Methods

The study population consisted of 3,922 consecutive patients with known or suspected CAD who underwent DSE from January 1990 to January 2003. Only patients with stress-induced ischemia on DSE were included (n = 1,191). Early coronary revascularization was defined as PCI or CABG ≤90 days after DSE. Patients who underwent late revascularization (defined as >90 days after DSE) were excluded (n = 286). The reason for this exclusion was based on the primary goal of the present study, that is, to evaluate the impact of early revascularization (≤90 days after DSE). The decision to revascularization was made on clinical grounds. The final study cohort consisted of 905 patients. The test was requested for diagnostic reasons in 517 patients (57%), for preoperative cardiac risk assessment in 211 (23%), or for evaluation of viable myocardium in 177 (20%) with left ventricular dysfunction. Clinical data were collected at the time of DSE. Hypercholesterolemia was defined as total cholesterol >200 mg/dl or use of lipid-lowering medications. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication. Diabetes was defined in the presence of fasting blood glucose ≥140 mg/dl or requirement for insulin or oral hypoglycemic agents. Heart failure was defined according to the New York Heart Association classification. This study was not subject to the Dutch Medical Research Involving Human Subjects Act. Therefore, approval from the local research ethics committee to conduct this prospective follow-up study was not required at the time of enrollment. The study was conducted according to the Declaration of Helsinki. All patients consented participation in this study.

After baseline echocardiography, dobutamine was infused at a starting dose of 5 μg/kg/min for 3 minutes, followed by 10 μg/kg/min for 3 minutes (low-dose stage). The dobutamine dose was increased by 10 μg/kg/min every 3 minutes, up to a maximum dose of 40 μg/kg/min. Atropine (up to 1 mg) was administered intravenously at the end of the last stage if the target heart rate was not achieved. End points of the test were an achievement of the target heart rate (85% of the maximal heart rate predicted for age), the maximal dose of dobutamine and atropine, >2 mV downsloping ST-segment depression measured 80 ms from the J point compared with baseline, hypertension (blood pressure >240/120 mm Hg), a decrease in systolic blood pressure of >40 mm Hg, and significant arrhythmias. Typical angina during dobutamine stress testing was defined as substernal chest discomfort provoked by dobutamine stress and relieved by withdrawing dobutamine.

Echocardiographic images (2 dimensional, using standard views) were acquired at rest and continuously during the test and recovery. The interpretation of images was performed by 2 independent blinded observers. In case of disagreement, a third observer also interpreted the images. In our laboratory, the inter- and intraobserver agreement for DSE assessments are 92% and 94%, respectively. Regional wall motion and systolic wall thickening were scored using a standard 16-segment left ventricular model. Each segment was scored using a 5-point scale as follows: 1 = normal, 2 = mild hypokinesis, 3 = severe hypokinesis, 4 = akinesis, and 5 = dyskinesis. Ischemia was defined as new or worsened wall motion abnormalities during stress, which is indicated by an increase of ≥1 grade in ≥1 segment of the wall motion score. A biphasic response in an akinetic or severely hypokinetic segment was considered as an ischemic response. When akinetic segments at rest became dyskinetic during stress, this was not considered as ischemia. DSE results were defined as abnormal if there was ischemia during stress or fixed wall motion abnormalities. The wall motion score index (WMSI) was calculated by dividing the sum of segment scores by 16. The WMSI was obtained at rest and at peak stress. A DSE with a peak WMSI of 1.1 to 1.7 was considered mild to moderately abnormal and >1.7 was markedly abnormal.

Outcome data were obtained by a questionnaire, evaluation of hospital records, contacting the patient’s general practitioner, and/or review of civil registries. The online municipal civil registry was used to determine the patient’s present survival status. The date of response was used to calculate follow-up time. The end points considered were all-cause and cardiac mortality. Causes of death were obtained from the Central Bureau of Statistics Netherlands. A death caused by acute MI, significant arrhythmias, refractory heart failure, or sudden death without other explanation was defined as cardiac mortality.

Continuous data were presented as mean ± SD and were compared using the Student t test. Categorical data were presented as percentages and were compared using the chi-square test. Correlation between continuous variables was estimated with Pearson’s correlation coefficient. Survival curves were generated using the Kaplan-Meier method to assess the probability of (event free) survival and were compared using the log-rank test. The impact of early coronary revascularization on survival was investigated using univariable and multivariable Cox’s proportional hazard regression models. The multivariable model was performed using known prognostic factors, including clinical characteristics and DSE results. The risk of a variable was expressed as a hazard ratio with a corresponding 95% confidence interval; p <0.05 was considered statistically significant. All analyses were performed with IBM SPSS statistical software, version 22, Armonk, New York.

Results

The clinical characteristics of the 905 patients with myocardial ischemia on DSE are presented in Table 1 . The mean age was 61 years, and the majority of the patients were men (76%). During the dobutamine stress test, heart rate increased from a mean of 70 ± 13 beats/min to 128 ± 19 beats/min (p <0.001), whereas overall systolic blood pressure did not significantly change (132 ± 25 mm Hg at rest and 132 ± 29 mm Hg at stress). During dobutamine stress testing, 295 patients (33%) experienced typical angina, and ST-segment changes occurred in 293 patients (32%).

All patients had myocardial ischemia on DSE. A total of 445 patients (49%) had a peak WMSI >1.7. Patients with a peak WMSI >1.7 had more cardiac mortality compared with those with a peak WMSI ≤1.7 (30% vs 23%, respectively, p = 0.013). Early coronary revascularization was performed in 222 patients (25%); a total of 113 patients underwent PCI (51%) and 109 patients underwent CABG (49%); a total of 3 patients (1%) underwent both PCI and CABG. The mean interval between DSE and early revascularization was 37 ± 6 days. The remaining 683 patients with myocardial ischemia were treated medically. Patient groups were comparable according to age, male gender, smoking, hypertension, diabetes mellitus and the use of diuretics, digoxin, and platelet inhibitors. Patients who underwent early revascularization more frequently had a history of cardiac disease (previous MI and heart failure) and less frequently had a previous revascularization. Mean rest WMSI and mean peak WMSI were 1.68 ± 0.60 and 1.79 ± 0.50, respectively. Both rest WMSI and peak WMSI were significantly higher in patients who underwent early revascularization ( Table 1 ). This probably has contributed to the reason for intervention.

During a median follow-up time of 10 years (range 8 to 15), 474 deaths (52%) occurred, of which were 241 (51%) due to cardiac causes. Kaplan-Meier survival curves showed that patients with myocardial ischemia on DSE who underwent early revascularization had a lower risk for all-cause mortality (event-free survival: 80% vs 65% at 5 years, 65% vs 46% at 10 years; overall p <0.001, Figure 1 ) and cardiac mortality (event-free survival: 86% vs 77% at 5 years, 83% vs 66% at 10 years; overall p <0.001, Figure 2 ). Figures 3 and 4 demonstrates the event-free survival for all-cause mortality and cardiac mortality, respectively, according to strata of revascularization and peak WMSI. In the 445 patients with markedly abnormal DSE results, early revascularization was associated with better long-term outcomes compared with those without early revascularization (all-cause mortality [ Figure 3 ] and cardiac mortality [ Figure 4 ] both p <0.001). Also, in the 460 patients with mild-to-moderately abnormal DSE results, early revascularization was associated with better long-term outcomes compared with those without early revascularization (all-cause mortality, p <0.008, Figure 3 ; cardiac mortality, p <0.001, Figure 4 ).

Kaplan-Meier curves for all-cause mortality according to strata of early coronary revascularization.

Kaplan-Meier curves for cardiac mortality according to strata of early coronary revascularization.

Kaplan-Meier curves for all-cause mortality according to strata of WMSI and early coronary revascularization.

Kaplan-Meier curves for cardiac mortality according to strata of WMSI and early coronary revascularization.

Univariable associations of long-term outcome are presented in Tables 2 and 3 . Univariable predictors of all-cause mortality were age, male gender, hypertension, hypercholesterolemia, history of heart failure, previous revascularization, and rest and peak WMSI ( Table 2 ). Univariable predictors of cardiac mortality were age, male gender, hypercholesterolemia, history of heart failure, previous revascularization, previous MI, and rest and peak WMSI ( Table 3 ). The univariable analysis demonstrated that early revascularization was inversely related to both end points of interest.

Table 2

Univariable and multivariable predictors of all-cause mortality

Variable	Univariable		Multivariable
	HR	95% CI	HR	95% CI
Age ∗	1.05	1.04-1.06	1.05	1.04-1.06
Men	1.31	1.06-1.63	1.24	0.98-1.56
Hypertension	1.33	1.10-1.61	1.46	1.18-1.79
Diabetes mellitus	0.92	0.76-1.29	1.06	0.80-1.40
Hypercholesterolemia	0.67	0.54-0.84	0.69	0.55-0.88
Smoking	1.19	0.99-1.43	1.48	1.21-1.82
Heart failure	1.46	1.18-1.81	1.30	1.02-1.66
Previous revascularization	0.44	0.25-0.77	0.42	0.23-0.76
Previous MI	1.10	0.92-1.32	0.94	0.77-1.16
Rest WMSI	1.51	1.29-1.75	1.31	0.90-1.89
Peak WMSI	1.53	1.29-1.80	1.34	0.90-2.01
Early revascularization	0.64	0.50-0.83	0.60	0.46-0.79

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