Prognostic Value of Lung Sestamibi Uptake in Myocardial Perfusion Imaging of Patients With Known or Suspected Coronary Artery Disease

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1 Journal of the American College of Cardiology Vol. 45, No. 10, by the American College of Cardiology Foundation ISSN /05/$30.00 Published by Elsevier Inc. doi: /j.jacc Prognostic Value of Lung Sestamibi Uptake in Myocardial Imaging of Patients With Known or Suspected Coronary Artery Disease William D. Leslie, MD, MSC,* Shawn A. Tully, MD,* Marina S. Yogendran, MSC, Linda M. Ward, RT(NM),* Khaled A. Nour, MD,* Colleen J. Metge, PHD Winnipeg, Canada Cardiac Imaging OBJECTIVES We sought to determine whether lung uptake of technetium-99m ( 99m Tc)-based myocardial perfusion tracers predicts cardiac events. BACKGROUND Increased lung uptake of thallium-201 during myocardial perfusion scintigraphy can predict important clinical outcomes. It is unclear whether lung uptake of 99m Tc-based myocardial perfusion tracers can be used in a similar way. METHODS Stress lung-to-heart ratio (slhr) was determined in 718 patients undergoing 99m Tcsestamibi single-photon emission computed tomographic stress imaging. The primary outcome was acute myocardial infarction or death. RESULTS During a mean follow-up of 5.6 years, a primary end point occurred in 114 patients (16%). The slhr was significantly greater in those with an adverse outcome (p ). The likelihood of an adverse outcome increased by a factor of 1.5 (95% confidence interval 1.2 to 1.7) for each standard deviation increase in slhr after adjustment for all other variables. The slhr provided a small but significant improvement in risk stratification when added to clinical, stress test, perfusion, and left ventricular volume information (global chi-square vs , p ). CONCLUSIONS Stress LHR is an adjunctive prognostic measure in patients with known or suspected coronary artery disease. (J Am Coll Cardiol 2005;45: ) 2005 by the American College of Cardiology Foundation The assessment of myocardial perfusion using radioactive tracers has consistently been shown to provide important prognostic information in patients with known or suspected coronary artery disease (CAD). Increased lung uptake of thallium-201 ( 201 Tl) after a stress procedure has been strongly associated with severe CAD and cardiac events (1,2). It is currently unclear whether the assessment of lung uptake on technetium-99m ( 99m Tc)-based perfusion scintigraphy provides clinically useful ancillary information or not. Although some groups have shown that 99m Tcsestamibi lung uptake correlates with left ventricular (LV) dysfunction and CAD severity (3 5), this index has not yet been shown to predict important cardiac events. METHODS Study population. Between January 1994 and April 1999, consecutive patients who underwent stress and rest 99m Tcsestamibi single-photon emission computed tomographic (SPECT) myocardial perfusion imaging on the same imaging system (Elscint 409; Haifa, Israel) were considered for inclusion in the study cohort (n 1,027). The study cohort, From the *Department of Nuclear Medicine, St. Boniface General Hospital, Winnipeg; and Manitoba Centre for Health Policy, Winnipeg, Canada. This study was supported by grants from the Canadian Institute for Health Research and the Rx & D Foundation. Manuscript received June 24, 2004; revised manuscript received February 3, 2005, accepted February 8, stress procedures, and image processing used in our laboratory have been previously described (6). Exclusion criteria included planar imaging or imaging not completed on the designated camera (n 36), corrupted (n 102) or poor quality image data (n 2), nonstandard stress procedures (n 4), or the inability to link patient data to the Manitoba Population Health Research Data Repository (n 140). For patients undergoing more than one scan during the study period, only the first scan was included in the analysis (n 25). The study protocol was approved by the local Research Ethics Board and provincial Health Information Privacy Committee. Stress protocols and imaging. A two-day protocol utilizing treadmill exercise is the preferred procedure in our laboratory. Whenever possible, beta-blockers and calcium channel antagonists are withheld for 24 to 48 h before the stress procedure, and nitrates are avoided for at least 6 h. Symptom-limited treadmill exercise was performed with tracer injection at peak exercise. Individuals unable to achieve a satisfactory exercise workload underwent pharmacologic stress with dipyridamole. Supine, nongated SPECT imaging commenced 30 to 60 min after stress and 45 to 75 min after the resting injection. Scintigraphic interpretation. Initial visual interpretation of the scan data was performed without image quantification using two variables: a normal scan (normal or equivocal) versus abnormal scan (abnormal with fixed or reversible

2 JACC Vol. 45, No. 10, 2005 May 17, 2005: Leslie et al. Sestamibi Lung Uptake 1677 Abbreviations and Acronyms AMI acute myocardial infarction CAD coronary artery disease dlhr difference in lung-to-heart ratios LHR lung-to-heart ratio LV left ventricle rlhr rest lung-to-heart ratio SDS summed difference score slhr stress lung-to-heart ratio SPECT single-photon emission computed tomography SRS summed rest score SSS summed stress score 201 Tl thallium m Tc technetium-99m defects); and no reversibility (normal, equivocal, or abnormal with fixed defects) versus reversibility (abnormal with fully reversible or partially reversible defects). Image data were subsequently reprocessed using commercial software (AutoSPECT and QPS AutoQUANT, Cedar Sinai Medical Center and ADAC Laboratories, Milpitas, California). Left ventricular contours were checked visually and manually adjusted if the computer-generated automatic contours were found to be incorrect. This software provides quantitative defect scores for the summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) based on a 20-segment model (7,8). We have previously shown close agreement between the visual and automated quantitative assessment in terms of diagnosis and prognosis (6,9). Visual interpretation and the quantitative analysis were performed without knowledge of patient outcomes. of 99m Tc-sestamibi was calculated as the lung-to-heart ratio (LHR), using a validated automated technique (3). The LHR was measured on stress (slhr) and rest projection data (rlhr), and the difference (dlhr) was derived by subtraction. Mean slhr was identical for exercise only and pharmacologic stress, and these groups were combined in subsequent analysis. Excellent interobserver agreement in LHR measurements was confirmed in 30 blindly reprocessed cases (slhr: R 0.97, p , mean difference 0.01; and rlhr: R 0.95, p , mean difference 0.01). An automated calculation of ungated s after stress and at rest was obtained (10). Transient ischemic dilation was derived from the endocardial volumes as the ratio of at stress divided by the volume at rest. Outcomes assessment. Cohort follow-up was performed through the Manitoba Population Health Research Data Repository, which links computerized data bases of physician services and hospitalizations for all residents of the province of Manitoba (11). The primary outcome was death (from Vital Statistics) or acute myocardial infarction (AMI; hospital diagnosis ICD-9-CM 410.xx). Clinical and stress variables were primarily obtained from chart review. The Repository was used to identify diabetes or previous AMI. Statistical analysis. Statistical analysis was performed with a commercial software package (Statistica Version 6.1, StatSoft Inc., Tulsa, Oklahoma). Continuous variables are reported as the mean value SD, and p 0.05 is considered to represent a statistically significant difference. Group comparisons were performed using analysis of variance (ANOVA) or chi-square testing. Kaplan-Meier survival curves were compared using Gehan s Wilcoxon test. Receiver operating characteristic (ROC) curves were generated with SPSS version 11.0 (SPSS Inc., Chicago, Illinois). Multivariate survival analysis used Cox proportional hazards modeling. One model was developed for the complete study cohort using clinical variables, stress modality, perfusion,, and LHR measurements. A second model was developed for those undergoing treadmill exercise only and also included exertional chest pain, electrocardiographic ischemia, peak workload, peak heart rate, peak systolic blood pressure, and peak double product. An initial (partial) regression was limited to competing variables from within each of the clinical, exercise, volume, and lung uptake variable subgroups in order to select the final (combined) regression variables. If significant collinearity was identified (R 0.5), only the factor with the strongest association was entered. RESULTS Patient characteristics. Of the 718 patients included in the analysis, 380 (53%) were males, 186 (26%) had a history of MI, 112 (16%) had undergone a previous coronary artery bypass graft surgery or coronary angioplasty, 90 (13%) were diabetic, and 556 (77%) had treadmill exercise as the only stress method. measurements. Overall, mean slhr ( ) was slightly greater than the rlhr ( ; p by paired comparison). measurements showed significant differences according to the severity of perfusion abnormality, as reflected in the SSS, with greater stress and rlhr in association with more extensive perfusion abnormalities (Table 1). Survival analysis. During a mean follow-up of years, 114 patients (16%) experienced a primary event. There were 81 deaths and 62 AMIs, including 29 patients recorded as having AMI followed by death. Mean slhr was higher in individuals who had an adverse outcome, as compared with those who remained event-free ( vs , p ). This was even identified in the subgroup with normal SSS ( vs , p 0.002). Two-way ANOVA confirmed higher slhr in relation to an adverse clinical outcome (p ), independent of the SSS category. Individuals with an adverse outcome also had a higher mean rlhr ( vs , p ) and dlhr ( vs , p 0.02). The ROC analysis confirmed a significant association between adverse outcomes over the range of slhr mea-

3 1678 Leslie et al. JACC Vol. 45, No. 10, 2005 Sestamibi Lung Uptake May 17, 2005: Table 1. Relationship Between Lung Uptake and Summed Stress Score* Category Overall (n 718) Normal (n 367) Mild (n 136) Moderate (n 78) Severe (n 137) slhr rlhr dlhr p value: slhr vs. rlhr *The summed stress score (SSS) was categorized as normal ( 3) or mildly (4 to 8), moderately (9 to 13), and severely abnormal ( 13). Analysis of variance between SSS categories: p , p Data are presented as the mean value SD. dlhr, rlhr, and slhr difference in, rest, and stress lung-to-heart ratio, respectively. surements (Fig. 1). The area under the curve was 0.65 for slhr (95% confidence interval [CI] 0.59 to 0.71, p ), 0.62 for rlhr (95% CI 0.57 to 0.69, p ), and 0.56 for dlhr (95% CI 0.51 to 0.62, p 0.04). For comparison, the area under the curve was 0.67 for SSS (95% CI 0.61 to 0.73), 0.67 for SRS (95% CI 0.61 to 0.73), and 0.63 for SDS (95% CI 0.57 to 0.68). The area under the curve for slhr was similar for the individual end points of death (0.65, 95% CI 0.58 to 0.72, p 0.001) and AMI (0.67, 95% CI 0.60 to 0.74, p 0.001). Subgroup analysis for individuals with a normal SSS gave an area under the curve for slhr (0.64, 95% CI 0.52 to 0.75, p 0.01), similar to the overall group. Event-free survivals according to slhr tertiles (Fig. 2) were significantly different (p ). Table 2 summarizes the univariate analysis for the complete study cohort. Multivariate analysis identified six variables as independent predictors of death or AMI (Table 3). These were older age (p ), previous MI (p 0.001), diabetes (p ), pharmacologic stress (p ), stress (p ), and slhr (p ). The relative hazard increased by a factor of 1.5 (95% CI 1.2 to 1.8) for each standard deviation (SD) increase in slhr after adjustment for all other variables. A secondary analysis was performed in those 556 patients undergoing treadmill exercise only (Table 4). Multivariate analysis identified five variables as independent predictors of an adverse outcome (Table 5). These were male gender (p 0.01), diabetes (p 0.006), peak workload (p ), stress (p ), and slhr (p 0.003). The relative hazard increased by a factor of 1.4 (95% CI 1.1 to 1.8) for each SD increase in slhr after adjustment for all other variables. Incremental contribution. Figure 3 shows the incremental improvement in the global chi-square for predicting death or AMI, using variables that were found to be independent predictors of outcome. As no perfusion variables were in these final models, we also included SSS. There was a statistically significant increase when the model using clinical variables alone (global chi-square 92.1) was augmented with variables related to the stress test (122.0, p ), perfusion data (127.0, p 0.08), left volume (150.7, p ), and lung uptake (168.6, p ). In the exercise-only subgroup, the inclusion of slhr also provided a small but significant incremental improvement in risk stratification when added to clinical, stress test, perfusion, and volume information (global chi-square 85.5 vs. 77.1, p 0.004). DISCUSSION This study provides direct evidence that 99m Tc-sestamibi slhr predicts subsequent AMI or death. Furthermore, this Figure 1. Receiver operating characteristic analysis for predicting death or acute myocardial infarction from stress lung-to-heart ratio (LHR) (solid line) or summed stress score (SSS) (dotted line). Figure 2. Kaplan-Meier plots of event-free survival according stress lungto-heart ratio (LHR) tertile.

4 JACC Vol. 45, No. 10, 2005 May 17, 2005: Leslie et al. Sestamibi Lung Uptake 1679 Table 2. Baseline Characteristics, Stress Procedure, and Scan Findings in Relation to the Occurrence of a Primary Event for All Patients Total (n 718) Events (n 114) No Events (n 604) p Value Age (yrs) Gender (male) 380 (53%) 78 (68%) 302 (50%) Previous AMI 186 (26%) 56 (49%) 130 (22%) Previous revascularization 112 (16%) 22 (19%) 90 (15%) 0.2 Diabetes 90 (13%) 33 (29%) 57 (9%) Stress test modality Exercise 556 (77%) 59 (52%) 497 (82%) Dipyridimole 162 (23%) 55 (48%) 107 (18%) Visually abnormal 330 (46%) 83 (73%) 247 (41%) Visual reversibility 281 (39%) 65 (57%) 216 (36%) SSS SRS SDS Stress (ml) Rest (ml) TID slhr rlhr dlhr Data are presented as the mean value SD or number (%) of cases. AMI acute myocardial infarction; LV left ventricular; SDS summed difference score; SRS summed rest score; SSS summed stress score; TID transient ischemic dilation; other abbreviations as in Table 1 information appears to be incremental when combined with other clinical and test-related information. measurements. The LHR measurements increased in association with worsening stress perfusion abnormalities. of 201 Tl after stress has been correlated with a rise in pulmonary capillary wedge pressure due to exercise-induced LV dysfunction (12). Increased resting pulmonary 201 Tl uptake has also been correlated with LV dysfunction, the extent of CAD, and resting perfusion abnormalities (13,14). Hurwitz et al. (15) reported that lung sestamibi was elevated in 15% to 17% of exercise studies using planar images obtained 4 min after injection, versus 9% to 10% on delayed acquisitions. Increased values were related to ischemic and fixed perfusion defects, LV dilation, LV dysfunction, and coronary stenoses. This suggests that the mechanism for enhanced 99m Tcsestamibi lung uptake is similar to lung uptake of 201 Tl. The disadvantage of early imaging is that it negates much of the convenience and scheduling efficiency of sestamibi over thallium. A direct comparison of the relative prognostic Table 3. Stepwise Regression Analysis for the Occurrence of a Primary Event for All Patients Initial Partial Models Final Combined Model HR* (95% CI) p Value HR* (95% CI) p Value Age (yrs) 1.7 ( ) ( ) Gender (male) 1.7 ( ) Previous AMI 2.3 ( ) ( ) Diabetes 2.9 ( ) ( ) Stress test Pharmacologic stress (vs. exercise) 4.0 ( ) ( ) SSS 1.6 ( ) Stress 1.6 ( ) ( ) TID 1.2 ( ) slhr 1.8 ( ) ( ) dlhr 0.9 ( ) 0.2 *Hazard ratios (HR) for continuous variables expressed per SD. CI confidence interval; HR hazard ratio; other abbreviations as in Tables 1 and 2.

5 1680 Leslie et al. JACC Vol. 45, No. 10, 2005 Sestamibi Lung Uptake May 17, 2005: Table 4. Baseline Characteristics, Exercise Results, and Scan Findings in Relation to the Occurrence of a Primary Event for Patients Who Performed Treadmill Exercise Stress Only Total (n 556) Events (n 59) No Events (n 497) p Value Age (yrs) Gender (male) 303 (54%) 42 (71%) 261 (53%) Previous AMI 136 (24%) 27 (46%) 109 (22%) Previous revascularization 83 (15%) 13 (22%) 70 (14%) 0.11 Diabetes 51 (9%) 13 (22%) 38 (8%) Exercise Chest pain 114 (21%) 22 (37%) 92 (19%) Ischemic ECG 115 (21%) 12 (20%) 103 (21%) 0.2 Resting heart rate (beats/min) Resting systolic blood pressure (mm Hg) Peak heart rate (beats/min) Peak systolic blood pressure (mm Hg) Peak double product ( 1,000) Peak workload (METs) Visually abnormal 229 (41%) 39 (66%) 190 (38%) Visual reversibility 193 (35%) 29 (49%) 164 (33%) 0.01 SSS SRS SDS Stress (ml) Rest (ml) TID slhr rlhr dlhr Data are presented as the mean value SD or number (%) of patients. ECG electrocardiogram; METs metabolic equivalents; other abbreviations as in Tables 1 and 2. Table 5. Stepwise Regression Analysis for the Occurrence of a Primary Event for Patients Who Performed Treadmill Exercise Stress Only Initial Partial Models Final Combined Model HR* (95% CI) p Value HR* (95% CI) p Value Age (yrs) 1.2 ( ) 0.11 Gender (male) 1.9 ( ) ( ) 0.01 Previous AMI 2.1 ( ) Diabetes 2.5 ( ) ( ) Exercise Chest pain 1.8 ( ) 0.03 Peak double product 0.7 ( ) Peak workload (METs) 0.6 ( ) ( ) SSS 1.6 ( ) Stress (ml) 1.7 ( ) ( ) TID 1.0 ( ) 0.2 slhr 1.9 ( ) ( ) dlhr 0.9 ( ) 0.2 *Hazard ratios (HR) for continuous variables expressed per SD. Abbreviations as in Tables 1 to 4.

6 JACC Vol. 45, No. 10, 2005 May 17, 2005: Leslie et al. Sestamibi Lung Uptake 1681 Figure 3. Incremental contribution of clinical, stress procedure, perfusion, left ventricular volume, and lung uptake variables on prediction of acute myocardial infarction (MI) or death (see text for details). (A) All patients. (B) Treadmill exercise patients only. value of early lung uptake characterization and delayed imaging is needed. Survival analysis. The slhr and rlhr were significantly higher in individuals who experienced AMI or death than in those individuals who remained event-free. The degree of univariate risk stratification, as determined by ROC analysis, was similar for slhr, rlhr, and SSS. In contrast, a change in lung uptake provided minimal risk stratification. Other reports have emphasized that prognostic variables may differ in terms of predicting AMI and death (16), but in our cohort, slhr provided similar risk stratification for these individual end points. The variables independently associated with a lower event-free survival were older age, previous MI, diabetes, use of pharmacologic stress, larger stress LV chamber size, and slhr. In the exercise only subgroup, peak workload was also predictive. Surprisingly, perfusion, as assessed by SSS, was no longer a significant predictor after adjustment for all other information. This finding is consistent with the observation that increased lung thallium uptake was the strongest predictor of a cardiac event (relative risk 3.5, 95% CI 2.2 to 5.4) (1). Incremental contribution. The slhr was additive to a model containing clinical, stress, perfusion, and LV volume information. Although the incremental improvement was modest, LHR measurement is available without any additional cost. Because no attempt was made to standardize the time between tracer injection and scanning, there was no interference with optimal camera utilization. Study limitations and clinical implications. Although elevated lung uptake of sestamibi (highest tertile) is a strong univariate predictor of death or AMI (annualized event rate 4.8% per year), uptake in the lowest tertile is still associated with an intermediate risk (annualized event rate 1.6% per year), and other clinical and laboratory information must be considered in clinical decisionmaking. A limitation of our study is the lack of information on LV performance. Prognostic information can be obtained from the gated SPECT measurement of LV ejection fraction when combined with an assessment of perfusion (17). Our use of ungated as a surrogate for LV ejection fraction is not ideal but can be justified from the strong inverse relationship between these two parameters (18). Reliance on administrative data for assessing end points could also be questioned, although the Manitoba Population Health Research Data Repository has been used to validate prediction rules of mortality after AMI, and there is unlikely to be disagreement over the occurrence of death (19). Conclusions. The slhr appears to be another adjunctive prognostic measure in patients with known or suspected CAD. Before this measurement is routinely used for clinical decision-making, further studies are required to confirm our finding that lung uptake measurements can enhance risk stratification over conventional prognostic variables, and these studies should include a direct measurement of LV ejection fraction. Acknowledgments We are indebted to Health Information Management at Manitoba Health for providing data. The results and conclusions are those of the authors, and no official endorsement by Manitoba Health is intended or should be inferred. The authors would like to thank Ms. D. Rutledge for assistance with manuscript preparation. Reprint requests and correspondence: Dr. William D. Leslie, Department of Medicine (C5121), 409 Tache Avenue, Winnipeg, Canada R2H 2A6. bleslie@sbgh.mb.ca.

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