Cost-Effective Utilization of CK-MB Mass and Activity Assays

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1 CHEMISTRY Lokinendi V. Rao, PhD, SC(ASCP) John R. Petersen, PhD, DABCC Amin A. Mohammad, PhD, DABCC Michael G. Bissell, MD, PhD, MPH Anthony. Okorodudu, PhD, MS(MCS), DABCC Cost-Effective Utilization of CK-MB Mass and Activity Assays Evaluation of Patients With Chest Pain in the Emergency Department Managed care and fixed capitation payments are fundamentally changing the economics of health care. In response to these changes, health care organizations are exploring ways to reduce costs while maintaining quality. Reduction of unit cost per procedure, efficient use of services, and improvement of patient care outcomes are currently the key indicators monitored by administrators. During this economic period, clinical laboratory tests are being evaluated relative to diagnoses and management of patients, and new laboratory tests that may enhance patient care are being introduced. New tests in diagnosis of the cause of chest pain include myoglobin,1 troponin,2 and creatine kinase M and B isoforms (CK-MB).3 Despite aggressive investigation aimed at defining the diagnostic advantage of the new tests, at best they are still equivalent to the traditional CK-MB test if it is used as recommended by the World Health Organization (WHO) standard for the diagnosis of acute myocardial infarction (AMI).4 Emergency department health care providers spend a large proportion of their time evaluating and caring for more than 1.7 million patients with chest pain each year.5 The cost of providing health care for these patients is estimated at $5 billion to $1 billion per year,6 and is projected to increase substantially in the future because of the new diagnostic cardiac markers. To curtail this increasing cost, health care providers must optimize clinical assessment protocols to ensure accurate diagnosis, timely intervention, and appropriate discharge of patients with chest pain. From the Clinical Chemistry Division, Department of Pathology, University of Texas Medical Branch, Galveston (Drs Rao, Petersen, Mohammad, Okorodudu); and the Division of Clinical Pathology, Allegheny General Hospital, Pittsburgh (Dr Bissell). Reprint requests to Dr Okorodudu, Clinical Chemistry Division, Department of Pathology, University of Texas Medical Branch, Galveston, TX ; or utmb.edu ABSTRACT Effective use of creatine kinase M and B isoform (CK-MB) test results for the diagnosis or exclusion of acute myocardial infarction (AMI) requires repeated analyses at defined intervals after the onset of chest pain. An increase in serum CK-MB is evaluated relative to typical angina-like chest pain of at least 3 minutes duration and electrocardiographic changes per World Health Organization (WHO) standards. Two or more of the threefindingsmust be abnormal for the diagnosis of AMI. We assessed the appropriateness (clinical usefulness) and cost-effectiveness of CK-MB mass and activity levels in the care of patients with complaints of chest pain seen in our emergency department. The total CK and CK-MB (mass and activity) results for 86 patients during 2 months in 1995 were reviewed retrospectively c relative to the discharge diagnosis. According to the discharge 3 Q diagnoses based on the WHO diagnostic criteria for AMI, e only 54 patients (6.3%) had acute myocardial infarction. 3 E Three or more CK-MB tests (mass and activity measuree o ments) were performed in 6.5% of patients, and only one U o test was performed in the remaining 39.5%. Abnormal CKc MB mass or activity was determined with the following «'u criteria: Protocol 1: CK-MB mass >5 ng/ml, total CK >194 W U/L, index >2.5%; Protocol 2: CK-MB activity >16 U/L, total CK >65 U/L, index >5%; Protocol 3: CK-MB activity >1 c U/L, total CK >65 U/L, index >2.2%. Based on these criteria, CK-MB mass and activity protocols gave positive predictive values of 38.2%, 36.1%, and 35.4% for protocols 1, 2, and 3, respectively. The negative predictive value was 99% for CKMB mass (Protocol 1), and 98% and 98.9% for CK-MB activity (Protocols 2 and 3). These results indicate that both CK-MB mass and activity protocols have equivalent clinical usefulness. However, given the technologic limitation of two platforms for Protocol 1 vs one assay platform for Protocols 2 and 3, the CK-MB activity protocol is more cost-effective for patient testing in the emergency department laboratory. on 12 December 217 O VOLUME 3, NUMBER 4 LABORATORY MEDICINE 271

Table 1. CK-MB Test Ordering Patterns in Patients With Chest Pain in the Emergency Department: University of Texas Medical Branch, September-October 1995 _ No. of patients 86 No.

2 Table 1. CK-MB Test Ordering Patterns in Patients With Chest Pain in the Emergency Department: University of Texas Medical Branch, September-October 1995 _ No. of patients 86 No. of tests performed 2,44 No. of patients for whom only 1 test was performed 34 (39.5%) No. of patients for whom 3 or more tests were performed 52 (6.5%) No. of patients with final discharge diagnosis of myocardial infarction Fig 1. Reaction creatine kinase (CK) activity Clinical signs and symptoms, history of coronary disease, and electrocardiogram findings appear to be reliable indices of risk for AMI and are usually the basis for diagnosis.7 However, these subjective indices must be supported with other quantitative criteria such as cardiac markers. The need for cardiac markers is further justified in that in approximately 5% of patients with chest pain the diagnosis cannot be made with certainty on the basis of electrocardiogram findings.8'9 Currently, the most predominantly used cardiac marker in the protocols established to rule out AMI is serum CK-MB.1,11 To make the diagnosis, physicians rely on results obtained from serial electrocardiograms and CK-MB tests performed from 24 to 36 hours after the onset of chest pain. The analytical (instrument) part of the determination of CK-MB takes approximately 6.5 to 14.5 minutes, depending on whether the laboratory uses a CK-MB mass assay or CK-MB activity assay protocol. The CK-MB mass measurement is a fluorometric enzyme immunoassay, and the CKMB activity measurement is an immunoinhibition assay. Immunoinhibition assays are widely used because they are inexpensive, available on standard high-volume clinical laboratory instruments, and easily adaptable to current workflow. The diagnostic efficiency of CK-MB mass vs CK-MB activity in patients with AMI continues to be controversial.12'13 The indication for AMI with the CK-MB test was based on the following criteria: Creatine Phosphate + ADP ATP + Glycerol H Leukodye Protocol 1: CK-MB mass result >5 ng/ml, total CK result >194 U/L, index >2.5% Protocol 2: CK-MB activity result >16 U/L, total CK result >65 U/L, index >5% Protocol 3: CK-MB activity result >1 U/L, total CK result >65 U/L, index >2.2% We retrospectively evaluated CK-MB mass and total CK concentration vs CK-MB activity and total CK protocols. These protocols were evaluated in terms of sensitivity, specificity, positive predictive value, and negative predictive value as determined by the discharge diagnosis. The appropriate choice of either CK-MB mass or CKMB activity assay protocol in improvement of triage of patients with chest pain can result in substantial cost savings to the health care system. Patients and Methods We retrospectively reviewed data for 86 patients obtained during September and October All patients had chest pain and were seen in the emergency department at the University of Texas Medical Branch, Galveston. Table 1 shows the CK-MB test ordering pattern for all patients during the study period. A total of 2,44 CK-MB tests for mass and activity measurements were retrieved from the patients' electronic records, and total CK and CK-MB mass and activity indices were evaluated relative to discharge diagnoses. CK Creatine + ATP NAC, M g 2 f GK a-glycerophosphate + ADP a-glycerophosphate (6.3%) Dihydroxyacetone Phosphate + H 2 2 POD 272 LABORATORY MEDICINE VOLUME 3, NUMBER 4 on 12 December 217 * Dye + H 2

$Anti-CK-M Antibody CK-MM + CK-MB CK-B Creatine Phosphate + ADP a-glycerophosphate +, H 2 2 + Leukodye Total CK and CK-MB Activity Assays l\/ir _i_ C\( UIN-IVID l\/1m _i_ P l ^ D D + ur\-ivirvi +$

3 Anti-CK-M Antibody CK-MM + CK-MB CK-B Creatine Phosphate + ADP a-glycerophosphate +, H Leukodye Total CK and CK-MB Activity Assays l\/ir _i_ C\( UIN-IVID l\/1m _i_ P l ^ D D + ur\-ivirvi + I^N-DD GK Creatine + ATP a-gpo a-glycerophosphate + ADP Dihydroxyacetone Phosphate + H 2 2 POD Dye + H 2 CK-MB Mass Assay 15 Total CK and CK-MB activity assays were performed on an Ektachem 7XRC analyzer (Johnson & Johnson Clinical Diagnostics, Rochester, NY). The activities were measured by conversion of creatine phosphate to creatine and adenosine triphosphate (ATP). The generated ATP is reacted with glycerol in a reaction catalyzed by glycerol kinase to produce a-glycerophosphate, which is converted to dihydroxyacetone phosphate and hydrogen peroxide. The hydrogen peroxide is reacted with a leucodye to form a colored product. The enzyme activity is proportional to the rate of change in the reflection density produced by the colored product (Fig 1). To measure CK-MB activity, an anti-ck-m antibody is used to inhibit the M subunit in the CK-MB molecule prior to the enzymatic activity (Fig 2). The resultant activity in the immunoinhibition reaction is multiplied by a factor of 2 to obtain CK-MB activity, reported as units per liter. CV CK-M Inhibition -» NAC, M g 2 + ATP + Glycerol 14 - _ CK-MB mass assays were performed with the Stratus fluorometric enzyme immunoassay (Dade International, Deerfield, 111).16 This two-site sandwich immunoassay measures immunologic activity of CK-MB, not enzyme activity (Fig 3). The assay utilizes the reaction of CK-MB in the sample with immobilized monoclonal anti-ck-mb antibody on a glass fiber paper. After a short incubation an alkaline phosphatase-conjugated anti-ck-bb antibody is added to the glass filter paper. The labeled antibody reacts with the B subunit of the antibody-bound CK-MB to form a sandwich of antibody and antigen-labeled antibody. A substrate wash solution is added to remove unbound conjugate. The resultant fluorescent intensity is directly proportional to the CKMB mass in the sample. The results are reported in nanograms per milliliter. Anti-CK-MB Antibody ^ ^ ^ A I-, r\/ Fig 2. Reaction creatine kinase (CK)-MB activity Fig 3. Reaction creatine kinase (CK)-MB mass i\ A n A D, - Ulx-IVILJ Enzyme-labeled AbrCK-MB - Anti-CK-BB -». Ah CK M R Ah (Elution of unbound enzyme-labeled anti-ck-bb) 4-methylumbelliferylphosphate AbrCK-MB-Ab2 on 12 December 217 _ Methylumbelliferone + Phosphate VOLUME 3. NUMBER 4 LABORATORY MEDICINE

4 Table 2. Diagnostic Characteristics of CK-MB Mass and Activity Assays in Final Diagnosis of Acute Myocardial Infarction Parameter True positive CK-MB Mass Protocol 1 47 CK-MB Activity Protocol 2 Protocol I 15 8 True negative False positive Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) False negative Data Analysis The CK-MB mass protocol (Protocol 1) and CKMB activity protocols (Protocols 2 and 3) were used to retrospectively evaluate the discharge diagnoses for sensitivity, specificity, and positive and negative predictive values. Only patients with a final diagnosis of AMI were included as true positives for AMI; all the other patients were classified as negative for AMI, and further classification was not warranted. The cost of CK-MB mass vs CKMB activity protocols was estimated relative to true analytical time. Results and Discussion Fifty-four (6.3%) of 86 patients with chest pain had a final discharge diagnosis of AMI. This is similar to the prevalence rate of AMI across the United States. On average, 2.8 CK-MB measurements were obtained in each patient (Table 1). Thorough evaluation of the data reveals a discrepancy between patients for CK-MB testing. Multiple (three or more) measurements were obtained in approximately 6.5% of patients, compared with only one measurement in 39.5%. This discrepancy may in part be explained by the fact that Sfe clinical findings at presentation and electrocardiogram results did not support further CK-MB testing after the first set of results. Table 2 summarizes the data for sensitivity, specificity, and positive and negative predictive values. Diagnostic sensitivity was comparable for CK-MB mass with Protocol 1 (87.%) and CK-MB activity with Protocol 3 (85.2%). The poorer diagnostic sensitivity for CKMB activity with Protocol 2 is attributable to the choice of reference cutoff value. It is expected that receiver operating characteristic (ROC) curve analysis for optimum determination of the reference value for CK-MB activity will enhance the diagnostic sensitivity of the CK-MB activity assay. Results for diagnostic specificity and predictive values were comparable for the three protocols. The impact of the three protocols on diagnostic time is shown in Table 3. The time presented in this table is for analysis only with instruments. Approximately 8 more minutes are required to perform the tests with the CK-MB mass Protocol 1 than with the CK-MB activity Protocols 2 and 3. Any attempt to aliquot the samples prior to analysis in Protocol 1 will introduce additional variables, such as pipetting and other technical errors. Table 3. Estimated Time for Analysis of CK-MB and Total CK* Protocol 1 CK-MB mass assay Step A Total CK assay with Ektachem 7XRC analyzer: approximately 7 min Step B CK-MB mass assay with Stratus Intellect: approximately 8 min StepC Manual entry of CK-MB results in laboratory information system, calculation of index, and result verification: 2-3 min Protocols 2 and 3 CK-MB activity assay Step A Total CK and CK-MB activity assays with Ektachem 7XRC analyzer: approximately 8 min Step B Online result transmission and automatic calculation of index: 1-2 min E *An 8-min difference in time is noted for Protocol 1 compared with Protocol 2 or 3. The Ektachem 7XRC is manufactured by Johnson & Johnson Clinical Diagnostics (Rochester, NY); the Stratus Intellect is manufactured by Dade International (Deerfield, III). 274 LABORATORY MEDICINE VOLUME 3, NUMBER 4 on 12 December 217

5 Conclusion References Increased use of health services seems inevitable as our population increases and ages. This pattern of growth calls for innovative cost management if we are to remain in business in this economic era of managed care, health maintenance organizations, and intense competitive pricing schemes. Costcutting measures must include thorough evaluation of clinical outcome of patient care. We retrospectively evaluated the use of CK-MB mass vs activity measurements in the management of patients with chest pain. The results obtained are comparable to those of previous reports6'17"19 for diagnostic sensitivity, specificity, and predictive values. It is therefore unequivocally documented that CK-MB mass and CK-MB activity assays can lead to the same clinical outcome when used as recommended by the WHO standard for the diagnosis of AMI.6 Given the clinical equivalence of the two CKMB assays, laboratories must address the need for faster turnaround times to ensure that therapeutic interventions are initiated promptly. The operational setup for Protocol 1 requires the use of two different analyzers (Ektachem and Stratus), which means higher operational cost than for Protocols 2 and 3. The cost includes time for daily and periodic scheduled maintenance, and acquisition. Additional cost is associated with the minimum of 8 minutes required for the assay in Protocol 1 relative to Protocols 2 and 3. This cost for a protocol that does not add any tangible benefit to patient care is estimated to be in excess of $5, at our institution. In summary, the CK-MB mass and activity protocols are equivalent with respect to clinical outcome for the patient with chest pain. Testing protocols should be evaluated per the WHO recommended standard, which requires serial determination of CK-MB. Reports that deviate from the recommended testing protocol may lead to incorrect clinical outcomes. In this period of managed health care, it is recommended that laboratories evaluate the testing platforms relative to patient care outcomes and cost. 1. Vaidya HC. Myoglobin. Lab Med. 1992;23: Katus HA, Scheffold T, Remppis A, et al. Cardiac troponins in patients with chest pain. N Engl J Med. 1998;338(18): Wu HB. Creatine kinase MM and MB isoforms. Lab Med. 1992;23: World Health Organization. Criteria for the Diagnosis of Acute Myocardial Infarction: Proposal for the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease. Geneva, Switzerland: Cardiovascular Disease Unit of World Health Organization; American Heart Association. 199 Heart Facts. Dallas, Tex: American Heart Association National Center. 199; Gibler WB, Runyon JP, Levy RC, et al. A rapid diagnostic and treatment center for patients with chest pain in the emergency department. Ann Emerg Med. 1995;25: Gillum RF, Fortmann SP, Prineas R), et al. International diagnostic criteria for acute myocardial infarction and acute stroke. Am Heart]. 1984;18: Young GP, Green TR. The role of singe ECG, creatine kinase, and CKMB in diagnosing patients with acute chest pain. Am J Emerg Med. 1993; 11: Gibler WB, Lewis LM, et al. Early detection of myocardial infarction in patients presenting with acute pain and nondiagnostic ECGs: serial CKMB sampling in the emergency department. Ann Emerg Med. 199;19: Adams IE III, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury: Is MB creatine kinase the choice for the 199s? Circulation. 1993;88: ll.bhayana V, Henderson AR. Biochemical markers of myocardial damage. Clin Biochem. 1995;28: Van Blerk M, Maes V, Huyghens L, et al. Analytical and clinical evaluation of creatine kinase MB mass assay by Imx: comparison with MB isoenzyme activity and serum myoglobin for early diagnosis of myocardial infarction. Clin Chem. 1992;38: Ooi DS, Maddock MJ, Livesey JR, et al. Creatine kinase-mb by immunoinhibition in the diagnosis of suspected acute myocardial infarction. Clin Biochem. 1996;29: Kodak Ektachem Clinical Chemistry Slide (CK). Kodak test methods manual. 1992; Publ No. MP Kodak Ektachem Clinical Chemistry Slide (CK-MB). Kodak test methods manual. 1992; Publ No. MP Stratus CK-MB Fluorometric Enzyme Immunoassay, for determination of CK-MB levels in human serum Ipackage insert]. Deerfield, 111: Dade International. 17. Mair I, Morandell D, Genser N, et al. Clin Chem. 1995;41: Mohler E, Ryan T, Segar DS, et al. Clinical utility of troponin T levels and echocardiography in the emergency department. Am Heart J. 1998;135: Painter PC, Meter SV, Dabbs RL, et al. Analytical evaluation and comparison of Dupont aca lactate dehydrogenase-1 isoenzyme assay diagnostic efficiency for acute myocardial infarction detection with other LD1 methods and aca CKMB. / VascDis. 1994;45: on 12 December 217 VOLUME 3. NUMBER 4 LABORATO

BIOCHEMICAL INVESTIGATIONS IN THE DIAGNOSTICS OF CARDIOVASCULAR DISORDERS. As. MARUSHCHAK M.I.

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