Michael Freese

Universitätsspital Basel, Bâle, Basel-City, Switzerland

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Publications (27)239.64 Total impact

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    ABSTRACT: It is currently unknown, whether and to what extent sensitive cardiac troponin (s-cTn) allows shortening of the time required for safe rule-out and rule-in of acute myocardial infarction (AMI). We aimed to develop and validate early rule-out and rule-in algorithms for AMI using a thoroughly-examined and commonly used s-cTnI assay in a prospective multicenter study including 2173 patients presenting to the emergency department with suspected AMI. S-cTnI was measured in a blinded fashion at 0h, 1h, and 2h. The final diagnosis was centrally adjudicated by two independent cardiologists. In the derivation cohort (n=1496), we developed 1h- and 2h-algorithms assigning patients to "rule-out", "rule-in", or "observe". The algorithms were then prospectively validated in the validation cohort (n=677). AMI was the adjudicated diagnosis in 17% of patients. After applying the s-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 65% of patients were classified as "rule-out", 12% as "rule-in", and 23% to "observe". The negative predictive value for AMI in the "rule-out" group was 98.6% (95% CI, 96.9-99.5), the positive predictive value for AMI in the "rule-in" group 76.3% (95% CI, 65.4-85.1). Overall, 30-day mortality was 0.2% in the "rule-out" group, 1.0% in the "observe" group, and 3.0% in the "rule-in" group. Similar results were obtained for the 2h-algorithm. When used in conjunction with other clinical information including the ECG, a simple algorithm incorporating s-cTnI values at presentation and after 1h (or 2h) will allow safe rule-out and accurate rule-in of AMI in the majority of patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 09/2015; 195. DOI:10.1016/j.ijcard.2015.05.079 · 6.18 Impact Factor
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    ABSTRACT: -Misdiagnosis of acute myocardial infarction (AMI) may significantly harm patients and may result from inappropriate clinical decision values (CDV) for cardiac troponin (cTn) due to limitations in the current regulatory process. -In an international prospective multicenter study we quantified the incidence of inconsistencies in the diagnosis of AMI using fully characterized and clinically available high-sensitivity cTn assays (hs-cTnI Abbott and hs-cTnT Roche) among 2300 consecutive patients with suspected AMI. We hypothesized that the approved CDV for the two assays are not biologically equivalent and might therefore contribute to inconsistencies in the diagnosis of AMI. Findings were validated using gender-specific CDV as well as with parallel measurements of other hs-cTnI assays. AMI was the adjudicated diagnosis in 473 patients (21%). Among these, 86 patients (18.2%) had inconsistent diagnoses using the approved uniform CDV. Using gender-specific CDV, 14.1 % of female and 22.7% of male AMI patients had inconsistent diagnoses. Using biologically equivalent CDV reduced inconsistencies to 10% (p<0.001). These findings were confirmed with parallel measurements of other hs-cTn assays. The incidence of inconsistencies was only 7.0% for assays with CDV that were nearly biologically equivalent. Patients with inconsistent AMI had comparable long-term mortality as compared to patients with consistent diagnoses (p=ns), and a trend to higher long-term mortality than patients diagnosed with unstable angina (p=0.05). -Currently approved CDV are not biologically equivalent and contribute to major inconsistencies in the diagnosis of AMI. One out of five AMI patients will receive a diagnosis other than AMI if managed with the alternative hs-cTn assay. Clinical Trial Registration Information-http://clinicaltrials.gov/. Identifier:NCT00470587.
    Circulation 05/2015; 131(23). DOI:10.1161/CIRCULATIONAHA.114.014129 · 14.95 Impact Factor
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    ABSTRACT: -It is unknown, whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cut-off levels in this vulnerable patient population have not been defined previously. -In this multicenter study we examined the clinical utility of seven more sensitive cTn-assays (three sensitive, four high-sensitivity cTn-assays) in patients presenting with symptoms suggestive of acute myocardial infarction (AMI). Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as estimated MDRD-GFR <60ml/min/1.73m(2)). The final diagnosis was centrally adjudicated by two independent cardiologists using all available information including coronary angiography and serial levels of high-sensitivity cTnT. AMI was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn-levels (≥99(th) percentile), AMI was the most common diagnosis for all assays (range 45-80%). In patients with renal dysfunction diagnostic accuracy at presentation, quantified by the area under the receiver-operator-characteristic (ROC) curve (AUC), was 0.87-0.89 with no significant differences between the seven more sensitive cTn-assays and further increased to 0.91-0.95 at 3h. Overall, AUC in patients with renal dysfunction was only slightly lower than in patients with normal renal function. Optimal ROC-derived cTn-cut-off-levels in patients with renal dysfunction were significantly higher versus patients with normal renal function (factor 1.9-3.4). -More sensitive cTn-assays maintain high diagnostic accuracy also in patients with renal dysfunction. To ensure best possible clinical use, assay-specific optimal cut-off levels, which are higher in patients with renal dysfunction, should be considered. Clinical Trial Registration Information-www.clinicaltrials.gov. Identifier, NCT00470587.
    Circulation 05/2015; 131(23). DOI:10.1161/CIRCULATIONAHA.114.014245 · 14.95 Impact Factor
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    ABSTRACT: We aimed to prospectively validate a novel 1-hour algorithm using high-sensitivity cardiac troponin T measurement for early rule-out and rule-in of acute myocardial infarction (MI). In a multicentre study, we enrolled 1320 patients presenting to the emergency department with suspected acute MI. The highsensitivity cardiac troponin T 1-hour algorithm, incorporating baseline values as well as absolute changes within the first hour, was validated against the final diagnosis. The final diagnosis was then adjudicated by 2 independent cardiologists using all available information, including coronary angiography, echocardiography, follow-up data and serial measurements of high-sensitivity cardiac troponin T levels. Acute MI was the final diagnosis in 17.3% of patients. With application of the high-sensitivity cardiac troponin T 1-hour algorithm, 786 (59.5%) patients were classified as "rule-out," 216 (16.4%) were classified as "rule-in" and 318 (24.1%) were classified to the "observational zone." The sensitivity and the negative predictive value for acute MI in the rule-out zone were 99.6% (95% confidence interval [CI] 97.6%-99.9%) and 99.9% (95% CI 99.3%-100%), respectively. The specificity and the positive predictive value for acute MI in the rule-in zone were 95.7% (95% CI 94.3%-96.8%) and 78.2% (95% CI 72.1%-83.6%), respectively. The 1-hour algorithm provided higher negative and positive predictive values than the standard interpretation of high-sensitivity cardiac troponin T using a single cut-off level (both p < 0.05). Cumulative 30-day mortality was 0.0%, 1.6% and 1.9% in patients classified in the rule-out, observational and rule-in groups, respectively (p = 0.001). This rapid strategy incorporating high-sensitivity cardiac troponin T baseline values and absolute changes within the first hour substantially accelerated the management of suspected acute MI by allowing safe rule-out as well as accurate rule-in of acute MI in 3 out of 4 patients. Clinical Trials.gov, NCT00470587. © 8872147 Canada Inc.
    Canadian Medical Association Journal 04/2015; 187(8). DOI:10.1503/cmaj.141349 · 5.81 Impact Factor
  • Journal of the American College of Cardiology 03/2015; 65(10):A135. DOI:10.1016/S0735-1097(15)60135-8 · 15.34 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the value of a novel high-sensitivity cardiac troponin I (hs-cTnI) measurement to rule-out exercise-induced myocardial ischemia in patients without known coronary artery disease. We included 714 patients without previously known coronary artery disease referred for rest/stress myocardial perfusion single photon emission tomography (MPI-SPECT). All clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of exercise-induced myocardial ischemia using a visual analogue scale twice: once prior and once after bicycle exercise stress-testing. Hs-cTnI measurements were obtained before stress-testing in a blinded manner. The presence of exercise-induced myocardial ischemia was adjudicated based on MPI-SPECT combined with coronary angiography findings. Exercise-induced myocardial ischemia was detected in 167 (23.4%) participants. Hs-cTnI levels were significantly higher in patients with exercise-induced myocardial ischemia (4.0 ng/l [95%CI 2.8-8.6] vs. 2.6 ng/l [95%CI 1.8-4.1], p<0.001) and remained an independent predictor of ischemia in multivariable analysis (p<0.001). Combining clinical judgment prior to exercise testing with hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver-operating curve from 0.64 to 0.73 (p<0.001), which tended to be superior also to clinical judgment after exercise testing (0.69, p=0.056). A single resting hs-cTnI measurement provided similar diagnostic accuracy as integrated clinical judgment after exercise testing including work load, as well as symptoms and ECG changes (0.70 vs. 0.69, p=ns). hs-cTnI measurements seem to complement non-invasive clinical assessment in the patients with suspected coronary artery disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    The American Journal of Medicine 01/2015; 128(6). DOI:10.1016/j.amjmed.2015.01.009 · 5.30 Impact Factor
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    ABSTRACT: Aim It is unknown whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the early diagnosis of acute myocardial infarction without ST segment elevation (NSTEMI). Methods and results In a prospective multicentre study, we measured cTnI and cTnT using clinically available high-sensitivity assays (hs-cTnI Abbott and hs-cTnT Roche) and compared their diagnostic and prognostic accuracies in consecutive patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by two independent cardiologists using all information pertaining to the individual patient. The mean follow-up was 24 months. Among 2226 consecutive patients, 18% had an adjudicated final diagnosis of NSTEMI. Diagnostic accuracy at presentation as quantified by the area under the receiver-operating-characteristics curve (AUC) for NSTEMI was very high and similar for hs-cTnI [AUC: 0.93, 95% confidence interval (CI) 0.92-0.94] and hs-cTnT (0.94, 95% CI: 0.92-0.94) P = 0.62. In early presenters (, 3 h since chest pain onset) hs-cTnI showed a higher diagnostic accuracy (AUC: 0.92, 95% CI: 0.89-0.94) when compared with hs-cTnT AUC (0.89, 95% CI: 0.86-0.91) (P = 0.019), while hs-cTnT was superior in late presenters [ AUC hs-cTnT 0.96 (95% CI: 0.94-0.96) vs. hs-cTnI 0.94 (95% CI: 0.93-0.95); P = 0.007]. The prognostic accuracy for all-cause mortality, quantified by AUC, was significantly higher for hs-cTnT (AUC: 0.80; 95% CI: 0.78-0.82) when compared with hs-cTnI (AUC: 0.75; 95% CI: 0.73-0.77; P < 0.001). Conclusion Both hs-cTnI and hs-cTnT provided high diagnostic and prognostic accuracy. The direct comparison revealed small but potentially important differences that might help to further improve the clinical use of hs-cTn.
    European Heart Journal 05/2014; 35(34). DOI:10.1093/eurheartj/ehu188 · 14.72 Impact Factor
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    ABSTRACT: Background Myocardial ischemia has been shown to be associated with increased levels of B-type natriuretic peptide (BNP). However, it remains unclear whether and how BNP levels could be used clinically in patients with suspected exercise-induced myocardial ischemia. Methods We enrolled 274 consecutive patients with suspected exercise-induced myocardial ischemia referred for evaluation by rest/bicycle myocardial perfusion single-photon emission computed tomography (SPECT).All clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analogue scale twice: once prior and once after bicycle exercise stress testing. BNP measurements were obtained before, immediately and 2h after stress testing in a blinded manner. The presence of myocardial ischemia was adjudicated based on perfusion SPECT combined with coronary angiography findings. Results Exercise-induced myocardial ischemia was adjudicated to be present in 103 (38%) patients. BNP levels were significantly higher at all time points in patients with myocardial ischemia as compared to those without (p<0.01 for all).The accuracy of BNP levels as quantified by the area under the ROC curve (AUC) was similar among the time points evaluated (AUC 0.677-0.697). Combining clinical judgment prior exercise testing with BNP levels at rest increased diagnostic accuracy from AUC 0.708 to 0.754 (p=0.018). When combining clinical judgment after exercise testing with BNP levels, AUC increased from 0.741 to 0.771. (p=0.055). Conclusion Combining clinical judgment with BNP levels increased the diagnostic accuracy regarding the presence of myocardial ischemia.
    The American journal of medicine 05/2014; 127(5). DOI:10.1016/j.amjmed.2014.01.009 · 5.30 Impact Factor
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    ABSTRACT: Endothelial dysfunction plays a major role in cardiovascular diseases, including acute myocardial infarction (AMI). However, its quantification has not been available as a clinical tool. In a prospective international multicentre study, we analyzed the diagnostic and prognostic utility of endothelial dysfunction as quantified by C-terminal proendothelin-1 (CT-proET-1) in 658 consecutive patients presenting with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long-term for mortality. The adjudicated final diagnosis was AMI in 145 patients (22%). The diagnostic performance of CT-proET-1 for AMI was moderate; its area under the receiver operating characteristic (ROC) curve amounted to 0.66 (95% confidence interval [CI], 0.61-0.72; P < 0.001). There was no significant increase in the AUC when CT-proET-1 was added to either cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT). Seventy four percent of patients who died during the first 24 months (n = 50) were in the fourth quartile of the CT-proET-1 presentation value (>82 pmol/L). The prognostic accuracy of CT-proET-1 regarding mortality was tantamount to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outperformed cTnT and hs-cTnT both in patients with AMI and in patients without acute coronary syndrome. CT-proET-1 at presentation yielded high prognostic accuracy that was similar to that of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score could be significantly improved by adding CT-proET-1 (integrated discriminatory improvement [IDI] of 0.074 P = 0.004). Use of CT-proET-1 improves risk stratification of unselected patients with suspected AMI. CT-proET-1 did not provide additional diagnostic value.
    The Canadian journal of cardiology 02/2014; 30(2):195-203. DOI:10.1016/j.cjca.2013.11.020 · 3.94 Impact Factor
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    ABSTRACT: Midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-vasopressin (copeptin) are novel biomarkers providing prognostic information in various settings. We aimed to (1) assess the kinetics of MR-proADM and copeptin during cardiopulmonary exercise testing (CPET); (2) assess the relationship of MR-proADM and copeptin measured at rest with peak oxygen consumption (peak VO2) and other key CPET parameters; (3) compare this relationship to that of B-type natriuretic peptide (BNP). In 162 patients undergoing symptom-limited CPET for evaluation of exercise intolerance, MR-proADM, copeptin, and BNP were measured at rest and peak exercise. There was a significant rise in copeptin and BNP (p < 0.001) but not in MR-proADM (p = 0.60) from rest to peak exercise. MR-proADM (r = -0.57; p < 0.001) and BNP (r = -0.49; p < 0.001) but not copeptin were significantly and inversely related to peak VO2. MR-proADM was inversely correlated to the percentage of predicted heart rate achieved and peak oxygen pulse and directly related to the peak ventilation/carbon dioxide production relationship, the physiological dead space-to-tidal volume ratio, and the alveolo-arterial oxygen gradient (p ≤ 0.01 for all), and these associations were at least as strong as for BNP. In contrast, copeptin was not significantly related to any of these parameters (p > 0.05 for all). In contrast to BNP and copeptin, MR-proADM is not immediately affected by a maximal exercise test. MR-proADM but not copeptin is at least as good an indicator of low peak VO2 and CPET parameters reflecting an impaired cardiac output reserve, ventilatory efficiency and diffusion capacity as BNP, and thereby a global cardiopulmonary stress marker.
    Arbeitsphysiologie 01/2014; 114(4). DOI:10.1007/s00421-013-2815-4 · 2.30 Impact Factor
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    ABSTRACT: Several high-sensitivity cardiac troponin (hs-cTn) assays have recently been developed. It is unknown which hs-cTn provides the most accurate prognostic information and to what extent early changes in hs-cTn predict mortality. In a prospective, international multicentre study, cTn was simultaneously measured with three novel [high-sensitivity cardiac Troponin T (hs-cTnT), Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI, Siemens] and a conventional assay (cTnT, Roche Diagnostics) in a blinded fashion in 1117 unselected patients with acute chest pain. Patients were followed up 2 years regarding mortality. Eighty-two (7.3%) patients died during the follow-up. The 2-year prognostic accuracy of hs-cTn was most accurate for hs-cTnT [area under the receivers operating characteristic curve (AUC) 0.78 (95% CI: 0.73-0.83) and outperformed both hs-cTnI (Beckman-Coulter, 0.71 (95% CI: 0.65-0.77; P = 0.001 for comparison), hs-cTnI (Siemens) 0.70 (95% CI: 0.64-0.76; P < 0.001 for comparison)] and cTnT 0.67 (95% CI: 0.61-0.74; P < 0.001 for comparison). Absolute changes of hs-cTnT were more accurate than relative changes in predicting mortality, but inferior to presentation values of hs-cTnT. Combining changes of hs-cTnT within the first 6 h with their presentation values did not further improve prognostic accuracy. Similar results were obtained for both hs-cTnI assays regarding the incremental value of changes. Hs-cTn concentrations remained predictors of death in clinically challenging subgroups such as patients with pre-existing coronary artery disease, impaired renal function, and patients older than 75 years. High-sensitivity cardiac Troponin T is more accurate than hs-cTnI in the prediction of long-term mortality. Changes of hs-cTn do not seem to further improve risk stratification beyond initial presentation values.
    European Heart Journal 07/2013; 35(6). DOI:10.1093/eurheartj/eht218 · 14.72 Impact Factor
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    ABSTRACT: Objective To analyse whether levels of high-sensitivity cardiac troponin (hs-cTn) below their respective 99th percentile can be used as a single parameter to rule out acute myocardial infarction (AMI) at presentation. Design Prospective, multicentre study. Main outcome measures We measured hs-cTn using four different methods (hs-cTnT Roche, hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting to the emergency department with acute chest pain. Two independent cardiologists adjudicated the final diagnosis. Patients were followed for death or AMI during a mean period of 24 months. Results Among 2072 consecutive patients with hs-cTnT measurements available, 21.4% had an adjudicated diagnosis of AMI (sensitivity 89.6%, 95% CI 86.4% to 92.3%, negative predictive value (NPV): 96.5%, 95% CI 95.4% to 97.4%). Among 1180 consecutive patients with hs-cTnI Siemens measurements available, 20.0% had AMI (sensitivity 94.1%, 95% CI 90.3% to 96.7%, NPV: 98.0%, 95% CI: 96.6% to 98.9%). Among 1151 consecutive patients with hs-cTnI Beckman Coulter measurements available, 19.7% had AMI (sensitivity 92.1%, 95% CI 87.8% to 95.2%, NPV: 97.5%, 95% CI 96.0% to 98.5%). Among 1567 consecutive patients with hs-cTnI Abbott measurements available, 20.0% had AMI (sensitivity 77.2%, 95% CI 72.1% to 81.7%, NPV: 94.3%, 95% CI 92.8% to 95.5%). Conclusions Normal hs-cTn levels at presentation should not be used as a single parameter to rule out AMI as 6%–23% of adjudicated AMI cases had normal levels of hs-cTn levels at presentation. Our data highlight the lack of standardisation among hs-cTnI assays resulting in substantial differences in sensitivity and NPV at the 99th percentile.
    Heart (British Cardiac Society) 04/2013; 99(21). DOI:10.1136/heartjnl-2013-303643 · 6.02 Impact Factor
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    ABSTRACT: OBJECTIVE: To investigate the diagnostic and prognostic role of heart-type fatty acid-binding protein (hFABP) compared with copeptin and in addition to high-sensitivity cardiac troponin T (hs-cTnT) in patients with chest pain suspected of acute myocardial infarction (AMI). DESIGN: Diagnostic and prognostic performances of hFABP, copeptin and hs-cTnT were evaluated and compared. The final diagnosis was adjudicated by two independent cardiologists. SETTING: This prospective observational multicentre study took place in four primary and one secondary hospital from April 2006 to September 2009. PATIENTS: We enrolled 1247 consecutive patients with suspected AMI to the emergency department. For analysis, patients were included, if baseline levels for hs-cTnT and hFABP were available (n=1074), patients with ST-segment elevation myocardial infarction (STEMI) were excluded for the diagnostic analysis (n=43). INTERVENTIONS: Treatment was left to the discretion of the emergency physician. MAIN OUTCOME MEASURES: AMI and mortality. RESULTS: 4% of the patients had STEMI and 16% of the patients had non-STEMI. Patients with AMI had significantly higher levels of hFABP at presentation (p<0.001). Neither the combination with hFABP nor with copeptin increased the diagnostic accuracy of hs-cTnT at admission, quantified by the area under the receiver operating characteristic curve (AUC) (p>0.05). The negative predictive value regarding 90-day, 1-year and 2-year mortality was 100% (99-100), 99% (98-100) and 98% (96-99), respectively, for hFABP levels below the median (p<0.001). The accuracy of hFABP to predict 90-day mortality was moderate (AUC 0.83; 95% CI 0.77 to 0.90). CONCLUSIONS: hFABP and copeptin do not improve the diagnosis of patients with chest pain without ST-segment elevation, but may be useful for risk stratification beyond hs-TnT.
    Heart (British Cardiac Society) 03/2013; 99(10). DOI:10.1136/heartjnl-2012-303325 · 6.02 Impact Factor
  • Circulation 01/2013; 127(3):e355-6. DOI:10.1161/CIRCULATIONAHA.112.145201 · 14.95 Impact Factor
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    ABSTRACT: The study objective was to compare the incidence and prognosis of acute myocardial infarction when using high-sensitivity cardiac troponin assays instead of a standard cardiac troponin assay for the diagnosis of acute myocardial infarction. In a prospective international multicenter study, we enrolled 1124 consecutive patients presenting with suspected acute myocardial infarction. Final diagnoses were adjudicated by 2 independent cardiologists 2 times using all available clinical information: first using standard cardiac troponin levels and second using high-sensitivity cardiac troponin T levels for adjudication. Patients were followed up for a mean of 19±9 months. The use of high-sensitivity cardiac troponin T instead of standard cardiac troponin resulted in an increase in the incidence of acute myocardial infarction from 18% to 22% (242 vs 198 patients), a relative increase of 22%. Of the 44 additional acute myocardial infarctions, 35 were type 1 acute myocardial infarctions and 9 were type 2 acute myocardial infarctions. This was accompanied by a reciprocal decrease in the incidence of unstable angina (unstable angina, 11% vs 13%). The most pronounced increase was observed in patients adjudicated with cardiac symptoms of origin other than coronary artery disease with cardiomyocyte damage (83 vs 31 patients, relative increase of 268%). Cumulative 30-month mortality rates were 4.8% in patients without acute myocardial infarction, 16.4% in patients with a small acute myocardial infarction detected only by high-sensitivity cardiac troponin T but not standard cardiac troponin, and 23.9% in patients with a moderate/large acute myocardial infarction according to standard cardiac troponin assays and high-sensitivity cardiac troponin T (P<.001). The introduction of high-sensitivity cardiac troponin assays leads to only a modest increase in the incidence of acute myocardial infarction. The novel sensitive assays identify an additional high-risk group of patients with increased mortality, therefore appropriately classified with acute myocardial infarction (Advantageous Predictors of Acute Coronary Syndromes Evaluation; NCT00470587).
    The American journal of medicine 12/2012; 125(12):1205-1213.e1. DOI:10.1016/j.amjmed.2012.07.015 · 5.30 Impact Factor
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    ABSTRACT: BACKGROUND High-sensitivity cardiac troponin (hs-cTn) assays seem to improve the early diagnosis of acute myocardial infarction (AMI), but it is unknown how to best use them in clinical practice. Our objective was to develop and validate an algorithm for rapid rule-out and rule-in of AMI. METHODS A prospective multicenter study enrolling 872 unselected patients with acute chest pain presenting to the emergency department. High-sensitivity cardiac troponin T (hs-cTnT) was measured in a blinded fashion at presentation and after 1 hour. The final diagnosis was adjudicated by 2 independent cardiologists. An hs-cTnT algorithm incorporating baseline values as well as absolute changes within the first hour was derived from 436 randomly selected patients and validated in the remaining 436 patients. The primary prognostic end point was death during 30 days of follow-up. RESULTS Acute myocardial infarction was the final diagnosis in 17% of patients. After applying the hs-cTnT algorithm developed in the derivation cohort to the validation cohort, 259 patients (60%) could be classified as "rule-out," 76 patients (17%) as "rule-in," and 101 patients (23%) as in the "observational zone" within 1 hour. Overall, this resulted in a sensitivity and negative predictive value of 100% for rule-out, a specificity and positive predictive value of 97% and 84%, respectively, for rule-in, and a prevalence of AMI of 8% in the observational zone group. Cumulative 30-day survival was 99.8%, 98.6%, and 95.3% (P < .001) in patients classified as rule-out, observational zone, and rule-in, respectively. CONCLUSIONS Using a simple algorithm incorporating hs-cTnT baseline values and absolute changes within the first hour allowed a safe rule-out as well as an accurate rule-in of AMI within 1 hour in 77% of unselected patients with acute chest pain. This novel strategy may obviate the need for prolonged monitoring and serial blood sampling in 3 of 4 patients.
    Archives of internal medicine 08/2012; 172(16):1211-8. DOI:10.1001/archinternmed.2012.3698 · 13.25 Impact Factor
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    ABSTRACT: Background-We hypothesized that high-sensitivity cardiac troponin (hs-cTn) and its early change are useful in distinguishing acute myocardial infarction (AMI) from acute cardiac noncoronary artery disease. Methods and Results-In a prospective, international multicenter study, hs-cTn was measured with 3 assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI Siemens) in a blinded fashion at presentation and serially thereafter in 887 unselected patients with acute chest pain. Accuracy of the combination of presentation values with serial changes was compared against a final diagnosis adjudicated by 2 independent cardiologists. AMI was the adjudicated final diagnosis in 127 patients (15%); cardiac noncoronary artery disease, in 124 (14%). Patients with AMI had higher median presentation values of hs-cTnT (0.113 μg/L [interquartile range, 0.049 -0.246 μg/L] versus 0.012 μg/L [interquartile range, 0.006 -0.034 μg/L]; P<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 μg/L [interquartile range, 0.007- 0.067 μg/L] versus 0.001 μg/L [interquartile range, 0-0.003 μg/L]; P<0.001) than patients with cardiac noncoronary artery disease. Similar findings were obtained with the hs-cTnI assays. Adding changes of hs-cTn in the first hour to its presentation value yielded a diagnostic accuracy for AMI as quantified by the area under the receiver-operating characteristics curve of 0.94 for hs-cTnT (0.92 for both hs-cTnI assays). Algorithms using ST-elevation, presentation values, and changes in hs-cTn in the first hour accurately separated patients with AMI and those with cardiac noncoronary artery disease. These findings were confirmed when the final diagnosis was readjudicated with the use of hs-cTnT values and validated in an independent validation cohort. Conclusion-The combined use of hs-cTn at presentation and its early absolute change excellently discriminates between patients with AMI and those with cardiac noncoronary artery disease.
    Circulation 05/2012; 126(1):31-40. DOI:10.1161/CIRCULATIONAHA.112.100867 · 14.95 Impact Factor
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    ABSTRACT: It is unknown to what extent noncardiac causes, including renal dysfunction, may contribute to high-sensitivity cardiac troponin T levels. In an observational international multicenter study, we enrolled consecutive patients presenting with acute chest pain to the emergency department. Of 1181 patients enrolled, 572 were adjudicated by 2 independent cardiologists to have a noncardiac cause of chest pain. Multiple linear regression analyses were used to determine the important predictors of log-transformed high-sensitivity cardiac troponin T. Kaplan-Meier curve was used to assess the prognostic significance of high-sensitivity cardiac troponin T>0.014 μg/L (99th percentile). A total of 88 patients (15%) had high-sensitivity cardiac troponin T>0.014 μg/L. Less than 50% of cardiac troponins could be explained by known cardiac or noncardiac diseases. In decreasing order of importance, age, estimated glomerular filtration rate, hypertension, previous myocardial infarction, and chronic kidney disease (adjusted r(2) 0.44) emerged as significant factors in linear regression analysis to predict high-sensitivity cardiac troponin T. High-sensitivity cardiac troponin T was best explained by a linear curve with age as ≤0.014 μg/L. Patients with high-sensitivity cardiac troponin T levels>0.014 μg/L were at increased risk for all-cause mortality (hazard ratio 3.0; 95% confidence interval, 0.8-10.6; P=.02) during follow-up. Among the known covariates, age and not renal dysfunction is the most important determinant of high-sensitivity cardiac troponin T. Because known cardiac and noncardiac factors, including renal dysfunction, explain less than 50% of high-sensitivity cardiac troponin T levels among patients with a noncardiac cause of chest pain, unknown or underestimated cardiac involvement during the acute presenting condition seems to be the major cause of elevated high-sensitivity cardiac troponin T.
    The American journal of medicine 05/2012; 125(5):491-498.e1. DOI:10.1016/j.amjmed.2011.10.031 · 5.30 Impact Factor
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    ABSTRACT: BACKGROUND: Patients with acute chest pain having serial undetectable cardiac troponin (cTn) levels, as measured with conventional assays, are considered at very low risk. The aim of this multicenter study was to determine the accuracy of multiple biomarkers in these patients. METHODS: We enrolled 1247 consecutive patients with suspected AMI. Of these, 325 had undetectable levels of cTnT (Roche, 4th generation assay) at presentation and at 6h. Fourteen novel markers quantifying cardiomyocyte damage, inflammation and/or plaque rupture, and neurohormonal activation were measured at presentation. The occurrence of death or acute myocardial infarction (AMI) (primary end point) and unplanned coronary revascularization (secondary endpoint) were recorded during long-term follow-up. RESULTS: During a mean follow-up of 668±241days, death/AMI occurred in 23 patients (7%), unplanned revascularization in 46 (14%). Among all biomarkers, high-sensitive cTnT (hs-cTnT), Midregional pro-adrenomedullin (MR-proADM) and growth differentiation factor-15 (GDF-15) were independently associated with future death/AMI; hs-cTnT was 0.013 (0.008-0.017) μg/l versus 0.006 (0.003-0.010) μg/l, MR-proADM was 0.78 (0.66-1.09) nmol/l versus 0.60 (0.18-0.80) nmol/l and GDF-15 was 1800 (1600-2200) ng/l versus 1100 (800-1700) ng/l in patients with versus without death/AMI during follow-up (p<0.001 each). The area under the receiver-operating characteristics curve to predict death/AMI was 0.73 (95%CI 0.63-0.83) for hs-cTnT, 0.71 (95% CI 0.62-0.81) for MR-proADM and 0.78 (95%CI 0.71-0.86) for GDF-15. CONCLUSION: Patients with serial undetectable levels of cTnT using the contemporary 4th generation assay are at low but not negligible risk of future cardiac events. Hs-cTnT, MR-proADM and/or GDF-15 might help to further improve risk-stratification in this group.
    International journal of cardiology 04/2012; 167(4). DOI:10.1016/j.ijcard.2012.03.117 · 6.18 Impact Factor
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    ABSTRACT: The early diagnosis of acute myocardial infarction (AMI) can be particularly challenging in patients with known coronary artery disease (CAD) due to pre-existing ECG changes and chronic increases in cardiac troponin (cTn) levels. Of 1170 consecutive patients presenting with symptoms suggestive of AMI, 433 (37%) with pre-existing CAD were analysed in a prospective multicentre study and the diagnostic and prognostic impact of copeptin in combination with either fourth generation cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT) was evaluated. AMI was the final diagnosis in 78 patients with pre-existing CAD (18%). Copeptin was significantly higher in patients with AMI than in those without (26 pmol/l (IQR 9-71) vs 7 pmol/l (IQR 4-16), p<0.001). The diagnostic accuracy for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was significantly higher for the combination of copeptin and cTnT than for cTnT alone (0.94 vs 0.86, p<0.001). The combination of copeptin and hs-cTnT (0.94) was trending to superiority compared with hs-cTnT alone (0.92, p=0.11). The combination of copeptin and the cTn assays was able to improve the negative predictive value up to 99.5% to rule out AMI. Copeptin was a strong and independent predictor of 1-year mortality (HR 4.18-4.63). Irrespective of cTn levels, patients with low levels of copeptin had an excellent prognosis compared with patients with raised levels of both copeptin and cTn (360-day mortality 2.8-3.6% vs 23.1-33.8%, p<0.001). In patients with pre-existing CAD, copeptin significantly improves the diagnostic accuracy if used in addition to cTnT, but only trended to superiority compared with hs-cTnT alone. Copeptin provides independent prognostic information, largely by overcoming the challenging interpretation of mild increases in hs-cTnT. ClinicalTrials Gov number NCT00470587.
    Heart (British Cardiac Society) 02/2012; 98(7):558-65. DOI:10.1136/heartjnl-2011-301269 · 6.02 Impact Factor