Troponin T in patients with low grade or atypical angina

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1 European Heart Journal (1998) 19, Article No. hj Troponin T in patients with low grade or atypical angina Identification of a high risk group for short- and long-term cardiovascular events M. Möckel*, T. Störk, G. Heller Jr., L. Röcker, O. Danne*, K. gr. Darrelmann*, H. Eichstädt and U. Frei* *Department of Nephrology/Intensive Care Medicine, Department of Cardiovascular Imaging, Charité/Virchow-Klinikum, Humboldt University, Berlin; Department of Cardiology/Intensive Care Medicine, Karl Olga Hospital, Stuttgart; Department of Medical Sociology, University Marburg, Marburg; Department of Physiology, Free University Berlin, Berlin, Germany Aims Cardiac troponin T is an established marker of cardiovascular risk in patients with severe angina pectoris. Data are scarce on patients admitted to a coronary care unit with low grade or atypical angina pectoris to rule out myocardial infarction. Methods and Results We investigated 106 patients (57 4 SD 11 6 years) with low grade (Braunwald class I) or atypical symptoms out of 702 patients admitted to the coronary care unit with suspected acute myocardial infarction. Serum concentrations of troponin T were measured at admission and 4 h later. In hospital cardiovascular events including acute myocardial infarction, life threatening cardiac arrhythmias, congestive heart failure, and death were recorded. Patients were additionally observed after 3 and 6 months post-discharge regarding acute myocardial infarction, unstable angina, rehospitalization for cardiac causes and death. The patients were divided into a troponin T positive ( 0 2 μg.l 1 at admission or 4 h later; n=11) and a troponin T negative group. The mean value of troponin T 4 h after admission in the positive group was 0 58 μg.l 1. Of the troponin T positive patients, 0 82 (0 95 CI: ) had a cardiovascular event during their stay in hospital vs 0 41 (0 95 CI: ) of troponin T negative patients (P<0 05). In the troponin T positive group 0 64 (0 95 CI: ) developed myocardial infarction in hospital vs 0 07 (0 95 CI: ) in the troponin T negative group (P<0 001). Troponin T predicts outcome after 3 and 6 months significantly (P<0 05). Conclusion Troponin T identifies patients with low grade or atypical angina at risk of severe short- and long-term cardiovascular events. Therefore, troponin T adds substantial information in patients with ruled out acute myocardial infarction. Troponin T positive patients have to be observed carefully regardless of their symptom intensity and may have to receive early cardiac catheterization; troponin T negative patients could be released safely from the coronary care unit early. (Eur Heart J 1998; 19: ) Key Words: Cardiac troponin T, risk of cardiovascular events, rule out myocardial infarction, long-term follow-up. See page 1749 for the Editorial comment on this article Introduction Cardiac troponin T was characterized and evaluated some years ago as being a reliable marker of myocardial damage in patients with acute myocardial infarction [1 3]. Revision submitted 6 July 1998, and accepted 12 July Correspondence: Dr Martin Möckel, MD, Nephrology/ Intensive Care Medicine, Charité/Campus Virchow-Klinikum, Augustenburger Platz 1, D Berlin, Germany X/98/ $18.00/0 The elevation of troponin T in patients with severe angina pectoris (Braunwald class III [4] ) accurately predicts the development of acute myocardial infarction in the following days or weeks [5,6]. Others have confirmed the high sensitivity of troponin T for acute myocardial infarction detection in patients admitted less than 10 h after the onset of chest pain. In a population with 0 53 prevalence of acute myocardial infarction, 0 26 had elevated troponin T levels without acute myocardial 1998 The European Society of Cardiology

2 Troponin T and risk of cardiovascular events 1803 infarction [7]. This is probably because troponin T could be increased in patients with severe unstable angina. Until recently it had been thought that myocardial damage would not occur in these patients, but now minor myocardial damage has to be considered [8]. The additional prognostic information from troponin T measurements compared to traditional markers, such as creatine kinase and its isoenzyme MB is substantial [5]. Nevertheless, the symptoms of patients [9], especially if classified in Braunwald s score [10], are of great prognostic value. Even non-diagnostic ST-T wave changes on the ECG [11] are important. It is questionable whether troponin T is of additional clinical significance in this highly symptomatic population, where coronary angiography is frequently applied because of the known high short-term morbidity of these patients [12]. There are no data on troponin T in subgroups admitted with suspected acute myocardial infarction and low grade (Braunwald class I) or atypical symptoms. In such a patient population with a low acute myocardial infarction incidence, in whom infarction is ruled out at admission using WHO criteria, troponin T is hypothesized to identify patients at high risk of future cardiovascular events [13] and should therefore add new information for risk stratification. Methods Study protocol and patients The hypothesis was that patients with low-grade unstable angina or atypical angina pectoris, out of those admitted with suspected acute myocardial infarction, could be divided into low and high risk groups for the primary end-point acute myocardial infarction or the combined end-point: cardiovascular events (in hospital: acute myocardial infarction, congestive heart failure, life-threatening cardiac arrhythmias, death, and post discharge: acute myocardial infarction, recurrent unstable angina according to Braunwald s score (see below [4] ), death and rehospitalization) by measuring cardiac troponin T at admission and 4 h later. The troponin positive group was defined by a value greater than or equal to 0 2 μg.l 1, at least at one of the two points of measurements. Inclusion criteria were suspected myocardial damage due to patient history, ECG changes or acute symptoms judged by an experienced cardiologist as suspected acute myocardial infarction. Exclusion criteria were definite signs of acute myocardial infarction at admission using standard WHO diagnostic rules (including symptoms, ECG changes and laboratory findings of cardiac enzymes [14] ), severe unstable angina (Braunwald class II or III), obvious non-cardiac source of chest pain, inability to give informed consent, other severe diseases such as cancer or infections, symptomatic congenital heart disease or congestive heart failure NYHA class III/IV. Diagnoses and assessment of Braunwald and NYHA 702 patients with suspected AMI 106 (0 15) patients with low grade angina (Braunwald IB, 1 2) no ST elevation no significant CK MB changes TnT+ at admission or 4 h n = 11 (0 1) Major event n = 9 (0 82) No event n = 2 (0 18) TnT at admission or 4 h n = 95 (0 9) Major event n = 39 (0 41) No event n = 56 (0 59) Figure 1 Patient selection and in hospital events. AMI=acute myocardial infarction; TnT+ =TnT 0 2 μg.l 1 ; TnT =TnT<0 2 μg.l 1 ; major events (in hospital) were: AMI, death, life threatening cardiac arrhythmias and congestive heart failure; values are numbers of patients and decimal fraction. classifications were made by an experienced cardiologist at the time of admission. Braunwalds s classification [4] consists of three severity classes (i) new onset, severe, or accelerated angina; (ii) angina at rest, subacute; (iii) angina at rest, acute, and three classes of clinical circumstances (a) secondary unstable angina (intensified angina due to anaemia, infection, fever etc.); (b) primary unstable angina; (c) post-infarction unstable angina. A third class describes the intensity of treatment at the time of onset of unstable angina (1) no or minimal treatment; (2) standard therapy for chronic stable angina; (3) maximally tolerated doses of all three categories of oral therapy including intravenous nitroglycerin. Screening took place in 702 consecutive patients who were admitted with suspected acute myocardial infarction to our coronary care unit from Acute myocardial infarction was diagnosed retrospectively following WHO criteria [14], echocardiography and coronary angiography in 421 (0 6) of the patients during hospitalization. All 106 eligible patients who passed the inclusion and exclusion criteria (Fig. 1) gave informed consent prior to the first blood sample. Measurements of troponin T, myoglobin, white blood cells, creatinine, creatine-kinase and, if applicable (creatine kinase >100U/l), its isoenzyme MB were performed for study purposes. Treatment included intravenous aspirin, heparin and nitrates. All patients were monitored for at least 24 h. Blood samples of cardiac enzymes were obtained every 4 8 h in the first 24 h. ECG recordings and assessment of symptoms were carried out by experienced staff. The coronary care unit personnel was blinded to the results of troponin T measurements. The study protocol was approved by the local ethics committee.

3 1804 M. Möckel et al. Sample handling and laboratory methods Table 1 Clinical characteristics of the 106 patients The blood samples were centrifugated within 60 min and serum was stored immediately at 20 C. Over the next 6 h samples were transferred to a 80 C freezer. Cardiac troponin T was measured by an enzyme immunoassay with one specific antibody against cardiac troponin T and one polyclonal capture-antibody against both skeletal and cardiac troponin T (Boehringer Mannheim, Germany). The intra-assay coefficient of variation was ; the interassay coefficient of variation was The detection limit was 0 04 μg.l 1 and the measurement range to 15 μg.l 1. The cut-off level was assumed to be 0 2 μg.l 1 from information supplied by the company. The samples were analysed within 3 months. The 3 month storage stability of troponin T was evaluated by the company. Myoglobin was determined using a standard turbidimetric technique (Behringwerke Marburg, Germany). Follow up Patient observation took place during hospitalization, and after 3 and 6 months post discharge according to the above-defined cardiovascular events. Post-discharge events were assessed by telephone contacts with either the patient or the family physician. The follow up was complete for all patients in hospital, 0 91 after 3 months and 0 85 after 6 months post-discharge. Patient drop-out was due to moving after discharge without leaving a new address or telephone number. Statistical analysis Univariate analysis of 2 2 tables was performed by calculating exact binomial confidence intervals and exact Fisher tests. In addition, in order to predict the occurrence of acute myocardial infarction and cardiovascular events (primary and secondary end-point), a multivariate logistic regression model comprising troponin T, age, sex, known coronary disease and ST-T segment changes as dependent variables was performed. All variables except age were recoded and encountered as binomial in the model. All procedures were calculated using the statistical software package WINSPSS V 7 5. Due to intention-to-treat principles no data were excluded from the analysis. Results Table 1 gives the patients clinical characteristics. No significant differences occurred between the two groups. By applying Braunwald s criteria of unstable angina, all patients are classified as IB,1 2 [4]. Table 2 lists the laboratory findings and the probabilities of events in hospital in both groups. The risk of an acute myocardial TnT+ (n=11) TnT (n=95) Age (years) 61 (43 72) 57 (21 82) Male sex 0 64 ( ) 0 70 ( ) BMI (kg. m 2 ) 28 0 ( ) 27 6 ( ) Smoking 0 70 ( ) 0 66 ( ) Hypertension 0 64 ( ) 0 58 ( ) Diabetes mellitus 0 33 ( ) 0 16 ( ) Positive family history 0 20 ( ) 0 42 ( ) Abnormal ECG* 0 82 ( ) 0 65 ( ) Braunwald score IB1 2 IB1 2 Known CAD 0 36 ( ) 0 61 ( ) BMI=body mass index; CAD=coronary artery disease; decimal fractions and 0 95 confidence intervals or median values and range (quantitative variables); *ST/T changes without ST elevations. infarction (P<0 001) or an event in general (P=0 013) was significantly elevated in troponin positive patients. Troponin T positive patients suffered an acute myocardial infarction in 0 64 (0 95 CI: ); one patient died. In contrast, only 0 07 of patients in the troponin T negative group (0 95 CI: ) developed an acute myocardial infarction in hospital. Logistic regression for the target variable acute myocardial infarction in hospital with age, sex, history of coronary artery disease, ST-T segment changes in the ECG and troponin T positive resulted in the significant independent influence of troponin T alone (odds ratio 22 0; 0 95 CI: ; P<0 001). Troponin T predicted cumulative acute myocardial infarction incidence in the follow-up after 3 months (odds ratio 14 4; 0 95 CI: ; P=0 001) or 6 months (odds ratio 12 7; 0 95 CI: ; P=0 01). Cardiovascular events (combined end-point) in hospital were predicted by troponin T alone (odds ratio 8 9; 0 95 CI: ; P=0 012). Troponin T predicted cumulative incidence of the secondary end-point in the follow-up after 3 months (odds ratio 10 0; 0 95 CI: ; P=0 039) or 6 months (odds ratio 9 3; 0 95 CI: ; P=0 047). Figure 2 shows the event free survival of patients. In the 3 and 6 month follow-ups, additional significant event difference occurred only with respect to readmission in troponin T positive patients after 3 months (P=0 042). Troponin T positive patients had no further acute myocardial infarction and none died; two acute myocardial infarctions occurred in the troponin T negative group in the 3 month follow-up, one died from acute myocardial infarction and one died after elective CABG surgery. One additional troponin T negative patient died from acute myocardial infarction during the 6-month follow-up. Table 3a shows the events in detail during the 3 and 6 month follow-up periods and the cumulative incidence of events is displayed in Table 3b. The negative predictive value of troponin T negative for the exclusion of an acute myocardial infarction was 0 93 for the in-hospital period, 0 98 for

4 Troponin T and risk of cardiovascular events 1805 Table 2 In-hospital results. Laboratory findings at admission (except troponin T at 4 h), in-hospital cardiovascular events and essential diagnostic features TnT+ (n=11) TnT (n=95) TnT (μg.l 1 ) 0 58 ( ) 0 (0 0 18)*** CK (U. l 1 ) 63 (22 146) 36 5 (7 161) CK-MB (U. l 1 ) # 7 5 (2 18)# Myoglobin (μg.l 1 ) 55 (49 440) 49 (49 391)* Creatinine (mg. dl 1 ) 1 0 ( ) 1 1 ( ) WBC (/nl) 12 8 (7 9 19) 8 9 ( )*** Cardiovascular events 0 82 ( ) 0 41 ( )* AMI 0 64 ( ) 0 07 ( )*** Cardiac arrhythmias 0 27 ( ) 0 24 ( ) CHF 0 09 ( ) 0 02 ( ) Death 0 09 ( ) Coronary angiography 0 64 ( ) 0 61 ( ) No CAD 0 15 ( ) 1-vessel-disease 0 27 ( ) 0 16 ( ) 2-vessel-disease 0 18 ( ) 0 12 ( ) 3-vessel-disease 0 18 ( ) 0 19 ( ) Interventions 0 18 ( ) 0 25 ( ) CABG 0 09 ( ) 0 05 ( ) PTCA 0 09 ( ) 0 20 ( ) AP before admission (h) 8 (1 48) 5 ( ) CAD in final diagnosis 1 00 ( 0 72) 0 76 ( ) TnT=cardiac troponin T; CK=creatine kinase; WBC=white blood cells; AMI=acute myocardial infarction; CHF=congestive heart failure; CAD=coronary artery disease; CABG=coronary artery bypass grafting; PTCA=percutaneous transluminal coronary angioplasty; AP=angina pectoris; for further abbreviations see text. =Seven patients had values 0 2 μg.l 1 at admission, one patient was troponin T positive at admission only. #=creatine kinase-mb was not measured if creatine kinase was less than 100 U. l 1. Two troponin T positive patients had 15 and 17 U. l 1 creatine kinase-mb activity respectively, in troponin T negative creatine kinase-mb measured from 14 samples. *=P<0 05, ***=P< Quantitative variables as median values and range; qualitative variables as decimal fractions with 0 95 confidence intervals (CI); =one-sided CI. the 3 month follow-up and 0 99 for the follow-up at 6 months. Discussion Many recent studies have elucidated the value of cardiac troponin T in the diagnosis of acute myocardial infarction [1,3,12,15 20]. Additionally, troponin T elevation seems to be a marker of increased cardiac morbidity in patients with severe unstable angina [5,6,21,22]. Our study Admission Discharge Troponin T Troponin T + 3 months 6 months Figure 2 Event free survival of troponin T positive (+) and negative ( ) patients. addressed the question of whether troponin T measurement at admission and 4 h later gives significant information in a subgroup of patients with low grade or atypical symptoms in whom acute myocardial infarction was initially excluded using WHO criteria. We showed that troponin T is a risk marker for future acute myocardial infarction or other cardiovascular events in hospital and after 3 or 6 months. No additional significant differences occurred between troponin T positive or negative patients after 3 or 6 months (Fig. 2), although there was a tendency towards higher readmission of troponin T positive patients after the 3 month follow-up (Table 3(a)). Due to time of data collection, , the troponin test used in our study had a cut-off level of 0 2 μg.l 1. With the lower cut-off of the second generation assay, more patients at risk may have been identified. Another study has consistently shown that troponin T predicts long-term prognosis [11]. Of the included patients in that study, 0 37 had an acute myocardial infarction [11] in contrast to 0 13 in our study group. Nevertheless, the symptoms of patients [9], are also of great prognostic value, especially if classified in Braunwald s score [10]. Even non-diagnostic ST-T wave changes in the ECG are important [11]. As our group of patients was less symptomatic, the detection of elevated troponin T levels seems to add

5 1806 M. Möckel et al. Table 3(a) Cardiovascular events (CARD-E) during the 3 and 6 months follow-up 3-month follow-up 6-month follow-up TnT+ TnT TnT+ TnT CARD-E 0 44 ( ) 0 27 ( ) 0 13 ( ) 0 17 ( ) AMI 0 02 ( ) 0 01 ( ) Death 0 02 ( ) 0 01 ( ) Unstable AP 0 11 ( ) 0 21 ( ) 0 13 ( ) 0 12 ( ) Readmission 0 44 ( )* 0 14 ( ) 0 07 ( ) Readmission=admission to a hospital for cardiac causes after initial discharge; AP=angina pectoris; decimal fractions and 0 95 confidence intervals; *P=0 042 from logistic regression: troponin T predicted readmission; for further abbreviations see Table 2. Table 3(b) Cumulative cardiovascular events (CARD-E-C) until the 3 and 6 months follow up Admission 3-month follow-up Admission 6-month follow-up TnT+ TnT TnT+ Tnt CARD-E-C 0 91 ( )* 0 57 ( ) 0 91 ( )* 0 61 ( ) AMI 0 64 ( )* 0 10 ( ) 0 64 ( )* 0 12 ( ) Death 0 10 ( ) 0 02 ( ) 0 11 ( ) 0 03 ( ) Unstable AP 0 11 ( ) 0 21 ( ) 0 13 ( ) 0 21 ( ) Readmission 0 44 ( )* 0 14 ( ) 0 44 ( ) 0 20 ( ) Readmission=admission to a hospital for cardiac causes after initial discharge; AP=angina pectoris; decimal fractions and 0 95 confidence intervals; *=P<0 05 from logistic regression for troponin T prediction of cumulative events; for further abbreviations see Table 2. substantial information regarding the risk of acute myocardial infarction, which could not be achieved by the conventional criteria, such as symptoms, ECG changes and small changes in cardiac enzymes. The rise of troponin T indicates minor myocardial damage [8,23,24] which could preceed acute myocardial infarction or other cardiovascular events in patients with suspected acute myocardial infarction. The time course of this minor myocardial damage prior to the admission is unclear (hours, days?). Also patients with clinically silent infarction up to 14 days before admission are possibly included in the troponin T positive group. The long-term prognosis differed only due to the initially higher event rate of troponin T positive patients in our study. This could be explained by a relatively high incidence of cardiovascular events in the troponin T negative group. As all patients were admitted with suspected acute myocardial infarction, the known high morbidity of this population [12] was confirmed. On the other hand, only 11 patients were troponin T positive. One died from acute myocardial infarction in hospital initially and one patient moved after discharge and could not be contacted again. One refused the interview at 6 months, but was at least alive and not in hospital at that time. Thus, follow-up was complete in nine out of 10 patients at risk after 3 months and eight at 6 months. Nevertheless a selection bias is possible. Troponin T is obviously not the only prognostic marker in patients with unstable angina. In particular, clinical information and symptoms, ECG-changes and other biochemical markers such as creatine kinase MB mass concentration and troponin I identify patients at higher risk [9 11,25,26]. Recent studies indicate that troponin I may have the same prognostic value as troponin T [23,27]. Further studies will show which protocol of diagnostic measures in patients with suspected myocardial ischaemia will give the most economic and reliable information [28]. Conclusions Troponin T identifies patients with low grade or atypical angina at risk for severe short- and long-term cardiovascular events. Therefore, troponin T adds substantial information in patients with ruled out acute myocardial infarction. Troponin T positive patients have to be observed carefully regardless of their symptom intensity and possibly receive early cardiac catheterization. Patients who are troponin T negative have high negative predictive values for the exclusion of an acute myocardial infarction: 0 93 for the in-hospital period, 0 98 for the 3-month follow-up and 0 99 for the follow-up at 6 months and therefore could be released safely from the coronary care unit early. We are very grateful to Dr E. Spanuth (Boehringer Mannheim, Germany) for the troponin T testkits, Prof Dr R. Schnell

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