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Usefulness of Positive Troponin-T and Negative Creatine Kinase Levels in Identifying High-Risk Patients With Unstable Angina Pectoris
Usefulness of Positive Troponin-T and Negative Creatine Kinase Levels in Identifying High-Risk Patients With Unstable Angina Pectoris Trent L. Pettijohn, MD, Thomas Doyle, MD, A. Michael Spiekerman, PhD, Linley E. Watson, MD, Mark W. Riggs, PhD, and Mark E. Lawrence, DO ixty percent of patients with unstable angina are at S low risk, but 10% to 20% have conditions that progress to nonfatal myocardial infarction or death within 6 months of diagnosis.1 An early serum marker stratifying the patient with unstable angina into low or high risk should prove cost-effective by shortening the length of stay for low-risk patients and identifying those high-risk patients requiring hospitalization and revascularization. This study identifies patients who have negative enzyme criteria for acute myocardial infarction with negative creatine kinase-MB (CK-MB) and compares 6-month cardiac event rates in those with normal to those with elevated serum troponin-T levels. •••
Between September and December of 1994, 263 patients who were admitted to the cardiology service at Scott & White Memorial Hospital with chest pain had both serum creatine kinase and troponin-T levels drawn at admission and again at 8 and 16 hours. Patients were followed for at least 6 months for death, myocardial infarction, and coronary revascularization. Patients were excluded from analysis if they had renal failure (serum creatinine $3 mg/dl) or known trauma. Patients (n 5 119) with elevated CK-MB (.5% of total CK) and elevated troponin-T ($0.1 mg/L) were omitted from the study because they had a myocardial infarction by standard criteria. The remaining 129 patients were divided into 2 groups based on the results of the serum markers as follows: group I (n 5 94) had normal CK-MB and normal troponin-T, and group II (n 5 35) had normal CK-MB and elevated troponin-T. No patient had elevated CK-MB and normal troponin-T levels. Blood samples were analyzed for CK-MB, using the Helena CK electrophoresis for electrophoretic separation (Helena Laboratories, Helena Corp., Beaumont, Texas). For troponin-T, an enzymun test (ES300), (Boehringer Mannheim, Mannheim, Germany), ELISA/1-STEP sandwich assay using streptavidin technology was used.2 The 6-month event rate was compared between patients with positive and negative troponin-T using the chi-square test. The odds ratio was also computed, comparing the odds of an event in patients with a positive troponin-T to that in a patient with a negative From the Scott & White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A & M University Health Science Center, College of Medicine, Temple, Texas. Dr. Lawrence’s address is: Scott White Clinic, 2401 South 31st Street, Temple, Texas 75608. Manuscript received December 10, 1996; revised manuscript received and accepted April 24, 1997.
510
©1997 by Excerpta Medica, Inc. All rights reserved.
troponin-T. In addition, 95% confidence intervals were computed for event rates and odds ratio. A p value ,0.05 was considered statistically significant. In group I, 12% (11 of 94) had cardiac events: 4 coronary artery bypass grafts, 4 myocardial infarction, and 3 deaths (all cardiac related). In group II, 34% (12 of 35) had cardiac events: 6 coronary artery bypass graft, 4 myocardial infarction, and 2 deaths (all cardiac-related). The difference in clinical events between groups I and II was significant (p ,0.01). Table I lists the clinical events in patients with chest pain and positive troponin-T but a negative CK-MB. The odds ratio was 3.9, indicating that a patient with chest pain and with negative CK-MB, but a positive troponin-T, had a 3.9 times greater risk of subsequent coronary events within 6 months. The study groups were similar with respect to demographic variables, preexisting medical conditions, and electrocardiogram on presentation. None of the variables diminished the association of elevated troponin-T with further cardiac events (Table II). Table III summarizes the sensitivity, specificity, and positive and negative predictive values using troponin-T to predict subsequent coronary events at 6 months in patients who ‘‘rule-out’’ for myocardial infarction using CK-MB criteria. •••
This prospective study shows that patients admitted with chest pain who have elevated troponin-T (.0.1 ng/ml) but a negative CK-MB have an increased chance of having a cardiac event within the next 6 months. These results differ from a recent report in which elevated troponin-T in patients with negative CK was associated with a higher mortality (12.3% vs 4.1%) but no difference in composite end points.3 One reason for this difference may be that the overall event rate for CK-negative patients in that study was much higher than that in the present investigation (77% vs 19%). Our study is in closer agreement with Ravkilde et al,4 in which the 28-month clinical event rate for patients without acute myocardial infarction, but with elevated troponin-T, was 23% compared with 4% in patients without myocardial infarction but with normal troponin-T levels. Many studies have shown that troponin-T is an independent indicator of poor prognosis in patients with unstable angina. Many of these studies used the World Health Organization criteria to define myocardial infarction (ST elevation or Q waves and CK-MB elevation).4,5 However, this may have limited their sensitivity for detecting myocardial infarctions because some non–Q-wave myocardial in0002-9149/97/$17.00 PII S0002-9149(97)00405-0
TABLE I Six-Month Outcomes for Patients
TABLE III Clinical Value of Troponin-T When Creatine Kinase is Negative
Events Within Six Months Troponin-T #0.1 ng/ml $0.1 ng/ml Total
Event (%)
No Event
Total
11 (12) 12 (34) 23 (18)
83 23 106
94 35 129
Chi-square p value ,0.01; odds ratio 5 3.9 (95% confidence interval 1.5 to 10.1).
TABLE II Troponin-T Odds Ratio (OR) Adjusted for Baseline Characteristics in the Two Groups* Adjustment Factor Electrocardiogram on presentation: normal Electrocardiogram on presentation: ST changes b Blockers Smoking history History of coronary disease Known hyperlipidemia Known family history Hypertension
Adjusted OR† 4.0 3.8 3.9 3.7 3.9 3.7 3.8 4.1
*Odds ratio for positive troponin-T was 3.9. † The p value for all groups was ,0.01.
farctions have only minor electrocardiographic changes. Our study evaluates the independent value of an elevated troponin-T level in patients with chest pain and normal CK-MB. This information is helpful to many clinicians, because patients not meeting World Health Organization criteria for acute myocardial infarction but found to have a normal CK-MB and elevated troponin-T should be put into a higher risk group. Our study demonstrated that in patients with chest pain and negative CK-MB isoenzymes, there is a 34% positive predictive value and a 88% negative predic-
Ratio (%) Sensitivity Specificity PPV NPV
12/23 83/106 12/35 83/94
(52) (78) (34) (88)
95% CI 31 69 19 80
to to to to
73 86 52 94
CI 5 confidence interval; PPV 5 positive predictive value; NPV 5 negative predictive value.
tive value for future coronary events. The odds of an event in a patient with a positive troponin-T but negative CK-MB are 3.9 times greater than a patient with a negative troponin-T, therefore allowing risk stratification into high- and low-risk groups. Thus a high-risk group of patients with unstable angina may be further identified by using serum troponin-T levels. Acknowledgment: We thank Janice E. Hudgins, Lisa Elliott Blaschke, and Jill White for their assistance in preparing this manuscript.
1. van Miltenburg-van Zijl AJ, Simoons ML, Veerhoek RJ, Bossuyt PM. Inci-
dence and follow-up of Braunwald subgroups in unstable angina pectoris. J Am Coll Cardiol 1995;25:1286 –1292. 2. Wu AH, Valdes R Jr, Apple FS, Gornet T, Stone MA, Mayfield-Stokes S, Ingersoll-Stroubs AM, Wilder B. Cardiac troponin-T immunoassay for diagnosis of acute myocardial infarction. Clin Chem 1994;40:900 –907. 3. Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, O’Hanesian MA, Wagner GS, Kleiman NS, Harrell FE Jr, Califf RM, Topol EJ. Cardiac troponin-T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333–1341. 4. Ravkilde J, Nissen H, Horder M, Thygesen K. Independent prognostic value of serum creatine kinase isoenzyme, MB mass, cardiac troponin-T, and myosin light chain levels in suspected acute myocardial infarction. J Am Coll Cardiol 1995;25:574 –581. 5. Lindahl B, Toss H, Venge P, Wallentin L. Troponin-T is a strong prognostic marker for subsequent cardiac events in patients with unstable angina (abstr). Eur Heart J 1995;16(suppl):40.
BRIEF REPORTS
511
Between September and December of 1994, 263 patients who were admitted to the cardiology service at Scott & White Memorial Hospital with chest pain had both serum creatine kinase and troponin-T levels drawn at admission and again at 8 and 16 hours. Patients were followed for at least 6 months for death, myocardial infarction, and coronary revascularization. Patients were excluded from analysis if they had renal failure (serum creatinine $3 mg/dl) or known trauma. Patients (n 5 119) with elevated CK-MB (.5% of total CK) and elevated troponin-T ($0.1 mg/L) were omitted from the study because they had a myocardial infarction by standard criteria. The remaining 129 patients were divided into 2 groups based on the results of the serum markers as follows: group I (n 5 94) had normal CK-MB and normal troponin-T, and group II (n 5 35) had normal CK-MB and elevated troponin-T. No patient had elevated CK-MB and normal troponin-T levels. Blood samples were analyzed for CK-MB, using the Helena CK electrophoresis for electrophoretic separation (Helena Laboratories, Helena Corp., Beaumont, Texas). For troponin-T, an enzymun test (ES300), (Boehringer Mannheim, Mannheim, Germany), ELISA/1-STEP sandwich assay using streptavidin technology was used.2 The 6-month event rate was compared between patients with positive and negative troponin-T using the chi-square test. The odds ratio was also computed, comparing the odds of an event in patients with a positive troponin-T to that in a patient with a negative From the Scott & White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A & M University Health Science Center, College of Medicine, Temple, Texas. Dr. Lawrence’s address is: Scott White Clinic, 2401 South 31st Street, Temple, Texas 75608. Manuscript received December 10, 1996; revised manuscript received and accepted April 24, 1997.
510
©1997 by Excerpta Medica, Inc. All rights reserved.
troponin-T. In addition, 95% confidence intervals were computed for event rates and odds ratio. A p value ,0.05 was considered statistically significant. In group I, 12% (11 of 94) had cardiac events: 4 coronary artery bypass grafts, 4 myocardial infarction, and 3 deaths (all cardiac related). In group II, 34% (12 of 35) had cardiac events: 6 coronary artery bypass graft, 4 myocardial infarction, and 2 deaths (all cardiac-related). The difference in clinical events between groups I and II was significant (p ,0.01). Table I lists the clinical events in patients with chest pain and positive troponin-T but a negative CK-MB. The odds ratio was 3.9, indicating that a patient with chest pain and with negative CK-MB, but a positive troponin-T, had a 3.9 times greater risk of subsequent coronary events within 6 months. The study groups were similar with respect to demographic variables, preexisting medical conditions, and electrocardiogram on presentation. None of the variables diminished the association of elevated troponin-T with further cardiac events (Table II). Table III summarizes the sensitivity, specificity, and positive and negative predictive values using troponin-T to predict subsequent coronary events at 6 months in patients who ‘‘rule-out’’ for myocardial infarction using CK-MB criteria. •••
This prospective study shows that patients admitted with chest pain who have elevated troponin-T (.0.1 ng/ml) but a negative CK-MB have an increased chance of having a cardiac event within the next 6 months. These results differ from a recent report in which elevated troponin-T in patients with negative CK was associated with a higher mortality (12.3% vs 4.1%) but no difference in composite end points.3 One reason for this difference may be that the overall event rate for CK-negative patients in that study was much higher than that in the present investigation (77% vs 19%). Our study is in closer agreement with Ravkilde et al,4 in which the 28-month clinical event rate for patients without acute myocardial infarction, but with elevated troponin-T, was 23% compared with 4% in patients without myocardial infarction but with normal troponin-T levels. Many studies have shown that troponin-T is an independent indicator of poor prognosis in patients with unstable angina. Many of these studies used the World Health Organization criteria to define myocardial infarction (ST elevation or Q waves and CK-MB elevation).4,5 However, this may have limited their sensitivity for detecting myocardial infarctions because some non–Q-wave myocardial in0002-9149/97/$17.00 PII S0002-9149(97)00405-0
TABLE I Six-Month Outcomes for Patients
TABLE III Clinical Value of Troponin-T When Creatine Kinase is Negative
Events Within Six Months Troponin-T #0.1 ng/ml $0.1 ng/ml Total
Event (%)
No Event
Total
11 (12) 12 (34) 23 (18)
83 23 106
94 35 129
Chi-square p value ,0.01; odds ratio 5 3.9 (95% confidence interval 1.5 to 10.1).
TABLE II Troponin-T Odds Ratio (OR) Adjusted for Baseline Characteristics in the Two Groups* Adjustment Factor Electrocardiogram on presentation: normal Electrocardiogram on presentation: ST changes b Blockers Smoking history History of coronary disease Known hyperlipidemia Known family history Hypertension
Adjusted OR† 4.0 3.8 3.9 3.7 3.9 3.7 3.8 4.1
*Odds ratio for positive troponin-T was 3.9. † The p value for all groups was ,0.01.
farctions have only minor electrocardiographic changes. Our study evaluates the independent value of an elevated troponin-T level in patients with chest pain and normal CK-MB. This information is helpful to many clinicians, because patients not meeting World Health Organization criteria for acute myocardial infarction but found to have a normal CK-MB and elevated troponin-T should be put into a higher risk group. Our study demonstrated that in patients with chest pain and negative CK-MB isoenzymes, there is a 34% positive predictive value and a 88% negative predic-
Ratio (%) Sensitivity Specificity PPV NPV
12/23 83/106 12/35 83/94
(52) (78) (34) (88)
95% CI 31 69 19 80
to to to to
73 86 52 94
CI 5 confidence interval; PPV 5 positive predictive value; NPV 5 negative predictive value.
tive value for future coronary events. The odds of an event in a patient with a positive troponin-T but negative CK-MB are 3.9 times greater than a patient with a negative troponin-T, therefore allowing risk stratification into high- and low-risk groups. Thus a high-risk group of patients with unstable angina may be further identified by using serum troponin-T levels. Acknowledgment: We thank Janice E. Hudgins, Lisa Elliott Blaschke, and Jill White for their assistance in preparing this manuscript.
1. van Miltenburg-van Zijl AJ, Simoons ML, Veerhoek RJ, Bossuyt PM. Inci-
dence and follow-up of Braunwald subgroups in unstable angina pectoris. J Am Coll Cardiol 1995;25:1286 –1292. 2. Wu AH, Valdes R Jr, Apple FS, Gornet T, Stone MA, Mayfield-Stokes S, Ingersoll-Stroubs AM, Wilder B. Cardiac troponin-T immunoassay for diagnosis of acute myocardial infarction. Clin Chem 1994;40:900 –907. 3. Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, O’Hanesian MA, Wagner GS, Kleiman NS, Harrell FE Jr, Califf RM, Topol EJ. Cardiac troponin-T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333–1341. 4. Ravkilde J, Nissen H, Horder M, Thygesen K. Independent prognostic value of serum creatine kinase isoenzyme, MB mass, cardiac troponin-T, and myosin light chain levels in suspected acute myocardial infarction. J Am Coll Cardiol 1995;25:574 –581. 5. Lindahl B, Toss H, Venge P, Wallentin L. Troponin-T is a strong prognostic marker for subsequent cardiac events in patients with unstable angina (abstr). Eur Heart J 1995;16(suppl):40.
BRIEF REPORTS
511