Dipyridamole and Dobutamine-Atropine Stress Echocardiography in the Diagnosis of Coronary Artery Disease

Dipyridamole and Dobutamine-Atropine Stress Echocardiography in the Diagnosis of Coronary Artery Disease* Comparison With Exercise Stress Test, Analysis of Agreement, and Impact of Antianginal Treatment Jose Alberto San Roman, MD; lsidre Vilacosta, MD; Juan Antonio Castillo, MD; Maria Jesris Rollan, MD; Vicente Feral, MD; Luis Sanchez-Harguindey, MD; and Francisco Fernandez-Aviles, MD

Study objectives: To compare the usefulness of dipyridamole echocardiography, dohutamine-atropine echocardiography, and exercise stress testing in the diagnosis of coronary artery disease and to analyze the agreement among the tests. Design: Performance of these three tests in random order on a consecutive cohort of patients. Setting: A tertiary care and university center. Patients: One hundred two consecutive patients with chest pain and no history of coronary artery disease. Interventions: Dipyridamole echocardiography, dobutamine-atropine echocardiography, exercise stress testing, and coronary angiography. Measurements and results: Dobutamine-atropine test was positive in 49 (77%) of 63 patients with coronary artery disease, dipyridamole test in 49 (77%), and exercise stress test in 44 (68%; p=NS). Both echocardiographic tests showed an overall specificity (dipyridamole, 97%; dobutamine, 95%) higher than exercise stress test (79%; p<0.05). Sensitivity of dipyridamole testing decreased from 93 to 61% (p=0.002) if patients were receiving antianginal treatment but sensitivity of dobutamine-atropine testing was not affected (77% in patients receiving and not receiving treatment). When results were considered as positive-negative, agreement between dipyridamole and dobutamineatropine echocardiography was 85% (kappa=O. 70). With regards to regional analysis, concordance was good (93% for segments, kappa=O. 76; and 95% for coronary arteries, kappa=0.92). Major complications were more frequent during dobutamine-atropine (n=7) than during dipyridamole infusion (n=2) (p=0.06). Conclusions: Dobutamine-atropine and dipyridamole echocardiography have a similar sensitivity and a higher specificity than that obtained by exercise ECG for the diagnosis of coronary artery disease. Similar information is obtained with dipyridamole and dobutamine-atropine echocardiography. It is our thought that pharmacologic stress echocardiography should be used as a rrrst-step test to rule out coronary artery disease in patients not capable of exercising. (CHEST 1996; 110:1248-54) Key words: coronary artery disease; exercise stress test; stress echocardiography

Jn 1933, Goldhammer and Scherf combined ECG 1

with exercise to detect coronary artery disease. Since then, many attempts have been made to obtain an accurate, feasible, safe, and inexpensive method to help clinicians in the diagnosis and assessment of this life-threatening disease. *From the Division of Cardiology, Hospital Universitario, Valladolid (Drs. San Roman and Femandez-Aviles); and the Division of Cardiology, Hospital Universitario San Carlos (Drs. Vilacosta, Castillo, Rollan, Peral, and Sanchez-Harguindey), Madrid, 5_pain. Manuscript received February 1, 1996; revision accepted Jufy 5. Reprint requests: Dr. San Rorruin, Servicio de Cardiologia, HospitaT Universitario, C/Ram6n y Cajal 3, Valladolid 4701I, Spain 1248

During the past decade, pharmacologic stress echocardiography has become widely accepted as a very useful tool in assessing patients sus~ected of having or with known ischemic heart disease. ·3 Currently investigations are directed to define which pharmacologic stress is more adequate and whether drugs are better than exercise to detect coronary artery disease. Several r~ports have been desi~ed to shed ~ht on these questions. Some compare different drugs -8 and others compare drugs with exercise. 8-12 The heterogeneous characteristics of patients enrolled, the use of antianginal therapy, and the absence of universally acClinical Investigations

cepted protocols account for the controversial results obtained and no definite conclusions can be drawn from these studies. To the best of our knowledge, there is to date no study that specifically compares dipyridamole echocardiography, dobutamine-atropine echocardiography, and exercise stress testing in patients with no previous diagnosis of coronary artery disease. This study was designed to determine the diagnostic accuracy of dipyridamole echocardiography, dobutamine-atropine echocardiography, and exercise stress testing in a large consecutive, homogeneous, and unselected group of patients with chest pain and no history of coronary artery disease. All patients underwent coronary angiography. Sensitivity and specificity for coronary artery disease and side effects of these tests were compared. The hemodynamic parameters of these tests at ischemic threshold were also determined. Finally, agreement between tests has been analyzed. MATERIALS AND METHODS

Study Patients

The study group consisted of 102 consecutive patients, 57 men and 45 women with mean age of 62± 11 years, who were admitted to the hospital for evaluation of chest pain and had no previous diagnosis of coronary artery disease. Patients with myocardial infarction and those \vith angiographically proved coronary artery disease were excluded. Other exclusion criteria were cardiac failure, angina uncontrolled with medical treatment, congenital or valvular disease, and cardiomyopathy. Clinical history revealed chest pain on exertion in 25 patients, at rest in 61, and both on exertion and at rest in 16. Patients were receiving antianginal treatment when indicated by their referring physicians (21 receiving beta-blockers, 35 receiving calcium antagonists, and 55 were not receiving treatment). Tests were performed on different days and in random order within a period of 7 days. No events occurred in the meantime. This study has been approved by our hospital's ethical committee and all patients gave informed consent. Exercise Stress Test

All patients performed a motor-driven treadmill test following a standard Bruce protocol. A 3-lead ECG and heart rate were continuously monitored and a 12-lead ECG and BP were recorded every 3 min. A positive test was considered when typical angina developed and!or a downsloping or horizontal ST segment depression of more than 0.1 mV from baseline at 0.08 s from the J point was visualized on the ECG. Exercise test results were interpreted by an experienced cardiologist who was blinded to other test findings. Phamzacologic Stress Infitsion Protocols

Dipyridamole was infused at a dose of 0.84 mglkg over 6 min. IV aminophylline (240 mg over 1 to 3 min) was given when myocardial ischemia developed. Nitroglycerin was administered if aminophylline-resistant ischemia was noted. Dobutamine was administered IV at an initial dose of 10 pglkgl min. Tbe dose was increased 10 pgtkglmin every 3 min up to 40 pgtkglmin, which was maintained for 6 min. When the test result was still negative and heart rate was under 85% of the age-genderpredicted maximum hemt rate, 1 mg of atropine was infused. Propranolol (0.5 to l mg IV) was given if a positive response appeared. Both dipyridamole and dobutamine were immediately interrupted if areas of transient asynergy, severe hypertension (systolic

and diastolic BP higher than 220 mm Hg and 120 mm Hg, respectively), severe hypotension (>40 mm Hg BP decrease), or sustained ventricular arrhythmias developed. Echocardiographic Studies

Two-dimensional echocardiographic monitoring was performed during and up to 10 min after dipyridamole or dobutamine infusion was discontinued using a commercially available echocardiography machine (Toshiba SSH-160). New wall motion abnormalities were sought in the parasternal long-axis and short-axis views and the apical four- and two-chamber views by rapidly moving the transducer. BP and a 12-lead ECG were obtained every 3 min and when required by the echocardiographer. Echocardiographic recordings were stored on video tape in conventional motion format with the possibility of frame-by-frame analysis, and subsequently, all studies were evaluated by two independent and experienced (>100 studies performed) observers who were blinded to patients' clinical data. In case of disagreement (4 patients; 4%), a third observer was required and his/her opinion was binding. For putposes of analysis, the left ventricle was divided in seven segments: proximal septal, distal septal, apical, anterolateral, posterolateral, posterobasal, and diaphragmatic. This simplified classification takes into account the coronary anatomy and is based on that proposed by the American Society of Echocardiography. 13 The proximal septal, distal septal, apical, and anterolateral segments were ascribed to the left anterior descending coronary artery; the posterolateral to the left circumflex; and the diaphragmatic and posterobasal to the right coronary artery. A qualitative analysis was performed and wall motion was graded as normal, mild hypokinesia, severe hypokinesia, akinesia, and dyskinesia. A test result was considered positive when areas of transient asynergy were visualized in one or more segments that were absent or oflesser degree in the baseline examination. The absence of hyperkinesia in response to dobutamine infusion was not interpreted as a positive result. Coronary Angiography

All patients undenvent selective coronary arteriography with the Judkin's technique. Multiple views of each coronary artery and high-qualityimages were obtained in all cases. Coronary angiograms were evaluated by hand-held electronic calipers. Significant coronary stenosis was considered when at least 50% reduction in the luminal diameter in 1 or more of the major vessels or their main branches was present. Statistical Analysis

Data are expressed as mean±SD. Continuous variables comparison was performed using a Student's t test. Chi-square test or Fisher's Exact Test, when indicated, were used to compare qualitative variables. A p value less than 0.0.5 was considered to be statistically significant. A p value between 0.05 and 0.1 was considered to approach significance. Agreement between tests was defined as the percent of concordant diagnosis. \Vhen regional analysis was considered, agreement was defined as the percent of segments \vith concordant response to the drug (asynergy of new onset vs normal movement). Kappa was measured to assess the agreement in excess of that expected by chance. Kappa values over 0. 70 were considered indicative of good agreement; those between 0.40 and 0.70 were indicative of moderate and those under 0.40 were indicative of poor agreement. RESULTS

Stress Echocardiographic Findings

All patients had technically adequate two-dimensional echocardiograms in basal and stress conditions. CHEST I 110 I 5 I NOVEMBER, 1996

1249

Table 1-Results of Coronary Angiography, Exercise Stress Test, and Phannacologic Stress Echocardiography in Patients With Significant Coronary Stenosis and Negative Result of Either Dipyridamole or Dobutamine Echocardiography or Both ("False-Negative")*

No.

2 3 4 5 6 7 8 9 10 ll

12 13 14 15 16 17 18 19 20 21

LAD, RCA RCA

ex

RCA LAD RCA LAD LAD LAD, RCA LAD LAD LAD, ex

ex ex

LAD, RCA LAD LAD LAD,CX,RCA LAD, ex RCA LAD, ex

Dobutamine

Dipyridamole

Exercise Angiography, Severe Stenosis

Result

min

Ang Negative AngST Negative ST ST ST Negative AngST ST Negative AngST AngST Negative Negative Negative ST Negative ST Negative AngST

3 6 4

3 1

5 6 4 8

6

16 2

Segments Negative Negative Negative :'\legative Negative Negative DS, AP, AL AL AP Negative Negative AP,AL PL Negative Negative Negative Negative DS, AP, DI Negative Negative DS, AP

min

6

5 2

5 6

6

3

Segments

min

AP,PB,DI Negative PB DI Negative PB Negative Negative Negative AP,PL,PB Negative Negative Negative PL AP Negative Negative Negative Negative Negative Negative

4

13 6

12

At

13 At

*Ang=angina; At=atropine; ST=ST segment depression; AP=apical; AL=anterolateral; Dl=diaphragmatic; PB=posterobasal; PL=posterolateral; DS=distal septal; min=minute at which the test result became positive; LAD=left anterior descending artery; CX=circumflex artery; RCA=right coronary artery.

Stress echocardiographic, exercise stress test, and angiographic results of patients with either normal dipyridamole or dobutamine echocardiography (considered as "false-negative") and significant coronary artery disease are depicted in Table 1. Fifty patients had a positive dipyridamole test result. Dipyridamole time (time from the onset of dipyridamole infusion to development of asynergy) was 5.3±2.1 min. Forty-three of the 50 patients with a positive dipyridamole test result also had a positive dobutamine test result. Dipyridamole infusion was discontinued before reaching 6 min in 27 patients because of positivity of the test. All cases of asynergy were localized and movement of the unaffected walls was normal or hyperkinetic. Fifty-one patients developed asynergy during dobutamine infusion. Eight patients had a positive dobutamine test result in whom dipyridamole echocardiography was normal: seven with coronary disease (Table 1) and one without coronary artery disease. Atropine had to be given to 48 patients, 14 of whom developed transient asynergy. Dobutamine time (time from the onset of dobutamine infusion to development of asynergy) was 9.2±4.1 min. A good correlation was found between dipyridamole and dobutamine times (r=0.69; p<0.05). Ten of the 24 patients with a dobutamine time under 9 min had a dipyridamole time under 5 min. Of the 11 patients with 1250

a dobutamine time over 13 min, 5 also had a dipyridamole time over 6 min. A basal ECG demonstrated ST and T abnormalities in 12 and 20 patients, respectively. Left bundle branch block was present in 5 patients and 15 met classic criteria of left ventricular hypertrophy. ECG during dipyridamole infusion showed ischemic ST depression in 40 patients (32 with positive and 8 with negative echocardiographic findings). During dobutamine testing, 47 patients had ST depression (37 with positive and 10 with negative echocardiographic findings). No ST segment elevation was found with either dipyridamole or dobutamine infusion. ST altemans was noted in one patient during dobutamine infusion and the echocardiogram demonstrated generalized akinesia. Exercise Stress Test

Exercise stress test results were positive in 52 patients (2 developed angina, 21 developed ST changes, and 29 developed both angina and ST changes). Among the 50 patients with negative test results, 31 did not achieve 85% of the maximal predicted heart rate. Patients exercised 5.9±3.2 min (range, 1 to 18 min). Peak heart rate was 127±23 beats/min (range, 79 to 182 min). Clinical investigations

Herrwdynamic Findings

Exercise, dipyridamole, and dobutamine-atropine increased heart rate. Heart rate at peak stress with dobutamine-atropine (133:±:23) was higher than that achieved during exercise (127±22; p=0.04) and during dipyridamole infusion (90:±:16; p
Sixty-three patients had significant coronary artery disease: 29 single-vessel, 26 two-vessel, and 8 threevessel disease. Dipyridamole echocardiographic test results were positive in 18 patients with single-vessel disease (62% ), 23 with two-vessel disease (89%), and all 8 with three-vessel disease (100%). One patient without severe coronary stenoses had a positive dipyridamole test result. The overall sensitivity and specificity of dipyridamole echocardiography were 77% and 97%, respectively. Dobutamine-atropine resulted in segmental asynergy detected by echocardiography in 20 patients with single-vessel disease (68% ), 22 with two-vessel disease (85%), and 7 with three-vessel disease (87%). Two patients with no coronary disease had a positive dobutamine test result. The overall sensitivity and specificity of dobutamine-atropine echocardiography were 77% and 95%, respectively. No statistical differences were found between these results and those obtained by dipyridamole echocardiography. Exercise stress test results were positive in 8 patients with no coronary artery disease, 18 with single-vessel disease (sensitivity: 62% ), 21 with two-vessel disease (80%), and 5 with three-vessel disease (62%). Thus, exercise stress testing showed an overall sensitivity and specificity of 68% and 79%, respectively. Both pharmacologic echocardiography tests had a higher specificity (p<0.05). Twelve of the 31 patients with normal results of exercise stress tests and who did not achieve 85% of the maximum predicted heart rate had coronary artery disease. Impact of Treatment on Pharmacologic Stress Test Results

Thirty-one of the 63 patients with coronary artery disease were not receiving treatment. Transient asynergy developed in 29 (93%) with dipyridamole infusion, and in 24 (77%) with dobutamine. The remain-

ing 32 patients were receiving antianginal treatment. Dipyridamole stress test result was positive in 20 (61%) (p=0.002) and dobutamine test results were positive in 25 (78% ). The same percentage of patients in both groups (with and without treatment) had multi-vessel disease. Agreement Between Tests

For detection of presence or absence of coronary artery disease, a moderate overall agreement was obtained between exercise stress testing and pharmacologic stress echocardiography: 74% with dipyridamole (kappa=0.48) and 71% with dobutamine-atropine (kappa=0.42). A good agreement was found when dipyridamole and dobutamine-atropine were compared: 85% (kappa=0.70). When regional analysis was considered, agreement between dipyridamole and dobutamine-atropine echocardiography was encountered in 636 of the 695 segments studied (92%; kappa=0.72). Nineteen poorly visualized segments were not included in the analysis. Finally, analysis of concordance for diagnosis of diseased vessel was carried out in patients with positive echocardiographic response in both tests. Asynergies provoked by dipyridamole and dobutamine-atropine appeared in territories nourished by the same artery in 95% of cases (kappa=0.92). Side Effects

The incidence of major complications was slightly higher during dobutamine-atropine infusion compared with dipyridamole (7% vs 2%; p=0.06). During dobutamine-atropine testing, one patient had left-sided heart failure, two needed pharmacologic support because of severe hypotension, and two developed a sustained ventricular tachycardia. Systolic arterial pressure increased to 250 mm Hg in 2 patients. Nonsustained ventricular and supraventricular arrhythmias were more frequent with dobutamine-atropine than with dipyridamole (8% vs 3%; p=NS). Minor side effects (palpitations, headache, nausea, vomiting, flushing) were as frequent with dipyridamole (37%) as with dobutamine-atropine (35%; p=NS). DISCUSSION

Several drugs have been utilized in combination with echocardiography to detect coronary artery disease. Studies designed to compare different types of pharmacologic and nonpharmacologic (exercise) stress would be useful to identify the safest and most effective test. Three studies in which dipyridamole and dobutamine are compared obtain different results. Martin et al5 conclude that dobutamine is more sensitive, CHEST I 110 I 5 I NOVEMBER, 1996

1251

whereas comparable sensitivities and specificities have been reported by Previtali et al4 and Salustri et al. 6 The differences may be related to different characteristics of population, use of antianginal therapy, or different drug-infusion protocols. Several investigators report quite poor results with dipyridamole echocardiography compared with exercise stress test12 and exercise and dobutamine echocardiography.8·9·12 There are, nevertheless, important methodologic differences with the present study. First, patients with previous known coronary artery disease and myocardial infarction have been included. Localized wall motion abnormalities in the baseline examination present in many of their patients tend to overestimate sensitivity of the test assessed14 and may have biased results. And second, differences in clinical characteristics of study groups are present, including a low incidence of coronary artery disease9 or incidence of single-vessel disease as high as 79%. 8 Instead, a major contribution of our study relates to the homogeneous patient study group enrolled. Also, a better diagnostic accuracy of exercise echocardiography compared with dobutamine echocardiography has been reported, 8 but atropine was not infused when necessary, despite the fact that atropine increases dobutamine echocardiography sensitivity for coronary artery disease.l5 In an experimental model, Fung et al 16 suggested that dipyridamole could be the pharmacologic agent to use in perfusion imaging and dobutamine in stress echocardiography. Nevertheless, clinical studies do not confirm their results. Dipyridamole echocardiography has been reported to show sensitivity as good as dipyridamole scintigraphy. 7·17·18 Likewise, a similar sensitivity has been obtained with dobutamine infusion combined with perfusion imaging and dobutamine echocardiography. 19-21 Methodologic differences between the study by Fung et al16 and clinical studies, including our investigation, may contribute to explain this discrepancy. It is well established that sensitivity of dipyridamole echocardiography decreases when patients are receiving antianginal treatment. 22 ·23 Dipyridamole induces flow maldistribution, but it does not necessarily cause ischemia. 24•25 During dobutamine infusion, as well as when exercising, an increased myocardial oxygen demand is produced and a wall motion abnormality represents ischemia. Experimental and clinical data are concordant in that treatment does not affect the hyperemic response of dipyridamole, but does avoid the appearance of asynergy. 26·27 In our patient population with coronary artery disease, dipyridamole testing was positive in 93% of patients who were not receiving treatment and only in 61% receiving treatment (p=0.002). On the contrary, dobutamine testing was 1252

not influenced by treatment. Although it has been suggested that beta-blockers may reduce dobutamine test sensitivity,28 some authors have obtained different results. Sawada et al29 reported an apparently unexpected similar sensitivity of dobutamine stress testing in patients irrespective of whether they were receiving beta-blockers. Our experience is similar. Besides, the effect of atropine in increasing the diagnostic yield in patients taking beta-blockers is well known. False-negative results are relatively frequent with both pharmacologic tests (Table 1). This issue is far from clear. One can argue that the linkage between the percent diameter stenosis and the physiologic importance of a coronary stenosis remains unclear. 30 In other words, assessment of the functional significance of a coronary stenosis is complex. It can be speculated that angiography is a "false-positive result" in some patients with negative pharmacologic stress results and coronary stenosis. It may be hypothesized, also, that ischemia may be present with no abnormalities in ventricular contraction. Subendocardial ischemia with minor degrees of transmural involvement may lack regional dysfunction. 31 Finally, it has to be assumed that abnormalities in contraction of small territories and duration may be missed by continuous monitoring with echocardiography. To our knowledge, this is the first study in which agreement between dipyridamole and dobutamineatropine echocardiography has been specifically analyzed. The good agreement both in detection of presence or absence of coronary artery disease and of regional asynergy indicates that not complementary but redundant information is provided by both pharmacologic stress tests. In addition, as far as regional analysis is concerned, the agreement was excellent when not only segments but also the "culprit" coronary artery was considered (kappa=0.92). Our results discourage the use of both tests in the same patient in the clinical setting. It is noteworthy that sensitivity of exercise stress testing is similar to that obtained with both dipyridamole and dobutamine stress echocardiography. Importantly, when patients unable to achieve 85% of the maximum predicted heart rate are excluded, sensitivity rises up to 88%. It is likely that exercise stress testing is the technique of choice to detect coronary artery disease when a conclusive result can be achieved. Nevertheless, this issue awaits further investigation. Major side effects are slightly more frequent with dobutamine than with dipyridamole. These results are in keeping with those ofBeleslin et al. 8 In contrast with other reports, 10·29·32-35 major side effects with dobutamine infusion, although not frequent, are present. Our dobutamine infusion protocol is more aggressive Clinical Investigations

than protocols from those studies. We include atropine after dobutamine administration if the test result is still negative and the patient has not achieved 85% of maximal predicted heart rate. Mertes et al35 reported no complications with dobutamine administration in 1,118 patients. This population had a low incidence of coronary artery disease compared with patients herein studied. Fifty percent of their patients underwent echocardiography stress test for noncardiac reasons (preoperative risk assessment of noncardiac surgery or other indications). Our patients, however, were studied for suspected coronary artery disease. We performed a qualitative analysis and, therefore, side-by-side assessment of the digitized rest and stress images could not be done. That digitized analysis enhances sensitivity without diminishing specificity remains speculative because no study (to our knowledge) addresses this issue. If we had been using digitized images, overall results might have been changed, but comparison between both pharmacologic tests, impact of antiaginal treatment, and assessment of agreement would not have been affected. We conclude that dipyridamole and dobutamine echocardiography are as useful as exercise stress testing in diagnosing coronary artery disease. Information provided by both echocardiographic tests is similar with regards to overall results and segmental analysis. Clinical Implications

Based on these results, our current policy to diagnose coronary artery disease is to perform exercise stress testing when possible. If the patient cannot exercise or if exercise does not give enough information, we perform dipyridamole testing when the patient is not receiving treatment to avoid dobutamine complications and dobutamine testing when the patient is receiving treatment to avoid a lower sensitivity of dipyridamole. ACKNOWLEDGMENTS: We gratefullY. acknowledge the technical assistance ofJosefina Albujar, Olga Alfonso, Ana Espaiia, Ines Gomez, and Mana Sanchez. REFERENCES

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Clinical investigations