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Background Ruling out myocardial infarction in patients coming to the emergency room with chest pain is hindered by the lack of a specific early diagnostic marker. Less than 30 percent of patients admitted to coronary care units have infarction, resulting in substantial unnecessary expenditures. We developed a rapid assay of the subforms of creatine kinase MB (CK-MB) and prospectively analyzed its sensitivity and specificity in diagnosing myocardial infarction in the first six hours after the onset of chest pain.
Methods In 1110 consecutive patients who came to the emergency room with chest pain, blood samples were collected every 30 to 60 minutes until at least 6 hours after the onset of symptoms; in patients who were then admitted to the hospital, samples were collected every 4 hours for up to 48 hours. The samples were analyzed for CK-MB subforms, and the diagnosis of myocardial infarction was confirmed by conventional CK-MB analysis.
Results Of the 1110 patients evaluated, 121 had myocardial infarction. The sensitivity of the assay of CK-MB subforms to detect myocardial infarction in the first six hours after the onset of symptoms was 95.7 percent, as compared with only 48 percent for the conventional CK-MB assay; the specificity was 93.9 percent among patients hospitalized without myocardial infarction and 96.2 percent among those sent home. Among the patients with myocardial infarction, definitive results of the subform assay were available a mean (±SD) of 1.22 ±1.17 hours after their arrival in the emergency room.
Conclusions The assay of CK-MB subforms reliably detected myocardial infarction within the first six hours after the onset of symptoms, and its use could reduce admission to the coronary care unit by 50 to 70 percent, thereby reducing costs. .
In the initial hours after the onset of myocardial infarction, the amount of CK-MB released from the myocardium is minimal; it is diluted by the circulatory volume and is often not enough to exceed the upper limit of the normal range of values11,12. Although there is only one form13 of CK-MB in myocardial tissue (CK-MB2), on its release into the blood, lysine carboxypeptidase cleaves the positively charged terminal lysine from the M subunit,14 producing a more negatively charged molecule (CK-MB1). Normally, CK-MB2 and CK-MB1 are in equilibrium, and the absolute levels may be as low as 0.5 to 1 U per liter11,12. With the use of a rapid assay for CK-MB subforms,11 we showed that a CK-MB2 level 
1.0 U per liter, with a ratio of CK-MB2 to CK-MB1 1.5, provides improved sensitivity and specificity for the diagnosis of myocardial infarction within six hours after the onset of symptoms, as compared with the sensitivity and specificity of conventional assays for total CK-MB11,12. We prospectively analyzed the sensitivity and specificity of this subform assay in detecting myocardial infarction within six hours after the onset of symptoms in patients with suspected myocardial infarction seen in the emergency room.
Methods
Study Design
Patients evaluated in the emergency room of Ben Taub General Hospital in Houston for chest pain occurring at rest during the preceding 24 hours and lasting at least 30 minutes were eligible for enrollment. All patients were required to sign consent forms of the Baylor College of Medicine Institutional Review Board before enrolling in the study. Patients suspected of having myocardial infarction were monitored for cardiac rhythm, if necessary, in the emergency room. Enrollment was consecutive, with the exception that patients who needed intravenous vasopressor therapy or mechanical ventilation or had been resuscitated after cardiac arrest were excluded.
Blood samples were obtained every 30 to 60 minutes until at least 6 hours had elapsed since the onset of chest pain; among patients subsequently admitted to the hospital, blood samples were obtained every 4 hours for up to 48 hours. The samples were collected in vacuum tubes pretreated with preservatives, as previously reported11. The assay for plasma MB2 and MB1 activity was performed with rapid high-voltage electrophoresis on an automated analyzer (Rep, Helena Laboratories, Beaumont, Tex.)11; the performance time was 25 minutes. CK-MB subforms to be used as standards were initially purified from human myocardium15 and generated with the use of lysine carboxypeptidase, but more recently, they have been produced in recombinant form16. Blood samples were analyzed for total CK-MB activity by the hospital laboratory with the quantitative glass-bead assay,17,18 which has an upper limit of normal of 14 U per liter.
At the discretion of the physicians in the emergency room, patients were admitted to the coronary care unit or a non-coronary care medical unit or were discharged home. Those with abnormal electrocardiograms and a history of chest discomfort consistent with myocardial ischemia were generally admitted to the coronary care unit. Patients with pain suggestive of myocardial ischemia, a normal electrocardiogram, and no history of documented coronary disease were admitted to an intermediate-care unit for continuous electrocardiographic monitoring. Patients with pain thought to be noncardiac in origin were admitted to a general medical unit or sent home at the discretion of the emergency room physicians. The diagnostic evaluation and care of all patients were conducted by physicians who were unaware of the results of the assays for CK-MB subforms, and the subform assays were performed by personnel who were unaware of the clinical outcomes in the patients and other clinical data, including the results of the routine assays of total CK-MB. Among patients admitted to the hospital, the final clinical diagnosis was determined by the team of the coronary care unit or, in the case of patients admitted to the general medical unit, by a cardiology consultant. The type of infarction (Q wave or non-Q wave) was determined from the electrocardiogram19,20.
For each patient, the results of the assay for CK-MB subforms and the conventional assay of total CK-MB were analyzed separately and independently by at least two of the investigators without knowledge of the clinical findings. The diagnosis of myocardial infarction was confirmed or excluded solely on the basis of abnormal or normal total CK-MB activity, respectively, according to criteria that have been outlined previously18,21. The criteria for myocardial infarction were as follows: a CK-MB level 14 U per liter in two or more sequential blood samples obtained 6 to 12 hours apart; a CK-MB level 14 U per liter in a single sample, if the value represented a threefold increase above the previous value; and a single CK-MB value 14 U per liter if only one sample was analyzed. In all the patients with myocardial infarction, except the three who died early, serial blood samples were obtained over a period of 24 to 48 hours. The diagnostic criteria for myocardial infarction, based on the subform levels, were an MB2 level 1.0 U per liter and a ratio of MB2 to MB1 1.5, occurring within six hours after the onset of symptoms12. The diagnosis of myocardial infarction by subform analysis was confirmed if one or more samples obtained during the six-hour interval met the subform criteria and was excluded if none of the samples obtained during that interval met the subform criteria.
Statistical Analysis
The statistical significance of differences in the time from the onset of symptoms to arrival in the emergency room between patients with myocardial infarction and patients without myocardial infarction was determined by the (two-sample) Wilcoxon test22. The significance of differences in the proportions of male patients in the group with myocardial infarction and in the group without infarction was determined by chi-square analysis22. Exact confidence intervals for binomial proportion were calculated for sensitivity and specificity22. Confidence intervals for the relative risk of myocardial infarction were determined from the log transformation of relative risk23. The receiver operating characteristics were calculated as previously described22. All P values are based on two-sided comparisons.
Results
During the 14-month study period, 5741 blood samples were obtained from 1110 consecutive patients evaluated in the emergency room because of chest pain that had occurred within 24 hours before their arrival. The diagnosis of myocardial infarction was confirmed in 121 of the patients. A total of 531 patients (47.8 percent) were admitted to the coronary care unit; 118 received a subsequent diagnosis of myocardial infarction confirmed by serial elevation of plasma CK-MB levels; in the other 413 patients, myocardial infarction was ruled out. Of the 129 patients (11.6 percent) admitted to an inpatient unit other than the coronary care unit, 3 subsequently received a diagnosis of myocardial infarction. A total of 450 patients (40.5 percent) were discharged home from the emergency room. Thus, 121 patients received a subsequent diagnosis of myocardial infarction (65 with Q-wave infarction and 56 with non-Q-wave infarction), of whom 118 were admitted to the coronary care unit, accounting for 22.2 percent of all admissions to the coronary care unit during the study period.
Fifty-nine of the 65 patients with Q-wave infarction presented with typical ST-segment elevation; 4 of the 56 patients with non-Q-wave infarction presented with ST-segment elevation. The other patients with non-Q-wave infarction presented with either ST-segment depression or T-wave inversion. The sex and mean age of the patients are shown in Table 1. Patients with myocardial infarction presented significantly earlier after the onset of symptoms than did the patients without myocardial infarction (P<0.001) (Table 1).
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1.5 with a CK-MB2 level 1 U per liter. Although this ratio was selected on the basis of previous data,12 receiver operating characteristics were analyzed for a ratio of CK-MB2 to CK-MB1 ranging from 0.75 to 3.0 and an absolute CK-MB2 value ranging from 0.6 to 3.0 U per liter. The sensitivity was plotted against 1 minus the specificity at each diagnostic cutoff point. A similar plot was calculated for total CK-MB ranging from 5.0 to 17.0 U per liter. The receiver operating characteristics were analyzed for results four and six hours after the onset of symptoms, and at each interval the area under the curve was calculated. The assay for CK-MB subforms was consistently more sensitive than the assay for total CK-MB, with equal or greater specificity over a wide range of diagnostic cutoff points (Figure 1). The sensitivity was 95.7 percent and the specificity 93.9 percent with a ratio of CK-MB2 to CK-MB1 of 1.5 at six hours, which represents the best diagnostic cutoff value at that time. In contrast, when the same cutoff value was used four hours after the onset of symptoms, the sensitivity was only 56 percent, with a specificity of 93 percent. A ratio of 0.75 with a CK-MB2 level of 1.0 U per liter resulted in a sensitivity of 69 percent and a specificity of 91 percent. Figure 2 compares the sensitivity of the conventional CK-MB assay with that of the subform assay two hours after the onset of symptoms in the patients with myocardial infarction (0 percent [0 of 24] and 8.3 percent [2 of 24], respectively), four hours after the onset of symptoms (22.7 percent [17 of 75] and 56.0 percent [42 of 75], respectively), and six hours after the onset (47.8 percent [44 of 92] and 95.7 percent [88 of 92], respectively).
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Myocardial infarction was ruled out by the conventional assay of plasma CK-MB in 539 patients admitted to the hospital. The test of plasma CK-MB subforms was abnormal in only 33 of these patients (specificity, 93.9 percent; 99 percent confidence interval, 91 to 96 percent); 26 (78.8 percent) had unstable angina; of the other 7 patients (21.2 percent), 2 had rhabdomyolysis, 2 had hypothyroidism, and in 3 the diagnosis was unknown.
The assay of CK-MB subforms was negative in 432 of the 450 patients (96 percent) sent home from the emergency room (18 patients left the emergency room before six hours had elapsed since the onset of symptoms). The activity of plasma CK-MB subforms was abnormal in 17 of the 450 patients sent home (specificity, 96.2 percent; 99 percent confidence interval, 93 to 98 percent). Four patients were readmitted to the Ben Taub General Hospital and two were admitted to another hospital within 36 hours after their initial discharge; all six of these patients had elevated total CK-MB activity and were given the diagnosis of non-Q-wave infarction. Seven patients had no other symptoms and appeared to do well. Four patients could not be reached. Thus, the estimated false positive result of 3.8 percent is probably an overestimate, but in view of the time lapse, we could not be certain that the two sets of CK-MB values represented the same clinical event, so no changes were made in the estimate for false positive results. It is also possible that the sensitivity of the assay in patients who were discharged home was overestimated, since we had no follow-up data on patients with normal plasma CK-MB subforms who were discharged home.
For the total study population, the risk of myocardial infarction within six hours after the onset of symptoms was 164 times greater (99 percent confidence interval, 45 to 598) if the subform test was positive than if it was negative and 99 times greater (99 percent confidence interval, 27 to 359) if the patient was admitted to the hospital. The risk of death among hospitalized patients with normal plasma CK-MB subforms six or more hours after the onset of symptoms was 0.004 (99 percent confidence interval, 0.0002 to 0.018, unadjusted for the length of the hospital stay).
With an admission policy whereby patients with elevated plasma subform activity were admitted to the coronary care unit and those with normal plasma subform activity for six hours after the onset of symptoms were admitted to a non-coronary care unit, 114 of the 118 patients (96.6 percent) with myocardial infarction would have been admitted to the coronary care unit, and the total number of admissions to that unit would have been reduced from 531 to 164, a 69.1 percent reduction. Seventy percent of the patients admitted to the coronary care unit under this policy would have had myocardial infarction, as compared with 22.2 percent with the use of standard clinical criteria.
Discussion
We found that the sensitivity and specificity of a rapid assay of CK-MB subforms to diagnose myocardial infarction within six hours after the onset of symptoms were 95.7 and 93.9 percent, respectively, as compared with 48.2 and 94.0 percent, respectively, for the conventional CK-MB assay. The emergency room physicians, who were unaware of the results of the subform assay, discharged 40.5 percent of the patients home, admitted 47.8 percent to the coronary care unit, and admitted 11.6 percent to the non-coronary care unit. The frequency of myocardial infarction was 10.9 percent (121 patients), which is similar to that reported in the emergency rooms of both university and community hospitals2,3,4,5,6. Among the 450 patients discharged home, only 3.8 percent had abnormal plasma subform activity, and of the 539 patients admitted to the hospital without myocardial infarction, only 6.1 percent had abnormal plasma subform activity, of whom 79 percent had a diagnosis of unstable angina at discharge. Of the 17 patients sent home with abnormal subform activity, 6 were subsequently found to have myocardial infarction. It is possible that several of the patients with unstable angina who were admitted to the hospital had small areas of myocardial necrosis that were below the threshold of detection of the conventional assay24. However, the possibility that very small quantities of CK were released because of transient ischemia cannot be excluded25,26.
In this study the sensitivity (95.7 percent) and specificity (93.9 percent) of the subform assay indicate that it accurately identifies patients with myocardial infarction within the first six hours after the onset of symptoms. Based on high-voltage (1450 V) rather than conventional (150 V) electrophoresis, this assay is simple and highly reproducible, and it separates the subforms in six minutes, as compared with the conventional assay, which takes one hour11. The subform assay can be performed in any community hospital at a cost similar to that of standard isoenzyme electrophoresis and requires altogether only 25 minutes. An increase in the ratio of plasma CK-MM3 to plasma CK-MM1 isoforms or in the level of plasma myoglobin has also been documented in the early hours of myocardial infarction27,28,29. However, both markers are present in skeletal muscle, and their elevation in the blood is not as specific as CK-MB for detecting myocardial injury30,31. The assay of CK-MB subforms would also be expected to be falsely positive in patients with muscular dystrophy32 or severe skeletal-muscle damage,33 such as rhabdomyolysis, as we observed in two patients in our study. Although one group of investigators has reported three subforms of CK-MB,34 we have detected only two subforms in human plasma. The early detection of myocardial infarction by sensitive nonradioactive immunoassays has also been reported,35 although others have not found these assays to be useful for the diagnosis of myocardial infarction in the emergency room36.
If one were to use a system of triage based on the results of the assay for CK-MB subforms obtained within six hours after the onset of symptoms and to assume that all patients with negative results, even those with unstable angina, could be adequately cared for in a regular hospital unit, the number of patients admitted to the coronary care unit would be reduced by nearly 70 percent. Since it costs an estimated $4 billion per year to care for patients in the coronary care unit who do not have myocardial infarction, admission to a regular hospital unit would reduce the cost substantially. The cost of the subform assay is the same as that of the conventional CK-MB assay, but since testing is discontinued at six hours, this portion of the cost, albeit minor, would be reduced. Several studies have shown that the incidence of death or serious complications before discharge is low in patients in whom myocardial infarction has been ruled out,7,8,37 including those with unstable angina. Exclusion of the possibility of myocardial infarction has not been feasible in practice, since the clinical history and electrocardiographic findings lack specificity9 and conventional markers require a delay of up to 12 hours after the onset of symptoms for a reliable diagnosis of myocardial infarction9,10,12,38. Another approach has been the establishment of a special unit for the purpose of ruling out myocardial infarction,39 necessitating additional dedicated beds. Such a unit, used in combination with the assay of CK-MB subforms, would probably be efficient and cost effective.
The protocol proposed here requires no additional facilities or staff. One concern is the time patients may have to remain in the emergency room; however, this was not a problem among our patients with myocardial infarction, most of whom received the diagnosis within two hours after their arrival in the emergency room (within one hour in 57 percent). It should be emphasized that patients who have ST-segment elevation and are otherwise candidates for thrombolytic therapy should receive such therapy immediately. Among patients without myocardial infarction, a negative subform assay is not reliable unless the blood sample is obtained at least six hours after the onset of symptoms. In this study patients without myocardial infarction arrived at the emergency room much later than those with myocardial infarction; consequently, among the patients without infarction, the diagnosis was ruled out within 2 hours after their arrival (mean, 1.18 hours).
Supported in part by a grant from the American Heart Association Bugher Foundation for Molecular Biology of the Cardiovascular System (86-2216) and a Specialized Center of Research (SCOR) in Heart Failure grant (P50-HL42267) from the National Heart, Lung, and Blood Institute.
We are indebted to Kay Dunn, Ph.D., for assistance in the statistical analysis; to Sayed Jaffri, M.D., Saleem Quidwai, M.D., Glenda Sellars, Fernando Mora, M.D., Arturo Alfaro, M.D., and Leah White for technical assistance; to Debora H. Weaver and Alexandra Pinckard for assistance in the preparation of the manuscript; and to the medical house officers of Baylor College of Medicine.
Source Information
From the Department of Medicine, Section of Cardiology, Christ Hospital, Cincinnati (P.R.P.); and the Department of Medicine, Sections of Cardiology (D.M., C.W., C.B.T., S.W., R.J.H., N.A., S.D.O., J.F.T., M.B.P., R.R.) and Critical Care (J.L.Z.), Baylor College of Medicine, Houston.
Address reprint requests to Dr. Roberts at Baylor College of Medicine, 6535 Fannin, MS F905, Houston, TX 77030.
References
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Related Letters:
Subforms of Creatine Kinase MB in the Diagnosis of Myocardial Infarction
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