Myocardial Perfusion Imaging for Evaluation and Triage of Patients With Suspected Acute Cardiac Ischemia JAMA. 2002;288:

ORIGINAL CONTRIBUTION Myocardial Perfusion Imaging for Evaluation and Triage of Patients With Suspected Acute Cardiac Ischemia A Randomized Controlle...
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ORIGINAL CONTRIBUTION

Myocardial Perfusion Imaging for Evaluation and Triage of Patients With Suspected Acute Cardiac Ischemia A Randomized Controlled Trial James E. Udelson, MD Joni R. Beshansky, RN, MPH Daniel S. Ballin, MD James A. Feldman, MD John L. Griffith, PhD Gary V. Heller, MD, PhD Robert C. Hendel, MD J. Hector Pope, MD Robin Ruthazer, MPH Ethan J. Spiegler, MD Robert H. Woolard, MD Jonathan Handler, MD Harry P. Selker, MD, MSPH

E

ACH YEAR IN THE UNITED STATES,

more than 6 million patients present to emergency departments (EDs) with chest pain or other symptoms suggestive of acute cardiac ischemia (ie, either acute myocardial infarction [MI] or unstable angina pectoris).1 The majority of these patients are admitted to the hospital or to an observation unit, because the initial clinical examination, electrocardiogram (ECG) results, and initial cardiac enzyme levels are insufficient to eliminate the possibility of acute infarction or unstable angina.1-4 Nevertheless, most patients without obvious ischemic ECG changes who are hospitalized or observed in special units ultimately prove not to have acute ischemia.2,4-6 MoreFor editorial comment see p 2745.

Context Observational studies of acute myocardial perfusion imaging in emergency department (ED) patients with chest pain have suggested high sensitivity and negative predictive value for acute cardiac ischemia, but use of this method has not been prospectively tested. Objective To assess whether incorporating acute resting perfusion imaging into an ED evaluation strategy for patients with suspected acute ischemia but no initial electrocardiogram (ECG) changes diagnostic of acute ischemia improves clinical decision making for initial ED triage. Design, Setting, and Patients Prospective, randomized controlled trial conducted at 7 academic medical centers and community hospitals between July 1997 and May 1999 among 2475 adult ED patients with chest pain or other symptoms suggestive of acute cardiac ischemia and with normal or nondiagnostic initial ECG results. Intervention Patients were randomly assigned to receive either the usual ED evaluation strategy (n=1260) or the usual strategy supplemented with results from acute resting myocardial perfusion imaging using single-photon emission computed tomography with injection of 20 to 30 mCi of Tc-99m sestamibi (n=1215), interpreted in real time by local staff physicians and with results provided to the ED physician for incorporation into clinical decision making. Main Outcome Measure Appropriateness of triage decision either to admit to hospital/observation or to discharge directly home from the ED. Results Among patients with acute cardiac ischemia (ie, acute myocardial infarction [MI] or unstable angina; n=329), there were no differences in ED triage decisions between those receiving standard evaluation and those whose evaluation was supplemented by a sestamibi scan. Among patients with acute MI (n=56), 97% vs 96% were hospitalized (relative risk [RR], 1.00; 95% confidence interval [CI], 0.89-1.12), and among those with unstable angina (n=273), 83% vs 81% were hospitalized (RR, 0.98; 95% CI, 0.87-1.10). However, among patients without acute cardiac ischemia (n=2146), hospitalization was 52% with usual care vs 42% with sestamibi imaging (RR, 0.84; 95% CI, 0.77-0.92). Conclusions Sestamibi perfusion imaging improves ED triage decision making for patients with symptoms suggestive of acute cardiac ischemia without obvious abnormalities on initial ECG. In this study, unnecessary hospitalizations were reduced among patients without acute ischemia, without reducing appropriate admission for patients with acute ischemia. www.jama.com

JAMA. 2002;288:2693-2700

Author Affiliations and Financial Disclosures are listed at the end of this article. Corresponding Author and Reprints: James E.

©2002 American Medical Association. All rights reserved.

Udelson, MD, Tufts-New England Medical Center, 750 Washington St, Box 70, Boston, MA 02111 (e-mail: [email protected]).

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over, among patients discharged directly from the ED, an important minority actually have acute ischemia, leading to unfavorable outcomes.6-8 Since the predominant pathophysiology of acute cardiac ischemia is a reduction in coronary blood flow, myocardial perfusion imaging in the ED setting is conceptually attractive. The feasibility of imaging in this setting was established over 20 years ago using thallium 201,9 but its use in the real-time ED setting was impractical. The logistics of the use of newer technetium Tc 99m–based perfusion agents are more suitable for use in the ED.10 The technetium Tc 99m label is associated with generally higher-quality images, and there is minimal redistribution after initial injection. Thus, imaging may occur at a later time point after injection, with the resulting image reflecting myocardial blood flow at the time of injection. Several observational studies have demonstrated a very high negative predictive value of acute perfusion imaging using technetium Tc 99m–labeled isotopes in confirming the absence of acute infarction or subsequent cardiac events.11-15 No previous study has prospectively tested the impact of an imaging vs a nonimaging strategy.16 Therefore, we conducted a randomized trial to determine whether incorporating myocardial perfusion imaging into an ED evaluation protocol for patients with symptoms suggestive of acute cardiac ischemia would improve clinical decision making. METHODS Study Design

This trial was designed to compare the clinical effectiveness of 2 ED evaluation strategies for patients suspected of having acute cardiac ischemia but without diagnostic initial ECG changes of acute ischemia: the usual care strategy (the standard clinical evaluation strategy used in each hospital’s ED), and the scan strategy (the same standard clinical evaluation strategy but also incorporating results derived from immediate resting single-photon emission computed tomography [SPECT] myocardial perfu2694

sion imaging with technetium Tc 99m sestamibi). The study protocol was approved by the institutional review boards of all participating centers. Between July 1997 and May 1999, all potentially eligible patients (defined as any initial clinical suspicion of acute ischemia) were screened at the EDs of 7 diverse hospitals during daytime hours. Eligible ED patients who consented were immediately randomized, using simple unrestricted randomization, by means of a central computerized telephone randomization system. Screened patients who were ineligible, and eligible patients who did not consent to participate, were entered anonymously into a registry for comparison with randomized patients. For patients randomized to the scan strategy, injection of 20 to 30 mCi of technetium Tc 99m sestamibi (DuPont Pharmaceuticals, Wilmington, Del) was performed in the ED, generally by a nuclear medicine technologist, as soon as possible after randomization. SPECT imaging was performed beginning 30 to 60 minutes later in the nuclear cardiology laboratory, with images acquired in the gated SPECT mode for simultaneous evaluation of resting perfusion and systolic left ventricular function. 17 The images were interpreted on site in real time by the appropriate staff physicians at each site, with results reported immediately to the responsible physician. Based on all available results, a triage decision was made by the physician to hospitalize the patient (to an observation unit, ward, telemetry unit, or cardiac care unit [CCU]) or to discharge the patient directly home. The decision-making physician was not directed by protocol to admit or discharge the patient based on certain scan results; rather, imaging results were given to the physicians who then incorporated the data into the information base they used to make a clinical decision regarding their patient’s disposition. Patient Eligibility

Included were all patients 30 years of age or older (unless there was a history of

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recent cocaine use, in which case they were required to be 18 years or older) who had chest pain or any other symptoms suggestive of acute cardiac ischemia (eg, shortness of breath) and, according to the evaluating ED physician, an ECG either normal or nondiagnostic for acute ischemia or infarction. To be included, patients’ symptoms were required to be ongoing or to have resolved no longer than 3 hours prior to consent. Excluded were patients with a history of MI, since such patients will most often have an abnormal resting perfusion pattern. Written informed consent was obtained from all patients. Acute Sestamibi Perfusion Imaging

Gated SPECT images were obtained using acquisition and processing parameters standard at each study site. Images were classified as normal (no obvious perfusion abnormalities with normal regional and global ventricular function), abnormal (definite perfusion abnormality and/or regional or global function), or equivocal (images that did not clearly fit into the other categories). Physicians were advised to consider equivocal results as mildly abnormal, based on a previous study showing that patients with equivocal scans in this setting have a slightly higher event rate than patients with normal scans.12 Data Analysis

For characterization of final diagnosis (acute cardiac ischemia or not), all patients had follow-up ECGs, measurement of cardiac enzyme levels, and protocol-specified follow-up stress testing with perfusion or echocardiographic imaging. For patients initially admitted, this was usually accomplished during the observation or hospitalization period. For all ED patients initially discharged directly home, a return visit to the study site 24 to 36 hours later was made for follow-up biomarker measurements, ECGs, and stress testing. The confirmed diagnosis was assigned by the site principal investigator based on all available data, including enzymatic, ECG, and stress testing data, as

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well as cardiac catheterization data when available; principal investigators were blinded to the randomization assignment and to initial scan result for patients randomized to the scan strategy. For all patients whose final diagnosis was MI, for the majority of patients whose final diagnosis was unstable angina, and for an equal and randomly chosen group of patients whose final diagnosis was not acute ischemia, medical records were reviewed at the coordinating center by an independent investigator who was blinded to the original confirmed diagnosis assignment. This independent assignment of confirmed diagnosis was concordant in 98% of cases. Patients were contacted at 30 days following initial ED presentation to determine vital status and the occurrence of other cardiac events and procedures; follow-up was 99% complete. The primary end point of the trial was the appropriateness of initial ED triage decision, assuming that patients with acute infarction or unstable angina should have been hospitalized (to a CCU, telemetry unit, ward, or chest pain unit), and that patients without acute ischemia (ie, those with negative serial enzyme test results, no evolutionary ECG changes on serial testing, and a negative follow-up stress test result) ideally should not have been hospitalized or admitted for observation.

variables, and the Pearson ␹2 test or Fisher exact test for dichotomous variables. P⬍.05 was used to determine statistical significance. Trial data were analyzed based on an intent-to-treat strategy. The effect of imaging on ED triage was analyzed by computing the relative risk (RR) and the 95% confidence intervals (CIs) for hospitalization vs discharge to home, using the Cochran-Mantel-Haenszel method to adjust for hospital differences. Odds ratios for the effect of imaging on admission were computed for different subgroups using logistic regression analyses, including terms for the treatment effect, subgroup effect, the interaction between treatment and subgroup, and terms for hospital effects to adjust for possible hospital differences for factors that were not directly hospital related (ie, hospital volume). Possible interactions between patient and site subgroups and the effect of the scan strategy on admission rate were analyzed using Wald ␹2 testing

from results of logistic regression analysis. With the exception of the site stratifications, all P values were adjusted for site effects. To facilitate interpretation of these results, the adjusted odds ratios from these analyses were converted to RRs using the method of Zhang and Yu,18 in which the strata-specific admission rates for the nonacute cardiac ischemia usual care groups were used as the control prevalence. All analyses were performed using SAS v8.0 (SAS Institute Inc, Cary, NC). RESULTS Study Patients

During 20 months of recruitment, 7955 patients were screened for inclusion (FIGURE), on the basis of presenting symptoms suspicious for acute ischemia. Of these, 2908 consecutive patients met all study eligibility criteria and were eligible for consent, of whom 2475 patients (85%) consented to participate and were randomized to 1 of

Figure. Flow of Patients Through the Trial 7955 Patients Assessed for Eligibility 4802 Ineligible 1737 Had Diagnostic ECG for Acute Ischemia 1349 Had History of Prior MI 425 Had Both of Above 510 Symptoms Ended >3 h Earlier 221 Clinically Became Unstable 102 Previously Enrolled 83 Needed Ventilation-Perfusion Scan 375 Other 3153 Protocol Eligible

Statistical Analysis

The study was designed to have 80% power to detect a reduction (10% to 3%) in ED discharges to home for patients ultimately diagnosed with acute cardiac ischemia, and to have 80% power to detect a reduction in unnecessary admissions for patients without acute ischemia from a 45% unnecessary admission rate to 39%, ie, an absolute risk reduction of 6% and a relative risk reduction of 15%. A data and safety monitoring board reviewed results at an interim time point, to ensure that triage was not unfavorably affected by the intervention. Patient characteristics were compared using the t test for continuous

245 Not Eligible for Consent 177 Physician Refused 25 Left Against Medical Advice 5 Transferred to Another Hospital 38 Other 2908 Eligible for Consent 433 Refused Participation 2475 Randomized

1215 Assigned to Scan Strategy 1191 Underwent Scan as Assigned

1260 Assigned to Usual Care

1208 Completed 30-Day Follow-up

1249 Completed 30-Day Follow-up

1213 Included in Primary Analysis 2 Missing Data

1260 Included in Primary Analysis

ECG indicates electrocardiogram; MI, myocardial infarction.

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the 2 ED evaluation strategies. Of the 5047 protocol- or consent-ineligible patients, exclusion was most often because of either an ECG diagnostic for acute ischemia or infarction (34%) or a history of prior infarction (27%). Other less common reasons for ineligibility included: resolution of symptoms more than 3 hours prior to presentation (10%), patient became unstable in the ED (4%), evaluating physician or primary physician refused enrollment (3%), patient previously enrolled in the study (2%), and patient unable to sign informed con-

sent appropriately (2%). Among eligible patients, those who were protocoleligible but did not sign informed consent were older than those consenting (mean [SD] age, 57 [16] vs 53 [14] years; P =.001) and were slightly more often women (55% vs 49%; P =.03). Among randomized patients, 1260 were randomized to usual care and 1215 were randomized to the strategy incorporating sestamibi perfusion imaging. Baseline characteristics for the groups are shown in TABLE 1. Other than the slight difference in proportion of women between groups, there

Table 1. Baseline Characteristics* No. (%) Scan Strategy (n = 1215) 53 (13) 566 (47)

Characteristic Age, mean (SD), y Women Race White Black Hispanic Asian Other Chief complaint of chest pain Symptoms on ED arrival History of coronary artery disease History of hypertension History of hypercholesterolemia History of diabetes Current smoker Final diagnosis Acute cardiac ischemia Acute myocardial infarction Unstable angina Not acute cardiac ischemia

Usual Care (n = 1260) 53 (14) 642 (51)

P Value .68 .03

753 (62) 309 (25) 129 (11) 21 (2) 3 (0.3) 1043 (86) 1048 (86) 162 (13) 526 (43) 421 (35) 153 (13) 345 (28)

810 (64) 277 (22) 150 (12) 18 (1) 5 (0.4) 1081 (86) 1102 (87) 149 (12) 538 (43) 460 (37) 188 (15) 334 (26)

.98 .41 .26 .76 .35 .10 .30

165 (14) 26 (2) 139 (11) 1050 (86)

164 (13) 30 (2) 134 (11) 1096 (87)

.68 .69 .53 .68

.26

*Percentages have been rounded. ED indicates emergency department.

Table 2. Effect of Sestamibi Imaging on ED Triage Decisions* No. (%)

Hospital admission rate Triage disposition CCU Telemetry ward Chest pain unit Home from ED

Scan Strategy (n = 1215)

Usual Care (n = 1260)

576 (47.5)‡ 1212§ 76 (6.3) 368 (30.4) 131 (10.8) 637 (52.6)

707 (56.1) 1258§ 66 (5.2) 465 (37.0) 174 (13.8) 553 (44.0)

RR (95% CI) 0.87 (0.81-0.93)

P Value† ⬍.001

⬍.001

*RR indicates relative risk; CI, confidence interval; CCU, coronary care unit; and ED, emergency department. †Cochran-Mantel-Haenzel P values adjusted for site effect. ‡n = 1213, as 2 patients were missing data for admission status (and for triage disposition). §For scan strategy, 3 patients were missing data; for usual care, 2 patients were missing data.

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were no significant clinical or demographic differences at baseline. Overall confirmed diagnoses of acute cardiac ischemia were made in 13% of patients: 2% had acute MI, while 11% had unstable angina. Diagnoses other than acute cardiac ischemia were confirmed for 87% overall of patients in each group (Table 1). Patients randomized to the scan strategy had a lower rate of hospital admission than patients randomized to usual care (47.5% vs 56.1%, respectively; RR, 0.87; 95% CI, 0.81-0.93; P⬍.001), and a higher rate of direct discharge home from the ED (TABLE 2). The increase in direct discharges home from the ED in the scan strategy group was predominantly due to a reduction in admission to a telemetry unit or ward, or to a chest pain unit. Despite fewer admissions in the group randomized to the imaging strategy, there were no outcome differences 30 days after ED presentation between patients receiving usual ED care and those receiving sestamibi imaging (TABLE 3). Thus, similar outcomes were observed with fewer hospital admissions in the group randomized to the imaging strategy. The median time from ED presentation to admission or discharge home for patients in the usual care group was 4.7 hours (interquartile range, 3.4-6.4 hours), and for those randomized to the scan strategy, 5.3 hours (interquartile range, 4.0-7.0 hours) (P⬍.001). Impact on Triage for Patients With Acute Cardiac Ischemia

The impact of ED sestamibi imaging on hospitalization for patients with acute cardiac ischemia is shown in TABLE 4. Among all patients with acute ischemia, there was no difference in the appropriate hospitalization rate of approximately 85%. For patients with acute infarction, there was also no difference in the hospitalization rate, appropriately high at 96% overall: one such patient in each group was inappropriately sent home from the ED. Follow-up testing showed the inappropriately discharged patient in the usual

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care group to have an inferior wall infarction with an inferior wall motion abnormality. The inappropriately discharged patient in the sestamibi group had a normal sestamibi scan in the ED, as well as normal results of echocardiography and follow-up stress perfusion testing, but had positive enzyme test results on follow-up. Among those with unstable angina, there also was no difference in the appropriate admission rate between the 2 groups, nor were there differences in specific in-hospital locations for admitted ED patients (Table 4). Impact on Triage for Patients Without Acute Cardiac Ischemia

Among the 2146 patients whose final confirmed diagnosis was not acute cardiac ischemia, 52% of patients randomized to usual care were hospitalized, who, retrospectively, could be classified as unnecessary admissions (TABLE 5). In the sestamibi scan group, this unnecessary admission rate was reduced to 42%, a 10% absolute reduction, and a 20% relative change (RR, 0.84, 95% CI, 0.77-0.92, P⬍.001). Results were similar when the location of admission triage from the ED to hospital was subcategorized as CCU, telemetry ward, or chest pain unit. The reduction in hospitalization of patients without acute ischemia who had sestamibi scans occurred at 6 of the 7 study hospitals, the exception being 1 site with a very low baseline admission rate that followed a prolonged evaluation process. As shown in TABLE 6, perfusion imaging increased direct ED discharges to home in patients without acute ischemia in both men and women, in both younger and older patients, and in both those with and without risk factors for coronary disease. The effect of incorporating perfusion imaging into the evaluation strategy on increasing direct ED discharges to home was similar at sites with an established chest pain center protocol compared with those sites without such a protocol, and was also similar in patients whose initial evaluation included a troponin I value

compared with those without an initial value. There were trends toward greater effect of imaging for patients

without a history of coronary disease and in those with chest pain as their primary presenting symptom.

Table 3. Thirty-Day Outcomes According to Randomized Strategy* No./Total (%) Scan Strategy 1215 4/1208 (0.3) 156/1130 (13.8)

Usual Care 1260 2/1249 (0.2) 162/1185 (13.7)

P Value†

Any PTCA or stent placement Any CABG surgery Any revascularization procedure‡ Patients with ACI Death Any catheterization

46/1124 (4.1) 18/1123 (1.6) 63/1125 (5.6) 165 3/164 (1.8) 87/162 (54)

50/1182 (4.2) 30/1184 (2.5) 77/1182 (6.5) 164 2/164 (1.2) 93/163 (57)

.87 .15 .40

Any PTCA or stent placement Any CABG surgery Any revascularization procedure‡ Patients without ACI Death Any catheterization Any PTCA or stent placement Any CABG surgery Any revascularization procedure‡

43/160 (27) 17/159 (11) 59/161 (37) 1050 1/1044 (0.1) 69/968 (7) 3/964 (0.3) 1/964 (0.1) 4/964 (0.4)

48/162 (30) 28/162 (17) 73/162 (45) 1096 0/1085 (0) 69/1022 (7) 2/1020 (0.2) 2/1022 (0.2) 4/1020 (0.4)

.91 .06 .19

All patients Death Any catheterization

.37 .85

.62 .81

.28 .72 .62 .72 .87

*PTCA indicates percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft; and ACI, acute cardiac ischemia. †Cochran-Mantel-Haenzel P values adjusted for site effect. ‡PTCA, stent placement, or CABG surgery.

Table 4. Effect of Sestamibi Imaging on ED Triage Decisions in Patients With ACI* No. (%) Scan Strategy 165 138 (84)

Usual Care 164† 140 (85)

33 (20) 86 (52) 19 (12) 27 (16)

39 (24) 86 (53) 14 (9) 24 (15)

Acute myocardial infarction Hospital admission rate Triage disposition CCU Telemetry ward Chest pain unit Home from ED

26 25 (96)

30 29 (97)

15 (58) 10 (39) 0 (0) 1 (4)

17 (57) 10 (33) 2 (7) 1 (3)

Unstable angina Hospital admission rate Triage disposition CCU Telemetry ward Chest pain unit Home from ED

139 113 (81)

134 111 (83)

18 (13) 76 (55) 19 (14) 26 (19)

22 (17) 76 (57) 12 (9) 23 (17)

All patients with ACI Hospital admission rate Triage disposition CCU Telemetry ward Chest pain unit Home from ED

RR (95% CI) 0.98 (0.90-1.08)

P Value .74

.71

1.00 (0.89-1.12)

⬎.99

.92

0.98 (0.87-1.10)

.68

.58

*ED indicates emergency department; ACI, acute cardiac ischemia; RR, relative risk; CI, confidence interval; and CCU, coronary care unit. †One patient missing data for triage disposition.

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MYOCARDIAL IMAGING IN SUSPECTED ACUTE ISCHEMIA Relation of Sestamibi Imaging Results to Clinical Outcomes

Table 5. Effect of Sestamibi Imaging on ED Triage Decisions in Patients Without ACI* No. (%)

Hospital admission rate Triage disposition CCU Telemetry ward Chest pain unit Home from ED

Scan Strategy (n = 1050)† 438 (42)

Usual Care (n = 1096)‡ 567 (52)

43 (4) 282 (27) 112 (11) 610 (58)

27 (3) 379 (35) 160 (15) 529 (48)

RR (95% CI) 0.84 (0.77-0.92)

P Value ⬍.001

.002

*ED indicates emergency department; ACI, acute cardiac ischemia; RR, relative risk; CI, confidence interval; and CCU, coronary care unit. †Two patients missing data for admission status; 3 patients missing data for triage disposition. ‡One patient missing data for triage disposition.

Table 6. Effect of Sestamibi Imaging on ED Triage in Patient Subgroups* Risk Factor Sex Men Women Age, y ⱕ49 ⬎49 Coronary artery disease No Yes Hypertension No Yes Hypercholesterolemia No Yes Diabetes mellitus No Yes Current smoker No Yes Family history of heart disease No Yes Chest pain primary ED symptom No Yes Site comparisons High-volume ED Low-volume ED Site experience§ Less More Chest pain center protocol No Yes Initial troponin I level obtained in ED No Yes

No. (%)

RR (95% CI)

P Value†

P Value‡

1069 (50) 1075 (50)

0.83 (0.71-0.94) 0.83 (0.73-0.96)

.003 .007

.83

1092 (51) 1052 (49)

0.80 (0.72-0.95) 0.85 (0.72-0.95)

.006 .006

.99

1049 (84) 195 (16)

0.80 (0.73-0.91) 0.99 (0.71-1.25)

⬍.001 .94

.24

1263 (59) 881 (41)

0.83 (0.74-0.96) 0.83 (0.69-0.94)

.005 .004

.68

1419 (66) 725 (34)

0.83 (0.74-0.94) 0.83 (0.69-0.98)

.002 .02

.99

1875 (87) 269 (13)

0.83 (0.75-0.93) 0.84 (0.58-1.04)

⬍.001 .10

.79

1533 (72) 610 (28)

0.82 (0.74-0.93) 0.83 (0.69-1.00)

⬍.001 .06

.83

816 (38) 1314 (62)

0.78 (0.65-0.92) 0.86 (0.76-0.97)

.001 .01

.33

311 (15) 1833 (85)

0.95 (0.74-1.17) 0.81 (0.73-0.91)

.71 ⬍.001

.23

1800 (84) 344 (16)

0.82 (0.75-0.93) 0.82 (0.54-0.92)

⬍.001 .006

.30

906 (42) 1238 (58)

0.87 (0.69-0.94) 0.77 (0.72-0.93)

.004 ⬍.001

.99

1235 (58) 909 (42)

0.89 (0.76-0.96) 0.73 (0.68-0.93)

.006 .002

.49

895 (42) 1249 (58)

0.86 (0.73-0.97) 0.80 (0.72-0.94)

.002 .02

.88

*Relative risk (RR) indicates the RR of hospitalization or observation in the scan vs usual care groups. ED indicates emergency department; CI, confidence interval. †Testing null hypothesis that RR, adjusted for site, is equal to 1.0 (or null hypothesis that treatment has no impact). ‡Testing equivalence of RRs between factor levels. §Subgrouping of study sites based on any prior experience with imaging in the ED setting.

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Among the 1215 patients randomized to the scan strategy, the imaging results were related to the risk of an adverse outcome. Among patients with normal, equivocal, or abnormal scan results, the risk of acute MI was 0.6%, 0.8%, and 10.3%, respectively (RR for equivocal or abnormal vs normal scan, 6.61; 95% CI, 2.47-17.67; P⬍.001). A similar relationship was observed between scan findings and any cardiovascular event at 30 days, defined as acute MI, death, or revascularization. Among patients with normal, equivocal, and abnormal scan results, the risk of a cardiac event defined as such was 3.0%, 6.1%, and 20.5%, respectively (RR for equivocal or abnormal vs normal scan, 3.83; 95% CI, 2.36-6.21; P⬍.001). COMMENT This trial indicates that incorporating results from acute resting perfusion imaging with technetium Tc 99m sestamibi into an ED evaluation strategy for patients with suspected acute cardiac ischemia improves triage decision making. Specifically, unnecessary hospitalization of patients without acute cardiac ischemia was reduced, without affecting appropriate hospitalization of patients with acute ischemia. Accordingly, the reduction in hospital admission related to the use of perfusion imaging was associated with unchanged 30-day clinical outcomes. Although several observational studies11-15,19 supported the incorporation of perfusion imaging into an ED evaluation strategy, these studies examined the prognostic value of imaging results but did not examine the impact of imaging on ED triage decision making. Thus, this “effectiveness” trial was designed to determine how imaging would affect ED triage decisions when incorporated into usual care at a diverse group of hospitals, including academic medical centers, urban public teaching hospitals, and moderate to large community hospitals. The inclusion criteria were designed to capture all low- to moderate-risk patients with

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MYOCARDIAL IMAGING IN SUSPECTED ACUTE ISCHEMIA

possible acute cardiac ischemia in whom the triage decision regarding admission or direct discharge to home is often difficult.1-3 At each site, the SPECT perfusion images were read on site and in real time by the usual interpreting physician. The rates of acute infarction (2%) and unstable angina (12%) among study patients are lower than those observed in previous studies evaluating imaging or other technologies in this setting.12-15 This is likely a result of the broader inclusion criteria of this trial, allowing inclusion of patients with any symptoms suggestive of acute ischemia. Other studies with higher proportions of patients who prove to have acute infarction have used narrower inclusion criteria, studying only patients with angina-like chest pain and nondiagnostic ECGs,12 or patients for whom the decision to hospitalize had already been made.15 The inclusion criteria in this trial were designed so that trial results would be applicable to the broad array of ED patients presenting with possible acute ischemia. Few ED diagnostic technologies or evaluation strategies for acute ischemia have been rigorously tested in controlled clinical trials.1 Predictive instruments for acute cardiac ischemia or infarction have improved triage effectiveness in some trials20-22 but not others.23 Controlled trials have also addressed the use of an “accelerated diagnostic protocol” or a chest pain evaluation unit as a means to create uniform, efficient evaluations for such patients, and have shown shorter lengths of stay, fewer standard hospital admissions, and lower resource utilization with similar outcomes.24,25 In these studies of accelerated protocols or observation units, the majority of patients were ultimately diagnosed as not having acute ischemia.24,25 The results of the present trial suggest that incorporating perfusion imaging into such ED evaluation strategies should afford the possibility of determining the presence or absence of acute ischemia even earlier in the ED evaluation process, facilitating an earlier

triage decision and diminishing the need for observation in a chest pain unit or a similar pathway. In this regard, Kontos et al14 reported that resting perfusion imaging with sestamibi was 92% sensitive for detecting acute infarction in studies performed early in the ED, whereas initial measurement of troponin I levels in the ED had only 39% sensitivity. In that study, the sensitivity of troponin I levels became similar to that of sestamibi imaging within the first 24 hours,14,26 consistent with its known release kinetics after myocardial injury.27 Others reported that optimal sensitivity and prognostic value of levels of troponins T or I are not achieved until 18 hours after symptom onset.28,29 The finding that 42% of patients ultimately found to be without acute ischemia in the scan group were admitted to the hospital suggests that even further improvement in ED triage decision-making is possible. Such improvement may result from further confidence in imaging results with increasing familiarity, or may require a combination of imaging results with other probability estimates. Future studies should address which populations benefit most from incorporating imaging into the evaluation process, and whether there is a threshold of probability, as might be provided by a predictive instrument, above or below which imaging or any other technology is not needed. Patients who had a perfusion image performed but were still admitted may also have had falsepositive images, potentially resulting from diaphragmatic or breast attenuation, or motion artifact. Whether the data from this trial can be applied to smaller or more rural hospitals is not clear, as such institutions were not represented in this trial. However, the trial results are potentially generalizable to hospitals with on-site imaging facilities, since hospitals with little or no experience in using perfusion imaging in the ED demonstrated a similarly favorable triage effect as those with some experience (Table 5). The safety of increasing direct discharges to home

©2002 American Medical Association. All rights reserved.

from the ED by incorporation of a resting perfusion imaging strategy as seen in the current study presumes incorporation of a follow-up evaluation after ED discharge. In the current study, follow-up stress testing was directed per protocol. This study was conducted during expanded daytime hours, and thus whether the data generalize to use during nighttime hours cannot be determined with certainty. In summary, incorporating acute resting sestamibi myocardial perfusion imaging into an ED evaluation strategy for patients with symptoms suggestive of acute cardiac ischemia reduced unnecessary hospitalizations among patients without acute ischemia (ie, improved the specificity of the admitting decision), without reducing appropriate admission of patients with acute ischemia (maintained sensitivity), thereby improving the overall clinical effectiveness of the ED triage process. Author Affiliations: Divisions of Clinical Care Research (Drs Udelson, Griffith, and Selker, and Mss Beshansky and Ruthazer) and Cardiology (Dr Udelson), and Department of Emergency Medicine (Dr Ballin), Tufts-New England Medical Center, Boston, Mass; Department of Emergency Medicine, Boston Medical Center, Boston (Dr Feldman); Division of Cardiology, Hartford Hospital, Hartford, Conn (Dr Heller); Division of Cardiology (Dr Hendel) and Department of Emergency Medicine (Dr Handler), Northwestern Memorial Hospital, Chicago, Ill; Department of Emergency Medicine, Baystate Medical Center, Springfield, Mass (Dr Pope); Division of Nuclear Medicine, St Agnes Health Care System, Baltimore, Md (Dr Spiegler); and Department of Emergency Medicine, Rhode Island Hospital, Providence (Dr Woolard). Financial Disclosures: Dr Udelson has received research funding/honoraria from Bristol-Myers Squibb Medical Imaging. Dr Heller has served on the speakers bureau for, and performed research for, BristolMyers Squibb Medical Imaging. Author Contributions: Study concept and design: Udelson, Beshansky, Feldman, Griffith, Heller, Hendel, Pope, Ruthazer, Selker. Acquisition of data: Udelson, Beshansky, Ballin, Heller, Hendel, Pope, Spiegler, Woolard, Handler, Selker. Analysis and interpretation of data: Udelson, Beshansky, Ballin, Feldman, Griffith, Heller, Hendel, Pope, Ruthazer, Spiegler, Woolard, Handler, Selker. Drafting of the manuscript: Udelson, Beshansky, Selker. Critical revision of the manuscript for important intellectual content: Udelson, Beshansky, Ballin, Feldman, Griffith, Heller, Hendel, Pope, Ruthazer, Spiegler, Woolard, Handler, Selker. Statistical expertise: Beshansky, Griffith, Ruthazer, Selker. Obtained funding: Udelson, Beshansky, Feldman, Griffith, Pope, Selker. Administrative, technical, or material support: Udelson, Beshansky, Ballin, Feldman, Pope, Spiegler, Woolard, Handler, Selker. Study supervision: Udelson, Beshansky, Ballin, Feldman,

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MYOCARDIAL IMAGING IN SUSPECTED ACUTE ISCHEMIA Heller, Hendel, Pope, Spiegler, Woolard, Handler, Selker. Funding/Support: This study was supported by Agency for Healthcare Research and Quality grant RO1HS09110, as well as in part by the General Clinical Research Centers at Tufts-New England Medical Center (MO1-RR00054), Northwestern Memorial Hospital (MO1-RR00048), and Boston Medical Center (MO1RR00533), funded by the National Institutes of Health National Center for Research Resources. The technetium Tc-99m sestamibi isotope used in the trial was supplied by DuPont Radiopharmaceuticals (now BristolMyers Squibb Medical Imaging). Disclaimer: Neither the Agency for Healthcare Research and Quality, the National Institutes of Health,

nor DuPont had any role in or access to the design and conduct of the study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript. Study Personnel: Coordinating Center Staff, Division of Clinical Care Research, Tufts-New England Medical Center, Boston Mass: Deborah Crane, Bonnie MacLeod, Gabe Sayre, Joanne Berdebes. Data Safety and Monitoring Board: Robert Zalenski, MD, Falah Shamsa, PhD; Study sites: Baystate Medical Center, Springfield, Mass: Del Blank, RN, MBA, Geoff Scriver, Pagona Papadopoulos, Lindsay Baum, Robert Dann, MD; Boston Medical Center, Boston, Mass: Patricia Mitchell, RN, Clara Safi, RN, Victor Lee, MD, Sheilah Bernard, MD; Northwestern Memorial

Hospital, Chicago, Ill: Michelle Woods, RN, Stacey Bello, RN, Robert Bonow, MD; Hartford Hospital, Hartford, Conn: Giselle Cyr, RN, Alan Ahlberg, MA, Carol McGill, LPN, Deborah Katten, RN; St Agnes Hospital, Baltimore, Md: Robin White, RN, CNMT, Mary Pat Rizzo, CCT, Raymond Bahr, MD; New England Medical Center, Boston, Mass: Clare Kinney, Karie Puopolo, Elizabeth Oates, MD, Gregory Corrodi, MD; Rhode Island Hospital, Providence: Marianne Warren, RN, Christine Goulette, BS, MAT, Jac Scheiner, MD, Robert Sidman, MD. Acknowledgment: We thank Clare Kinney and Karie Puopolo of the coordinating center for their diligence and tremendous effort put forth to make this study a success.

11. Varetto T, Cantalupi D, Altieri A, et al. Emergency room technetium-99m sestamibi imaging to rule out acute myocardial ischemic events in patients with nondiagnostic electrocardiography. J Am Coll Cardiol. 1993;22:1804-1808. 12. Hilton TC, Thompson RC, Williams H, et al. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol. 1994;23:1016-1022. 13. Tatum JL, Jesse Rl, Kontos MC, et al. Comprehensive strategy for the evaluation and triage of the chest pain patient. Ann Emerg Med. 1997;29:116125. 14. Kontos MC, Jesse RL, Anderson P, et al. Comparison of myocardial perfusion imaging and cardiac troponin I in patients admitted to the emergency department with chest pain. Circulation. 1999;99:20732078. 15. Heller GV, Stowers SA, Hendel RC, et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic myocardial perfusion imaging in patients with acute chest pain and nondiagnostic electrocardiograms. J Am Coll Cardiol. 1998;31:1011-1017. 16. Beller GA. Acute radionuclide perfusion imaging for evaluation of chest pain in the emergency department: need for a large clinical trial. J Nucl Cardiol. 1996; 3(6 pt 1):546-549. 17. Jafary F, Udelson JE. Assessment of myocardial perfusion and left ventricular function in acute coronary syndromes: implications for gated SPECT imaging. In: Germano G, Berman DS, eds. Clinical Gated Cardiac SPECT. Armonk, NY: Futura Publishing; 1999. 18. Zhang J, Yu KF. What’s the relative risk? a method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280:1690-1691. 19. Hilton TC, Fulmer H, Abuan T, et al. Ninety-day follow-up of patients in the emergency department with chest pain who undergo initial single-photon emission computed tomographic perfusion scintigraphy with technetium 99m-labeled sestamibi. J Nucl Cardiol. 1996;3:308-311. 20. Pozen MW, D’Agostino RB, Selker HP, Sytkowski PA, Hood WB Jr. A predictive instrument to

improve coronary care unit admission practices in acute ischemic heart disease: a prospective multicenter clinical trial. N Engl J Med. 1984;310:1273-1278. 21. Sarasin FP, Reymond JM, Griffith JL, et al. Impact of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) on the speed of triage decision making for emergency department patients presenting with chest pain: a controlled clinical trial. J Gen Intern Med. 1994;9:187-194. 22. Selker HP, Beshansky JR, Griffith JL, et al. Use of the acute cardiac time-insensitive predictive instrument (ACI-TIPI) to assist with triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia: a multicenter, controlled clinical trial. Ann Intern Med. 1998;129:845-855. 23. Lee TH, Pearson DS, Johnson PA, et al. Failure of information as an intervention to modify clinical management: a time-series trial in patients with acute chest pain. Ann Intern Med. 1995;122:434-437. 24. Roberts RR, Zalenski RJ, Mensah EK, et al. Costs of an emergency department-based accelerated diagnostic protocol vs hospitalization in patients with chest pain: a randomized controlled trial. JAMA. 1997; 278:1670-1676. 25. Farkouh ME, Smars P, Reeder GS, et al. A clinical trial of a chest pain observation unit for patients with unstable angina. N Engl J Med. 1998;339:18821888. 26. Duca MD, Giri S, Wu AHB, et al. Comparison of acute rest myocardial perfusion imaging and serum markers of myocardial injury in patients with chest pain syndromes. J Nucl Cardiol. 1999;6:570-576. 27. Adams JE III, Bodor GS, Davila-Roman VG, et al. Cardiac troponin I: a marker with high specificity for cardiac injury. Circulation. 1993;88:101-106. 28. Zimmerman J, Fromm R, Meyer D, et al. Diagnostic marker cooperative study for the diagnosis of myocardial infarction. Circulation. 1999;99:16711677. 29. Newby LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. Circulation. 1998;98:1853-1859.

REFERENCES 1. Selker HP, Zalenski RJ. An evaluation of technologies for detecting acute cardiac ischemia in the emergency department: a report from a National Heart Attack Alert Program Working Group. Ann Emerg Med. 1997;29:13-87. 2. Pope JH, Ruthazer R, Beshansky JR, et al. Clinical features of emergency department patients presenting with symptoms suggestive of acute cardiac ischemia: a multicenter study. J Thromb Thrombolysis. 1998; 6:63-74. 3. Braunwald E, Mark DB, Jones RH, et al. Unstable angina: diagnosis and management. Rockville, Md: Agency for Health Care Policy and Research, US Public Health Service, US Dept of Health and Human Services; 1994. Clinical Practice Guideline No. 10. 4. Fineberg HV, Scadden D, Goldman L. Care of patients with a low probability of acute myocardial infarction: cost-effectiveness of alternatives to coronary care unit admission. N Engl J Med. 1984;310: 1301-1307. 5. McCarthy BD, Wong JB, Selker HP. Detecting acute cardiac ischemia in the emergency department: a review of the literature. J Gen Intern Med. 1990;5:365373. 6. Lee TH, Rouan GW, Weisberg MC, et al. Clinical characteristics and natural history of patients sent home from the emergency room. Am J Cardiol. 1987;60: 219-224. 7. McCarthy BD, Beshansky JR, D’Agostino RB, Selker HP. Missed diagnoses of acute myocardial infarction in the emergency department: results from a multicenter study. Ann Emerg Med. 1993;22:579-582. 8. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342:11631170. 9. Wackers FJT, Lie KI, Liem KL, et al. Potential value of thallium-201 scintigraphy as a means of selecting patients for the coronary care unit. Br Heart J. 1979; 41:111-117. 10. Beller GA. Radiopharmaceuticals in nuclear cardiology. In: Beller GA, ed. Clinical Nuclear Cardiology. Philadelphia, Pa: Saunders; 1995:37-81.

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LETTERS

CORRECTIONS Incorrect Byline: In the Original Contribution entitled “Myocardial Perfusion Imaging for Evaluation and Triage of Patients With Suspected Acute Cardiac Ischemia: A Randomized Controlled Trial” published in the December 4, 2002, issue of THE JOURNAL (2002;288:2693-2700), the order of authors in the byline was incorrect. Jonathan Handler, MD, should have been listed between John L. Griffith, PhD, and Gary V. Heller, MD, PhD. Incorrect Data in Table: In the Original Contribution entitled “Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)” published in the December 18, 2002, issue of THE JOURNAL (2002;288:2981-2997), there were incorrect data in TABLE 6. This table replaces the one on page 2992. The new data do not affect the results or conclusions of the original article.

Table 6. Causes of Death by Antihypertensive Treatment Group* No. (6-Year Rate per 100 Persons)

Total deaths Cardiovascular Myocardial infarction Definite CHD Possible CHD Stroke Heart failure Other CVD Noncardiovascular Cancer Kidney disease Unintentional injury/suicide/homicide Other non−CVD Unknown

P Value

Chlorthalidone (n = 15 255) 2203 (17.3) 996 (8.0) 296 (2.4)

Amlodipine (n = 9048) 1256 (16.8) 603 (8.5) 169 (2.3)

Lisinopril (n = 9054) 1314 (17.2) 618 (8.5) 157 (2.2)

Amlodipine vs Chlorthalidone .20 .76 .66

Lisinopril vs Chlorthalidone .90 .39 .25

118 (1.1) 128 (1.1) 162 (1.4) 114 (1.0) 178 (1.4) 1067 (8.9) 515 (4.3) 36 (0.4) 66 (0.6) 450 (4.0) 140 (1.2)

72 (1.2) 71 (1.1) 92 (1.4) 83 (1.4) 116 (1.7) 571 (8.0) 285 (3.8) 24 (0.5) 19 (0.4) 243 (3.7) 82 (1.2)

77 (1.0) 95 (1.4) 121 (1.7) 68 (1.1) 100 (1.5) 616 (8.6) 302 (4.1) 27 (0.5) 28 (0.4) 259 (3.9) 80 (1.1)

.88 .62 .71 .17 .46 .04 .31 .68 .005 .21 .89

.52 .10 .06 .98 .66 .57 .86 .37 .14 .68 .78

*CHD indicates coronary heart disease; CVD, cardiovascular disease.

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