The validation study included 660 patients, of which 87 (13.2%) had ACS. Prescription of combined antiplatelet strategy to patients with >8% probability of ACS had greater utility than aspirin alone. CONCLUSION: Treatment with ticagrelor appears to yield greater net benefit for patients when the probability of ACS >8%. The clinical and cost-effectiveness of this 'precision medicine' approach warrants further study.

BET 1: IN PATIENTS WITH SUSPECTED ACUTE CORONARY SYNDROME, DOES WELLENS' SIGN ON THE ELECTROCARDIOGRAPH IDENTIFY CRITICAL LEFT ANTERIOR DESCENDING ARTERY STENOSIS?

Wellens' syndrome consists of a history suggestive of an acute coronary syndrome and biphasic or deeply inverted T waves in ECG leads V2-V3. A shortcut review was carried out to establish whether this ECG pattern identifies patients with a critical left anterior descending artery stenosis. Six relevant papers were found. The clinical bottom line is that biphasic T-wave inversion in lead V2-V3 should alert the clinician to a probable critical stenosis of the left anterior descending artery.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Is ST elevation in aVR a sure sign of left main coronary artery stenosis?

A shortcut review was carried out to establish whether ST elevation in aVR accurately identifies acute myocardial infarction caused by left main coronary artery stenosis. 141 unique papers were found in Medline, EMBASE, Cochrane Database of Systematic Reviews, ACP Journal Club and the Database of Abstracts of Reviews of Effects using the reported searches. Of these, 12 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that ST elevation in aVR can identify high-risk patients for early intensive investigation, particularly when found alongside widespread ST depression. It has insufficient utility to identify patients who require immediate revascularisation.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Which form of aspirin is the fastest to inhibit platelet aggregation in emergency department patients with non-ST segment elevation myocardial infarction?

A short cut review was carried out to establish whether, in patients with suspected acute coronary syndromes presenting to the emergency department, what form of aspirin has the most rapid onset of action. Papers comparing the speed of onset of chewable aspirin, or soluble aspirin or solid aspirin were included. This summarises all three parts of a combined best evidence topic report (BET). The clinical bottom line is that chewable aspirin may be faster than soluble aspirin at decreasing the amount of time to achieve platelet inhibition in a patient. Soluble aspirin is faster than whole solid aspirin, which is faster than enteric-coated aspirin.

Diagnostic accuracy of a high-sensitivity troponin I assay and external validation of 0/3 h rule out strategies.

AIMS: The timely diagnosis and exclusion of acute coronary syndromes in the Emergency Department (ED) remains a challenge. This study aims to evaluate the diagnostic accuracy of a high-sensitivity cardiac troponin I assay (Siemens TNIH) on serial sampling for ED patients as standalone test and in rule-out algorithms as recommendations remain assay specific. METHODS AND RESULTS: This secondary analysis from a prospective diagnostic accuracy study at 14 centres included ED patients presenting with chest pain of suspected cardiac nature. Serum drawn on arrival and 3 h later was batchtested for TNIH. The target condition was an adjudicated diagnosis of acute myocardial infarction (AMI). We evaluated the diagnostic accuracy of absolute and relative delta criteria and four rule-out strategies. Of 802 included patients, 13.8% had AMI. Absolute delta criteria had superior accuracy to relative criteria (C-statistic 0.94 vs. 0.76, P < 0.001). However, no delta criteria achieved >95.5% sensitivity for AMI when used alone. Ruling out AMI with TNIH below the 99th percentile at 0 and 3 h had 88.3% (95% confidence interval 80.8-93.6%) sensitivity. The adapted European Society of Cardiology (ESC) 0/2 h algorithm had higher sensitivity (98.2%) than both High-STEACS (93.7%, P = 0.03) and the ESC 0/3 h algorithm (79.3%, P < 0.001). These pathways ruled out 63%, 74%, and 88% patients, respectively. CONCLUSION: With serial sampling over 3 h, the Siemens TNIH assay should be used with a validated algorithm incorporating bespoke cut-offs and absolute delta criteria. In our analysis, the adapted ESC 0/2 h algorithm had greatest sensitivity. 'Ruling out' AMI using the 99th percentile of the assay cannot be recommended.

Can Emergency Physician Gestalt "Rule In" or "Rule Out" Acute Coronary Syndrome: Validation in a Multicenter Prospective Diagnostic Cohort Study.

BACKGROUND: Chest pain is a common problem presenting to the emergency department (ED). Many decision aids and accelerated diagnostic protocols have been developed to help clinicians differentiate those needing admission from those who can be safely discharged. Some early evidence has suggested that clinician judgment or gestalt alone could be sufficient. OBJECTIVES: Our aim was to externally validate whether emergency physician's gestalt could "rule in" or "rule out" acute coronary syndromes (ACS). METHODS: We performed a multicenter prospective diagnostic accuracy study including consenting patients presenting to the ED in whom the physician suspected ACS. At the time of arrival, clinicians recorded their perceived probability of ACS using a 5-point Likert scale. The primary outcome was a diagnosis of ACS, defined as acute myocardial infarction or major adverse cardiac events within 30 days. RESULTS: A total of 1,391 patients were included; 240 (17.3%) had ACS. Overall, gestalt had fair diagnostic accuracy with a C-statistic of 0.75 (95% confidence interval = 0.72 to 0.79). If ACS was "ruled out" in the 60 (4.3%) patients where clinicians perceived that the diagnosis was "definitely not" ACS, a sensitivity of 98.0% and negative predictive value of 95.0% could have been achieved. If ACS was only ruled out in patients who also had no electrocardiographic (ECG) ischemia and a normal initial cardiac troponin (cTn) concentration, 100.0% sensitivity and NPV could be achieved. However, this strategy only applied to 4.1% of patients. If patients with "probably not" ACS who had normal ECG and cTn were also ruled out (n = 418, 30.8%), sensitivity fell to 86.2% with 99.2% NPV. Using gestalt "definitely" ACS to rule in ACS gave a specificity of 98.5% and positive predictive value of 71.2%. CONCLUSION: Clinician gestalt is not sufficiently accurate or safe to either rule in or rule out ACS as a decision-making strategy. This study will enable emergency physicians to understand the limitations of our clinical judgment.

Single test rule-out of acute myocardial infarction using the limit of detection of a new high-sensitivity troponin I assay.

OBJECTIVES: To determine the diagnostic accuracy of a high-sensitivity cardiac troponin I (hs-cTnI) assay in patients presenting to the Emergency Department (ED) with suspected acute coronary syndromes. Specifically, we evaluated the use of a single blood test at the time of arrival in the ED, using low hs-cTnI cut-offs. METHODS: In a prospective diagnostic test accuracy study at 14 centers, we included patients presenting to the ED with suspected ACS within 12 h of symptom onset. We drew blood for hs-cTnI (Siemens ADVIA Centaur, overall 99th percentile 47 ng/L, limit of quantification [LoQ] 2.50 ng/L) on arrival. Patients underwent serial cardiac troponin testing over 3-6 h. The primary outcome was an adjudicated diagnosis of acute myocardial infarction (AMI). We evaluated the incidence of major adverse cardiac events (MACE: death, AMI or revascularization) after 30 days. Test characteristics for hs-cTnI were calculated using previously reported cut-offs set at the LoQ and 5 ng/L. RESULTS: We included 999 patients, including 131 (13.1%) with an adjudicated diagnosis of AMI. Compared to the LoQ (100.0% sensitivity [95% CI 95.9-100.0%]), 99.7% negative predictive value [NPV; 95% CI 97.6-100.0%]), a 5 ng/L cut-off had slightly lower sensitivity (99.2%; 95% CI 95.8-100.0%) and similar NPV (99.8%; 95% CI 98.6-100.0%) but would rule out more patients (28.6% at the LoQ vs 50.4% at 5 ng/L). MACE occurred in 2 (0.7%) patients with hs-cTnI below the LoQ and 7 (1.4%) patients with hs-cTnI < 5 ng/L. Accounting for time from symptom onset or ECG ischemia did not further improve sensitivity. CONCLUSION: The Siemens ADVIA Centaur hs-cTnI assay has high sensitivity and NPV to rule out AMI with a single blood test in the ED. At the LoQ cut-off a sensitivity > 99% can be achieved. At a 5 ng/L cut-off it may be possible to rule out AMI for over 50% patients.

Diagnostic accuracy of the T-MACS decision aid with a contemporary point-of-care troponin assay.

OBJECTIVES: The rapid turnaround time of point-of-care (POC) cardiac troponin (cTn) assays is highly attractive for crowded emergency departments (EDs). We evaluated the diagnostic accuracy of the Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid with a POC cTn assay. METHODS: In a prospective diagnostic accuracy study at eight EDs, we included patients with suspected acute coronary syndromes (ACS). Blood drawn on arrival and 3 hours later was analysed for POC cTnI (i-Stat, Abbott Point of Care). The primary outcome was a diagnosis of ACS, which included both an adjudicated diagnosis of acute myocardial infarction (AMI) based on serial laboratory cTn testing and major adverse cardiac events (death, AMI or coronary revascularisation) within 30 days. RESULTS: Of 716 patients included, 105 (14.7%) had ACS. Using serial POC cTnI concentrations over 3 hours could have 'ruled out' ACS in 198 (31.2%) patients with a sensitivity of 99.0% (95% CI 94.4% to 100.0%) and negative predictive value 99.5% (95% CI 96.5% to 99.9%). No AMIs were missed. T-MACS 'ruled in' ACS for 65 (10.4%) patients with a positive predictive value of 91.2% (95% CI 82.1% to 95.9%) and specificity 98.9% (97.6% to 99.6%). CONCLUSION: With a POC cTnI assay, T-MACS could 'rule out' ACS for approximately one-third of patients within 3 hours while 'ruling in' ACS for another 10%. The rapid turnaround time and portability of the POC assay make this an attractive pathway for use in crowded EDs or urgent care centres. Future work should also evaluate use in the prehospital environment.

The De Winter ECG pattern: morphology and accuracy for diagnosing acute coronary occlusion: systematic review.

The De Winter ECG pattern has been reported to indicate acute left anterior descending coronary artery occlusion and is often considered to be an 'ST elevation myocardial infarction (STEMI) equivalent'. We aimed to investigate the morphology of the 'De Winter ECG pattern' and evaluate the test characteristics of the De Winter pattern for the diagnosis of acute coronary occlusion. We identified papers through the Medline, EMBASE and COCHRANE databases and screened for bias using QUADAS-2. First, measurements were recorded from every ECG reported in the literature and aggregated. Second, diagnostic accuracy data from eligible cohort studies were extracted. The primary outcome was defined as at least 70% angiographic stenosis of a major epicardial vessel. Thirteen papers reported data relevant to question 1 and three papers reported data relevant to question 2. All ECGs showed maximal up-sloping ST depression in lead V3 with a median amplitude of 0.3 mV (interquartile range: 0.2-4 mV). T-wave height peaked in lead V3 with a median amplitude 0.9 mV (interquartile range: 0.8-1.1 mV). The De Winter pattern had positive predictive values of 95.2% (95% confidence interval: 76.2-99.9%), 100% (69.2-100.0%) and 100% (51.7-100%) in the three respective diagnostic studies. There is limited evidence that the De Winter ECG pattern is a 'STEMI equivalent'. The available data suggest that the pattern has high positive predictive value for acute occlusion. Further research is required to evaluate specificity and to determine whether rapid revascularization improves mortality.

The interobserver reliability of a novel qualitative point of care assay for heart-type fatty acid binding protein.

BACKGROUND: Heart-type fatty acid-binding protein (h-FABP) may help to improve the early diagnosis of acute coronary syndromes in patients presenting to the Emergency Department (ED) with chest pain. A novel qualitative point of care h-FABP lateral flow immunoassay (True Rapid, FABPulous BV) could provide results to clinicians within just 5min. Given the qualitative nature of this test and prior to evaluation in a large diagnostic study, we aimed to determine inter-observer reliability when interpreted contemporaneously by staff in the ED. METHODS: In a nested prospective cohort study including adult patients with suspected cardiac chest pain, venous blood samples were tested for h-FABP (FABPulous BV) on arrival and 3h later. Each test result was independently interpreted by two different investigators after 5min. The investigators were blinded to each other's interpretation and recorded their findings on separate case report forms. We determined interobserver reliability by calculating the Cohen's kappa score and 95% confidence intervals. RESULTS: A total of 43 test results (from 31 patients) were each interpreted by two independent investigators. Absolute agreement between investigators was 93.0%, with a Cohen's kappa of 0.81 (95% CI 0.6-1.0), indicating near perfect agreement. In total there were three (7.0%) disagreements. In each case one investigator reported a 'weak positive' result while the other interpreted the result as 'negative'. CONCLUSIONS: These findings demonstrate the interobserver reliability of a qualitative point of care h-FABP assay. Further work must evaluate diagnostic accuracy and determine the clinical implications of the small rate of disagreement.

A brief addition to the article titled "Wellens syndrome left anterior descending coronary T-wave syndrome" / Un breve anexo al artículo titulado "Síndrome de Wellens -Síndrome de la onda T de la coronaria descendente anterior izquierda"

We warmly applaud the effort taken by Khanna and Bustamante1 in raising awareness about Wellen's syndrome. As the authors report, the syndrome is strongly associated with critical stenosis in the left anterior descending artery and it is frequently overlooked as cardiac biomarkers may not be raised. We feel obliged to respectfully point out 1 error in their otherwise excellent report: the T-wave changes occur predominantly in leads V2 to V3 not V3 to V5.

Aplaudimos sinceramente el esfuerzo realizado por Khanna y Bustamante1 para dar a conocer el síndrome de Wellen. Como informan los autores, el síndrome está fuertemente asociado a la estenosis crítica en la arteria descendente anterior y con frecuencia se pasa por alto, ya que los biomarcadores cardíacos pueden no estar elevados. Nos sentimos obligados a señalar respetuosamente un error en su informe, que por lo demás es excelente: los cambios en las ondas T se producen predominantemente en las derivaciones V2 a V3, no en las V3 a V5.