Ruling out acute myocardial infarction early with two serial creatine kinase-mb mass determinations

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1 European Heart Journal (1999) 20, Article No. euhj , available online at on Ruling out acute myocardial infarction early with two serial creatine kinase-mb mass determinations R. J. de Winter*, R. Bholasingh*, A. B. Nieuwenhuijs*, R. W. Koster*, R. J. G. Peters* and G. T. Sanders *Department of Cardiology, Department of Clinical Chemistry, Academic Medical Centre, University of Amsterdam, The Netherlands Aims We studied the diagnostic value for acute myocardial infarction of serial creatine kinase-mb mass measurements on admission and at 7 h after the onset of symptoms. Methods and Results Patients presenting to our chest pain unit with symptoms of <5-h duration were eligible. Patients were kept under observation at least until 12 h after onset of symptoms. Blood samples were drawn on admission and 7 and 10 h after onset of symptoms. Creatine kinase-mb mass >7 0 μg.l 1 (upper reference limit for acute myocardial infarction), or an increase >2 0 μg.l 1 (reference change value) between admission and at 7 h was considered abnormal. Of a total of 470 patients, 248 patients had acute myocardial infarction: 100 out of the 248 patients had a single creatine kinase-mb mass >7 0 μg.l 1 on admission (sensitivity 40%, 95% CI:34 46%), 234/248 patients at 7 h (sensitivity 94%, 95% CI:91 97%), and 240/248 at 10 h (sensitivity 97%, 95% CI:94 99%). At 7 h, 246/248 patients had either a single creatine kinase-mb >7 0 μg.l 1 or a significant increase between admission and 7 h (sensitivity 99%, 95% CI:98 100%). Of 222 patients without acute myocardial infarction, 214 had a normal serial creatine kinase-mb mass (specificity 96%, 95% CI:93 98%). Conclusion In patients with symptoms of <5-h duration, acute myocardial infarction can be ruled out using serial creatine kinase-mb mass taken on admission and at 7 h. (Eur Heart J 1999; 20: ) Key Words: Acute myocardial infarction, cardiac enzymes, creatine kinase MB isoenzyme, diagnosis. See page 925 for the Editorial comment on this article Introduction Early diagnosis of acute myocardial infarction may improve treatment and reduce complications. Conversely, identification of low-risk patients without myocardial infarction may allow for early triage and the rational use of intensive care facilities. Goldman et al. [1], evaluating the need for intensive care in patients with acute chest pain, showed that the risk of major complications could be estimated on the basis of clinical presentation (symptoms, physical examination, electrocardiogram) and an additional 12 h observation period. However, others have demonstrated that 4 8% of patients with myocardial infarction may be missed [2]. Patients in whom the diagnosis of myocardial infarction is missed, and who are inadvertently discharged from Revision submitted 20 November 1998, and accepted 26 November Correspondence: Robbert J. de Winter, MD, Department of Cardiology, Rm B2-137, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands X/99/ $18.00/0 the emergency department, have increased short-term mortality compared with admitted patients [3]. New rapid assays for creatine kinase-mb mass with excellent precision in the normal concentration range are now available for early and more accurate diagnosis of myocardial infarction [4 6]. We [7] and others [8,9] have shown that, with the high precision of creatine kinase- MB mass assays, a so-called reference change-value (or critical difference) can be calculated. A significant increase in serial creatine kinase-mb mass, which can occur within the reference limit, is defined as a difference larger than the reference change-value, and such an increase signifies myocardial damage [10]. Using this definition in the interpretation of serial creatine kinase-mb measurements could increase sensitivity for the early detection of myocardial damage. We have shown previously that sensitivity of a single value does not reach 100% until h after the onset of symptoms [11].In the present study, we assessed the diagnostic value of two creatine kinase-mb mass samples taken on admission and at 7 h, and the additional value of a third sample at 10 h. The study question was whether 1999 The European Society of Cardiology

2 968 R. J. de Winter et al. myocardial infarction could already be recognized or ruled out with high sensitivity on the basis of an abnormal serial creatine kinase-mb mass measured on admission and at 7 h. Methods From the 1996 database of the cardiac emergency room or chest pain unit of the Academic Medical Centre in Amsterdam (The Netherlands), all patients were reviewed with admission diagnosis of typical chest pain. Patients were included when the onset of symptoms was <5 h before admission, and when a complete series of creatine kinase-mb mass measurements was available from admission, 7 and 10 h after the onset of symptoms according to our routine protocol. Hospital records were reviewed to assess patients characteristics, in-hospital clinical course and discharge diagnosis. Acute myocardial infarction was prospectively defined according to World Health Organization criteria [12], using a typical history, definite electrocardiogram changes and an increase in creatine kinase-mb mass levels. A final diagnosis of acute myocardial infarction was retrospectively established by one of the investigators (R.B.) combining discharge diagnosis from hospital records, electrocardiogram findings and creatine kinase-mb mass results from all time points. The upper reference limit for myocardial infarction was 7 0 μg.l 1. Creatine kinase-mb mass was measured with the IMMUNO-1 analyser (Bayer, Leverkusen, Germany); the coefficient of variation was 2 5% at 5 0 μg.l 1, the turn-around time of the assay was 1 h. In all patients, creatine kinase-mb mass was measured on admission and at 7 and 10 h. When creatine kinase- MB mass at any of these three time points was >7 0 μg.l 1 or when a significant increase between the two samples (>2 0 μg.l 1 ) was present, patients were admitted to the cardiac care unit and additional creatine kinase-mb measurements were made at 12 h and at 4 h intervals thereafter until a peak value was reached. Patients who had recurrent symptoms with concomitant electrocardiographic changes while under observation in the cardiac emergency room were diagnosed as severely unstable angina and admitted to the coronary care unit irrespective of creatine kinase-mb mass results, as were all other patients in whom the attending cardiologist decided that coronary care unit monitoring was necessary. Patients without evidence of myocardial damage, and without recurrent symptoms while under observation until 12 h after the onset of symptoms, were usually discharged. Symptom-limited exercise tests, echocardiograms or other diagnostic procedures before discharge from the cardiac emergency room were ordered at the discretion of the attending cardiologist. Interpretation of serial creatine kinase-mb mass samples was as follows: creatine kinase-mb mass >7 0 μg.l 1 were considered indicative of myocardial infarction. A difference between admission and 7 h >2 0 μg.l 1 (significant increase), was considered abnormal (Fig. 1). A creatine kinase-mb mass 7 0 μg.l 1 both on admission and at 7 h in combination with a difference between admission and 7 h 2 0 μg.l 1 (no significant increase), was considered normal. Sensitivity for the detection of myocardial infarction (a diagnosis which included a creatine kinase- MB mass >7 0 μg.l 1 on admission, at 7 h, 10 h, or any time point thereafter) was calculated for a single creatine kinase-mb at time points admission, at 7 h, and for the serial creatine kinase-mb combining these two time points. Confidence intervals for sensitivity and specificity were calculated with the formula for a binomial distribution (p 1 96 s.e., where s.e.= [p(1 p)/n]. The investigation conformed with the principles outlined in the Declaration of Helsinki. Results The database included 1179 patients coded for presenting with chest pain. A total of 670 patients were excluded owing to admission later than 5 h after the onset of symptoms (235 patients), or because of atypical chest pain, arrhythmias, congestive heart failure or non-cardiac disease where creatine kinase-mb samples were not drawn according to protocol (438 patients). In seven patients, creatine kinase-mb samples were missing owing to cardiogenic shock or large myocardial infarction, where urgent treatment interfered with marker measurements. The remaining 499 patients were presenting within 5 h after the onset of symptoms and had a complete series of creatine kinase-mb mass samples taken on admission, and at 7 and 10 h. Because of incomplete, equivocal or missing hospital records, another 29 patients were excluded and therefore 470 patients comprised the study group. Table 1 shows the patients characteristics which were representative of those of chest pain patients admitted to the cardiac emergency room. Myocardial infarction was diagnosed in 248 patients (Table 2): 100 patients with a creatine kinase- MB mass >7 0 μg.l 1 on admission (sensitivity: 40%, 95% CI: 34 46), 234 patients with a creatine kinase- MB mass >7 0 μg.l 1 at 7 h (sensitivity: 94%, 95% CI: 91 97), and 240 patients with a creatine kinase-mb mass >7 0 μg.l 1 at 10 h (sensitivity: 97%, 95% CI: 94 99). A total of 254 patients had an abnormal serial creatine kinase-mb mass : 237 patients with a creatine kinase- MB mass >7 0 μg.l 1 either on admission and/or at 7 h, and 17 patients with a significant increase between admission and 7 h but no creatine kinase-mb mass >7 0 μg.l 1 at either time point. Of these 17 patients, nine were diagnosed as myocardial infarction with a creatine kinase-mb mass release curve that continued to increase above 7 0 μg.l 1 at 10 h (Table 3, patients 1 9; Fig. 1). The other 8 patients had a significant increase between admission and 7 h but a creatine kinase-mb mass at 10 h below 7 0 μg.l 1 (Table 3, patients 10 17; Fig. 1). Of 216 patients with a normal serial creatine

3 Creatine kinase-mb mass and acute myocardial infarction CK-MBmass (µg.l 1 ) Upper reference limit (7 µg.l 1 ) (B) (A) 2 RCV Admission Time after onset of symptoms (h) 25 Figure 1 Creatine kinase-mb release curves in the first 24 h after the onset of symptoms. The shaded area depicts the reference change value (RCV) of 2 0 μg.l 1 or the maximal change that can be explained by the combined biological and analytical variation. Release curve (A) is from a patient with a small myocardial infarction with a peak creatine kinase-mb of 10 1 μg.l 1 at 10 h after the onset of symptoms (patient no. 9 in Table 3). The samples on admission and at 7 h are below the upper reference limit (7 0 μg.l 1 ), but the difference between admission and 7 h is larger than the reference change value of 2 0 μg.l 1, identifying an abnormal creatine kinase-mb release curve. Release curve (B) is from a patient without myocardial infarction but with a difference between admission and 7 h >2 0 μg.l 1, which may signify minor myocardial damage (patient no. 13 in Table 3). kinase-mb mass on admission and at 7 h, 214 patients had a creatine kinase-mb mass below 7 0 μg.l 1 at 10 h. Two patients had a creatine kinase-mb mass at 10 h above 7 0 μg.l 1 ; one of these patients (who was diagnosed as myocardial infarction) was resuscitated outside the hospital and admitted to the emergency room in cardiogenic shock, the other patient was admitted with severe unstable angina with repetitive episodes of recurrent angina after admission and later diagnosed as myocardial infarction (Table 3, patients a and b). There were 137 patients with ST-elevation on the admission electrocardiogram, 131 with myocardial infarction and six without myocardial infarction. ST-depression or T-wave change was present in 167 patients, 67 with myocardial infarction and 100 without myocardial infarction. Of the remaining 166 patients with either a non-diagnostic or a normal electrocardiogram, 50 had myocardial infarction and 116 did not have myocardial infarction. The sensitivity and specificity of an abnormal serial creatine kinase-mb according to the admission electrocardiogram is depicted in Fig. 2, demonstrating no significant differences between groups. In summary, of 248 patients diagnosed as myocardial infarction, 246 were identified with serial creatine kinase-mb mass on admission and at 7 h (sensitivity 99%, 95% CI: ). Of 222 patients not diagnosed as myocardial infarction, 214 had a normal serial creatine kinase-mb mass (specificity 96%, 95% CI: 93 99). Discussion In the present study we analysed the value of serial samples taken on admission (before 5 h) and at 7 h after the onset of symptoms, and compared this with a single measurement taken on admission, at 7 h and at 10 h. The combined information from the creatine kinase-mb measurement on admission and at 7 h had a sensitivity of 99%, higher than for a single measurement at each of these three time points. Of 216 patients with a normal serial creatine kinase-mb mass, in only two patients did creatine kinase-mb mass at 10 h increase (unexpectedly) above 7 0 μg.l 1. One patient was resuscitated outside the hospital but the onset of symptoms was thought to have occurred prior to the time of cardiac arrest; the other was admitted with severe unstable angina and may have had another episode of severe ischaemia after admission that caused a late increase of creatine kinase- MB. Both these patients had a clinical presentation that made admission to the coronary care unit necessary, irrespective of the creatine kinase-mb mass results. The specificity of the presented algorithm was only 96%:

4 970 R. J. de Winter et al. Table 1 Characteristics of the 470 study patients with chest pain suggestive of myocardial ischaemia presenting within 5 h after the onset of symptoms Characteristic Number (%) Males 328 (70) Females 142 (30) Age (years; median, range) 64 (31 93) History Myocardial infarction 157 (33) CABG 80 (17) PTCA 90 (19) Angina 251 (53) Smoking 153 (33) Hypertension 156 (33) Diabetes mellitus 73 (16) Hyperlipidaemia 100 (21) Positive family history 127 (27) Medication Aspirin 188 (40) Beta-blockers 160 (34) Nitrates 191 (41) Ca-antagonists 167 (36) No medication 175 (37) Admission ECG ST-elevation 153 (32) ST-depression/T-wave changes 125 (27) Non-diagnostic/normal 192 (41) Myocardial infarction=acute myocardial infarction; CABG= coronary artery bypass grafting; PTCA=percutaneous transluminal coronary angioplasty. eight patients had an increase between admission and 7 h >2 0 μg.l 1 but no diagnosis of myocardial infarction, thus lowering specificity (although it could be argued that these patients had indeed signs of myocardial damage). The sensitivity of this algorithm was similarly high in patients with ST-elevation, STdepression or non-diagnostic or normal electrocardiograms on admission. Specificity was 83% (five of six) in the small group of patients with ST-elevation but without infarction. The upper reference limit of the creatine kinase- MB mass assay was established using the 95th percentile of the distribution of healthy donors (7 0 μg.l 1 for the IMMUNO-1 assay in our institution). However, the distribution of healthy donors is heavily skewed to the right, and for most healthy individuals the normal creatine kinase-mb mass is around μg.l 1. For these individuals a creatine kinase-mb mass of, for example, 5 0 μg.l 1 can be abnormal, although it is still within the reference limits. Using serial sampling with carefully timed blood samples, the difference between samples detects abnormal creatine kinase-mb mass changes within the reference limits. New assays for creatine kinase-mb mass have very good precision in the normal concentration range; the assay used in this study had a correlation coefficient of 2 5% in the range of 5 0 μg.l 1. Moreover, biological variation of creatine kinase-mb mass is small [7,9], therefore, the reference change-value or the maximum change in creatine kinase- MB mass due to analytical and biological variation is only 2 0 μg.l 1 for values within the reference limits. The analytical variation for creatine kinase-mb mass of 2 5% at 5 0 μg.l 1 with the IMMUNO-1 assay in our laboratory is somewhat better than the 6 8% recently reported by Ross et al. for the CIBA-Corning ACS creatine kinase-mb mass assay [10] and much better than the 12 5% at 6 μg.l 1 reported for the Stratus II assay [13]. Serial sampling of creatine kinase-mb mass in the emergency room was shown previously to have good sensitivity and specificity for the diagnosis of myocardial infarction [14,15]. However, in these studies the emphasis was on detecting rather than ruling out myocardial infarction, and the presence of a significant increase Table 2 Number of patients with and without myocardial infarction diagnosed with a creatine kinase-mb mass >7 0 μg.l 1 at admission or 7 h after the onset of symptoms and additional patients identified with a significant increase between these time points Myocardial infarction (n=248) No myocardial infarction (n=222) CK-MB mass >7 0 μg.l 1 Ta and/or T7 237 Significant increase Ta T7 and CK-MB mass 9 >7 0 μg.l 1 at T10 No significant increase Ta T7 and CK-MB mass 2 >7 0 μg.l 1 at T10 Significant increase Ta 17 and CK-MB mass μg.l 1 at T10 No significant increase Ta T7 and CK-MB mass 7 0 μg.l 1 Ta or T7 214 CK=creatine kinase; Ta=time of admission; T7=time 7 h after the onset of symptoms; T10=time 10 h after the onset of symptoms. Patients were included if they presented within 5 h after the onset of symptoms, and samples from Ta and T7 were taken at least 2 h apart.

5 Creatine kinase-mb mass and acute myocardial infarction 971 Table 3 Creatine kinase-mb mass results in individual patients Patient no. Ta T7 ΔCK-MB (T7 Ta) T a b Ta=time of admission; T7=7 h after the onset of symptoms; CK=creatine kinase; T10=10 h after the onset of symptoms. CK-MB mass results in nine patients (patients 1 9) with a significant increase (>2 0 μg.l 1 ) between admission and 7 h after the onset of symptoms and with a CK-MB above 7 0 μg.l 1. There were eight patients (patients 10 17) with a significant increase between admission and at 7 h after the onset of symptoms but with a CK-MB mass at T10 below 7 0 μg.l 1. An additional two patients did not have a significant increase between admission and at 7 h after the onset of symptoms but with a CK-MB mass at T10 above 7 0 μg.l 1 (patients a and b). between serial samples was not studied. Patients with a significant increase suggestive of minor myocardial damage can also be identified by release of small amounts of other biochemical markers such as troponin T or troponin I [5,16 18]. Early triage of chest pain patients was shown to be possible with troponin T or troponin I [13,19,20]. In these studies, troponin T or I was suggested to be superior to creatine kinase-mb mass for the identification of patients at risk for subsequent cardiac events. However, the presence of a significant increase in serial creatine kinase-mb mass samples within the reference limits was not considered in these studies. We have shown previously that most patients with elevated troponin T can be identified by a significant increase in creatine kinase-mb mass sampled within 24 h [7], whereas others have demonstrated that a significant increase in creatine kinase-mb mass has prognostic implications [8,9]. There are some limitations to the study. Including only those patients in the study presenting within 5 h after onset of symptoms and with a complete series of creatine kinase-mb samples may have preferentially selected patients with myocardial infarction and patients with a clear time of onset of symptoms. However, in Sensitivity/specificity (%) ST-elevation n=137 ami= ST-depression / T-wave changes Non-diagnostic normal ECG / n=167 ami=67 n=166 ami=50 Figure 2 Sensitivity (shaded columns) and specificity (solid columns) of the algorithm for an abnormal serial creatine kinase-mb (>7 0 μg.l 1 on admission or at 7 h or a rise between admission and 7 h >2 0 μg.l 1 ) for the diagnosis of acute myocardial infarction (ami). Patients are grouped according to the admission electrocardiogram (ECG): the presence of ST-elevation, ST-depression or T-wave changes, or non-diagnostic or normal. There were no significant differences in sensitivity and specificity between groups. many patients who were coded presenting with chest pain in the database, creatine kinase-mb measurements were not performed owing to a low suspicion of ischaemic myocardial injury. Therefore, patients in whom creatine kinase-mb measurements were considered relevant were included in the study. Secondly, our study was a retrospective study, and whether a sampling protocol with two serial creatine kinase-mb mass measurements on admission and at 7 h will allow safe discharge at that time point of patients with normal results (both creatine kinase-mb mass results 7 0 μg.l 1, difference <2 0 μg.l 1 ) cannot be answered with our data. In addition, the turn around time of the assay should be taken into account to assess the earliest moment a decision can be made on the basis of the creatine kinase-mb mass results. The turn around time of the IMMUNO-1 assay is 1 h, but new assays with a shorter turn around time or point-of-care testing may allow even earlier triage. Our rule-out myocardial infarction protocol included an observation period up to 12 h after the onset of symptoms, and therefore the detection or exclusion of myocardial damage with creatine kinase-mb mass was always completed within that period. However, our data indicate that a short rule-out protocol should be evaluated in a prospective study assessing clinical outcomes. We conclude that with two serial creatine kinase- MB mass samples, on admission and at 7 h after the onset of symptoms in patients under observation in the cardiac emergency room who presented within 5 h, myocardial infarction can be ruled out in 99% of cases. We are grateful to Ms Irma Hoogendonk for the careful and accurate management of the cardiac emergency room database and the team of nurses of the coronary care unit of the Academic Medical Centre.

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