Article, Cardiology

Myeloperoxidase and C-reactive protein in patients with cocaine-associated chest pain

a b s t r a c t

Background: Myeloperoxidase and C-reactive protein (CRP) are markers of inflammation and elevated levels have been found in patients with acute coronary syndrome (ACS) unrelated to cocaine. We evaluated the utility of MPO and CRP for diagnosis of ACS and the prediction of 30-day adverse cardiovascular events in patients with cocaine-related chest pain.

Methods: This is a secondary analysis from a prospective cohort study of ED patients who received evaluation for ACS. Structured data collection at presentation included demographics, chest pain history, laboratory results, and electrocardiographic data. Our primary outcome was diagnosis of ACS at index visit and 30-day adverse events. As a secondary analysis, we provide data on a matched cohort without cocaine use.

Results: Baseline data and CRP were available for 95 cocaine users; 82 had MPO data also. Patients had a mean age of 46.6 (SD 8.1) years, 90% were black, and 62% were male. Acute coronary syndrome occurred in 7% of cocaine users. With respect to diagnosis of ACS, the area under the curve was poor for both MPO (0.65; 95% confidence interval [CI]: 0.40-0.91) and CRP (0.63; 95% CI: 0.39-0.88). Similar results were found for 30-day events. With respect to prognosis of 30-day adverse cardiovascular events, the area under the curve was 0.68 (95% CI: 0.45-0.91) for MPO and 0.67 (95% CI: 0.45-0.90) for CRP.

Similar results were found for 30-day events. In the matched cohort of patients who were not cocaine users, performance of MPO (n = 66) and CRP (n = 86) was also poor.

Conclusions: Myeloperoxidase and CRP are not useful for diagnosis or prognosis of patients with cocaine- associated chest pain.

(C) 2013

  1. Introduction

In 2009, an estimated 14.4 million Americans reported prior cocaine use, 1.6 million of whom had used cocaine within the past month [1]. Cocaine use leads to up to 40% of all emergency department (ED) drug-related encounters [2,3]. Chest pain is a common feature of cocaine-related ED visits, occurring in up to 40% of Patient presentations [4]. In ED patients presenting with chest pain, acute coronary syndrome (ACS) and acute myocardial infarction (AMI) were found to occur 4 times more often in recent cocaine users, with a nearly 24-fold increase in incidence within the first hour after cocaine use [5,6].

Recently, higher levels of the inflammatory markers myeloperox- idase (MPO) and C-reactive protein (CRP) have been found to be associated with higher rates of adverse cardiovascular events, including AMI and ACS [7-10].

The pathophysiology of cocaine-associated ACS may be different than that of ACS unrelated to cocaine. Cocaine can cause coronary

* Corresponding author. Tel.: +1 215 662 2767.

E-mail address: [email protected] (J.E. Hollander).

artery vasospasm, but also causes inflammation and increased platelet aggregation [11-13]. Thus, it is theoretically possible that MPO and CRP may be more strongly associated with ACS in patients with cocaine-associated chest pain.

Our primary aim was to evaluate the utility of MPO and CRP in the diagnosis and prognosis of ACS in patients presenting to the ED with cocaine-associated chest pain. For purposes of context, we also provide data on a matched cohort of non-cocaine-using patients.

  1. Methods
    1. Study design

This was a secondary analysis of prospectively collected data from prior cohort studies of patients presenting to the ED with chest pain from 2004 to 2008. The primary aim of the overall study is to develop and evaluate novel biomarkers. Prior analysis from these studies, but not biomarker results, has been previously reported for subsets of patients [14-16]. For this analysis, our primary aim is to evaluate the utility of MPO and CRP in the diagnosis and prognosis of ACS in patients presenting to the ED with cocaine-associated chest pain. This

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study included clinical data from the initial ED visit, blood samples collected at presentation, hospital course, and data collected via telephone 30 days after ED visit. The Institutional Review Board approved the study. Informed consent was obtained from each patient.

Setting

The study was conducted in an urban tertiary referral center with an annual ED census between 55,000 and 59,000 during the enrollment period.

Selection of participants

Patients presenting with chest pain consistent with potential ACS, who received an electrocardiogram (ECG) during their visit, were enrolled. This represents a nondifferentiated chest pain population that presents to an urban ED. Patients were excluded if they had chest trauma within the past week, temperature greater than 101?F, pregnancy, use of home oxygen, and/or metastatic cancer.

From the overall subject population of patients presenting with chest pain, we selected patients with recent cocaine use. Cocaine use was determined by patient-reported cocaine use in the week before presentation or presence of cocaine metabolites in urine specimen. Patients older than 18 years were eligible to be included if they had self-reported cocaine use; patients not reporting cocaine use were eligible if older than 30 years. We then matched a comparison group of chest pain patients without recent cocaine use to those with cocaine use based on demographic attributes of age, sex, and race. The comparison group was not intended to be statistically compared with the cocaine group, but rather to place the results in context.

Data collection and processing

Patients presenting with chest pain consistent with ACS were identified prospectively by trained research personnel who were present in the ED from 7:00 AM to midnight, 7 days a week. Structured data collection was performed using the Standardized reporting Guidelines [17] in accordance with the Key Definitions [18] and was documented by the treating physician. This information includes patient-reported demographic characteristics, cardiac risk factors, chest pain characteristics, associated symptoms, medications, initial vital signs, ECG, treatment, and disposition.

Methods of measurement

Blood samples were collected at the time of presentation after informed consent was obtained. Samples were obtained in lithium- heparin tubes for MPO measurement and serum separator tubes for CRP measurement. Serum/plasma was isolated via centrifugation at 3000g for 10 minutes and frozen within 2 hours of sample acquisition. Samples were stored at -80?C. Samples were shipped to Diazyme Laboratories (Poway, CA) where they were maintained at -80?C or colder and measured after first thaw.

myeloperoxidase levels were measured using the Diazyme MPO Enzymatic Assay Kit (Diazyme Laboratories). The assay range for MPO was 20 to 1300 ng/mL, with a detection limit of 13.1 ng/mL and total imprecision (coefficient of variation) of 4.1%, 2.8%, and 1.5% at MPO concentrations of 105, 300, and 720 ng/mL.

C-reactive protein levels were measured using Diazyme High Sensitivity C-Reactive Protein Assay (Diazyme Laboratories), a quantitative immunoturbidimetric assay. The assay range for CRP was 0.2 to 20 mg/L, with a detection limit of 0.13 mg/L and total imprecision (coefficient of variation) of 7.3%, 2.4%, and 1.6% at CRP concentrations of 1.18, 3.62, and 15.56 mg/L.

Outcome measures

The primary outcome was diagnosis of ACS during ED visit and a composite of death, AMI, and/or revascularization at 30 days. Diagnosis of AMI was consistent with the European Society of Cardiology/American College of Cardiology/American Heart Associa- tion guidelines [19-21]. Acute coronary syndrome was defined as an AMI or objective confirmation of unstable angina (reversible ischemia on provocative testing or coronary angiography demonstrating stenosis 70% or greater) per Guideline recommendations [17]. Revascularization included percutaneous coronary intervention and Coronary artery bypass grafting.

Medical record reviews and telephone follow-up interviews (performed without knowledge of the MPO and CRP results) were used to determine clinical outcomes during the 30-day period following ED visit. Patients were questioned regarding diagnosis of ACS or AMI, cardiac procedures, and rehospitalizations within 30 days of index visit. Standardized diagnoses were determined and adjudi- cated by trained research personnel. For patients not reachable by telephone, follow-up was conducted via the Social Security Death Index and review of institutional medical records more than a year after the initial telephone call.

Primary data analysis

Continuous variables are described using means and stan- dard deviations or medians and interquartile ranges, depending on normalcy.

Analysis of biomarkers’ diagnostic and prognostic performance

receiver operating characteristic curves were calculated for each biomarker using aggregated data from the entire cohort (cocaine users and non-cocaine users). We chose to define a single cut point for each marker so that it would be clinically sensible: clinicians are not receptive to using different cut points in different patient populations. From these data, we derived the cut point value for each biomarker that would optimize sensitivity and specificity in diagnosis of ACS. We then applied this cut point to assess the number of ACS outcomes it would have diagnosed in each group compared with the standardized diagnoses determined by our protocol.

For each biomarker within each group (cocaine use or no cocaine use), ROC curves were calculated using continuous variables for biomarkers and dichotomous outcome variables assigned as ACS or not ACS. Areas under the ROC curves (AUCs) were calculated with 95% confidence intervals (CIs).

Receiver operating characteristic curves were also calculated for each biomarker using continuous variables for biomarkers and dichotomous outcome variables assigned to 30-day outcomes. Thirty-day outcomes were classified as adverse cardiovascular events, which included death, AMI, or revascularization, or no adverse cardiovascular event, which was defined as the absence of any reported death, AMI, or revascularization. Areas under the ROC curves were calculated with 95% CIs. We maintained the same cut point for prognosis as we used for diagnosis because we believe this is the way clinicians use laboratory values.

  1. Results

Baseline and biomarker data were available for 181 chest pain patients presenting to the ED during the enrollment period. Ninety- five patients were classified as cocaine users; 66 of these patients reported cocaine use within the past week, and 29 patients who reported no cocaine use were found to have cocaine metabolites in their urine at ED presentation. Our matched nonusers group of 86 patients comprised the remaining patients who reported no cocaine

use within the past week and had a negative urine test result for cocaine metabolites. All 181 patients had CRP results available. Myeloperoxidase results were available for 82 of 95 cocaine users and 66 of 86 non-cocaine users. Some samples could not be used because of hemolysis of samples. Follow-up outcomes were available for 174 patients through direct follow-up (96%); a review of Social Security Death Index and medical records was performed for the remaining 7 patients.

The baseline characteristics of the subject populations are presented in Table; mean age was 46.6 (SD 8.1) years, 90% were black, and 62% were male. Cocaine users were more likely than non- cocaine users to be current Tobacco users. Cocaine users and non- cocaine users did not differ significantly in any other baseline characteristics, such as history of hypertension, hyperlipidemia, or Thrombolysis in Myocardial Infarction risk score [22].A final diagnosis of ACS was just as likely in the patients with recent cocaine use compared with those without cocaine use (7% vs 9%; P = .6).

No significant difference in biomarker levels was found between the 2 groups overall. Median MPO levels were similar for cocaine users and non-cocaine users (162 vs 136 ng/mL).The optimal cut point to maximize sensitivity and specificity was 242 ng/mL, with an overall sensitivity of 0.43 and a specificity of 0.75.

Median CRP levels were similar for cocaine users and non-cocaine users (3 vs 5 mg/L). The optimal cut point was 11.91 mg/L, with a sensitivity of 0.67 and a specificity of 0.79.

ROC curvesdiagnosis of ACS

The AUC for MPO for the diagnosis of ACS was poor. In cocaine users, it was 0.65 (95% CI: 0.40-0.91), as compared with 0.46 (95% CI: 0.19-0.74) in non-cocaine users (Fig. 1). The 95% CIs for cocaine users and non-cocaine users overlap. Using the optimal cut point for a diagnosis of ACS, only 57% of the cocaine users and 29% of the non- cocaine users would have been correctly identified as having ACS. Of the patients who were not diagnosed with ACS, 75% of the cocaine users and 76% of non-cocaine users would have been correctly identified as not having ACS.

Similarly, the AUC for CRP in cocaine users was poor. It was 0.63 (95% CI: 0.39-0.88), as compared with 0.73 (95% CI: 0.52-0.95) in

non-cocaine users (Fig. 2). The 95% CIs for cocaine user and non- cocaine users overlap. Using the optimal cut point, only 43% of the cocaine users and 88% of the non-cocaine users would have been correctly identified as having ACS by an elevated CRP. Of the patients not diagnosed with ACS, 85% of the cocaine users and 72% of non-cocaine users would have been correctly identified as not having ACS.

ROC curves30-day prognosis of adverse cardiovascular events

The AUC for MPO for prognosis of 30-day adverse cardiovascular events in cocaine users was poor for both cocaine users (0.68; 95% CI:

Table

Baseline characteristics of study participants

Cocaine users (n = 95) Nonusers (n = 86) P value

Demographics Age (years)

46.1

(39.7, 52.7)

46.7

(42.7, 51.9)

Matched

Male

57

62%

57

66%

Matched

Black

88

93%

77

90%

Matched

White

6

6%

9

11%

Matched

Asian

Risk factors

1

1%

0

0.0%

Matched

Weight (lb)

178

(155, 215)

210

(180, 251)

.2

Tobacco use

68

72%

38

44

b.0001

Hypertension

62

65%

56

65%

.98

Hyperlipidemia

16

17%

24

28%

.07

Diabetes mellitus

15

16%

24

28%

.05

Family history of CAD

11

12%

9

11%

.8

TIMI risk score

Low (0-2)

84

88%

75

87%

.9

Moderate (3-5)

11

12%

11

13%

High (N 5) Cardiovascular history

Prior MI

0

26

0%

27%

0

11

0%

13%

.02

Prior CABG

1

1

3

4%

.3

CHF

15

16%

18

21%

.8

CAD

25

26%

16

19%

.2

Arrhythmia

5

5%

7

8%

.4

Presenting characteristics

Heart rate

88

(75, 98)

86

(73, 98)

.3

Systolic BP (mm Hg)

138

(126, 158)

140

(122, 155)

.7

Diastolic BP (mm Hg)

88

(79, 96)

87

(78, 98)

.9

ST elevation

5

5%

3

3%

.3

ST depression

7

7%

5

6%

.4

T-wave abnormality

34

36%

21

24%

.1

Bundle branch block

5

5%

1

1%

.3

Medication taken/prescribed in past week

ASA

29

31%

23

27%

.6

Antiplatelets

6

6%

6

7%

.9

?-Blockers

24

25%

21

24%

.9

Ca blockers

17

18%

17

20%

.7

Nitro

17

18%

3

4%

.002

ACE inhibitors

12

13%

20

25%

.03

Statins

11

12%

19

22%

.06

Biomarkers

MPO (ng/mL)

162

(101, 253)

136

(111, 235)

.8

CRP (mg/L)

3

(1, 9)

5

(1, 15)

.08

Data are shown as number (percentage) for dichotomous variables and median (25th, 75th percentile) for continuous variables. CAD, coronary artery disease; TIMI, thrombolysis in myocardial infarction; MI, myocardial infarction; CABG, coronary artery bypass grafting; CHF, congestive heart failure; BP, blood pressure.

Fig. 1. Receiver operating characteristic curve for MPO comparing cocaine users to non-

cocaine users for diagnosis of ACS.

Fig. 3. Receiver operating characteristic curve for MPO comparing cocaine users to non-

cocaine users for diagnosis of 30-day adverse cardiovascular events.

0.45-0.91) and non-cocaine users (0.45; 95% CI: 0.21-0.70) (Fig. 3). The 95% CIs for cocaine user and non-cocaine users overlap. Using the cut point of 242 ng/mL, 57% of the cocaine users and 38% of the non- cocaine users with 30-day adverse cardiovascular events would have been correctly identified.

Similarly, the AUC for CRP for prognosis of 30-day adverse cardiovascular events was poor for both cocaine users (0.67; 95% CI: 0.45-0.90) and non-cocaine users (0.76; 95% CI: 0.56-0.96) (Fig. 4). The 95% CIs for cocaine user and non-cocaine users overlap. Using the cut point of 11.91 mg/L, 43% of the cocaine users and 63% of the non- cocaine users with 30-day adverse cardiovascular events would have been correctly identified with elevated CRP.

  1. Discussion

There has been no clear consensus on the role of MPO and CRP as markers of ACS in patients with ACS unrelated to cocaine. Preliminary studies indicated potential utility for MPO, but those results lacked broad applicability [7-9]. Prior to use of comtemporary troponin assays, Brennan et al [7] found diagnostic utility for MPO in a group with an unusually high ACS prevalence of 41%, not typical of an undifferentiated population presenting to the ED with chest pain [25]. Rudolph et al [26] found some utility in the subset of patients who presented within the first 120 minutes of symptom onset; however, most patients do not present this soon after symptom onset [27]. In contrast to these preliminary studies, our results align with

Fig. 2. Receiver operating characteristic curve for CRP comparing cocaine users to non- cocaine users for diagnosis of ACS.

multicenter studies finding that MPO and CRP do not have independent utility for the diagnosis of ACS in a typical undiffer- entiatED chest pain patient population presenting to the ED [28-31].

A significant body of research supports the value of these biomarkers for predicting long-term cardiovascular outcomes with definite ACS [32-37]. Evidence also points to the utility of MPO in predicting long-term incidence of coronary artery disease (CAD), regardless of ACS [38-40]. Apple et al [41] found MPO to have significant discriminatory utility for the prediction of 30-day adverse cardiovascular outcomes. Schaub et al [29] found MPO to be predictive of all-cause mortality rather than specifically adverse cardiovascular outcomes. CRP was predictive of all adverse outcomes [29]. Our results, which focus on cocaine users, found that neither biomarker is sufficiently informative.

Our findings indicate that both MPO and CRP have limited utility in the Acute diagnosis of ACS and 30-day prognosis in cocaine-associated chest pain. One potential explanation for this finding is that MPO is a marker of plaque instability and CRP is a marker of inflammation [10,23,24]. Although both plaque instability and inflammation may exist in patients with cocaine-associated ACS, cocaine-associated ACS is, in part, attributed to vasoconstriction in the setting of increased myocardial oxygen demand [11]. Thus, ischemia can occur without the inflammation and Plaque rupture that typically precipitate ACS in non-cocaine users [10,23,24]. In addition, although MPO and CRP may predict risk of CAD, cocaine use is not associated with early development of CAD [42].

Fig. 4. Receiver operating characteristic curve for CRP comparing cocaine users to non- cocaine users for diagnosis of 30-day adverse cardiovascular events.

We believe that our findings suggest that MPO and CRP do not have sufficient utility to justify being incorporated into the acute care clinical environment [43-45], especially in patients with cocaine- associated chest pain.

  1. Limitations

Despite a relatively small sample size, our results showed sufficiently poor utility for these biomarkers, such that the upper limit of the CI still would not find these biomarkers useful. It is possible that ACS outcomes in our population were underreported given that not all patients received advanced diagnostic testing or High-sensitivity troponin Testing, either of which could detect a greater number of ACS outcomes. However, our rates of ACS were similar to other prior ED-based chest pain studies of cocaine users and nondifferentiated populations [25,46].

In addition, we evaluated the biomarkers using one internally derived cut point from the maximal area under our ROC curve in a combined cohort of cocaine- and non-cocaine-using patients, rather than validating against empirically developed standards. As Morrow and Cook highlighted [47], the optimal process for evaluating a Diagnostic biomarker must build on prior research and validate against previously tested cut points, rather than only using internally derived cut points. Our approach would bias our study toward finding more utility for the markers than they might truly have, and yet we found them not to be useful. In addition, our cut point for CRP (11.91 mg/L) lies between 2 common standards referenced in National Academy of Clinical Biochemistry laboratory medicine practice guidelines for ACS (10 and 15 mg/L) [48]. Our MPO cut point of 242 ng/mL is higher than the values in most previously published values, which have ranged from 76 to 210 ng/mL [9,28,34,38,41].

Preanalytical bias may have occurred because MPO samples were collected in lithium heparin tubes, rather than EDTA tubes [49], and without knowledge of heparin administration and timing.

Data were not available for elapsed time between symptom onset and Blood draw, so the influence of this factor could not be considered [26]. Finally, because cocaine use was determined by presence of cocaine metabolites in urine and/or self-report of any cocaine use within the past week, there may be variation in the acuity of cocaine intoxication affecting the cocaine-use patients at the time of clinical assessment.

  1. Conclusions

Myeloperoxidase and CRP do not provide sufficiently discrimina- tory diagnostic or prognostic utility in patients presenting to the ED with cocaine-associated chest pain.

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