Effectiveness of Myocardial Perfusion Scintigraphy to Predict Coronary Anatomy in Patients with Non-ST Elevation Acute Coronary Syndrome

Effectiveness of Myocardial Perfusion Scintigraphy to Predict Coronary Anatomy in Patients with Non-ST Elevation Acute Coronary Syndrome Brian J. Potter, MDa, Marc Dorais, MScb, Samer Mansour, MDb,c, Katarzyna Orlicka, MDa, François Gobeil, MDc, and Stéphane Rinfret, MD, SMb,d,* The risk stratification of conservatively managed patients presenting with non–ST elevation (NSTE) acute coronary syndromes (ACS) is frequently accomplished by the use of myocardial perfusion scintigraphy (MPS) in clinical practice. However, whether one can predict the extent of coronary artery disease (CAD) on angiography by MPS in this setting is unknown. In this study, the correspondence of findings on MPS to those on coronary angiography was retrospectively analyzed in 55 patients presenting with NSTE ACS. Patients’ mean age was 64 years, 55% were men, and 87% had positive troponins. Of these patients, 42% of patients with perfusion defects involving the anterior wall presented with significant extensive CAD on coronary angiography, consisting of left main disease, 3-vessel disease, or 2-vessel disease involving the left anterior descending coronary artery. In patients with perfusion defects limited to 1 territory, 50% also had extensive CAD. A “negative” result on MPS was associated with extensive CAD in 37% of patients and the absence of significant lesions in only 8%. In conclusion, these findings suggest that MPS alone may be of limited clinical utility in distinguishing troponin-positive NSTE ACS patients with extensive CAD from those with more limited disease and should prompt further investigation of the use of MPS for this indication. © 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:644 – 647) In the management of non–ST elevation (NSTE) acute coronary syndromes (ACS) (including NSTE myocardial infarction and unstable angina), either an early invasive or a conservative approach may be used on the basis of patients’ risk profiles at presentation or patients’ preferences.1 This practice of selecting patients on the basis of risk profiles for one or the other strategy has been supported by a recent meta-analysis.2 A conservative (or selectively invasive) approach in patients with troponin-positive NSTE ACS was also shown to be noninferior to an early invasive strategy in a large recent trial,3,4 during which patients received contemporary medical care. Half of the patients managed conservatively in this same study, however, ultimately went on to coronary angiography. The decision to proceed with coronary angiography in patients managed conservatively depends on further risk stratification based primarily on the evolution of symptoms and on the results of functional testing.5 Despite its wide use in clinical practice for this indication, whether one can predict the extent of coronary artery disease (CAD; i.e., determine an ischemic threshold beyond which diagnostic coronary angiography

a

University of Montreal; bCentre Hospitalier de l’Université de Montréal Research Centre; cDivisions of General and Interventional Cardiology, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec; and dDivisions of General and Interventional Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada. Manuscript received February 28, 2009; revised manuscript received and accepted April 6, 2009. *Corresponding author: Tel: 418-656-8711; fax: 418-656-4544. E-mail address: [email protected] (S. Rinfret). 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.04.051

becomes necessary) on the basis of the results of myocardial perfusion scintigraphy (MPS) in the setting of NSTE ACS is not known. Methods The charts of 952 patients who presented with ACS from December 5, 2001, to December 5, 2002, were systematically reviewed for the purposes of quality of care control at Centre Hospitalier de l’Université de Montréal. Of these, 164 presented with ST elevation myocardial infarctions and 788 with NSTE ACS. Of the patients with NSTE ACS, 277 underwent stratification with MPS. At our center, MPS is performed principally by dipyridamole sestamibi radionuclide scanning. A smaller group of patients (30% overall) underwent exercise MPS. Of the 277 patients with NSTE ACS who underwent MPS, 55 also underwent subsequent coronary angiography. Descriptive baseline data were collected for all 277 patients with NSTE ACS who underwent functional testing by MPS, and the findings on MPS and coronary angiography were analyzed in the 55 patients for whom the 2 data categories were available. The presence or absence of disease was based on chart review and patient interviews at admission and did not reflect subsequent diagnoses during index hospitalization. The results of MPS were evaluated for evidence of a significant perfusion defect on the basis of the nuclear medicine report. We considered signs of myocardial ischemia (reversible defects) or necrosis (fixed defects) as indicative of potential CAD in the vessel supplying the territory. The presence and localization of defects were www.AJConline.org

Coronary Artery Disease/MPS and Coronary Anatomy in ACS

645

Table 1 Baseline data and type of myocardial perfusion defect by sestamibi imaging in patients with non–ST elevation acute coronary syndromes Variable

No Coronary Angiography (n ⫽ 222)

Coronary Angiography (n ⫽ 55)

p Value

64.2 ⫾ 12.4 119 (54%) 129 (58%) 66 (30%) 123 (55%) 174 (78%) 99 (45%) 54.3 ⫾ 14.0 (n ⫽ 78)

63.9 ⫾ 11.3 30 (55%) 36 (66%) 20 (36%) 40 (73%) 47 (86%) 27 (49%) 61.3 ⫾ 15.5 (n ⫽ 22)

0.86 0.90 0.32 0.34 0.02 0.24 0.55 0.04

113 (59%) 22 (9.9%) 21 (9.5%) 74 (33%) 0 52 (23%) 72 (32%) 54 (24%) 20 (9.0%) 92 (41%) 17 (7.7%) 195 (88%)

26 (55%) 12 (22%) 6 (11%) 25 (46%) 0 17 (31%) 19 (35%) 9 (16%) 3 (5.5%) 27 (49%) 5 (9.1%) 48 (87%)

0.66 0.02 0.75 0.09

59 (27%) 62 (28%)

23 (42%) 15 (27%)

0.03 0.92

Baseline data Age (years) Men Hypertension Diabetes mellitus Dyslipidemia Known or suspected CAD Positive family history LVEF on admission (%) Medications Aspirin Thienopyridines Anticoagulants ␤ blockers Calcium channel blockers Nitrates ACE inhibitors/ARBs Diuretics Antiarrhythmic agents Statins Other lipid-lowering agents Positive troponin T Perfusion defects on MPS Reversible defects Fixed defects

0.25 0.77 0.21 0.39 0.30 0.72 0.91

Data are expressed as mean ⫾ SD or as number (percentage). ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker; LVEF ⫽ left ventricular ejection fraction. Table 2 Location and extent of myocardial perfusion defects by sestamibi imaging and associated coronary lesions (ⱖ70%) in 55 patients with non–ST elevation acute coronary syndromes Location of Perfusion Defect

n

LMD or 3VD

LAD ⫹ LCX or LAD ⫹ RCA

LCX ⫹ RCA

LAD

LCX

RCA

Normal or ⬍70%

Percentage on Target

Anterior/septal/apical Inferior Lateral Anterior ⫹ inferior or lateral Inferior ⫹ lateral Anterior ⫹ inferior ⫹ lateral No signs of ischemia/myocardial infarction

7 12 1 5 6 0 24

4 (57%) 4 (33%) 1 (100%) 1 (20%) 0 0 8 (33%)

0 1 (8%) 0 0 1 (17%) 0 1 (4%)

0 0 0 0 4 (67%) 0 6 (25%)

2 (29%) 0 0 1 (20%) 0 0 3 (13%)

0 1 (8%) 0 1 (20%) 1 (17%) 0 2 (8%)

1 (14%) 4 (33%) 0 2 (40%) 0 0 2 (8%)

0 2 (17%) 0 0 0 0 2 (8%)

29% 42% 0% 20% 83% — 8%

LAD ⫽ left anterior descending coronary artery; LCX ⫽ left circumflex coronary artery; LMD ⫽ left main coronary artery disease; RCA ⫽ right coronary artery; 3VD ⫽ 3-vessel disease.

recorded. Angiographic data were also analyzed using the catheterization laboratory report. A coronary vessel was considered significantly diseased when a ⱖ70% stenosis in the main vessel or a large branch (ⱖ2 mm in diameter) was documented. The findings on MPS (territory at risk) were then compared to the anatomy on coronary angiography. We assumed that anterior, septal, and apical defects were indicative of left anterior descending coronary artery disease; inferior defects of right coronary artery or left circumflex disease or 2-vessel disease; lateral defects of left circumflex disease; inferior and lateral defects of right coronary artery or left circumflex disease or 2-vessel disease; anterior, septal, or apical with inferior or lateral de-

fects of either left anterior descending coronary artery with left circumflex or right coronary artery disease, or even left main disease or 3-vessel disease; and anterior plus inferior plus lateral defects of left main disease or 3-vessel disease. In patients without perfusion defects, no significant coronary stenoses were expected. Baseline clinical characteristics and data from MPS were compared (using Student’s t tests for continuous data and chi-square tests for categorical data) between patients who underwent catheterization after MPS and those who did not. Correlation matrices were built for patients who underwent catheterization, with the presumed anatomy as suggested by MPS on the left and the actual anatomy on the right. Sta-

646

The American Journal of Cardiology (www.AJConline.org)

tistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). Results Table 1 lists the baseline data as well as the number of patients with fixed or reversible myocardial perfusion defects found in all 277 myocardial perfusion scintigraphic studies performed in patients with NSTE ACS during the study period, comparing the 55 patients who also underwent coronary angiography to the 222 patients who did not. Overall, patients who underwent coronary angiography had similar baseline characteristics compared to those who did not undergo angiography. Notable differences were a higher rate of reported dyslipidemia in the group that underwent coronary angiography, as well as higher rates of treatment with thienopyridines. Not surprisingly, patients who underwent angiography were more likely to have reversible defects. However, the territorial distribution of the perfusion defects was similar between the 2 groups (data not shown). Of the 55 patients who underwent coronary angiography, 87.3% had positive troponin levels. Patients’ mean age was 63.9 years, 55% were men, 36% had diabetes, 66% had previous diagnoses of hypertension, and 73% had previous diagnoses of dyslipidemia. The incidence of different patterns of perfusion defects on MPS and the corresponding findings on coronary angiography in this group using a cutoff of 70% stenosis are listed in Table 2. The last column (percentage on target) lists the proportion of patients in which the coronary anatomy would have been considered correctly predicted by the distribution of the myocardial perfusion defects on MPS. Of patients presenting with perfusion defects involving the anterior wall, 42% presented with significant extensive CAD, consisting of left main disease, 3-vessel disease, or 2-vessel disease involving the left anterior descending coronary artery. In addition, 50% of patients with reversible or fixed defects localized to a single territory also had left main disease, 3-vessel disease, or 2-vessel disease involving the left anterior descending coronary artery. Moreover, ⬎37% of patients with NSTE ACS treated conservatively with “negative” results on MPS had extensive CAD. If 2-vessel disease not involving the left anterior descending coronary artery is included, approximately 62% of patients with normal results on MPS had at least 2-vessel disease (with ⱖ70% stenosis). Prediction of the extent of significant CAD was poor in cases of an absence of a perfusion defect, with only 8% of these patients in fact not presenting with significant CAD on angiography. Prediction was slightly better but still weak in cases of localized ischemia (limited to the anterior, inferior, or lateral wall only). Indeed, most patients with such patterns had multivessel disease rather than single-vessel disease, as suggested by MPS. Finally, prediction was good only with multiple (ⱖ2) areas of ischemia or fixed defects sparing the anterior wall. Discussion In the present study of patients who presented with NSTE ACS and who were initially selected for conservative

management, abnormal results on MPS, showing fixed or reversible perfusion defects, even when limited to 1 territory, were often associated with multivessel CAD. Moreover, a negative result on MPS was also frequently associated with significant CAD. In fact, a patient in this population with a negative result had a very low chance of being free of significant CAD on subsequent angiography. Therefore, our analysis suggests that clinicians must not presume the extent of CAD on the basis of the results of MPS alone in such a population, unless several territories are involved. Although the long-term clinical outcomes of these patients were not included in this analysis, it merits underlining that this high-risk cohort of patients with data from MPS and coronary angiography were similar overall to the entire MPS cohort, and most had multivessel disease even in cases with normal results on MPS. The most recent NSTE ACS guidelines recommend that patients be evaluated for their risk for CAD at presentation and that, on the basis of this evaluation, they be selected for either an early invasive or a conservative management strategy.1 This recommendation is based on a number of trials comparing the 2 strategies, including the Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial,3,4 in which a conservative strategy was shown to be noninferior to the early invasive strategy in biomarker-positive patients with a more contemporary medical regimen. The recommendation for the selective management of patients on the basis of their risk profiles in this setting has also been upheld by a recent meta-analysis.2 In the subsequent evaluation of patients selected for conservative management, functional testing and imaging studies (either echocardiography or MPS) are recommended. This recommendation rests in part on studies such as the Adenosine Sestamibi Post-Infarction Evaluation (INSPIRE) trial, in which up to 1/3 of patients with ACS were successfully discharged from the hospital on the basis of the results of MPS.5 As a result, the use of MPS, such as dipyridamole sestamibi, for the selection of conservatively managed patients for angiography is a widespread practice. However, the accuracy of MPS in this setting has been insufficiently studied. Furthermore, the perfusion defect (ischemic) threshold beyond which a patient should be referred for catheterization has not been well defined. Various small-scale studies using different methods of mapping the myocardium have shown that one’s ability to identify the anatomic location and extent of CAD outside of the setting of NSTE ACS is quite poor in the absence of knowledge of the coronary anatomy.6 – 8 The ability of MPS to accurately predict the extent of CAD in the setting of NSTE ACS when coronary anatomy is frequently unknown is not as well understood. Given the widespread use of MPS for this indication, the implications of our findings are significant. Given the high likelihood of significant multivessel or left main disease in this sample, even in the absence of an extensive perfusion defect, we believe that most patients with similar clinical features should be referred for coronary angiography. In patients raising a strong clinical suspicion of CAD (positive troponins, significant electrocardiographic changes, typical and possibly recurring chest pain), the threshold for coronary angiography should

Coronary Artery Disease/MPS and Coronary Anatomy in ACS

remain low in the context of NSTE ACS, irrespective of MPS. Our study had several limitations that must be acknowledged. First, these data represent a single-center experience and as such remain to be confirmed in future studies. Although a small group of patients with NSTE ACS in this study were initially managed with MPS, our data reflect a “real-world” selectively invasive management of patients with NSTE ACS that is consistent with established guidelines.1 Second, as stated previously, clinical outcomes and the actual coronary anatomy of patients with minimal or no ischemia who were not referred for coronary angiography were unknown. Therefore, the clinical accuracy (sensitivity and specificity) of MPS in the population studied could not be determined. Our study questions the ability of MPS to accurately evaluate the extent of CAD, which often dictates subsequent immediate management, but not its ability to stratify patients with respect to their risk for events over the long term. Third, although the baseline characteristics of patients who underwent nuclear imaging with or without subsequent angiography were overall similar, patients who did ultimately go on to coronary angiography more often demonstrated a reversible perfusion defect on MPS imaging. It is possible therefore that this group represents a higher risk population. Moreover, despite apparently reassuring results on MPS, some patients presented a clinical picture that ultimately prompted coronary evaluation by angiography. We believe that it is an important conclusion of this study that the results of MPS should not trump the clinical picture or a physician’s index of suspicion outright. Conversely, most of the patients enrolled in INSPIRE5 were notably at lesser risk clinically, which could have biased the results of that study in a way more favorable to stratification by MPS. Our findings of a high proportion of patients with extensive CAD despite normal results on MPS remain nevertheless surprising. This may suggest “balanced” ischemic defects resulting in pseudonormal perfusion patterns. Alternatively, collateralization may account for some of the false-negative results. Fourth, our small sample size allowed for the performance of descriptive statistics only. Fifth, our analysis was based solely on the angiographic severity of coronary artery lesions. It is possible that intracoronary functional assessment of the lesions with fractional flow reserve9 would have yielded divergent results. That being said, it remains the normative practice, in accordance with established practice guidelines,10 to intervene on angiographically significant lesions, while submitting intermediate lesions to further transluminal interrogation. Moreover, in the present analysis, only lesions ⱖ70% were considered, even where lesions of the left main coronary were concerned. Finally, the present study was one of the clinical effectiveness of MPS with dipyridamole sestamibi to predict the coronary anatomy in conservatively managed, mainly biomarker positive NSTE ACS and the results may not necessarily extrapolate to other techniques of MPS or in cases in which the diagnosis of ACS is unclear,11 nor do they speak to the usefulness of MPS for guiding coronary revascularization.

647

1. Anderson JL, Admas CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochmna, JS, Levin TN, Lincoff AM, Petersen ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholtz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1– e157. 2. O’Donoghue M, Boden WE, Braunwald E, Cannon CP, Clayton TC, de Winter RJ, Fox KA, Lagerqvist B, McCullough PA, Murphy SA, Spacek R, Swahn E, Wallentin L, Windhausen F, Sabatine MS. Early invasive vs conservative treatment strategies in women and men with unstable angina and non–ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2008;300:71– 80. 3. de Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, Bendermacher PE, Michels HR, Sanders GT, Tijssen JG, Verheugt FW; Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095–1104. 4. Hirsch A, Windhausen F, Tijssen JG, Verheugt FW, Cornel JH, de Winter RJ; Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Long-term outcome after an early invasive versus selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome and elevated cardiac troponin T (the ICTUS trial): a follow-up study. Lancet 2007;369:827– 835. 5. Mahmarian JJ, Shaw LJ, Filipchuk NG, Dakik HA, Iskander SS, Ruddy TD, Henzlova MJ, Keng F, Allam A, Moyé LA, Pratt CM; INSPIRE Investigators. A multinational study to establish the value of early adenosine technetium-99m sestamibi myocardial perfusion imaging in identifying a low-risk group for early hospital discharge after acute myocardial infarction. J Am Coll Cardiol 2006;48:2448 –2457. 6. Husmann L, Wiegand M, Valenta I, Gaemperli O, Schepis T, Siegrist PT, Namdar M, Wyss CA, Alkadhi H, Kaufmann PA. Diagnostic accuracy of perfusion imaging with single photon emission computed tomography and positron emission tomography: a comparison with coronary angiography. Int J Cardiovasc Imaging 2007;24:511–518. 7. Segall GM, Atwood JE, Botvinick EH, Dae MW, Lucas JR. Variability of normal coronary anatomy: implications for the interpretation of thallium-SPECT myocardial perfusion images in single-vessel disease. J Nucl Med 1995;36:944 –951. 8. Pereztol-Valdés O, Candell-Riera J, Santana-Boado C, Angel J, Aguadé-Bruix S, Castell-Conesa J, Garcia EV, Soler-Soler J. Correspondence between left ventricular 17 myocardial segments and coronary arteries. Eur Heart J 2005;26:2637–2643. 9. Bishop AH, Samady H. Fractional flow reserve: critical review of an important physiologic adjunct to angiography. Am Heart J 2004;147: 792– 802. 10. Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA; American College of Cardiology Foundation Appropriateness Criteria Task Force. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2009;53:530 –553. 11. Dorbala S, Giugliano RP, Logsetty G, Vangala D, Mishra R, Crugnale S, Yang D, Di Carli MF. Prognostic value of SPECT myocardial perfusion imaging in patients with elevated cardiac troponin I levels and atypical clinical presentation. J Nucl Cardiol 2007;14:53–58.