Prognostic Value of Dobutamine-Atropine Stress ^99mTc-Tetrofosmin Myocardial Perfusion SPECT in Patients with Known or Suspected Coronary Artery Disease

Patient Selection

Between 1994 and 2000, 721 consecutive patients with limited exercise capacity were referred for dobutamine-atropine stress ^99mTc-tetrofosmin SPECT for evaluation of suspected or known CAD. Follow-up was successful in 719 of 721 patients (99.7%). Twenty-eight patients who underwent coronary revascularization within 3 mo of scintigraphy were excluded from analysis. In these patients, the decision to revascularize may be influenced by test results. Consequently, the prognostic data reported are based on 693 patients. All patients gave informed consent before testing. The Hospital Ethics Committee approved the protocol.

Clinical Data

Before the dobutamine stress test, a structured interview and clinical history, including assessment of cardiac risk factors, were obtained. Hypertension was defined as a blood pressure of ≥140/90 mm Hg or treatment with antihypertensive medication. Diabetes mellitus was defined as a fasting glucose level of ≥7.8 mmol/L or the need for insulin or oral hypoglycemic agents. Hypercholesterolemia was defined as a total cholesterol of ≥6.4 mmol/L or treatment with lipid-lowering medication.

Dobutamine Stress Test

The dobutamine-atropine stress test was performed as described (7). Dobutamine was administered intravenously, starting at a dose of 5 μg/kg/min for 3 min, then 10 μg/kg/min for 3 min, increasing by 10 μg/kg/min every 3 min up to a maximum dose of 40 μg/kg/min. If the test endpoint was not reached at a dobutamine dose of 40 μg/kg/min, atropine (up to 2 mg) was given intravenously. Blood pressure, heart rate, and electrocardiography were monitored continuously. Test endpoints were achievement of target heart rate (85% of maximum age-predicted heart rate), horizontal or downsloping ST-segment depression of >2 mm, ST-segment elevation of >1 mm in patients without previous myocardial infarction, severe angina, systolic blood pressure fall of >40 mm Hg, blood pressure of >240/120 mm Hg, or significant arrhythmia. Metoprolol was available to reverse the (side) effects of dobutamine or atropine if these did not revert spontaneously after termination of dobutamine infusion.

SPECT

Approximately 1 min before the termination of the stress test, an intravenous dose of 370 MBq ^99mTc-tetrofosmin was administered. For resting studies, 370 MBq tetrofosmin were injected at least 24 h after the stress study. Image acquisition was performed with a triple-head gamma-camera system (Prism 3000 XP; Picker International, Cleveland, OH). For each study, 6 oblique (short axis) slices from the apex to the base and 3 sagittal (vertical long axis) slices were defined. Each of the 6 short-axis slices was divided into 8 equal segments. The septal part of the 2 basal slices was excluded from analysis because this region corresponds to the fibrous portion of the interventricular septum and normally exhibits reduced uptake. Therefore, 47 segments were identified (3 long axis and 44 short axis). The interpretation of the scan was performed semiquantitatively by visual analysis assisted by analysis of the circumferential profiles. Stress and rest tomographic views were reviewed side by side by an experienced observer who was unaware of each patient’s clinical data. A reversible perfusion defect was defined as a perfusion defect on stress images that partially or completely resolved at rest in ≥2 contiguous segments or slices in the 47-segment model. A fixed perfusion defect was defined as a perfusion defect on stress images in ≥2 contiguous segments or slices, which persists on rest images in the 47-segment model. An abnormal study was considered in the presence of a fixed or reversible perfusion defect (or both). To assess the severity of perfusion abnormalities, the left ventricular myocardium was divided into 6 segments: anterior, inferior, septal anterior, septal posterior, posterolateral, and apical. Each of the 6 major left ventricular segments was scored using a 4-grade scoring method (0 = normal, 1 = slightly reduced, 2 = moderately reduced, 3 = severely reduced or absent uptake). The perfusion defect score was derived by the summation of the score of the 6-myocardial segments at stress (SSS) and at rest (SRS). The difference was expressed as the summed difference score (SDS).

Patient Follow-Up

Follow-up data were obtained in 2000. The mean follow-up period was 37 ± 17 mo. The present status was determined by contacting the patient’s general practitioner or by review of hospital records. The date of the last review or consultation was used to calculate the follow-up time. Outcome events were overall death, cardiac death, nonfatal myocardial infarction, and late (>3 mo) coronary revascularization. Cardiac death was defined as death caused by acute myocardial infarction, significant cardiac arrhythmias, or refractory congestive heart failure. Sudden death occurring without another explanation was included as cardiac death. Nonfatal myocardial infarction was defined by cardiac enzyme levels and electrocardiographic changes.

Statistical Analysis

Data were expressed as mean value ± SD or number and compared using the Student t test or χ² test. Univariate and multivariate Cox proportional-hazards regression models were used to identify independent predictors of late cardiac events. Variables were selected in a stepwise forward selection manner with entry and retention set at a significance level of 0.05. The risk of a variable was expressed as a hazard ratio with a corresponding 95% confidence interval. The incremental value of myocardial perfusion scintigraphy over the clinical variables in the prediction of events was performed according to 2 models. In model 1, the only scan variable entered was the presence of an abnormal scan. In model 2, the presence of a fixed defect or reversible defect was included separately. The probability of survival was calculated using the Kaplan-Meier method, and survival curves were compared using the log-rank test. P < 0.05 was considered statistically significant.

Demographics and Stress Test Results

Clinical characteristics are presented in Table 1. During the dobutamine-atropine stress test, there was a significant increase of heart rate (from 77 ± 17 to 133 ± 17 beats per minute; P < 0.0001) and systolic blood pressure (from 144 ± 23 to 155 ± 32 mm Hg; P < 0.0001). The highest dobutamine dose was 10 μg/kg/min in 1% of the patients, 20 μg/kg/min in 16%, 30 μg/kg/min in 17%, and 40 μg/kg/min in 66%. Atropine was added in testing 258 patients (37%); it was administered more frequently in testing patients who received β-blocker therapy (150/253 [59%]) than in patients who did not (108/440 [25%]; P < 0.001). The test was inconclusive (failure to achieve the target heart rate in the absence of perfusion abnormalities) in 7% of the patients. The cardiac event rate in patients who did not achieve the target heart rate did not differ from the event rate in patients with a complete test (P = 0.48). No relationship was found between the achieved final stage of dobutamine infusion and subsequent cardiac death or infarction.

Side effects during dobutamine-atropine stress were short ventricular tachycardia (<10 complexes) in 23 patients (3.3%), atrial fibrillation in 7 patients (1.0%), severe hypotension (decrease in systolic blood pressure of >40 mm Hg) in 7 patients (1.0%), and severe hypertension (blood pressure of >240/130 mm Hg) in 5 patients (0.7%). Minor side effects were chills in 52 patients (7.5%), headache in 46 patients (6.6%), and nausea in 38 patients (5.5%). No patient experienced a myocardial infarction or ventricular fibrillation.

SPECT and Follow-Up Results

Myocardial perfusion abnormalities were present in 381 of the 693 patients (55%) and included fixed defects alone in 190 patients (27%) and reversible defects in 191 patients (28%). These defects were completely reversible in 61 patients (9%) and partially reversible in 130 patients (19%). There were 150 deaths (22%) during follow-up, of which 62 were attributed to cardiac causes. Nonfatal myocardial infarction occurred in 23 patients (3%), and late coronary revascularization (>3 mo) was performed on 21 patients (3%).

Univariate Analysis

The cardiac death rate (adjusted for number of patients at risk) was 1%/y in patients with normal scans versus 5.1%/y in patients with abnormal scans during the 5-y follow-up period (P < 0.0001) (Fig. 1). Patients with a normal ^99mTc-tetrofosmin SPECT scan had a hard-event rate (cardiac death or myocardial infarction) of 1.5%/y compared with 5.5%/y in those with abnormal scans (P < 0.0001). Univariate predictors of endpoints of interest are shown in Table 2. The most powerful predictor for cardiac death, cardiac death or (re)infarction, coronary revascularization, and all events was abnormal perfusion. Moreover, the extent and severity of the defect (expressed by the SSS, SRS, and SDS) were related to cardiac death or nonfatal myocardial infarction.

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FIGURE 1.

Kaplan-Meier curves for cardiac death during follow-up in patients with normal and abnormal ^99mTc-tetrofosmin SPECT scans.

Multivariate Analysis

A stepwise logistic regression model showed that an abnormal scan was the strongest independent predictor of cardiac death. Multivariate predictors of cardiac death are presented in Table 3. The addition of the perfusion parameters to the clinical variables was performed according to 2 models. In the first model (Table 3, model 1) the presence of an abnormal scan was added to the clinical characteristics, stress electrocardiographic data, and hemodynamic data. In model 2 the presence of a fixed or reversible perfusion defect was added separately. The presence of an abnormal scan (model 1) provided incremental prognostic value over clinical, stress electrocardiographic, and hemodynamic data (log-likelihood, −324 to −305; P < 0.0001). Model 2 also offered incremental prognostic information compared with the clinical, stress electrocardiographic, and hemodynamic parameters (log-likelihood, −324 to −313; P < 0.0001).