Ursina Honegger

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

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.

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.

Clinical benefit of high-sensitivity cardiac troponin I in the detection of exercise-induced myocardial ischemia

BACKGROUND A pilot study using a novel high-sensitivity cardiac troponin I (hs-cTnI) assay suggested that cTnI might be released into blood during exercise-induced myocardial ischemia. We investigated the potential clinical value of this signal. METHODS We included 819 patients with suspected exercise-induced myocardial ischemia referred for rest/bicycle myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: prior and after stress testing. High-sensitivity cTnI measurements were obtained before, immediately after peak stress, and 2 hours after stress testing in a blinded manner. Myocardial ischemia was adjudicated using perfusion single-photon emission computed tomography and coronary angiography findings. RESULTS Exercise-induced myocardial ischemia was detected in 278 (34%) patients. High-sensitivity cTnI levels were significantly higher at all time points in patients with myocardial ischemia as compared with those without (P < .001 for all). Combining clinical judgment prior exercise testing with baseline hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) from 0.672 to 0.757 (P < .001). Combining clinical judgment after exercise testing (AUC 0.704) with baseline or poststress hs-cTnI levels also increased the diagnostic accuracy (AUC 0.761-0.771, P < .001 for all). In contrast, exercise-induced changes in hs-cTnI during exercise did not seem useful, as they were small and similar in patients with or without myocardial ischemia. CONCLUSIONS High-sensitivity cTnI concentrations at rest and after exercise, but not its exercise-induced changes, provide substantial incremental value to clinical judgment including exercise electrocardiography regarding the presence of myocardial ischemia.

Impact of haemoconcentration during acute heart failure therapy on mortality and its relationship with worsening renal function.

Treatment goals in acute heart failure (AHF) are poorly defined. We aimed to characterize further the impact of in‐hospital haemoconcentration and worsening renal function (WRF) on short‐ and long‐term mortality.

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.

Prediction of mortality using quantification of renal function in acute heart failure

BACKGROUND Renal function, as quantified by the estimated glomerular filtration rate (eGFR), is a predictor of death in acute heart failure (AHF). It is unknown whether one of the clinically-available serum creatinine-based formulas to calculate eGFR is superior to the others for predicting mortality. METHODS AND RESULTS We quantified renal function using five different formulas (Cockroft-Gault, MDRD-4, MDRD-6, CKD-EPI in patients<70 years, and BIS-1 in patients≥70 years) in 1104 unselected AHF patients presenting to the emergency department and enrolled in a multicenter study. Two independent cardiologists adjudicated the diagnosis of AHF. The primary endpoint was the accuracy of the five eGFR equations to predict death as quantified by the time-dependent area under the receiver-operating characteristics curve (AUC). The secondary endpoint was the accuracy to predict all-cause readmissions and readmissions due to AHF. In a median follow-up of 374 days (IQR: 221 to 687 days), 445 patients (40.3%) died. eGFR as calculated by all equations was an independent predictor of mortality. The Cockcroft-Gault formula showed the highest prognostic accuracy (AUC 0.70 versus 0.65 for MDRD-4, 0.55 for MDRD-6, and 0.67 for the combined formula CKD-EPI/BIS-1, p<0.05). These findings were confirmed in patients with varying degrees of renal function and in three vulnerable subgroups: women, patients with severe left ventricular dysfunction, and the elderly. The prognostic accuracy for readmission was poor for all equations, with an AUC around 0.5. CONCLUSIONS Calculating eGFR using the Cockcroft-Gault formula assesses the risk of mortality in patients with AHF more accurately than other commonly used formulas.

Prevalence, characteristics and outcome of non-cardiac chest pain and elevated copeptin levels

Objective Copeptin, a quantitative marker of endogenous stress, seems to provide incremental value in addition to cardiac troponin in the early rule-out of acute myocardial infarction (AMI). Prevalence, characteristics and outcome of acute chest pain patients with causes other than AMI and elevated copeptin are poorly understood. Methods A total of 984 consecutive patients with non-cardiac chest pain were selected from a prospective multicentre study of acute chest pain patients presenting to the emergency department. Levels of copeptin were determined in a blinded fashion and considered elevated if above 13 pmol/L (the 97,5th centile of healthy individuals). The final diagnosis was adjudicated by two independent cardiologists. Median duration of follow-up was 756 days. Results Elevated copeptin levels were seen in 215 patients (22%). In comparison to patients with normal copeptin levels, patients with elevated levels were older, had more pre-existing cardiac and non-cardiac disorders, more silent cardiomyocyte injury and increased haemodynamic stress as quantified by levels of high-sensitivity cardiac troponin T (9.6 ng/L (3.6–18.3) vs 5.8 ng/L (2.9–9.4)) and B-type natriuretic peptide (75 ng/L (37–187) vs 35 ng/L (15–77)) (both p<0.001), more electrocardiographic abnormalities, more often an adjudicated diagnosis of gastroesophageal reflux or bronchitis/pneumonia and higher 2- year mortality (HR 2.9, 95% CI 1.5 to 5.7). The increased mortality rate seemed to be largely explained by age and comorbidities. Conclusions Elevated levels of copeptin are present in about one in five patients with non-cardiac chest pain and are associated with aging, cardiac and non-cardiac comorbidities as well as mortality.

B-type Natriuretic Peptide and Clinical Judgment in the Detection of Exercise-induced Myocardial Ischemia

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 before and once after bicycle exercise stress testing. BNP measurements were obtained before, immediately after, and 2 hours after stress testing in a blinded manner. The presence of myocardial ischemia was adjudicated on the basis of perfusion SPECT combined with coronary angiography findings. RESULTS Exercise-induced myocardial ischemia was adjudicated to be present in 103 patients (38%). BNP levels were significantly higher at all time points in patients with myocardial ischemia compared with those without (P < .01 for all). The accuracy of BNP levels as quantified by the area under the receiver operating characteristic curve (AUC) was similar among the time points evaluated (AUC, 0.677-0.697). Combining clinical judgment before exercise testing with BNP levels at rest increased diagnostic accuracy from AUC 0.708 to 0.754 (P = .018). When combining clinical judgment after exercise testing with BNP levels, AUC increased from 0.741 to 0.771 (P = .055). CONCLUSIONS Combining clinical judgment with BNP levels increased the diagnostic accuracy regarding the presence of myocardial ischemia.