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Comparison of cardiac marker concentrations in healthy blood donors and hospital patients without acute coronary syndrome
Comparison of Cardiac Marker Concentrations in Healthy Blood Donors and Hospital Patients Without Acute Coronary Syndrome Alexander Kratz, MD, PhD, MPH, Kent B. Lewandrowski, MD, James L. Januzzi, James G. Flood, PhD, and Elizabeth Lee-Lewandrowski, PhD, MPH crucial component in the establishment of cutoff values for laboratory tests is the selection of the A appropriate reference population. Reference values 1
are often derived from healthy volunteers with no history of coronary artery disease or heart failure.2,3 However, cumulative clinical experience with creatine kinase (CK)-MB and troponin suggests that these markers may be elevated in a number of disease states other than acute coronary syndrome (ACS), including renal disease, chronic heart failure, and cardiomyopathies.4 An alternative to healthy volunteers is to use patients with diseases other than ACS for establishing reference values. Such an approach can be called a “goal-oriented concept of health.”5 To compare the implications of using different populations for reference values, we analyzed the concentrations of the cardiac markers CK-MB and troponin in healthy blood donors and compared them with those of hospitalized inpatients without ACS, heart failure, and renal disease. •••
Paired serum, heparin plasma, and ethylenediaminetetraacetic acid (EDTA) plasma samples were collected from 52 healthy blood bank donors (27 men and 25 women, average age 42 years). Unpaired serum (n ⫽ 47), heparin plasma (n ⫽ 46), and EDTA plasma (n ⫽ 44) samples were obtained from a total of 137 hospitalized patients (81 men and 56 women, average age 54 years). A staff physician reviewed the charts of all inpatients; patients with active ACS, heart failure, and renal failure were excluded from the study. Some inpatients had a history of prior coronary disease that was inactive at the time of the study. The Vitros ECi immunodiagnostics system, an automated enhanced chemiluminescence analyzer for plasma and serum samples (Ortho-Clinical Diagnostics, Rochester, New York), was used to determine concentrations of CK-MB and troponin I on all samples (sera, heparin plasma, and EDTA plasma). According to the manufacturer, the within-run coefficient of variation of this instrument at the lower cutoff investigated here is 2.8% for troponin I and 2.5% for CK-MB. In addition, sera were also analyzed for concentrations of CK-MB From the Divisions of Laboratory Medicine and Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. This report was supported in part by a grant from OrthoClinical Diagnostics, Rochester, New York. Dr. Lee-Lewandrowski’s address is: Clinical Laboratories, Massachusetts General Hospital, 55 Fruit Street, GRB 5 Chemistry, Boston, Massachusetts 02114-9206. E-mail: [email protected]. Manuscript received January 2, 2002; revised manuscript received and accepted March 21, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 July 15, 2002
MD,
and troponin T with the Roche Elecsys 1010 system, an electroluminescence immunoassay (Roche Diagnostics Corporation, Indianapolis, Indiana). According to the manufacturer, this instrument has a coefficient of variation of 4.2% for troponin T and of 1.5% for CK-MB at low concentrations. Average concentrations of cardiac markers were not markedly different in healthy blood donors compared with inpatients without ACS (Table 1). Except for troponin T on the Elecsys 1010 analyzer, the differences in the average concentrations in the 2 populations were not statistically significant (p ⬎0.05, 2-tailed t test). However, because of the larger variation in the hospital inpatients, 99th percentile cutoffs derived from blood donors were markedly different from those derived from inpatients. The clinical consequences of the population used for determining cutoff values are demonstrated in Table 2: If the 99th percentile cutoffs derived from the “healthy” donor population had been applied to hospital inpatients, a significant percentage of them (5% to 13%) would have had “elevated” cardiac marker concentrations. •••
The ramifications of these data are considerable, because it has been demonstrated that even minor ACS-related elevations in cardiac marker concentrations have significant implications for patient triage, therapy selection, and prognosis after ACS.6 –10 Importantly, the data in these studies have been generated from clinical trial populations enriched with a high percentage of patients with unstable coronary disease, wherein an elevated cardiac marker concentration is more likely related to acute coronary ischemia. In our population of non-ACS patients, despite a significant percentage of subjects demonstrating similar minor elevations in cardiac markers, no benefit would have been expected from such aggressive therapies. Previous discussions in published reports have focused on the value of the optimal cutoff for cardiac markers (i.e., the 97.5 percentile vs the 99th percentile).11–13 Our results stress the crucial role of the appropriate reference population used to derive the cutoff values for these diagnostic tests. The fundamental idea behind the concept of reference values is that they come from subjects who are relevant controls for patients under study.1 Because the population of patients presenting with symptoms of ACS is more similar to hospital patients than to healthy blood donors, it could be argued that such inpatients without ACS are better suited for establishing cutoff concen0002-9149/02/$–see front matter PII S0002-9149(02)02447-5
177
TABLE 1 Cardiac Marker Concentrations (in ng/ml) in Healthy Blood Donors and In-hospital Inpatients Without Acute Cardiac Syndromes Mean ⫾ SE
99th Percentile
Heparin Plasma
Serum
EDTA Plasma
Serum
Heparin Plasma
EDTA Plasma
3.74 6.87
2.68 10.64
2.63 16.34
0.01 0.16
0.19 1.83
Creatine Kinase-MB Vitros Donors Inpatients Elecsys Donors Inpatients
1.31 ⫾ 0.13 1.61 ⫾ 0.30
0.88 ⫾ 0.10 1.71 ⫾ 0.51
0.96 ⫾ 0.09 2.36 ⫾ 0.82
2.25 ⫾ 0.16 2.37 ⫾ 0.33
5.11 7.30 Troponin I (Vitros ECi System)
0.02 ⫾ 0.00 0.05 ⫾ 0.02
Donors Inpatients
0.00 ⫾ 0.00 0.01 ⫾ 0.01
0.05 ⫾ 0.01 0.19 ⫾ 0.10
0.11 0.37
Troponin T (Elecsys System) (Serum)
(Serum)
0.01 ⫾ 0 0.03 ⫾ 0.01
Donors Inpatients
0.01 0.15
TABLE 2 Hospital Inpatients Without Acute Coronary Syndrome Who Would Have Had Elevated Cardiac Marker Concentrations if Cutoffs Were Derived from Healthy Blood Donors CK-MB (Vitros ECi) Serum 13% (6/47)
CK-MB (Elecsys)
Troponin I (Vitros ECi)
Troponin T (Elecsys)
Heparin Plasma
EDTA Plasma
Serum
Serum
Heparin Plasma
EDTA Plasma
Serum
15% (7/46)
5% (2/44)
6% (3/47)
11% (5/47)
11% (5/46)
9% (4/44)
11% (5/47)
trations for cardiac markers than totally healthy volunteers. An elevation in cardiac-specific troponins in patients without ACS has been described in published data.14,15 It is possible that the cardiac specificity of these biomarkers is increased by careful selection of the most appropriate reference population. Similar discussions about optimal reference populations and cutoff values are already taking place for a variety of other laboratory markers, most notably prostate-specific antigen.16 We speculate that for cardiac markers, different patient populations will require the use of different cutoff values. Clearly, before the 99th percentile cutoff is established for cardiac markers, further studies of more heterogenous patient populations are crucially necessary. In summary, cutoff values for the cardiac markers troponin I and T and CK-MB derived from inpatients without ACS were always higher than thresholds derived from healthy blood donors. 1. Grasbeck R. Reference values, why and how. Scand J Clin Lab Invest
1990;201(suppl):45–53. 2. Lewis JS, Taylor JF, Miklos AZ, Virgo KS, Creer MH, Ritter DG. Clinical
significance of low-positive troponin I by AxSYM and ACS:180. Am J Clin Pathol 2001;116:396 –402. 3. Venge P, Lindahl B, Wallentin L. New generation cardiac troponin I assay for the Access immunoassay system. Clin Chem 2001;47:959 –960. 4. Adams JE, Miracle VA. Cardiac biomarkers: past, present, and future. Am J Crit Care 1998;7:418 –423.
178 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
5. Solberg HE. Establishment and use of reference values. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia: WB Saunders, 1999:336 –358. 6. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. J Am Coll Cardiol 1997;29:43–48. 7. Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljungdahl L, Goldman B, Katus HA. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327:146 –150. 8. Olatidoye AG, Wu AHB, Feng Y-J, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies. Am J Cardiol 1998;81:1405–1410. 9. Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol 2001;38:478 –485. 10. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, et al, and TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA2001:286:2405–2412. 11. Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M, Katus H. It’s time for a change to a troponin standard. Circulation 2000;102:1216 –1220. 12. Apple FS, Wu AHB. Myocardial infarction redefined: role of cardiac troponin testing. Clin Chem 2001;47:377–379. 13. Antman E, Bassand J-P, Klein W, Ohman M, Sendon JLL, Ryden L, Simoons M, Tendera M. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000:36:959 – 969. 14. Wright SA, Sawyer DB, Sacks DB, Chyu S, Goldhaber SZ. Elevation of troponin I levels in patients without evidence of myocardial injury. JAMA 1997;278:2144. 15. Ng SM, Krishnaswamy P, Morrisey R, Clopton P, Fitzgerald R, Maisel AS. Mitigation of the clinical significance of spurious elevations of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers. Am J Cardiol 2001;87:994 –999. 16. Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery—what we have learned and where we are going. J Urol 1999;162: 293–306.
JULY 15, 2002
are often derived from healthy volunteers with no history of coronary artery disease or heart failure.2,3 However, cumulative clinical experience with creatine kinase (CK)-MB and troponin suggests that these markers may be elevated in a number of disease states other than acute coronary syndrome (ACS), including renal disease, chronic heart failure, and cardiomyopathies.4 An alternative to healthy volunteers is to use patients with diseases other than ACS for establishing reference values. Such an approach can be called a “goal-oriented concept of health.”5 To compare the implications of using different populations for reference values, we analyzed the concentrations of the cardiac markers CK-MB and troponin in healthy blood donors and compared them with those of hospitalized inpatients without ACS, heart failure, and renal disease. •••
Paired serum, heparin plasma, and ethylenediaminetetraacetic acid (EDTA) plasma samples were collected from 52 healthy blood bank donors (27 men and 25 women, average age 42 years). Unpaired serum (n ⫽ 47), heparin plasma (n ⫽ 46), and EDTA plasma (n ⫽ 44) samples were obtained from a total of 137 hospitalized patients (81 men and 56 women, average age 54 years). A staff physician reviewed the charts of all inpatients; patients with active ACS, heart failure, and renal failure were excluded from the study. Some inpatients had a history of prior coronary disease that was inactive at the time of the study. The Vitros ECi immunodiagnostics system, an automated enhanced chemiluminescence analyzer for plasma and serum samples (Ortho-Clinical Diagnostics, Rochester, New York), was used to determine concentrations of CK-MB and troponin I on all samples (sera, heparin plasma, and EDTA plasma). According to the manufacturer, the within-run coefficient of variation of this instrument at the lower cutoff investigated here is 2.8% for troponin I and 2.5% for CK-MB. In addition, sera were also analyzed for concentrations of CK-MB From the Divisions of Laboratory Medicine and Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. This report was supported in part by a grant from OrthoClinical Diagnostics, Rochester, New York. Dr. Lee-Lewandrowski’s address is: Clinical Laboratories, Massachusetts General Hospital, 55 Fruit Street, GRB 5 Chemistry, Boston, Massachusetts 02114-9206. E-mail: [email protected]. Manuscript received January 2, 2002; revised manuscript received and accepted March 21, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 July 15, 2002
MD,
and troponin T with the Roche Elecsys 1010 system, an electroluminescence immunoassay (Roche Diagnostics Corporation, Indianapolis, Indiana). According to the manufacturer, this instrument has a coefficient of variation of 4.2% for troponin T and of 1.5% for CK-MB at low concentrations. Average concentrations of cardiac markers were not markedly different in healthy blood donors compared with inpatients without ACS (Table 1). Except for troponin T on the Elecsys 1010 analyzer, the differences in the average concentrations in the 2 populations were not statistically significant (p ⬎0.05, 2-tailed t test). However, because of the larger variation in the hospital inpatients, 99th percentile cutoffs derived from blood donors were markedly different from those derived from inpatients. The clinical consequences of the population used for determining cutoff values are demonstrated in Table 2: If the 99th percentile cutoffs derived from the “healthy” donor population had been applied to hospital inpatients, a significant percentage of them (5% to 13%) would have had “elevated” cardiac marker concentrations. •••
The ramifications of these data are considerable, because it has been demonstrated that even minor ACS-related elevations in cardiac marker concentrations have significant implications for patient triage, therapy selection, and prognosis after ACS.6 –10 Importantly, the data in these studies have been generated from clinical trial populations enriched with a high percentage of patients with unstable coronary disease, wherein an elevated cardiac marker concentration is more likely related to acute coronary ischemia. In our population of non-ACS patients, despite a significant percentage of subjects demonstrating similar minor elevations in cardiac markers, no benefit would have been expected from such aggressive therapies. Previous discussions in published reports have focused on the value of the optimal cutoff for cardiac markers (i.e., the 97.5 percentile vs the 99th percentile).11–13 Our results stress the crucial role of the appropriate reference population used to derive the cutoff values for these diagnostic tests. The fundamental idea behind the concept of reference values is that they come from subjects who are relevant controls for patients under study.1 Because the population of patients presenting with symptoms of ACS is more similar to hospital patients than to healthy blood donors, it could be argued that such inpatients without ACS are better suited for establishing cutoff concen0002-9149/02/$–see front matter PII S0002-9149(02)02447-5
177
TABLE 1 Cardiac Marker Concentrations (in ng/ml) in Healthy Blood Donors and In-hospital Inpatients Without Acute Cardiac Syndromes Mean ⫾ SE
99th Percentile
Heparin Plasma
Serum
EDTA Plasma
Serum
Heparin Plasma
EDTA Plasma
3.74 6.87
2.68 10.64
2.63 16.34
0.01 0.16
0.19 1.83
Creatine Kinase-MB Vitros Donors Inpatients Elecsys Donors Inpatients
1.31 ⫾ 0.13 1.61 ⫾ 0.30
0.88 ⫾ 0.10 1.71 ⫾ 0.51
0.96 ⫾ 0.09 2.36 ⫾ 0.82
2.25 ⫾ 0.16 2.37 ⫾ 0.33
5.11 7.30 Troponin I (Vitros ECi System)
0.02 ⫾ 0.00 0.05 ⫾ 0.02
Donors Inpatients
0.00 ⫾ 0.00 0.01 ⫾ 0.01
0.05 ⫾ 0.01 0.19 ⫾ 0.10
0.11 0.37
Troponin T (Elecsys System) (Serum)
(Serum)
0.01 ⫾ 0 0.03 ⫾ 0.01
Donors Inpatients
0.01 0.15
TABLE 2 Hospital Inpatients Without Acute Coronary Syndrome Who Would Have Had Elevated Cardiac Marker Concentrations if Cutoffs Were Derived from Healthy Blood Donors CK-MB (Vitros ECi) Serum 13% (6/47)
CK-MB (Elecsys)
Troponin I (Vitros ECi)
Troponin T (Elecsys)
Heparin Plasma
EDTA Plasma
Serum
Serum
Heparin Plasma
EDTA Plasma
Serum
15% (7/46)
5% (2/44)
6% (3/47)
11% (5/47)
11% (5/46)
9% (4/44)
11% (5/47)
trations for cardiac markers than totally healthy volunteers. An elevation in cardiac-specific troponins in patients without ACS has been described in published data.14,15 It is possible that the cardiac specificity of these biomarkers is increased by careful selection of the most appropriate reference population. Similar discussions about optimal reference populations and cutoff values are already taking place for a variety of other laboratory markers, most notably prostate-specific antigen.16 We speculate that for cardiac markers, different patient populations will require the use of different cutoff values. Clearly, before the 99th percentile cutoff is established for cardiac markers, further studies of more heterogenous patient populations are crucially necessary. In summary, cutoff values for the cardiac markers troponin I and T and CK-MB derived from inpatients without ACS were always higher than thresholds derived from healthy blood donors. 1. Grasbeck R. Reference values, why and how. Scand J Clin Lab Invest
1990;201(suppl):45–53. 2. Lewis JS, Taylor JF, Miklos AZ, Virgo KS, Creer MH, Ritter DG. Clinical
significance of low-positive troponin I by AxSYM and ACS:180. Am J Clin Pathol 2001;116:396 –402. 3. Venge P, Lindahl B, Wallentin L. New generation cardiac troponin I assay for the Access immunoassay system. Clin Chem 2001;47:959 –960. 4. Adams JE, Miracle VA. Cardiac biomarkers: past, present, and future. Am J Crit Care 1998;7:418 –423.
178 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
5. Solberg HE. Establishment and use of reference values. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia: WB Saunders, 1999:336 –358. 6. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. J Am Coll Cardiol 1997;29:43–48. 7. Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljungdahl L, Goldman B, Katus HA. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327:146 –150. 8. Olatidoye AG, Wu AHB, Feng Y-J, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies. Am J Cardiol 1998;81:1405–1410. 9. Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol 2001;38:478 –485. 10. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, et al, and TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA2001:286:2405–2412. 11. Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M, Katus H. It’s time for a change to a troponin standard. Circulation 2000;102:1216 –1220. 12. Apple FS, Wu AHB. Myocardial infarction redefined: role of cardiac troponin testing. Clin Chem 2001;47:377–379. 13. Antman E, Bassand J-P, Klein W, Ohman M, Sendon JLL, Ryden L, Simoons M, Tendera M. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000:36:959 – 969. 14. Wright SA, Sawyer DB, Sacks DB, Chyu S, Goldhaber SZ. Elevation of troponin I levels in patients without evidence of myocardial injury. JAMA 1997;278:2144. 15. Ng SM, Krishnaswamy P, Morrisey R, Clopton P, Fitzgerald R, Maisel AS. Mitigation of the clinical significance of spurious elevations of cardiac troponin I in settings of coronary ischemia using serial testing of multiple cardiac markers. Am J Cardiol 2001;87:994 –999. 16. Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery—what we have learned and where we are going. J Urol 1999;162: 293–306.
JULY 15, 2002