J. Vollert

Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study

Abstract Aims This randomized controlled trial (RCT) evaluated whether a process with single combined testing of copeptin and troponin at admission in patients with low-to-intermediate risk and suspected acute coronary syndrome (ACS) does not lead to a higher proportion of major adverse cardiac events (MACE) than the current standard process (non-inferiority design). Methods and results A total of 902 patients were randomly assigned to either standard care or the copeptin group where patients with negative troponin and copeptin values at admission were eligible for discharge after final clinical assessment. The proportion of MACE (death, survived sudden cardiac death, acute myocardial infarction (AMI), re-hospitalization for ACS, acute unplanned percutaneous coronary intervention, coronary artery bypass grafting, or documented life threatening arrhythmias) was assessed after 30 days. Intention to treat analysis showed a MACE proportion of 5.17% [95% confidence intervals (CI) 3.30–7.65%; 23/445] in the standard group and 5.19% (95% CI 3.32–7.69%; 23/443) in the copeptin group. In the per protocol analysis, the MACE proportion was 5.34% (95% CI 3.38–7.97%) in the standard group, and 3.01% (95% CI 1.51–5.33%) in the copeptin group. These results were also corroborated by sensitivity analyses. In the copeptin group, discharged copeptin negative patients had an event rate of 0.6% (2/362). Conclusion After clinical work-up and single combined testing of troponin and copeptin to rule-out AMI, early discharge of low- to intermediate risk patients with suspected ACS seems to be safe and has the potential to shorten length of stay in the ED. However, our results need to be confirmed in larger clinical trials or registries, before a clinical directive can be propagated.

Lipoprotein-associated phospholipase A2 for early risk stratification in patients with suspected acute coronary syndrome: a multi-marker approach: the North Wuerttemberg and Berlin Infarction Study-II (NOBIS-II).

AimsNumerous markers have been identified as useful predictors of major adverse cardiac events (MACE) in patients with suspected acute coronary syndrome (ACS). However, only little is known about the relative benefit of the single markers in risk stratification and the best combination for optimising prognostic power.The aim of the present study was to define the role of the emerging cardiovascular risk marker lipoprotein-associated phospholipase A2 (Lp-PLA2) in a multi-marker approach in combination with troponin I (TnI), NT-proBNP, high sensitivity (hs)CRP, and D-dimer in patients with ACS.Methods and resultsA total of 429 consecutive patients (age 60.5±14.1 years, 60.6% male) who were admitted to the emergency room with suspected ACS were analysed in the study. Biochemical markers were measured by immunoassay techniques. All patients underwent point-of-care TnI testing and early coronary angiography if appropriate, in accordance with the current guidelines. Classification and regression trees (CART) and logistic regression techniques were employed to determine the relative predictive power of markers for the primary end-point defined as any of the following events within 42 days after admission: death, non-fatal myocardial infarction, unstable AP requiring admission, admission for decompensated heart failure or shock, percutaneous coronary intervention, coronary artery bypass grafting, life threatening arrhythmias or resuscitation. The incidence of the primary end-point was 13.1%, suggesting a mild to moderate risk population. The best overall risk stratification was obtained using NT-proBNP at a cut-off of 5000 pg/mL (incidence of 40% versus 10.3%, relative risk (RR) 3.9 (95% CI 2.4–6.3)). In the remaining lower risk group with an incidence of 10.3%, further separation was performed using TnI (cut-off 0.14 µg/L; RR= 3.1 (95% CI 1.7–5.5) 23.2% versus 7.5%) and again NT-proBNP (at a cut-off of 140 ng/L) in patients with negative TnI (RR=3.2 (95% CI 1.3–7.9), 11.7% versus 3.6%). A final significant stratification in patients with moderately elevated NT-proBNP levels was achieved using Lp-PLA2 at a cut-off of 210 µg/L) (17.9% versus 6.9%; RR=2.6 (95% CI 1.1–6.6)). None of the clinical or ECG variables of the TIMI (Thrombolysis In Myocardial Infarction) risk score provided comparable clinically relevant information for risk stratification.ConclusionsIn the setting of stateof- the-art coronary care for patients with suspected ACS in the emergency room, NT-proBNP, troponin I, and Lp-PLA2 are effective independent markers for risk stratification that proved to be superior to the TIMI risk score. Lp-PLA2 turned out to be a more effective risk marker than hsCRP in these patients.

Development of an optimized multimarker strategy for early risk assessment of patients with acute coronary syndromes

BACKGROUND A multitude of biomarkers have been suggested for early risk-assessment in patients admitted to the emergency department with suspected acute coronary syndromes. We used logistic regression synergistically with classification and regression tree (CART) analysis to define a multimarker strategy and the cut-off values and sequencing needed to optimize risk stratification in a low to moderate risk population of the emergency department. METHODS 432 unselected patients (59.7+/-14.5 y, 60.4% male) admitted to the emergency department (ED) with acute coronary syndromes (ACS) were enrolled. Cardiac troponin I (cTnI), N-terminal pro-B-Type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), placental growth factor (PlGF), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and D-dimers were measured by immunoassay and whole blood choline (WBCHO) and plasma choline (PLCHO) were measured using LC/MS from baseline samples. Logistic regression and CART analysis were used to define the importance of the various biomarkers tested and to define their hierarchy with respect to the prediction of major adverse cardiac events (MACE; cardiac death, non-fatal MI, unstable angina, CHF requiring admission, urgent PCI and CABG) over the 42-day follow-up period. RESULTS A combination of NT-proBNP, WBCHO and Lp-PLA2 with cutoffs identified by CART-analysis was optimal for risk-stratification and superior to all other possible combinations of markers. Increased concentrations of both NT-proBNP (>1400 ng/l) and WBCHO (>21 micromol/l) identified patients with very high risk (RR=2.4, 39% primary endpoint) while low concentrations of NT-proBNP (< or = 1400 ng/l), WBCHO (< or = 17 micromol/l) and LP-PLA2 (< or = 210 microg/l) indicated very low risk (0% primary endpoint). WBCHO > 17 micromol/l additionally identified a subgroup with intermediate risk (RR=3.0, 13.5% primary endpoint) in patients with NT-proBNP concentrations < or = 1400 ng/l. Troponin when increased was highly prognostic but was not often positive in this early cohort. CONCLUSIONS A multimarker strategy defined synergistically by logistic regression and by classification and regression tree (CART) analysis can stratify patients into risk groups ranging from very low risk (0% MACE) to very high risk (39.5% MACE) based on admission values.

Comparison of Direct Stenting With Conventional Stent Implantation in Acute Myocardial Infarction

Small studies have suggested that direct stenting without balloon predilatation in ST-segment elevation myocardial infarction may reduce microcirculatory dysfunction. To examine the clinical benefits of direct stenting in a large cohort of patients who underwent primary percutaneous coronary intervention treated with contemporary pharmacotherapy, the 1-year outcomes from the multicenter, randomized Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial were analyzed. A total of 3,602 patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention were enrolled. The present study cohort consisted of 2,528 patients in whom single lesions (excluding bypass grafts) were treated with stent implantation. At operator discretion, direct stenting was attempted in 698 patients (27.6%), and stenting was performed after predilatation in 1,830 patients (72.4%). Propensity-score matching was performed to reduce bias. Direct stenting was successful in 677 patients (97.0%). ST-segment resolution at 60 minutes after the procedure was improved in patients who underwent direct compared to conventional stenting (median 74.8% vs 68.9%, respectively, p = 0.01). At 1-year follow-up, direct compared to conventional stenting was associated with a significantly lower rate of all-cause death (1.6% vs 3.8%, p = 0.01) and stroke (0.3% vs 1.1%, p = 0.049), with nonsignificant differences in target lesion revascularization, myocardial infarction, stent thrombosis, and major bleeding. Death at 1 year remained significantly lower in the direct stenting group after multivariate adjustment (hazard ratio 0.42, 95% confidence interval 0.21 to 0.86, p = 0.02) and in a propensity score-based analysis (hazard ratio 0.92, 95% confidence interval 0.88 to 0.95, p = 0.02). In conclusion, compared to stent implantation after predilatation, direct stenting is safe and effective in appropriately selected lesions in patients with ST-segment elevation myocardial infarction who undergo primary percutaneous coronary intervention and may result in improved survival.

N-terminal pro brain natriuretic peptide in the management of patients in the medical emergency department (PROMPT): correlation with disease severity, utilization of hospital resources, and prognosis in a large, prospective, randomized multicentre trial

N‐terminal pro brain natriuretic peptide (NT‐proBNP) is a potent marker of heart failure and other cardiac diseases. The value of NT‐proBNP testing in the medical emergency department (ED) was assessed in patients >65 years old.

Autoantibodies against cardiac troponin I in patients with congestive heart failure

In this randomized, double‐blind clinical study, we investigated the relationship between autoantibodies against cardiac troponin I (cTnI) and disease severity in elderly congestive heart failure (CHF) patients before and after titration of beta‐blocker therapy.

Prognostic Value of Undetectable hs Troponin T in Suspected Acute Coronary Syndrome

BACKGROUND The search for improved strategies for safe and early discharge of patients with suspected acute coronary syndrome in emergency departments is ongoing. This Biomarkers in Cardiology (BIC)-8 biomarker substudy evaluated the usefulness of high-sensitivity troponin T (hsTnT) below or above the limit of detection (LoD) in low-to-intermediate-risk patients with suspected acute coronary syndrome in the emergency department. METHODS Patients were categorized into hsTnT ≥ the 99th percentile, between the 99th percentile and LoD, or undetectable hsTnT (<LoD). HsTnT and copeptin were measured at admission, using a copeptin cut-off of 10 pmol/L. The primary endpoint was death and myocardial infarction within 90 days after admission. RESULTS Of 882 patients with all biomarker results, 577 (65.4%) had detectable hsTnT levels (≥LoD). Among the 305 patients (34.6%) with undetectable hsTnT, no myocardial infarctions or deaths occurred within 90 days. In patients with detectable hsTnT at admission (≥LoD but ≤99th percentile), the combined endpoint occurred in 1.5% (6/410) of the copeptin-negative patients and in 6.3% (6/96) of copeptin-positive patients within 90 days (hazard ratio 4.39; 95% confidence interval, 1.42-13.61; P = .01). In patients with an initially elevated hsTnT (≥14 ng/L), 9.7% (3/31) of the copeptin-negative patients and 15.4% (4/26) of the copeptin-positive patients experienced the combined endpoint (hazard ratio 1.61; 95% confidence interval, 0.36-7.17; P = .536). CONCLUSIONS In low-to-intermediate-risk patients with suspected acute coronary syndrome, undetectable hsTnT values at admission allow a safe discharge without occurrence of death or myocardial infarction within 90 days.

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.

The role of myeloperoxidase (MPO) for prognostic evaluation in sensitive cardiac troponin I negative chest pain patients in the emergency department

Background: The diagnostic work-up of patients with acute chest pain in the emergency department (ED) is a challenging task. Serial troponin testing is required to rule-out acute myocardial infarction. Objective: To evaluate the value of myeloperoxidase (MPO) testing in sensitive cardiac troponin I (cTnI) negative patients with suspected acute coronary syndromes (ACS) in the routine setting of an ED. Methods: MPO was assessed in 432 consecutive patients presenting to the ED with ACS. In 266 patients, serial blood samples were available. After 6 weeks, major adverse cardiac events (MACE) were assessed. MPO and cTnI were measured in all available samples. For cTnI, a sensitive assay was used. Cut-off values were derived from an independent sample of 300 healthy volunteers. Results: Incidence of MACE in our population was 13%. MPO levels revealed sensitivity (Sens) of 82.1% and specificity (Spec) of 37.2% for MACE compared with 60.7% Sens and 61.4% Spec for sensitive cTnI. In serial sensitive cTnI negative patients (n=218), MACE incidence was 6.4%. MPO continued to demonstrate significant discriminatory power for the prognosis of MACE. Multivariate analyses confirmed these findings. Conclusion: MPO has an independent prognostic value overall and most notably in patients tested negative with a higher sensitive cardiac troponin I assay. MPO could be a promising biomarker for the initial evaluation of patients in chest pain units and is worth further investigation.

Thrombin activity throughout the acute phase of acute ST-elevation myocardial infarction and the relation to outcome.

Background: Thrombin and plasmin play a central role in ongoing thrombosis and platelet activation in patients with acute ST-elevation myocardial infarction (STEMI). Data of thrombin and plasmin activity in the early course of STEMI and the relation to outcome are scarce. Methods: We included 68 consecutive patients (53 male, 59 ± 11.4 years) with STEMI who underwent acute catheter-based reperfusion therapy within the first 12 h after onset of symptoms. Blood samples were taken at admission and after 4, 8, 12 and 24 h. Thrombin activity and generation was measured by changes in the thrombin/antithrombin-III complex (TAT) and prothrombin fragment (F1.2); plasmin was measured by changes in the plasmin-α2/antiplasmin complex (PAP). A follow-up with respect to the combined primary endpoint consisting of death, acute myocardial infarction or urgent need for revascularization up to 6 weeks post-discharge was carried out. Results: TAT values showed no significant change over time in patients with and without the primary endpoint but there was a borderline difference between these groups at 4 h after admission (event group 9.0 vs no event group 4.7 μg l−1, p = 0.057). F1.2 values were different between groups only after 24 h (event group 1.5 vs no event group 0.9 nmol l−1, p = 0.028) and did not differ in serial sampling of 24 h. PAP values were higher in patients with events after 4 and 8 h and declined over time in the group without events (p <0.001). Odds ratios (OR) with respect to the primary endpoint were highest for TAT >4.8 μg l−1 at 0 h and TAT >8.4 μg l−1 at 4 h (OR 7.1, 95% confidence interval (CI) 1.5–34, p = 0.015 and OR 5.5, 95% CI 1.5–20.0, p = 0.01, respectively). The predictive value of plasmin concentrations were equally high after 4 h (PAP >962 μg l−1; OR 6.8, 95% CI 1.8–26.2, p = 0.005) and 8 h (PAP >495 μg l−1, OR 6.7, 95% CI 1.4–32.9, p = 0.024). Values for F1.2 were only predictive after 24 h (F1.2 >0.85 nmol l−1, OR 13, 95% CI 1.4–117.8, p = 0.023). Conclusions: Markers of thrombin and plasmin activity in acute STEMI are related to outcome. The marker for thrombin generation F1.2 becomes a significant predictor of outcome at 24 h after admission, reflecting the potentially adverse effects of ongoing thrombin generation. This underlines the potential for direct thrombin inhibition and individualization of treatment by thrombin markers in STEMI.