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J Am Coll Cardiol, 1999; 34:1769-1777 © 1999 by the American College of Cardiology Foundation |
a CNR Institute of Clinical Physiology, Pisa, Italy
b Visiting Fellow from the Albert Szent-Györgyi University Medical School, Szeged, Hungary with a grant "Eötvös" of the Hungarian Government
Manuscript received July 20, 1998; revised manuscript received June 8, 1999, accepted August 12, 1999.
Reprint requests and correspondence: Dr. Alessandro Pingitore, CNR, (Consiglio Nazionale Ricerche), Institute of Clinical Physiology, Via Savi 8, 56100 Pisa, Italy
pingi{at}ifc.pi.cnr.it
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Abstract |
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The study compared the prognostic value of dipyridamole and dobutamine stress echocardiography in patients with known or suspected coronary artery disease.
BACKGROUND
Extensive information is available on the relative diagnostic accuracy of the two tests assessed in a head-to-head fashion, whereas comparative data on their prognostic yield are largely preliminary to date.
METHODS
Dipyridamole (up to 0.84 mg/kg over 10 min) atropine (up to 1 mg over 4 min) (DIP) and dobutamine (up to 40 µg/kg/min)-atropine (1 mg over 4 min) (DOB) stress tests were performed in 460 patients with known or suspected coronary artery disease. Patients were followed up for 38 ± 21 months.
RESULTS
The DIP was negative in 253 and positive in 207 patients. The DOB was negative in 242 and positive in 218 patients. During the follow-up, there were 80 cardiac events. For all cardiac events, the negative and positive predictive value were 83% and 17% for DOB, 84% and 19% for DIP, respectively (p = NS). Considering only cardiac death, by univariate analysis Wall-Motion Score Index (WMSI) at DIP peak dose (chi-square 13.80, p < 0.0002) was the strongest predictor, followed by WMSI DOB (
2 = 8.02, p < 0.004) and WMSI at rest (2 = 6.85, p < 0.008). By stepwise analysis, WMSI at DIP peak dose was the most important predictor (RR [relative risk] 7.4, p < 0.0001).
CONCLUSIONS
In patients at low-to-moderate risk of cardiac events, pharmacological stress echocardiography with either dobutamine or dipyridamole allows effective and grossly comparable, risk stratification on the basis of the presence, severity and extension of the induced ischemia.
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Methods |
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Stress echocardiographic protocols.
Dobutamine-atropine
Dobutamine was infused in 3-min dose increments, starting from 5 µg/kg/min and increased to 10, 20, 30, and 40 µg/kg/min (10,15). When no end point was reached, atropine (in four divided doses of 0.25 mg up to a maximum of 1 mg) was added to the continuing 40 µg/kg/min dobutamine infusion.
Dipyridamole-atropine
Dipyridamole was infused intravenously at a dose of 0.56 mg/kg body weight over 4 min, followed by 4 min of no dose and then, if the test was still negative, 0.28 mg/kg over 2 min. When no end point was reached at 3 min after the end of dipyridamole infusion, atropine (in four divided doses of 0.25 mg up to a maximum of 1 mg) was given (16).
Echocardiographic analysis. Two-dimensional echocardiographic monitoring was performed throughout and up to 10 min after stopping the drug infusion. Two-dimensional images were recorded at baseline and at the end of each step. Regional wall-motion analysis was evaluated at baseline and at peak stress with a semiquantitative assessment of a Wall-Motion Score Index (WMSI), with the 16-segment model of the left ventricle, each segment ranging from 1 = normal/hyperkinetic to 4 = dyskinetic, according to recommendations of the American Society of Echocardiography (17). The WMSI was derived by dividing the sum of individual segment scores by the number of interpretable segments (17). Test positivity was defined as the occurrence of at least one of the following conditions: 1) new dyssynergia in a region with normal rest function (i.e., normokinesia becoming hypokinesia, akinesia or dyskinesia); 2) worsening of rest dyssynergy (i.e., hypokinesia becoming akinesia or dyskinesia). Resting akinesia becoming dyskinesia was not considered a criterion of positivity, because this can result from passive stretching phenomena rather than from active ischemia (18). The extension and severity of induced ischemia was expressed as a Delta WMSI: a variation between the resting WMSI and peak WMSI without considering functional recovery of basally asynergic segments.
Furthermore, the extension of induced ischemia was also expressed as the number of ischemic segments at peak stress. Nonechocardiographic test end points were the following (10): peak atropine dose; 85% of target heart rate; achievement of conventional end points (such as severe chest pain and/or diagnostic ST segment changes). The test was also stopped, in the absence of diagnostic end points, for one of the following reasons of submaximal, nondiagnostic test (10): intolerable symptoms; limiting asymptomatic side effects, consisting of a) hypertension (systolic blood pressure >220 mm Hg; diastolic blood pressure >120 mm Hg); b) hypotension (relative or absolute): >30 mm Hg fall of blood pressure; c) supraventricular arrhythmias: supraventricular tachycardia or atrial fibrillation; d) ventricular arrhythmias: ventricular tachycardia; frequent, polymorphous premature ventricular beats.
Quality control of stress echocardiographic readings. Quality control of the diagnostic performance in the different centers was of critical importance in acquiring meaningful information into the data bank. In the enrolled centers, the quality control was performed based upon two criteria, each one having to be met to fulfill the quality-control requirements (19).
The first criterion was tested on a videotape with 20 stress echocardiographic studies prepared in the coordinating center (Institute of Clinical Physiology in Pisa, Italy). In all these 20 studies the reading of two experienced independent observers was concordant as to presence and site of dyssynergy, and the stress results were in full agreement with presence and site of coronary stenoses during coronary angiography. The unanimous reading of the two observers was arbitrarily assumed to be the "gold standard" against which to evaluate the reading of each participating center. The reader from each center interpreted the videotape in a blinded fashion, with no access either to clinical and angiographic data or to the interpretation given by other observers. It was assumed a priori that the minimum threshold of concordance to pass this part of the quality control had to be 90%. The second criterion consisted in random-sampling 20 consecutive studies from each contributing center. These 20 studies were examined in a blinded fashion by an experienced cardiologist-echocardiographist of the coordinating center and whose reading was arbitrarily assumed to be the "gold standard." It was assumed a priori that the minimum threshold of concordance to pass the quality control had to be 80%. The lower concordance cutoff in comparison with the first type of reading was due to the fact that this second set of tapes was not selected on the basis of the superior quality but randomly sampled from each center in a consecutive fashion. All 14 enrolled centers met the minimum requirements of quality control.
Follow-up data. The follow-up data were obtained from at least one of four sources: review of the patient’s hospital record; personal communication with the patient’s physician and review of the patient’s chart; a telephone interview with the patient conducted by trained personnel; a staff physician visiting the patients at regular intervals in the outpatient clinic (19). Events were defined as cardiac-related deaths, nonfatal myocardial infarction, and revascularization procedures. For patients who died in the hospital or at home, the cause of death was elucidated from the medical record, from the family, and from the local physician who signed the death certificate. The definition of cardiac-related death required documentation of significant arrhythmias or cardiac arrest, or both, or death attributable to congestive heart failure or myocardial infarction in the absence of any other precipitating factors. In case of death out of hospital for which no autopsy was performed, sudden unexpected death was attributed to a cardiac cause. Myocardial infarction was defined as a cardiac event requiring hospital admission to the hospital, with development of new electrocardiograph (ECG) changes and cardiac enzyme-level increases. Revascularization procedures were considered only when they had been performed three months after the tests. Test results were available to the referring physician who was responsible for the decision to submit a patient to a revascularization procedure. As always, this decision was made after considering all the clinical, echocardiographical, and angiographic variables.
Statistical analysis. Values are expressed as mean ± standard deviation. The individual effect of certain variables on event-free survival was evaluated with the use of the Cox regression model (BMDP 2L, Department of Biomathematics, University of California at Los Angeles, revised 1987). The analysis was performed according to the unmodified forward selection stepwise procedure. In this case, the variables were entered in the model on the basis of a computed significance probability; accordingly, the variable that has the most significant relation to dependent outcome is selected first for inclusion in the model, and a solution to the functional form of the equation is computed. At the second and subsequent steps, the set of variables remaining at each point is evaluated, and the most significant is included if it improves the prediction of the outcome (dependent variable), but in this case this probability was conditional on the presence of the variable already selected. The algorithm ceases to select variables when there is no further significant improvement in the prediction of the entire model. Selected variables were the following: age, sex, history of angina, previous myocardial infarction, concomitant antianginal therapy, recent acute uncomplicated myocardial infarction, previous angioplasty (history of PTCA; percutaneous transluminal coronary angioplasty), previous coronary artery bypass graft (CABG) surgery (history of CABG), WMSI at rest (resting WMSI), dipyridamole and dobutamine-atropine stress echocardiography positivity, WMSI at peak dobutamine (DOB WMSI) and at peak dipyridamole (DIP WMSI), Delta-WMSI of DIP and DOB (Delta DIP and Delta DOB WMSI), number of ischemic segments during DIP, number of ischemic segments during DOB, dipyridamole and dobutamine time (i.e., test duration to time of echocardiographically detected ischemia).
Continuous variables were compared by the paired two-sample t test. Proportions were compared by the chi-square statistic; the Fisher exact test was used when appropriate. Kaplan-Meier survival curves event-free of cardiac death were used to summarize the follow-up experience in these patients and to clarify presentation. Differences of survival curves were tested with the log-rank statistic. A p value below 0.05 was considered statistically significant. Receiver-operating characteristics analysis was used to determine the optimal cutoff value for prediction of cardiac death with respect to the DIP and DOB WMSI and the number of ischemic segments during both tests. The best cutoff value was defined as the point with the highest sum of sensitivity and specificity.
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Results |
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Stress echocardiographic findings.
The resting WMSI was 1.37 ± 0.38 for the overall population. The DIP test was negative in 253 and positive in 207 patients. Of the positive tests, 73 were positive at low dose (
8 min), 90 at high dose (>8 min up to 12 min), and 44 during or after atropine infusion. The DOB test was negative in 242 and positive in 218 patients. Of the positive tests, 99 were positive at low dose (12 min) and 92 at high dose (>12 min up to 17 min), and 27 during or after atropine infusion. The WMSI at peak dose increased up to 1.70 ± 0.35 during DIP (p < 0.001 vs. rest WMSI) and up to 1.61 ± 0.39 during DOB (p < 0.005 vs. rest WMSI). Delta WMSI was 0.28 ± 0.16 for DIP and 0.29 ± 0.18 for DOB (p = NS). According to a cutoff of 0.37, 57 patients had a value of Delta WMSI higher than 0.37 with DIP and 56 with DOB.
Follow-up data. Patients were followed up for 38 ± 21 months (range 1 to 82 months). Eighty-three patients underwent revascularization procedure within three months of stress testing (PTCA n = 50, CABG n = 33) and therefore were censored. During the follow-up period, there were 18 cardiac-related deaths, 22 acute nonfatal myocardial infarctions and 40 revascularization procedures (angioplasty n = 17; coronary artery bypass graft n = 23). All events occurred in 41 of the 253 patients with negative and in 39 of the 207 patients with positive DIP (16% vs. 19%, p = NS). Among the subset with positive DIP, eight events occurred in the 44 patients with atropine, 15 in the 90 patients with high dose and 16 in the 73 patients with low dose positivity (18% vs. 16.6% vs. 22%, p = NS). Considering DOB, events occurred in 42 of the 242 patients with negative and in 38 of the 218 patients with positive test (16% vs. 19%, p = NS). Among the subset with positive DOB, six events occurred in the 27 patients with atropine, 16 in the 92 with high dose and 16 in the 99 patients with low dose positivity (22% vs. 17% vs. 16%, p = NS). The relationship between all cardiac events and different stress-test responses is shown in Table 1.
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Discussion |
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0.37). These data are in agreement with previous stress echocardiographic studies (19,20) and are consistent with the linear relationship described between WMSI at peak stress and extension and severity of underlying coronary artery disease (21), which is a well-known angiographic predictor of unfavorable prognosis (22). Both DIP and DOB had a comparable prognostic value, with a marginal—albeit statistically significant when cardiac death is considered—edge in favor of DIP. This may be due to a higher number of diagnostic studies obtained with DIP than with DOB in our series, in keeping with previous reports (7,9–11). In addition, when compared to dobutamine, dipyridamole stress echocardiography positivity more frequently occurs with prognostically unfavorable angiographic patterns, such as plaque morphology of the complex type (23–25) or in the presence of coronary occlusion and coronary collateral circulation (24,26). Finally, positivity of DOB—with negativity of DIP—is more often found in patients with normal coronary arteries and in patients with single-vessel disease of mild-to-moderate severity (12,25), which define prognostically benign subsets.
Comparison with previous studies. The results of this study confirm the data of two recent studies by Minardi et al. (13) and Schröeder et al. (14) showing a similar prognostic value of dipyridamole and dobutamine assessed in a head-to-head comparison. However, these studies were performed in a small sample size and needed the use of soft cardiac events, such as revascularization procedures, to document the prognostic power of the two tests. Our results confirm and expand these previous observations. In fact, in the present study, we assessed the prognostic yield of dipyridamole and dobutamine in a large patient population, with more than three years’ follow-up. This sample size allowed us to document the prognostic value also using only cardiac-related death as the end point in a subset of patients at low-to-moderate risk for cardiac events (i.e., patients in stable clinical conditions with relatively well-preserved left ventricular function). In this subset of patients, the predictive value of any diagnostic test is usually low, and this may be the reason for the modest, but significant, value of the relative risk of WMSI at peak stress in comparison to other studies that enrolled patients at higher risk for cardiac events (22–29).
Study limitations. The prognostic yield of myocardial viability was not assessed in this study. However, as documented in patients with recent myocardial infarction, recognition of myocardial viability during dobutamine is prognostically important only for predicting unstable angina, but not cardiac-related death. Viability, recognized with echocardiographic methods, predicts cardiac death only in patients with severe left ventricular dysfunction (28), who were excluded from the present study. Even in those patients, the prognostic value of viability is outperformed by ischemia, which is the major determinant of cardiac death, especially if its severity is titrated through the WMSI (20,28–30).
In addition, the number of events in the study was limited: only 18 cardiac deaths (3.9% of the total population), despite the high number of enrolled patients (n = 460) and the long duration of the follow-up (38 months on average). Our population was clearly at low risk for cardiac events, consisting of clinically stable patients, with preserved left ventricular function, undergoing two stresses in a few days. Any stress test for coronary artery disease looks much better when faced with more extensive forms of disease, with high incidence of events, and much less well in patients with milder forms of disease, with low incidence of events (31).
Conversely, the literature is inflated by studies in which the assessment of the outcome is based on soft and pathophysiologically heterogeneous events, such as revascularization procedures, unstable angina, nonfatal reinfarction, and cardiac death, in a population at high cardiac risk. However, the goal of the present study was not to establish, in absolute terms, the prognostic impact of the two tests in a well-selected population, but rather to assess their relative prognostic value in a garden variety of patients representing the entire spectrum of population usually referred to the echocardiography laboratory.
Moreover, our study was observational, not randomized, and the decision of medical treatment over coronary revascularization was made by the referring physician on the basis of clinical, anatomical and stress echocardiographic findings. This might have contributed to diluting the positive predictive value of the stress test for hard end points as the beneficial effects of ischemia-guided coronary revascularization procedures are well known (29). However, most of our patients with negative stress echocardiogram had no revascularization procedures: thereby, the extremely high negative predictive value of the two tests is likely to reflect largely a natural history follow-up. Our data also emphasize that what is best for diagnosis is not necessarily ideal for prognostic stratification: atropine coadministration, especially with dobutamine, did not efficiently stratify patients with a higher risk in comparison to those with negative results. When prognostic stratification is the main target, more conservative protocols are probably warranted.
Clinical implications. Pharmacological stress echocardiographic tests with dipyridamole and dobutamine are feasible and safe. Both tests are able to predict cardiac death, confirming—even in a population at low cardiac risk—the prognostic power already documented in several subgroups of patients (19,27–29), when the positive response is stratified on the basis of timing, severity, and extension of induced ischemia. The prognostic power of the two tests is substantially similar, with a slight advantage for dipyridamole. From a practical point of view, both tests should be implemented—to be used as equally suitable alternatives in the individual patient—for an optimization of diagnostic and prognostic performance of a stress echocardiography laboratory. There are three main reasons for this policy: 1) Each patient being referred for stress evaluation may suffer from relative or absolute contraindications to either stress modality, or may undergo a therapy clearly lowering the diagnostic potential of a given stress; 2) both dipyridamole and dobutamine have excellent overall tolerability and feasibility, as shown by large-scale multicenter experience (32,33). Nevertheless, submaximal nondiagnostic tests do occur in some patients because of side effects; therefore, these patients may be referred to the other stress test; 3) for the detection of minor, less extensive and severe forms of coronary artery disease, a combined pharmacological stress procedure may be needed at least when diagnosis, rather than prognosis, is the mission of testing (34). It is important that all stress echocardiographic laboratories become familiar with both stress procedures for a flexible and versatile diagnostic approach that may allow tailoring the best stress test to individual patient needs (3).
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