Contemporary strategies to rule out myocardial infarction

EVOLVING KNOWLEDGE

on the ability of TnT to perform effectively remains an area where further investigation is needed. The most salient feature of TnT measurement is its unique ability to risk stratify patients after either MI or unstable angina. However, risk stratification probably requires multiple quantitative determinations to detect the transient lowlevel release associated with an adverse outcome. Importantly, the presence of a negative TnT value must not be used as the sole criterion for electing conservative treatment or early discharge. In selecting the most appropriate treatment course, no marker can substitute for clinical judgement, which requires consideration of all of the variables, including patient demographics, risk factors, history and the ECG.

are 30 to 90 minutes into the course of their AMI. This review will examine the role of currently available diagnostic tools as they relate to this strategy of expeditious diagnosis. Electrocardiogram The quickest, easiest and least expensive test to obtain is a 12-lead electrocardiogram (ECG). Although physicians typically expect to find ST segment elevation in patients presenting with AMI, this change is not always evident within the aforementioned time frame. In the Multicenter Chest Pain Study, only 45% of patients presenting with AMI had ST segment elevation, while 10% of patients had normal or nondiagnostic ECGs. Despite this, admission ECGs demonstrating any evidence of ischemia had a 79% sensitivity and an 83% specificity for diagnosing AMI (1). In an era in which rapid, accurate diagnosis is essential to maximize the benefits of proven interventions, the ECG alone may not suffice in all instances.

Summary TnT is a relatively new cardiac marker with considerable promise. Currently available data suggest no clear superiority over CKMB, except for two clinical scenarios—the ability of low-level release of TnT in predicting adverse outcomes and the value of delayed washout curve in identifying late presenting MI patients. As new data become available and clinical algorithms are tested, the ability to utilize cardiac TnT likely will be further refined.

Biochemical Markers After myocardial necrosis, biological markers including myoglobin, creatine kinase, creatine kinase isoforms, lactic dehydrogenase and cardiac troponins become elevated. The standard for diagnosing AMI traditionally has been creatine kinase MB (CK-MB) levels, which become elevated within 3–8 hours of cell necrosis. This delay in serum elevation limits its utility in the emergency department (ED), and reliance on elevated levels would result in unacceptable delays in instituting thrombolytic therapy or proceeding to primary angioplasty. Recently, cardiac troponin T and I, (TnT, TnI) which are highly specific for myocardial tissue, have been identified. Cardiac troponins are expressed only within myocardial cells, and their limited distribution allows for detection of very small serum elevations. Like CK-MB, elevations occur within 3–6 hours and peak at 12–24 hours. However, unlike CK-MB, they remain elevated for several days and are not specific for AMI. A meta-analysis of studies comparing cardiac TnT to CK-MB showed similar sensitivities (98.2% vs. 96.8%) but lower specificity (68.8% vs. 89.6%) using cardiac TnT to diagnose AMI (2). To date, no large study or meta-analysis comparing cardiac TnI to CK-MB has been performed. However, in one study, cardiac TnI had a 97% sensitivity and a 98% specificity for diagnosing AMI within 24 hours of admission (3). Using the serum obtained at the time of admission, cardiac TnI accurately identified 49 patients (79%) while CK-MB only identified 27 patients (44%), suggesting cardiac TnI may be superior to CK-MB for early diagnosis of AMI. Elevated levels of both cardiac troponins have been associated with a worse prognosis. The meta-analysis of studies using cardiac TnT demonstrated that elevated levels had a cumulative odds ratio of 10.8 (95% CI 4.6–25.6) for predicting subsequent AMI or cardiac death within 6 weeks of evaluation. Similarly, elevated cardiac TnI levels have been associated with an increased 4-week mortality rate and incidence of nonfatal MI

REFERENCES The authors have submitted an important and timely list of references that are available by contacting the Editorial Office at (317) 630-6447 or FAX (317) 274-4469.

Address correspondence and reprint requests to Ellen S. McErlean, RN, MSN, Clinical Nurse Specialist, Acute Coronary Syndromes, The Cleveland Clinic Foundation, Division of Nursing/M13, 9500 Euclid Avenue, Cleveland, OH 44195.

PERSPECTIVE

Contemporary Strategies to Rule Out Myocardial Infarction Thomas J. Lewandowski, MD and William F. Armstrong, MD. University of Michigan, Division of Cardiology, Ann Arbor, Michigan Rapid accurate diagnosis of acute myocardial infarction (AMI) is an essential element in modern management of acute ischemic syndromes. As medical costs have escalated, the need for rapid strategies for diagnosing AMI has increased as have demands on diagnostic methods. The goal of any technique designed to diagnose AMI is rapid accurate diagnosis within 30 minutes of presentation in patients who

ACC CURRENT JOURNAL REVIEW November/December 1998 © 1998 by the American College of Cardiology Published by Elsevier Science Inc.

35

1062-1458/98/$19.00 PII S1062-1458(98)00063-4

EVOLVING KNOWLEDGE

Table 1. THALLIUM-201, MYOCARDIAL INFARCTION AND UNSTABLE ANGINA Investigators Myocardial Infarction Wackers et al. (1975) Wackers et al. (1976)

Ritchie et al. (1978)

Unstable Angina Wackers et al. (1978)

Brown et al. (1983) Freeman et al. (1989)

Population Studied

Findings

10 AMI patients imaged 2–5 days from MI 200 AMI patients imaged ,1–10 days from MI

Defect in 10/10 (100%) patients Defect corresponded with electrocardiogram location Defect in 44/44 (100%) patients imaged , 6 hours after symptom onset Defect in 90/96 (94%) patients imaged , 24 hours after symptom onset Defect in 75/104 (72%) patients imaged . 24 hours after symptom onset Defect in 123/145 (85%) patients Defect in 90/111 (81%) patients w/ first MI. Mean time to imaging 4.6 days for patients w/defect vs. 8.7 days in patients w/o defect

145 AMI patients at 3 centers imaged 1–34 days from MI (mean 5.4 days)

98 unstable angina patients imaged 0–18 hours from last anginal attack

31 unstable angina patients 34 chronic angina patients 66 unstable angina patients imaged at 5.6 hours (mean) from last anginal attack

Defect in 39/98 (40%) patients, equivocal in 27/98 (28%) patients, normal in 32/98 (32%) within 6 hours 28/56 (50%) patients had defect within 6–18 hours 11/42 (26%) patients had defect 9/11 (82%) patients w/refractory angina, MI or required coronary artery bypass graft had defect Defect in 19/19 (100%) patients w/accelerating vs. 3/12 (25%) patients w/rest angina defect in 4/34 (12%) patients w/chronic exertional angina Defect in 27/33 (82%) patients w/CAS $ 50% vs. 5/10 (50%) patients w/CAS , 50% segmental wall motion abnormalities correlated with area of defect 11/18 (61%) patients w/defect vs. 8/25 (32%) w/o defect had cardiac event

AMI, acute myocardial infarction; CAS, coronary artery stenosis.

(27.3% vs. 5.8%, p 5 0.02) (4). Even in patients without AMI, elevated cardiac TnI levels have been associated with increased cardiac events up to 1 year after evaluation. Although rapid bedside tests have been developed, the delay associated with serum appearance of cardiac troponins may limit their ability to aid in the decision to administer thrombolytic therapy. Because cardiac troponins remain elevated for several days, they should be considered for use in making the diagnosis of AMI in patients presenting several days after the onset of chest pain. However, because of their sustained elevation, cardiac troponins may be less suitable for monitoring of recurrent myocardial ischemia or infarction. As cardiac troponins are not expressed in skeletal muscle, they are ideal for diagnosing peri- or postoperative MI.

Table 1 (5–10). These studies demonstrated that the occurrence of perfusion defects decrease with smaller infarct size and with increased delay in imaging. Perfusion defects occurring in patients with both infarction and ischemia have been associated with a higher incidence of subsequent cardiac events. More recently, technetium-99m sestamibi (Tc-99m mibi) has been utilized to detect myocardial ischemia or infarction. Like Tl201, Tc-99m mibi accumulates in myocardial cells in proportion to blood flow and cellular activity, but, unlike Tl201, it does not redistribute to any significant degree, resulting in persistent defects. Consequently, imaging can be performed up to several hours after Tc-99m mibi administration. Several investigations demonstrating the utility of Tc-99m mibi in AMI and unstable angina are listed in Table 2 (11–14). Despite its high sensitivity in identifying myocardial infarction, the lower specificity reflects the inability of a single image to differentiate between infarction and ischemia. Despite lower specificity, Tc-99m mibi perfusion defects have been associated with a worse prognosis. Multivariate regression analysis comparing clinical history, cardiac risk factors, patient age, history of previous AMI and presence of a perfusion defect identified only a perfusion defect as a predictor of subsequent AMI or cardiac events (13,14). Similarly, in the study by Varetto et al. (12), patients presenting without perfusion defects remained free of clinical evidence of cardiac disease for up to 18 months. In order for either Tl201 or Tc-99m mibi to be useful in the ED, image acquisition must be performed immediately us-

Cardiac Imaging In the ischemic cascade, both nuclear perfusion image heterogeneity and echocardiographic wall motion abnormalities occur before the development of ECG changes, chest pain or myocardial necrosis. Therefore, nuclear and echocardiographic imaging can identify areas of myocardial ischemia and infarction long before biochemical markers appear in serum. Consequently, both imaging modalities have been used to hasten identification of patients with an AMI. Nuclear perfusion imaging In 1975, Wackers et al. (5) demonstrated that areas of AMI can be identified using thallium-201 (Tl201). Subsequent studies have confirmed the utility of Tl201 and are outlined in

ACC CURRENT JOURNAL REVIEW November/December 1998

36

EVOLVING KNOWLEDGE

Table 2. TECHNETIUM-99M SESTAMIBI IMAGING, AMI AND CORONARY ARTERY DISEASE Investigators

Population Studied

Sensitivity AMI/CAD

Specificity AMI/CAD

Bilodeau et al. (1991) Varetto et al. (1993) Hilton et al.* (1994) Kontos et al. (1997)

45 patients with unstable angina 64 patients with nondiagnostic ECG and chest pain 102 patients with nondiagnostic ECG and chest pain 532 patients with nondiagnostic ECG and chest pain

Unknown/96% 100%/100% 100%/94% 93%/unknown

Unknown/79% 67%/92% 78%/83% 71%/unknown

CAD, coronary artery disease; ECG, electrocardiogram; other abbreviations as in Table 1. *This investigation combines abnormal and equivocal scans as diagnostic for myocardial ischemia.

hypokinetic or even akinetic with full thickness myocardium. As such, these old infarctions can be confused with acute ischemia, and this is reflected in the lower specificity of echocardiography to diagnose AMI. Regardless of the age of the abnormality, echocardiographic wall motion abnormalities have important prognostic implications. Studies have demonstrated almost uniformly that the future risk of an adverse cardiac event increases with both the presence and extent of wall motion abnormalities. Gibson et al. (19) demonstrated that the echocardiographic wall motion index determined at the time of admission was predictive of subsequent hemodynamic deterioration. Other studies have shown that severe wall motion abnormalities outside the zone of infarction correlated with increased mortality, cardiogenic shock, reinfarction, progression of heart failure and angina. In the Sabia et al. (18) study, 180 patients presenting to the ED with chest pain were evaluated. Although 11 (6%) of the patients had inadequate echocardiographic windows, echocardiographic imaging had an overall 93% sensitivity for diagnosing AMI. Despite a specificity of 62%, the investigators were able to retrospectively demonstrate that a combination of echocardiographic, ECG and clinical criteria could be used to effectively rule out AMI while reducing hospital costs. Using their algorithm, there would have been an estimated 32% reduction in total hospital admissions, 25% reduction in admissions to the coronary care unit and a 41% reduction in admissions to the cardiac step down unit. This would have resulted in a 24% reduction in both the

ing multihead scanners and computers with quick processors to limit test performance to under 30 minutes. Physicians must then act on perfusion defects in order to prevent several hours of further delay associated with serial imaging used to differentiate infarcted from ischemic tissue. Whether or not protocols using a combination of ECG criteria and nuclear perfusion image criteria to guide interventional therapy provide any additional benefit over current criteria remains to be evaluated. However, in light of the prognostic implications of perfusion defects, algorithms utilizing these combinations may reduce both morbidity and mortality in patients with acute cardiac syndromes and therefore warrants further evaluation. Echocardiographic imaging Almost immediately after the onset of ischemia, involved myocardial segments develop abnormal contraction. This is manifest on echocardiographic imaging as a regional wall motion abnormality. The severity of the abnormality depends on the extent and duration of ischemia. Several investigators successfully have used echocardiographic detection of wall motion abnormalities to diagnose AMI (Table 3) (15–18). All studies except that of Loh et al. (16) had a high proportion of Q-wave MI. Despite this, echocardiography had a cumulative 92% sensitivity for diagnosing AMI in the four studies cited. Although old transmural infarctions usually appear thin, bright and akinetic, which suggest that the tissue is scarred, myocardial segments can become akinetic if $20% of the involved myocardial thickness is infarcted. Therefore, old, small and non Q-wave myocardial infarctions may appear Table 3. ECHOCARDIOGRAPHY IN DIAGNOSING AMI Investigators

Population Studied

% AMI

% Nondiagnostic or Normal ECG

Echo Diagnosis

Inadequate Echo Window

Horowitz et al. (1982)

80 patients with chest pain

(33/80) 51%

(33/65) 55%

(15/80) 19%

Loh et al.* (1982)

30 patients with chest pain, normal ECG, good Echo

(12/30) 40%

(12/12) 100%

Peels et al. (1990)

43 patients with chest pain, MI and nondiagnostic ECG

(43/43) 100%

(43/43) 100%

Sabia et al. (1991)

180 patients with chest pain

(29/180) 16%

(20/29) 69%

Sensitivity 94% Specificity 84% Sensitivity 83% Specificity 100% Sensitivity 92% Specificity 53% Sensitivity 93% Specificity 62%

(0/30) 0% unknown (11/180) 6%

% AMI, percent of population studied having an acute myocardial infarction; % Nondiagnostic or Normal ECG, % of patients with an AMI having a nondiagnostic or normal electrocardiogram; other abbreviations as in Table 1 and 2. *All patients had Non Q-wave infarction.

ACC CURRENT JOURNAL REVIEW November/December 1998

37

EVOLVING KNOWLEDGE

total hospital costs ($214,950) and the costs associated with diagnosing each AMI ($7,165). In 1995, Di Pasquale et al. (20) used echocardiographic wall motion abnormalities in conjunction with ECG criteria to identify patients for thrombolysis. In this prospective study, thrombolytics were administered if patients had both ECG and echocardiographic changes consistent with infarction or echocardiographic changes alone. While 37 of 256 AMI patients (14%) were identified by echocardiography alone, 87 of 135 patients (64%) with unstable angina were misclassified as AMI and administered thrombolytics. Therefore, it remains unclear if this approach improves overall morbidity and mortality when compared with utilizing ECG criteria alone, and further evaluation is warranted.

have the sensitivity to be combined with the admission ECG and potentially improve identification of patients for intervention. It remains to be demonstrated that such combinations will improve morbidity and mortality enough to warrant the increased costs associated with performing these tests. However, in light of their prognostic abilities, increased cost potentially may be offset by a reduction in costs from fewer hospitalizations and admissions to the coronary care unit. The true impact on care will remain unknown until such protocols are devised and evaluated.

REFERENCES The authors have submitted an important and timely list of references that are available by contacting the Editorial Office at (317) 630-6447 or FAX (317) 274-4469.

Conclusion All diagnostic tests discussed have the ability to diagnose AMI. Thus far, however, only the ECG is routinely used in the decision to administer thrombolytic therapy. Cardiac troponins, nuclear perfusion imaging and echocardiography

Address correspondence and reprint requests to William F. Armstrong, MD, 1500 East Medical Center Drive, B1-F245, Ann Arbor, MI 48109.

ACC CURRENT JOURNAL REVIEW November/December 1998

38