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(Circulation. 1997;96:1776-1782.)
© 1997 American Heart Association, Inc.

Articles

Assessment of Coronary Reperfusion After Thrombolysis With a Model Combining Myoglobin, Creatine Kinase–MB, and Clinical Variables

Robert H. Christenson, PhD; E. Magnus Ohman, MD; Eric J. Topol, MD; Steven Peck, PhD; L. Kristin Newby, MD; Show-Hong Duh, PhD; Dean J. Kereiakes, MD; Seth J. Worley, MD; Gladys L. Alosozana, MD; Thomas C. Wall, MD; Robert M. Califf, MD; ; 7 Study Group ;

From the Department of Pathology (R.H.C., S.-H.D., G.L.A.), University of Maryland School of Medicine, Baltimore; Department of Medicine (E.M.O., S.P., L.K.N., R.M.C.), Division of Cardiology, Duke University Medical Center, Durham, NC; Department of Cardiology (E.J.T.), Cleveland Clinic Foundation, Cleveland, Ohio; The Christ Hospital (D.J.K.), Cincinnati, Ohio; Lancaster (Pa) General Hospital (S.J.W.); and Moses Cone Hospital (T.C.W.), Greensboro, NC.

Correspondence to Dr Robert H. Christenson, Clinical Pathology, University of Maryland Medical Center, 22 S Greene St, Baltimore, MD 21201.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Several biochemical markers have been investigated for the noninvasive assessment of reperfusion after myocardial infarction. Because myoglobin is released very soon after myocardial injury and clears rapidly after reperfusion, it may prove to be an excellent marker of occlusion and reperfusion.

Methods and Results We examined the relation between various myoglobin measures and Thrombolysis In Myocardial Infarction (TIMI) flow grade in 96 patients enrolled in a study of front-loaded thrombolysis who underwent 90-minute angiography. We also combined myoglobin measures with models that include clinical and creatine kinase–MB variables. The myoglobin level measured within 10 minutes of acute angiography showed the best overall performance and was used for later analyses. Of the clinical variables examined, only time from symptom onset to thrombolysis and chest pain grade at angiography discriminated among TIMI flow grades. Combining the 90-minute myoglobin level and these clinical variables showed a significant difference (P<.0001) between both TIMI 3 versus TIMI 0 through 2 and TIMI 2 or 3 versus TIMI 0 or 1 flow. When the 90-minute myoglobin level was added to an established predictive model containing clinical variables and creatine kinase–MB measures, its contribution remained significant (P=.044). The area under the receiver operator characteristic curve for this combined model was .88.

Conclusions A single myoglobin measurement obtained 90 minutes after the start of thrombolysis, combined with select clinical variables and creatine kinase–MB levels, enhances the noninvasive prediction of reperfusion after myocardial infarction.

Key Words: creatine kinase • myoglobin • reperfusion • thrombolysis

	Introduction

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The importance of establishing coronary artery reperfusion with thrombolytic agents has been demonstrated clearly.^{1 2 3 4 5} The "open-artery hypothesis" has been proven by better outcomes^{6 7 8 9} and increased left ventricular function¹⁰ as a result of reestablishment of patency in the coronary artery responsible for the MI. Thus, assessment of coronary patency is important because rescue angioplasty or another intervention may be appropriate if thrombolysis fails.^{6 7 8 9 10 11}

Coronary angiography remains the "gold standard" for assessment of coronary patency. However, because it is associated with high cost, limited availability, and increased morbidity when performed acutely, this invasive procedure is not practical or prudent for all patients receiving thrombolytic therapy.^{12 13 14 15} Hence, there is substantial interest in noninvasive methods to identify the 20% to 25% of patients in whom the coronary occlusion persists.^{5 7} Clinical indicators such as cessation of pain and "reperfusion" arrhythmias have been proposed as noninvasive markers of coronary artery patency; however, these indicators alone were found to be relatively unreliable.^{16 17 18 19}

There has been substantial interest in biochemical markers such as CK-MB,^{20 21 22 23 24} the MM and MB subtypes of creatine kinase,^{25 26 27 28} and troponin T²⁹ for the noninvasive assessment of reperfusion. However, no biochemical marker shows the early release characteristics of myoglobin, which is elevated as early as 1 hour after myocardial injury^{30 31 32} and is washed out rapidly after coronary reperfusion.^{30 32 33 34 35 36}

CK-MB release measurement strategies, including a single sample obtained 90 minutes after thrombolytic therapy, (90-minute value/prethrombolytic therapy level), slope of CK-MB release, and CK-MB ratio (90-minute value/prethrombolytic level), have been compared directly.²⁰ Of these, the slope of CK-MB release yielded the greatest separation between groups of patients having TIMI 0 or 1 and TIMI 2 or 3 flow (²=12.9, P<.0003).²⁰

In the present study, we examined various myoglobin measures in a cohort of MI patients who received thrombolytic therapy and underwent acute angiography. We sought to identify the value of myoglobin and the CK-MB release measurement strategy, in combination with clinical variables, for the noninvasive assessment of patency after thrombolysis.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Population
Of the total 207 patients enrolled in the TAMI-7 study of accelerated tissue plasminogen activator dose regimens,³⁷ 96 had blood specimens collected within 10 minutes of cardiac catheterization and were included in the present study. TAMI-7 included patients younger than 76 years old who had symptoms of acute MI for <6 hours and ECG ST-segment elevation; excluded were patients with prior stroke, bleeding diathesis, recent surgery or trauma, uncontrolled hypertension, or prior Q-wave infarction in the same ECG distribution. The procedures followed in TAMI-7 were in accordance with each participating center's Institutional Review Board policies.

Acute Coronary Angiography
To evaluate patency in the infarct-related artery, all patients were to undergo acute angiography 90 minutes after thrombolytic therapy was given. Coronary blood flow in the infarct-related artery was graded according to the TIMI classifications.⁴ Two classifications of successful reperfusion were analyzed. The first defined reperfusion as TIMI grade 2 or 3 flow in the infarct artery; grade 0 or 1 flow denoted failed thrombolysis. The second defined reperfusion as only TIMI grade 3 flow in the infarct artery; grade 0, 1, or 2 flow was considered unsuccessful thrombolysis.^{38 39} All angiograms were interpreted in the angiographic core laboratory by personnel blinded to the enzyme results and patient information.

Specimen Collection
Blood was collected in tubes containing no anticoagulant, allowed to clot, and centrifuged at 1000g for 10 minutes. The resulting serum aliquots were poured into freezer vials, then frozen within 90 minutes and maintained at -70°C until analysis. Blood was collected at the following time windows: baseline, ranging between 0 and 10 minutes from the start of thrombolytic therapy (mean±SD, 0.14±1.02 minutes; median [25th, 75th percentiles], 0 [0, 0] minutes); 30 minutes, which was defined as 12 to 60 minutes after beginning thrombolytic therapy (34.3±8.03 and 32 [30, 37] minutes); 90 minutes, defined as 62 to 135 minutes after thrombolytic therapy (97.7±16 and 93 [89, 105 minutes]); and 3 hours, defined as 138 to 239 minutes after thrombolytic therapy (175±26.8 and 175 [152, 195] minutes). All 96 of the patients in this study had a specimen collected within 10 minutes of acute angiography; this blood specimen is subsequently referred to as the "near-catheterization" sample. Specimens were categorized according to these time windows; however, the exact time of collection was recorded for all specimens and used to calculate rates of release (slopes) and other time-dependent variables. For myoglobin measurement, the near-catheterization and baseline specimens were used for analysis. For the analyses that included the established model,²⁰ the other sampling times listed above were also used.

Myoglobin Measurement
All myoglobin measurements were performed with the instrumentation and associated reagents available with the Stratus II system (Dade International, Inc). This quantitative 10-minute assay uses two monoclonal antibodies in a "sandwich" radial-partition immunoassay format. The detection limit of this test is 2.2 µg/L, and the typical coefficient of variation is 5%. Other characteristics of this assay have been defined elsewhere.⁴⁰

Myoglobin Variables
We performed analyses with the following four myoglobin variables:

Ratio. The myoglobin value in the near-catheterization sample divided by the value in the baseline sample (Ratio=Near Catheterization/Baseline).

. The difference in myoglobin value between the near-catheterization and the baseline samples (=Near Catheterization-Baseline).

Slope. The rate of myoglobin release from baseline to near catheterization (Slope=[Near Catheterization-Baseline]/Elapsed Time).

Near-catheterization value. The myoglobin concentration in the near-catheterization sample.

Clinical Variables
The age, sex, race, time from symptom onset to thrombolytic therapy, time of first dye injection for angiography, and ECG location of infarction were recorded for all patients enrolled in TAMI-7. In addition, patients graded the intensity of their infarction-related pain on a scale of 0 (no pain) to 10 at the time of acute catheterization.

CK-MB Measurement
All reported CK-MB measurements were quantified with devices and associated reagents available with the ICON CK-MB kit (Hybritech, Inc) and were performed according to the manufacturer's instructions. This two-site immunoassay, or mass assay, has a claimed detection limit of 2 ng/L; all values <2 ng/L were reported as 0 ng/L. All analyses were performed in an enzymatic core laboratory by personnel who were unaware of the treatment or patency status of the patients.

Statistical Analysis
Continuous variables are presented as mean±SD and medians with 25th and 75th percentiles. Discrete variables are expressed as percentages. Only patients who had blood collected at least twice before acute angiography were included in the analysis. Logistic multiple regression was used to construct predictive models for patency.⁴¹ The following models were constructed: the myoglobin variables alone, selected clinical variables, myoglobin and clinical variables combined, and myoglobin combined with an established model that contains CK-MB slope, time from chest pain onset to thrombolytic therapy, and chest pain grade (from 0 to 10, with 0 being no pain) at catheterization.²⁰ A C-index, which reflects the area under the ROC curve, was calculated for each model to evaluate its ability to predict patency. In all analyses, P<.05 was considered significant. All statistics and plots were generated using S-Plus 3.3 software (Statistical Sciences, Inc).

	Results

Top Abstract Introduction Methods Results Discussion References

 
The baseline characteristics of the 96 patients are shown in Table 1 according to TIMI flow grade at 90 minutes. There were significant differences among the groups with regard to chest pain grade at catheterization and time from chest pain onset to thrombolytic therapy.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics in the TAMI-7 Study

The discriminating abilities of the ratio, , slope, and near-catheterization myoglobin variables to predict patency in the infarct-related artery are indicated in Table 2. The near-catherization variable, which represented a single myoglobin measurement, demonstrated the best overall performance and was used for all subsequent analyses. For the near-catherization myoglobin variable alone, logistic regression model output for TIMI grade 3 flow ranged from 0.21 to 0.68 (0.28/0.44/0.68, 25th percentile/median/75th percentile) versus a range of 0.27 to 0.68 (0.49/0.68/0.68) for TIMI grade 0, 1, or 2 flow. When the TIMI 2 or 3 patency group was considered successful reperfusion, model output ranged from 0.11 to 0.68 (0.11/0.11/0.27), whereas the TIMI 0 or 1 group ranged from 0.11 to 0.62 (0.21/0.46/0.56).

View this table: [in this window] [in a new window]   Table 2. Strategies for Discrimination of Patency With Myoglobin Only

Table 3 displays the results for all patients having measurements of myoglobin in the near-catherization sample, graded chest pain at catheterization, and time from chest pain to thrombolytic therapy variables as well as the results from combining these variables. Myoglobin measurement in the near-catherization sample contributed significantly to the ability of the model to discriminate patency both alone and in combination with the other variables. The C-index values for the combined model were .82 and .71 for the discrimination of TIMI grade 2 or 3 flow versus grade 0 or 1 flow and TIMI grade 3 versus grade 0 or 2 flow, respectively.

View this table: [in this window] [in a new window]   Table 3. Modeling With Myoglobin and Clinical Variables

Fig 1 (A and B) displays the distribution of patient data from the logistic regression model combining the near-catherization myoglobin level and the clinical variables of time from chest pain to thrombolytic therapy and chest pain graded from 0 to 10. In Fig 1A, patency classified as TIMI 3 flow showed model output results that were 0.31/0.42/0.64 (25th percentile/median/75th percentile) and 0.52/0.66/0.72 for TIMI 0, 1, or 2. For Fig 1B, TIMI 2 or 3 model output values were 0.06/0.11/0.21, whereas the values were 0.31/0.40/0.58 for TIMI 0 or 1. Fig 1C and 1D show the distribution of model outputs for combining myoglobin in the near-catherization sample with the established model, which included CK-MB slope from baseline to the near-catherization time and clinical variables of time from chest pain to thrombolytic therapy and chest pain graded from 0 to 10. Fig 1C model outputs were 0.22/0.35/0.62 for TIMI 3 flow and 0.56/0.63/0.70 for TIMI 0, 1, or 2 flow. For Fig 1D, the model output values were 0.04/0.08/0.17 for TIMI 2 or 3 flow and 0.33/0.44/0.78 for TIMI 0-1 flow.

View larger version (0K): [in this window] [in a new window]   Figure 1. Box-and-whiskers plots showing the range (whiskers) and 25th percentile/median/75th percentile (box) of predicted probabilities from the logistic regression model for open- and closed-artery patient groups. A, Predicted probabilities resulting from modeling myoglobin plus clinical variables for TIMI 3 versus TIMI 0, 1, or 2 patency. B, Predicted probabilities for modeling myoglobin plus clinical variables for TIMI 2 or 3 versus TIMI 0 or 1 patency. C, Predicted probabilities for the established model plus near-catheterization myoglobin for TIMI 3 versus TIMI 0, 1, or 2 patency. D, Predicted probabilities resulting from the established model plus near-catheterization myoglobin for TIMI 2 or 3 versus TIMI 0 or 1 patency. The broken lines in Fig 1D correspond to various cutoffs indicated in the ROC curve plotted in Fig 2. Myoglobin refers to a single myoglobin value in a blood sample obtained within 10 minutes of cardiac catheterization. Clinical variables included were time from chest pain to thrombolytic therapy, and chest pain graded from 0 to 10. Established model refers to a published model20 that included CK-MB slope between baseline and the near-catheterization time and clinical variables including time from chest pain to thrombolytic therapy and chest pain graded from 0 to 10.

Fig 2 displays the ROC curve for the plot displayed in Fig 1D. By standard ROC curve interpretation, the model output of 0.24 indicated in both Fig 1D and Fig 2 would be considered the optimum decision limit if the consequences of false-negative results (predicting the artery is open when it is actually closed) and false-positive results (predicting the artery is closed when it is actually open) were equal. At this example of a decision limit, 18 of the 71 open-artery patients and 5 of the 25 closed-artery patients (24% overall) would have been misclassified. Positions on the ROC curve corresponding to higher sensitivity (model output of 0.10) and higher specificity (model output of 0.40) are also indicated in both Fig 2 and Fig 1D. At the output value of 0.1, 39 of the 71 open-artery patients and 3 of the 25 closed-artery patients would have been misclassified (43.7% overall); at an output of 0.4, 14 of the 71 open-artery patients and 15 of the 25 closed-artery patients would have been misclassified (30.2% overall).

View larger version (0K): [in this window] [in a new window]   Figure 2. ROC curve for assessing performance of the established model (CK-MB slope and clinical variables) plus near-catheterization myoglobin for predicting TIMI 2 or 3 versus TIMI 0 or 1 patency. This ROC curve represents the data displayed in Fig 1D; the points indicated on the curve correspond to the broken lines in Fig 1D.

Table 4 shows the performance of a model that combined near-catherization myoglobin with an established model that included clinical variables and CK-MB slope measures.²⁰ The contribution of near-catherization myoglobin to this combined model was significant, having a ² of 4.04 (P=.044). When the 28 patients having TIMI 1 and 2 flow were considered nonexistent, a C-index of .93 resulted for the near-catherization myoglobin sample combined with the established model; the contribution of myoglobin remained significant (²=5.19; P<.023).

View this table: [in this window] [in a new window]   Table 4. Comparison of Myoglobin and an Established Model for the Prediction of Reperfusion

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Myoglobin, alone or in combination with other biochemical markers, has been investigated for noninvasive assessment of myocardial perfusion after thrombolytic therapy.^{21 22 24 27 28 30 33 34 35 36} The present study included early and frequent myoglobin sampling in patients whose infarct-artery patency status was confirmed by angiography. Building on an established strategy that included the slope of CK-MB release and clinical variables,²⁰ we showed that inclusion of a second biochemical marker, ie, a single myoglobin measurement obtained 90 minutes after beginning thrombolytic therapy, contributed significant information, as shown in Table 4.

Recent reports have indicated that TIMI grade 3 blood flow results in improved patient outcomes compared with TIMI grade 2 flow.³⁸ The improved survival of patients with TIMI grade 3 flow provides indirect evidence that TIMI grade 2 flow represents an intermediate point between grade 0 or 1 flow and grade 3 flow.^{38 39} For this reason, we examined the data considering successful reperfusion both as TIMI grade 3 flow only and as the original TAMI-7 end point of TIMI grade 2 or 3 flow.³⁷ As shown in Table 2, the C-index values for the more rigorous definition of TIMI grade 3 flow alone were less satisfactory, and thus discriminating TIMI grade 3 from TIMI grade 0 or 2 may be problematic for clinical use, even with the approach presented here.

Among the various myoglobin variables examined, the single value collected between 60 and 150 minutes after initiating thrombolytic therapy had the best performance for indicating successful reperfusion. This single-sample strategy also represents the most convenient and least costly alternative. The near-catherization myoglobin sample alone and combined strategies were compared using the C-index, which directly corresponds to the area under the ROC curve. When tests or strategies are compared, those having the largest C-index (approaching unity) demonstrate the best diagnostic performance. The C-index values for the near-catheterization myoglobin sample alone were .78 and .73 for the prediction of TIMI grade 2 or 3 versus grade 0 or 1 flow and TIMI grade 3 versus grade 0, 1, or 2 flow, respectively. All other strategies included more than one myoglobin level; these additional measurements did not contribute substantial additional prognostic information and would be more expensive.

Selected clinical variables by themselves have been reported to show significant ability to discriminate between patients with TIMI grade 0 or 1 flow and those with grade 2 or 3 coronary flow; however, these indicators are unreliable for routine clinical use.¹⁶ We found that clinical variables, including chest pain graded from 0 to 10 at catheterization and time from symptom onset to thrombolytic therapy, achieved significance for indicating reperfusion. These clinical variables added to the performance of the near-catheterization myoglobin sample, as shown by the respective C-index values of .82 for TIMI grade 2 or 3 versus 0 or 1 flow and .71 for TIMI grade 3 versus grade 0, 1, or 2 flow.

Obtaining a myoglobin measurement significantly contributed to an established model that included serial CK-MB measurements and clinical variables.²⁰ In the present study, the combined model that included the near-catheterization myoglobin value, CK-MB slope, and clinical variables had the largest C-index values for indicating successful reperfusion: .88 for TIMI grade 2 or 3 blood flow (versus grade 0 or 1 flow) and .74 for TIMI grade 3 flow (versus grade 0, 1, or 2 flow).

The ROC curve displayed in Fig 2 indicates three examples of decision limits. If the consequences of a false-positive result (predicting the artery is closed when it is actually open) or false-negative result (predicting that the artery is open when it is closed) are equal, then the optimum decision limit would be a model output of 0.24; 24% of patients would have been misclassified at this decision limit. Use of the other decision limits indicated in Fig 2 will either improve sensitivity at the expense of specificity or improve specificity at the expense of sensitivity. For example, when model output is changed from 0.24 to 0.1, the number of false negatives decreased by 2 from 5 to 3 (40% improvement); however, false-positive results increased by 21 from 18 to 39 (117%). When model output is changed from 0.24 to 0.4, the number of false positives decreased by 4 from 18 to 14 (22% improvement); on the other hand, false-negative results increased by 10 from 5 to 15 (200%). Clearly there is a need to test any potential decision limits derived from the present study in an appropriately designed prospective trial.

Although combining near-catheterization myoglobin samples, CK-MB, and clinical variables yielded a C-index of .88, the model will not accurately predict reperfusion status in all patients. This may be unavoidable for at least three physiologically based reasons. First, strategies that use biochemical markers are based on differences in the washout phenomenon that occurs after patency has been reestablished.⁴² The washout model often used to characterize biochemical markers showing promise for the assessment of patency is acute angioplasty. However, this model may not rigorously simulate the washout phenomenon that occurs after thrombolytic therapy, because angioplasty restores patency abruptly, resulting in dramatic increases in the biochemical markers.⁴³ In contrast, the restoration of patency after thrombolytic therapy is a more dynamic process in which many patients have repeated opening and closing of the infarct-related artery in a stuttering pattern. Intermittent patency is probably caused by alterations in coagulation factors, platelet function, or other potentiating factors that affect procoagulant activity and contractility of coronary arterial muscle, which could blunt the washout of biochemical markers. Second, individual patient variables such as extent of infarction, collateral flow to the infarcted area, and blood pressure may influence noninvasive strategies for assessing patency. A third issue involves the use of angiography to adjudicate patency. Although it is the "gold standard" for evaluating coronary patency, angiography cannot show how long the measured perfusion status has existed in the infarct-related artery, which would influence washout. Thus, some discrepancy must be expected because of the dynamic physiological nature of patency restoration after thrombolytic therapy and the uncertainties in angiographic measurement.

Limitations
This study included 96 patients, which must be considered a relatively small sample. The C-index values resulted from multiple comparisons and may be lower in actual practice. Thus, these data must be considered a "learning" data set that should be validated prospectively.

Although the state-of-the-art mass assay used for CK-MB measurement in the present study demonstrates good correlation with other CK-MB tests, we have also shown that results of CK-MB curves can show significant differences despite good agreement.⁴⁴ This issue, which may be true for myoglobin as well, indicates that the models developed are valid only for the assays used.

The combined model used to predict patency includes data from both the laboratory and clinical areas. For effective use, facile means of combining these data must be developed with future technology.

The present study shows that a single myoglobin measurement obtained between 60 and 150 minutes after thrombolytic therapy adds significantly to a model that includes CK-MB levels and clinical variables. The high C-index for this strategy suggests that it may provide an important clinical tool to assess patency after thrombolytic therapy.

	Selected Abbreviations and Acronyms

 

C-index = concordance probability index CK-MB = creatine kinase–MB MI = myocardial infarction ROC = receiver operator characteristic TAMI-7 = Thrombolysis and Angioplasty in Myocardial Infarction-7 TIMI = Thrombolysis In Myocardial Infarction

	Acknowledgments

 
The TAMI-7 study was funded in part by grants from Hybritech Inc, San Diego, Calif; Genentech, Inc, South San Francisco, Calif; and Eli Lilly, Indianapolis, Ind. The authors gratefully acknowledge the exceptional contributions of Carol K. Pizzo (technical assistance) and Pat Williams (editorial assistance).

Received December 16, 1996; revision received April 14, 1997; accepted April 18, 1997.

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