Published online before print September 11, 2007, doi: 10.1161/CIRCULATIONAHA.107.697714
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(Circulation. 2007;116:1540-1548.)
© 2007 American Heart Association, Inc.
Coronary Heart Disease |
Growth Differentiation Factor 15 for Risk Stratification and Selection of an Invasive Treatment Strategy in Non–ST-Elevation Acute Coronary Syndrome
From the Department of Cardiology and Angiology (K.C.W., T.K., T.A., T.P., H.D.), Hannover University Medical School, Hannover, Germany, and the Department of Internal Medicine (Cardiology and Clinical Chemistry) and Uppsala Clinical Research Center (B. Lagerqvist, B. Lindahl, S.O., A.S., P.V., L.W.), University of Uppsala, Uppsala, Sweden.
Correspondence to Dr Lars Wallentin, Uppsala Clinical Research Center, 75185 Uppsala, Sweden. E-mail lars.wallentin{at}ucr.uu.se
Received February 19, 2007; accepted July 10, 2007.
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Abstract |
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Background— An invasive treatment strategy improves outcome in patients with non–ST-elevation acute coronary syndrome at moderate to high risk. We hypothesized that the circulating level of growth differentiation factor 15 (GDF-15) may improve risk stratification.
Methods and Results— The Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial randomized patients with non–ST-elevation acute coronary syndrome to an invasive or conservative strategy with a follow-up for 2 years. GDF-15 and other biomarkers were determined on admission in 2079 patients. GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (>1800 ng/L) in 493 patients (23.7%). Elevated levels of GDF-15 independently predicted the risk of the composite end point of death or recurrent myocardial infarction in the conservative group (P=0.016) but not in the invasive group. A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point. The occurrence of the composite end point was reduced by the invasive strategy at GDF-15 levels >1800 ng/L (hazard ratio, 0.49; 95% confidence interval, 0.33 to 0.73; P=0.001), between 1200 and 1800 ng/L (hazard ratio, 0.68; 95% confidence interval, 0.46 to 1.00; P=0.048), but not <1200 ng/L (hazard ratio, 1.06; 95% confidence interval, 0.68 to 1.65; P=0.81). Patients with ST-segment depression or a troponin T level >0.01 µg/L with a GDF-15 level <1200 ng/L did not benefit from the invasive strategy.
Conclusions— GDF-15 is a potential tool for risk stratification and therapeutic decision making in patients with non–ST-elevation acute coronary syndrome as initially diagnosed by ECG and troponin levels. A prospective randomized trial is needed to validate these findings.
Key Words: coronary disease • growth differentiation factor 15 • myocardial infarction • revascularization • risk factors • treatment outcome
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Introduction |
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The risk of death and recurrent myocardial infarction (MI) varies considerably across the spectrum of patients with non–ST-elevation acute coronary syndrome (NSTE-ACS), which necessitates individually tailored treatment strategies. An invasive strategy is currently the recommended treatment for patients at moderate to high risk for ischemic complications as identified by clinical history, signs of ischemia in the ECG, and biomarkers of myocyte necrosis.1,2 This recommendation is based on the benefits observed with an invasive strategy in the group of patients who present with ST-segment depression or elevated troponin levels in 2 pivotal randomized trials.3–8
Clinical Perspective p 1548
Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor β cytokine superfamily and is induced in the myocardium after ischemia and reperfusion injury.9 Recently, we demonstrated that GDF-15 levels are elevated and independently associated with mortality in NSTE-ACS patients treated with a conservative strategy.10 Here, we hypothesized that the circulating level of GDF-15 might improve risk stratification and therapeutic decision making in NSTE-ACS. We therefore evaluated the levels of GDF-15 on admission and their relation to outcome in the Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial, which randomized patients with NSTE-ACS to an invasive or a conservative strategy.3
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Methods |
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Study Design
FRISC-II was a prospective multicenter trial that randomized 2457 patients with NSTE-ACS in a factorial design to an invasive or conservative strategy and to extended treatment with dalteparin or placebo for 3 months. The protocol and main results of the trial have been published.3 The primary end point was a composite of death or MI at 6 months; the present study uses the 2-year outcome to allow comparisons with previous reports on other biomarkers with the same follow-up.11–16 Patients were eligible if admitted with symptoms of NSTE-ACS within the last 48 hours. Myocardial ischemia had to be verified by ECG (ST depression
0.1 mV or T-wave inversion 0.1 mV) or biochemical markers of MI. Exclusion criteria included previous heart surgery, percutaneous coronary intervention within the last 6 months, increased risk of bleeding, and a serum creatinine concentration >150 µmol/L. In the invasive group, the aim was to perform coronary angiography and, if appropriate, revascularization within 7 days. Coronary angiograms were assessed by the operator on the basis of a detailed evaluation form. A significant stenosis was considered present if a 50% reduction in vessel diameter was present. Revascularization was recommended in patients with a 70% diameter stenosis in any artery that supplied a substantial proportion of the myocardium. The conservative strategy recommended angiography only in patients with refractory or recurrent symptoms despite maximal medical therapy or severe ischemia at a predischarge symptom-limited exercise test. Percutaneous coronary intervention was recommended at 1 or 2 blood flow–limiting lesions; coronary artery bypass graft surgery was preferred in patients with 3-vessel or left main disease. The study protocol also recommended an echocardiographic examination performed in the hospital before coronary angiography. All examinations were stored on videotape and analyzed at each participating center. From the parasternal and apical views, left ventricular ejection fraction (LVEF) was graded as normal (>55%), mildly depressed (45% to 55%), moderately depressed (30% to 44%) or severely depressed (<30%). During long-term follow-up, invasive procedures were considered, regardless of randomized strategy, for all patients with incapacitating symptoms, recurrence of instability, or MI.
The patients were assessed for outcome events while in the hospital, by telephone contact after 2 weeks, by outpatient visits after 6 weeks, 3 months, and 6 months, and by telephone contacts after 1 and 2 years. During the first 6 months, all reported deaths, MIs, elevation of biochemical markers in relation to percutaneous coronary intervention procedures, and new Q-waves reported by the ECG core laboratory were adjudicated by an independent clinical events committee. After the first 6 months, information on further events was based on investigator report forms, outpatient visits, or telephone contacts. Written informed consent was obtained from all participants; the protocol was approved by all local ethics committees.
Laboratory Analyses
Blood samples were collected in EDTA-containing tubes on admission. Samples were centrifuged, and plasma was stored frozen at –70°C within 30 minutes. For the present study, plasma samples were available from 2079 patients. The GDF-15 levels were determined by immunoradiometric assay.17 Risk stratification was performed according to 2 prespecified GDF-15 cut-off levels: 1200 and 1800 ng/L. A GDF-15 level of 1200 ng/L corresponds to the upper reference limit in apparently healthy elderly individuals that were matched for age and gender to patients in the FRISC-II trial.17 The GDF-15 level of 1200 ng/L also corresponds to the rounded lower tertile boundary in 2081 patients with NSTE-ACS included in the Global Utilization of Strategies To Open occluded arteries IV (GUSTO-IV) trial, whereas 1800 ng/L corresponds to the rounded upper tertile boundary in that patient population.10 Troponin T was determined by a third-generation assay, N-terminal pro–B-type natriuretic peptide (NT-proBNP) by a sandwich immunoassay, both on an Elecsys 2010 from Roche Diagnostics (Mannheim, Germany). High-sensitivity C-reactive protein (CRP) measurements were performed with the N Latex CRP reagent and a BN ProSpec analyzer from Dade Behring (Deerfield, Ill). Levels of interleukin-6 (IL-6) were analyzed with the Immulite assay (Diagnostic Products Corp, Los Angeles, Calif) with a detection limit of 5 ng/L. The creatinine level was determined at the individual study sites with standard methodologies. The Cockroft-Gault equation was used to calculate creatinine clearance. All biomarker measurements were performed by investigators that were not aware of patients’ characteristics and outcomes.
Statistics
Baseline characteristics are presented as numbers and proportions; continuous data are given as medians (25th to 75th percentiles). Because the randomized dalteparin treatment had no influence on outcome, these groups were combined with regard to the outcome analyses. Comparisons of continuous or categorical variables between the invasive and conservative strategies were evaluated by Mann-Whitney U-test or Fisher exact test, respectively. To evaluate the relations between the levels of GDF-15 and baseline characteristics, the levels of troponin T, NT-proBNP, CRP, IL-6, and creatinine clearance, both Spearman rank-correlation coefficients between the GDF-15 level and these factors and the Cochran-Armitage trend test for relations between proportions in several groups were used. Multiple linear regression was used to evaluate the association of GDF-15 as the dependent variable with other variables. With the use of simple and multiple logistic-regression analyses, ST-segment depression and the levels of troponin T, NT-proBNP, CRP, IL-6, creatinine clearance, and GDF-15 were evaluated together with baseline characteristics (age, gender, diabetes mellitus, history of MI) to identify predictors of outcome at 2 years. For NT-proBNP, CRP, and GDF-15, the natural logarithms were used in these analyses, whereas troponin T was dichotomized to >0.01 µg/L and 
0.01 µg/L and IL-6 was dichotomized to 5 ng/L and <5 ng/L. The FRISC score was calculated as described.15 Areas under 2 receiver-operating characteristics curves were compared with the 
2 test.18 The primary efficacy outcome was further examined with regard to variation of the effect of the randomized treatment within subgroups. For each covariate, analysis consisted of the multiple logistic regression model that incorporated terms for treatment group, the subgroups and the treatment group defined by covariate interaction. For these analyses, patients were stratified with use of predefined cut-off levels for ST-segment depression (0.1 mV) and troponin T (0.01 µg/L),6 NT-proBNP (1000 ng/L),19 CRP (10 mg/L), and IL-6 (5 ng/L),12 creatinine clearance (median, 68 mL/min), and GDF-15 (1200 and 1800 ng/L).10 The Kaplan-Meier method was used to illustrate the timing of events during follow-up in relation to strata of GDF-15 and statistical assessment was performed with the log-rank test. The differences in proportions in outcome events (death, recurrent MI, and the composite end point during 2 years) in the different strata of GDF-15 levels were judged with hazard ratios and Wald’s 2 test. Data analyses were performed with the SAS 9.1 statistical program (SAS Institute Inc, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Baseline Characteristics and Overall Study Results
The median age of the patients was 66 years (25th to 75th percentiles, 58 to 72 years), and 69.7% were males. Patients were admitted, on average, 38 hours (25th to 75th percentiles, 27 to 54 hours) after the last episode of chest pain; 44.4% of the patients presented with ST-segment depression, 73.3% with a troponin T level >0.01 µg/L. Baseline characteristics are shown in Table 1. After 2 years, 288 of 2079 patients reached the composite end point of death or recurrent MI; 85 patients died, and 230 patients had a recurrent MI. The invasive strategy reduced the risk of the composite end point (119 [11.4%] versus 169 [16.3%] events; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55 to 0.87; P=0.002), and the risks of the individual end points of death (30 [2.9%] versus 55 [5.3%] events; HR, 0.53; 95% CI, 0.34 to 0.83; P=0.006) and recurrent MI (95 [9.1%] versus 135 [13.1%] events; HR, 0.69; 95% CI, 0.53 to 0.90; P=0.006).
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GDF-15 Levels on Admission in Relation to Baseline Variables
The concentration of GDF-15 on admission ranged from 397 to 53 444 ng/L, with a median of 1345 ng/L (25th to 75th percentiles, 1008 to 1767 ng/L). GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (>1800 ng/L) in 493 patients (23.7%). Patients with increased levels of GDF-15 tended to be older, presented later after symptom onset, and were less likely to be current smokers, but they were more likely to have a history of hypertension, diabetes mellitus, MI, or heart failure (Table 1). Elevated levels of GDF-15 were associated with ST-segment depression, higher levels of troponin T, NT-proBNP, CRP, and IL-6, and a reduced creatinine clearance on admission (Table 1). By multiple linear regression analysis, with the natural logarithm of GDF-15 as the dependent variable, GDF-15 was independently related to age (P<0.001), male gender (P<0.001), current smoking (P<0.001), hypertension (P=0.021), diabetes mellitus (P<0.001), a history of MI (P=0.001), NT-proBNP (P<0.001), CRP (P<0.001), and IL-6 (P<0.001), and a reduced creatinine clearance (P=0.001). The R2 value of this model was 0.38, which indicated that these factors explained only part of the variation in the GDF-15 levels. GDF-15 was not independently related to ST-segment depression (P=0.25) and the level of troponin T (P=0.67). As shown in the invasive group, where coronary angiograms were available in all patients, patients with elevated levels of GDF-15 were more likely to have left main or 3-vessel disease (Figure 1A). In patients with available echocardiograms (n=1698), patients with elevated levels of GDF-15 were more likely to have depressed LVEF (Figure 1B).
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Relation of GDF-15 and Other Risk Markers to Outcome
In patients randomized to the conservative strategy, ST-segment depression and increased levels of troponin T, NT-proBNP, and GDF-15 were all related to increased risks of the composite end point, and the individual end points of death and recurrent MI; a reduced creatinine clearance was related to the risks of the composite end point and recurrent MI; increased levels of IL-6 and CRP were related only to the risk of death (Table 2). After adjustment for age, gender, diabetes mellitus, history of previous MI, and markers related to outcome with P<0.1 in the simple model, GDF-15 remained independently related to the risks of the composite end point (P=0.016), recurrent MI (P=0.015), and death (P=0.002) (Table 2). Besides GDF-15, troponin T emerged as an independent marker of the composite end point and recurrent MI, and low CRP levels were independently related to recurrent MI (Table 2). When LVEF was similarly added to the multiple model, GDF-15 remained independently related to the risks of the composite end point (P=0.042) and death (P=0.002), and GDF-15 still tended to be related to the risk of recurrent MI (P=0.081). However, information on LVEF was not available in 
20% of the patients, which reduced the statistical power of this analysis. No independent relations existed between GDF-15 and outcome in patients randomized to the invasive strategy (not shown). GDF-15 added prognostic information to the FRISC score in patients randomized to the conservative arm but not in patients from the invasive arm (Table I, online-only Data Supplement).
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Interaction of GDF-15 With Treatment Strategy
A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point (Table 3). Conversely, no significant interactions were observed for ST-segment depression, troponin T, NT-proBNP, creatinine clearance, CRP, and IL-6 (Table 3). With regard to recurrent MI alone, GDF-15, along with ST-segment depression and creatinine clearance, showed a significant interaction with treatment strategy (Table II, online-only Data Supplement). With regard to the risk of death, none of these markers, including GDF-15, showed a significant interaction with treatment strategy; yet, it must be noted that the number of deaths was relatively small, which limited the power of these analyses (Table III, online-only Data Supplement).
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GDF-15 Levels and Benefit From an Invasive Strategy
A graded relationship existed between the levels of GDF-15 and the effects of the invasive strategy on the composite and the individual end points (Figure 2). In patients with GDF-15 levels >1800 ng/L, the invasive strategy resulted in a 50% reduction of the risk of the composite end point (HR, 0.49; 95% CI, 0.33 to 0.73; P=0.001). In this cohort, the invasive strategy resulted in significant reductions, both of mortality (HR, 0.46; 95% CI, 0.25 to 0.83; P=0.010) and recurrent MI (HR, 0.41; 95% CI, 0.26 to 0.67; P<0.001) (Figure 2). In patients with GDF-15 levels between 1200 and 1800 ng/L, the invasive strategy was associated with a significant reduction of the composite end point (HR, 0.68; 95% CI, 0.46 to 1.00; P=0.048) and also with a trend to reduce the individual end points of death (HR, 0.52; 95% CI, 0.22 to 1.21; P=0.13) and recurrent MI (HR, 0.76; 95% CI, 0.50 to 1.16; P=0.21) (Figure 2). Patients with GDF-15 levels <1200 ng/L did not derive a significant benefit from the invasive strategy (Figure 2). The timing of events according to treatment strategy and GDF-15 levels on admission is shown in Figure 3.
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Combination of GDF-15 With ECG and Troponin T to Select Patients for an Invasive Strategy
To explore whether GDF-15 adds information to the ECG and troponin, the analyses were stratified according to occurrence of ST-segment depression and the level of troponin T. The invasive strategy significantly reduced the risk of the composite end point in the groups that presented with ST-segment depression or troponin T levels >0.01 µg/L but not in patients without these findings (Figure 4). In patients with ST-segment depression and GDF-15 levels <1200 ng/L, the risk of the composite end point was not influenced by the invasive strategy. Similarly, patients with troponin T levels >0.01 µg/L and a GDF-15 level <1200 ng/L did not significantly benefit from the invasive strategy. Conversely, patients with ST-segment depression or elevated levels of troponin T who also presented with a GDF-15 level 1200 ng/L derived a significant benefit from the invasive strategy, with the greatest benefit observed in patients with GDF-15 levels >1800 ng/L (Figure 4). Although patient and event numbers were relatively small in these subgroups, interaction probability values approached the level of significance in patients with ST-segment depression and a GDF-15 level >1800 ng/L (P=0.05) and in patients with elevated troponin T levels and a GDF-15 level >1800 ng/L (P=0.08) (Figure 4).
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Discussion |
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Randomized trials indicate that an invasive strategy reduces the risk of major cardiovascular events in patients with NSTE-ACS at moderate to high risk,3,4,8,20 although this approach may even be harmful in low-risk patients.8,21 The occurrence of ST-segment depression and elevation of troponin on admission are risk stratification criteria that have consistently been shown to separate patient groups with different responses to an invasive strategy.1–8,15 The present study shows that a single measurement of GDF-15 on admission provides independent prognostic information on the risks of death and recurrent MI and improves the identification of patients who will benefit from an invasive strategy.
GDF-15 was initially cloned on the basis of its enhanced expression during macrophage activation and has been linked to inflammatory states in many tissue beds.22 Recently, GDF-15 has been identified as a gene that is strongly expressed in the myocardium after ischemia and reperfusion injury.9 Rapid induction of GDF-15 after an episode of ischemia and reperfusion is followed by a prolonged expression in the reperfused myocardium, which may be related to increased levels of oxidative stress, inflammation, and infarct healing.23 Accordingly, increased circulating levels of GDF-15 may signal a need for enhanced oxidative metabolism and tissue repair, as it might be obtained by revascularization of the affected myocardium.
In the present NSTE-ACS cohort, the levels of GDF-15 were comparable to the recently presented GUSTO-IV data10 and significantly higher than in a matched control group of apparently healthy elderly subjects.17 In agreement with the GUSTO-IV results, the level of GDF-15 was independently related to age, male gender, current smoking, hypertension, diabetes mellitus, a history of MI, cardiac dysfunction (NT-proBNP), inflammation (CRP, IL-6), and renal dysfunction. Conversely, no independent relation existed between the level of GDF-15 and ST-segment depression or the level of troponin T, which supports the conclusion that GDF-15 does not reflect ongoing ischemia and infarction during an episode of NSTE-ACS.10 In the present patient population, the relations between GDF-15 and markers of increased cardiovascular risk were further corroborated by significant relations to the severity of coronary artery disease and reduced LVEF.
In the conservative treatment arm, the present study verified the graded relationship between the level of GDF-15 and mortality in NSTE-ACS.10 In the present population with longer follow-up, we also demonstrated a graded relationship with recurrent MI and the composite of death or MI. Notably, GDF-15 added prognostic information to the FRISC score, which has been developed as an integrative tool for risk stratification in NSTE-ACS based on a retrospective analysis of the FRISC-II patient population.15 After adjustment for age, gender, established prognostic factors (ie, diabetes mellitus and history of previous MI),15 ST-segment depression, and other biomarkers related to outcome in the simple model, GDF-15 emerged as the only biomarker that provided independent prognostic information on all 3 end points. Besides GDF-15, troponin T provided independent information on the risks of MI and the composite end point. CRP was inversely related to the risk of MI in the multiple model, which may be related to the fact that GDF-15, with its close relation to inflammatory markers, carried the prognostic information provided by inflammation in the multiple model.
A graded relationship existed between the level of GDF-15 and the absolute and relative benefits from an invasive strategy. The invasive strategy significantly reduced the risks of the composite end point and the individual end points at 2 years in patients with GDF-15 levels 1200 ng/L, with the greatest benefit observed in patients with GDF-15 levels >1800 ng/L. Conversely, patients with GDF-15 levels within the normal range (<1200 ng/L) did not benefit from routine invasive procedures.
Current guidelines for the treatment of NSTE-ACS recommend that patients with ST-segment depression or elevated levels of troponin be scheduled for angiography and revascularization.1,2 Among patients who present with ST-segment depression or elevated levels of troponin T, GDF-15 levels improved the identification of patients who benefited from invasive management. As previously shown, other clinical and biochemical factors (eg, those used in the FRISC score),15 may contribute to the selection of patients for an invasive treatment strategy. As the GDF-15 level was independently related to age, male gender, diabetes mellitus, history of MI, and increased inflammatory markers, it might integrate much of the prognostic information in these 5 variables used in the FRISC score. The level of GDF-15 was also independently related to the level of NT-proBNP and to reduced creatinine clearance, which are 2 other biomarkers that might contribute to the identification of high-risk patients with a greater potential for benefit from an invasive strategy.14,16 However, we found the level of GDF-15 to be only partly explained by, and to carry independent prognostic information beyond, these factors. This information might be related to the pathophysiological role of GDF-15 during myocardial ischemia and infarct healing.9 Notably, GDF-15 was not independently related to the 2 key variables currently used for risk stratification in clinical practice, ST-segment depression and troponin T, and combination of GDF-15 with ST-segment depression and troponin T enabled a significant improvement in risk stratification and identification of patients who will benefit from an invasive strategy.
In conclusion, we have shown that GDF-15 is a potential new tool for risk stratification and therapeutic decision making in patients with NSTE-ACS. It should be noted that the FRISC-II study was conducted >8 years ago and that there have been changes in clinical practice since that time. Although our study shows a relationship between GDF-15 and the benefit of an invasive strategy, only a prospective randomized trial would be able to validate these findings. Current recommendations to use the ECG and results from troponin testing for therapeutic decision making in NSTE-ACS are based on similar post hoc analyses of historic strategy trials,3–8 which further emphasizes the need for a prospective trial to explore the role of traditional and new biomarkers in patient management and resource allocation in NSTE-ACS.
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Acknowledgments |
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Sources of Funding
This study was supported by grants from the German Ministry of Education and Research to Dr Wollert (BMBF, BioChancePlus program) and the Swedish Heart-Lung Foundation to Dr Wallentin. The FRISC-II trial was supported by and organized in collaboration with Pharmacia and Upjohn.
Disclosures
Drs Wollert, Kempf, Drexler, and Wallentin have filed a patent and have a contract with Roche Diagnostics to develop a commercial assay for GDF-15 used for diagnosis and prognosis in cardiovascular disease. The remaining authors report no conflicts.
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Footnotes |
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The online-only Data Supplement, consisting of tables, is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.697714/DC1.
Related Article:
Circulation 2007 116: 1525.
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