The impact of adjunctive adenosine infusion during exercise myocardial perfusion imaging: results of the Both Exercise and Adenosine Stress Test (BEAST) trial

The impact of adjunctive adenosine infusion during exercise myocardial perfusion imaging: Results of the Both Exercise and Adenosine Stress Test (BEAST) trial Thomas A. Holly, MD,a Aaron Satran, MD,b David S. Bromet, MD,b Jennifer H. Mieres, MD,c Martin J. Frey, MD,d Michael D. Elliott, MD,a Gary V. Heller, MD, PhD,e and Robert C. Hendel, MDb Background. Failure to achieve an adequate heart rate limits the sensitivity of exercise myocardial perfusion imaging (MPI) for the detection of coronary artery disease. In addition, it is often not possible to discontinue medications that may blunt the heart rate response to exercise, because of conditions such as hypertension or angina. However, if pharmacologic stress testing is performed, the ability to assess functional capacity is lost. Accordingly, we developed a protocol that incorporates adenosine stress with symptom-limited exercise. Methods and Results. As part of a multicenter study, 35 patients were enrolled prospectively and underwent both exercise MPI and exercise MPI with a 4-minute adenosine infusion on a separate day. Technetium 99m sestamibi was injected at or near peak exercise (exercise only) and at 2 minutes into the adenosine infusion (combined exercise and adenosine). The perfusion images were interpreted in a blinded fashion. The combined adenosine and exercise protocol was well tolerated. The summed stress scores and summed difference scores were greater in the exercise-plus-adenosine group than in the exercise-only group (10.0 vs 8.5, P ⴝ .02, and 4.9 vs 3.3, P ⴝ .002, respectively). Exercise time was slightly but significantly less with the exerciseplus-adenosine protocol (8 minutes 46 seconds vs 8 minutes 11 seconds, P ⴝ .027). Conclusion. A protocol combining 4 minutes of adenosine infusion with symptom-limited exercise was safe and well tolerated. Furthermore, this protocol resulted in a greater amount of myocardial ischemia detected on MPI while allowing for the assessment of functional capacity. A combined exercise and adenosine protocol may be a useful test for patients undergoing MPI who are unlikely to achieve an adequate chronotropic response. (J Nucl Cardiol 2003;10:291-6.) Key Words: Myocardial perfusion imaging • symptom-limited exercise • adenosine

The diagnostic accuracy of exercise stress testing combined with myocardial perfusion imaging (MPI) is reduced among patients who are unable to achieve a sufficient workload. Failure to attain an adequate heart rate response during exercise reduces the sensitivity of stress MPI for detecting coronary artery disease (CAD) and also diminishes the extent of defects seen on perfuFrom the Northwestern University Medical School and Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL; North Shore University Hospital, Manhasset, NY; Sarasota Heart Center, Sarasota, Fla; and Hartford Hospital, Hartford, Conn. Funding provided in part through Fujisawa Healthcare, Inc. T.A.H. is a recipient of a Schweppe Foundation Career Development Award. Received for publication Aug 7, 2002; final revision accepted Nov 25, 2002. Reprint requests: Robert C. Hendel, MD, 1725 W Harrison, Suite No. 020, Chicago, IL 60612; [email protected]. Copyright © 2003 by the American Society of Nuclear Cardiology. 1071-3581/2003/$30.00 ⫹ 0 doi:10.1016/S1071-3581(02)43236-9

sion imaging.1-5 Among patients specifically referred for exercise MPI, many are unable to achieve an adequate heart rate response, resulting in a substantial number (up to 25%) of false-negative results.6-8 Common reasons for suboptimal exercise include pulmonary, musculoskeletal, neurologic, or peripheral vascular disease. Heart rate responsiveness is also frequently affected by the use of medications, particularly ␤-blockers. Given these limitations, it is usually recommended that patients discontinue cardiac medications before exercise stress testing. Unfortunately, such an approach is often difficult because of coexisting hypertension or angina. Furthermore, there are potentially serious complications of this diagnostic strategy such as rebound hypertension or tachycardia. In such cases, pharmacologic stress testing with adenosine or dipyridamole can be substituted for exercise testing. However, frequent side effects, contraindications to the medication (such as high-grade atrioventricular [AV] block or asthma), high 291

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protocol would be safe and well tolerated, and would improve diagnostic accuracy among patients receiving antianginal medications or those unable to generate an adequate heart rate response during exercise, as compared with a standard exercise-only protocol. METHODS

Figure 1. Schematic representation of the standard exercise protocol and the experimental exercise-plus-adenosine protocol. In both protocols, patients performed symptom-limited exercise testing according to the Bruce protocol. Sestamibi (MIBI) was injected 1 minute before the completion of exercise in the standard protocol and 2 minutes into the adenosine infusion in the experimental protocol.

extracardiac tracer uptake, and arrhythmias are commonly encountered in up to 80% of patients.9 In addition, clinically useful information such as functional capacity and exercise-induced symptoms cannot be ascertained with the use of pharmacologic stress testing when performed in a standard fashion. At present, it is not always possible to predict which patients will not achieve the target heart rate when performing an exercise stress test. We therefore sought to develop a protocol that would allow the maximal assessment of ischemia while still permitting a determination of functional capacity. Treadmill exercise combined with adenosine infusion has been shown to be a safe and feasible option for patients undergoing MPI.10-15 Elliott et al10 demonstrated that a 4-minute adenosine infusion with concomitant treadmill exercise not only reduced the quantity and severity of adenosine-related effects but also improved image quality. This finding was also seen by Muller-Suur et al,16 who found enhancement of image quality when performing an adenosine perfusion study versus an exercise (bicycle) protocol in patients receiving ␤-blockade. In addition, Samady et al14 found that a 6-minute adenosine infusion with concomitant low-level treadmill exercise reduced unfavorable side effects, enhanced image quality, and may have resulted in greater detection of ischemia. However, these findings are in contrast to a study by Jamil et al11 who showed no change in defect size or severity compared with a standard 6-minute adenosine infusion. To date, there has been no direct comparison between standard exercise testing and standard exercise testing combined with adenosine. In this study, we hypothesized that a protocol combining a 4-minute adenosine infusion with a standard treadmill exercise

The study protocol was reviewed and approved by the institutional review board at each of the 5 participating institutions. After providing informed consent, 35 patients scheduled to undergo elective exercise MPI were enrolled in a prospective manner. This group included patients with documented or suspected CAD who were taking antianginal medications (␤-blockers, calcium channel blockers, or nitrates) or patients deemed to have confounding factors that might not allow them to achieve the target heart rate. Exclusion criteria were as follows: women of childbearing potential, unless the results of a pregnancy test were negative; women who were breast-feeding; inability to perform exercise on a treadmill; a nuclear medicine study within the preceding 30 days; a contraindication to adenosine (moderate to severe chronic obstructive pulmonary disease or asthma, second- or third-degree AV block or sinus node disease, known hypersensitivity to adenosine); left bundle branch block or artificial ventricular pacemaker; hemodynamic instability (blood pressure ⬎210/110 mm Hg or ⬍90/60 mm Hg), decompensated congestive heart failure; or the use of theophylline or dipyridamole within the preceding 48 hours. On separate days, patients underwent rest thallium 201 perfusion imaging, followed by either the standard or experimental stress treadmill exercise Tc-99m sestamibi single photon emission computed tomography (SPECT) imaging study (exercise only). On the subsequent day, only the second stress imaging study was performed. The experimental stress protocol consisted of a 4-minute adenosine Tc-99m sestamibi SPECT study with symptom-limited treadmill exercise (exercise plus adenosine). The protocols are depicted schematically in Figure 1. Treadmill exercise was performed according to the standard Bruce protocol. For the adenosine-plus-exercise protocol, intravenous adenosine (140 ␮g · kg⫺1 · min⫺1) was infused at the start of exercise and continued for a total of 4 minutes. Tc-99m sestamibi (approximately 25 mCi or 9.3 ⫻ 108 becquerels) was injected at 2 minutes into the adenosine infusion. During the exercise-only protocol, Tc-99m sestamibi (25 mCi or 9.3 ⫻ 108 becquerels) was injected approximately 1 minute before the termination of exercise. The tests were performed within 14 days, and the order of the tests were randomly determined at the time of enrollment. Each institution used its standard imaging protocol, with the second study performed in an identical manner. Both protocols used continuous electrocardiographic monitoring during the stress portion of the test and for at least 5 minutes during recovery or until symptoms, significant hemodynamic changes, or significant changes had resolved. Blood pressure and pulse measurements were obtained every minute during the exercise-plus-adenosine protocol and once each stage during the exercise-only protocol. Patients were queried

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with regard to symptoms every minute during the exerciseplus-adenosine protocol and once each stage during the exercise-only protocol. A 12-lead electrocardiogram was obtained every minute during the stress and recovery period of the exercise-plus-adenosine protocol and once each stage during the exercise-only protocol. Raw perfusion data was processed in a uniform manner at the core laboratory (Rush-Presbyterian-St Luke’s Medical Center, Chicago, Ill). A Butterworth filter (rest study: 0.66 cutoff, 5 order; stress study: 0.5 cutoff, 10 order) was used for image reconstruction. After reorientation, the perfusion data was displayed in a 17-segment model as per the American Society of Nuclear Cardiology guidelines17 and was scored by 2 expert readers. The readers were blinded to the patient identity and type of stress test, and the studies were reviewed in a random order. Specifically, whereas the stress and rest studies were interpreted together in the usual manner, the order of the 70 studies that were read (35 standard and 35 experimental) were randomized so as not to bias the expert readers. The expert readers interpreted the studies together and formed a consensus interpretation of each study. The 17 segments were scored from 0 to 4, in which 0 showed no perfusion defect and 4 was absent tracer. Participating sites were permitted to evaluate their experimental protocol images for their own patients as clinically indicated, but local reading was not included in the analysis. All data are expressed as the mean ⫾ SD. Comparisons between the two stress test variables were made by 2-tailed paired t tests. P ⬍ .05 was considered to be statistically significant.

RESULTS The demographic data of the 35 patients in this trial are shown in Table 1. Their mean age was 62 years (range, 41-87 years). Hypertension, hyperlipidemia, and diabetes were present in 77%, 51%, and 23% of the patients, respectively. The majority (54%) had sustained a previous myocardial infarction, and 46% had previously undergone either percutaneous coronary intervention or coronary artery bypass grafting. ␤-Blockers were being taken by 80% of patients, calcium channel blockers by 23%, and long-acting nitrates by 14%. The stress testing data is presented in Table 2. The mean percentage of maximal predicted heart rate achieved was similar between the two studies: 82% ⫾ 14.6% in the exercise-plus-adenosine study versus 83% ⫾ 14.3% in the exercise-only study (P ⫽ not significant [NS]). In the exercise-plus-adenosine study, 43% of patients achieved 85% of maximal predicted heart rate. In the exercise-only study, 40% did so. Of note, the mean maximal treadmill time was slightly but significantly greater in the exercise-only study (8 minutes 46 seconds vs 8 minutes 11 seconds, P ⫽ .027). There were no significant differences in the incidence of chest pain (9% in the exercise-plus-adenosine group vs 15% in the

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Table 1. Baseline patient characteristics

Characteristic

Data

Age, (y) (mean ⫾ SD) Men Prior myocardial infarction Prior percutaneous coronary intervention Prior coronary artery bypass grafting Calcium channel blockers ␤-Blockers Nitrates Hypertension Diabetes Hyperlipidemia Current tobacco use Family history

62 ⫾ 12 26 (76%) 19 (54%) 16 (46%) 16 (46%) 8 (23%) 28 (80%) 5 (14%) 27 (77%) 8 (23%) 18 (51%) 3 (9%) 17 (49%)

exercise-only group, P ⫽ NS) and no significant electrocardiographic changes between the studies (37% in the exercise-plus-adenosine study vs 29% in the exercise-only study, P ⫽ NS). Furthermore, there were no episodes of high-degree AV block in either study. The perfusion imaging results are shown graphically in Figure 2. The summed rest scores were similar for both studies (5.2 ⫾ 5.9 versus 5.1 ⫾ 6.4, P ⫽ NS). However, the summed stress scores were significantly greater in the exercise-plus-adenosine study when compared with the exercise-only study (10 ⫾ 8.4 vs 8.6 ⫾ 7.4, P ⫽ .02). A significantly greater summed difference score was observed in the adenosine-plus-exercise study versus the exercise-only study (4.9 ⫾ 4.5 vs 3.3 ⫾ 3.9, P ⫽ .002). The summed difference scores were higher with the experimental protocol in 62% of patients, the summed difference scores were the same in 21% of cases, and in 17% of cases the exercise-only summed difference score was higher than with the experimental protocol. DISCUSSION We have shown that a protocol combining a 4-minute adenosine infusion with symptom-limited exercise is safe and feasible in patients referred for exercise stress testing who are taking antianginal medications or who might not otherwise be able to reach the target heart rate because of physical limitations. This protocol allowed for the assessment of functional capacity, and the higher summed difference scores suggest that there is enhanced detection of ischemic burden in both the size and severity of the defect (Figure 3). Exercise has been successfully combined with aden-

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Table 2. Stress testing data

Measurement % Maximal heart rate Peak SBP (mm Hg) Peak DBP (mm Hg) Treadmill time ECG changes Chest pain High-degree AV block

Experimental 82 ⫾ 14.6 171 ⫾ 28 84 ⫾ 11 8 min 11 s 37% 15% 0%

Standard

P value

83 ⫾ 14.3 177 ⫾ 30 84 ⫾ 12 8 min 46 s 29% 9% 0%

NS NS NS 0.027 NS NS NS

Experimental, Exercise-plus-adenosine protocol; Standard, exercise-only protocol; SBP, systolic blood pressure; DBP, diastolic blood pressure, ECG, electrocardiographic.

Figure 2. Perfusion imaging results for the two stress protocols. Compared with the exercise-only group, the summed stress scores (SSS) and summed difference scores (SDS) were significantly greater in the adenosine-plus-exercise group. There were no significant differences in the summed rest scores (SRS) between the two groups.

osine in other protocols.10-14,16 Pennell et al12 examined 3 groups of patients who underwent adenosine stress testing; one group received 6 minutes of adenosine alone, a second group received 6 minutes of adenosine and underwent submaximal semi-supine bicycle exercise, and a third group received continuous adenosine and underwent symptom-limited semi-supine bicycle exercise. No difference was noted in the sensitivity or specificity for the detection of CAD among the groups, although there was a trend toward improved sensitivity in the combined exercise groups. The authors also reported significant reductions in noncardiac side effects and major arrhythmias. Furthermore, heart-to-background ratios were higher in the exercise groups, and these ratios (heart:lung, heart:liver, and heart:gut) correlated with the exercise level achieved. However, semisupine bicycle exercise is not commonly used for stress

testing in the United States. In addition, their symptomlimited exercise protocol involved the infusion of adenosine throughout exercise, which can be problematic, given that in usual practice the duration of exercise cannot be determined beforehand. Thus the dose of adenosine needed is unknown, or an excess may be prepared, leading to added expense. In our protocol, a 4-minute adenosine infusion was used, and all 35 subjects were able to complete the infusion without difficulty. Side effects are common during standard adenosine stress testing. However, there were no significant side effects attributable to the adenosine infusion during our study. In addition, as noted, there were no episodes of advanced AV block. This is not surprising, as other authors have shown the benefit of concomitant exercise in reducing side effects from adenosine. Elliott et al10 demonstrated that a 4-minute adenosine infusion combined with low-level exercise significantly reduced the quantity and severity of adenosine-related effects. With the use of a 6-minute protocol, Samady et al14 recently obtained similar results, also using low-level treadmill exercise. In that study, combining adenosine with low-level exercise was found to be safe, significantly reduced unfavorable side effects, enhanced imaging quality, and reduced artifacts. Pennell et al12 had similar findings with their protocol of adenosine plus semi-supine bicycle exercise. One benefit of our adenosine–plus–symptom-limited exercise protocol was enhanced detection of myocardial ischemia as demonstrated by the greater summed difference scores in this study, which confirms the findings by Pennell et al12 and Samady et al.14 However, using a protocol combining exercise with a 4-minute adenosine infusion, Jamil et al11 showed no difference in defect size or severity compared with a standard 6-minute adenosine protocol. One reason for the different findings may be that the adenosine stress test in our study was compared with a treadmill exercise stress test, which may have been inadequate in many patients as a result of physical

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Figure 3. A, Short-axis, dual-isotope SPECT images of sample patient with the standard, exercise-only protocol. The arrows indicate a partially reversible perfusion defect. B, Adenosineplus-exercise protocol images from the same patient, demonstrating the larger, more severe area of ischemia. In addition, transient ischemic cavity dilatation is noted in B.

limitations or continuation of antianginal medications. It is important to point out, however, that although the patients in our study performed maximal symptomlimited exercise when participating in the experimental protocol, the isotope was injected 2 minutes after the start of adenosine, irrespective of exercise duration. Thus the effect of higher heart rate and workload beyond the 4-minute infusion had no effect on MPI. The mean peak heart rate in both studies was less than 85% of the maximal predicted heart rate (based on age), a commonly used threshold for “adequate” stress. The combined protocol also allowed for assessment of functional capacity in patients who may otherwise have been converted to pharmacologic stress testing. However, the exercise time was slightly shorter with the combined protocol. This difference was influenced by 2 patients whose exercise times were markedly shorter during the experimental protocol; one of these patients underwent coronary angiography soon after completing both stress protocols and was found to have a significant coronary lesion. Therefore, even though the exercise times differed, this may have been a result of the

induction of more ischemia with the combined stress protocol in patients with obstructive coronary disease. Our findings suggest that a protocol combining a 4-minute adenosine infusion with symptom-limited treadmill exercise is a valid approach for the assessment of functional status and detection of ischemia in the population described. This protocol may be an optimal technique for stress testing in selected patients, incorporating both treadmill exercise and adenosine without halting cardiac medications. Although other studies have also shown the addition of adenosine to exercise stress testing to be safe and well tolerated, one limitation of our study is that only 35 patients were tested. As such, plans are already under way to attempt a larger trial with this protocol to further demonstrate both the safety and utility of an exercise protocol combining adjunctive adenosine infusion with symptom-limited maximal treadmill exercise when performing MPI. Acknowledgment The authors have indicated they have no financial conflicts of interest.

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References 1. Iskandrian AS, Heo J, Askenase A, Segal BL, Auerbach N. Dipyridamole cardiac imaging. Am Heart J 1988;15:432-43. 2. Brown KA. Prognostic value of thallium-201 myocardial perfusion imaging: a diagnostic tool comes of age. Circulation 1991;83:36381. 3. Brown KA, Rowen MA. Impact of antianginal medications, peak heart rate, and stress level on the prognostic value of a normal exercise myocardial perfusion imaging study. J Nucl Med 1993; 34:1467-71. 4. Iskandrian AS, Heo J, Kong B, Lyons E. Effect of exercise level on the ability of thallium-201 tomographic imaging in detecting coronary artery disease: analysis of 461 patients. J Am Coll Cardiol 1989;14:1477-86. 5. Heller GV, Ahmed I, Tilkemeier PL, Barbour MM, Garber CE. Influence of exercise intensity on the presence, distribution, and size of thallium-201 defects. Am Heart J 1992;123:909-16. 6. Casale PN, Buiney TE, Strauss HW, Boucher CA. Simultaneous low-level treadmill exercise and intravenous dipyridamole stress thallium imaging. Am J Cardiol 1988;62(10 Pt 1):799-802. 7. Stern S, Greenberg ID, Come RA. Qualification of walking exercise required for improvement of dipyridamole thallium-201 image quality. J Nucl Med 1992;33:2061-6. 8. Igasezewski AP, McCormick LX, Heslip PG, McEwan AJ, Humen DP. Safety and clinical utility of combined intravenous dipyridamole symptom-related exercise stress test with thallium-201 imaging in patients with known or suspected coronary artery disease. J Nucl Med 1993;34:2053-61. 9. Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS. Safety profile of adenosine stress perfusion imaging. Results from the Adenoscan Multicenter Trial Registry [editorial]. J Am Coll Cardiol 1994;23:384-9.

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10. Elliott MD, Holly TA, Leonard SM, Hendel RC. Impact of an abbreviated adenosine protocol incorporating adjunctive treadmill exercise on adverse effects and image quality in patients undergoing stress myocardial perfusion imaging. J Nucl Cardiol 2000;7: 584-9. 11. Jamil G, Ahlberg AW, Elliott MD, et al. Impact of limited treadmill exercise on adenosine Tc-99m sestamibi SPECT myocardial perfusion imaging in patients with coronary artery disease. Am J Cardiol 1999;84:400-3. 12. Pennell DJ, Mavrogeni SI, Forbat SM, Karwatowski SP, Underwood SR. Adenosine combined with dynamic exercise for myocardial perfusion imaging. J Am Coll Cardiol 1995;25:1300-9. 13. Thomas GS, Prill NV, Majmundar H, et al. Treadmill exercise during adenosine infusion is safe, results in fewer adverse reactions, and improves myocardial perfusion image quality. J Nucl Cardiol 2000;7:439-46. 14. Samady H, Wackers FJTh, Joska TM, Zaret BL, Jain D. Pharmacologic stress perfusion imaging with adenosine: role of simultaneous low-level treadmill exercise. J Nucl Cardiol 2002;9:18896. 15. Hashimoto A, Palmer EL, Scott JA, et al. Complications of exercise and pharmacologic stress tests: differences in younger and elderly patients. J Nucl Cardiol 1999;6:612-9. 16. Muller-Suur R, Eriksson SV, Standberg LE, Mesko L. Comparison of adenosine and exercise stress test for quantitative perfusion imaging in patients on beta blocker therapy. Cardiology 2001;95: 112-8. 17. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. J Nucl Cardiol 2002;9: 240-5.

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