- Email: [email protected]
Myoglobin, creatine-kinase-MB and cardiac troponin-I 60-minute ratios predict infarct-related artery patency after thrombolysis for acute myocardial infarction
Journal of the American College of Cardiology © 1999 by the American College of Cardiology Published by Elsevier Science Inc.
Vol. 34, No. 3, 1999 ISSN 0735-1097/99/$20.00 PII S0735-1097(99)00274-0
Myocardial Infarction
Myoglobin, Creatine-Kinase-MB and Cardiac Troponin-I 60-Minute Ratios Predict Infarct-related Artery Patency After Thrombolysis for Acute Myocardial Infarction Results from the Thrombolysis in Myocardial Infarction Study (TIMI) 10B Milenko J. Tanasijevic, MD,* Christopher P. Cannon, MD,† Elliott M. Antman, MD,† Donald R. Wybenga, MD,* George A. Fischer, PHD,* Christine Grudzien,* C. Michael Gibson, MD,‡ James W. Winkelman, MD,* Eugene Braunwald, MD,† for the TIMI 10B Investigators Boston and West Roxbury, Massachusetts OBJECTIVES
We examined the diagnostic performance of serum myoglobin, creatine-kinase-MB (CKMB) and cardiac Troponin-I (cTnI) for predicting the infarct-related artery (IRA) patency in patients receiving TNK-tissue plasminogen activator (TNK-tPA) therapy for acute myocardial infarction (AMI) in the Thrombolysis in Myocardial Infarction (TIMI) 10B trial.
BACKGROUND A reliable noninvasive serum marker of IRA patency is desired to permit early identification of patients with a patent IRA after thrombolysis. METHODS
We measured myoglobin, CK-MB and cTnI concentrations in sera obtained just before thrombolysis (T0) and 60 min later (T60) in 442 patients given TNK-tPA and who underwent coronary angiography at 60 min.
RESULTS
Angiography at 60 min showed a patent IRA (TIMI flow grade 2, 3) in 344 and occluded IRA (TIMI flow grade 0, 1) in 98 patients. The median serum T60 concentration, the ratio of the T60 and T0 serum concentration (60-min ratio) and the slope of increase over 60 min for each serum marker were significantly higher in patients with patent arteries compared with patients with occluded arteries. The area under the receiver-operating characteristic (ROC) curve for diagnosis of occlusion was 0.71, 0.70 and 0.71 for the 60-min ratio of myoglobin, cTnI and CKMB, respectively. The 60-min ratios of ⱖ4.0 for myoglobin, ⱖ3.3 for CK-MB and ⱖ2.0 for cTnI yielded a probability of patency of 90%, 88% and 87%, respectively.
CONCLUSIONS The diagnostic performance of serum myoglobin, CK-MB and cardiac Tropinin-I (cTnI) 60-min ratios was similar. The probability of a patent IRA was very high (90%) in patients with 60-min myoglobin ratio ⱖ4.0, and early invasive interventions to establish IRA patency may not be necessary in this group. Serum marker determinations at baseline and 60-min after thrombolysis may permit rapid triage of patients receiving thrombolytic therapy by ruling out IRA occlusion. (J Am Coll Cardiol 1999;34:739 – 47) © 1999 by the American College of Cardiology
Early thrombolysis in patients with acute myocardial infarction (AMI) has a strong beneficial influence on short- and long-term outcome (1,2). The therapeutic goal of infarctrelated artery (IRA) patency may be achieved with novel From the *Clinical Laboratories and †Department of Medicine, Brigham and Women’s Hospital, Boston, and ‡Department of Medicine, VA Medical Center, West Roxbury, Massachusetts. This work was supported by Dade Behring, Inc., Newark, Delaware. The TIMI 10B Clinical Centers were supported by Genentech, South San Francisco, California. Dr. Milenko Tanasijevic is a consultant for Dade Behring International. Manuscript received November 6, 1998; revised manuscript received April 7, 1999, accepted May 16, 1999.
thrombolytic agents or percutaneous coronary interventions (3– 6). The availability of a reliable marker of IRA patency status may permit early identification of patients with patent IRA, for whom repeat thrombolysis or rescue percutaneous transluminal coronary angioplasty (PTCA) may not be necessary. Although coronary angiography has been considered the gold standard for this purpose (4,5), it is costly and often unavailable for routine care of most patients. Because the currently used noninvasive clinical and electrocardiographic indexes of IRA patency status are not sufficiently sensitive nor specific (7,8), several serum cardiac markers
740
Tanasijevic et al. Cardiac Markers in Thrombolysis
Abbreviations and Acronyms AMI ⫽ acute myocardial infarction AUC ⫽ area under the receiver-operating characteristic curve CK-MB ⫽ creatine-kinase-MB cTnI ⫽ cardiac Troponin-I ECG ⫽ electrocardiogram IRA ⫽ infarct-related artery PTCA ⫽ percutaneous transluminal coronary angioplasty ROC ⫽ receiver-operating characteristics TIMI ⫽ Thrombolysis in Myocardial Infarction TNK-tPA ⫽ TNK-tissue plasminogen activator
have been investigated and proposed as alternatives. The serum markers that have been investigated include creatine kinase-MB (CK-MB) (9 –12), total creatine kinase (CK) (10,13), myoglobin (12,14 –16), cardiac Troponin-T (17– 20), CK isoforms (21,22), cardiac Troponin-I (cTnI) (12,23) and combinations of the above (12,18,24,25). The current study was undertaken to examine the diagnostic performance of serum myoglobin, CK-MB and cTnI obtained immediately before, and within 60 min of initiation of thrombolysis, for predicting the IRA patency in patients receiving TNK-tissue plasminogen activator (TNK-tPA) therapy in the Thrombolysis in Myocardial Infarction (TIMI) 10B trial.
METHODS TIMI 10B trial. The TIMI 10B trial, a phase-II, doseranging trial was conducted in the U.S. and Europe between March 1996 and March 2, 1997. It evaluated the new thrombolytic agent, TNK-tPA, in patients with AMI (26). The study patients were between the ages of 19 and 80 years, had episodes of ischemic discomfort lasting ⱖ30 min and presented within 12 h from symptom onset, associated with ST segment elevation ⱖ0.1 mV in two or more contiguous electrocardiogram (ECG) leads. Major exclusion criteria included prior stroke or transient ischemic attack, a reliably obtained blood pressure ⬎180/110 mm Hg, significant bleeding within six months and other contraindications to thrombolysis. Eligible patients were randomized to receive either a single bolus of 30, 40 or 50 mg TNK-tPA (Genentech, Inc., South San Francisco, California) or front-loaded (t-PA). All patients received aspirin and intravenous heparin. Patients underwent coronary angiography at 90 min, and 60 and 75 min when feasible. All angiograms were analyzed at the Angiographic Core Laboratory (VA Medical Center, West Roxbury, Massachusetts), which was blinded to dose assignment. Thrombolysis in myocardial infarction flow grade was analyzed according to prespecified definitions (27). The TIMI 10B study protocol was reviewed and ap-
JACC Vol. 34, No. 3, 1999 September 1999:739–47
proved by each hospital’s Institutional Review Board, and written informed consent was obtained from each patient before enrollment. Study population. In an ancillary study reported here, blood specimens for serum marker analyses were collected in 826 patients. The patients with no available information regarding the time interval between the onset of chest pain and the initiation of thrombolysis (n ⫽ 31) were excluded. Only patients for whom the 60-min angiogram was available (n ⫽ 442) were included in the statistical analyses. Separate statistical analyses were performed on the subset of patients that received thrombolytic treatment within 6 h from the onset of ischemic discomfort (n ⫽ 378). Serum marker analyses. Serum specimens were obtained by centrifugation at each site, and were stored locally at ⫺20°C. They were then mailed on dry ice to the Covance Core Laboratory (Indianapolis, Indiana), where they were stored at ⫺70°C. The specimens were shipped to the Cardiac Serum Marker Core Laboratory, at the Clinical Chemistry Laboratory of the Brigham and Women’s Hospital (Boston), and stored at ⫺20°C until analysis. The cardiac marker proteins remain stable when handled in this manner (data on file; Dade Behring Inc., Newark, Delaware). In the current study, the specimens were thawed and analyzed in batches by individuals blinded to the clinical data. Cardiac Troponin I, CK-MB and myoglobin were measured by the Stratus fluorometric enzyme immunoassays (Dade Behring). The analysis time is 15 min for each marker. The cTnI assay uses two cTnI-specific monoclonal antibodies that recognize two different cTnI epitopes (28,29). This assay shows no cross-reactivity with human skeletal muscle TnI (28,30). The myoglobin sandwich immunoassay uses two myoglobin-specific monoclonal antibodies (31,32). Creatine-kinase-MB concentrations were measured with an immunoassay based on a monoclonal antibody specific for the CK-MB isoenzyme (33,34). All CK-MB and cTnI results below the lower detection limit of their respective assays (i.e., ⬍0.4 ng/ml for both markers) were collectively expressed as 0.4 ng/ml. The imprecision of the cardiac marker assays, expressed as between-run coefficient of variation (%CV), was assessed over a period of 15 months, using the quality control materials provided by the manufacturer (Dade Behring). The imprecision of the myoglobin assay for concentrations of 47.3, 223.1 and 442.3 ng/ml was 8.6%, 6.2% and 6.1%, respectively. The between-run CV of the CK-MB assay for concentrations of 5.6, 32.1 and 81.2 ng/ml was 8.2%, 7.8% and 6.2%, respectively. The imprecision of the cTnI assays for concentrations of 1.1, 4.6, 18.5 and 33.6 ng/ml was 7.8%, 6.6%, 7.5% and 5.6%, respectively. Study end points. End points in this substudy included the diagnostic characteristics for the following measurements and indexes for each marker: value obtained 60 min after initiation of treatment (T60); ratio of the 60-min (T60)
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47
741
Table 1. Baseline Characteristics for the Study Population All Patients Study Population (n ⴝ 422) Age (yr) Male gender (%) Time from pain onset to treatment (h) Infarct-related artery (%)
TIMI flow grade at 60 min (%)
Patency TIMI Persistent Occlusion Flow 2 or 3 TIMI Flow 0 or 1 (n ⴝ 344) (n ⴝ 98) p Value
60 (51–69) 75.4 2.9 (2.0–4.2)
60 (51–69) 75.1 2.7 (2.0–4.0)
60 (50–69) 75.0 3.5 (2.3–5.3)
NS NS ⬍ 0.001
LAD 38 LCx 11 RCA 51 0 1 2 3
40 10 50
31 16 53 19 3
NS
29 49 Time Since Pain <6 h
Study Population (n ⴝ 378) Age (yr) Male gender (%) Time from pain onset to treatment (h) Infarct-related artery (%)
TIMI flow grade at 60 min (%)
Patency TIMI Persistent Occlusion Flow 2 or 3 TIMI Flow 0 or 1 (n ⴝ 299) (n ⴝ 79) p Value
59 (50–69) 78.1 2.7 (1.9–3.5)
59 (50–69) 81.0 2.5 (1.9–3.3)
59 (50–71) 69.6 3.0 (2.1–4.0)
NS NS ⬍ 0.004
LAD 34 LCx 14 RCA 52 0 1 2 3
36 13 51
26 18 56 18 3
NS
28 51
Results are expressed as medians (25th and 75th) percentiles. LAD ⫽ left anterior descending artery; LCx ⫽ left circumflex artery; RCA ⫽ right coronary artery; TIMI ⫽ Thrombolysis in Myocardial Infarction.
over baseline (T0) value (T60/T0); 60-min slope, calculated by dividing the difference of the values at initiation of therapy and 60 min thereafter by 60 ([T60-T0]/60), and expressed in nanograms per milliliter/min. The TIMI flow grade at 60 min was used as a gold standard (12). A TIMI flow grade ⱖ2 was considered a patent IRA (n ⫽ 344) and a TIMI flow grade ⱕ1 was considered an occluded IRA (n ⫽ 98). Statistical analyses. Baseline patient characteristics and all other results are expressed as medians ⫾ interquartile ranges. Statistical comparison of the baseline characteristics between patients with patent and occluded IRAs were performed via the chi-square test for categorical variables and the Mann-Whitney test for continuous variables. The significance of the differences between the marker values or indexes obtained in the two groups of patients was determined by the Mann-Whitney test. Receiver-operating characteristic (ROC) curves were constructed for the T0, T60, 60-min ratio and 60-min slope of each marker studied, by plotting sensitivity against (1⫺specificity) (35). Statistical
differences associated with a p ⬍ 0.05 were considered significant.
RESULTS Patient characteristics. The baseline demographic and clinical characteristics of the 442 patients included in this analysis are summarized in Table 1. There were 333 men and 109 women with a median age of 60 years. The time interval from the onset of chest pain to start of thrombolytic therapy was 2.9 h (2.0 to 4.2 h). In 344 (78%) patients, angiography at 60 min revealed TIMI flow grade 2 or 3. In the remaining 98 (22%) patients, the TIMI flow grade was 0 or 1. The time interval from the onset of chest pain to start of thrombolytic therapy was shorter (p ⬍ 0.001) in patients with patent IRA (Table 1). The median age among the subset of patients that received thrombolysis within 6 h from pain onset was 59 years. The time interval from the pain onset to start of thrombolytic therapy in this subgroup was 2.7 h (1.9 to 3.5 h). Angiography at 60 min revealed TIMI flow grade 2
742
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47
Table 2. Serum Cardiac Marker Concentrations and Indexes in the Study Group All Patients
Myoglobin T0 T60 60-min ratio 60-min slope* CK-MB mass T0 T60 60-min ratio 60-min slope* cTnI T0 T60 60-min ratio 60-min slope*
Patency TIMI Grades 2–3 (n ⴝ 344)
Persistent Occlusion TIMI Grades 0–1 (n ⴝ 98)
p Value
98.5 (47, 251) 1131 (376, 2589) 7.3 (1.8, 26.3) 14.2 (2.3, 38.9)
172 (69, 462) 510 (174, 978) 1.9 (1.2, 3.7) 2.7 (0.8, 7.1)
⬍ 0.001 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001
2.0 (0.4, 5.6) 19.0 (6.3, 43.8) 6.1 (2.0, 21.0) 0.22 (0.05, 0.59)
4.1 (1.3, 13.6) 9.7 (5.0, 34.3) 2.1 (1.3, 3.7) 0.09 (0.02, 0.22)
⬍ 0.0001 ⬍ 0.06 ⬍ 0.0001 ⬍ 0.0001
0.4 (0.4, 0.8) 2.8 (0.4, 11.5) 3.3 (1.0, 13.0) 0.03 (0.0, 0.16)
0.4 (0.4, 2.8) 1.1 (0.4, 5.9) 1.0 (1.0, 2.2) 0.0 (0.0, 0.03)
⬍ 0.004 ⬍ 0.006 ⬍ 0.0001 ⬍ 0.0001
Time Since Pain <6 h Myoglobin T0 (ng/ml) T60 (ng/ml) 60-min ratio 60-min slope* CK-MB mass T0 (ng/ml) T60 (ng/ml) 60-min ratio 60-min slope* cTnI T0 T60 60-min ratio 60-min slope*
89 (46, 217) 1279 (389, 2820) 9.0 (2.1, 30.6) 16.7 (3.0, 42.5)
140 (66, 275) 474 (169, 950) 2.2 (1.5, 5.1) 2.9 (0.8, 8.6)
⬍ 0.02 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001
1.4 (0.4, 4.5) 18.5 (6.1, 43.4) 7.3 (2.3, 24.0) 0.22 (0.06, 0.61)
2.7 (1.1, 6.7) 7.9 (4.8, 22.2) 2.4 (1.6, 4.0) 0.09 (0.03, 0.18)
⬍ 0.004 ⬍ 0.002 ⬍ 0.001 ⬍ 0.001
0.4 (0.4, 0.5) 2.7 (0.4, 11.4) 3.7 (1.0, 14.5) 0.03 (0.0, 0.16)
0.4 (0.4, 1.2) 0.7 (0.4, 2.4) 1.0 (1.0, 2.2) 0.0 (0.0, 0.02)
NS ⬍ 0.0002 ⬍ 0.0001 ⬍ 0.0001
Results displayed in median and 25th and 75th percentiles. *60-min slope expressed as ng/ml/min. CK-MB ⫽ creatine-kinase-MB; cTnI ⫽ cardiac Troponin-I; TIMI ⫽ Thrombolysis in Myocardial Infarction.
or 3 in 299 (79%) and TIMI flow grade 0 or 1 in 79 (21%) of these patients. Similar to the entire patient population, the time interval from pain onset to start of thrombolytic therapy was shorter (p ⬍ 0.004) in patients with a patent IRA. Changes in serum marker levels in thrombolysis. Table 2 summarizes the changes in serum levels of myoglobin, CK-MB and cTnI before and 60 min after initiation of thrombolytic therapy. In the overall study population of 442 patients, the baseline (T0) concentrations for all three serum markers were significantly higher in the patients with an occluded IRA (p ⬍ 0.001, p ⬍ 0.0001 and p ⬍ 0.004 for myoglobin, CK-MB and cTnI, respectively), possibly due to the larger extent of myocardial injury in this group. However, this trend was reversed 60 min after thrombolysis, as
evidenced by the significantly higher T60 concentrations of myoglobin (p ⬍ 0.0001) and cTnI (p ⬍ 0.006) and borderline significantly higher CK-MB (p ⬍ 0.06) in the patients with a patent IRA. Median ratios of the serum concentration 60 min after the start of thrombolysis and at baseline (60-min ratio) were consistently higher in patients in whom a patent IRA was found, compared with those of patients with an occluded IRA. The differences reached high statistical significance for all three serum markers (p ⬍ 0.0001). Similarly, the medians of the slopes of increase for each serum marker within the first 60 min (60-min slope) were significantly higher in patients with a patent IRA (p ⬍ 0.0001). These observations were sustained in the subgroup of 378 patients who received thrombolysis within 6 h of ischemic discomfort.
JACC Vol. 34, No. 3, 1999 September 1999:739–47
Tanasijevic et al. Cardiac Markers in Thrombolysis
743
Figure 1. ROC curves of the 60-min value (top), 60-min ratio (middle) and 60-min slope (bottom) of myoglobin, CK-MB and cardiac Troponin-I (cTnI), for noninvasive prediction of occlusion after thrombolysis.
Diagnostic performance of serum markers in thrombolysis. Because the myoglobin, CK-MB and cTnI assays produce results along a continuum, an ROC analysis was employed to compare their diagnostic value for noninvasive assessment of a patent IRA 60 min after initiation of thrombolysis. Comparison of the area under the ROC curve (AUC) for the 60-minute ratios in the overall patient population (Fig. 1, middle), showed equivalent performance between myoglobin (AUC ⫽ 0.71), cTnI (AUC ⫽ 0.71) and CK-MB (AUC ⫽ 0.70). The difference in the AUC between the 60-min ratios for the three markers was not statistically significant. The peformance of the 60-min ratios for all three markers in the subset of patients that were treated within 6 h from onset of ischemic discomfort was identical to the overall patient population. Analysis of the T60 concentration (Fig. 1, top) and the 60-min slopes (Fig. 1, bottom) revealed suboptimal AUC for all three markers, with exception of the 60-min myoglobin slope (AUC ⫽ 0.70). The data obtained from the ROC analyses were applied to determine the cut-points for the 60-min ratios of all three serum markers, above which the probability of a patent IRA could be predicted with a high degree of diagnostic accuracy. The performance of all three markers was very similar
in the overall patient population, as well as in patients treated within 6 h from onset of ischemic discomfort (Table 3). In the overall patient population, the 60-min myoglobin ratio of ⬍4.0 yielded slightly better sensitivity (74%) and specificity (64%) for occlusion of the IRA than the other two serum markers. When the 60-min myoglobin ratio was ⱖ4.0, the probability of a patent IRA was 90%, and only 23 out of 229 (10%) patients with values above these levels showed documented occlusion of the IRA at angiography performed 60 min after thrombolysis. The probability of patent IRA increased further with increasing myoglobin 60-min ratios (Fig. 2). The probability of occlusion was low (37%), even with 60-min myoglobin ratios of ⬍4.0 (Tables 3 and 4). The predictive value for occlusion increased by only 4% when the combination of myoglobin 60-min ratios of ⬍4.0 for myoglobin, ⬍2.0 for cTnI and ⬍3.3 for CK-MB was considered evidence of occlusion. Further analyses were performed to determine whether the performance of the 60-min ratios for all three markers could be improved by segregating the patients based on whether the initial serum myoglobin or cTnI values were higher or lower than their respective diagnostic cutoffs for AMI (⬎110 and ⬎0.4 ng/ml, respectively). Some improvement in clinical performance was observed for the 60-min
744
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47
Table 3. Performance Characteristics of Serum Markers All Patients Serum Marker
ROC Area
Diagnostic Cut-point
Sensitivity for Occlusion (%)
Specificity for Occlusion (%)
Probability of Patency (> Cut-point)
Probability of Occlusion (< Cut-point)
Myo 60-min ratio CK-MB 60-min ratio cTnI 60-min ratio
0.71 0.70 0.71
4.0 3.3 2.0
74 70 69
64 63 60
90 88 87
37 35 33
89 87 88
36 34 31
Time Since Pain <6 h Myo 60-min ratio CK-MB 60-min ratio cTnI 60-min ratio
0.71 0.70 0.71
4.0 3.3 2.0
69 62 68
68 68 62
CK-MB ⫽ creatine-kinase-MB; cTnI ⫽ cardiac Troponin-I; Myo ⫽ myoglobulin; ROC ⫽ receiver-operating characteristics.
cTnI ratio using the diagnostic cutpoint of 2.5, in the subgroup of patients with elevated baseline myoglobin (AUC ⫽ 0.77) or cTnI values (AUC ⫽ 0.72). However, the probability of occlusion when the cTnI 60-min ratio was ⬍2.5 ng/ml was only 46% in this subgroup. This is only marginally higher than the probability of occlusion of 37% yielded by the 60-min myoglobin ratios of ⬍4.0 in the entire patient population. None of the markers was sufficiently accurate to differentiate patients with TIMI flow grade 3 from TIMI flow grade ⱕ2 (e.g., AUC ⫽ 0.64 for myoglobin 60-min ratio).
The probability of TIMI flow grade of 3 when the 60-min myoglobin ratio was ⱖ4.0 was only 59%.
DISCUSSION The aim of the current study was to assess the diagnostic performance of serum myoglobin, CK-MB and cTnI concentration obtained before and 60 min after initiation of thrombolytic therapy, in predicting myocardial IRA patency, the most important aspect of early AMI care (36). To
Figure 2. Probability of IRA patency according to the myoglobin 60-min ratio. The probability of patency corresponds to the myoglobin 60-min ratio values greater than or equal to the specific cutpoints.
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47 Table 4. Diagnostic Performance of the 60-min Myoglobin Ratio Myoglobin 60-min Ratio
Probability of patency Probability of occlusion Number of patients
<4.0
>4.0
63% 37% 190 (45%)
90% 10% 229 (55%)
our knowledge, the current study is the largest study to date to address this important clinical problem. Diagnostic performance of serum markers. The 60-min myoglobin ratio of ⱖ4.0 yielded 90% probability of a patent IRA (Fig. 2, and Tables 3 and 4), suggesting that emergency coronary angiography to determine their IRA status may be unnecessary when this pattern of release of myoglobin is observed. In our series, 229 (55%) patients had 60-min myoglobin ratios ⱖ4.0, indicating that a strategy utilizing myoglobin marker would have allowed noninvasive determination of IRA patency in a significant number of patients. However, the probability of a patent IRA was still substantial even with 60-min myoglobin ratios of ⬍4.0 (Tables 3 and 4). Moreover, the combined use of the 60-min ratios of all three markers did not result in a significant improvement of the predictive value for occlusion. The use of serum markers in combination with other noninvasive markers of IRA patency, including resolution of ST segment elevation and chest pain (8), may improve the specificity for detection of IRA occlusion. If confirmed through appropriate studies, such improved predictive accuracy may allow rapid triage of patients to rescue angioplasty, when the clinical and laboratory findings are consistent with IRA occlusion. The diagnostic performance of myoglobin, CK-MB and cTnI in the current study is similar to that found in our previous pilot study (12). The performance of the single 60-min serum marker value was unsatisfactory for all three markers. It is probable that the single time point, 60-min serum marker measurement correlated not only with the IRA patency status, but also with the extent of initial myocardial injury. An extensive AMI may have yielded a 60-min myoglobin ratio ⱖ4.0 in the absence of IRA patency. Conversely, a small AMI may have resulted in a lower 60-min serum marker value, despite IRA patency. The usefulness of serum myoglobin for noninvasive prediction of infarct artery patency, either alone or in combination with other cardiac marker proteins, has been demonstrated by our group (12) and by other investigators (14 –16,18,24,25,37,38). Ellis et al. (15) reported that in 42 patient receiving thrombolytic therapy, the myoglobin 60min ratio cutoff of 4.6 conferred 100% sensitivity and 85% specificity for the detection of occlusion. Similarly, Apple et al. (23) found that in 25 consecutive patients given thrombolysis for AMI, the myoglobin 90-min cutoff of 5.0
745
conferred 100% sensitivity and 76.5% specificity for detection of occlusion. In comparison, in the present study the myoglobin 60-min ratio at the cutoff of 4.0 yielded sensitivity and specificity for occlusion of 74% and 64%, respectively. The higher sensitivity and specificity of the 60-min myoglobin ratio observed in the studies by Ellis et al. (15) and Apple et al. (23) may be due to their small sample size. Despite a considerable body of literature showing its utility for noninvasive assessment of reperfusion, the measurement of serum myoglobin for this purpose has not become widely adopted into clinical care, possibly because the previous studies included a modest number of patients and concerns were raised about myoglobin’s nonspecificity for cardiac muscle (39). However, our findings indicate that nonspecific elevation of myoglobin is infrequent in patients with AMI and ST segment elevations who are selected to receive thrombolytic therapy. The short turnaround time of approximately 30 min (measured from test ordering until availability of result) for urgent myoglobin determinations performed in the central laboratory, and possibly even less when performed in the emergency department, would enhance myoglobin’s utility in noninvasive assessment of IRA patency status. Apple et al. (23) have found in a series of 25 patients that early serial measurements of cTnI were a more accurate predictor of early IRA patency status 90 min after thrombolytic therapy than were CK-MB or myoglobin. The performance of the 60-min cTnI ratio in our series was no better than that of the 60-min myoglobin or CK-MB mass ratios. Although the molecular mass of cTnI (23.5 kDa) subunit is close to that of myoglobin (17.8 kDa), its initial rate of increase might be slightly slower due to its predominantly (97%) myofibrillar distribution (40). In addition, because all cTnI results below the lower detection limit of the assay were collectively expressed as 0.4 ng/ml, it is possible that this may have resulted in an underestimation of the cTnI 60-min ratio, and that higher ratios may have been observed using an assay capable of measuring cTnI values between 0.0 and 0.39 ng/ml. Limitations of the study. There are limits to the conclusions that we can draw from the present study. It has been previously shown that combined analysis of noninvasive markers (i.e., CK peak and resolution of ST segment elevation) (13), continuous ST segment monitoring (41) and the combination of resolution of ischemic discomfort, reperfusion arrhythmias and normalization of electrocardiogram (7) can improve evaluation of infarct-related artery patency. The other clinical data noted earlier in the article were not available in the TIMI 10B trial, but studies in progress at our institution are evaluating the contribution of the biochemical markers, when used in combination with clinical and ECG markers of IRA patency. The performance of the cardiac markers in the current study should be interpreted in the context of the overall patency rate (78%) achieved at 60 min by the thrombolytic
746
Tanasijevic et al. Cardiac Markers in Thrombolysis
agents used in the TIMI 10B study. The efficacy of cardiac markers in detecting IRA patency may vary depending on the type of the agent and adjunctive therapy used. Conclusions. Our findings indicate that early identification of patients with patent IRA after thrombolysis is possible with biochemical markers. The diagnostic performance of serum myoglobin, CK-MB and cTnI 60-min ratios was similar. The probability of a patent IRA was the highest (90%) in patients with 60-min myoglobin ratio ⱖ4.0, and early invasive interventions such as rescue angioplasty may not be necessary in this group. Thus, serum marker determinations at baseline and 60 min after thrombolysis may permit rapid triage of patients receiving thrombolytic therapy by ruling out IRA occlusion. Reprint requests and correspondence: Dr. Milenko J. Tanasijevic, Clinical Laboratories, Brigham and Women’s Hospital, Amory building, 215 A, 75 Francis Street, Boston, Massachusetts 02115. E-mail: [email protected].
REFERENCES 1. Gruppo Italiano per lo Studio Della Streptochinasi Nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397– 401. 2. ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349 – 60. 3. The Gusto Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673– 82. 4. Braunwald E. The open-artery theory is alive and well—again. N Engl J Med 1993;329:1650 –2. 5. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–22. 6. Cannon CP, McCabe CH, Diver DJ, et al. Comparison of frontloaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 Trial. TIMI 4 Investigators. J Am Coll Cardiol 1994;24:1602–10. 7. Kircher BJ, Topol EJ, O’Neill WW, Pitt B. Prediction of infarct coronary artery recanalization after intravenous thrombolytic therapy. Am J Cardiol 1987;59:513–5. 8. Califf RM, O’Neil W, Stack RS, et al. Failure of simple clinical measurements to predict perfusion status after intravenous thrombolysis. Ann Int Med 1988;108:658 – 62. 9. Garabedian HD, Gold HK, Yasuda T, et al. Detection of coronary artery reperfusion with creatine kinase-MB determinations during thrombolytic therapy: correlation with acute angiography. J Am Coll Cardiol 1988;11:729 –34. 10. Lewis BS, Ganz W, Laramee P, et al. Usefulness of a rapid initial increase in plasma creatine kinase activity as a marker of reperfusion during thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1988;62:20 – 4. 11. Ohman EM, Christenson RH, Califf RM, et al. Noninvasive detection of reperfusion after thrombolysis based on serum creatine kinase MB changes and clinical variables. TAMI 7 Study Group. Am Heart J 1993;126:819 –26. 12. Tanasijevic MJ, Cannon CP, Wybenga DR, et al., for the TIMI 10A Investigators. Myoglobin, CK-MB and cardiac Troponin-I for noninvasive assessment of reperfusion after thrombolysis for acute myocardial infarction. Results from TIMI 10A. Am Heart J 1997;134: 622–30. 13. Hohnloser SH, Zabel M, Kasper W, Meinertz T, Just H. Assessment
JACC Vol. 34, No. 3, 1999 September 1999:739–47
14. 15. 16.
17.
18.
19. 20.
21. 22. 23. 24.
25. 26.
27. 28.
29. 30. 31. 32. 33.
34.
of coronary artery patency after thrombolytic therapy: accurate prediction utilizing the combined analysis of three noninvasive markers. J Am Coll Cardiol 1991;18:44 –9. Ellis AK, Little T, Masud AR, Klocke FJ. Patterns of myoglobin release after reperfusion of injured myocardium. Circulation 1985;72: 639 – 47. Ellis AK, Little T, Masud AR, Liberman HA, Morris DC, Klocke FJ. Early noninvasive detection of successful reperfusion in patients with acute myocardial infarction. Circulation 1988;78:1352–7. Ishii J, Nomura M, Ando T, et al. Early detection of successful coronary reperfusion based on serum myoglobin concentration: comparison with serum creatine kinase isoenzyme MB activity. Am Heart J 1994;128:641– 8. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac Troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol 1991;67:1360 –7. Zabel M, Hohnloser SH, Koster W, Prinz M, Kasper W, Just H. Analysis of creatine kinase, CK-MB, myoglobin, and troponin T time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation 1993;87:1542–50. Remppis A, Scheffold T, Karrer O, et al. Assessment of reperfusion of the infarct zone after acute myocardial infarction by serial cardiac troponin T measurements in serum. Br Heart J 1994;71:242– 8. Apple FS, Voss E, Lund L, Preese L, Berger CR, Henry TD. Cardiac troponin, CK-MB and myoglobin for the early detection of acute myocardial infarction and monitoring of reperfusion following thrombolytic therapy. Clin Chim Acta 1995;237:59 – 66. Puleo PR, Perryman MB, Bresser MA, Rokey R, Pratt CM, Roberts R. Creatine kinase isoform analysis in the detection and assessment of thrombolysis in man. Circulation 1987;75:1162–9. Christenson RH, Ohman EM, Topol EJ, et al. Creatine kinase MM and MB isoforms in patients receiving thrombolytic therapy and acute angiography. TAMI Study Group. Clin Chem 1995;41:844 –52. Apple FS, Henry TD, Berger CR, Landt YA. Early monitoring of serum cardiac Troponin I for assessment of coronary reperfusion following thrombolytic therapy. Am J Clin Pathol 1996;105:6 –10. Katus HA, Diederich KW, Scheffold T, Uellner M, Schwarz F, Kubler W. Non-invasive assessment of infarct reperfusion: the predictive power of the time to peak value of myoglobin, CKMB, and CK in serum. Eur Heart J 1988;9:619 –24. Laperche T, Steg PG, Dehoux M, et al. A study of biochemical markers of reperfusion early after thrombolysis for acute myocardial infarction. The PERM Study Group. Circulation 1995;92:2079 – 86. Cannon CP, Gibson M, McCabe CH, et al. TNK-Tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B Trial. TIMI 10B Investigators. Circulation 1998;98:2805–14. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) Trial. Phase I findings. N Engl J Med 1985;312:932– 6. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of monoclonal antibodies for an assay of cardiac Troponin I and preliminary results in suspected cases of myocardial infarction. Clin Chem 1992;38:2203–14. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific Troponin-I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342–9. Adams JE, Bodor GS, Davilla-Roman VG, et al. Cardiac Troponin I: a marker with high specificity for cardiac injury. Circulation 1993;88: 101– 6. Silva DP, Landt Y, Porter SE, Ladenson JH. Development and application of monoclonal antibodies to human cardiac myoglobin in a rapid fluorescence immunoassay. Clin Chem 1991;37:1356 – 64. Woo J, Lacbawan FL, Sunheimer R, LeFever D, McCabe JB. Is myoglobin useful in the diagnosis of acute myocardial infarction in the emergency department setting? Am J Clin Pathol 1995;103:725–9. Vaidya HC, Maynard Y, Dietzler DN, Ladenson JH. Direct measurement of creatine kinase-MB activity in serum after extraction with a monoclonal antibody specific to the MB isoenzyme. Clin Chem 1986;32:657– 63. Chapelle JP, El Allaf M. Automated quantification of creatine kinase MB isoenzyme in serum by radial partition immunoassay, with use of the Stratus analyzer. Clin Chem 1990;36:99 –101.
JACC Vol. 34, No. 3, 1999 September 1999:739–47 35. Hanley JA, Mcneil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143: 29 –36. 36. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival. Should the paradigm be expanded? Circulation 1989;79:441– 4. 37. Miyata M, Abe S, Arima S, et al. Rapid diagnosis of coronary reperfusion by measurement of myoglobin level every 15 min in acute myocardial infarction. J Am Coll Cardiol 1994;23:1009 –15. 38. Lavin F, Kane M, Forde A, Gannon F, Daly K. Comparison of five
Tanasijevic et al. Cardiac Markers in Thrombolysis
747
cardiac markers in the detection of reperfusion after thrombolysis in acute myocardial infarction. Br Heart J 1995;73:422–7. 39. Vaananen HK, Syrjala H, Rahkila P, Vuori J, et al. Serum carbonic anhydrase III and myoglobin concentrations in acute myocardial infarction. Clin Chem 1990;36:635– 8. 40. Adams JE, Schechtman KB, Landt Y, Ladenson JH, Jaffe AS. Comparable detection of acute myocardial infarction by creatine kinase MB isoenzyme and cardiac Troponin I. Clin Chem 1994;40:1291–5. 41. Krucoff MW, Green CE, Satler LF, et al. Noninvasive detection of coronary artery patency using continuous ST-segment monitoring. Am J Cardiol 1986;57:916 –22.
Vol. 34, No. 3, 1999 ISSN 0735-1097/99/$20.00 PII S0735-1097(99)00274-0
Myocardial Infarction
Myoglobin, Creatine-Kinase-MB and Cardiac Troponin-I 60-Minute Ratios Predict Infarct-related Artery Patency After Thrombolysis for Acute Myocardial Infarction Results from the Thrombolysis in Myocardial Infarction Study (TIMI) 10B Milenko J. Tanasijevic, MD,* Christopher P. Cannon, MD,† Elliott M. Antman, MD,† Donald R. Wybenga, MD,* George A. Fischer, PHD,* Christine Grudzien,* C. Michael Gibson, MD,‡ James W. Winkelman, MD,* Eugene Braunwald, MD,† for the TIMI 10B Investigators Boston and West Roxbury, Massachusetts OBJECTIVES
We examined the diagnostic performance of serum myoglobin, creatine-kinase-MB (CKMB) and cardiac Troponin-I (cTnI) for predicting the infarct-related artery (IRA) patency in patients receiving TNK-tissue plasminogen activator (TNK-tPA) therapy for acute myocardial infarction (AMI) in the Thrombolysis in Myocardial Infarction (TIMI) 10B trial.
BACKGROUND A reliable noninvasive serum marker of IRA patency is desired to permit early identification of patients with a patent IRA after thrombolysis. METHODS
We measured myoglobin, CK-MB and cTnI concentrations in sera obtained just before thrombolysis (T0) and 60 min later (T60) in 442 patients given TNK-tPA and who underwent coronary angiography at 60 min.
RESULTS
Angiography at 60 min showed a patent IRA (TIMI flow grade 2, 3) in 344 and occluded IRA (TIMI flow grade 0, 1) in 98 patients. The median serum T60 concentration, the ratio of the T60 and T0 serum concentration (60-min ratio) and the slope of increase over 60 min for each serum marker were significantly higher in patients with patent arteries compared with patients with occluded arteries. The area under the receiver-operating characteristic (ROC) curve for diagnosis of occlusion was 0.71, 0.70 and 0.71 for the 60-min ratio of myoglobin, cTnI and CKMB, respectively. The 60-min ratios of ⱖ4.0 for myoglobin, ⱖ3.3 for CK-MB and ⱖ2.0 for cTnI yielded a probability of patency of 90%, 88% and 87%, respectively.
CONCLUSIONS The diagnostic performance of serum myoglobin, CK-MB and cardiac Tropinin-I (cTnI) 60-min ratios was similar. The probability of a patent IRA was very high (90%) in patients with 60-min myoglobin ratio ⱖ4.0, and early invasive interventions to establish IRA patency may not be necessary in this group. Serum marker determinations at baseline and 60-min after thrombolysis may permit rapid triage of patients receiving thrombolytic therapy by ruling out IRA occlusion. (J Am Coll Cardiol 1999;34:739 – 47) © 1999 by the American College of Cardiology
Early thrombolysis in patients with acute myocardial infarction (AMI) has a strong beneficial influence on short- and long-term outcome (1,2). The therapeutic goal of infarctrelated artery (IRA) patency may be achieved with novel From the *Clinical Laboratories and †Department of Medicine, Brigham and Women’s Hospital, Boston, and ‡Department of Medicine, VA Medical Center, West Roxbury, Massachusetts. This work was supported by Dade Behring, Inc., Newark, Delaware. The TIMI 10B Clinical Centers were supported by Genentech, South San Francisco, California. Dr. Milenko Tanasijevic is a consultant for Dade Behring International. Manuscript received November 6, 1998; revised manuscript received April 7, 1999, accepted May 16, 1999.
thrombolytic agents or percutaneous coronary interventions (3– 6). The availability of a reliable marker of IRA patency status may permit early identification of patients with patent IRA, for whom repeat thrombolysis or rescue percutaneous transluminal coronary angioplasty (PTCA) may not be necessary. Although coronary angiography has been considered the gold standard for this purpose (4,5), it is costly and often unavailable for routine care of most patients. Because the currently used noninvasive clinical and electrocardiographic indexes of IRA patency status are not sufficiently sensitive nor specific (7,8), several serum cardiac markers
740
Tanasijevic et al. Cardiac Markers in Thrombolysis
Abbreviations and Acronyms AMI ⫽ acute myocardial infarction AUC ⫽ area under the receiver-operating characteristic curve CK-MB ⫽ creatine-kinase-MB cTnI ⫽ cardiac Troponin-I ECG ⫽ electrocardiogram IRA ⫽ infarct-related artery PTCA ⫽ percutaneous transluminal coronary angioplasty ROC ⫽ receiver-operating characteristics TIMI ⫽ Thrombolysis in Myocardial Infarction TNK-tPA ⫽ TNK-tissue plasminogen activator
have been investigated and proposed as alternatives. The serum markers that have been investigated include creatine kinase-MB (CK-MB) (9 –12), total creatine kinase (CK) (10,13), myoglobin (12,14 –16), cardiac Troponin-T (17– 20), CK isoforms (21,22), cardiac Troponin-I (cTnI) (12,23) and combinations of the above (12,18,24,25). The current study was undertaken to examine the diagnostic performance of serum myoglobin, CK-MB and cTnI obtained immediately before, and within 60 min of initiation of thrombolysis, for predicting the IRA patency in patients receiving TNK-tissue plasminogen activator (TNK-tPA) therapy in the Thrombolysis in Myocardial Infarction (TIMI) 10B trial.
METHODS TIMI 10B trial. The TIMI 10B trial, a phase-II, doseranging trial was conducted in the U.S. and Europe between March 1996 and March 2, 1997. It evaluated the new thrombolytic agent, TNK-tPA, in patients with AMI (26). The study patients were between the ages of 19 and 80 years, had episodes of ischemic discomfort lasting ⱖ30 min and presented within 12 h from symptom onset, associated with ST segment elevation ⱖ0.1 mV in two or more contiguous electrocardiogram (ECG) leads. Major exclusion criteria included prior stroke or transient ischemic attack, a reliably obtained blood pressure ⬎180/110 mm Hg, significant bleeding within six months and other contraindications to thrombolysis. Eligible patients were randomized to receive either a single bolus of 30, 40 or 50 mg TNK-tPA (Genentech, Inc., South San Francisco, California) or front-loaded (t-PA). All patients received aspirin and intravenous heparin. Patients underwent coronary angiography at 90 min, and 60 and 75 min when feasible. All angiograms were analyzed at the Angiographic Core Laboratory (VA Medical Center, West Roxbury, Massachusetts), which was blinded to dose assignment. Thrombolysis in myocardial infarction flow grade was analyzed according to prespecified definitions (27). The TIMI 10B study protocol was reviewed and ap-
JACC Vol. 34, No. 3, 1999 September 1999:739–47
proved by each hospital’s Institutional Review Board, and written informed consent was obtained from each patient before enrollment. Study population. In an ancillary study reported here, blood specimens for serum marker analyses were collected in 826 patients. The patients with no available information regarding the time interval between the onset of chest pain and the initiation of thrombolysis (n ⫽ 31) were excluded. Only patients for whom the 60-min angiogram was available (n ⫽ 442) were included in the statistical analyses. Separate statistical analyses were performed on the subset of patients that received thrombolytic treatment within 6 h from the onset of ischemic discomfort (n ⫽ 378). Serum marker analyses. Serum specimens were obtained by centrifugation at each site, and were stored locally at ⫺20°C. They were then mailed on dry ice to the Covance Core Laboratory (Indianapolis, Indiana), where they were stored at ⫺70°C. The specimens were shipped to the Cardiac Serum Marker Core Laboratory, at the Clinical Chemistry Laboratory of the Brigham and Women’s Hospital (Boston), and stored at ⫺20°C until analysis. The cardiac marker proteins remain stable when handled in this manner (data on file; Dade Behring Inc., Newark, Delaware). In the current study, the specimens were thawed and analyzed in batches by individuals blinded to the clinical data. Cardiac Troponin I, CK-MB and myoglobin were measured by the Stratus fluorometric enzyme immunoassays (Dade Behring). The analysis time is 15 min for each marker. The cTnI assay uses two cTnI-specific monoclonal antibodies that recognize two different cTnI epitopes (28,29). This assay shows no cross-reactivity with human skeletal muscle TnI (28,30). The myoglobin sandwich immunoassay uses two myoglobin-specific monoclonal antibodies (31,32). Creatine-kinase-MB concentrations were measured with an immunoassay based on a monoclonal antibody specific for the CK-MB isoenzyme (33,34). All CK-MB and cTnI results below the lower detection limit of their respective assays (i.e., ⬍0.4 ng/ml for both markers) were collectively expressed as 0.4 ng/ml. The imprecision of the cardiac marker assays, expressed as between-run coefficient of variation (%CV), was assessed over a period of 15 months, using the quality control materials provided by the manufacturer (Dade Behring). The imprecision of the myoglobin assay for concentrations of 47.3, 223.1 and 442.3 ng/ml was 8.6%, 6.2% and 6.1%, respectively. The between-run CV of the CK-MB assay for concentrations of 5.6, 32.1 and 81.2 ng/ml was 8.2%, 7.8% and 6.2%, respectively. The imprecision of the cTnI assays for concentrations of 1.1, 4.6, 18.5 and 33.6 ng/ml was 7.8%, 6.6%, 7.5% and 5.6%, respectively. Study end points. End points in this substudy included the diagnostic characteristics for the following measurements and indexes for each marker: value obtained 60 min after initiation of treatment (T60); ratio of the 60-min (T60)
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47
741
Table 1. Baseline Characteristics for the Study Population All Patients Study Population (n ⴝ 422) Age (yr) Male gender (%) Time from pain onset to treatment (h) Infarct-related artery (%)
TIMI flow grade at 60 min (%)
Patency TIMI Persistent Occlusion Flow 2 or 3 TIMI Flow 0 or 1 (n ⴝ 344) (n ⴝ 98) p Value
60 (51–69) 75.4 2.9 (2.0–4.2)
60 (51–69) 75.1 2.7 (2.0–4.0)
60 (50–69) 75.0 3.5 (2.3–5.3)
NS NS ⬍ 0.001
LAD 38 LCx 11 RCA 51 0 1 2 3
40 10 50
31 16 53 19 3
NS
29 49 Time Since Pain <6 h
Study Population (n ⴝ 378) Age (yr) Male gender (%) Time from pain onset to treatment (h) Infarct-related artery (%)
TIMI flow grade at 60 min (%)
Patency TIMI Persistent Occlusion Flow 2 or 3 TIMI Flow 0 or 1 (n ⴝ 299) (n ⴝ 79) p Value
59 (50–69) 78.1 2.7 (1.9–3.5)
59 (50–69) 81.0 2.5 (1.9–3.3)
59 (50–71) 69.6 3.0 (2.1–4.0)
NS NS ⬍ 0.004
LAD 34 LCx 14 RCA 52 0 1 2 3
36 13 51
26 18 56 18 3
NS
28 51
Results are expressed as medians (25th and 75th) percentiles. LAD ⫽ left anterior descending artery; LCx ⫽ left circumflex artery; RCA ⫽ right coronary artery; TIMI ⫽ Thrombolysis in Myocardial Infarction.
over baseline (T0) value (T60/T0); 60-min slope, calculated by dividing the difference of the values at initiation of therapy and 60 min thereafter by 60 ([T60-T0]/60), and expressed in nanograms per milliliter/min. The TIMI flow grade at 60 min was used as a gold standard (12). A TIMI flow grade ⱖ2 was considered a patent IRA (n ⫽ 344) and a TIMI flow grade ⱕ1 was considered an occluded IRA (n ⫽ 98). Statistical analyses. Baseline patient characteristics and all other results are expressed as medians ⫾ interquartile ranges. Statistical comparison of the baseline characteristics between patients with patent and occluded IRAs were performed via the chi-square test for categorical variables and the Mann-Whitney test for continuous variables. The significance of the differences between the marker values or indexes obtained in the two groups of patients was determined by the Mann-Whitney test. Receiver-operating characteristic (ROC) curves were constructed for the T0, T60, 60-min ratio and 60-min slope of each marker studied, by plotting sensitivity against (1⫺specificity) (35). Statistical
differences associated with a p ⬍ 0.05 were considered significant.
RESULTS Patient characteristics. The baseline demographic and clinical characteristics of the 442 patients included in this analysis are summarized in Table 1. There were 333 men and 109 women with a median age of 60 years. The time interval from the onset of chest pain to start of thrombolytic therapy was 2.9 h (2.0 to 4.2 h). In 344 (78%) patients, angiography at 60 min revealed TIMI flow grade 2 or 3. In the remaining 98 (22%) patients, the TIMI flow grade was 0 or 1. The time interval from the onset of chest pain to start of thrombolytic therapy was shorter (p ⬍ 0.001) in patients with patent IRA (Table 1). The median age among the subset of patients that received thrombolysis within 6 h from pain onset was 59 years. The time interval from the pain onset to start of thrombolytic therapy in this subgroup was 2.7 h (1.9 to 3.5 h). Angiography at 60 min revealed TIMI flow grade 2
742
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47
Table 2. Serum Cardiac Marker Concentrations and Indexes in the Study Group All Patients
Myoglobin T0 T60 60-min ratio 60-min slope* CK-MB mass T0 T60 60-min ratio 60-min slope* cTnI T0 T60 60-min ratio 60-min slope*
Patency TIMI Grades 2–3 (n ⴝ 344)
Persistent Occlusion TIMI Grades 0–1 (n ⴝ 98)
p Value
98.5 (47, 251) 1131 (376, 2589) 7.3 (1.8, 26.3) 14.2 (2.3, 38.9)
172 (69, 462) 510 (174, 978) 1.9 (1.2, 3.7) 2.7 (0.8, 7.1)
⬍ 0.001 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001
2.0 (0.4, 5.6) 19.0 (6.3, 43.8) 6.1 (2.0, 21.0) 0.22 (0.05, 0.59)
4.1 (1.3, 13.6) 9.7 (5.0, 34.3) 2.1 (1.3, 3.7) 0.09 (0.02, 0.22)
⬍ 0.0001 ⬍ 0.06 ⬍ 0.0001 ⬍ 0.0001
0.4 (0.4, 0.8) 2.8 (0.4, 11.5) 3.3 (1.0, 13.0) 0.03 (0.0, 0.16)
0.4 (0.4, 2.8) 1.1 (0.4, 5.9) 1.0 (1.0, 2.2) 0.0 (0.0, 0.03)
⬍ 0.004 ⬍ 0.006 ⬍ 0.0001 ⬍ 0.0001
Time Since Pain <6 h Myoglobin T0 (ng/ml) T60 (ng/ml) 60-min ratio 60-min slope* CK-MB mass T0 (ng/ml) T60 (ng/ml) 60-min ratio 60-min slope* cTnI T0 T60 60-min ratio 60-min slope*
89 (46, 217) 1279 (389, 2820) 9.0 (2.1, 30.6) 16.7 (3.0, 42.5)
140 (66, 275) 474 (169, 950) 2.2 (1.5, 5.1) 2.9 (0.8, 8.6)
⬍ 0.02 ⬍ 0.0001 ⬍ 0.0001 ⬍ 0.0001
1.4 (0.4, 4.5) 18.5 (6.1, 43.4) 7.3 (2.3, 24.0) 0.22 (0.06, 0.61)
2.7 (1.1, 6.7) 7.9 (4.8, 22.2) 2.4 (1.6, 4.0) 0.09 (0.03, 0.18)
⬍ 0.004 ⬍ 0.002 ⬍ 0.001 ⬍ 0.001
0.4 (0.4, 0.5) 2.7 (0.4, 11.4) 3.7 (1.0, 14.5) 0.03 (0.0, 0.16)
0.4 (0.4, 1.2) 0.7 (0.4, 2.4) 1.0 (1.0, 2.2) 0.0 (0.0, 0.02)
NS ⬍ 0.0002 ⬍ 0.0001 ⬍ 0.0001
Results displayed in median and 25th and 75th percentiles. *60-min slope expressed as ng/ml/min. CK-MB ⫽ creatine-kinase-MB; cTnI ⫽ cardiac Troponin-I; TIMI ⫽ Thrombolysis in Myocardial Infarction.
or 3 in 299 (79%) and TIMI flow grade 0 or 1 in 79 (21%) of these patients. Similar to the entire patient population, the time interval from pain onset to start of thrombolytic therapy was shorter (p ⬍ 0.004) in patients with a patent IRA. Changes in serum marker levels in thrombolysis. Table 2 summarizes the changes in serum levels of myoglobin, CK-MB and cTnI before and 60 min after initiation of thrombolytic therapy. In the overall study population of 442 patients, the baseline (T0) concentrations for all three serum markers were significantly higher in the patients with an occluded IRA (p ⬍ 0.001, p ⬍ 0.0001 and p ⬍ 0.004 for myoglobin, CK-MB and cTnI, respectively), possibly due to the larger extent of myocardial injury in this group. However, this trend was reversed 60 min after thrombolysis, as
evidenced by the significantly higher T60 concentrations of myoglobin (p ⬍ 0.0001) and cTnI (p ⬍ 0.006) and borderline significantly higher CK-MB (p ⬍ 0.06) in the patients with a patent IRA. Median ratios of the serum concentration 60 min after the start of thrombolysis and at baseline (60-min ratio) were consistently higher in patients in whom a patent IRA was found, compared with those of patients with an occluded IRA. The differences reached high statistical significance for all three serum markers (p ⬍ 0.0001). Similarly, the medians of the slopes of increase for each serum marker within the first 60 min (60-min slope) were significantly higher in patients with a patent IRA (p ⬍ 0.0001). These observations were sustained in the subgroup of 378 patients who received thrombolysis within 6 h of ischemic discomfort.
JACC Vol. 34, No. 3, 1999 September 1999:739–47
Tanasijevic et al. Cardiac Markers in Thrombolysis
743
Figure 1. ROC curves of the 60-min value (top), 60-min ratio (middle) and 60-min slope (bottom) of myoglobin, CK-MB and cardiac Troponin-I (cTnI), for noninvasive prediction of occlusion after thrombolysis.
Diagnostic performance of serum markers in thrombolysis. Because the myoglobin, CK-MB and cTnI assays produce results along a continuum, an ROC analysis was employed to compare their diagnostic value for noninvasive assessment of a patent IRA 60 min after initiation of thrombolysis. Comparison of the area under the ROC curve (AUC) for the 60-minute ratios in the overall patient population (Fig. 1, middle), showed equivalent performance between myoglobin (AUC ⫽ 0.71), cTnI (AUC ⫽ 0.71) and CK-MB (AUC ⫽ 0.70). The difference in the AUC between the 60-min ratios for the three markers was not statistically significant. The peformance of the 60-min ratios for all three markers in the subset of patients that were treated within 6 h from onset of ischemic discomfort was identical to the overall patient population. Analysis of the T60 concentration (Fig. 1, top) and the 60-min slopes (Fig. 1, bottom) revealed suboptimal AUC for all three markers, with exception of the 60-min myoglobin slope (AUC ⫽ 0.70). The data obtained from the ROC analyses were applied to determine the cut-points for the 60-min ratios of all three serum markers, above which the probability of a patent IRA could be predicted with a high degree of diagnostic accuracy. The performance of all three markers was very similar
in the overall patient population, as well as in patients treated within 6 h from onset of ischemic discomfort (Table 3). In the overall patient population, the 60-min myoglobin ratio of ⬍4.0 yielded slightly better sensitivity (74%) and specificity (64%) for occlusion of the IRA than the other two serum markers. When the 60-min myoglobin ratio was ⱖ4.0, the probability of a patent IRA was 90%, and only 23 out of 229 (10%) patients with values above these levels showed documented occlusion of the IRA at angiography performed 60 min after thrombolysis. The probability of patent IRA increased further with increasing myoglobin 60-min ratios (Fig. 2). The probability of occlusion was low (37%), even with 60-min myoglobin ratios of ⬍4.0 (Tables 3 and 4). The predictive value for occlusion increased by only 4% when the combination of myoglobin 60-min ratios of ⬍4.0 for myoglobin, ⬍2.0 for cTnI and ⬍3.3 for CK-MB was considered evidence of occlusion. Further analyses were performed to determine whether the performance of the 60-min ratios for all three markers could be improved by segregating the patients based on whether the initial serum myoglobin or cTnI values were higher or lower than their respective diagnostic cutoffs for AMI (⬎110 and ⬎0.4 ng/ml, respectively). Some improvement in clinical performance was observed for the 60-min
744
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47
Table 3. Performance Characteristics of Serum Markers All Patients Serum Marker
ROC Area
Diagnostic Cut-point
Sensitivity for Occlusion (%)
Specificity for Occlusion (%)
Probability of Patency (> Cut-point)
Probability of Occlusion (< Cut-point)
Myo 60-min ratio CK-MB 60-min ratio cTnI 60-min ratio
0.71 0.70 0.71
4.0 3.3 2.0
74 70 69
64 63 60
90 88 87
37 35 33
89 87 88
36 34 31
Time Since Pain <6 h Myo 60-min ratio CK-MB 60-min ratio cTnI 60-min ratio
0.71 0.70 0.71
4.0 3.3 2.0
69 62 68
68 68 62
CK-MB ⫽ creatine-kinase-MB; cTnI ⫽ cardiac Troponin-I; Myo ⫽ myoglobulin; ROC ⫽ receiver-operating characteristics.
cTnI ratio using the diagnostic cutpoint of 2.5, in the subgroup of patients with elevated baseline myoglobin (AUC ⫽ 0.77) or cTnI values (AUC ⫽ 0.72). However, the probability of occlusion when the cTnI 60-min ratio was ⬍2.5 ng/ml was only 46% in this subgroup. This is only marginally higher than the probability of occlusion of 37% yielded by the 60-min myoglobin ratios of ⬍4.0 in the entire patient population. None of the markers was sufficiently accurate to differentiate patients with TIMI flow grade 3 from TIMI flow grade ⱕ2 (e.g., AUC ⫽ 0.64 for myoglobin 60-min ratio).
The probability of TIMI flow grade of 3 when the 60-min myoglobin ratio was ⱖ4.0 was only 59%.
DISCUSSION The aim of the current study was to assess the diagnostic performance of serum myoglobin, CK-MB and cTnI concentration obtained before and 60 min after initiation of thrombolytic therapy, in predicting myocardial IRA patency, the most important aspect of early AMI care (36). To
Figure 2. Probability of IRA patency according to the myoglobin 60-min ratio. The probability of patency corresponds to the myoglobin 60-min ratio values greater than or equal to the specific cutpoints.
Tanasijevic et al. Cardiac Markers in Thrombolysis
JACC Vol. 34, No. 3, 1999 September 1999:739–47 Table 4. Diagnostic Performance of the 60-min Myoglobin Ratio Myoglobin 60-min Ratio
Probability of patency Probability of occlusion Number of patients
<4.0
>4.0
63% 37% 190 (45%)
90% 10% 229 (55%)
our knowledge, the current study is the largest study to date to address this important clinical problem. Diagnostic performance of serum markers. The 60-min myoglobin ratio of ⱖ4.0 yielded 90% probability of a patent IRA (Fig. 2, and Tables 3 and 4), suggesting that emergency coronary angiography to determine their IRA status may be unnecessary when this pattern of release of myoglobin is observed. In our series, 229 (55%) patients had 60-min myoglobin ratios ⱖ4.0, indicating that a strategy utilizing myoglobin marker would have allowed noninvasive determination of IRA patency in a significant number of patients. However, the probability of a patent IRA was still substantial even with 60-min myoglobin ratios of ⬍4.0 (Tables 3 and 4). Moreover, the combined use of the 60-min ratios of all three markers did not result in a significant improvement of the predictive value for occlusion. The use of serum markers in combination with other noninvasive markers of IRA patency, including resolution of ST segment elevation and chest pain (8), may improve the specificity for detection of IRA occlusion. If confirmed through appropriate studies, such improved predictive accuracy may allow rapid triage of patients to rescue angioplasty, when the clinical and laboratory findings are consistent with IRA occlusion. The diagnostic performance of myoglobin, CK-MB and cTnI in the current study is similar to that found in our previous pilot study (12). The performance of the single 60-min serum marker value was unsatisfactory for all three markers. It is probable that the single time point, 60-min serum marker measurement correlated not only with the IRA patency status, but also with the extent of initial myocardial injury. An extensive AMI may have yielded a 60-min myoglobin ratio ⱖ4.0 in the absence of IRA patency. Conversely, a small AMI may have resulted in a lower 60-min serum marker value, despite IRA patency. The usefulness of serum myoglobin for noninvasive prediction of infarct artery patency, either alone or in combination with other cardiac marker proteins, has been demonstrated by our group (12) and by other investigators (14 –16,18,24,25,37,38). Ellis et al. (15) reported that in 42 patient receiving thrombolytic therapy, the myoglobin 60min ratio cutoff of 4.6 conferred 100% sensitivity and 85% specificity for the detection of occlusion. Similarly, Apple et al. (23) found that in 25 consecutive patients given thrombolysis for AMI, the myoglobin 90-min cutoff of 5.0
745
conferred 100% sensitivity and 76.5% specificity for detection of occlusion. In comparison, in the present study the myoglobin 60-min ratio at the cutoff of 4.0 yielded sensitivity and specificity for occlusion of 74% and 64%, respectively. The higher sensitivity and specificity of the 60-min myoglobin ratio observed in the studies by Ellis et al. (15) and Apple et al. (23) may be due to their small sample size. Despite a considerable body of literature showing its utility for noninvasive assessment of reperfusion, the measurement of serum myoglobin for this purpose has not become widely adopted into clinical care, possibly because the previous studies included a modest number of patients and concerns were raised about myoglobin’s nonspecificity for cardiac muscle (39). However, our findings indicate that nonspecific elevation of myoglobin is infrequent in patients with AMI and ST segment elevations who are selected to receive thrombolytic therapy. The short turnaround time of approximately 30 min (measured from test ordering until availability of result) for urgent myoglobin determinations performed in the central laboratory, and possibly even less when performed in the emergency department, would enhance myoglobin’s utility in noninvasive assessment of IRA patency status. Apple et al. (23) have found in a series of 25 patients that early serial measurements of cTnI were a more accurate predictor of early IRA patency status 90 min after thrombolytic therapy than were CK-MB or myoglobin. The performance of the 60-min cTnI ratio in our series was no better than that of the 60-min myoglobin or CK-MB mass ratios. Although the molecular mass of cTnI (23.5 kDa) subunit is close to that of myoglobin (17.8 kDa), its initial rate of increase might be slightly slower due to its predominantly (97%) myofibrillar distribution (40). In addition, because all cTnI results below the lower detection limit of the assay were collectively expressed as 0.4 ng/ml, it is possible that this may have resulted in an underestimation of the cTnI 60-min ratio, and that higher ratios may have been observed using an assay capable of measuring cTnI values between 0.0 and 0.39 ng/ml. Limitations of the study. There are limits to the conclusions that we can draw from the present study. It has been previously shown that combined analysis of noninvasive markers (i.e., CK peak and resolution of ST segment elevation) (13), continuous ST segment monitoring (41) and the combination of resolution of ischemic discomfort, reperfusion arrhythmias and normalization of electrocardiogram (7) can improve evaluation of infarct-related artery patency. The other clinical data noted earlier in the article were not available in the TIMI 10B trial, but studies in progress at our institution are evaluating the contribution of the biochemical markers, when used in combination with clinical and ECG markers of IRA patency. The performance of the cardiac markers in the current study should be interpreted in the context of the overall patency rate (78%) achieved at 60 min by the thrombolytic
746
Tanasijevic et al. Cardiac Markers in Thrombolysis
agents used in the TIMI 10B study. The efficacy of cardiac markers in detecting IRA patency may vary depending on the type of the agent and adjunctive therapy used. Conclusions. Our findings indicate that early identification of patients with patent IRA after thrombolysis is possible with biochemical markers. The diagnostic performance of serum myoglobin, CK-MB and cTnI 60-min ratios was similar. The probability of a patent IRA was the highest (90%) in patients with 60-min myoglobin ratio ⱖ4.0, and early invasive interventions such as rescue angioplasty may not be necessary in this group. Thus, serum marker determinations at baseline and 60 min after thrombolysis may permit rapid triage of patients receiving thrombolytic therapy by ruling out IRA occlusion. Reprint requests and correspondence: Dr. Milenko J. Tanasijevic, Clinical Laboratories, Brigham and Women’s Hospital, Amory building, 215 A, 75 Francis Street, Boston, Massachusetts 02115. E-mail: [email protected].
REFERENCES 1. Gruppo Italiano per lo Studio Della Streptochinasi Nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397– 401. 2. ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349 – 60. 3. The Gusto Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673– 82. 4. Braunwald E. The open-artery theory is alive and well—again. N Engl J Med 1993;329:1650 –2. 5. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615–22. 6. Cannon CP, McCabe CH, Diver DJ, et al. Comparison of frontloaded recombinant tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 Trial. TIMI 4 Investigators. J Am Coll Cardiol 1994;24:1602–10. 7. Kircher BJ, Topol EJ, O’Neill WW, Pitt B. Prediction of infarct coronary artery recanalization after intravenous thrombolytic therapy. Am J Cardiol 1987;59:513–5. 8. Califf RM, O’Neil W, Stack RS, et al. Failure of simple clinical measurements to predict perfusion status after intravenous thrombolysis. Ann Int Med 1988;108:658 – 62. 9. Garabedian HD, Gold HK, Yasuda T, et al. Detection of coronary artery reperfusion with creatine kinase-MB determinations during thrombolytic therapy: correlation with acute angiography. J Am Coll Cardiol 1988;11:729 –34. 10. Lewis BS, Ganz W, Laramee P, et al. Usefulness of a rapid initial increase in plasma creatine kinase activity as a marker of reperfusion during thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1988;62:20 – 4. 11. Ohman EM, Christenson RH, Califf RM, et al. Noninvasive detection of reperfusion after thrombolysis based on serum creatine kinase MB changes and clinical variables. TAMI 7 Study Group. Am Heart J 1993;126:819 –26. 12. Tanasijevic MJ, Cannon CP, Wybenga DR, et al., for the TIMI 10A Investigators. Myoglobin, CK-MB and cardiac Troponin-I for noninvasive assessment of reperfusion after thrombolysis for acute myocardial infarction. Results from TIMI 10A. Am Heart J 1997;134: 622–30. 13. Hohnloser SH, Zabel M, Kasper W, Meinertz T, Just H. Assessment
JACC Vol. 34, No. 3, 1999 September 1999:739–47
14. 15. 16.
17.
18.
19. 20.
21. 22. 23. 24.
25. 26.
27. 28.
29. 30. 31. 32. 33.
34.
of coronary artery patency after thrombolytic therapy: accurate prediction utilizing the combined analysis of three noninvasive markers. J Am Coll Cardiol 1991;18:44 –9. Ellis AK, Little T, Masud AR, Klocke FJ. Patterns of myoglobin release after reperfusion of injured myocardium. Circulation 1985;72: 639 – 47. Ellis AK, Little T, Masud AR, Liberman HA, Morris DC, Klocke FJ. Early noninvasive detection of successful reperfusion in patients with acute myocardial infarction. Circulation 1988;78:1352–7. Ishii J, Nomura M, Ando T, et al. Early detection of successful coronary reperfusion based on serum myoglobin concentration: comparison with serum creatine kinase isoenzyme MB activity. Am Heart J 1994;128:641– 8. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac Troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol 1991;67:1360 –7. Zabel M, Hohnloser SH, Koster W, Prinz M, Kasper W, Just H. Analysis of creatine kinase, CK-MB, myoglobin, and troponin T time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation 1993;87:1542–50. Remppis A, Scheffold T, Karrer O, et al. Assessment of reperfusion of the infarct zone after acute myocardial infarction by serial cardiac troponin T measurements in serum. Br Heart J 1994;71:242– 8. Apple FS, Voss E, Lund L, Preese L, Berger CR, Henry TD. Cardiac troponin, CK-MB and myoglobin for the early detection of acute myocardial infarction and monitoring of reperfusion following thrombolytic therapy. Clin Chim Acta 1995;237:59 – 66. Puleo PR, Perryman MB, Bresser MA, Rokey R, Pratt CM, Roberts R. Creatine kinase isoform analysis in the detection and assessment of thrombolysis in man. Circulation 1987;75:1162–9. Christenson RH, Ohman EM, Topol EJ, et al. Creatine kinase MM and MB isoforms in patients receiving thrombolytic therapy and acute angiography. TAMI Study Group. Clin Chem 1995;41:844 –52. Apple FS, Henry TD, Berger CR, Landt YA. Early monitoring of serum cardiac Troponin I for assessment of coronary reperfusion following thrombolytic therapy. Am J Clin Pathol 1996;105:6 –10. Katus HA, Diederich KW, Scheffold T, Uellner M, Schwarz F, Kubler W. Non-invasive assessment of infarct reperfusion: the predictive power of the time to peak value of myoglobin, CKMB, and CK in serum. Eur Heart J 1988;9:619 –24. Laperche T, Steg PG, Dehoux M, et al. A study of biochemical markers of reperfusion early after thrombolysis for acute myocardial infarction. The PERM Study Group. Circulation 1995;92:2079 – 86. Cannon CP, Gibson M, McCabe CH, et al. TNK-Tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B Trial. TIMI 10B Investigators. Circulation 1998;98:2805–14. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) Trial. Phase I findings. N Engl J Med 1985;312:932– 6. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of monoclonal antibodies for an assay of cardiac Troponin I and preliminary results in suspected cases of myocardial infarction. Clin Chem 1992;38:2203–14. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific Troponin-I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342–9. Adams JE, Bodor GS, Davilla-Roman VG, et al. Cardiac Troponin I: a marker with high specificity for cardiac injury. Circulation 1993;88: 101– 6. Silva DP, Landt Y, Porter SE, Ladenson JH. Development and application of monoclonal antibodies to human cardiac myoglobin in a rapid fluorescence immunoassay. Clin Chem 1991;37:1356 – 64. Woo J, Lacbawan FL, Sunheimer R, LeFever D, McCabe JB. Is myoglobin useful in the diagnosis of acute myocardial infarction in the emergency department setting? Am J Clin Pathol 1995;103:725–9. Vaidya HC, Maynard Y, Dietzler DN, Ladenson JH. Direct measurement of creatine kinase-MB activity in serum after extraction with a monoclonal antibody specific to the MB isoenzyme. Clin Chem 1986;32:657– 63. Chapelle JP, El Allaf M. Automated quantification of creatine kinase MB isoenzyme in serum by radial partition immunoassay, with use of the Stratus analyzer. Clin Chem 1990;36:99 –101.
JACC Vol. 34, No. 3, 1999 September 1999:739–47 35. Hanley JA, Mcneil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143: 29 –36. 36. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival. Should the paradigm be expanded? Circulation 1989;79:441– 4. 37. Miyata M, Abe S, Arima S, et al. Rapid diagnosis of coronary reperfusion by measurement of myoglobin level every 15 min in acute myocardial infarction. J Am Coll Cardiol 1994;23:1009 –15. 38. Lavin F, Kane M, Forde A, Gannon F, Daly K. Comparison of five
Tanasijevic et al. Cardiac Markers in Thrombolysis
747
cardiac markers in the detection of reperfusion after thrombolysis in acute myocardial infarction. Br Heart J 1995;73:422–7. 39. Vaananen HK, Syrjala H, Rahkila P, Vuori J, et al. Serum carbonic anhydrase III and myoglobin concentrations in acute myocardial infarction. Clin Chem 1990;36:635– 8. 40. Adams JE, Schechtman KB, Landt Y, Ladenson JH, Jaffe AS. Comparable detection of acute myocardial infarction by creatine kinase MB isoenzyme and cardiac Troponin I. Clin Chem 1994;40:1291–5. 41. Krucoff MW, Green CE, Satler LF, et al. Noninvasive detection of coronary artery patency using continuous ST-segment monitoring. Am J Cardiol 1986;57:916 –22.