Johan Fischer

Multiple Biomarkers at Admission Significantly Improve the Prediction of Mortality in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction

OBJECTIVES We investigated whether multiple biomarkers improve prognostication in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention. BACKGROUND Few data exist on the prognostic value of combined biomarkers. METHODS We used data from 1,034 STEMI patients undergoing primary percutaneous coronary intervention in a high-volume percutaneous coronary intervention center in the Netherlands and investigated whether combining N-terminal pro-brain natriuretic peptide, glucose, C-reactive protein, estimated glomerular filtration rate, and cardiac troponin T improved the prediction of mortality. A risk score was developed based on the strongest predicting biomarkers in multivariate Cox regression. The additional prognostic value of the strongest predicting biomarkers to the established prognostic factors (age, body weight, diabetes, hypertension, systolic blood pressure, heart rate, anterior myocardial infarction, and time to treatment) was assessed in multivariable Cox regression. RESULTS During follow-up (median, 901 days), 120 of the 1,034 patients died. In Cox regression, glucose, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide were the strongest predictors for mortality (p < 0.05, for all). A risk score incorporating these biomarkers identified a high-risk STEMI subgroup with a significantly higher mortality when compared with an intermediate- or low-risk subgroup (p < 0.001). Addition of the 3 biomarkers to established prognostic factors significantly improved prediction for mortality, as shown by the net reclassification improvement (0.481, p < 0.001) [corrected] and integrated discrimination improvement (0.0226, p = 0.03) [corrected]. CONCLUSIONS Our data suggest that addition of a multimarker to a model including established risk factors improves the prediction of mortality in STEMI patients undergoing primary percutaneous coronary intervention. Furthermore, the use of a simple risk score based on these biomarkers identifies a high-risk subgroup.

C-reactive protein and coronary events following percutaneous coronary angioplasty

Abstract Purpose We investigated the associations between baseline C-reactive protein levels in patients undergoing percutaneous coronary angioplasty and death, nonfatal myocardial infarction, and repeat revascularization during 14 months of follow-up. Methods In a single-center, prospective, cohort study, plasma levels of C-reactive protein were measured in 1458 consecutive patients undergoing elective or urgent coronary angioplasty. Patients were followed at 12 to 14 months for the occurrence of death, nonfatal myocardial infarction, and repeat revascularization. Results The incidence of death or myocardial infarction was 6.1% (44/716) in patients with an increased C-reactive protein level (>3 mg/L) and 1.5% (11/742) in patients with a normal level (relative risk [RR] = 4.4; 95% confidence interval [CI]: 2.2 to 8.5; P P = 0.0001). The incidence of repeat revascularization was similar in patients with or without an increased C-reactive protein level (23% [168/716] vs. 22% [163/742], P = 0.54). Statin therapy at the time of the procedure was associated with a lower mean (± SD) C-reactive protein level (5.8 ± 9.7 mg/L vs. 7.2 ± 12.1 mg/L, P = 0.02), but was not associated with the risk of death, nonfatal myocardial infarction, and repeat revascularization during follow-up. Conclusion An increased C-reactive protein level is an independent prognostic indicator for the occurrence of death or nonfatal myocardial infarction following coronary angioplasty, but is not associated with the need for repeat revascularization.

Predictive Value of Plasma Glucose Level on Admission for Short and Long Term Mortality in Patients With ST-Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention

Published reports describe a strong association between plasma glucose levels on admission and mortality in patients who undergo primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. The aim of this study was to assess the predictive value of admission glucose levels for early and late mortality. From 2005 to 2007, 1,646 patients underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction and were stratified according to admission plasma glucose level in category 1 (<7.8 mmol/L; n = 747), category 2 (7.8 to 11.0 mmol/L; n = 620), or category 3 (>11 mmol/L; n = 279). Event rates were estimated using the Kaplan-Meier method. A landmark survival analysis to 3-year follow-up was performed, with a landmark set at 30 days. Time-extended Cox regression was used to assess the predictive value of admission glucose levels. Furthermore, a stratified analysis was performed for known diabetes mellitus status at admission. Thirty-day mortality was 2.4% in category 1, 6% in category 2, and 22% in category 3 (p <0.01). Three-year mortality in 30-day survivors was 5.9% in category 1, 8.2% in category 2, and 7.1% in category 3 (p = 0.27). Glucose level on admission was a strong predictor of 30-day mortality: for every 1 mmol/L increase, the hazard increased by 14% (hazard ratio 1.14, 95% confidence interval 1.09 to 1.19, p <0.01) in patients without diabetes, by 12% (hazard ratio 1.12, 95% confidence interval 1.05 to 1.19, p <0.01) in those with diabetes, and by 13% (hazard ratio 1.13, 95% confidence interval 1.09 to 1.17, p <0.01) in the total cohort. After 30 days, glucose level at admission lost its predictive value. In conclusion, in patients with and those without diabetes, glucose level at admission is an independent predictor of early but not late mortality.

Cystatin C for Enhancement of Risk Stratification in Non–ST Elevation Acute Coronary Syndrome Patients with an Increased Troponin T

BACKGROUND We assessed the value of cystatin C for improvement of risk stratification in patients with non-ST elevation acute coronary syndrome (nSTE-ACS) and increased cardiac troponin T (cTnT), and we compared the long-term effects of an early invasive treatment strategy (EIS) with a selective invasive treatment strategy (SIS) with regard to renal function. METHODS Patients (n = 1128) randomized to an EIS or an SIS in the ICTUS trial were stratified according to the tertiles of the cystatin C concentration at baseline. The end points were death within 4 years and spontaneous myocardial infarction (MI) within 3 years. RESULTS Mortality was 3.4%, 6.2%, and 13.5% in the first, second, and third tertiles, respectively, of cystatin C concentration (log-rank P < 0.001), and the respective rates of spontaneous MI were 5.5%, 7.5%, and 9.8% (log-rank P = 0.03). In a multivariate Cox regression analysis, the cystatin C concentration in the third quartile remained independently predictive of mortality [hazard ratio (HR), 2.04; 95% CI, 1.02-4.10; P = 0.04] and spontaneous MI (HR, 1.95; 95% CI, 1.05-3.63; P = 0.04). The mortality rate in the second tertile was lower with the EIS than with the SIS (3.8% vs 8.7%). In the third tertile, the mortality rates with the EIS and the SIS were, respectively, 15.0% and 12.2% (P for interaction = 0.04). Rates of spontaneous MI were similar for the EIS and the SIS within cystatin C tertiles (P for interaction = 0.22). CONCLUSIONS In patients with nSTE-ACS and an increased cTnT concentration, mild to moderate renal dysfunction is associated with a higher risk of death and spontaneous MI. Use of cystatin C as a serum marker of renal function may improve risk stratification.

Safe discharge from the cardiac emergency room with a rapid rule-out myocardial infarction protocol using serial CK-MB mass

OBJECTIVE To determine whether a new protocol, using a rapid and sensitive CK-MBmass assay and serial sampling, can rule out myocardial infarction in patients with chest pain and decrease their length of stay in the cardiac emergency room without increasing risk. DESIGN The combined incidence of cardiac death and acute myocardial infarction at 30 days, six months, and 24 months of follow up were compared between patients discharged home from the cardiac emergency room after ruling out myocardial infarction with a CK-MBactivity assay in 1994 and those discharged home after a rapid CK-MBmass assay in 1996. SETTING Cardiac emergency room of a large university hospital. PATIENTS In 1994 and 1996, 230 and 423 chest pain patients, respectively, were discharged home from the cardiac emergency room with a normal CK-MB and an uneventful observation period. RESULTS The median length of stay in the cardiac emergency room was significantly reduced, from 16.0 hours in 1994 to 9.0 hours in 1996 (p < 0.0001). Mean event rates in patients from the 1994 and 1996 cohorts, respectively, were 0.9% (95% confidence interval (CI) −0.3% to 2.1%)v 0.7% (95% CI −0.1% to 1.5%) at 30 days, 3.0% (95% CI 0.8% to 5.2%) v 2.8% (95% CI 1.2% to 4.4%) at six months, and 7.0% (95% CI 3.7% to 10.3%) v 5.7% (95% CI 3.5% to 7.9%) at 24 months. Kaplan–Meier survival analysis showed no difference in mean event-free survival at 30 days, six months, and 24 months of follow up. CONCLUSIONS Using a rule-out myocardial infarction protocol with a rapid and sensitive CK-MBmass assay and serial sampling, the length of stay of patients with chest pain in the cardiac emergency room can be reduced without compromising safety.

Growth-differentiation factor 15 for long-term prognostication in patients with non-ST-elevation acute coronary syndrome: An Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) substudy

BACKGROUND No five-year long-term follow-up data is available regarding the prognostic value of GDF-15. Our aim is to evaluate the long-term prognostic value of admission growth-differentiation factor 15 (GDF-15) regarding death or myocardial infarction (MI) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS This is a subanalysis from the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial, including troponin positive NSTE-ACS patients. The main outcome for the current analysis was 5-year death or spontaneous MI. GDF-15 samples were available in 1151 patients. The prognostic value of GDF-15, categorized into <1200 ng/L, 1200-1800 ng/L and >1800 ng/L, was assessed in unadjusted and adjusted Cox regression models. Adjustments were made for identified univariable risk factors. The additional discriminative and reclassification value of GDF-15 beyond the independent risk factors was assessed by the category-free net reclassification improvement (1/2 NRI(>0)) and the integrated discrimination improvement (IDI) RESULTS: Compared to GDF-15<1200 ng/L, a GDF-15>1800 ng/L was associated with an increased hazard ratio for death or spontaneous MI, mainly driven by mortality. GDF-15 levels were predictive after adjustments for other identified predictors. Additional discriminative value was shown with the IDI, not with the NRI. CONCLUSION In patients presenting with NSTE-ACS and elevated troponin T, GDF-15 provides prognostic information in addition to identified predictors for mortality and spontaneous MI and can be used to identify patients at high risk during long-term follow-up.

Comparison of the usefulness of N-terminal pro-brain natriuretic peptide to other serum biomarkers as an early predictor of ST-segment recovery after primary percutaneous coronary intervention.

Data on the ability of serum biomarkers to predict microvascular obstruction by ST-segment recovery after primary percutaneous coronary intervention (PCI) is largely absent. Therefore, we determined the association between 5 serum biomarkers, obtained before emergency coronary angiography, and immediate ST-segment recovery in patients who had undergone primary PCI for ST-segment elevation myocardial infarction. We measured N-terminal pro-brain natriuretic peptide (NT-pro-BNP), cardiac troponin T, creatinine kinase-MB fraction, high-sensitivity C-reactive protein, and serum creatinine from blood samples obtained through the arterial sheath at the start of primary PCI. Serial 12-lead electrocardiograms were recorded in the catheterization laboratory before arterial puncture and at the end of the PCI. ST-segment recovery was defined as incomplete if <50%. Of 662 included patients with ST-segment elevation myocardial infarction, 338 (51%) had incomplete ST-segment recovery. An elevated NT-pro-BNP level (> or = 608 ng/L) was the strongest predictor of incomplete ST-segment recovery (adjusted odds ratio 2.6, 95% confidence interval 1.6 to 4.1; p <0.001) compared to other serum biomarkers and clinical predictors. An elevated NT-pro-BNP level was more strongly predictive in patients without a history of coronary artery disease or hypertension (adjusted odds ratio 4.7, 95% confidence interval 2.4 to 9.2; p <0.001). NT-pro-BNP was the best contributor to both net reclassification (0.43; p <0.001) and integrated discrimination improvement (0.04; p <0.001) when added to a multivariate model with clinical predictors of incomplete ST-segment recovery. In conclusion, NT-pro-BNP was the strongest independent predictor of ST-segment recovery at the end of primary PCI for ST-segment elevation myocardial infarction compared to the other serum biomarkers reflecting myocardial cell damage, renal function, and inflammation.

Different time frames for the occurrence of elevated levels of cardiac troponin T and C-reactive protein in patients with acute myocardial infarction.

Abstract The baseline plasma level of C-reactive protein (CRP) is considered to be a parameter for risk stratification in patients with an acute coronary syndrome, independent of the level of cardiac troponin T (cTnT) or cardiac troponin I. However, myocardial tissue necrosis following prolonged arterial occlusion also induces release of CRP. Both phenomena may have their own kinetic behaviour with respect to changes in concentration of CRP. Therefore, in this study the time frame after onset of symptoms for measurement of CRP as an independent parameter is established. For this purpose, we evaluated patients with proven myocardial damage due to acute myocardial infarction (AMI) with respect to changes of creatine kinase (CK)-MB mass, cTnT and CRP during 24 hours after onset of symptoms. Our results show that two subgroups can be discerned in patients with AMI: those with initially normal and those with already elevated concentration CRP on admission. Furthermore, based on the results of this study we conclude that for use of CRP as an independent prognostic parameter in patients with acute coronary syndrome, CRP should be measured in blood samples drawn as early as possible after the onset of symptoms to avoid contribution of a process of myocardial tissue necrosis, whereas estimation of cTnT should be performed at 6–12 hours.

NT-pro-BNP is associated with inducible myocardial ischemia in mildly symptomatic type 2 diabetic patients

Baseline levels of N-terminal fragment of the brain natriuretic peptide prohormone (NT-pro-BNP) are associated with myocardial ischemia in non-diabetic patients with stable angina pectoris. A total of 281 patients with diabetes mellitus type 2 and stable angina pectoris underwent myocardial perfusion scintigraphy (MPS). Myocardial ischemia on MPS was present in 140 (50%) patients. These ischemic patients had significantly higher NT-pro-BNP levels compared with patients without ischemia: 183 pg/ml (64-324 pg/ml) vs. 88 pg/ml (34-207 pg/ml), respectively (p<0.001). In addition, NT-pro-BNP ≥180 pg/ml was an independent predictor of the presence of myocardial ischemia (OR 2.36, 95%CI 1.40-3.97, p=0.001). Possible confounding factors such as age and creatinine clearance were of no influence on the predictive value in this specific patient population. These findings strengthen the idea that NT-pro-BNP may be of value in the early detection of diabetic patients with hemodynamic significant coronary artery disease.

Relation of N-Terminal Pro B-Type Natriuretic Peptide Levels After Symptom-Limited Exercise to Baseline and Ischemia Levels

Circulating levels of B-type natriuretic peptide (BNP) and the amino-terminal portion of the prohormone (NT-proBNP) have been reported to increase immediately after myocardial ischemia. The association between extent of exercise-induced myocardial ischemia measured using myocardial perfusion scintigraphy and the magnitude and time course of changes in NT-proBNP was studied. One hundred one patients underwent symptom-limited exercise myocardial perfusion scintigraphy. Myocardial ischemia was assessed semiquantitatively. Serum samples were obtained before the start of exercise (baseline), at maximal exercise, and every hour up to 6 hours after maximal exercise. Myocardial ischemia was present in 37 patients (37%). NT-proBNP rapidly increased during exercise (to 113%, interquartile range 104 to 144, and 118%, interquartile range 106 to 142, of baseline, respectively), with a second peak at 4 (141%, interquartile range 119 to 169) and 5 hours (136%, interquartile range 93 to 188), respectively. Absolute changes between NT-proBNP at baseline and at maximum exercise in patients with versus without ischemia were similar (median, 30 pg/ml, interquartile range 7 to 45 vs 15, interquartile range 4 to 46, respectively, p = 0.230), but absolute change between baseline and the secondary peak was higher in patients with ischemia than in patients without ischemia (median 64 pg/ml, interquartile range 32 to 172 vs 34, interquartile range 19 to 85, respectively, p = 0.024). In multivariate linear stepwise regression analysis of determinants of changes in NT-proBNP after exercise, baseline NT-proBNP was the only independent determinant of absolute changes at maximum exercise, whereas the presence of ischemia was not predictive. Baseline NT-proBNP, cystatin C, and end-systolic volume were independent determinants of the absolute increase to secondary peak levels. In conclusion, myocardial ischemia per se did not lead to additional increases in NT-proBNP within 6 hours after exercise.