Nils Arne Sörensen

Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I 1-Hour Algorithm.

IMPORTANCE Rapid and accurate diagnosis of acute myocardial infarction (AMI) currently constitutes an unmet need. OBJECTIVE To test a 1-hour diagnostic algorithm to diagnose AMI using a high-sensitivity troponin I assay with a new cutoff level of 6 ng/L. DESIGN, SETTING, AND PARTICIPANTS The Biomarkers in Acute Cardiac Care study is a prospective study that investigated the application of the troponin I assay for the diagnosis of AMI in 1040 patients presenting to the emergency department with acute chest pain from July 19, 2013, to December 31, 2014. Results were validated in 2 independent cohorts of 4009 patients. Final follow-up was completed on July 1, 2015, and data were assessed from July 2 to December 15, 2015. EXPOSURE Acute chest pain suggestive of AMI. MAIN OUTCOMES AND MEASURES Accurate diagnosis or exclusion of AMI and 12-month mortality in patients with acute chest pain. RESULTS Of the 1040 patients included from the study cohort, 673 (64.7%) were male and had a median age of 65 (interquartile range, 52-75) years. With application of a low troponin I cutoff value of 6 ng/L, the rule-out algorithm showed a high negative predictive value of 99.8% (95% CI, 98.6%-100.0%) after 1 hour for non-ST-segment elevation MI type 1. The 1-hour approach was comparable to a 3-hour approach. Similarly, a rule-in algorithm based on troponin I levels provided a high positive predictive value with 82.8% (95% CI, 73.2%-90.0%). Moreover, application of the cutoff of 6 ng/L resulted in lower follow-up mortality (1.0%) compared with the routinely used 99th percentile (3.7%) for this assay. Two independent cohorts further validated the performance of this algorithm with high negative and positive predictive values. CONCLUSIONS AND RELEVANCE Patients with possible AMI can be triaged within 1 hour after admission with no loss of safety compared with a 3-hour approach, when a low and sensitive cutoff is applied. This concept enables safe discharge or rapid treatment initiation after 1 hour.

High-sensitivity assays for troponin in patients with cardiac disease

Troponin is a widely used biomarker in patients with cardiac disease. The use of troponin is well established in patients with suspected acute myocardial infarction (AMI), but troponin measurement is also used in other acute and nonacute settings. In patients with suspected AMI, early decision-making is crucial to allow rapid treatment and further diagnostic evaluation. Current guidelines recommend serial measurements of troponin with a cut-off concentration at the 99th percentile to triage patients in the emergency department. Newer, high-sensitivity assays for troponin enable the detection of distinctly lower concentrations. Using these assays and very low cut-off concentrations, several rapid diagnostic strategies have been reported to improve diagnosis in acute cardiac care. Furthermore, noncoronary and nonacute applications of troponin assays — for example as a biomarker in patients with heart failure, pulmonary embolism, or stable coronary artery disease — are on the horizon and might improve individual risk stratification. In this Review, we provide an overview on the development of high-sensitivity assays for troponin, and their application in patients with cardiac disease.

Immediate Rule-Out of Acute Myocardial Infarction Using Electrocardiogram and Baseline High-Sensitivity Troponin I

AIMS Serial measurements of high-sensitivity troponin are used to rule out acute myocardial infarction (AMI) with an assay specific cutoff at the 99th percentile. Here, we evaluated the performance of a single admission troponin with a lower cutoff combined with a low risk electrocardiogram (ECG) to rule out AMI. METHODS Troponin I measured with a high-sensitivity assay (hs-TnI) was determined at admission in 1040 patients presenting with suspected AMI (BACC study). To rule out AMI we calculated the negative predictive value (NPV) utilizing the optimal hs-TnI cutoff combined with a low risk ECG. The results were validated in 3566 patients with suspected AMI [2-h Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) studies]. Patients were followed for 6 or 12 months. RESULTS 184 of all patients were diagnosed with AMI. An hs-TnI cutoff of 3 ng/L resulted in a NPV of 99.3% (CI 97.3-100.0), ruling out 35% of all non-AMI patients. Adding the information of a low risk ECG resulted in a 100% (CI 97.5-100.0) NPV (28% ruled out). The 2 validation cohorts replicated the high NPV of this approach. The follow-up mortality in the ruled out population was low (0 deaths in BACC and Stenocardia, 1 death in ADAPT). CONCLUSIONS A single hs-TnI measurement on admission combined with a low risk ECG appears to rule out AMI safely without need for serial troponin testing. TRIAL REGISTRATION www.clinicaltrials.gov (NCT02355457).

Discrimination of patients with type 2 myocardial infarction

Aims The differentiation of type 1 and type 2 myocardial infarction (T1MI, T2MI) is important, but challenging in the emergency department. We aimed to investigate the clinical characteristics and cardiovascular outcome of T2MI patients and to develop a clinical decision tool to differentiate T1MI and T2MI patients. Methods and results We prospectively enrolled 1548 patients with suspected MI. All patients were followed for up to 2 years to assess mortality. We used logistic regression with backward step-down selection to determine the most important predictors of T2MI. Based on these regression coefficients, we developed a diagnostic prediction model (score) to diagnose T2MI. T2MI was the final diagnosis of 99 patients. Patients with T2MI showed a high 1-year mortality rate (13.8%), which equals that of T1MI patients (9.4%). Female sex (Beta 1.27 [95% confidence interval; CI 0.67-1.90]), not having radiating chest pain (Beta 1.62 [CI 0.96-2.34]) and a baseline high-sensitivity troponin I concentration ≤ 40.8 ng/L (Beta 1.30 [CI 0.74-1.89]) were the strongest predictors for T2MI. Their combination resulted in an area under the curve of 0.71 to discriminate T1MI and T2MI. The binary score based on this model assigns one point to each of the predictors. Patients with the highest score value of 3 had a 72% probability of T2MI. Conclusion T2MI patients are a heterogeneous population with high-cardiovascular risk. A score based on laboratory and clinical parameters might help to differentiate T1MI and T2MI patients. The additional use of this score in clinical routine needs to be investigated prospectively. Trial registration www.clinicaltrials.gov (NCT02355457).

Early diagnosis of acute myocardial infarction using high-sensitivity troponin I

Objective There is a clinical need for early and accurate diagnosis of acute myocardial infarction (AMI). Current European Society of Cardiology (ESC) guidelines recommend diagnosis of non-ST-elevation AMI based on serial troponin measurements. We aimed to challenge the ESC guidelines using 1) a high-sensitivity troponin I (hs-TnI) baseline cutoff, 2) an absolute hs-TnI change after 1 hour and 3) additional application of an ischemic ECG. Methods 1,516 patients with suspected AMI presenting to the emergency department were included. Hs-TnI was measured directly at admission, after 1 and 3 hours. We investigated baseline concentrations, absolute changes of hs-TnI and additional application of an ischemic ECG to diagnose AMI. A positive predictive value (PPV) of more than 85% was targeted. Results The median age of the study population was 65 years; 291 patients were diagnosed with AMI. The PPV of the 3-hours ESC algorithm was 85.5% (CI 79.7, 90.1) and 65.8% (CI 60.5,70.8) for the 1-hour algorithm. Using a high baseline hs-TnI concentration of 150 ng/L resulted in a PPV of 87.8% (CI 80.9,92.9). Alternatively, a hs-TnI change of 20 ng/L after 1 hour, resulted in a PPV of 86.5% (80.9,91.0), respectively for the diagnosis of AMI. Additional use of an ischemic ECG increased the PPV to 90.5% (CI 83.2,95.3), while reducing the efficacy. Conclusion The diagnosis of AMI based on hs-TnI is challenging. The application of absolute hs-TnI changes after 1 hour may facilitate rapid rule-in of patients. Trial registration www.clinicaltrials.gov (NCT02355457).

Challenging the 99th percentile: A lower troponin cutoff leads to low mortality of chest pain patients

BACKGROUND Rule-out of non-ST-elevation myocardial infarction is based on consecutive measurements of cardiac troponins using the 99th percentile of the respective assay as cutoff. The new ESC guidelines alternatively offer rapid 1h algorithms with lower cutoffs than the 99th percentile for rule-out of non-ST-elevation myocardial infarction. We aimed to compare a recently introduced 1h algorithm based on a high-sensitivity cardiac troponin I (hs-TnI) cutoff of 6ng/L at 0h and 1h to the current standard of care using the 99th percentile (27ng/L) as cutoff with reference to follow-up events in a large chest pain cohort. METHODS Hs-TnI was measured at three time points (0h, 1h and 3h) in 1625 patients presenting with suspected myocardial infarction to the emergency department of the University-Medical Center Hamburg-Eppendorf. Seventy-five patients with ST-elevation myocardial infarction were excluded from the analysis. All-cause mortality, cardiac death, acute myocardial infarction, revascularization and cardiac rehospitalization after 12months were assessed. RESULTS Patients ruled out by the 1h algorithm showed significantly less cardiac rehospitalizations (12.84% vs. 17.66%; p<0.001), and overall mortality (1.30% vs 3.46%, p<0.001) compared to using the 99th percentile as cutoff. The majority of deaths were caused by non-cardiac reasons. Cardiac deaths were rare using the 1h algorithm (0.21%). CONCLUSION The commonly used 99th percentile as cutoff neglects patients with a high risk in the setting of acute chest pain. TRIAL REGISTRATION www.clinicaltrials.gov (NCT02355457).

High-sensitivity troponin and novel biomarkers for the early diagnosis of non-ST-segment elevation myocardial infarction in patients with atrial fibrillation:

Aims: To evaluate the diagnostic performance of high-sensitivity troponin I (hsTnI) and other novel biomarkers for diagnosing non-ST-segment elevation myocardial infarction (NSTEMI) in patients with atrial fibrillation. Methods: In an acute chest pain cohort (N=1673), mean age 61.4±13.6 (34% female), we measured hsTnI and 13 established and novel biomarkers reflecting ischaemia, necrosis, inflammation, myocardial stress, angiogenesis on admission and after three hours in order to investigate their diagnostic accuracy for NSTEMI. Results: In atrial fibrillation patients (N=299) hsTnI on admission had the best discriminatory ability for NSTEMI (area under the curve 0.97) with only two novel biomarkers, copeptin and heart-type fatty acid binding protein, having area under the curve >0.70. Measured biomarkers showed comparable discriminatory ability in atrial fibrillation and non-atrial fibrillation patients. The combination of hsTnI on admission with additional biomarkers did not clinically significantly improve diagnostic performance. In atrial fibrillation patients, hsTnI concentrations ⩽21.7 ng/L (99th percentile in a healthy German cohort) on admission gave a negative predictive value of ~100% (95% confidence interval 97–100%). The combination of hsTnI on admission and absolute change of hsTnI concentration after three hours of ⩾40 ng/L resulted in a positive predictive value of 81.2% and sensitivity of 88.6%. Diagnostic accuracy was validated in an independent cohort (N=1076). Conclusion: The diagnostic accuracy of hsTnI in patients with acute chest pain and atrial fibrillation is high and comparable to those without atrial fibrillation. Absolute change in hsTnI concentration enhanced diagnostic performance. No clinically relevant improvement was achieved by adding other biomarkers.

Cardiovascular Biomarkers in Hypertensive Patients with Medical Treatment—Results from the Randomized TEAMSTA Protect I Trial

BACKGROUND High blood pressure (BP) is associated with an increased rate of cardiovascular events and mortality. Cardiovascular biomarkers are able to predict long-term risk in the general population, particularly in diseased cohorts. We undertook an investigation of the effect of 2 different antihypertensive treatments on cardiovascular biomarkers in a randomized trial. METHODS The TEAMSTA study included 481 hypertensive patients. They were randomized to either 80-mg telmisartan + 5-mg amlodipine (TA) or 40-mg olmesartan + 12.5-mg hydrochlorothiazide (OH). The trial was performed as a prospective, randomized, double-blinded, controlled, single-center study. We measured BP, high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity cardiac troponin T (hs-cTnT), B-type natriuretic peptide (BNP), and N-terminal-pro-BNP (NT-proBNP) before randomization and after 6 months. RESULTS Individuals were randomized into 2 groups: 230 individuals to the OH-group and 251 to the TA-group. After 6 months of treatment, a reduction in BP (systolic/diastolic) was seen, from 135.2/85.2 mmHg to 122.5/75.7 mmHg with similar effects in both groups. hs-cTnT concentrations were measureable in 26.2% of the study population, while hs-cTnI was detected in 98.3%. hs-cTnI concentrations were significantly reduced from 4.6 to 4.2 ng/L in the overall population, from 4.7 to 4.4 ng/L in the OH-group, and from 4.6 to 4.0 ng/L in the TA-group (all P < 0.001). No significant changes of hs-cTnT were observed. BNP and NT-proBNP concentrations decreased from 15.0 to 12.4 ng/L (P < 0.001) and from 64.8 to 53.3 ng/L (P < 0.001), respectively, after 6 months. CONCLUSIONS The reduction in BP was associated with a decrease of high-sensitivity troponin I, BNP, and NT-proBNP concentrations, which might represent a cardiovascular risk reduction. CLINICAL TRIAL REGISTRATION EudraCT 2009-017010-68.

Relations of Sex to Diagnosis and Outcomes in Acute Coronary Syndrome

Background The atypical presentation of women with acute coronary syndrome (ACS) has been related to delayed diagnosis and treatment, which may explain worse outcome compared with men. Methods and Results We analyzed pooled data of 2520 patients of 2 prospective cohorts in terms of differences in presentation and management of women and men suggestive of ACS. Using logistic regression, we established 2 diagnostic models and tested their diagnostic performance in both sexes separately. Sex‐specific differences in management of patients with ACS were ascertained and a 2‐year follow‐up was performed. Women were older than men (median 67 versus 61 years, P=0.001), had more often dyspnea (22% versus 18%, P=0.024), nausea or vomiting (26% versus 16%, P=0.001) and radiating chest pain (47% versus 40%, P=0.001). Classical risk factors (smoking, diabetes mellitus, dyslipidemia or known coronary artery disease) were less frequent in women. Diagnostic models showed no significant sex‐related differences in diagnostic performance in a “first contact” setting (medical history and symptoms) or after “complete triage” (including ECG and biomarkers). Women with ACS underwent coronary angiography (73.8% versus 84.3%, P<0.001) and revascularization (53.8% versus 70.1%, P<0.001) less frequently. Two‐year incidence of myocardial infarction and death was similar in both sexes, but revascularization and cardiac rehospitalization were more frequent in men. Conclusions In a large cohort of patients with suspected ACS, sex differences in clinical presentation did not impair diagnostic accuracy. Two‐year outcomes were comparable. Our findings suggest a benefit of chest pain units to minimize sex differences in ACS management and prognosis. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02355457 (BACC), NCT03227159 (stenoCardia).

Right bundle branch block in patients with suspected myocardial infarction

Aims: The new European Society of Cardiology guideline for ST-segment elevation myocardial infarction recommends that left and right bundle branch block should be considered equal for recommending urgent angiography in patients with suspected myocardial infarction. We aimed to evaluate this novel recommendation in two prospective studies of patients with suspected myocardial infarction. Methods and results: We included 4067 patients presenting to the emergency department with suspected myocardial infarction. All patients had an ECG recorded immediately upon admission. Patients were classified as having right bundle branch block (RBBB), left bundle branch block (LBBB), bifascicular block (BFB) or no bundle branch block. All patients were followed for up to two years to assess mortality. In the overall population 125 (3.1%) patients had RBBB, 281 (6.9%) LBBB and 60 (1.5%) BFB. The final diagnosis of myocardial infarction was adjudicated in 20.8% (RBBB), 28.5% (LBBB), 23.3% (BFB) and 21.6% (no complete block) of patients. The mortality rate after one year was 10.7% (RBBB), 7% (LBBB), 17.5% (BFB) and 3.2% (no complete block). The adjusted hazard ratios were 1.29 (95% confidence interval (CI) 0.71–2.34; P=0.40) for RBBB, 1.71 (95% CI 1.17–2.50; P=0.006) for LBBB and 2.27 (95% CI 1.28–4.05; P=0.005) for BFB. Conclusion: Our results support the new European Society of Cardiology ST-segment elevation myocardial infarction guideline describing RBBB as a high risk for mortality in patients with suspected myocardial infarction. However, the data challenge the concept of RBBB as a trigger of acute angiography because the likelihood of myocardial infarction in a chest pain unit setting is equally frequent in patients without bundle branch block.