Clinical Chemistry 57:4 603–608 (2011)
Proteomics and Protein Markers
Myeloperoxidase Improves Risk Stratification in Patients with Ischemia and Normal Cardiac Troponin I Concentrations Fred S. Apple,1* Stephen W. Smith,2 Lesly A. Pearce,3 Karen M. Schulz,1 Ranka Ler,1 and MaryAnn M. Murakami1
BACKGROUND: We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value.
We used Siemens (n ⫽ 400) and Abbott (n ⫽ 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan–Meier method and compared with the log-rank statistic.
METHODS:
RESULTS:
At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P ⬍ 0.001) for increased cTnI and 2.7 (P ⫽ 0.006) for increased MPO for the Siemens assays and were 5.5 (P ⬍ 0.001) for increased cTnI and 2.9 (P ⫽ 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P ⫽ 0.002) and 6 months (18.1% vs 5.0%, P ⫽ 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P ⫽ 0.03) and at 6 months (16.2% vs 5.1%, P ⫽ 0.01) than those with normal values.
CONCLUSIONS: A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone.
1
Departments of Laboratory Medicine and Pathology and 2 Emergency Medicine, Hennepin County Medical Center, University of Minnesota School of Medicine and Minneapolis Medical Research Foundation, Minneapolis, MN; 3 Biostatistical Consulting, Minot ND. * Address correspondence to this author at: Hennepin County Medical Center, 701 Park Ave., Clinical Labs P4, Minneapolis MN 55415. Fax 612-904-4229; e-mail
[email protected].
Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal. © 2011 American Association for Clinical Chemistry
Biomarkers of nonpathologic and/or pathologic processes are often used as surrogate end points to predict clinical outcomes (1 ). Myeloperoxidase (MPO),4 a heme protein stored in leukocytes and released in response to activation by inflammation (2, 3 ), has been shown to play a role in the development of atherosclerosis (4 ). Several clinical studies have found an association between the MPO concentration in plasma and the presence of cardiovascular disease in patients who present with a moderate to high risk of acute coronary syndrome (ACS) (5– 8 ). Whether patients who present with ACS and increased MPO are at increased risk of adverse cardiac events is unclear. Both Baldus et al. (5 ) and Brennan et al. (6 ) have reported that moderate- to high-risk patients who present with chest pain and have an increased MPO concentration (as measured with a research-based ELISA method) are at significantly higher risk [hazard ratio (HR) ⱖ2.0] of a major adverse cardiac event (MACE) at 30 days and 6 months. Other studies, however, have reported that MPO provides no clinically relevant information regarding the risk of short- or long-term mortality or as a biomarker for the diagnosis of myocardial infarction (MI) (9, 10 ). Additionally, Shah et al. reported that MPO lacks diagnostic and prognostic utility in patients presenting with dyspnea (11 ), whereas Mocatta et al., in contrast, reported that MPO is an effective predictor of 5-year mortality after acute MI (AMI) (12 ). The clinical utility of MPO as a biomarker requires not only the availability of accurate and reproducible
Received October 13, 2010; accepted January 7, 2011. Previously published online at DOI: 10.1373/clinchem.2010.158014 4 Nonstandard abbreviations: MPO, myeloperoxidase; ACS, acute coronary syndrome; HR, hazard ratio; MACE, major adverse cardiac event; MI, myocardial infarction; AMI, acute MI; cTnI, cardiac troponin I; MDRD, Modification of Diet in Renal Disease.
603
measurement methods but also appropriate and thorough attention to the specimen type and sample handling (preanalytical variables). Several studies have shown that heparin increases the plasma MPO concentration when used in vivo or in vitro, whereas MPO concentrations appear to be stable in EDTAcontaining plasma (13, 14 ). MPO assays have not been adequately compared with contemporary cardiac troponin assays as a pathophysiologically distinct, independent predictor of adverse cardiac events among heterogeneous patients who present with ischemic symptoms suggestive of ACS. In the current study, we evaluated the ability of 2 automated MPO assays to identify patients at increased risk of MACE among those who present with ischemic symptoms suggestive of ACS and have a normal cardiac troponin I (cTnI) value. Materials and Methods After institutional review board approval, the remainder of plasma samples that had been drawn into tubes containing EDTA were prospectively collected from 400 consecutive patients who had presented with symptoms suggestive of ACS and had been admitted through an inner-city emergency department, Hennepin County Medical Center (Minneapolis, MN), to rule in or rule out the occurrence of AMI. Samples were obtained from each patient at the time of presentation (baseline). Eighty-five percent of the patients presented ⬍24 h after the acute onset of ischemia symptoms. No additional data were available regarding the exact time of the index event. Plasma samples were initially stored refrigerated at 4 °C and then frozen at ⫺80 °C within 48 –72 h after collection. We initially designed the study to measure MPO with the Siemens Dimension assay (EDTA-containing plasma) and cTnI (heparinized plasma) with the Siemens Stratus CS assay; however, when sample volume permitted we were also able to use the Abbott ARCHITECT analyzer to measure MPO in EDTAcontaining plasma and cTnI in heparinized plasma in a subset (n ⫽ 350) of the 400 samples. For the Siemens assays, the cutpoints used were those recommended by the manufacturer: the 99th percentile for cTnI (⬍0.1 g/L) and the 95th percentile for MPO (633 pmol/ L). The total CV for the MPO assay was ⬍10% at 633 pmol/L and 10% at 16 pmol/L; the CV for the cTnI assay was 10% at 0.03 g/L. For the Abbott ARCHITECT assays, the cutpoints used were those recommended by the manufacturer: the 99th percentile for cTnI (0.028 g/L) and the 99th percentile for MPO (527 pmol/L). The cTnI CV was 15% at 0.028 g/L and 10% at 0.032 g/L; the CV for MPO was ⬍7% at 527.1 pmol/L. 604 Clinical Chemistry 57:4 (2011)
Patient demographics, medical histories, and clinical diagnoses were obtained by chart review after the patients had enrolled in the study. Record review was carried out blinded to the MPO results. Chart reviews or telephone follow-up interviews (performed without knowledge of the cTnI and MPO findings) were used to determine clinical outcomes during the 6-month follow-up period. Criteria for AMI were defined according to the European Society of Cardiology/American College of Cardiology redefinition of MI guidelines (15 ). The diagnosis of AMI is based on evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia at presentation. A diagnosis of AMI required the detection of an increase or decrease in cTnI concentration (as measured in serial samples taken per hospital protocol over the 24 h after presentation) according to the Siemens Stratus CS assay with concentrations greater than the 99th percentile reference value (⬍0.1 g/L; total CV of 12% at 0.12 g/L), and at least one of the following: symptoms of ischemia, new ST-T changes on the electrocardiogram, development of Q waves on the electrocardiogram, or imaging evidence of new loss of viable myocardium. The primary end point for assessing the shortterm prognostic value of MPO was MACE (i.e., the first event of MI, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting, or placement of stent from the time of presentation, including events at the index hospitalization). Exposure was computed from the date of blood draw until the date of first event, with censoring at the time of last contact (30 days or 6 months). Cumulative event rates were estimated with the Kaplan–Meier method and compared with the log-rank statistic. Cox proportional hazards models were used to estimate relative risk (HRs) and 95% CIs, with stepwise forward and backwards modeling used to identify independent predictors. Statistical significance was accepted at the 0.05 level, and all statistical tests were 2-sided. Statistical analyses were performed with MedCalc software (version 11.3.0.0; MedCalc Software, http://www.medcalc.be) and SPSS for Windows (version 15.0; SPSS). Results The characteristics of the entire 400-patient cohort and the subgroup of 350 patients were similar (Table 1). Nearly 80% of the patients presented with chest pain, and the median time in the hospital was 2 days (range, 0 –51 days). MPO AND cTnI MEASURED BY THE SIEMENS ASSAYS
Of the 400 patients evaluated with the Siemens assays, 18% presented with an increased cTnI concentration,
Myeloperoxidase Improves Risk Stratification
Table 1. Demographics and discharge diagnoses.
Age, yearsa
Siemens assays (n ⴝ 400)
Abbott assays (n ⴝ 350)
56 (14)
56 (14)
Male sex, %
57
56
Caucasian race, %
46
45
Current smoker, %
37
37
Presents with chest pain/pressure, %
78
79
7
8
15
15
Diabetes
32
33
Hypertension
69
70
Hyperlipidemia
37
38
Heart failure
13
13
New Q waves on admit ECG,b % New ST-segment elevation on admit ECG, % Patient history, %
10
9
Prior MI, %
Renal failure
23
24
Prior PTCA/PCI/stent, %
17
17
8
8
Prior CABG, % Duration of hospitalization, daysc
2.0 (0–51)
2.0 (0–51)
Discharge codes, % MI (410.x1) Other acute and subacute IHD (411.xx) Other noncardiac chest discomfort (786.59)
13
11
5
5
41
42
a
Data are presented as the mean (SD). ECG, electrocardiogram; PTCA, percutaneous transluminal coronary angioplasty; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; IHD, ischemic heart disease. c Data are presented as the median (range). b
and 50 patients (12.5%) were diagnosed with AMI during hospitalization. One or more MACE events occurred in 69 patients during the 30-day follow-up period and in 77 patients during the 6-month follow-up. Patients who had MPO values in the third and fourth quartiles or values greater than the MPO cutpoint (633 pmol/L) showed an increased risk of MACE at 30 days and 6 months (Table 2). After we adjusted for age, sex, and impaired renal function [estimated glomerular filtration rate, ⬍60 mL 䡠 min⫺1 䡠 (1.73 m2)⫺1 with the MDRD (Modification of Diet in Renal Disease) equation], an increased cTnI concentration (HR, 3.9; 95% CI, 2.4 – 6.4; P ⬍ 0.001) and an increased MPO concentration (HR, 2.7; 95% CI, 1.3–5.6; P ⫽ 0.006) measured
at presentation remained independently predictive of MACE at 30 days. We obtained similar findings for the 6-month follow-up period for both increased cTnI (HR, 4.0; 95% CI, 2.5– 6.3; P ⬍ 0.001) and increased MPO (HR, 2.4; 95% CI, 1.3– 4.6; P ⫽ 0.001) (Fig. 1). Among the patients with a normal cTnI value (n ⫽ 329), those with an increased MPO value (n ⫽ 219) demonstrated significantly higher rates of MACE than those with a normal MPO value (n ⫽ 110): 16.1% vs 3.6% at 30 days (P ⫽ 0.002); 18.1% vs 5.0% at 6 months (P ⫽ 0.002). Among the 350 patients who did not rule in for an MI, an increased MPO value was associated with an increased risk of MACE. Twenty-four of 234 patients with an increased MPO value had a MACE within 6 months, compared with 3 of 116 patients with a normal MPO value (13.5% vs 3.5%, P ⫽ 0.01). The adjusted HR (age, sex, impaired renal function) was 3.7 (95% CI, 1.1–12; P ⫽ 0.03), although the number of events in the analysis was small. An increased cTnI concentration provided less information about the risk of MACE in this group of patients. Seven of 42 patients with an increased cTnI value had a MACE, compared with 20 of 308 patients with a normal cTnI value (22.7% vs 7.9%, P ⫽ 0.06). MPO AND cTnI MEASURED WITH ABBOTT ASSAYS
Of the 350 patients evaluated with the Abbott assays, 17% presented with an increased cTnI value, and 40 patients (11.4%) were diagnosed with AMI during hospitalization. One or more MACE events occurred in 55 patients during the 30-day follow-up period and in 62 patients by 6 months of follow-up. Patients who had MPO values in the third and fourth quartiles or values greater than the cutpoint of 527 pmol/L showed an increased risk of MACE at 30 days and 6 months (Table 2). After adjustment for age, sex, and impaired renal function [estimated glomerular filtration rate, ⬍60 mL 䡠 min⫺1 䡠 (1.73 m2)⫺1], an increased cTnI concentration (HR, 5.5; 95% CI, 3.0 –10; P ⬍ 0.001) and an increased MPO concentration (HR, 2.9; 95% CI, 1.5– 5.4; P ⫽ 0.001) at presentation remained independently predictive of a MACE by 30 days of follow-up. Similar findings were observed for the 6-month follow-up period for both an increased cTnI value (HR, 4.9; 95% CI, 2.8 – 8.6; P ⬍ 0.001) and an increased MPO value (HR, 3.0; 95% CI, 1.6 –5.3; P ⬍ 0.001) (Fig. 1). Among patients with a normal cTnI concentration (n ⫽ 246), those with an increased MPO concentration (n ⫽ 117) demonstrated significantly higher rates of MACE than those with a normal MPO concentration (n ⫽ 129): 12.3% vs 3.9% at 30 days (P ⫽ 0.03) and 16.2% vs 5.1% at 6 months (P ⫽ 0.01). Among patients with increased cTnI values (n ⫽ 104), those with an increased MPO value (n ⫽ 63) demonstrated signifiClinical Chemistry 57:4 (2011) 605
Table 2. Relative risk of 30-day and 6-month MACE by MPO quartile.
n
Cumulative MACE rate, %
Unadjusted HR (95% CI)
Q1 (94–580 pmol/L)
100
8.0
Reference group
Q2 (585–894 pmol/L)
101
11.6
1.4 (0.5–3.4)
0.5
Q3 (901–1630 pmol/L)
99
21.3
2.6 (1.1–5.8)
0.03
100
31.1
3.9 (1.8–8.6)
P
Siemens MPO quartile and follow-up duration 30-Day follow-up
Q4 (1666–5000⫹ pmol/L)
0.0001
0.001 ⬍0.0001
6-Month follow-up Q1 (94–580 pmol/L)
100
11.1
Reference group
Q2 (585–894 pmol/L)
101
11.6
1.1 (0.5–2.5)
0.9
Q3 (901–1630 pmol/L)
99
26.7
2.4 (1.1–5.0)
0.02
100
36.3
3.5 (1.7–7.1)
0.001
MPO ⬍633 pmol/L
124
7.3
Reference group
MPO ⬎633 pmol/L
276
22.9
3.1 (1.5–6.2)
MPO ⬍633 pmol/L
124
9.7
Reference group
MPO ⬎633 pmol/L
276
26.8
2.8 (1.5–5.3)
Q1 (51–319 pmol/L)
88
6.8
Reference group
Q2 (323–543 pmol/L)
87
9.2
1.3 (0.5–3.9)
0.6
Q3 (548–1054 pmol/L)
89
22.4
3.2 (1.3–8.0)
0.01
Q4 (1073–10 000⫹ pmol/L)
86
26.7
3.9 (1.6–10)
0.003
Q1 (51–319 pmol/L)
88
10.3
Reference group
Q2 (323–543 pmol/L)
87
9.2
1.0 (0.4–2.6)
Q4 (1666–5000⫹ pmol/L) Siemens MPO cutpoint and follow-up duration 30-Day follow-up
0.005
6-Month follow-up
0.002 0.0006 0.002
Abbott MPO quartile and follow-up duration 30-Day follow-up
6-Month follow-up 1.0
Q3 (548–1054 pmol/L)
89
28.8
2.8 (1.3–6.4)
0.01
Q4 (1073–10 000⫹ pmol/L)
86
31.1
3.3 (1.5–7.2)
0.004
Abbott MPO cutpoint and follow-up duration 30-Day follow-up
0.0002
MPO ⬍527 pmol/L
170
8.3
Reference group
MPO ⬎527 pmol/L
180
23.9
2.9 (1.6–5.2)
MPO ⬍527 pmol/L
170
9.9
Reference group
MPO ⬎527 pmol/L
180
29.2
2.9 (1.6–5.1)
6-Month follow-up
0.0001
cantly higher rates of MACE than those with a normal MPO value (n ⫽ 41): 22.0% vs 45.0% at 30 days (P ⫽ 0.02) and 25.1% vs 50.7% at 6 months (P ⫽ 0.02). Among the 310 patients who did not rule in for an MI during initial hospitalization, an increased MPO value was associated with an increased risk of MACE: 18 of 152 patients with an increased MPO had a MACE within 6 months, compared with 4 of 606 Clinical Chemistry 57:4 (2011)
0.001
⬍0.001
158 patients with a normal MPO value (16.0% vs 3.1%, P ⫽ 0.001). The adjusted HR (age, sex, impaired renal function) was 5.1 (95% CI, 1.7–15; P ⫽ 0.004), although the number of events in the analysis was small. An increased cTnI value provided less information about the risk of MACE in this group of patients. Seven of 71 patients with an increased cTnI value had a MACE, compared with 15 of 239 patients
Myeloperoxidase Improves Risk Stratification
A
with a normal cTnI value (6-month MACE rates, 13.4% vs 7.7%; P ⫽ 0.5).
Siemens M PO and cTnI
100
Cu umulative MACE-free survival (%)
a
Discussion
90 b
80 70 60 c d
50 # at risk 110 219 14 57
40 30
73 130 6 23
64 100 5 21
14 30 1 10
120 60 Time from initial draw (days)
0
B
180
Abbott cTnI and M PO 100
Cumulative MACE-free surrvival (%)
a
90 b
80 c
70 60
d
50 # at risk 129 117 41 63
40 30 0
90 69 25 24
76 50 23 21
60 120 Time from initial draw (days)
17 14 7 11
180
Fig. 1. Cumulative MACE-free survival from the time of blood draw. MACE-free survival based on Siemens MPO and cTnI measurements (A) and on Abbott MPO and cTnI measurements (B). Survival curves are for those for normal cTnI and normal MPO values (a); for normal cTnI values and increased MPO values (b); for increased cTnI values and normal MPO values (c); and for increased cTnI and MPO values (d). Columns at the bottom of each panel are the numbers of patients at risk at each time point (top to bottom: a, b, c, d).
cTnI is a biomarker of necrosis (cell death), and MPO is a biomarker associated with plaque rupture. Not all patients with plaque rupture will have necrosis; thus, biomarkers may assist in assessing the pathophysiological state of this disease process (16 ). The combined use of MPO and cTnI in our study allowed the identification of a larger proportion of patients at risk of MACE at 30 days and at 6 months than the use of cTnI alone. To our knowledge, this study is the first to use these 2 biomarkers to examine a heterogeneous patient cohort presenting with symptoms suggestive of ACS. The findings obtained with the Abbott and Siemens MPO assays were similar. The relative risks for MACE by 30 days and 6 months were significantly greater when the MPO value, measured with either assay, was greater than the established cutoff value. In addition, the results obtained with the 2 assays showed that these risks were greater with increasing MPO quartile concentration. Overall, our findings for a heterogeneous group of patients who presented to an inner-city hospital with symptoms of ischemia suggest that MPO is a powerful predictor of cardiovascular risk, as has previously been shown in moderate- to highrisk ACS patients (4 – 6 ). This study used EDTA plasma samples, in which MPO concentrations have been shown to be stable (13, 14 ). Earlier studies that found higher MPO concentrations used serum or heparinized plasma samples, and the assays may have been prone to preanalytical stability problems caused by inadequate samplecollection procedures that led to inaccurate biomarker results. The 3 early clinical studies (4 – 6 ) that suggested a potential role for MPO as a biomarker of inflammation in atherosclerosis with implications for detecting a risk of myocardial cell necrosis or AMI, all used research assays. Subsequent studies have substantiated these findings (7, 8, 17, 18 ), but they also disagree regarding the value of using MPO measurements in addition to cTnI measurements (8 –10, 19 ). The potential weaknesses of many of these later studies included the specimen used and the inappropriately high cTnI cutpoint used for comparison. A recent review concluded that measurements of MPO in plasma improved risk stratification for cardiovascular disease above and beyond that achieved with the biomarkers routinely used in clinical practice (20 ). Although the current study has the limitation of being a single-center study of a small patient cohort, the findings remain important. As indicated in an editorial by Morrow (21 ), the available experimental and clinical Clinical Chemistry 57:4 (2011) 607
evidence (as substantiated by the findings of the current study) provide compelling evidence for maintaining an interest in MPO as a clinical tool. Morrow notes, however, that how an increased MPO value in the presence of a normal cTnI value would affect therapeutic intervention has not yet been defined. Future investigations need to focus on this area specifically. Our study has 2 additional potential limitations. First, we do not have any clinical information regarding the relationship (if any) between the time of heparin administration and the time of blood draw. Second, because we do not have the specific time of onset of the index event relative to the time the patient presented at the hospital, a more detailed analysis of the data regarding marker kinetics is not possible. Now that commercial assays on automated instrumentation are available (the FDA-cleared Siemens MPO assay, the automated Abbott research assay), laboratories and clinicians need to determine the cost– benefit ratio for offering a new test that would, in theory, detect plaque rupture before myocardial cell death. Until findings actually show that MPO measurement favorably alters patient manage-
ment and therapy, we are cautious about incorporating this biomarker into a multibiomarker approach in clinical practice.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: F.S. Apple, Abbott Laboratories. Stock Ownership: None declared. Honoraria: F.S. Apple, Abbott Laboratories and Siemens. Research Funding: F.S. Apple, Abbott Laboratories and Siemens. Expert Testimony: None declared. Role of Sponsor: The funding organizations played a direct role in the design of the study.
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