CLINICAL RESEARCH: DIABETES AND OBESITY
Prognostic Value of Pharmacological Stress Echocardiography in Diabetic and Nondiabetic Patients With Known or Suspected Coronary Artery Disease
Lauro Cortigiani, MD*,*,
Riccardo Bigi, MD ,
Rosa Sicari, MD ,
Patrizia Landi, BSc,
Francesco Bovenzi, MD* and
Eugenio Picano, MD
* Division of Cardiology, Lucca Hospital, Lucca, Italy
Cardiology, Department of Medicine and Surgery, University School of Medicine, Milan, Italy
Institute of Clinical Physiology, CNR, Pisa, Italy
Manuscript received June 29, 2005;
revised manuscript received September 8, 2005,
accepted September 12, 2005.
* Reprint requests and correspondence: Dr. Lauro Cortigiani, Divisione di Cardiologia, Ospedale "Campo di Marte," 55032 Lucca, Italy (Email: lacortig{at}tin.it).
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Abstract
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OBJECTIVES: We sought to compare the prognostic value of pharmacological stress echocardiography (SE) in diabetic and nondiabetic patients with known or suspected coronary artery disease.
BACKGROUND: Although SE is a useful tool for risk stratification of patients with diabetes, it has not been established whether it retains the same prognostic information in diabetic patients compared with nondiabetic patients.
METHODS: A total of 5,456 patients (749 diabetics) undergoing dipyridamole (n = 3,306) or dobutamine (n = 2,150) SE were prospectively followed up for the occurrence of hard events (death and/or nonfatal myocardial infarction).
RESULTS: During a median time of 31 months, 411 deaths and 236 infarctions occurred. There were 132 events in diabetic patients and 515 in nondiabetic patients (18% vs. 11%, respectively; p < 0.0001). Moreover, 1,607 (29%) patients underwent coronary revascularization and were censored. Ischemia at SE, resting wall motion score index, and age were independent predictors of death and hard events in both diabetic and nondiabetic patients. Compared with a normal test, ischemia and scar test patterns were associated to significantly lower age-corrected five-year hard event-free survival in diabetic as well as nondiabetic patients. However, a normal test was associated with a greater than two-fold annual event rate in diabetic patients as compared with nondiabetics who were either younger (2.6% vs. 1.0%) or older (5.5% vs. 2.2%) than 65 years of age.
CONCLUSIONS: Stress echocardiography is equally effective in risk stratifying diabetic and nondiabetic patients independently of age. However, the normal test result predicts a less favorable outcome in diabetic than in nondiabetic patients.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | SE = stress echocardiography | | WMSI = wall motion score index |
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Coronary artery disease (CAD) is the leading cause of mortality and morbidity in patients with diabetes. Approximately one-half of deaths are attributed to CAD in diabetic patients (1), whose risk of myocardial infarction or cardiac death is two- to four-fold as great compared with nondiabetic patients (2,3). Moreover, cardiac events are as frequent in diabetic patients without evidence of CAD as in nondiabetic patients with known CAD (4). The increased risk associated with diabetes calls for effective prevention (5–8) and risk stratification strategies to optimize therapeutic interventions (9). Exercise testing is of limited value in the diabetic population because exercise capacity is often impaired by peripheral vascular (10) or neuropathic disease (11). Furthermore, test specificity is less than ideal (12) because of the high prevalence of hypertension (13) and microvascular disease (14).
Stress echocardiography (SE) represents an established diagnostic (15) and prognostic modality (16–19) in diabetic patients. However, it is still undefined whether it retains the same prognostic value in diabetic and nondiabetic patients. Accordingly, we aimed at comparing the ability of pharmacological SE to risk stratify a large population of diabetic and nondiabetic patients with known or suspected CAD.
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Methods
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Patients.
From the prospective data bank of the Clinical Physiology Institute, Pisa, and Campo di Marte Hospital, Lucca, Italy, 5,566 patients undergoing pharmacological SE from 1986 to 2001 were initially selected. Exclusion criteria were significant valvular or congenital heart disease, prognostically relevant noncardiac diseases (i.e., cancer, end-stage renal disease, or severe obstructive pulmonary disease), and inadequate acoustic window. One hundred ten (2%) patients were lost to follow-up. The remaining 5,456 patients, 749 (14%) of whom were diabetics (20), had complete follow-up information and formed the study population. Indication of SE was suspected CAD in 3,268 (60%) and risk stratification of known CAD in 2,188 (40%) subjects. Coronary artery disease was defined as history of myocardial infarction or coronary revascularization and/or presence of more than one angiographically documented coronary stenosis >50%. Pharmachological stress was used because of inability to exercise maximally, nondiagnostic, or doubtful exercise electrocardiography result. The stressor (n = 3,306 dipyridamole and n = 2,150 dobutamine) agent was selected on the basis of clinical background and specific contraindications. Dobutamine was preferentially (63%) used in case of resting wall motion abnormalities.
Stress echocardiography was performed on and off antianginal therapy in 1,409 (36%) (beta-blockers in 644, calcium antagonists in 513, or nitrates in 916) and 4,047 (74%) patients, respectively. Hypertension (5) and hypercholesterolemia (21) were defined according to standard definitions.
Stress protocol.
Dipyridamole and dobutamine-atropine SE was performed according to established protocols (22,23). Starting in 1992, the dipyridamole protocol was modified to include the coadministration of atropine (24).
Echocardiographic analysis.
Echocardiographic images were semiquantitatively assessed using a 16-segment, four-point scale model of the left ventricle. A wall motion score index (WMSI) was derived by dividing the sum of individual segment scores by the number of interpretable segments. Ischemia was defined as stress-induced new and/or worsening of pre-existing wall motion abnormality, or biphasic response (i.e., low-dose improvement followed by high-dose deterioration). Scar was akinetic or dyskinetic myocardium, with no thickening during stress. A test was normal in case of no rest and stress wall motion abnormality. Electrocardiographic analysis was done according to standard criteria (22,23).
Follow-up.
Data collection was performed in 2002. Outcome was determined from patients’ interviews at the outpatient clinic, hospital chart reviews, and telephone interviews with the patient, his/her close relative, or referring physician. Death, nonfatal myocardial infarction, and coronary revascularization were registered as clinical events. To avoid misclassification of the cause of death (25), we considered overall mortality. Myocardial infarction was defined by typical symptoms, electrocardiographic, and cardiac enzyme changes. Follow-up data were analyzed for the prediction of death and hard events (death, myocardial infarction).
Statistical analysis.
Continuous variables are expressed as mean values ± SD. Differences between groups were compared using the Student t and chi-square tests, as appropriate. Survival rates were estimated with Kaplan-Meier curves and compared by the log-rank test. Patients undergoing coronary revascularization were censored at the time of the procedure. Only the first event was taken into account. Annual event rates were obtained from Kaplan-Meier estimates to take censoring of the data into account. The association of selected variables with outcome was assessed with the Cox’s proportional hazards survival model using univariate and stepwise multivariate procedures. A significance of 0.05 was required for a variable to be included into the multivariate model, whereas 0.1 was the cut-off value for exclusion. Hazard ratios with the corresponding 95% confidence intervals were estimated. The model was stratified by age according to the cut-off of 65 years. Statistical significance was set at p < 0.05. Moreover, clinical, rest, and stress-induced wall motion abnormalities sequentially were included into the model. The global chi-square value of the model was calculated from the log likelihood ratio; a significant increase after the addition of further variables indicated incremental prognostic value. Statistical Package for the Social Sciences (SPSS, Chicago, Illinois) was used for analysis.
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Results
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Stress echocardiography.
Ischemia was assessed in 2,040 (37%) patients (1,232 [61%] with resting wall motion abnormalities), 308 of whom were diabetic and 1,732 nondiabetic (41% vs. 37%, p = 0.02). Ischemia was more frequent in patients with than in those without resting wall motion abnormalities (48% vs. 28%; p < 0.0001). Among subjects with ischemia, the WMSI increased from 1.28 ± 0.31 to 1.56 ± 0.33 in diabetic patients and from 1.27 ± 0.31 to 1.54 ± 0.33 in nondiabetic patients (p = 0.37) during stress. The number of ischemic segments was similar in the two populations (2.54 ± 1.51 vs. 2.58 ± 1.50, p = 0.81).
A scar pattern was found in 229 diabetic and 1,132 nondiabetic patients (31% vs. 24%; p < 0.0001); diabetic patients had a greater WMSI (1.56 ± 0.33 vs. 1.49 ± 0.34; p = 0.004). A normal test was observed in 212 diabetic and 1,843 nondiabetic patients (28% vs. 39%; p < 0.0001). Clinical and echocardiographic characteristics of the study population are reported in Table 1.
Follow-up events.
The follow-up period ranged from 6 to 120 months (median, 31; first quartile 6, third quartile 65 months). A total of 647 hard events (411 deaths, 236 myocardial infarctions) were observed: 132 in diabetic and 515 in nondiabetic patients (18% vs. 11%; p < 0.0001). According to age, 58 events occurred in the 368 diabetic and 261 in the 2,938 nondiabetic patients younger than 65 years (16% vs. 9%; p < 0.0001), whereas 74 events occurred in the 381 diabetic and 254 in the 1,769 nondiabetic patients older than 65 years (19% vs. 14%; p < 0.0001). Among diabetic patients, 106 events occurred in the 537 patients with abnormal and 26 in the 212 with normal test (20% vs. 12%; p = 0.01). Among nondiabetic patients, 398 events occurred in the 2,864 patients with abnormal and 117 in the 1,843 with normal test (14% vs. 6%; p < 0.0001). In patients with scar, a higher WMSI was documented in both diabetic patients (1.65 ± 0.35 vs. 1.53 ± 0.31; p = 0.01), and nondiabetics (1.54 ± 0.37 vs. 1.48 ± 0.34; p = 0.03) with events as compared with their uneventful counterpart.
A total of 1,607 (29%) patients (263 [35%] diabetic and 1,344 [28%] nondiabetic patients; p = 0.0002) underwent coronary revascularization (675 surgery and 932 angioplasty): 743 (46%) within and 864 (54%) after three months from SE.
Outcome prediction.
The annual hard event rate was higher in diabetic than in nondiabetic patients either with (8.5% vs. 4.7%) or without (6.0% vs. 2.2%) known CAD. Of note, it was higher in diabetic patients without known CAD than in nondiabetic patients with known CAD.
Univariate and multivariate predictors of mortality in diabetic and nondiabetic patients are reported in Table 2. Ischemia at SE, resting WMSI, and age were independently associated with mortality in both groups. In nondiabetic patients, male gender also was a multivariate prognostic indicator. Compared with a normal test, ischemia and scar patterns predicted a significantly lower five-year survival in both diabetic (p < 0.001) and nondiabetic patients (p < 0.0001) (Fig. 1).
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Figure 1 Survival curves for diabetic and nondiabetic patients describing the group with ischemia, scar, and normal test.
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Ischemia at SE, resting WMSI, and age also were multivariate prognostic indicators of hard events (Table 3) in both patient groups. Furthermore, previous myocardial infarction, smoking habit, and left bundle branch block represented additional prognostic indicators in nondiabetics. Compared with a normal test, ischemia and scarring were associated with significantly lower five-year hard event-free survival in both diabetic (p < 0.0001) and nondiabetic patients (p < 0.0001; Fig. 2).
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Figure 2 Hard event-free survival curves for diabetic and nondiabetic patients describing the group with ischemia, scar, and normal test.
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The results of SE retained their prognostic value after grouping patients by age (Fig. 3). However, a normal test was associated with worse outcome in diabetic than in nondiabetic patients, particularly if they were older than 65 years (Fig. 3). Annual hard event rate associated with a normal test was approximately 2.5 times greater in diabetic patients than in nondiabetic patients who were both younger (2.6% vs. 1.0%) and older (5.5% vs. 2.2%) than 65 years. Six-month hard event rate was 0.9% in diabetics younger and 3% in those older than 65 years.
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Figure 3 Hard event-free survival curves for diabetic and nondiabetic patients ages <65 years and  65 years, describing the group with ischemia, scar, and normal test.
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Global chi-square of the clinical model for predicting outcome was 17.8 (p = 0.02) in diabetic and 209.5 (p < 0.0001) in nondiabetic patients. Sequential inclusion of resting and SE result increased it by 31% (23.4; p = 0.005) and 28% (29.9; p = 0.001) in diabetic and by 11% (232.0; p < 0.0001) and 16% (269.9; p < 0.0001) in nondiabetic patients, respectively.
Dipyridamole and dobutamine SE provided a similar increment in global chi-square in both diabetic (20% and 21%, respectively) and nondiabetic patients (16% and 17%, respectively). Annual hard event rate associated with a nonischemic test was greater in both diabetic (7.8% vs. 5.3%) and nondiabetic patients (3.8% vs. 2.1%) if the test was performed on rather than off antianginal therapy.
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Discussion
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The prognostic value of SE in diabetic patients with known or suspected CAD has been previously demonstrated (16–19). However, given their high-risk status for the development of cardiovascular diseases (1–4), diabetic patients present with a substantially increased pretest likelihood of adverse outcome. Thus, to verify whether the test conveys similar prognostic information in diabetic and nondiabetic patients is of primary clinical relevance. With this aim in mind, we analyzed the data of a large cohort of patients with and without diabetes mellitus who were referred for pharmacological SE. Diabetic patients had a higher risk profile, as demonstrated in the more advanced age and higher prevalence of CAD, hypertension, resting wall motion abnormalities, and ischemic or scar echocardiographic pattern. Moreover, they more frequently underwent coronary interventions and fared worse than nondiabetic patients independently of the presence of a known CAD. Diabetic patients with suspected CAD had a worse prognosis in comparison with nondiabetic patients with known CAD.
Despite these differences, clinical and echocardiographic findings allowed the effective risk stratification in both patient populations. In particular, age, ischemia at SE, and resting WMSI were independent predictors of outcome. Interestingly, SE added greater prognostic value to that of clinical and resting echo findings in diabetic than in nondiabetic patients independently of the stressor agent. Moreover, using the test result, we were able to separate subsets with different risk profiles in both groups of patients independently of age, even though a normal test was associated with a worse outcome in diabetic patients as compared with age-matched nondiabetic patients. Similar results were reported previously (26); however, as the scar pattern was included among the nonischemic results, the authors did not separately analyze the prognostic effect of a normal test. Short-term prognostic significance of a normal SE in diabetic patients was less favorable in the present as compared with a previous study reporting no event during the first two years (17).
Clinical implications.
Our results reinforce previous reports on the capability of SE to effectively stratify the risk of death (18) or combined hard events (16,17,19) in diabetic patients. However, further conclusions may be drawn. First, SE provides useful prognostic information in diabetics younger as well as older than 65 years. Moreover, diabetic patients with a normal test have a less favorable outcome as compared with their age-matched nondiabetic counterpart. Finally, a normal study is associated with a measurable "warranty period" in diabetics younger but not in those older than 65 years. On the basis of these findings, the achievement of as much metabolic control as possible, adequate treatment of risk factors (8), primary prevention measures (6,7), as well as close follow-up, including periodic assessment of myocardial ischemia, should represent pivotal targets of the management of diabetic patients with normal SE.
Study limitations.
Because patients were recruited over a long period of time, it is possible that progressive methodological and technological advancements in SE as well as in medical therapy may have affected our results. Moreover, dobutamine stress was preferentially administered to patients with resting wall motion abnormalities which may have caused a misinterpretation of the relationship between type of stressor and outcome.
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Abstract
Methods