Cardiac Troponin for Assessment of Myocardial Injury in COVID-19: JACC Review Topic of the Week.

Increases in cardiac troponin indicative of myocardial injury are common in patients with coronavirus disease-2019 (COVID-19) and are associated with adverse outcomes such as arrhythmias and death. These increases are more likely to occur in those with chronic cardiovascular conditions and in those with severe COVID-19 presentations. The increased inflammatory, prothrombotic, and procoagulant responses following severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection increase the risk for acute nonischemic myocardial injury and acute myocardial infarction, particularly type 2 myocardial infarction, because of respiratory failure with hypoxia and hemodynamic instability in critically ill patients. Myocarditis, stress cardiomyopathy, acute heart failure, and direct injury from SARS-CoV-2 are important etiologies, but primary noncardiac conditions, such as pulmonary embolism, critical illness, and sepsis, probably cause more of the myocardial injury. The structured use of serial cardiac troponin has the potential to facilitate risk stratification, help make decisions about when to use imaging, and inform stage categorization and disease phenotyping among hospitalized COVID-19 patients.

Integrated diagnostics: the future of laboratory medicine?

The current scenario of in vitro and in vivo diagnostics can be summarized using the "silo metaphor", where laboratory medicine, pathology and radiology are three conceptually separated diagnostic disciplines, which will increasingly share many comparable features. The substantial progresses in our understanding of biochemical-biological interplays that characterize many human diseases, coupled with extraordinary technical advances, are now generating important multidisciplinary convergences, leading the way to a new frontier, called integrated diagnostics. This new discipline, which is currently defined as convergence of imaging, pathology and laboratory tests with advanced information technology, has an enormous potential for revolutionizing diagnosis and therapeutic management of human diseases, including those causing the largest number of worldwide deaths (i.e. cardiovascular disease, cancer and infectious diseases). However, some important drawbacks should be overcome, mostly represented by insufficient information technology infrastructures, costs and enormous volume of different information that will be integrated and delivered. To overcome these hurdles, some specific strategies should be defined and implemented, such as planning major integration of exiting information systems or developing innovative ones, combining bioinformatics and imaging informatics, using health technology assessment for assessing cost and benefits, providing interpretative comments in integrated reports, developing and using expert systems and neural networks, overcoming cultural and political boundaries for generating multidisciplinary teams and integrated diagnostic algorithms.

Systematic assessment of decision-analytic models evaluating diagnostic tests for acute myocardial infarction based on cardiac troponin assays.

INTRODUCTION: Despite the emphasis on the clinical importance of cardiac troponin assays (cTn), there are insufficient cost-effectiveness comparisons of various troponin test protocols for the diagnosis of myocardial infarction (MI). Therefore, the purpose of the review was to identify and systematically assess published economic evaluations using decision-analytic models for diagnostic testing strategies based on cTn and to make recommendations for the development of future models. AREAS COVERED: MEDLINE, Science Direct, Cochrane Database, CRD Database, and gray literature were screened for full economic evaluation studies with relevant clinical outcomes over a defined time horizon addressing a population with suspected MI and comparison of different diagnostic test strategies. Standardized forms for data extraction and evidence tables were used for the summary of study design, methodological framework and data sources. Studies were assessed for quality using the CHEERS and the BMJ checklists. EXPERT COMMENTARY: Although there are 11 identified studies and several well-designed models, there remains a need for decision-analytic models including differential diagnosis for acute MI, different health facility configurations, clinician preferences, and behavioral components, and in the top of the subgroup analyses additional important personalized medicine aspects.

Assessment of the Utility of Ordering a Troponin in Low- and Intermediate-Risk Patients Presenting to the Emergency Department with Supraventricular Tachycardia: A Retrospective Chart Review.

BACKGROUND: A troponin assay is commonly sent for patients presenting to emergency departments (EDs) with supraventricular tachycardia (SVT). Multiple studies suggest that elevated troponin levels do not predict coronary artery disease in these patients. Patients with elevated troponins are more likely to have additional cardiac testing, which can lead to increased health care costs and unnecessary invasive procedures. OBJECTIVE: Our objective was to evaluate low- to intermediate-risk patients (HEART [history, electrocardiography, age, risk factors and troponin] Score 1-6) presenting to the ED with SVT. Our hypothesis was that an elevated troponin would not predict major adverse cardiac events (MACE), but would be associated with increased hospital admission rates and lengths of stay. METHODS: This was a retrospective cohort study of adult patients who presented with SVT to a large, urban, academic hospital ED over 4 years who had a troponin result. A total of 46 patients were included in the study. RESULTS: Patients with a positive troponin (>0.05 ng/mL) had a hospital admission rate of 86% versus 21% for patients with negative troponin (p = 0.006); rate of cardiology consult of 86% versus 21% (p < 0.001); and a mean total length of stay of 4157 min versus 1347 min (p = 0.04). At 3 months, none of the patients with a positive troponin had an MACE, death from any cause, or positive results of cardiac testing. CONCLUSIONS: Patients with a positive troponin result had significantly more admissions, cardiology consults, and longer hospital stays. These patients did not have an increased prevalence of MACE.

The assessment and management of chest pain in primary care: A focus on acute coronary syndrome

BACKGROUND: Chest pain is a common presentation and diagnosis can be challenging. There are many causes for chest pain, including life-threatening conditions such as acute coronary syndrome (ACS), which can prove difficult to diagnose. OBJECTIVE: This article focuses on diagnosis and early management of patients with possible ACS. Key differentials and essential primary care investigations and management are outlined. Hospital-based risk stratification and management are described, providing an outline of what patients can expect if referred to hospital. DISCUSSION: In primary care, an electrocardiogram (ECG) is the only investigation required for most patients while referral is made to hospital. Troponin testing should rarely be requested to investigate patients with suspected ACS in the primary care setting. Initial treatment may include aspirin, glyceryl trinitrate and oxygen if required. If ACS is suspected as the cause of the symptoms, urgent referral for definitive risk stratification is required.

Using expert elicitation to estimate the potential impact of improved diagnostic performance of laboratory tests: a case study on rapid discharge of suspected non-ST elevation myocardial infarction patients.

Early health technology assessment can provide insight in the potential cost-effectiveness of new tests to guide further development decisions. This can increase their potential benefit but often requires evidence which is lacking in early test development stages. Then, expert elicitation may be used to generate evidence on the impact of tests on patient management. This is illustrated in a case study on a new triple biomarker test (copeptin, heart-type fatty acid binding protein, and high-sensitivity troponin [HsTn]) at hospital admission. The elicited evidence enables estimation of the impact of using the triple biomarker on time to exclusion of non-ST elevation myocardial infarction compared with current serial HsTn measurement (performed 0, 2, and 6 h after admission). Cardiologists were asked to estimate the effect of the triple biomarker on patient's discharge rates and interventions performed, depending on its diagnostic performance. This elicited evidence was combined with Dutch reimbursement data and published evidence into a decision analytic model. Direct hospital costs and patients' discharge rates were assessed for 3 testing strategies including this triple biomarker (ie, only at admission or combined with HsTn measurements after 2 and 6 h). Direct hospital costs of suspected non-ST elevation myocardial infarction patients using serial HsTn measurements are estimated at €1825 per patient. Combining this triple biomarker with HsTn measurements after 2 and 6 hours is expected to be the most cost-effective strategy. Depending on the diagnostic performance of the triple biomarker, this strategy is estimated to reduce costs with €66 to €205 per patient (ie, 3.6%-11.3% reduction). Expert elicitation can be a valuable tool for early health technology assessment to provide an initial estimate of the cost-effectiveness of new tests prior to their implementation in clinical practice. As demonstrated in our case study, improved diagnostic performance of the triple biomarker may have benefits that should be further explored.

Improved Assessment of Chest pain Trial (IMPACT): assessing patients with possible acute coronary syndromes.

OBJECTIVE: To examine the safety and efficacy of the Improved Assessment of Chest pain Trial (IMPACT) protocol, a strategy for accelerated assessment of patients presenting to emergency departments (EDs) with chest pain. DESIGN, SETTING AND PARTICIPANTS: IMPACT was an intervention trial at a single tertiary referral hospital (Royal Brisbane and Women's Hospital) during February 2011 - March 2014. 1366 prospectively recruited patients presenting to the ED with symptoms of suspected acute coronary syndrome (ACS) were stratified into groups at low, intermediate or high risk of an ACS. INTERVENTION: High risk patients were treated according to NHFA/CSANZ guidelines. Low and intermediate risk patients underwent troponin testing (sensitive assay) 0 and 2 hours after presentation. Intermediate risk patients underwent objective testing after the second troponin test; low risk patients were discharged without further objective testing. MAIN OUTCOME MEASURES: The primary outcome was an ACS within 30 days of presentation. Secondary outcomes were ED and hospital lengths of stay (LOS). RESULTS: The IMPACT protocol stratified 244 (17.9%) patients to low risk, 789 (57.7%) to intermediate risk, and 333 (24.4%) to high risk categories. The overall 30-day ACS rate was 6.6%, but there were no ACS events in the low risk group, and 14 (1.8%) in the intermediate risk group. The median hospital LOS was 5.1 hours (IQR, 4.2-5.6 h) for low risk and 7.7 hours (IQR, 6.1-21 h) for intermediate risk patients. CONCLUSIONS: The IMPACT protocol safely and efficiently allowed a large proportion of patients presenting to EDs with chest pain to undergo accelerated assessment for risk of an ACS. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000206921.

The pharmacoeconomics of routine postoperative troponin surveillance to prevent and treat myocardial infarction after non-cardiac surgery.

BACKGROUND: A postoperative troponin leak that was previously considered clinically insignificant has been independently associated with 30-day mortality in unselected surgical patients ≥45 years of age following non-cardiac surgery. OBJECTIVES: To determine whether routine troponin surveillance following non-cardiac surgery and initiation of aspirin and statin therapy in troponin-positive patients is cost-effective. METHODS: Pharmacoeconomic analysis to determine the cost-effectiveness of routine postoperative surveillance for patients aged ≥45 years undergoing non-cardiac surgery. We compared the total expected cost of hospital care of patients who received routine troponin surveillance and subsequent introduction of statin and aspirin therapy for 30 days in troponin-positive patients with the cost of hospital care of patients who did not receive troponin surveillance. We estimated a 25% relative risk reduction following statin and aspirin therapy for postoperative vascular mortality and non-fatal myocardial infarction. RESULTS: Routine troponin surveillance with initiation of aspirin and statin therapy was cost-effective, with an incremental cost of -R16,724 per event avoided. CONCLUSION: Routine postoperative troponin surveillance in non-cardiac surgical patients ≥45 years of age requiring a postoperative night in hospital is potentially cost-effective.

Is it time for home treatment of pulmonary embolism?

Acute pulmonary embolism (PE) is a frequent cause of death, but not all patients are at high risk of an adverse early outcome. It has been proposed that selected patients may be considered for early discharge and home treatment, but it was only recently that improved risk assessment strategies permitted advances in the identification of low-risk PE. Clinical prediction rules, such as the Pulmonary Embolism Severity Index (PESI), and laboratory biomarkers, particularly natriuretic peptides and cardiac troponins, appeared capable of excluding severe PE and serious comorbidity. Recently, two randomised trials and two prospective cohort studies investigated the feasibility and safety of outpatient treatment. All excluded patients with haemodynamic instability and serious comorbidity, but only one trial used a validated clinical score (PESI) for patient inclusion, and only one cohort study employed a biomarker test. Overall, 90-day outcome was favourable and the results appear promising. To optimise patient selection, future trials will need to test simplified clinical scores combined with high-sensitivity biomarker assays, and it will have to be determined whether echocardiography and/or compression ultrasonography are also required before discharge. Furthermore, ongoing trials will show whether new oral anticoagulants are a safe and cost-effective option for managing patients out of hospital.

Mortality risk assessment and the role of thrombolysis in pulmonary embolism.

Acute venous thromboembolism remains a frequent disease, with an incidence ranging between 23 and 69 cases per 100,000 population per year. Of these patients, approximately one-third present with clinical symptoms of acute pulmonary embolism (PE) and two-thirds with deep venous thrombosis (DVT). Recent registries and cohort studies suggest that approximately 10% of all patients with acute PE die during the first 1 to 3 months after diagnosis. Overall, 1% of all patients admitted to hospitals die of acute PE, and 10% of all hospital deaths are PE-related. These facts emphasize the need to better implement our knowledge on the pathophysiology of the disease, recognize the determinants of death or major adverse events in the early phase of acute PE, and most importantly, identify those patients who necessitate prompt medical, surgical, or interventional treatment to restore the patency of the pulmonary vasculature.

[Clinical and economical evaluation of bivalirudin during percutaneous coronary interventions]. / Evaluations clinique et économique de la bivalirudine au cours des procédures d'angioplasties coronaires.

Bivalirudin, with provisional GP IIb/IIIa inhibitor use allows the same protection against ischemic complications while reducing the hemorrhagic complications compared with the systematic association of a GP IIb/IIIa inhibitor plus heparin (The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 [Replace-2]). In clinical practice, the use of heparin is not systematically associated with a GP IIb/IIIa inhibitor. That's why we studied the clinical and economic interest of bivalirudin only versus heparin (UFH) only. Opened pragmatic monocentric study carried out in 2007. We made a chronological matching: for each patient treated with bivalirudin, we included the next patient with the same clinical presentation treated with unfractionated heparin. Ninety-two patients were included (46 in each group). The need for a GP IIb/IIIa inhibitor during the PCI was not significantly different between the two groups (p=0.11). No major hemorrhagic complications were observed in the two groups. Prevalence of ecchymosis was not significantly different: 22 % in the UFH group versus 13 % in the bivalirudin group (p=0.27). The average troponin level the next day was significantly higher in the bivalirudin group (p=0,049), although the change in troponin levels before and after the procedure was similar in the two groups. The average cost by patient of anticoagulation by bivalirudin and HNF is very different, respectively 473+/-150 and 51+/-146 euro (p=0.0001). Bivalirudin can be an interesting alternative for patients with a high risk of having complications. But considering its cost this therapy must be used only for selected patients.

Simultaneous immunophenotypical assessment of troponin and extracellular matrix molecules in myocardium of patients with sudden cardiac death.

In patients with sudden unexpected cardiac death, there is a relationship between the interstitial fibrosis of the myocardium and matrix molecules with a role in global remodeling of the cardiac stroma. Tissue samples of left ventricular myocardium from 17 middle-aged patients with sudden cardiac death, following acute or chronic ischemic cardio(myo)pathies, were analyzed using standard HE stain and the indirect tristadial ABC peroxidase immunohistochemical method for a panel of four antibodies involved in the dynamic remodeling of extracellular matrix: matrix metalloproteinase 9 (MMP9), tenascin X (Tn-X), TGF-b, CD54 (ICAM-1), together with simultaneously assessment of troponin in myocardic fibers. The most sensitive reaction was noticed for ICAM-1 in 71% of cases, followed by MMP9 in 59% of cases and TGF-b in 47% of cases (with great specificity for capillary vessels), in the extracellular matrix of the residual cardiomyocytes. A direct correlation, statistically significant was recorded between troponin and MMP9 (r = 0.65, p = 0.01), troponin and ICAM-1 (r = 0.31, p = 0.02), respectively ICAM-1 and tenascin (r = 0.72, p = 0.01). The extensive expression of ICAM-1 in the extracellular matrix from the perilesional area probably plays a role in the stimulation of new developing adhesion substrates between residual cells and adjacent stroma, while the over expression of troponin in the residual cardiomyocytes is accompanied by a high expression of MMP9 in the myocardic interstitium, with heterogeneous remodeling of the ventricular stroma. The simultaneous IHC expression of tenascin and ICAM-1 suggests a colocalization required for the nerve sprouting in the residual myocardium and for developing new focal cell-matrix adhesion contacts.

Cardiac troponin T: a noninvasive marker for heart transplant rejection?

BACKGROUND: Diagnosis of acute rejection remains a major concern in heart transplant recipients. Currently, endomyocardial biopsy is the gold standard for detecting rejection. Given the risks and cost of endomyocardial biopsy, a noninvasive marker for rejection would be ideal. Cardiac troponin T (cTnT) is an established marker of myocyte damage, and a rat transplantation model of heart transplant rejection has suggested that cTnT may be of value in detecting rejection. METHODS: The cTnT levels were measured in 90 transplant recipients (67 men and 23 women) at the time of endomyocardial biopsy. There were a total of 256 cTnT levels and 256 biopsy samples. The cTnT levels were compared by use of International Society of Heart and Lung Transplantation rejection grades. RESULTS: Only one of the 12 grade 3 biopsy specimens had a corresponding elevated cTnT level. Of the 29 biopsy specimens with myocyte necrosis (grade 2 or grade 3), three had a corresponding elevated cTnT. The cTnT levels were elevated during the first 1 to 2 months after transplantation. There was no correlation between ischemic time and cTnT levels. CONCLUSION: CTnT is an insensitive marker of acute rejection, both early and late after heart transplantation. Elevation of cTnT after transplantation does not seem to be directly related to ischemic time.

Cardiac markers in the assessment of acute coronary syndromes.

Biochemical markers provide clinicians with an important tool for the assessment of acute coronary syndromes. Biochemical markers, including total creatine kinase (total CK), creatine kinase-MB (CK-MB), the MB isoforms, and myoglobin, as well as the troponins--cardiac troponin T (cTnT) and cardiac troponin I (cTnI)--are all used for assessment of the suspected acute myocardial infarction (AMI) patient. In the context of myocardial infarction (MI) diagnosis, total CK is a relatively sensitive marker, but it lacks myocardial specificity because skeletal muscle contains high concentrations of CK. CK-MB is the benchmark for biochemical markers and has both high sensitivity and specificity; however, CK-MB is also present in skeletal muscle and is not diagnostic until eight to twelve hours after onset of symptoms. The MB isoforms are diagnostic earlier but have the same cardiac specificity issues as CK-MB. Myoglobin becomes abnormal about one hour after onset of symptoms and is a sensitive marker for MI; however, myoglobin is cleared quickly and is not cardiac specific. Both cTnT and cTnI are cardiac specific and show high sensitivity and specificity for MI. Risk stratification of acute coronary syndrome patients is another role for biochemical markers; CK-MB, cTnT and cTnI have all been proposed for this function. Compared with CK-MB, both cTnT and cTnI are better able to predict short-term mortality following the index event. Analysis using a logistic regression model that included the electrocardiogram, cTnT, and cTnI showed that cTnT was the most useful marker for risk stratification. Finally, cTnT was reported to be able to predict which patients will benefit from treatment with regimens of low molecular weight heparin.

An overview and ranking of biochemical markers of cardiac disease. Strengths and limitations.

Comparing the performance of one biochemical marker of myocardial damage with another is bedeviled with many problems, including a lack of uniform calibration between instruments providing measurements of the same analyte and differing reference ranges and decision thresholds. Diagnostic groupings and various gold standards create difficulties in comparing analytic results. There is a lack of uniformity in test assessments and their use for diagnostic and prognostic purposes. Finally, there is an almost complete absence of data from economic and decision analyses of test usage. It is argued that a much more stringent and rigorous approach to these aspects is essential. The use of biochemical markers of cardiac damage is in a dynamic state, with new applications continually appearing and new markers being developed. It is therefore essential that a uniform and rigorous outlook be maintained to ensure both optimal and economic test utilization based on the previously outlined principles.

Troponin-T: improved diagnostic assessment of myocardial damage in childhood.

Troponin-T (cTnT) as a marker of myocardial damage is well established in adults, but not yet in children. cTnT was measured in 85 children (aged 1 day-204 months, mean 46 months). Twenty-five children were non-surgical patients, with possible myocardial damage suspected on clinical grounds. The other 60 patients had cardiac surgery leading to a defined myocardial damage. In these children, troponin-T (cTnT), creatine kinase activity (CK), creatine kinase-MB activity (CK-MB), and creatine kinase-MB-Mass (CK-MB-Mass) were measured preoperatively and 3-4 times during the first 55 postoperative h. Except in four children with probable preoperative myocardial damage, all troponin-T values were in the normal range (< 0.1 microg/l). All children with intracardiac surgery showed a postoperative increase in troponin-T. Children with extracardiac surgery of the great vessels showed no postoperative increase of troponin-T. For the assessment of myocardial damage, troponin-T was more specific and more sensitive than the other markers tested, troponin-T might significantly improve the diagnostic assessment of myocardial damage in children.

A decision tree for the early diagnosis of acute myocardial infarction in nontraumatic chest pain patients at hospital admission.

STUDY OBJECTIVE: To find an accurate algorithm for the diagnosis of acute myocardial infarction in nontraumatic chest pain patients on presentation to the emergency department. DESIGN: In a prospective clinical study, we compared the diagnostic performances of clinical symptoms, presenting ECG, creatinine kinase, creatine kinase MB activity and mass concentration, myoglobin, and cardiac troponin T test results of hospital admission blood samples. By classification and regression trees, a decision tree for the diagnosis of acute myocardial infarction was developed. SETTING: Emergency room of a Department of Internal Medicine (University Hospital). PATIENTS: One hundred fourteen nontraumatic chest pain patients (median delay from onset of chest pain to hospital admission, 3 h; range, 0.33 to 22): 26 Q-wave and 19 non-Q-wave myocardial infarctions, 49 patients with unstable angina pectoris, and 20 patients with chest pain caused by other diseases. MEASUREMENTS AND RESULTS: Of each parameter taken by itself, the ECG was tendentiously most informative (areas under receiver operating characteristic plots: 0.87 +/- 0.04 [ECG], 0.80 +/- 0.08 [myoglobin], 0.80 +/- 0.04 [creatine kinase MB mass], 0.77 +/- 0.04 [creatine kinase activity], 0.69 +/- 0.06 [clinical symptoms] 0.67 +/- 0.06 [creatine kinase MB activity], 0.67 +/- 0.05 [troponin T]). In patients presenting 3 h or less after the onset of chest pain, ECG signs of acute transmural myocardial ischemia were the best discriminator between patients with and without myocardial infarction. In patients presenting more than 3 h, however, creatine kinase MB mass concentrations (discriminator value, 6.7 micrograms/L) were superior to the ECG, clinical symptoms, and all other biochemical markers tested. This algorithm for diagnosing acute myocardial infarction was superior to each parameter by itself and was characterized by 0.91 sensitivity, a 0.90 specificity, a 0.90 positive and negative predictive value, and a 0.90 efficiency. CONCLUSIONS: We found an algorithm that could accurately separate the myocardial infarction patients from the others on admission to the emergency department. Therefore, this classifier could be a valuable diagnostic aid for rapid confirmation of a suspected myocardial infarction.