Prognostic Value of Biomarkers During and After Non ST-Segment Elevation Acute Coronary Syndrome

Transcription

1 Journal of the American College of Cardiology Vol. 54, No. 4, by the American College of Cardiology Foundation ISSN /09/$36.00 Published by Elsevier Inc. doi: /j.jacc Biomarkers Prognostic Value of Biomarkers During and After Non ST-Segment Elevation Acute Coronary Syndrome CME Kai M. Eggers, MD, PHD,* Bo Lagerqvist, MD, PHD,* Per Venge, MD, PHD, Lars Wallentin, MD, PHD,* Bertil Lindahl, MD, PHD* Uppsala, Sweden Objectives Background Methods Results Conclusions The aim of this study was to assess risk prediction by different biomarkers in patients with an ongoing non STsegment elevation acute coronary syndrome (NSTE-ACS) and after clinical stabilization. Different biomarkers reflect different aspects of the pathobiology in NSTE-ACS. However, there is little information regarding their relative prognostic value during the time course of disease. The N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), cardiac troponin I (ctni), and the estimated glomerular filtration rate (egfr) were measured at randomization and after 6 weeks and 6 months in 877 NSTE-ACS patients included in the FRISC (FRagmin and fast revascularization during InStability in Coronary artery disease) II trial. The biomarkers prognostic value during 5-year follow-up was evaluated by Cox regression models, calculation of the c-statistics, and estimation of the net reclassification improvement (NRI). Among the biomarkers measured at randomization, NT-proBNP was the strongest predictor for mortality (adjusted hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.3 to 2.1; p 0.001). Even during follow-up, NTproBNP demonstrated the strongest association to the composite end point of death/myocardial infarction (adjusted HR at 6 weeks: 1.5; 95% CI: 1.3 to 1.7; p 0.001; adjusted HR at 6 months: 1.4; 95% CI: 1.2 to 1.7; p 0.001). Even CRP was independently predictive at 6 months for the composite end point (adjusted HR: 1.3; 95% CI: 1.1 to 1.5; p 0.003). Only 6-week results of NT-proBNP provided significant incremental prognostic value to established risk indicators regarding the composite end point (c-statistics 0.69 [p 0.03]; NRI 0.11 [p 0.03]). The NT-proBNP is an independent risk predictor in patients with ongoing NSTE-ACS and after clinical stabilization. The CRP exhibits increasing predictive value at later measurements. However, only NT-proBNP provided incremental prognostic value and might therefore be considered as a complement for early follow-up controls after NSTE-ACS. (J Am Coll Cardiol 2009;54:357 64) 2009 by the American College of Cardiology Foundation Biochemical markers play a major role for risk assessment in patients with an ongoing non ST-segment elevation acute coronary syndrome (NSTE-ACS). In particular the cardiac troponins are generally recognized as important risk indicators but also markers of left ventricular performance (i.e., N-terminal pro-brain natriuretic peptide [NT-proBNP]), inflammation (i.e., C-reactive protein [CRP]), and renal function (i.e., estimated glomerular filtration rate [egfr]) Continuing Medical Education (CME) is available for this article. From the *Department of Medical Sciences, Cardiology, Uppsala University Hospital and Uppsala Clinical Research Centre; and the Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, Uppsala, Sweden. This study was supported by grants from the Swedish Heart and Lung Foundation (Stockholm, Sweden) and the Erik, Karin and Gösta Selander Foundation (Uppsala, Sweden). The reagents for the troponin I assay were provided by Beckman Coulter, Inc. (Fullerton, California). Dr. Venge has received research honoraria from Abbott, Beckman Coulter, Roche, and Siemens Diagnostics. Dr. Lindahl has served as a consultant for Beckman Coulter and Siemens and has received honoraria for educational lectures for Beckman Coulter, Siemens, and Roche. Manuscript received October 20, 2008; revised manuscript received January 30, 2009, accepted March 10, that provide strong prognostic information (1,2). Emerging evidence furthermore suggests that these biomarkers are prognostically useful even in the late phase after a NSTE- ACS (3 8), with the natriuretic peptides having been most extensively evaluated (3,4). However, the evolution of the prognostic implications of different biomarkers during and after an NSTE-ACS has not been assessed so far. See page 365 The purpose of this study was thus to investigate the prognostic value of cardiac troponin I (ctni), NT-proBNP, CRP, and the egfr relative to each other and in the context of other established risk indicators in patients with an ongoing NSTE-ACS and at 6 weeks and 6 months after clinical stabilization. Methods Patients and study design. The protocol and main results of the FRISC (FRagmin and fast revascularization during

2 358 Eggers et al. JACC Vol. 54, No. 4, 2009 Risk Prediction During and After NSTE-ACS July 21, 2009: Abbreviations and Acronyms AMI acute myocardial infarction CRP C-reactive protein ctni cardiac troponin I egfr estimated glomerular filtration rate NRI net reclassification improvement NSTE-ACS non STsegment elevation acute coronary syndrome NT-proBNP N-terminal pro-brain natriuretic peptide InStability in Coronary artery disease) II trial have been published elsewhere (9,10). This trial was a prospective, multicenter study randomizing 3,489 patients with NSTE-ACS between 1996 and 1998 in a factorial design to an early invasive or noninvasive strategy and to 3-month treatment with dalteparin or placebo. Patients were included in case of symptoms of unstable coronary artery disease with objective signs of myocardial ischemia, such as electrocardiographic changes (ST-segment depression 0.1 mv or T-wave inversion 0.1 mv) or elevated biochemical markers of myocardial necrosis. Major exclusion criteria were increased risk of bleeding, serum creatinine 150 mol/l, percutaneous coronary intervention during the last 6 months, and a decision to perform coronary angiography or percutaneous coronary intervention before randomization. Patients with a history of previous open heart surgery, advanced age, or poor general health and those included after completion of recruitment to the invasive versus noninvasive arm were treated primarily noninvasively and randomized only regarding prolonged treatment with dalteparin or placebo. In the invasive strategy, the aim was to perform coronary angiography and, if appropriate, revascularization within 7 days from admission. Patients randomized to the noninvasive strategy underwent coronary angiography only in case of refractory or recurrent angina or if they showed signs of severe ischemia on a pre-discharge exercise test. Informed consent was obtained from all patients, and the protocol was approved by all local ethics committees. Patients were followed after randomization by outpatient visits after 6 (range 4 to 7) weeks and 3 and 6 months. At these instances, a blood sampling program was performed at selected study centers including 1,380 patients. Further follow-up was performed by telephone contacts after 12 and 24 months. Thereafter and up to 5 years after randomization, all information on events was based on mandatory National Registries run by the Swedish Health Authority. Laboratory analysis. The ctni, NT-proBNP, and CRP were determined in frozen ( 70 C), not previously thawed, samples of ethylenediaminetetraacetic acid-plasma obtained at randomization and follow-up at 6 weeks and 6 months. For follow-up measurements, only results from patients without an acute myocardial infarction (AMI) or a coronary revascularization procedure during the previous 14 days were considered. The ctni was measured with the Access AccuTnI assay (Beckman Coulter, Inc., Fullerton, California). For randomization samples, the original version of this assay was used, and results were dichotomized at its 99th percentile of 0.04 g/l (11). Samples obtained during follow-up were analyzed with the refined assay version, which is characterized by an improved analytical performance at low ctni concentrations with g/l as the lowest concentration measurable with a coefficient of variation 10% and g/l as the lower level of detection (5). Following previous experiences, follow-up ctni results were dichotomized at 0.01 g/l (5). The NT-proBNP was measured at all instances with the Elecsys probnp sandwich immunoassay on an Elecsys 2010 instrument (Roche Diagnostics, Mannheim, Germany). The CRP was analyzed with the Immulite CRP assay (Diagnostic Products Corp., Los Angeles, California). Serum creatinine was determined locally, and the egfr was calculated according to the 4-variable version of the Modification of Diet in Renal Disease formula (12). Statistical analysis. The study end points for the present analysis were total mortality and AMI, alone or as composite, after each respective measurement instance. For patients with an AMI during the first 6 months of follow-up, the time to the next AMI or end of follow-up was calculated. The prognostic value of the tested biomarkers was investigated by different Cox proportional hazard models. Adjustment was made for age, sex, diabetes, a history of heart failure and a history of AMI (model 1). Covariates were defined as follows: Diabetes: history of diabetes (randomization results) and/or antidiabetic treatment and/or a pre-test fasting glucose 6.1 mmol/l (follow-up results). Heart failure: history of heart failure (randomization results) and/or left-ventricular ejection fraction 0.45 during the index hospital stay (follow-up results). Previous AMI: history of AMI (randomization results) and/or AMI as index event (defined as cardiac troponin T g/l at randomization [11]) and/or recurrent AMI during follow-up and before the respective measurement instance (follow-up results). Additional adjustment was made for the 4 tested biomarkers (model 2) and for coronary revascularization before the respective measurement instance during follow-up (model 3). We decided to focus on coronary revascularization instead for the randomized treatment strategy with regard to some crossover between the randomization arms during follow-up. The proportional hazard assumptions were checked by computing log[ log(event)] plots. The functional form of the association between outcome and each respective biomarker was assessed by the inspection of generalized additive model plots, which revealed nonlinear associations between the egfr (all measurements) and CRP (at randomization). Therefore we dichotomized the egfr at 75 ml/min/1.73 m 2 (13) and excluded randomization CRP results from all multivariable analyses, because the nonlinear association could not be compensated by mathematical transformations. The ctni was dichotomized on the basis of the respective cutoffs, whereas NT-proBNP and CRP (at 6 weeks and 6 months) were entered as ln transformed variables.

3 JACC Vol. 54, No. 4, 2009 July 21, 2009: Eggers et al. Risk Prediction During and After NSTE-ACS 359 The incremental prognostic value of the tested biomarkers during follow-up to the covariates applied in model 1 and regarding the composite end point was tested first, by calculating the respective c-statistics. The differences in c-statistics were estimated with the method described by Antolini et al. (14). The Hosmer-Lemeshow statistic was used to assess the goodness of fit of the applied models. Second, the increased discriminative value of the biomarkers regarding the composite end point was studied by assessing the net reclassification improvement (NRI) as described by Pencina et al. (15). This method determines the difference in the probabilities of a subject to belong to predefined risk categories before and after the addition of a specific marker. Two models were used for prognostic classification based on estimated risk tertiles and estimated risks of 10%, 10% to 19.9%, and 20%, respectively. Continuous variables are described as medians with 25th and 75th percentiles and were compared with the Mann- Whitney U test. Categoric variables are expressed as frequencies and percentages. Differences between categoric variables were analyzed with the chi-square test. In all tests, a p value 0.05 was considered significant. The statistical software packages SPSS version 14.0 (SPSS Inc., Chicago, Illinois) and SAS version 9.1 (SAS Institute Inc., Cary, North Carolina) were used. Results Clinical characteristics. Randomization results for all 4 biomarkers were available in 877 subjects. The sample sizes at 6 weeks and 6 months are given in Figure 1. The clinical characteristics of the sample population and the results of the tested biomarkers at the different measurement instances are demonstrated in Table 1. In total, 442 patients (50%) had been randomized to 3-month treatment with dalteparin. Three hundred sixty-five patients (42%) had been randomized to the invasive strategy, 365 to the noninvasive strategy (42%), and 147 patients (16%) had not been randomized regarding these strategies. Coronary revascularization had been performed at 6 weeks in 455 patients (52%) of the entire sample population and in 514 patients (60%) at 6 months. Figure 1 Patient Flow Chart Patient cohorts and occurrence of adverse events. AMI acute myocardial infarction; CABG coronary artery bypass grafting; PCI percutaneous coronary intervention; FRISC FRagmin and fast revascularization during InStability in Coronary artery disease trial.

4 360 Eggers et al. JACC Vol. 54, No. 4, 2009 Risk Prediction During and After NSTE-ACS July 21, 2009: Clinical at Randomization Characteristics Clinical andcharacteristics After of the 6 Weeks Studyof Population and the6 Study Months Population Table 1 at Randomization and After 6 Weeks and 6 Months Randomization (n 877) 6 Weeks (n 869) 6 Months (n 856) Age (yrs) 66.9 ( ) 67.1 ( ) 67.3 ( ) Male 625 (71.3) 617 (71.0) 607 (70.9) Previous smoking 321 (36.6) Current smoking 200 (22.8) Hypertension 288 (32.8) Heart failure 35 (4.0) 137 (15.8) 128 (15.0) Diabetes 112 (12.8) 159 (18.3) 153 (17.9) Previous stroke 42 (4.8) Previous AMI 242 (27.6) 716 (82.4) 706 (82.5) Previous PCI/CABG 91 (10.4) 455 (52.4) 514 (60.0) Treatment Acetylsalicylic acid 391 (44.6) 817 (95.6) Beta-blockers 336 (38.3) 707 (82.7) ACE inhibitors 120 (13.7) 158 (18.5) Calcium antagonists 160 (18.2) 169 (19.7) Digitalis 24 (2.7) 27 (3.2) Diuretics 150 (17.1) 162 (18.9) Long-acting nitrates 207 (23.6) 259 (30.3) Lipid-lowering drugs 113 (12.9) 460 (53.7) Biomarker results ctni 0.04 g/l 391 (44.6) ctni 0.01 g/l 414 (47.6) 301 (35.2) NT-proBNP (ng/ml) 518 ( ) 346 ( ) 232 ( ) CRP (mg/l) 5.9 ( ) 2.5 ( ) 2.3 ( ) egfr 75 ml/min/1.73 m (49.6) 488 (56.2) 484 (56.5) Values are shown as n (%) and median (25th to 75th percentiles). Smoking status, the prevalence of hypertension and new strokes, and medication had not been systematically assessed during follow-up. ACE angiotensin-converting enzyme; AMI acute myocardial infarction; CABG coronary artery bypass grafting; CRP C-reactive protein; ctni cardiac troponin I; egfr estimated glomerular filtration rate; NT-proBNP N-terminal pro-brain natriuretic peptide; PCI percutaneous coronary intervention. Prognostic evaluation. During 5-year follow-up, 79 patients (9.0%) died, 152 patients (17%) had at least 1 recurrent AMI, and 198 patients (23%) suffered the composite end point. The occurrence of events is illustrated in Figure 1. At randomization, NT-proBNP was the strongest predictor for mortality and ctni 0.04 g/l for both AMI and the composite end point (Table 2). The egfr at randomization did not provide independent prognostic information. When added as a ln transformed continuous variable, CRP neither altered the hazard ratios for the other tested markers considerably nor emerged as an independent predictor of events (data not shown). Even during follow-up, NT-proBNP was the strongest predictor for mortality and AMI. The CRP was also predictive for death and AMI, in particular at 6 months. The ctni and the egfr provided only limited prognostic value and before final adjustment. These associations remained unchanged when follow-up ctni results were entered into the multivariable analysis as ln transformed variables (data not shown). When the tested biomarkers were added to prognostic models based on conventional risk indicators, only NTproBNP at 6 weeks provided incremental value associated with a significant increase of the c-statistics from 0.66 to 0.69 (p 0.03). Even at 6 months, addition of NTproBNP resulted in the greatest increase of the c-statistics but without reaching statistical significance (Table 3). The NT-proBNP at 6 weeks was also the only marker to provide a significant NRI (Figs. 2A and 2B). This was due to a substantial proportion of patients being downgraded regarding their risk category after addition of NT-proBNP to the risk models (19% of all patients in both models). Discussion The prognostic importance of biomarkers reflecting different pathophysiologic entities related to risk is well established in the acute phase of NSTE-ACS. However, the evidence regarding the evolution of the prognostic information provided by biomarkers at later stages of the disease is still somewhat limited. Our results extend previous data from the FRISC II study (3,16), demonstrating that NTproBNP is a strong predictor of adverse events in NSTE- ACS, both throughout the entire 6-month sampling period and even in the context of other clinical risk indicators, including biomarkers of cardiomyocyte necrosis, inflammation, and renal dysfunction. The NT-proBNP levels were particularly predictive for mortality, probably because they reflect larger infarct size, progressive remodeling, and thus a more pronounced degree of myocardial dysfunction (17,18).

5 JACC Vol. 54, No. 4, 2009 July 21, 2009: Eggers et al. Risk Prediction During and After NSTE-ACS 361 Prognostic Table 2 Value Prognostic of Biochemical Value of Biochemical Markers Measured Markers atmeasured Different Time at Different Points Time Points Death AMI Randomization Model 1 (n 877) Model 2 (n 877) HR (95% CI) p Value HR (95% CI) p Value ctni 0.04 g/l 1.8 ( ) ( ) 0.82 NT-proBNP (ln) 1.7 ( ) ( ) egfr 75 ml/min/1.73 m ( ) ( ) 0.58 ctni 0.04 g/l 2.5 ( ) ( ) NT-proBNP (ln) 1.2 ( ) ( ) 0.76 egfr 75 ml/min/1.73 m ( ) ( ) Death or AMI ctni 0.04 g/l 2.2 ( ) ( ) NT-proBNP (ln) 1.2 ( ) ( ) 0.31 egfr 75 ml/min/1.73 m ( ) ( ) 0.10 Death AMI 6 Weeks Model 1 (n 869) Model 2 (n 869) Model 3 (n 869) HR (95% CI) p Value HR (95% CI) p Value HR (95% CI) p Value ctni 0.01 g/l 1.7 ( ) ( ) ( ) 0.38 NT-proBNP (ln) 1.8 ( ) ( ) ( ) CRP (ln) 1.4 ( ) ( ) ( ) 0.02 egfr 75 ml/min/1.73 m ( ) ( ) ( ) 0.60 Revascularization 0.6 ( ) 0.02 ctni 0.01 g/l 0.9 ( ) ( ) ( ) 0.33 NT-proBNP (ln) 1.4 ( ) ( ) ( ) CRP (ln) 1.2 ( ) ( ) ( ) 0.02 egfr 75 ml/min/1.73 m ( ) ( ) ( ) 0.34 Revascularization 0.6 ( ) Death or AMI ctni 0.01 g/l 1.1 ( ) ( ) ( ) 0.33 NT-proBNP (ln) 1.5 ( ) ( ) ( ) CRP (ln) 1.2 ( ) ( ) ( ) 0.02 egfr 75 ml/min/1.73 m ( ) ( ) ( ) 0.19 Revascularization 0.6 ( ) Death AMI 6 Months Model 1 (n 856) Model 2 (n 856) Model 3 (n 856) HR (95% CI) p Value HR (95% CI) p Value HR (95% CI) p Value ctni 0.01 g/l 2.4 ( ) ( ) ( ) 0.10 NT-proBNP (ln) 2.1 ( ) ( ) ( ) CRP (ln) 1.5 ( ) ( ) ( ) 0.02 egfr 75 ml/min/1.73 m ( ) ( ) ( ) 0.54 Revascularization 0.7( ) 0.11 ctni 0.01 g/l 1.5 ( ) ( ) ( ) 0.28 NT-proBNP (ln) 1.4 ( ) ( ) ( ) 0.06 CRP (ln) 1.3 ( ) ( ) ( ) 0.02 egfr 75 ml/min/1.73 m ( ) ( ) ( ) 0.80 Revascularization 0.6 ( ) 0.05 Death or AMI ctni 0.01 g/l 1.6 ( ) ( ) ( ) 0.22 NT-proBNP (ln) 1.6 ( ) ( ) ( ) CRP (ln) 1.4 ( ) ( ) ( ) egfr 75 ml/min/1.73 m ( ) ( ) ( ) 0.69 Revascularization 0.7 ( ) 0.02 Model 1: adjusted for age, sex, diabetes, heart failure, and previous AMI. Model 2: adjusted for the same variables as in Model 1 with the addition of ctni 0.04 g/l (randomization results) or 0.01 g/l (6 weeks and 6 months results), ln NT-proBNP, ln CRP (6 weeks and 6 months), and egfr 75 ml/min/1.73 m 2. Model 3: adjusted for the same variables as in Model 2 with the addition of coronary revascularization after randomization and before the respective measurement instance. CI confidence interval; HR hazard ratio; other abbreviations as in Table 1.

6 362 Eggers et al. JACC Vol. 54, No. 4, 2009 Risk Prediction During and After NSTE-ACS July 21, 2009: C-Statistics: Regarding the C-Statistics: CompositeIncremental Prognostic of Death orvalue Prognostic Myocardial of Biochemical Value Infarction of Biochemical Markers During 5-Year Markers Follow-Up Table 3 Regarding the Composite of Death or Myocardial Infarction During 5-Year Follow-Up Calibration Hosmer-Lemeshow C-Statistics p Value Chi-Square p Value 6 weeks Clinical risk indicators 0.66 ( ) Clinical risk indicators ctni 0.01 g/l 0.67 ( ) Clinical risk indicators NT-proBNP (ln) 0.69 ( ) Clinical risk indicators CRP (ln) 0.67 ( ) Clinical risk indicators egfr 75 ml/min/1.73 m ( ) months Clinical risk indicators 0.65 ( ) Clinical risk indicators ctni 0.01 g/l 0.66 ( ) Clinical risk indicators NT-proBNP (ln) 0.68 ( ) Clinical risk indicators CRP (ln) 0.67 ( ) Clinical risk indicators egfr 75 ml/min/1.73 m ( ) Clinical risk indicators include age, sex, diabetes at the respective measurement instance, heart failure at the respective measurement instance, and previous AMI before the respective measurement instance. Abbreviations as in Table 1. However, even myocardial ischemia augments the synthesis of the natriuretic peptides (19), which might explain the association between NT-proBNP upon early follow-up and recurrent ischemic events. Among the biomarkers measured at randomization, ctni was the strongest predictor for recurrent AMI but exhibited no independent association with mortality. This finding probably depends on the choice of the 99th percentile as a prognostic cutoff. This cutoff has been shown to reflect an increased likelihood of an unstable plaque with downstream microembolization of thrombotic material, which translates into a higher risk of recurrent ischemic events (20,21). The risk for mortality, in contrast, is known to increase at higher troponin peak levels, given the relation of troponin leakage to the amount of infarcted myocardium (18,22). Contrasting with the acute situation, ctni elevation at a threshold below the 99th percentile was not related to recurrent AMI but predicted mortality. This indicates that this lower cutoff might be more sensitive to detect left ventricular dysfunction after NSTE-ACS (23). However, ctni was no longer prognostic after adjustment for other biomarkers, including NT-proBNP, probably because the natriuretic peptides more appropriately reflect impaired cardiac performance (18). This does not exclude the possibility that ctni might exhibit stronger associations with risk at even later time points, given its independent relation to mortality in a recently assessed elderly community population (24). Even CRP emerged as an independent predictor when measured during follow-up and became, despite decreasing levels, more prognostic over time. Late after NSTE-ACS, CRP levels might reflect an increased myocardial cytokine activation leading to remodeling, paving the way for heart failure and thereby to poor outcome (25). However, given the prognostic value of CRP independent of NT-proBNP, it is more probable that the prognostic implications of CRP late after NSTE-ACS are mediated by extramyocardial mechanisms such as a chronic low-grade inflammation in the coronary vasculature, as described in other stable populations (26). We did not find, somewhat unexpectedly, associations between renal function and prognosis, which contrasts with previous studies in patients with ongoing or recent NSTE- ACS (8,13). We assume that these findings are biased, due to the exclusion of patients with renal failure in the FRISC II study. Our findings raise the question of whether and which biochemical markers should be assessed in the stable phase after NSTE-ACS to improve prognostication. Current follow-up routines focus on symptomatic assessment and modification of cardiovascular risk factors to halt the progression of atherosclerosis. However, these measures are in part operator dependent, and conventional risk factors might not completely account for the individual risk profile, which also is known to change over time (27). We found that measurement of NT-proBNP at 6 weeks might be particularly useful with regard to its incremental value to conventional risk indicators. Noteworthy, the assessment of NRI indicated that NT-proBNP levels allowed for the reclassification of a relative large subset of patients without events to lower categories of risk. Early measurement of NT-proBNP might also be useful for the identification of some high-risk subjects with persistent left ventricular dysfunction after NSTE-ACS in whom optimization pharmacological treatment is mandatory. C-reactive protein, in contrast, provided no incremental prognostic information in the tested models. However, with regard to its independent association with events at 6 months and the considerably improved calibration of our risk model at this time point after addition of CRP, testing for this biomarker could be useful for later follow-up controls when results would be integrated into more sophisticated risk prediction tools than the exploratory model applied in our analysis. Study limitations. This study is based on an NSTE-ACS population randomized more than 10 years ago (i.e., before

7 JACC Vol. 54, No. 4, 2009 July 21, 2009: Eggers et al. Risk Prediction During and After NSTE-ACS 363 Figure 2 NRI Regarding the Composite of Death or Myocardial Infarction During 5-Year Follow-Up After Addition of NT-proBNP Levels at 6 Weeks to Conventional Risk Indicators (A) Risk categories defined by estimated risk tertiles. (B) Risk categories defined by estimated risks of 10%, 10% to 19.9%, and 20%. Bars indicate numbers of patients within the respective risk categories, considering those who had been downgraded or upgraded and those who remained within the same risk category at 6 weeks after the addition of ln N-terminal pro-brain natriuretic peptide (NT-proBNP) levels to conventional risk indicators (age, sex, diabetes, heart failure, previous myocardial infarction). The solid parts of the bars depict the proportion of patients who met the composite end point after 6 weeks and within 5 years of follow-up. The number of patients with an event is given at the top of each bar. NRI net reclassification improvement. the current era of intense secondary prevention with adenosine diphosphate inhibition, angiotensin-converting enzyme inhibitors, and high-dose statins) and therefore needs to be validated in a contemporary sample. Furthermore, we assessed a pre-selected patient population, and the sample size was somewhat limited. Therefore we cannot exclude the possibility that CRP and the egfr might exhibit stronger associations with risk when assessed in a larger and more unselected population. Due to a lack of remaining samples, we could not perform re-analyses of ctni at randomization with the refined version of the AccuTnI assay. Thus, ctni results were obtained with 2 iterations of this assay with different prognostic cutoffs, which limits the transferability of results obtained at randomization to follow-up results. The focus on coronary revascularization versus no revascularization might have weakened the relationships between the biomarkers and risk, because the decision to revascularize patients from other than the invasive arm was based on clinical decisions with a potential higher rate of sicker patients with higher biomarker levels being treated with this prognostically beneficial therapy.

8 364 Eggers et al. JACC Vol. 54, No. 4, 2009 Risk Prediction During and After NSTE-ACS July 21, 2009: Conclusions Cardiac troponin I, NT-proBNP, and CRP exhibit different and changing relations to adverse events in patients with NSTE-ACS, both in the acute phase and after clinical stabilization. The NT-proBNP was independently predictive for adverse outcome throughout the entire 6-month observation period and should be considered for improvement of risk stratification during early follow-up. Even measurement of CRP might be a useful tool for risk stratification at a later time point (e.g., after 6 months). The eventual incremental value of slight elevations of troponin determined with highly sensitive assays will need further evaluation in larger patient cohorts with stable coronary artery disease. Acknowledgments The authors wish to thank Hans Garmo, Karin Jensevik, and Johan Lindbäck for their statistical support. Reprint requests and correspondence: Dr. Kai M. Eggers, Department of Medical Sciences, Cardiology, University Hospital Uppsala, S Uppsala, Sweden. kai.eggers@ucr.uu.se. REFERENCES 1. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. J Am Coll Cardiol 2000;35: James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108: Lindahl B, Lindbäck J, Jernberg T, et al. Serial analyses of N-terminal pro-type natriuretic peptide in patients with non ST-segment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol 2005;45: Morrow DA, de Lemos JA, Blazing MA, et al. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA 2005;294: Eggers KM, Lagerqvist B, Venge P, Wallentin L, Lindahl B. Persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome predicts adverse long-term outcome. Circulation 2007;116: Harb TS, Zareba W, Moss AJ, et al. Association of C-reactive protein and serum Amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol 2002;89: Jahn J, Hellmann I, Maass M, Giannitsis E, Dalhoff K, Katus HA. Time-dependent changes of hs-crp serum concentration in patients with non-st elevation acute coronary syndrome. Herz 2004;29: Jose P, Skali H, Anavekar N, et al. Increase in creatinine and cardiovascular risk in patients with systolic dysfunction after myocardial infarction. J Am Soc Nephrol 2006;17: The Fragmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354: Lagerqvist B, Husted S, Kontny F, et al. 5-year outcomes in the FRISC-II randomised trial of an invasive versus a non-invasive strategy in non-st-elevation acute coronary syndrome: a follow-up study. Lancet 2006;368: Apple FS, Wu AH, Jaffe AS. European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: how to use existing assays clinically and for clinical trials. Am Heart J 2002;144: Levey AS, Greene T, Kusek JW, Beck GJ, and the MDRD Study Group. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:155A. 13. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351: Antolini L, Nam BH, D Agostino RB. Inference on correlated discrimination measures in survival analysis: a nonparametric approach. Comm Statist Theory Methods 2004:33: Pencina MJ, D Agostino RB Sr., D Agostino RB Jr., Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27: Jernberg T, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease. J Am Coll Cardiol 2003;42: Nilsson JC, Groenning BA, Nielsen G, et al. Left ventricular remodelling in the first year after acute myocardial infarction and the predictive value of N-terminal pro brain natriuretic peptide. Am Heart J 2002;143: Steen H, Futterer S, Merten C, Jünger C, Katus HA, Giannitsis E. Relative role of NT-pro BNP and cardiac troponin T at 96 hours for estimation of infarct size and left ventricular function after acute myocardial infarction. J Cardiovasc Magn Reson 2007;9: Sabatine MS, Morrow DA, de Lemos JA, et al. Acute changes in circulating natriuretic peptide levels I relation to myocardial ischemia. J Am Coll Cardiol 2004;44: Heeschen C, van den Brand MJ, Hamm CW, Simoons ML. Angiographic findings in patients with refractory unstable angina according to troponin status. Circulation 1999;104: Lindahl B, Diderholm E, Lagerqvist B, Venge P, Wallentin L, and the FRISC II Investigators. Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy. J Am Coll Cardiol 2001;38: Panteghini M, Bonetti G, Pagani F, Stefini F, Giubbini R, Cuccia C. Measurement of troponin I 48 h after admission as a tool to rule out impaired left ventricular function in patients with a first myocardial infarction. Clin Chem Lab Med 2005;43: Eggers KM, Lagerqvist B, Oldgren J, Venge P, Wallentin L, Lindahl B. Pathophysiologic mechanisms of persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome. Am Heart J 2008;156: Zethelius B, Berglund L, Sundström J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008;358: Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation 1998;98: Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men (erratum in: N Engl J Med 1997;337:356). N Engl J Med 1997;336: Westerhout CM, Fu Y, Lauer MS, et al. Short- and long-term risk stratification in acute coronary syndrome. The added value of quantitative ST-segment depression and multiple biomarkers. J Am Coll Cardiol 2006;48: Key Words: acute coronary syndrome y biomarkers y risk assessment y stable coronary artery disease. Go to to take the CME quiz for this article.