Early diagnosis and risk stratification of patients with syncope

Background: Syncope is a common and challenging problem in the Emergency Department (ED), representing about 1-2% of patients visits. Early detection of the underlying cause is critical as it defines treatment and prognosis. Cardiac syncope is associated with the highest mortality of all syncope etiologies and requires specific interventions such as implantation of a pacemaker or defibrillator. ED clinicians struggle to rapidly identify the underlying cause and the threat of a possible serious cardiac origin which leads to numerous diagnostics and high hospitalisation rates. In an attempt to improve diagnosis and risk-stratification in syncope patients in the ED, several rules and scores were derived, mostly of mono-centric and rather small studies. Additionally, their external validity has never been assessed and their complexity represent a problem for a rapid and efficient implementation in the ED. Similarly, the diagnostic and prognostic value of some readily available cardiac biomarkers (such as cardiac troponins or B-type Natriuretic peptides) has been investigated in some pilot studies but the small number of patients assessed and the use of poorly sensitive assays resulted in varying results and did not allow for any definitive conclusions. Aim and Hypothesis: The aim of this thesis is to assess the accuracy of diagnostic and prognostic accuracy of scores and biomarkers in a large international cohort of syncope patients presenting to the ED. First, the accuracy of existing syncope-specific diagnostic and risk-stratification rules will be compared and their complexity put in perspective through a comparison with the CHADS2 score. Second, the diagnostic and prognostic performance of cardiac troponins, as assessed by three different assays, and BNP will be investigated. We hypothesize that complex syncope-specific scores might not reliably diagnose or risk-stratify syncope patients and that both assessed biomarkers, at least in certain subgroups of patients for which the determination of a precise etiology appears particularly difficult, could be of specific interest to improve the diagnosis and risk stratification of patients presenting with syncope to the ED. Patients and Methods: BASEL IX is an ongoing prospective international multicenter diagnostic cohort study coordinated by the University Hospital Basel. Patients >40y presenting to the ED with a syncope within the 12 last hours are enrolled and blood is drawn for the blinded analysis of the investigational biomarkers. All patients underwent clinical assessment that included standardized and detailed assessment of predefined details of the medical history and syncopal event. The adjudication of the final diagnosis is performed by two independent cardiologists based on all available information after diagnostic work-up of patients as well as the clinical follow-up at 12 months. Patients are followed up to 5 years. The diagnostic endpoint is the diagnostic accuracy for cardiac syncope, the prognostic endpoints are the accuracy to predict death or major cardiovascular events (MACE). Results: Syncope diagnostic and risk stratification rules showed a moderate accuracy in patients presenting with syncope to the ED (with Area Under The Receiver Operating Curve (AUC) between 0.67 and 0.75 for diagnostic endpoints and between 0.57 and 0.79 for prognostic endpoints) and most of them were, not superior to a readily calculable CHADS2 score. Both assessed biomarkers performed with a moderate-to-good accuracy for the diagnosis and risk stratification of the overall cohort (AUC for diagnostic endpoints between 0.76 and 0.77, AUC for prognostic endpoints between 0.73 and 0.8 depending on the chosen time-point). When assessed in patients for whom the diagnosis stayed unclear despite initial ED evaluation, these biomarkers could provide guidance to the ED physician regarding his decision for hospitalization and further testing. Conclusion: Diagnosis and risk-stratification of patients with syncope is a challenging task and currently available structured clinical assessments scores do not sufficiently help with initial ED evaluation. Common and readily available cardiac biomarkers seem to represent a valuable tool, especially in patients for whom a first evaluation did not lead to a satisfactory diagnosis

Early diagnosis and risk stratification of patients with syncope

Background: Syncope is a common and challenging problem in the Emergency Department (ED), representing about 1-2% of patients visits. Early detection of the underlying cause is critical as it defines treatment and prognosis. Cardiac syncope is associated with the highest mortality of all syncope etiologies and requires specific interventions such as implantation of a pacemaker or defibrillator. ED clinicians struggle to rapidly identify the underlying cause and the threat of a possible serious cardiac origin which leads to numerous diagnostics and high hospitalisation rates. In an attempt to improve diagnosis and risk-stratification in syncope patients in the ED, several rules and scores were derived, mostly of mono-centric and rather small studies. Additionally, their external validity has never been assessed and their complexity represent a problem for a rapid and efficient implementation in the ED. Similarly, the diagnostic and prognostic value of some readily available cardiac biomarkers (such as cardiac troponins or B-type Natriuretic peptides) has been investigated in some pilot studies but the small number of patients assessed and the use of poorly sensitive assays resulted in varying results and did not allow for any definitive conclusions. Aim and Hypothesis: The aim of this thesis is to assess the accuracy of diagnostic and prognostic accuracy of scores and biomarkers in a large international cohort of syncope patients presenting to the ED. First, the accuracy of existing syncope-specific diagnostic and risk-stratification rules will be compared and their complexity put in perspective through a comparison with the CHADS2 score. Second, the diagnostic and prognostic performance of cardiac troponins, as assessed by three different assays, and BNP will be investigated. We hypothesize that complex syncope-specific scores might not reliably diagnose or risk-stratify syncope patients and that both assessed biomarkers, at least in certain subgroups of patients for which the determination of a precise etiology appears particularly difficult, could be of specific interest to improve the diagnosis and risk stratification of patients presenting with syncope to the ED. Patients and Methods: BASEL IX is an ongoing prospective international multicenter diagnostic cohort study coordinated by the University Hospital Basel. Patients >40y presenting to the ED with a syncope within the 12 last hours are enrolled and blood is drawn for the blinded analysis of the investigational biomarkers. All patients underwent clinical assessment that included standardized and detailed assessment of predefined details of the medical history and syncopal event. The adjudication of the final diagnosis is performed by two independent cardiologists based on all available information after diagnostic work-up of patients as well as the clinical follow-up at 12 months. Patients are followed up to 5 years. The diagnostic endpoint is the diagnostic accuracy for cardiac syncope, the prognostic endpoints are the accuracy to predict death or major cardiovascular events (MACE). Results: Syncope diagnostic and risk stratification rules showed a moderate accuracy in patients presenting with syncope to the ED (with Area Under The Receiver Operating Curve (AUC) between 0.67 and 0.75 for diagnostic endpoints and between 0.57 and 0.79 for prognostic endpoints) and most of them were, not superior to a readily calculable CHADS2 score. Both assessed biomarkers performed with a moderate-to-good accuracy for the diagnosis and risk stratification of the overall cohort (AUC for diagnostic endpoints between 0.76 and 0.77, AUC for prognostic endpoints between 0.73 and 0.8 depending on the chosen time-point). When assessed in patients for whom the diagnosis stayed unclear despite initial ED evaluation, these biomarkers could provide guidance to the ED physician regarding his decision for hospitalization and further testing. Conclusion: Diagnosis and risk-stratification of patients with syncope is a challenging task and currently available structured clinical assessments scores do not sufficiently help with initial ED evaluation. Common and readily available cardiac biomarkers seem to represent a valuable tool, especially in patients for whom a first evaluation did not lead to a satisfactory diagnosis

Clinical Utility of D-Dimer for Rule-Out or Rule-In of Venous Thromboembolism in Syncope

Fig. 1 Diagnostic performance of D-dimer using two different assays in patients presenting with syncope. A Left: Receiver-operating characteristic curves quantifying the diagnostic performance of Innovance® D-dimer (blue) and hs-Loci-Innovance® D-dimer (red) for the diagnosis of venous thromboembolism (VTE). Right: Clinical application of D-dimer using the 2-level Wells-score with age-adjusted1 or fixed cutoffs versus the YEARS-algorithm with probability-adjusted cut offs2. B Left: Specificity for different cufoffs of Innovance® D-dimer (blue) and hs-Loci-Innovance® D-dimer (red) for the diagnosis of venous thromboembolism (VTE). Right: Percentage of patients ruled-in and correctly identified VTE patients for different cutoffs of Innovance® D-dimer (blue) and hs-Loci-Innovance® D-dimer (red). 1In patients 50 years or younger, D-dimer concentration < 0.5 mg/l was considered negative. For patients older than 50 years, we used the formula: age in years divided by 100. 2YEARS-algorithm: assessment of only three items from the Wells-score (clinical signs of deep vein thrombosis, hemoptysis, pulmonary embolism the most likely diagnosis) and using a D-dimer test threshold of 0.5 mg/l in presence, and 1.0 mg/l in absence of one of the YEARS-items. Keywords: Diagnostic testing; Pulmonary embolism; Syncop

Prognostic Value of H2FPEF Score in COVID-19

Study objective: This study sought to assess the predictive value of H2FPEF score in patients with COVID-19. Design: Retrospective study. Setting: Rush University Medical Center. Participants: A total of 1682 patients had an echocardiogram in the year preceding their COVID-19 admission with a preserved ejection fraction (≥50%). A total of 156 patients met inclusion criteria. Interventions: Patients were divided into H2FPEF into low (0–2), intermediate (3–5), and high (6–9) score H2FPEF groups and outcomes were compared. Main outcome measures: Adjusted multivariable logistic regression models evaluated the association between H2FPEF score group and a composite outcome for severe COVID-19 infection consisting of (1) 60-day mortality or illness requiring (2) intensive care unit, (3) intubation, or (4) non-invasive positive pressure ventilation. Results: High H2FPEF scores were at increased risk for severe COVID-19 infection when compared intermediate to H2FPEF score groups (OR 2.18 [CI: 1.01–4.80]; p = 0.049) and low H2FPEF score groups (OR 2.99 [CI: 1.22–7.61]; p \u3c 0.05). There was no difference in outcome between intermediate H2FPEF scores (OR 1.34 [CI: 0.59–3.16]; p = 0.489) and low H2FPEF score. Conclusions: Patients with a high H2FPEF score were at increased risk for severe COVID-19 infection when compared to patients with an intermediate or low H2FPEF score regardless of regardless of coronary artery disease and chronic kidney disease

Prohormones in the early diagnosis of cardiac syncope

Background--The early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional-pro-A-type natriuretic peptide (MRproANP), C-terminal proendothelin 1, copeptin, and midregionalproadrenomedullin. Methods and Results--We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1-year follow-up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes (P < 0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76-0.84), 0.69 (95% CI, 0.64-0.74), 0.58 (95% CI, 0.52-0.63), and 0.68 (95% CI, 0.63-0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82-0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87-0.93), which was significantly higher than for the ED probability alone (P=0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of < 77 pmol/L and an ED probability of < 20% had a sensitivity and a negative predictive value of 99%. Conclusions--The use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope

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

There is concern that high-sensitivity cardiac troponin (hs-cTn) may have low diagnostic accuracy in patients with low acute coronary syndrome (ACS) probability.; 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.; 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.; 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

Diagnostic and prognostic value of QRS duration and QTc interval in patients with suspected myocardial infarction

Background: While prolongation of QRS duration and QTc interval during acute myocardial infarction (AMI) has been reported in animals, limited data is available for these readily available electrocardiography (ECG) markers in humans. Methods: Diagnostic and prognostic value of QRS duration and QTc interval in patients with suspected AMI in a prospective diagnostic multicentre study were prospectively assessed. Digital 12-lead ECGs were recorded at presentation. QRS duration and QTc interval were automatically calculated in a blinded fashion. Final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 24 months of follow-up. Results: Among 4042 patients, AMI was the final diagnosis in 19% of patients. Median QRS duration and median QTc interval were significantly greater in patients with AMI compared to those with other final diagnoses (98 ms [IQR 88–108] vs. 94 ms [IQR 86–102] and 436 ms [IQR 414–462] vs. 425 ms [IQR 407–445], p &lt; 0.001 for both comparisons). The diagnostic value of both ECG signatures however was only modest (AUC 0.56 and 0.60). Cumulative mortality rates after 2 years were 15.9% vs. 5.6% in patients with a QRS &gt; 120 ms compared to a QRS duration ≤ 120 ms (p &lt; 0.001), and 11.4% vs. 4.3% in patients with a QTc &gt; 440 ms compared to a QRS duration ≤ 440 ms (p &lt; 0.001). After adjustment for age and important ECG and clinical parameters, the QTc interval but not QRS duration remained an independent predictor of mortality. Conclusions: Prolongation of QRS duration &gt; 120 ms and QTc interval &gt; 440 ms predict mortality in patients with suspected AMI, but do not add diagnostic value

Predicting Major Adverse Events in Patients With Acute Myocardial Infarction

Early and accurate detection of short-term major adverse cardiac events (MACE) in patients with suspected acute myocardial infarction (AMI) is an unmet clinical need.; The goal of this study was to test the hypothesis that adding clinical judgment and electrocardiogram findings to the European Society of Cardiology (ESC) high-sensitivity cardiac troponin (hs-cTn) measurement at presentation and after 1 h (ESC hs-cTn 0/1 h algorithm) would further improve its performance to predict MACE.; Patients presenting to an emergency department with suspected AMI were enrolled in a prospective, multicenter diagnostic study. The primary endpoint was MACE, including all-cause death, cardiac arrest, AMI, cardiogenic shock, sustained ventricular arrhythmia, and high-grade atrioventricular block within 30 days including index events. The secondary endpoint was MACE + unstable angina (UA) receiving early (≤24 h) revascularization.; Among 3,123 patients, the ESC hs-cTnT 0/1 h algorithm triaged significantly more patients toward rule-out compared with the extended algorithm (60%; 95% CI: 59% to 62% vs. 45%; 95% CI: 43% to 46%; p < 0.001), while maintaining similar 30-day MACE rates (0.6%; 95% CI: 0.3% to 1.1% vs. 0.4%; 95% CI: 0.1% to 0.9%; p = 0.429), resulting in a similar negative predictive value (99.4%; 95% CI: 98.9% to 99.6% vs. 99.6%; 95% CI: 99.2% to 99.8%; p = 0.097). The ESC hs-cTnT 0/1 h algorithm ruled-in fewer patients (16%; 95% CI: 14.9% to 17.5% vs. 26%; 95% CI: 24.2% to 27.2%; p < 0.001) compared with the extended algorithm, albeit with a higher positive predictive value (76.6%; 95% CI: 72.8% to 80.1% vs. 59%; 95% CI: 55.5% to 62.3%; p < 0.001). For 30-day MACE + UA, the ESC hs-cTnT 0/1 h algorithm had a higher positive predictive value for rule-in, whereas the extended algorithm had a higher negative predictive value for the rule-out. Similar findings emerged when using hs-cTnI.; The ESC hs-cTn 0/1 h algorithm better balanced efficacy and safety in the prediction of MACE, whereas the extended algorithm is the preferred option for the rule-out of 30-day MACE + UA. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE]; NCT00470587)

Perioperative Myocardial Injury After Non-cardiac Surgery: Incidence, Mortality, and Characterization

Perioperative myocardial injury (PMI) seems to be a contributor to mortality after noncardiac surgery. Because the vast majority of PMIs are asymptomatic, PMI usually is missed in the absence of systematic screening.; We performed a prospective diagnostic study enrolling consecutive patients undergoing noncardiac surgery who had a planned postoperative stay of ≥24 hours and were considered at increased cardiovascular risk. All patients received a systematic screening using serial measurements of high-sensitivity cardiac troponin T in clinical routine. PMI was defined as an absolute high-sensitivity cardiac troponin T increase of ≥14 ng/L from preoperative to postoperative measurements. Furthermore, mortality was compared among patients with PMI not fulfilling additional criteria (ischemic symptoms, new ECG changes, or imaging evidence of loss of viable myocardium) required for the diagnosis of spontaneous acute myocardial infarction versus those that did.; From 2014 to 2015 we included 2018 consecutive patients undergoing 2546 surgeries. Patients had a median age of 74 years and 42% were women. PMI occurred after 397 of 2546 surgeries (16%; 95% confidence interval, 14%-17%) and was accompanied by typical chest pain in 24 of 397 patients (6%) and any ischemic symptoms in 72 of 397 (18%). Crude 30-day mortality was 8.9% (95% confidence interval [CI], 5.7-12.0) in patients with PMI versus 1.5% (95% CI, 0.9-2.0) in patients without PMI (; P; &lt;0.001). Multivariable regression analysis showed an adjusted hazard ratio of 2.7 (95% CI, 1.5-4.8) for 30-day mortality. The difference was retained at 1 year with mortality rates of 22.5% (95% CI, 17.6-27.4) versus 9.3% (95% CI, 7.9-10.7). Thirty-day mortality was comparable among patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction (280/397, 71%) versus those with at least 1 additional criterion (10.4%; 95% CI, 6.7-15.7, versus 8.7%; 95% CI, 4.2-16.7;; P; =0.684).; PMI is a common complication after noncardiac surgery and, despite early detection during routine clinical screening, is associated with substantial short- and long-term mortality. Mortality seems comparable in patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction versus those patients who do.; URL: https://www.clinicaltrials.gov. Unique identifier: NCT02573532