Nicolas Schaerli

Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction

Aims High-sensitivity cardiac troponin (hs-cTn) assays provide higher diagnostic accuracy for acute myocardial infarction (AMI) when compared with conventional assays, but may result in increased use of unnecessary coronary angiographies due to their increased detection of cardiomyocyte injury in conditions other than AMI. Methods and results We evaluated the impact of the clinical introduction of high-sensitivity cardiac troponin T (hs-cTnT) on the use of coronary angiography, stress testing, and time to discharge in 2544 patients presenting with symptoms suggestive of AMI to the emergency department (ED) within a multicentre study either before (1455 patients) or after (1089 patients) hs-cTnT introduction. Acute myocardial infarction was more often the clinical discharge diagnosis after hs-cTnT introduction (10 vs. 14%, P < 0.001), while unstable angina less often the clinical discharge diagnosis (14 vs. 9%, P = 0.007). The rate of coronary angiography was similar before and after the introduction of hs-cTnT (23 vs. 23%, P = 0.092), as was the percentage of coronary angiographies showing no stenosis (11 vs. 7%, P = 0.361). In contrast, the use of stress testing was substantially reduced from 29 to 19% (P < 0.001). In outpatients, median time to discharge from the ED decreased by 79 min (P < 0.001). Mean total costs decreased by 20% in outpatients after the introduction of hs-cTnT (P = 0.002). Conclusion The clinical introduction of hs-cTn does not lead to an increased or inappropriate use of coronary angiography. Introduction of hs-cTn is associated with an improved rule-out process and thereby reduces the need for stress testing and time to discharge. Clinical Trial Registration Information www.clinicaltrials.gov. Identifier, NCT00470587.

Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I

Background: Four strategies for very early rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I (hs-cTnI) have been identified. It remains unclear which strategy is most attractive for clinical application. Methods: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnI levels were measured at presentation and after 1 hour in a blinded fashion. We directly compared all 4 hs-cTnI–based rule-out strategies: limit of detection (LOD, hs-cTnI<2 ng/L), single cutoff (hs-cTnI<5 ng/L), 1-hour algorithm (hs-cTnI<5 ng/L and 1-hour change<2 ng/L), and the 0/1-hour algorithm recommended in the European Society of Cardiology guideline combining LOD and 1-hour algorithm. Results: Among 2828 enrolled patients, acute myocardial infarction was the final diagnosis in 451 (16%) patients. The LOD approach ruled out 453 patients (16%) with a sensitivity of 100% (95% confidence interval [CI], 99.2%–100%), the single cutoff 1516 patients (54%) with a sensitivity of 97.1% (95% CI, 95.1%–98.3%), the 1-hour algorithm 1459 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%–99.2%), and the 0/1-hour algorithm 1463 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%–99.2%). Predefined subgroup analysis in early presenters (⩽2 hours) revealed significantly lower sensitivity (94.2%, interaction P=0.03) of the single cutoff, but not the other strategies. Two-year survival was 100% with LOD and 98.1% with the other strategies (P<0.01 for LOD versus each of the other strategies). Conclusions: All 4 rule-out strategies balance effectiveness and safety equally well. The single cutoff should not be applied in early presenters, whereas the 3 other strategies seem to perform well in this challenging subgroup. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Clinical Effect of Sex-Specific Cutoff Values of High-Sensitivity Cardiac Troponin T in Suspected Myocardial Infarction.

Importance It is currently unknown whether the uniform (universal clinical practice for more than 2 decades) or 2 sex-specific cutoff levels are preferable when using high-sensitivity cardiac troponin T (hs-cTnT) levels in the diagnosis of acute myocardial infarction (AMI). Objective To improve the management of suspected AMI in women by exploring sex-specific vs uniform cutoff levels for hs-cTnT. Design, Setting, and Participants In an ongoing prospective, diagnostic, multicenter study conducted at 9 emergency departments, the present study evaluated patients enrolled from April 21, 2006, through June 5, 2013. The participants included 2734 adults presenting with suspected AMI. Duration of follow-up was 2 years, and data analysis occurred from June 5 to December 21, 2015. Interventions The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including measurements of serial hs-cTnT blood concentrations twice: once using the uniform 99th percentile cutoff value level of 14 ng/L and once using sex-specific 99th percentile levels of hs-cTnT (women, 9 ng/L; men, 15.5 ng/L). Main Outcomes and Measures Diagnostic reclassification in women and men using sex-specific vs the uniform cutoff level in the diagnosis of AMI. Results Of the 2734 participants, 876 women (32%) and 1858 men (68%) were included. Median (interquartile range) age was 68 (55-77) and 59 (48-71) years, respectively. With the use of the uniform cutoff value, 127 women (14.5%) and 345 men (18.6%) received a final diagnosis of AMI. Among these, at emergency department presentation, levels of hs-cTnT were already above the uniform cutoff value in 427 patients (sensitivity, 91.3% [95% CI, 85%-95.6%] in women vs 90.7% [95% CI, 87.1%-93.5% in men]; specificity, 79.2% [95% CI, 76.1%-82.1%] in women vs 78.5% [95% CI, 76.4%-80.6%] in men). After readjudication using sex-specific 99th percentile levels, diagnostic reclassification regarding AMI occurred in only 3 patients: 0.11% (95% CI, 0.02-0.32) of all patients and 0.6% (95% CI, 0.13-1.85) of patients with AMI. The diagnosis in 2 women was upgraded from unstable angina to AMI, and the diagnosis in 1 man was downgraded from AMI to unstable angina. These diagnostic results were confirmed when using 2 alternative pairs of uniform and sex-specific cutoff values. Conclusions and Relevance The uniform 99th percentile should remain the standard of care when using hs-cTnT levels for the diagnosis of AMI.

Direct comparison of cardiac troponin I and cardiac troponin T in the detection of exercise-induced myocardial ischemia

BACKGROUND It is unknown, whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the detection of exercise-induced myocardial ischemia. METHODS We investigated patients with suspected myocardial ischemia referred for exercise or pharmacological rest/stress myocardial perfusion single-photon emission computed tomography (SPECT) to directly compare the diagnostic accuracy of high-sensitivity cTnI (hs-cTnI) and hs-cTnT. Diagnostic performance was analyzed separately according to stress modality. Hs-cTnI and hs-cTnT were measured before, immediately after, as well as 2h and 4h after maximal exercise in a blinded fashion. Further, all clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: once prior and once after stress-testing. The presence of stress-induced myocardial ischemia was adjudicated using SPECT combined with coronary angiography findings. RESULT A total of 403 consecutive patients were enrolled in our study, of which 229 underwent exercise stress and 174 patients pharmacological stress. Exercise-stress-induced myocardial ischemia was detected in 90 patients (39.3% of 229). Levels of hs-cTnI and hs-cTnT were both significantly higher at all time-points examined in patients with exercise-induced myocardial ischemia as compared to patients without myocardial ischemia (all p<0.001). Correlation of hs-cTnI and hs-cTnT was high in direct comparison of time-points (Spearmans rho all ≥0.7). The AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.71/0.71/0.72/0.69 vs. 0.74/0.73/0.71/0.72, respectively (all p=ns for hs-cTnI versus hs-cTnT). In patients undergoing pharmacological stress, the AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.66/0.66/0.68/0.67 and 0.61/0.62/0.64/0.59, respectively (all p=ns for hs-cTnI versus hs-cTnT). Also the combinations including clinical judgment or changes during serial sampling were similar for hs-cTnI and hs-cTnT (all p=ns). CONCLUSIONS Hs-cTnI and hs-cTnT provide comparable diagnostic information regarding exercise-induced myocardial ischemia. Overall, their diagnostic accuracy seems moderate. UNIQUE IDENTIFIER NCT01838148.

Prospective Validation of a Biomarker-Based Rule Out Strategy for Functionally Relevant Coronary Artery Disease

BACKGROUND This study aimed to prospectively advance a rule-out strategy for functionally significant coronary artery disease (CAD) by use of high-sensitivity cardiac troponin I (hs-cTnI) from bench to bedside, by application of a 3-step approach: validation in serum, correlation in plasma, and application on a clinical platform. METHODS Patients without known CAD referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT) were assigned to 3 consecutive cohorts: validation, correlation, and application. Functionally relevant CAD was adjudicated with the use of expert interpretation of MPI-SPECT/CT and, if available, coronary angiography. In the validation cohort resting hs-cTnI was measured in serum before stress testing with the research Erenna system, in serum and plasma in the correlation cohort with the research Erenna system, and in plasma in the application cohort with the clinical Clarity system. RESULTS Overall, functionally relevant CAD was adjudicated in 21% (304/1478) of patients. In the validation cohort (n = 613), hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (median 2.8 ng/L vs 1.9 ng/L, P < 0.001) as compared to patients without functionally relevant CAD and allowed a rule out with 95% sensitivity in 14% of patients. In the correlation cohort (n = 606), hs-cTnI concentrations in serum and plasma strongly correlated (Spearman r = 0.921) and had similar diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (0.686 vs 0.678, P = 0.425). In the application cohort (n = 555), very low hs-cTnI plasma concentrations (< 0.5 ng/L) ruled out functionally relevant CAD with 95% sensitivity in 10% of patients. CONCLUSIONS A single resting plasma hs-cTnI measurement can safely rule out functionally relevant CAD in around 10% of patients without known CAD.

Diagnostic value of ST-segment deviations during cardiac exercise stress testing: Systematic comparison of different ECG leads and time-points

BACKGROUND Exercise ECG stress testing is the most widely available method for evaluation of patients with suspected myocardial ischemia. Its major limitation is the relatively poor accuracy of ST-segment changes regarding ischemia detection. Little is known about the optimal method to assess ST-deviations. METHODS A total of 1558 consecutive patients undergoing bicycle exercise stress myocardial perfusion imaging (MPI) were enrolled. Presence of inducible myocardial ischemia was adjudicated using MPI results. The diagnostic value of ST-deviations for detection of exercise-induced myocardial ischemia was systematically analyzed 1) for each individual lead, 2) at three different intervals after the J-point (J+40ms, J+60ms, J+80ms), and 3) at different time points during the test (baseline, maximal workload, 2min into recovery). RESULTS Exercise-induced ischemia was detected in 481 (31%) patients. The diagnostic accuracy of ST-deviations was highest at +80ms after the J-point, and at 2min into recovery. At this point, ST-amplitude showed an AUC of 0.63 (95% CI 0.59-0.66) for the best-performing lead I. The combination of ST-amplitude and ST-slope in lead I did not increase the AUC. Lead I reached a sensitivity of 37% and a specificity of 83%, with similar sensitivity to manual ECG analysis (34%, p=0.31) but lower specificity (90%, p<0.001). CONCLUSION When using ECG stress testing for evaluation of patients with suspected myocardial ischemia, the diagnostic accuracy of ST-deviations is highest when evaluated at +80ms after the J-point, and at 2min into recovery.

Impact of age on the performance of the ESC 0/1h-algorithms for early diagnosis of myocardial infarction

Aims We aimed to evaluate the impact of age on the performance of the European Society of Cardiology (ESC) 0/1h-algorithms and to derive and externally validate alternative cut-offs specific to older patients. Methods and results We prospectively enrolled patients presenting to the emergency department (ED) with symptoms suggestive of acute myocardial infarction in three large diagnostic studies. Final diagnoses were adjudicated by two independent cardiologists. High-sensitivity cardiac troponin (hs-cTn) T and I concentrations were measured at presentation and after 1 h. Patients were stratified according to age [<55 years (young), ≥55 to <70 years (middle-age), ≥70 years (old)]. Rule-out safety of the ESC hs-cTnT 0/1h-algorithm was very high in all age-strata: sensitivity 100% [95% confidence interval (95% CI) 94.9-100] in young, 99.3% (95% CI 96.0-99.9) in middle-age, and 99.3% (95% CI 97.5-99.8) in old patients. Accuracy of rule-in decreased with age: specificity 97.0% (95% CI 95.8-97.9) in young, 96.1% (95% CI 94.5-97.2) in middle-age, and 92.7% (95% CI 90.7-94.3) in older patients. Triage efficacy decreased with increasing age (young 93%, middle-age 80%, old 55%, P < 0.001). Similar results were found for the ESC hs-cTnT 0/1h-algorithm. Alternative, slightly higher cut-off concentrations optimized for older patients maintained very high safety of rule-out, increased specificity of rule-in (P < 0.01), reduced overall efficacy for hs-cTnT (P < 0.01), while maintaining efficacy for hs-cTnI. Findings were confirmed in two validation cohorts (n = 2767). Conclusion While safety of the ESC 0/1h-algorithms remained very high, increasing age significantly reduced overall efficacy and the accuracy of rule-in. Alternative slightly higher cut-off concentrations may be considered for older patients, particularly if using hs-cTnI. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587 and NCT02355457 (BACC).

Direct Comparison of Cardiac Troponin T and I Using a Uniform and a Sex-Specific Approach in the Detection of Functionally Relevant Coronary Artery Disease

BACKGROUND We aimed to directly compare high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in the detection of functionally relevant coronary artery disease (fCAD). METHODS Consecutive patients referred with clinical suspicion of fCAD and no structural heart disease other than coronary artery disease were included. The presence of fCAD was based on rest/stress myocardial perfusion single-photon emission computed tomography/computed tomography and coronary angiography. hs-cTnI and hs-cTnT concentrations were measured in a blinded fashion. Diagnostic accuracy was quantified using the area under the ROC curve (AUC) and evaluated both for uniform use in all patients and for sex-specific use in women and men separately. The prognostic end point was major adverse cardiac events (MACEs; cardiovascular death or myocardial infarction) within 2 years. For the prognostic performance, we used a multivariable model comparison with the Akaike information criterion (AIC). RESULTS fCAD was detected in 613 of 2062 patients (29.7%) overall, 112 of 664 of women (16.9%), and 501 of 1398 of men (35.8%). hs-cTnI and hs-cTnT had comparable diagnostic accuracy when assessed for uniform use in all patients (AUC, 0.68 vs 0.66; P = 0.107) and separately in women (AUC, 0.68 vs 0.63; P = 0.068) and men (AUC, 0.65 vs 0.64; P = 0.475). However, women required lower rule-out cutoffs to achieve high sensitivity, and men needed higher rule-in cutoffs to achieve high specificity. hs-cTnI and hs-cTnT were strongly and independently associated with MACE within 2 years (P < 0.001), with comparable prognostic accuracies by the AIC. CONCLUSIONS hs-cTnI and hs-cTnT provide moderate and comparable diagnostic accuracy. Sex-specific cutoffs may be preferred. The prognostic utility of both troponins is comparable.

Diagnostic value of the cardiac electrical biomarker, a novel ECG marker indicating myocardial injury, in patients with symptoms suggestive of non-ST-elevation myocardial infarction

The cardiac electrical biomarker (CEB) is a novel electrocardiographic (ECG) marker quantifying the dipolar activity of the heart with higher levels indicating myocardial injury.

Combining high-sensitivity cardiac troponin and B-type natriuretic peptide in the detection of inducible myocardial ischemia

BACKGROUND Single biomarker approaches provide only moderate accuracy in the non-invasive detection of exercise-induced myocardial ischemia. We therefore assessed the combination of the two most promising single biomarkers: high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP). METHODS Consecutive patients with suspected myocardial ischemia referred to stress myocardial perfusion single-photon emission tomography imaging (MPI) were enrolled. Clinical judgment (CJ) of the treating cardiologist regarding myocardial ischemia, quantified using a visual analogue scale, and blood concentrations of hs-cTnI and BNP were determined before and after stress. The presence of myocardial ischemia was adjudicated by independent cardiologists using MPI, blinded to biomarker measurements. Death and acute myocardial infarction (AMI) during follow-up were the prognostic endpoints. RESULTS Among 1142 consecutive patients inducible myocardial ischemia was found in 456 (40%) of all patients. For the detection of inducible myocardial ischemia, CJ before exercise stress testing (CJb) showed an area under the receiver-operating-characteristics curve (AUC) of 0.66 (95%CI 0.63-0.69), hs-cTnI 0.70 (95%CI 0.67-0.73, p=0.07 vs CJb), and BNP 0.66 (95%CI 0.62-0.69, p=0.98). The use of a dual-biomarker strategy combining hs-cTnI and BNP with CJb did not provide a significant advantage over the combination of hs-cTnI alone and CJb (AUC 0.74, 95%CI 0.72-0.77 vs AUC 0.74, 95%CI 0.71-0.77, p=0.16). Hs-cTnI showed good prognostic value for AMI (HR 1.6, 95%CI 1.3-1.9), and BNP for death (HR 1.6, 95%CI 1.3-2.1). CONCLUSION A dual-biomarker strategy combing BNP and hs-cTnI does not further increase diagnostic accuracy on top of clinical judgment and hs-cTnI alone. SUMMARY AND HIGHLIGHTS We included 1142 consecutive patients with suspected inducible ischemia, and evaluated the added value of the biomarkers high-sensitivity cardiac troponin (hs-cTn) and B-type natriuretic peptide (BNP), alone and in combination, on top of clinical judgment. CLINICAL TRIAL REGISTRATION Biochemical and Electrocardiographic Signatures in the Detection of Exercise-induced Myocardial Ischemia (BASEL VIII), NCT01838148, https://clinicaltrials.gov/ct2/show/NCT01838148.