Tobias Reichlin

Early Diagnosis of Myocardial Infarction with Sensitive Cardiac Troponin Assays

BACKGROUND The rapid and reliable diagnosis of acute myocardial infarction is a major unmet clinical need. METHODS We conducted a multicenter study to examine the diagnostic accuracy of new, sensitive cardiac troponin assays performed on blood samples obtained in the emergency department from 718 consecutive patients who presented with symptoms suggestive of acute myocardial infarction. Cardiac troponin levels were determined in a blinded fashion with the use of four sensitive assays (Abbott-Architect Troponin I, Roche High-Sensitive Troponin T, Roche Troponin I, and Siemens Troponin I Ultra) and a standard assay (Roche Troponin T). The final diagnosis was adjudicated by two independent cardiologists. RESULTS Acute myocardial infarction was the adjudicated final diagnosis in 123 patients (17%). The diagnostic accuracy of measurements obtained at presentation, as quantified by the area under the receiver-operating-characteristic curve (AUC), was significantly higher with the four sensitive cardiac troponin assays than with the standard assay (AUC for Abbott-Architect Troponin I, 0.96; 95% confidence interval [CI], 0.94 to 0.98; for Roche High-Sensitive Troponin T, 0.96; 95% CI, 0.94 to 0.98; for Roche Troponin I, 0.95; 95% CI, 0.92 to 0.97; and for Siemens Troponin I Ultra, 0.96; 95% CI, 0.94 to 0.98; vs. AUC for the standard assay, 0.90; 95% CI, 0.86 to 0.94). Among patients who presented within 3 hours after the onset of chest pain, the AUCs were 0.93 (95% CI, 0.88 to 0.99), 0.92 (95% CI, 0.87 to 0.97), 0.92 (95% CI, 0.86 to 0.99), and 0.94 (95% CI, 0.90 to 0.98) for the sensitive assays, respectively, and 0.76 (95% CI, 0.64 to 0.88) for the standard assay. We did not assess the effect of the sensitive troponin assays on clinical management. CONCLUSIONS The diagnostic performance of sensitive cardiac troponin assays is excellent, and these assays can substantially improve the early diagnosis of acute myocardial infarction, particularly in patients with a recent onset of chest pain. (ClinicalTrials.gov number, NCT00470587.)

Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction

Background— Current guidelines for the diagnosis of acute myocardial infarction (AMI), among other criteria, also require a rise and/or fall in cardiac troponin (cTn) levels. It is unknown whether absolute or relative changes in cTn have higher diagnostic accuracy and should therefore be preferred. Methods and Results— In a prospective, observational, multicenter study, we analyzed the diagnostic accuracy of absolute (&Dgr;) and relative (&Dgr;%) changes in cTn in 836 patients presenting to the emergency department with symptoms suggestive of AMI. Blood samples for the determination of high-sensitive cTn T and cTn I ultra were collected at presentation and after 1 and 2 hours in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing AMI was significantly higher for 2-hour absolute (&Dgr;) versus 2-hour relative (&Dgr;%) cTn changes (area under the receiver operating characteristic curve [95% confidence interval], high-sensitivity cTn T: 0.95 [0.92 to 0.98] versus 0.76 [0.70 to 0.83], P<0.001; cTn I ultra: 0.95 [0.91 to 0.99] versus 0.72 [0.66 to 0.79], P<0.001). The receiver operating characteristic curve–derived cutoff value for 2-hour absolute (&Dgr;) change was 0.007 &mgr;g/L for high-sensitivity cTn T and 0.020 &mgr;g/L for cTn I ultra (both cutoff levels are half of the 99th percentile of the respective cTn assay). Absolute changes were superior to relative changes in patients with both low and elevated baseline cTn levels. Conclusions— Absolute changes of cTn levels have a significantly higher diagnostic accuracy for AMI than relative changes, and seem therefore to be the preferred criteria to distinguish AMI from other causes of cTn elevations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Incremental value of copeptin for rapid rule out of acute myocardial infarction.

OBJECTIVES The purpose of this study was to examine the incremental value of copeptin for rapid rule out of acute myocardial infarction (AMI). BACKGROUND The rapid and reliable exclusion of AMI is a major unmet clinical need. Copeptin, the C-terminal part of the vasopressin prohormone, as a marker of acute endogenous stress may be useful in this setting. METHODS In 487 consecutive patients presenting to the emergency department with symptoms suggestive of AMI, we measured levels of copeptin at presentation, using a novel sandwich immunoluminometric assay in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists using all available data. RESULTS The adjudicated final diagnosis was AMI in 81 patients (17%). Copeptin levels were significantly higher in AMI patients compared with those in patients having other diagnoses (median 20.8 pmol/l vs. 6.0 pmol/l, p < 0.001). The combination of troponin T and copeptin at initial presentation resulted in an area under the receiver-operating characteristic curve of 0.97 (95% confidence interval: 0.95 to 0.98), which was significantly higher than the 0.86 (95% confidence interval: 0.80 to 0.92) for troponin T alone (p < 0.001). A copeptin level <14 pmol/l in combination with a troponin T < or =0.01 microg/l correctly ruled out AMI with a sensitivity of 98.8% and a negative predictive value of 99.7%. CONCLUSIONS The additional use of copeptin seems to allow a rapid and reliable rule out of AMI already at presentation and may thereby obviate the need for prolonged monitoring and serial blood sampling in the majority of patients. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE]; NCT00470587).

Early diagnosis of acute myocardial infarction in the elderly using more sensitive cardiac troponin assays.

AIMS To examine the diagnostic accuracy of sensitive cardiac troponin (cTn) assays in elderly patients, since elevated levels with sensitive cTn assays were reported in 20% of elderly patients without acute myocardial infarction (AMI). METHODS AND RESULTS In this multi-centre study, we included 1098 consecutive patients presenting with symptoms suggestive of AMI, 406 (37%) were >70 years old. Measurement of three investigational sensitive cTn assays [Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, and Abbott-Architect cTnI) and the standard assay (Roche cTnT) was performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the adjudicated final diagnosis in 24% of elderly patients. Among elderly patients without AMI, baseline cTn levels were elevated above the 99th percentile in 51% with Roche hs-cTnT, in 17% with Siemens TnI-Ultra, and 13% with Abbott-Architect cTnI. The diagnostic accuracy as quantified by the area under the receiver operating characteristic (ROC) curve (AUC) was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.94; Siemens cTnI-Ultra, 0.95; and Abbott-Architect cTnI, 0.95 vs. AUC for the standard assay, 0.90; P < 0.05 for comparisons). The best cut-offs for the sensitive cTn-assays determined by the ROC-curve in elderly patients differed clearly from those in younger patients. Furthermore, the prognostic value regarding 90-day mortality varied among the sensitive cTn assays. CONCLUSION Sensitive cTn assays have high diagnostic accuracy also in the elderly. Mild elevations are common in elderly non-AMI patients, therefore the optimal cut-off levels are substantially higher in elderly as compared with younger patients. Furthermore, sensitive cTn assays yielded different prognostic value.

High-Sensitivity Cardiac Troponin in the Distinction of Acute Myocardial Infarction From Acute Cardiac Noncoronary Artery Disease

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 &mgr;g/L [interquartile range, 0.049–0.246 &mgr;g/L] versus 0.012 &mgr;g/L [interquartile range, 0.006–0.034 &mgr;g/L]; P<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 &mgr;g/L [interquartile range, 0.007–0.067 &mgr;g/L] versus 0.001 &mgr;g/L [interquartile range, 0–0.003 &mgr;g/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. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin

BACKGROUND We examined whether undetectable levels of high-sensitivity cardiac Troponin (hs-cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED). METHODS AND RESULTS In a prospective multicenter study we used 4 different hs-cTn assays (hs-cTnT Roche, and hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs-cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs-cTnT levels, 21% had an adjudicated diagnosis of AMI. Among AMI patients, 98.2% had initially detectable levels of hs-cTnT (sensitivity 98.2%, 95%CI 96.3%-99.2%, negative predictive value (NPV) 98.6%, 95%CI 97.0%-99.3%). Undetectable levels of hs-cTnT ruled out AMI in 26.5% of patients at presentation. The NPV was similar with the three hs-cTnI assays: among 1180 consecutive patients with available hs-cTnI (Siemens), the NPV was 98.8%; among 1151 consecutive patients with available hs-cTnI (Beckman Coulter), the NPV was 99.2%; among 1567 consecutive patients with available hs-cTnI (Abbott), the NPV was 100.0%. The percentage of patients with undetectable levels of hs-cTnI was similar among the three hs-cTnI assays and ranged from 11.4% to 13.9%. CONCLUSIONS Undetectable levels of hs-cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs-TnT as compared to the investigated hs-cTnI assays.

Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay

Background: 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). Methods: In a multicentre study, we enrolled 1320 patients presenting to the emergency department with suspected acute MI. The high-sensitivity 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. Results: 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 highsensitivity 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). Interpretation: 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. Trial registration: ClinicalTrials.gov, NCT00470587

Introduction of High-sensitivity Troponin Assays: Impact on Myocardial Infarction Incidence and Prognosis

OBJECTIVE 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. METHODS 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. RESULTS 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). CONCLUSIONS 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).

Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction

Background— It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined. Methods and Results— In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease–estimated glomerular filtration rate <60 mL·min−1·1.73 m−2). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction 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 curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve–derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9–3.4). Conclusions— More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Early diagnosis of acute myocardial infarction in patients with pre-existing coronary artery disease using more sensitive cardiac troponin assays

AIMS We sought to examine the diagnostic and prognostic utility of sensitive cardiac troponin (cTn) assays in patients with pre-existing coronary artery disease (CAD). METHODS AND RESULTS We conducted a multicentre study to examine the diagnostic accuracy of one high-sensitive and two sensitive cTn assays in 1098 consecutive patients presenting with symptoms suggestive of acute myocardial infarction (AMI), of whom 401 (37%) had pre-existing CAD. Measurements of Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, Abbott-Architect cTnI and the standard assay (Roche cTnT) were performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the final diagnosis in 19% of CAD patients. Among patients with diagnoses other than AMI, baseline cTn levels were elevated above the 99th percentile with Roche hs-cTnT in 40%, with Siemens TnI-Ultra in 15%, and Abbott-Architect cTnI in 13% of them. In patients with pre-existing CAD, the diagnostic accuracy at presentation, quantified by the area under the receiver operator characteristic curve (AUC), was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.92; Siemens cTnI-Ultra, 0.94; and Abbott-Architect cTnI, 0.93 vs. AUC for the standard assay, 0.87; P < 0.01 for all comparisons). Elevated levels of cTn measured with the sensitive assays predicted mortality irrespective of pre-existing CAD, age, sex, and cardiovascular risk factors. CONCLUSION Sensitive cTn assays have high-diagnostic accuracy also in CAD patients. Mild elevations are common in non-AMI patients and test-specific optimal cut-off levels tend to be higher in CAD patients than in patients without history of CAD. Sensitive cTn assays also retain prognostic value. (ClinicalTrials.gov number, NCT00470587).