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Comparison between dipyridamole and adenosine as pharmacologic coronary vasodilators in detection of coronary artery disease with thallium 201 imaging
Comparison between dipyridamole and adenosine as pharmacologic coronary vasodilators in detection of coronary artery disease with thallium 201 imaging Raymond Taillefer, MD, FRCP (c), Robert Amyot, MD, Sophie Turpin, MD, FRCP (c), Raymond Lambert, MD, FRCP (c), Claude Pilon, MD, FRCP (c), and Michel Jarry, MD, FRCP (c) Background. Both dipyridamole and adenosine are widely used as pharmacologic stressors with 2°aTl imaging for detection of coronary artery disease. The purpose of this study was to compare dipyridamole and adenosine 2°~Tl imaging directly in patients with angiographically proved coronary artery disease. Methods and Results. Fifty-four patients were submitted to two planar 2°lTl studies: one with dipyridamole and the other with adenosine. The interval between the two studies varied from 2 to 7 days and the order was assigned randomly. Three standard planar views were obtained 10 minutes and 4 hours after the injection of 3.0 mCi 2°Wl. Administration of dipyridamole was as follows: 0.142 mg/kg/min during 4 minutes, followed by a slight exercise and 2°aTl injection. The infusion of adenosine was as follows: 0.140 mg/kg/min during 6 minutes with injection of 2°1T1 after the third minute of infusion. Patients were asked to give their preference considering the number, type, severity, and duration of side effects on a scale from 0 (worst) to 5 (best). Reading was done by two experienced observers. The heart was divided into three segments per view. The change in systolic blood pressure was - 12 + 11 m m Hg for adenosine and - 5 + 10 m m Hg for dipyridamole (p < 0.001), and the change in heart rate was 18 + 10 beats/min for adenosine and 8 + 7 beats/min for dipyridamole (p < 0.001). With regions of interest, ischemic/normal wall ratios were determined: 0.78 + 0.06 for adenosine and 0.83 + 0.08 for dipyridamole (p < 0.001). Adenosine detected 295 normal, 170 ischemic, and 21 scar segments, whereas dipyridamole detected 326, 135, and 25 segments, respectively. Patients preferred adenosine (4.3 + 1.0 for adenosine vs 3.8 + 1.5 for dipyridamole; p < 0.04) mainly because of the short duration of side effects. Conclusion. This study shows that the use of adenosine with ~°ITI imaging may have some advantages over dipyridamole. (J Nucl Cardiol 1996;3:204-11.) Key Words: 2°1T1 i m a g i n g , adenosine ° dipyridamole The diagnostic value of pharmacologic coronary vasodilation with intravenous dipyridamole has been reported extensively for the noninvasive detection of coronary artery disease with radionuclide myocardial perfusion imaging, echocardiography, and positron emission tomography. '-8 Dipyridamole acts indirectly From the Department of Nuclear Medicine and the Division of Cardiology, H6tel-Dieude Montreal, Universitede Montreal, Montreal, Canada. Submitted for publication Nov. 2, 1995; revision accepted Dec. 1, 1995. Reprint requests: Raymond Taillefer, MD, H6tel-Dieu de Montreal, Departement de Medecine Nucldaire, 3840 St-Urbain, Montreal, H2W 1T8, Canada. Copyright © 1996 by American Society of Nuclear Cardiology. 1071-3581/96/$5.00+0 4311171076 204
inducing coronary vasodilation through the blockade of cellular adenosine uptake, leading to an increase in both myocardial and arterial wall adenosine concentrations. Although dipyridamole is an appropriate alternative to treadmill stress for myocardial perfusion imaging of patients with coronary artery disease, its indirect mechanism of action has some disadvantages such as a less optimal coronary vasodilation and a prolonged onset and duration of action that are sometimes associated with prolonged side effects. 9 Several authors have suggested the use of adenosine infusion in conjunction with myocardial perfusion imaging, m-~5 Adenosine, which is a naturally occurring molecule, regulates blood flow in various vascular beds and is a potent direct coronary vasodilator. When infused intravenously, adenosine induces coronary vasodi-
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lation comparable to that induced by intracoronary pap a v e r i n e . " The short effective half-life (<30 seconds) and rapid onset of the action of a d e n o s i n e ' " make it an interesting agent for perfusion imaging. Several reports have already established the safety, feasibility, and accuracy of adenosine scintigraphy. ~7-~9 Both dipyridamole and adenosine are n o w c o m m e r c i a l l y available. There are few studies c o m p a r i n g adenosine and dipyridamole side by side in the same patients. 2°-25 Studies have been performed in either normal volunteers or a small n u m b e r of patients. The purpose of this study was to compare adenosine and dipyridamole directly in the same patient population to evaluate differences in h e m o d y n a m i c changes, side effects, patient preference, and myocardial segmental analysis.
METHODS Study Patients. Fifty-four patients (48 men and six women; mean age 58 + 10 years; range 40 to 79 years) were enrolled in this prospective study, which was approved by the Institutional Review Board for Human Research of our institution. All patients gave signed, informed consent. Patients undergoing elective coronary arteriography for the evaluation of chest pain were referred by their physician if angiography revealed the presence of significant stenosis in one or more major coronary arteries. The coronary angiogram had to be performed within 12 weeks before the patient's enrollment. The patient's condition must have remained unchanged during this interval. Exclusion criteria for this study were recent myocardial infarction (<4 weeks), unstable angina, severe congestive heart failure (New York Heart Association class III or IV), symptomatic known valvular heart disease, uncontrolled arrhythmias, history of asthma or severe chronic obstructive pulmonary disease requiring the administration of streoids or bronchodilators, presence of wheezing during the physical examination before the test, second- or third-degree atrioventricular block, prior coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, known allergy to dipyridamole or aminophylline, severe hypertension (systolic blood pressure >200 mm Hg and diastolic blood pressure > 110 mm Hg), significant hypotension (systolic blood pressure <80 mm Hg), and inability to provide written, informed consent. Study Design. A prospective, randomized crossover design was used. Patients who had angiographically proved coronary artery disease and satisfied the inclusion criteria and had expressed willingness to participate in this study were submitted within 1 week to two planar 2°'T1 studies, one with dipyridamole and one with adenosine as pharmacologic stressors. A minimal interval of 48 hours separated the two studies. Patients were blinded to the type of pharmacologic agent and the order of the tests was assigned randomly. Patient Preparation. The preparation of patients was strictly identical for both adenosine and dipyridamole studies. All studies were performed after approximately 12 hours of fasting. Cardiac medications were continued until the night
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before the test. All methylxanthine-containing medications and oral dipyridamole were discontinued for at least 48 hours before each test. Ingestion of caffeine-containing beverages or foods (e.g., tea, coffee, chocolate, and soft drinks) was not allowed for at least 24 hours before both studies. Before both adenosine and dipyridamole studies, a 20gauge plastic cannula was inserted in an antecubital vein. A three-way stopcock was then fixed at the end of the cannula, close to the skin insertion, to reduce the dead-space volume, especially for adenosine administration. Thus a single intravenous line was used for both adenosine and dipyridamole administration. An electronic infusion pump was used for injection. Adenosine Infusion Protocol. Adenosine (Adenoscan) was supplied by Fujisawa Canada, Toronto, as a sterile, isotonic aqueous solution at a concentration of 3 mg/ml (150 mg/50 ml). Patients were placed in the supine position and adenosine was infused at a rate of 0.140 mg/kg/min for 6 minutes. A dose of 3.0 to 3.3 mCi 2°'TI was injected as a bolus through the three-way stopcock after the third minute of adenosine administration. The adenosine infusion was then temporarily stopped for approximately 1 to 2 seconds and resumed rapidly for 3 additional minutes after 2°'T1 injection. Heart rate, blood pressure, and a 12-lead electrocardiogram were obtained immediately before, at every minute during, and for 3 minutes after the adenosine infusion. Dipyridamole Infusion Protocol. A standard dipyridamole infusion protocol was used. With the patient in the supine position, baseline heart rate and blood pressure were recorded and a 12-lead electrocardiogram was obtained as for the adenosine infusion protocol. Dipyridamole was infused at a rate of 0.142 mg/kg/min for 4 minutes. Vital signs and an electrocardiogram were recorded every minute. After the infusion, the patient stood up and walked in place for 3 to 4 minutes. At the second minute, 3.0 to 3.3 mCi 2°'T1 was injected as a compact bolus into the cannula. The patient continued walking in place for 2 minutes and then lay down under the scintillation camera. During each study, aminophylline (2 mg/kg intravenously) was available to reverse any adverse effects. Aminophylline was not administered routinely to every patient at the end of the study. Z°'TIMyocardial Perfusion Imaging. Myocardial planar imaging was started 5 to 10 minutes after 2°~T1injection with a small-field-of-view scintillation camera with a low-energy, all purpose, parallel-hole collimator. The first image acquired was a 45-degree left anterior oblique view followed by the anterior and left lateral projections (the patient being placed in the right lateral decubitus position). Eight-minute images (approximately 450,000 counts) were acquired for each view (initial and delayed images), with the photopeak set at 80 keV with a 20% window. In all cases, redistribution images were obtained 4 to 5 hours later and the patient was instructed to eat only lightly during that time. Care was taken to position the patient identically for the initial and redistribution studies. Because different activity ratios had to be determined, planar myocardial perfusion imaging was preferred for this particular study. Assessment of Side Effects and Patient Preference. All potential side effects known to be associated with the administration of adenosine and dipyridamole had been ex-
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plained to the patients before they gave consent. Patients were instructed to report any side effects or adverse reactions occurring during and after (for a period of 6 hours) the administration of each pharmacologic stressor. At the end of the study, when the patients had completed the redistribution phase of the second study, the same investigator asked the following three questions: (1) Which of the two tests, the first or the second, did you prefer? (2) On an increasing scale from 0 to 5 (the score of 0 meaning that you would never undergo the test again, even if recommended by your physician, and the score of 5 meaning that you would undergo the test again at anytime without hesitation), how do you rate the first and the second test? (3) If the patient indicated a preference between the two tests, the third question was why did you prefer test number 1 or test number 2? Is your preference related to the type, duration, number, or intensity of side effects or to any other particular reason? Data Analysis. All scintigraphic studies were analyzed by two experienced observers without prior knowledge of the patient's history, electrocardiogram, coronary anatomy, or type of pharmacologic agent used. Disagreements were resolved by consensus. Both analog and digital displays were available for analysis. The heart was divided into three standard segments per view for a total of nine segments per patient. Myocardial segments were categorized as normal, ischemic, or scar. Regions of interest of the same size and same location for a given patient were drawn over the ischemic zones, normal myocardial walls, lung, and liver (right hepatic lobe). Ischemic/normal wall ratios were determined in 45 patients in accordance with the results of coronary angiography. The ischemic/normal wall ratio was not determined in the other nine patients either because no ischemic defects were found on both studies or only fixed defects were detected. Heart/lung and heart/liver ratios were also determined in the 54 patients. Cardiac Catheterization. All patients underwent coronary angiography and left ventriculography according to the Judkins technique, with multiple views of the right and left coronary arteries. Coronary angiograms were interpreted by two independent observers. Differences in interpretation were resolved by consensus. Significant coronary artery stenosis was defined as a 70% or greater reduction in luminal diameter. Statistical Analysis. All results are expressed as mean + SD. Changes in hemodynamic parameters and side effects of adenosine and dipyridamole were analyzed with a paired Student t test.
RESULTS Patient Characteristics. A total of 54 patients were evaluated prospectively. Their mean weight was 78 + 13 kg (51 to 110 kg). Seven patients had had a previous myocardial infarction. Twenty-five patients had single-vessel disease, 20 had double-vessel disease, and nine had triple-vessel disease. There were no cases of left main coronary artery disease. The order of the randomized injection sequence was as follows: adenosine-dipyridamole sequence in 28 patients and the dipyridamole-adenosine sequence in the remaining 26
JOURNALOFNUCLEARCARDIOLOGy May/June 1996 patients. The mean interval between adenosine and dipyridamole 2°1T1 imaging was 3 days (range 2 to 7 days). Hemodynamic Responses. Baseline values for both adenosine and dipyridamole studies were similar. However, the maximal heart rate was significantly higher (p < 0.001) with adenosine (83 + 13 beats/rain) than with dipyridamole (71 + 11 beats/min), and the maximal blood pressure was lower ( p < 0 . 0 0 1 ) after adenosine (126 + 17 mm Hg) than after dipyridamole administration ( 1 3 2 + 18 mm Hg). The increase in heart rate was significantly (p < 0.001) larger with adenosine ( 1 8 + 10 beats/min) than with dipyridamole (8 + 7 beats/min). Adenosine infusion showed a significantly (p < 0.001) larger decrease in systolic blood pressure (-12 + 11 m m Hg) than did dipyridamole (-5 + 10 m m Hg).
Side Effects of Adenosine and Dipyridamole. Of the 54 patients, 45 (83.3%) had at least one or more side effects with adenosine and 35 (64.8%) with dipyridamole. Most symptoms were well tolerated. Adenosine infusion was stopped after 5 minutes of administration in two patients because of severe chest pain. All other patients received the entire dose of adenosine. Eleven patients were treated with aminophylline and six with sublingual nitroglycerine, mostly for persistent headache and significant chest pain after the administration of dipyridamole. The different side effects related to adenosine and dipyridamole are listed in Table 1. Four side effects were significantly more frequent with adenosine than with dipyridamole: flushing (51.8% vs 7.4%; p < 0 . 0 0 0 1 ) , dyspnea (24.1% vs 1.8%; p < 0 . 0 0 1 ) , gastrointestinal discomfort (16.6% vs 3.7%; p < 0.05), and chest discomfort (20.4% vs 3.7%; p < 0.01), defined as chest pain different from the usual angina reported by the patients. All other side effects had a similar incidence with both pharmacologic stressors. Ischemic electrocardiographic ST segment alterations occurred in nine patients with adenosine and five patients with dipyridamole. Patient Preference. Adenosine was preferred to dipyridamole in 21 patients, whereas dipyridamole was preferred to adenosine in 13 patients. Both agents were judged equal in 20 patients. On the scale from 0 to 5, adenosine showed a score of 4.3 + 1.0 and dipyridamole a score of 3.8 + 1.5 (p < 0.04). Although side effects were more frequent with adenosine, overall the patients preferred adenosine to dipyridamole because of the short duration of side effects. Segmental Analysis. A total of 486 segments (nine segments per patient for 54 patients) were analyzed. Table 2 shows the comparison between adenosine and dipyridamole studies. The segmental agreement between the two studies was 87.0% (423/486 segments).
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Table 1. Side effects after the administration of adenosine and dipyridamole Side effect
Adenosine (%/n)
Dipyridamole (%/n)
p Value
Flushing Nausea Dizziness Dyspnea Gastrointestinal discomfort Headache Chest discomfort Angina Palpitations ST segment changes Any
51.8/28 1.8/ 1 7.4/4 24.1 / 13 16.6/9 14.8/8 20.4/11 38.9/21 0/0 16.6/9 83.3/45
7.4/4 7.4/4 11.1/6 1.8/ 1 3.7/2 22.2/12 3.7/2 37.0/20 1.8/ 1 9.2/5 64.8/35
<0.000 ! NS NS <0.00 l <0.05 NS <0.0 ! NS NS NS NS
NS, Not significant.
Adenosine imaging detected 170 ischemic segments, whereas dipyridamole imaging showed 135 ischemic segments. Forty-four myocardial segments were found ischemic on adenosine studies but normal on dipyridamole imaging, whereas the reverse was seen in 13 segments. All these segments corresponded to arteries with coronary stenosis. The sensitivity of 2°'T1 imaging in the detection of coronary artery disease was 90.7% (49/54 patients) with adenosine and 87.0% (47/54 patients) with dipyridamole (not statistically different). Activity Ratios. Three different activity ratios were determined for both adenosine and dipyridamole imaging. Table 3 summarizes these results. Ischemic/normal myocardial wall ratios were significantly (p <0.001) lower with adenosine than with dipyridamole (0.78 + 0.06 vs 0.83 _+0.08). This ratio was slightly but consistently lower in almost every patient with adenosine. The normal myocardial wall/lung ratio was slightly higher for adenosine (2.49 + 0.58) than for dipyridamole (2.43 + 0.57) but was not statistically significant. The heart/liver ratio was lower with adenosine (1.38 _+0.31) than with dipyridamole (1.70 _+0.43), but this difference approached statistical significance (p = 0.06). Subdiaphragmatic activity was more obvious in most patients with adenosine compared with dipyridamole (Figures 1 through 3). DISCUSSION The clinical utility of a pharmacologic coronary vasodilator for radionuclide myocardial perfusion imaging is influenced by several factors including the diagnostic accuracy, diagnostic certainty, hemodynamic profile, incidence of adverse effects, patient preference, availability, technical feasibility, and cost. Comparison of these factors becomes important when two agents with similar indications and contraindications are in-
Table 2. Segmental analysis: comparison between adenosine and dipyridamole Dipyridamole Adenosine Normal Ischemia Scar
Normal
ischemia
Scar
282 44 0
13 121 1
0 5 20
Segmental agreement: 87.0% (423/486). Kappa = 0.74. volved as is the case for dipyridamole and adenosine. These two pharmacologic vasodilators are now widely used with 2°~T1 or 99mTc-labeled sestamibi myocardial perfusion imaging in the detection and evaluation of patients with coronary artery disease. Their respective diagnostic accuracies and safety profiles are well known, but most of the data have been obtained in separate groups of patients. Only a few studies have reported a direct comparison between dipyridamole and adenosine in the same patient population. One of the most important comparative factors to consider is the safety profile and incidence of adverse effects of the two agents. Many large studies have shown the incidence of various adverse effects related to the administration of standard doses of either dipyridamole or adenosine. 17.26The results of our study are similar to those reported previously. The frequency of side effects with adenosine in our patient population was 83.3%, comparable to the incidence of 83% reported by Verani et al., ~ 88% by Nguyen et al., ~2 and 79% by Abreu et al. '7 The incidence of any side effects with dipyridamole in our study was 65%, which is moderately higher than the incidence of 47% reported by Ranhosky et al. 26 in 3911 patients. This might be
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Figure 1. Planar views (45-degree left anterior oblique) obtained after adenosine (upper panel) and dipyridamole (lower panel) in patient with 95% stenosis of proximal left anterior descending artery. Adenosine study clearly shows ischemic perfusion defect of anteroseptal wall (arrow) with transient dilation of left ventricle. Ischemic defect is less well seen on dipyridamole study and there is no transient dilation of left ventricle. Table 3. Determination of activity ratios with adenosine and dipyridamole Ratio
Adenosine
Dipyridamole
p Value
Ischemic/normal wall Heart/lung Heart/liver
0.78 + 0.06 2.49 _+0.58 1.38 + 0.31
0.83 + 0.08 2.43 + 0.57 1.70 + 0.43
<0.001 NS 0.06
NS, Not significant.
explained partially by the fact that, before enrollment in our study, each patient had been specifically instructed on all possible side effects of adenosine and dipyridamole and had been asked to report any symptoms. These directed explanations may "artificially" increase the incidence of reported side effects. Furthermore, routine prophylactic administration of aminophylline was not used in this study, because this is our current clinical practice. Overall, the side effects with adenosine were reported by our patients as being qualitatively similar to those with dipyridamole. However, four types of side effects were significantly more frequent with adenosine: flushing, dyspnea, chest discomfort, and gastrointestinal discomfort. It is important to note that a distinction was made in this study between chest discomfort and angina. Most of our patients, all having significant coronary artery disease, had had angina pectoris. Many of them reported a chest pain that they
defined as a "squeezing" retrosternal pain different from usual anginal chest pain. This has also been reported in normal volunteers, 2' the type of chest pain after administration of adenosine should be specified. No patient required aminophylline injection for reversal of the adenosine effect, and early termintion of adenosine administration was necessary in only two patients. On the other hand, 11 patients required aminophylline administration and six patients had sublingual nitroglycerine after dipyridamole injection. Although more patients had one or more side effects with adenosine, these were transient, mild, and well tolerated and disappeared within a few minutes of termination of infusion. Patient preference for a specific pharmacologic agent can be assessed only by a comparative study performed in the same population. The result of our study demonstrated that more patients preferred adenosine to dipyridamole. These results are similar to those reported by Lee
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Figure 2. Patient had 85% stenosis of right coronary artery. Adenosine study shows ischemic defect of inferior wall (arrow). However, defect is not detected on dipyridamole study.
Figure 3. Myocardial perfusion imaging studies performed in patient with 90% stenosis of left anterior descending artery origin. There is ischemic perfusion defect of anteroseptal wall (arrow) associated with slight transient dilation of left ventricle. These findings are less obvious on dipyridamole study.
et al. 2~ in normal volunteers. It must be emphasized, however, that although a semiquantitative grading system was used to score patient preference, it remains highly subjective. Nevertheless, there was a significant difference between the two agents in favor of adenosine. At first
glance, this might be seen as a conflicting result when the number of side effects only is considered, because more side effects were reported with adenosine. However, patients preferred adenosine mainly because of the relatively short duration of these side effects.
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A recent review summarized data on sensitivity and specificity of adenosine and dipyridamole radionuclide perfusion imaging performed in different patient populations. ~9 The overall sensitivity of dipyridamole was 82% for planar imaging and 89% for single-photon emission computed tomographic imaging, and the overall sensitivity of adenosine was 90%. Although it seems that there is a slight trend toward a better sensitivity for adenosine, these numbers can be considered similar. Several factors such as differences in patient population, referral bias, imaging modalities, and data analysis make comparisons between the two agents very difficult. In our study, more myocardial ischemic perfusion defects were detected with adenosine than with dipyridamole (170 segments for adenosine vs 135 segments for dipyridamole). Furthermore, ischemic/normal wall ratios were significantly lower with adenosine (0.78 for adenosine vs 0.83 for dipyridamole; p < 0.001). This finding suggests that it might be easier to detect ischemic defects on 2°~T1 imaging performed with adenosine than with dipyridamole. In our study the sensitivity of adenosine was slightly better than that of dipyridamole, but this difference was not significant, and data on the comparative sensitivity cannot be extrapolated to a general patient population because of the referral bias. It is also possible that adenosine produces significant coronary vasodilation more consistently than does dipyridamoleS -3° Limitations of the Study. The patients included in this study were highly selected because they had angiographically documented disease, precluding any conclusions on the relative specificity of the two tests. Furthermore, the reported sensitivity cannot be extrapolated to a general population seen in routine clinical practice. Because the major goal of the radionuclide part of the study was to calculate different activity ratios instead of determining the diagnostic accuracy of the two agents, planar imaging was preferred to single-photon emission computed tomographic imaging. Although there is a loss in contrast resolution, planar imaging provides better counting statistics per view, increasing the level of confidence of the different activity ratios obtained on an 8-minute image (compared with a 40- or 50-second image). Furthermore, the crossover design used in this study allowed for an adequate comparison of the two agents, regardless of the method of image acquisition. In some circumstances, as reported previously from our laboratory and others, 3'-32 a higher dose of dipyridamole (0.84 mg/kg for 6 minutes) is used instead of the standard dose administered in our study. The standard dose of dipyridamole was preferred because it represents the dosage that is used most commonly at the present time for myocardial perfusion imaging. The
JOURNALOFNUCLEARCARDIOLOGY May/June 1996 same concept was applied to the adenosine infusion protocol. It is possible that a higher dose of dipyridamole might have given results more similar to those of adenosine. Contrary to previous reports that used adenosine as a pharmacologic vasodilator, ~1 a single site of intravenous injection was used in this study for both adenosine and 2°1T1 bolus injection, although it was recognized that this procedure was not optimal or standard. The major reason for doing this was because we preferred to evaluate patients in technical conditions as similar as possible for both adenosine and dipyridamole studies. The advantages of having a single intravenous access site are obvious both on a practical basis and from the patient standpoint. The disadvantages are that adenosine infusion had to be stopped for approximately 1 to 2 seconds and an "adenosine-bolus effect" may occur. As shown in our study, the efficacy and sensitivity for the detection of ischemic segments was not affected. The adenosine-bolus effect has been mentioned as a possibility but has not been formally described. Theoretically, it may occur if a relatively large bolus of adenosine is injected. However, considering the length and the luminal diameter of the tubing, as well as the concentration of adenosine used, it is unlikely that a serious adverse effect related only to this bolus effect could happen. Conclusion. Our study has shown that, although adenosine and dipyridamole have similar overall characteristics, there are some differences favoring adenosine in the detection of ischemic perfusion defects as reflected by segmental analysis and determination of ischemic/normal wall ratios. Furthermore, although adenosine caused more adverse effects, patients preferred it to dipyridamole mainly because of the short duration of these effects. These preliminary results suggest that adenosine may have some advantages over dipyridamole for radionuclide myocardial perfusion imaging. These data must be validated in larger series to evaluate better the relative diagnostic accuracy of both agents in patient populations representative of clinical practice.
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4. Taillefer R, Lette J, Phaneuf DC, Leveille J, Lemire F, Essiambre R. Thallium-201 myocardial imaging during pharmacologic coronary vasodilation: comparison of oral and intravenous administration of dipyridamole. J Am Coll Cardiol 1986;8:76-83. 5. Leppo JA, Boucher CA, Okada RD, Newell JB, Strauss HW, Pohost GM. Serial thallium-201 myocardial imaging after dipyridamole infusion: diagnostic utility in detecting coronary stenoses and relationship to regional wall motion. Circulation 1982;66:64-67. 6. Leppo JA, O'Brien J, Rothendler JA, Gretchell JD, Lee VW. Dipyridamole-thallium-201 scintigraphy in the prediction of future cardiac events after acute myocardial infarction. N Engl J Med 1984;310:1014-8. 7. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. High dose dipyridamole echocardiography test in effort angina pectoris. J Am Coll Cardiol 1986;8:848-54. 8. Gould KL, Goldstein RA, Mullani NA, et al. Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic vasodilation, VIII: clinical feasibility of positron cardiac imaging without a cyclotron using generatorproduced rubidium-82. J Am Coll Cardiol 1986;7:775-89. 9. Granato JE, Watson DD, Belardinelli L, Cannon JM, Beller GA. Effects of dipyridamole and aminophylline on hemodynamics, regional myocardial blood flow and thallium-201 washout in the setting of a critical coronary stenosis. J Am Coll Cardiol 1990; 16:1760-70. 10. Wilson RE Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation 1990;82:1595-606. 11. VeraniMS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA. Diagnosis of coronary artery disease by controlled coronary vasodilation with adenosine and thallium-201 scintigraphy in patients unable to exercise. Circulation 1990;82:80-7. 12. Nguyen T, Heo J, Ogilby JD, Iskandrian AS. Single photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia: correlation with coronary arteriography, exercise thallium imaging and two-dimensional echocardiography. J Am Coll Cardiol 1990;16:1375-83. 13. Coyne ER Belvedere DA, VandeStreek PR, et al. Thallium-201 scintigraphy after intravenous infusion of adenosine compared with exercise thallium testing in the diagnosis of coronary artery disease. J Am Coll Cardiol 1991;17:1289-94. 14. Gup~a NC, Esterbrooks DJ, Hilleman DE, et al. Comparison of adenosine and exercise thallium-201 single-photon emission computed tomography (SPECT) myocardial perfusion imaging. J Am Coll Cardiol 1992;t9:248-57. 15. Iskandrian AS, Heo J, Nguyen T, et al. Assessment of coronary artery disease using single-photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia. Am J Cardiol 1991;67:1190-4. 16. Rossen JD, Quillen JE, Lopez JAG, Stenberg RG, Talman CL, Winniford MD. Comparison of coronary vasodilation with intravenous dipyridamole and adenosine. J Am Coll Cardiol 1991;18: 485-91.
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17. Abreu A, Mahmafian JJ, Nishimura S, Boyce TM, Verani MS. Tolerance and safety of pharmacologic coronary vasodilation with adenosine in association with thallium-201 scintigraphy in patients with suspected coronary artery disease. J Am Coll Cardiol t991; 18:730-5. 18. Siffring PA, Gupta NC, Mohiuddin SM, et al. Myocardial uptake and clearance of T1-201 in healthy subjects: comparison of adenosine-induced hyperemia and exercise stress. Radiology 1989; 173:769-74. 19. Mahmarian JJ, Verani MS. Myocardial perfusion imaging during pharmacologic stress testing. Cardiol Clin 1994;12:223-45. 20. Santos-Ocampo CD, Herman SD, Travin MI, et al. Comparison of exercise, dipyridamole, and adenosine by use of technetium 99m sestamibi tomographic imaging. J Nucl Cardiol 1994;1:57-64. 21. Lee J, Chae SC, Lee K, Heo J, Iskandrian AS. Biokinetics of thallium-201 in normal subjects: comparison between adenosine, dipyridamole, dobutamine and exercise. J Nucl Med 1994;35:53541. 22. Martin TW, Seaworth JF, Johns JE Pupa LE, Condos WR. Comparison of adenosine, dipyridamole, and dobutamine in stress echocardiography. Ann Intern Med 1992;116:190-6. 23. Chan SY, Brunken RC, Czernin J, et al. Comparison of maximal myocardial blood flow during adenosine infusion with that of intravenous dipyridamole in normal men. J Am Coll Cardiol 1992;20:979-85. 24. Mohiuddin SM, Gupta NC, Esterbrooks DJ, et al. Thallium-201 myocardial imaging in patients with coronary artery disease: comparison of intravenous adenosine and oral dipyridamole. Ann Pharmacother 1992;26:1352-7. 25. Pennell DJ, Ell PJ. Whole-body imaging of thallium-201 after six different stress regimens. J Nucl Med 1994;35:425-8. 26. Ranhosky A, Kempthorne-Rawson J. Intravenous Dipyridamole Thallium Imaging Study Group. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Circulation 1990;81:1205-9. 27. Iskandrian AS. Single-photon emission computed tomographic thallium imaging with adenosine, dipyridamole, and exercise. Am Heart J 1991;122:279-84. 28. Rossen JD, Simonetti I, Marans ML, Winniford MD. Coronary dilation with standard dose dipyridamole and dipyridamole combined with hand-grip. Circulation 1989;79:556-72. 29. Homma S, Gilliland Y, Quiney TE, Strauss HW, Boucher CA. Safety of intravenous dipyridamole for stress testing with thallium imaging. Am J Cardiol 1987;59:152-4. 30. Wackers FJT. Adenosine or dipyridamole: which is preferred for myocardial perfusion imaging? J Am Coll Cardiol 1991;17: I295-6. 31. Lalonde D, Talllefer R, Lambert R, et al. Thallium-201 dipyfidamole imaging: comparison between a standard dose and a high dose of dipyridamole in the detection of coronary artery disease. J Nucl Med 1994;35:1245-53. 32. Picano E, Pirelli S, Marzilli C, et al. Usefulness of high dose dipyridamole echocardiography test and coronary angioplasty. Circulation 1989;80:807-15.
inducing coronary vasodilation through the blockade of cellular adenosine uptake, leading to an increase in both myocardial and arterial wall adenosine concentrations. Although dipyridamole is an appropriate alternative to treadmill stress for myocardial perfusion imaging of patients with coronary artery disease, its indirect mechanism of action has some disadvantages such as a less optimal coronary vasodilation and a prolonged onset and duration of action that are sometimes associated with prolonged side effects. 9 Several authors have suggested the use of adenosine infusion in conjunction with myocardial perfusion imaging, m-~5 Adenosine, which is a naturally occurring molecule, regulates blood flow in various vascular beds and is a potent direct coronary vasodilator. When infused intravenously, adenosine induces coronary vasodi-
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lation comparable to that induced by intracoronary pap a v e r i n e . " The short effective half-life (<30 seconds) and rapid onset of the action of a d e n o s i n e ' " make it an interesting agent for perfusion imaging. Several reports have already established the safety, feasibility, and accuracy of adenosine scintigraphy. ~7-~9 Both dipyridamole and adenosine are n o w c o m m e r c i a l l y available. There are few studies c o m p a r i n g adenosine and dipyridamole side by side in the same patients. 2°-25 Studies have been performed in either normal volunteers or a small n u m b e r of patients. The purpose of this study was to compare adenosine and dipyridamole directly in the same patient population to evaluate differences in h e m o d y n a m i c changes, side effects, patient preference, and myocardial segmental analysis.
METHODS Study Patients. Fifty-four patients (48 men and six women; mean age 58 + 10 years; range 40 to 79 years) were enrolled in this prospective study, which was approved by the Institutional Review Board for Human Research of our institution. All patients gave signed, informed consent. Patients undergoing elective coronary arteriography for the evaluation of chest pain were referred by their physician if angiography revealed the presence of significant stenosis in one or more major coronary arteries. The coronary angiogram had to be performed within 12 weeks before the patient's enrollment. The patient's condition must have remained unchanged during this interval. Exclusion criteria for this study were recent myocardial infarction (<4 weeks), unstable angina, severe congestive heart failure (New York Heart Association class III or IV), symptomatic known valvular heart disease, uncontrolled arrhythmias, history of asthma or severe chronic obstructive pulmonary disease requiring the administration of streoids or bronchodilators, presence of wheezing during the physical examination before the test, second- or third-degree atrioventricular block, prior coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, known allergy to dipyridamole or aminophylline, severe hypertension (systolic blood pressure >200 mm Hg and diastolic blood pressure > 110 mm Hg), significant hypotension (systolic blood pressure <80 mm Hg), and inability to provide written, informed consent. Study Design. A prospective, randomized crossover design was used. Patients who had angiographically proved coronary artery disease and satisfied the inclusion criteria and had expressed willingness to participate in this study were submitted within 1 week to two planar 2°'T1 studies, one with dipyridamole and one with adenosine as pharmacologic stressors. A minimal interval of 48 hours separated the two studies. Patients were blinded to the type of pharmacologic agent and the order of the tests was assigned randomly. Patient Preparation. The preparation of patients was strictly identical for both adenosine and dipyridamole studies. All studies were performed after approximately 12 hours of fasting. Cardiac medications were continued until the night
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before the test. All methylxanthine-containing medications and oral dipyridamole were discontinued for at least 48 hours before each test. Ingestion of caffeine-containing beverages or foods (e.g., tea, coffee, chocolate, and soft drinks) was not allowed for at least 24 hours before both studies. Before both adenosine and dipyridamole studies, a 20gauge plastic cannula was inserted in an antecubital vein. A three-way stopcock was then fixed at the end of the cannula, close to the skin insertion, to reduce the dead-space volume, especially for adenosine administration. Thus a single intravenous line was used for both adenosine and dipyridamole administration. An electronic infusion pump was used for injection. Adenosine Infusion Protocol. Adenosine (Adenoscan) was supplied by Fujisawa Canada, Toronto, as a sterile, isotonic aqueous solution at a concentration of 3 mg/ml (150 mg/50 ml). Patients were placed in the supine position and adenosine was infused at a rate of 0.140 mg/kg/min for 6 minutes. A dose of 3.0 to 3.3 mCi 2°'TI was injected as a bolus through the three-way stopcock after the third minute of adenosine administration. The adenosine infusion was then temporarily stopped for approximately 1 to 2 seconds and resumed rapidly for 3 additional minutes after 2°'T1 injection. Heart rate, blood pressure, and a 12-lead electrocardiogram were obtained immediately before, at every minute during, and for 3 minutes after the adenosine infusion. Dipyridamole Infusion Protocol. A standard dipyridamole infusion protocol was used. With the patient in the supine position, baseline heart rate and blood pressure were recorded and a 12-lead electrocardiogram was obtained as for the adenosine infusion protocol. Dipyridamole was infused at a rate of 0.142 mg/kg/min for 4 minutes. Vital signs and an electrocardiogram were recorded every minute. After the infusion, the patient stood up and walked in place for 3 to 4 minutes. At the second minute, 3.0 to 3.3 mCi 2°'T1 was injected as a compact bolus into the cannula. The patient continued walking in place for 2 minutes and then lay down under the scintillation camera. During each study, aminophylline (2 mg/kg intravenously) was available to reverse any adverse effects. Aminophylline was not administered routinely to every patient at the end of the study. Z°'TIMyocardial Perfusion Imaging. Myocardial planar imaging was started 5 to 10 minutes after 2°~T1injection with a small-field-of-view scintillation camera with a low-energy, all purpose, parallel-hole collimator. The first image acquired was a 45-degree left anterior oblique view followed by the anterior and left lateral projections (the patient being placed in the right lateral decubitus position). Eight-minute images (approximately 450,000 counts) were acquired for each view (initial and delayed images), with the photopeak set at 80 keV with a 20% window. In all cases, redistribution images were obtained 4 to 5 hours later and the patient was instructed to eat only lightly during that time. Care was taken to position the patient identically for the initial and redistribution studies. Because different activity ratios had to be determined, planar myocardial perfusion imaging was preferred for this particular study. Assessment of Side Effects and Patient Preference. All potential side effects known to be associated with the administration of adenosine and dipyridamole had been ex-
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plained to the patients before they gave consent. Patients were instructed to report any side effects or adverse reactions occurring during and after (for a period of 6 hours) the administration of each pharmacologic stressor. At the end of the study, when the patients had completed the redistribution phase of the second study, the same investigator asked the following three questions: (1) Which of the two tests, the first or the second, did you prefer? (2) On an increasing scale from 0 to 5 (the score of 0 meaning that you would never undergo the test again, even if recommended by your physician, and the score of 5 meaning that you would undergo the test again at anytime without hesitation), how do you rate the first and the second test? (3) If the patient indicated a preference between the two tests, the third question was why did you prefer test number 1 or test number 2? Is your preference related to the type, duration, number, or intensity of side effects or to any other particular reason? Data Analysis. All scintigraphic studies were analyzed by two experienced observers without prior knowledge of the patient's history, electrocardiogram, coronary anatomy, or type of pharmacologic agent used. Disagreements were resolved by consensus. Both analog and digital displays were available for analysis. The heart was divided into three standard segments per view for a total of nine segments per patient. Myocardial segments were categorized as normal, ischemic, or scar. Regions of interest of the same size and same location for a given patient were drawn over the ischemic zones, normal myocardial walls, lung, and liver (right hepatic lobe). Ischemic/normal wall ratios were determined in 45 patients in accordance with the results of coronary angiography. The ischemic/normal wall ratio was not determined in the other nine patients either because no ischemic defects were found on both studies or only fixed defects were detected. Heart/lung and heart/liver ratios were also determined in the 54 patients. Cardiac Catheterization. All patients underwent coronary angiography and left ventriculography according to the Judkins technique, with multiple views of the right and left coronary arteries. Coronary angiograms were interpreted by two independent observers. Differences in interpretation were resolved by consensus. Significant coronary artery stenosis was defined as a 70% or greater reduction in luminal diameter. Statistical Analysis. All results are expressed as mean + SD. Changes in hemodynamic parameters and side effects of adenosine and dipyridamole were analyzed with a paired Student t test.
RESULTS Patient Characteristics. A total of 54 patients were evaluated prospectively. Their mean weight was 78 + 13 kg (51 to 110 kg). Seven patients had had a previous myocardial infarction. Twenty-five patients had single-vessel disease, 20 had double-vessel disease, and nine had triple-vessel disease. There were no cases of left main coronary artery disease. The order of the randomized injection sequence was as follows: adenosine-dipyridamole sequence in 28 patients and the dipyridamole-adenosine sequence in the remaining 26
JOURNALOFNUCLEARCARDIOLOGy May/June 1996 patients. The mean interval between adenosine and dipyridamole 2°1T1 imaging was 3 days (range 2 to 7 days). Hemodynamic Responses. Baseline values for both adenosine and dipyridamole studies were similar. However, the maximal heart rate was significantly higher (p < 0.001) with adenosine (83 + 13 beats/rain) than with dipyridamole (71 + 11 beats/min), and the maximal blood pressure was lower ( p < 0 . 0 0 1 ) after adenosine (126 + 17 mm Hg) than after dipyridamole administration ( 1 3 2 + 18 mm Hg). The increase in heart rate was significantly (p < 0.001) larger with adenosine ( 1 8 + 10 beats/min) than with dipyridamole (8 + 7 beats/min). Adenosine infusion showed a significantly (p < 0.001) larger decrease in systolic blood pressure (-12 + 11 m m Hg) than did dipyridamole (-5 + 10 m m Hg).
Side Effects of Adenosine and Dipyridamole. Of the 54 patients, 45 (83.3%) had at least one or more side effects with adenosine and 35 (64.8%) with dipyridamole. Most symptoms were well tolerated. Adenosine infusion was stopped after 5 minutes of administration in two patients because of severe chest pain. All other patients received the entire dose of adenosine. Eleven patients were treated with aminophylline and six with sublingual nitroglycerine, mostly for persistent headache and significant chest pain after the administration of dipyridamole. The different side effects related to adenosine and dipyridamole are listed in Table 1. Four side effects were significantly more frequent with adenosine than with dipyridamole: flushing (51.8% vs 7.4%; p < 0 . 0 0 0 1 ) , dyspnea (24.1% vs 1.8%; p < 0 . 0 0 1 ) , gastrointestinal discomfort (16.6% vs 3.7%; p < 0.05), and chest discomfort (20.4% vs 3.7%; p < 0.01), defined as chest pain different from the usual angina reported by the patients. All other side effects had a similar incidence with both pharmacologic stressors. Ischemic electrocardiographic ST segment alterations occurred in nine patients with adenosine and five patients with dipyridamole. Patient Preference. Adenosine was preferred to dipyridamole in 21 patients, whereas dipyridamole was preferred to adenosine in 13 patients. Both agents were judged equal in 20 patients. On the scale from 0 to 5, adenosine showed a score of 4.3 + 1.0 and dipyridamole a score of 3.8 + 1.5 (p < 0.04). Although side effects were more frequent with adenosine, overall the patients preferred adenosine to dipyridamole because of the short duration of side effects. Segmental Analysis. A total of 486 segments (nine segments per patient for 54 patients) were analyzed. Table 2 shows the comparison between adenosine and dipyridamole studies. The segmental agreement between the two studies was 87.0% (423/486 segments).
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Table 1. Side effects after the administration of adenosine and dipyridamole Side effect
Adenosine (%/n)
Dipyridamole (%/n)
p Value
Flushing Nausea Dizziness Dyspnea Gastrointestinal discomfort Headache Chest discomfort Angina Palpitations ST segment changes Any
51.8/28 1.8/ 1 7.4/4 24.1 / 13 16.6/9 14.8/8 20.4/11 38.9/21 0/0 16.6/9 83.3/45
7.4/4 7.4/4 11.1/6 1.8/ 1 3.7/2 22.2/12 3.7/2 37.0/20 1.8/ 1 9.2/5 64.8/35
<0.000 ! NS NS <0.00 l <0.05 NS <0.0 ! NS NS NS NS
NS, Not significant.
Adenosine imaging detected 170 ischemic segments, whereas dipyridamole imaging showed 135 ischemic segments. Forty-four myocardial segments were found ischemic on adenosine studies but normal on dipyridamole imaging, whereas the reverse was seen in 13 segments. All these segments corresponded to arteries with coronary stenosis. The sensitivity of 2°'T1 imaging in the detection of coronary artery disease was 90.7% (49/54 patients) with adenosine and 87.0% (47/54 patients) with dipyridamole (not statistically different). Activity Ratios. Three different activity ratios were determined for both adenosine and dipyridamole imaging. Table 3 summarizes these results. Ischemic/normal myocardial wall ratios were significantly (p <0.001) lower with adenosine than with dipyridamole (0.78 + 0.06 vs 0.83 _+0.08). This ratio was slightly but consistently lower in almost every patient with adenosine. The normal myocardial wall/lung ratio was slightly higher for adenosine (2.49 + 0.58) than for dipyridamole (2.43 + 0.57) but was not statistically significant. The heart/liver ratio was lower with adenosine (1.38 _+0.31) than with dipyridamole (1.70 _+0.43), but this difference approached statistical significance (p = 0.06). Subdiaphragmatic activity was more obvious in most patients with adenosine compared with dipyridamole (Figures 1 through 3). DISCUSSION The clinical utility of a pharmacologic coronary vasodilator for radionuclide myocardial perfusion imaging is influenced by several factors including the diagnostic accuracy, diagnostic certainty, hemodynamic profile, incidence of adverse effects, patient preference, availability, technical feasibility, and cost. Comparison of these factors becomes important when two agents with similar indications and contraindications are in-
Table 2. Segmental analysis: comparison between adenosine and dipyridamole Dipyridamole Adenosine Normal Ischemia Scar
Normal
ischemia
Scar
282 44 0
13 121 1
0 5 20
Segmental agreement: 87.0% (423/486). Kappa = 0.74. volved as is the case for dipyridamole and adenosine. These two pharmacologic vasodilators are now widely used with 2°~T1 or 99mTc-labeled sestamibi myocardial perfusion imaging in the detection and evaluation of patients with coronary artery disease. Their respective diagnostic accuracies and safety profiles are well known, but most of the data have been obtained in separate groups of patients. Only a few studies have reported a direct comparison between dipyridamole and adenosine in the same patient population. One of the most important comparative factors to consider is the safety profile and incidence of adverse effects of the two agents. Many large studies have shown the incidence of various adverse effects related to the administration of standard doses of either dipyridamole or adenosine. 17.26The results of our study are similar to those reported previously. The frequency of side effects with adenosine in our patient population was 83.3%, comparable to the incidence of 83% reported by Verani et al., ~ 88% by Nguyen et al., ~2 and 79% by Abreu et al. '7 The incidence of any side effects with dipyridamole in our study was 65%, which is moderately higher than the incidence of 47% reported by Ranhosky et al. 26 in 3911 patients. This might be
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Figure 1. Planar views (45-degree left anterior oblique) obtained after adenosine (upper panel) and dipyridamole (lower panel) in patient with 95% stenosis of proximal left anterior descending artery. Adenosine study clearly shows ischemic perfusion defect of anteroseptal wall (arrow) with transient dilation of left ventricle. Ischemic defect is less well seen on dipyridamole study and there is no transient dilation of left ventricle. Table 3. Determination of activity ratios with adenosine and dipyridamole Ratio
Adenosine
Dipyridamole
p Value
Ischemic/normal wall Heart/lung Heart/liver
0.78 + 0.06 2.49 _+0.58 1.38 + 0.31
0.83 + 0.08 2.43 + 0.57 1.70 + 0.43
<0.001 NS 0.06
NS, Not significant.
explained partially by the fact that, before enrollment in our study, each patient had been specifically instructed on all possible side effects of adenosine and dipyridamole and had been asked to report any symptoms. These directed explanations may "artificially" increase the incidence of reported side effects. Furthermore, routine prophylactic administration of aminophylline was not used in this study, because this is our current clinical practice. Overall, the side effects with adenosine were reported by our patients as being qualitatively similar to those with dipyridamole. However, four types of side effects were significantly more frequent with adenosine: flushing, dyspnea, chest discomfort, and gastrointestinal discomfort. It is important to note that a distinction was made in this study between chest discomfort and angina. Most of our patients, all having significant coronary artery disease, had had angina pectoris. Many of them reported a chest pain that they
defined as a "squeezing" retrosternal pain different from usual anginal chest pain. This has also been reported in normal volunteers, 2' the type of chest pain after administration of adenosine should be specified. No patient required aminophylline injection for reversal of the adenosine effect, and early termintion of adenosine administration was necessary in only two patients. On the other hand, 11 patients required aminophylline administration and six patients had sublingual nitroglycerine after dipyridamole injection. Although more patients had one or more side effects with adenosine, these were transient, mild, and well tolerated and disappeared within a few minutes of termination of infusion. Patient preference for a specific pharmacologic agent can be assessed only by a comparative study performed in the same population. The result of our study demonstrated that more patients preferred adenosine to dipyridamole. These results are similar to those reported by Lee
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Figure 2. Patient had 85% stenosis of right coronary artery. Adenosine study shows ischemic defect of inferior wall (arrow). However, defect is not detected on dipyridamole study.
Figure 3. Myocardial perfusion imaging studies performed in patient with 90% stenosis of left anterior descending artery origin. There is ischemic perfusion defect of anteroseptal wall (arrow) associated with slight transient dilation of left ventricle. These findings are less obvious on dipyridamole study.
et al. 2~ in normal volunteers. It must be emphasized, however, that although a semiquantitative grading system was used to score patient preference, it remains highly subjective. Nevertheless, there was a significant difference between the two agents in favor of adenosine. At first
glance, this might be seen as a conflicting result when the number of side effects only is considered, because more side effects were reported with adenosine. However, patients preferred adenosine mainly because of the relatively short duration of these side effects.
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A recent review summarized data on sensitivity and specificity of adenosine and dipyridamole radionuclide perfusion imaging performed in different patient populations. ~9 The overall sensitivity of dipyridamole was 82% for planar imaging and 89% for single-photon emission computed tomographic imaging, and the overall sensitivity of adenosine was 90%. Although it seems that there is a slight trend toward a better sensitivity for adenosine, these numbers can be considered similar. Several factors such as differences in patient population, referral bias, imaging modalities, and data analysis make comparisons between the two agents very difficult. In our study, more myocardial ischemic perfusion defects were detected with adenosine than with dipyridamole (170 segments for adenosine vs 135 segments for dipyridamole). Furthermore, ischemic/normal wall ratios were significantly lower with adenosine (0.78 for adenosine vs 0.83 for dipyridamole; p < 0.001). This finding suggests that it might be easier to detect ischemic defects on 2°~T1 imaging performed with adenosine than with dipyridamole. In our study the sensitivity of adenosine was slightly better than that of dipyridamole, but this difference was not significant, and data on the comparative sensitivity cannot be extrapolated to a general patient population because of the referral bias. It is also possible that adenosine produces significant coronary vasodilation more consistently than does dipyridamoleS -3° Limitations of the Study. The patients included in this study were highly selected because they had angiographically documented disease, precluding any conclusions on the relative specificity of the two tests. Furthermore, the reported sensitivity cannot be extrapolated to a general population seen in routine clinical practice. Because the major goal of the radionuclide part of the study was to calculate different activity ratios instead of determining the diagnostic accuracy of the two agents, planar imaging was preferred to single-photon emission computed tomographic imaging. Although there is a loss in contrast resolution, planar imaging provides better counting statistics per view, increasing the level of confidence of the different activity ratios obtained on an 8-minute image (compared with a 40- or 50-second image). Furthermore, the crossover design used in this study allowed for an adequate comparison of the two agents, regardless of the method of image acquisition. In some circumstances, as reported previously from our laboratory and others, 3'-32 a higher dose of dipyridamole (0.84 mg/kg for 6 minutes) is used instead of the standard dose administered in our study. The standard dose of dipyridamole was preferred because it represents the dosage that is used most commonly at the present time for myocardial perfusion imaging. The
JOURNALOFNUCLEARCARDIOLOGY May/June 1996 same concept was applied to the adenosine infusion protocol. It is possible that a higher dose of dipyridamole might have given results more similar to those of adenosine. Contrary to previous reports that used adenosine as a pharmacologic vasodilator, ~1 a single site of intravenous injection was used in this study for both adenosine and 2°1T1 bolus injection, although it was recognized that this procedure was not optimal or standard. The major reason for doing this was because we preferred to evaluate patients in technical conditions as similar as possible for both adenosine and dipyridamole studies. The advantages of having a single intravenous access site are obvious both on a practical basis and from the patient standpoint. The disadvantages are that adenosine infusion had to be stopped for approximately 1 to 2 seconds and an "adenosine-bolus effect" may occur. As shown in our study, the efficacy and sensitivity for the detection of ischemic segments was not affected. The adenosine-bolus effect has been mentioned as a possibility but has not been formally described. Theoretically, it may occur if a relatively large bolus of adenosine is injected. However, considering the length and the luminal diameter of the tubing, as well as the concentration of adenosine used, it is unlikely that a serious adverse effect related only to this bolus effect could happen. Conclusion. Our study has shown that, although adenosine and dipyridamole have similar overall characteristics, there are some differences favoring adenosine in the detection of ischemic perfusion defects as reflected by segmental analysis and determination of ischemic/normal wall ratios. Furthermore, although adenosine caused more adverse effects, patients preferred it to dipyridamole mainly because of the short duration of these effects. These preliminary results suggest that adenosine may have some advantages over dipyridamole for radionuclide myocardial perfusion imaging. These data must be validated in larger series to evaluate better the relative diagnostic accuracy of both agents in patient populations representative of clinical practice.
References 1. Belier GA. Dipyridamolethallium-201 scintigraphy: an excellent alternative to exercise scintigraphy. J Am Coil Cardiol 1989;14: 1642-4. 2. Gould KL, Westcott RJ, Albro PC, Hamilton GW. Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologiccoronaryvasodilation,II: clinical methodologyand feasibility. Am J Cardiol 1978;41:279-87. 3. Josephson MA, Brown BG, Hecht HS, Hopkins J, Pierce CD, Petersen RB. Noninvasivedetection and localization of coronary stenoses in patients: comparison of resting dipyridamole and exercise thallium-201 myocardialperfusion imaging.Am Heart J 1982;103:1008-18.
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4. Taillefer R, Lette J, Phaneuf DC, Leveille J, Lemire F, Essiambre R. Thallium-201 myocardial imaging during pharmacologic coronary vasodilation: comparison of oral and intravenous administration of dipyridamole. J Am Coll Cardiol 1986;8:76-83. 5. Leppo JA, Boucher CA, Okada RD, Newell JB, Strauss HW, Pohost GM. Serial thallium-201 myocardial imaging after dipyridamole infusion: diagnostic utility in detecting coronary stenoses and relationship to regional wall motion. Circulation 1982;66:64-67. 6. Leppo JA, O'Brien J, Rothendler JA, Gretchell JD, Lee VW. Dipyridamole-thallium-201 scintigraphy in the prediction of future cardiac events after acute myocardial infarction. N Engl J Med 1984;310:1014-8. 7. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. High dose dipyridamole echocardiography test in effort angina pectoris. J Am Coll Cardiol 1986;8:848-54. 8. Gould KL, Goldstein RA, Mullani NA, et al. Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic vasodilation, VIII: clinical feasibility of positron cardiac imaging without a cyclotron using generatorproduced rubidium-82. J Am Coll Cardiol 1986;7:775-89. 9. Granato JE, Watson DD, Belardinelli L, Cannon JM, Beller GA. Effects of dipyridamole and aminophylline on hemodynamics, regional myocardial blood flow and thallium-201 washout in the setting of a critical coronary stenosis. J Am Coll Cardiol 1990; 16:1760-70. 10. Wilson RE Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation 1990;82:1595-606. 11. VeraniMS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA. Diagnosis of coronary artery disease by controlled coronary vasodilation with adenosine and thallium-201 scintigraphy in patients unable to exercise. Circulation 1990;82:80-7. 12. Nguyen T, Heo J, Ogilby JD, Iskandrian AS. Single photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia: correlation with coronary arteriography, exercise thallium imaging and two-dimensional echocardiography. J Am Coll Cardiol 1990;16:1375-83. 13. Coyne ER Belvedere DA, VandeStreek PR, et al. Thallium-201 scintigraphy after intravenous infusion of adenosine compared with exercise thallium testing in the diagnosis of coronary artery disease. J Am Coll Cardiol 1991;17:1289-94. 14. Gup~a NC, Esterbrooks DJ, Hilleman DE, et al. Comparison of adenosine and exercise thallium-201 single-photon emission computed tomography (SPECT) myocardial perfusion imaging. J Am Coll Cardiol 1992;t9:248-57. 15. Iskandrian AS, Heo J, Nguyen T, et al. Assessment of coronary artery disease using single-photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia. Am J Cardiol 1991;67:1190-4. 16. Rossen JD, Quillen JE, Lopez JAG, Stenberg RG, Talman CL, Winniford MD. Comparison of coronary vasodilation with intravenous dipyridamole and adenosine. J Am Coll Cardiol 1991;18: 485-91.
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