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Circulation. 1996;93:1618-1620

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(Circulation. 1996;93:1618-1620.)
© 1996 American Heart Association, Inc.

Articles

Risk Stratification in Patients With Unstable Angina

`Déjà Vu All Over Again'?

Bertram Pitt, MD

From the Cardiology Division, University of Michigan Medical Center, Ann Arbor, Mich.

Correspondence to Bertram Pitt, MD, UM Medical Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0366.


Key Words: Editorials • risk factors • angina


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Considerable progress has occurred in our understanding of the pathophysiology and therapy of unstable angina pectoris.1 2 3 Knowledge concerning the importance of plaque rupture and thrombosis formation has led to the use of intravenous heparin, aspirin, and exploration of new antiplatelet strategies in conjunction with antianginal therapy. Despite this increased understanding in the use of antithrombotic and antianginal therapy, the fear of subsequent infarction and death remains great. These fears have led to a strategy in clinically determined high-risk and many intermediate-risk patients of coronary angiography and revascularization after stabilization before or soon after hospital discharge.1 Delay in performing coronary angiography for several weeks to months because of inadequate resources has been associated with a relatively high risk of ischemic events and death.4 While a strategy of coronary angiography and revascularization (often without prior stress testing) may reduce the risk of ischemic events and death, it is nevertheless associated with an increased risk of acute complications and restenosis as well as increased cost. New strategies such as the use of stents and/or the platelet 7E3 glycoprotein 2B3A antibody hold great promise for further benefit, with a reduction in ischemic events and restenosis, but may add to cost. While the strategy of coronary angiography, revascularization, and exploration of new but expensive antithrombotic strategies is in my opinion appropriate in patients at high or intermediate risk of recurrent ischemic events, it may not be necessary in all. One of the most important challenges in the management of patients with unstable angina is risk stratification, most importantly to identify patients at low risk of subsequent ischemic events who could be treated by conventional medical therapy without the need for new and expensive antiplatelet agents and/or revascularization.

Several studies have suggested that determination of biochemical markers such as myoglobin, CK-MB mass or isoforms, and/or troponin T may be a valuable addition to CK-MB in the early evaluation of patients with suspected myocardial infarction.5 6 7 8 Use of these markers has been suggested to be useful in triaging patients presenting to the emergency room with a diagnosis of "rule out myocardial infarction," confirming the presence and extent of myocardial necrosis, reperfusion, and reinfarction. Several studies have shown that the release of these biochemical markers in patients with unstable angina without other clinical, ECG, or enzyme evidence of acute myocardial infarction identifies a group who are at increased risk of subsequent ischemic events and death. These studies, however, have been relatively small with a short follow-up. Thus, the recent clinical practice guidelines—Unstable Angina: Diagnosis and Management—concluded in regard to determination of CK-MM, MB isoforms, troponin T, troponin I, myoglobin, and myosin light chains that "at present, none of these approaches has been established as providing more accurate diagnostic information than CK-MB. Thus, these tests are not currently recommended as part of standard practice."1 Since that time, there has been increasing evidence in patients with unstable angina that release of these markers identifies a group of patients, approximately one fifth to one third of all patients presenting with a diagnosis of unstable angina, who have an increased risk of ischemic events. For example, Wu et al9 identified 131 consecutive patients with unstable angina who underwent determination of CK, CK-MB, and troponin T. They found that 27 of the 131 (21%) had an elevated troponin T level (>=0.1 ng/mL) on admission compared with only 8 who had an elevated CK-MB, using a cutoff point of 5 or 10 ng/mL, all of whom also had an elevated troponin T level. Thirty percent of those with an elevated troponin T level had a myocardial infarction within the 3-week follow-up period compared with approximately 3% of those with a troponin T level <1 ng/mL. Overall, 26 of the 27 patients (96%) with an elevated troponin T level had a major coronary event compared with 46 of 104 (44%) with a level <0.1 ng/mL. In the GUSTO IIA Study, Ohman et al10 evaluated 334 patients with chest pain presenting without initial ST-segment elevation. Patients with a troponin T level >0.1 ng/mL had a 9% incidence of death, 6% shock, 11% myocardial infarction, and 16% incidence of congestive heart failure compared with 1%, 2%, 6%, and 7%, respectively, in those with a troponin T level less than this.10 Similarly, Ravkilde et al,11 in 124 consecutive patients with suspected acute myocardial infarction but without CK elevation or ECG evidence of myocardial infarction, found that 28% of the patients had an elevated serum CK-MB mass >=6 µg/L, 20% had a troponin T level >=0.2 µg/L, and 26% had elevated myosin light chain levels >=0.4 µg/L. The cardiac event rate within 28 months was 22% to 24% in those with biochemical evidence of necrosis compared with a 3% to 5% event rate in those without elevation of these biochemical markers or conventional criteria of myocardial infarction.

These observations have now been further extended by Lindahl et al,12 who in studying 976 patients with unstable coronary artery disease participating in a randomized study of low-molecular-weight heparin identified on a retrospective basis 593 with a diagnosis of unstable angina who were subsequently followed for a period of 5 to 6 months. Patients with unstable angina and a troponin T level <0.06 µg/L on admission, approximately one third of patients, had a risk of cardiac death or myocardial infarction of 4.4% compared with an 11.4% risk in those with a troponin T level of 0.06 to 0.18 µg/L and a 14% risk in those with a troponin T level >=0.18 µg/L. Patients with a troponin T level of <0.06 µg/L without ST-segment changes on their admission ECG had a 3% risk compared with an 18% risk in those with a troponin T level >0.18 µg/L and ST-T wave changes. The authors suggest that patients with a troponin T level <0.06 µg/L, who have a low risk of subsequent myocardial infarction and/or cardiac death, be discharged from the hospital early and followed on medical therapy as outpatients, whereas those at intermediate risk (troponin T level, 0.06 to 0.18 µg/L) be further stratified by other variables, such as the admission ECG, to determine a low-risk group that can be discharged on medical therapy. They suggest that the high-risk group, including those with a troponin T level >0.18 µg/L, require intensive medical and/or interventional therapy while in the hospital. The explanation for the increased risk in those with an elevated troponin T level but without clinical, ECG, or CK evidence of acute myocardial infarction is suggested to be due to subclinical myocardial necrosis and/or increased membrane permeability as a result of more extensive or prolonged ischemia.

While the ability to stratify patients with unstable angina by detection of subclinical myocardial necrosis is important, the concept is not new. Willerson et al,13 using the infarct avid imaging agent 99mTc pyrophosphate, found patients with the clinical diagnosis of unstable angina without CK elevation who had a positive pyrophosphate image. These patients have been shown to have evidence of myocardial necrosis at autopsy and a relatively poor prognosis. Although this information has been available for two decades, it has had relatively little impact on clinical practice. There may be several reasons for not using this information to affect clinical decision making, including difficulties in obtaining, timing, and interpreting, as well as the cost of pyrophosphate imaging. Biochemical markers such as troponin T or CK-MB mass, in contrast to pyrophosphate imaging, are easy to obtain, available relatively early, easy to interpret, and relatively inexpensive. However, I believe that we still need further information before we can reliably use the information from troponin T and other biochemical markers to alter current clinical practice. While elevated levels of troponin T >0.18 µg/L clearly identify a high-risk group that needs to be treated aggressively and evaluated for revascularization, if there are no contraindications, what is really needed is confidence in identifying a truly low-risk group (<=1% incidence of ischemic events per 6 months to 1 year). I do not believe that the finding of a troponin T level of <0.06 µg/L, which identifies a subset with a 3% to 4% 6-month risk of ischemic events, would allow discharge from the hospital for medical management without further testing, at the very least by pharmacological or exercise stress testing. However, it is likely that determination of troponin T in conjunction with other clinical variables, such as those recently described by Rizik et al,14 Holter ECG monitoring,15 determination of markers suggesting a hypercoagulable state,16 and/or increased cytokine activity,17 will be of value. Determination of absolute levels of markers indicative of a hypercoagulable state may not be as important as their timing, ie, persistence after optimal medical therapy. It is also likely, at least in those with intermediate or low risk by troponin T levels, that resting myocardial scanning and/or stress testing will be of value in identifying a truly low-risk group with <=1% ischemic events per 6 months to 1 year. For example, Stratmann et al,18 using resting 99mTc sestamibi myocardial tomography in 126 patients with unstable angina, found a 2% risk of recurrent ischemic events in patients with a negative sestamibi scan compared with a 25% incidence of ischemic events in patients with a reversible defect. Hilton et al,19 in 102 patients with chest pain and a nondiagnostic ECG on presentation to the emergency room, found an abnormal sestamibi scan to predict a 71% event rate compared with a 1.4% rate in those with a negative scan. Exercise or pharmacological stress testing also has been found to be valuable in identifying patients with unstable angina at low risk for subsequent ischemic events.20

Thus, the results of the study by Lindahl et al12 using troponin T to stratify patients with unstable angina are encouraging and will likely find important application in areas of the world with limited availability for coronary angiography and revascularization. However, I am not convinced that determination of troponin T alone, or any other marker of myocardial necrosis, will be sufficient to determine a truly low-risk group (<=1% risk of ischemic events per 6 months to 1 year) and alter clinical practice in the United States. The challenge is to use these encouraging, easily obtainable biochemical markers of myocardial necrosis in conjunction with clinical variables, markers of platelet activation, and the results of rest and/or stress myocardial imaging to feel confident in discharging a patient with unstable angina without considering the need for coronary angiography, revascularization, or other high-cost antithrombotic strategies. If we rush to apply the information from troponin T without further prospective clinical evaluation and confidence in the risk stratification algorithm, we may not alter clinical practice any more than we did two decades ago with 99mTc pyrophosphate imaging, and it will be "déjà vu all over again."21


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Braunwald E, Jones RH, Mark DB, Brown J, Brown L, Cheitlin MD, Concannon CA, Cowan M, Edwards C, Fuster V, Goldman L, Green LA, Grines CL, Lytle BW, McCauley KM, Mushlin AI, Rose GC, Smith EE III, Swain JA, Topol EJ, Willerson JT. Diagnosing and managing unstable angina: Agency for Health Care Policy and Research. Circulation. 1994;90:613-622. [Abstract/Free Full Text]
  2. Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes: part 1. N Engl J Med. 1992;326:242-250. [Medline] [Order article via Infotrieve]
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  4. Chester M, Chen L, Kaski JC. Identification of patients at high risk for adverse coronary events while awaiting routine coronary angioplasty. Br Heart J. 1995;73:216-222. [Abstract/Free Full Text]
  5. Katus HA, Yasuda T, Gold HK, Leinbach RC, Strauss HW, Waksmonski C, Haber E, Khaw BA. Diagnosis of acute myocardial infarction by detection of circulating cardiac myosin light chains. Am J Cardiol. 1984;54:964-970. [Medline] [Order article via Infotrieve]
  6. Katus HA, Remppis A, Neumann FJ, Scheffold T, Diederich KW, Vinar G, Noe A, Matern G, Kuebler W. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation. 1991;83:902-912. [Abstract/Free Full Text]
  7. Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljundahl L, Goldmann B, Katus HA. The prognostic value of serum troponin T in unstable angina. N Engl J Med. 1992;327:146-150. [Abstract]
  8. Pettersson T, Ohlsson O, Tryding N. Increased CKMB (mass concentration) in patients with traditional evidence of acute myocardial infarction: a risk indicator of coronary death. Eur Heart J. 1992;13:1387-1392. [Abstract/Free Full Text]
  9. Wu AHB, Abbas SA, Green S, Pearsall L, Dhakam S, Azar R, Onoroski M, Senaie A, McKay RG, Waters D. Prognostic value of cardiac troponin T in unstable angina pectoris. Am J Cardiol. 1995;76:970-972. [Medline] [Order article via Infotrieve]
  10. Ohman EM, Armstrong P, Califf RM, O'Hanesian MA, Hamm CW, Katus H, Granger CB, Christenson RH, Cianciolo C, Topol EJ, for the GUSTO-IIa Investigators. Risk stratification in acute ischemic syndromes using serum troponin T. J Am Coll Cardiol. 1995;SI:148A. Abstract.
  11. 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. [Abstract]
  12. Lindahl B, Venge P, Wallentin L, and the FRISC Study Group. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation. 1996;93:1651-1657. [Abstract/Free Full Text]
  13. Willerson JT, Parkey RW, Bonte FJ, Meyer SL, Atkins JM, Stokley EM. Technetium stannous pyrophosphate myocardial scintigrams in patients with chest pain of varying etiology. Circulation. 1975;51:1046. [Abstract/Free Full Text]
  14. Rizik DG, Healy S, Margulis A, Vandam D, Bakalyar D, Timmis G, Grines C, O'Neill WW, Schreiber TL. A new clinical classification for hospital prognosis of unstable angina pectoris. Am J Cardiol. 1995;75:993-997. [Medline] [Order article via Infotrieve]
  15. Bugiardini R, Borghi A, Pozzati A, Ruggeri A, Puddu P, Maseri A. Relation of severity of symptoms to transient myocardial ischemia and prognosis in unstable angina. J Am Coll Cardiol. 1995;25:597-604. [Abstract]
  16. Hoffmeister HM, Jur M, Wendel HP, Heller W, Seipel L. Alterations of coagulation and fibrinolytic and kallikrein-kinin systems in the acute and postacute phases in patients with unstable angina pectoris. Circulation. 1995;91:2520-2527. [Abstract/Free Full Text]
  17. Ikeda H, Takajo Y, Ichiki K, Ueno T, Maki S, Noda T, Sugi K, Imaizumi T. Increased soluble form of P-selectin in patients with unstable angina. Circulation. 1995;92:1693-1696. [Abstract/Free Full Text]
  18. Stratmann HG, Younis LT, Wittry MD, Amato M, Miller DD. Exercise technetium-99m myocardial tomography for the risk stratification of men with medically treated unstable angina pectoris. Am J Cardiol. 1995;76:236-240.[Medline] [Order article via Infotrieve]
  19. Hilton TC, Thompson RC, Williams HJ, Saylors R, Fulmer H, Stowers SA. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room for evaluation of chest pain. J Am Coll Cardiol. 1994;23:1016-1022. [Abstract]
  20. Beller GA. Radionuclide imaging in unstable angina pectoris. In: Beller GA, ed. Clinical Nuclear Cardiology. Philadelphia, Pa: WB Saunders Co; 1995:236-247.
  21. Berra, Yogi (Lawrence Peter). `It was déjà vu all over again.' Attribution. In: Bartlett J, Kaplan J, eds. Bartlett's Familiar Quotations. 16th ed. Boston, Mass: Little, Brown & Co; 1992:754.



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