Stress testing is useful for evaluating complaints of chest pain or dyspnea and to quantify functional capacity Although widely used as a screening test for coronary artery disease (CAD) in asymptomatic patients, the positive predictive value of the test is markedly decreased in a population with low pre-test probability of disease. The test is more useful for evaluating asymptomatic patients with multiple risk factors for coronary disease. This paper evaluates the literature pertaining to stress testing asymptomatic patients with diabetes mellitus (DM), which is so strongly associated with CAD that it is considered a coronary disease equivalent.1

DM is recognized as a major cause of cardiovascular (CV) morbidity and mortality worldwide and is increasing in prevalence. In the United States alone, 8% of the population, a 61% increase since 1990, is estimated to have diabetes.2 Of these patients, approximately 75% will die of CAD—twice the CV mortality rate of patients without diabetes.3 Many patients with diabetes experience accelerated atherosclerosis and are diagnosed with higher rates of multi-vessel disease, heart failure, and cardiac events than nondiabetic patients.4 Diabetic patients have become a prime target for early diagnosis, risk stratification, and treatment of concomitant CAD in the hope that patients will benefit from aggressive risk factor modification.5

Besides the high likelihood of the presence of CAD in patients with DM, there is another reason for interest in using the exercise test as a screening tool in this population. “Silent ischemia,” presumably from autonomic denervation and dysregulation, occurs more commonly in diabetic patients.6 Furthermore, data from the Framingham Heart Study show that the incidence of painless myocardial infarctions was higher in diabetic patients than those without the disease.7 Of concern, the presence of silent ischemia in diabetic patients portends poor survival and adverse clinical outcomes.8

Currently, no evidence-based guidelines exist for the use of stress testing in screening asymptomatic diabetic patients for CAD. Consensus guidelines issued by the American Diabetes Association (ADA) in 1998 recommend screening for CAD in asymptomatic diabetic patients who have peripheral arterial disease, resting electrocardiographic results indicative of coronary ischemia or infarction, or ≥2 additional risk factors.9 While multiple noninvasive modalities exist for detecting CAD, recent studies have focused on the use of myocardial perfusion imaging (MPI) in evaluating asymptomatic diabetic patients. The reasons for this include high sensitivity (88%) and specificity (74%) for detecting angiographically significant disease, the ability of diabetic patients to be studied regardless of their exercise capacity, and the ability of perfusion imaging to predict the risk of short- and long-term coronary events based on extent and severity of ischemia.10

In 2002, De Lorenzo and colleagues11 sought to assess the value of MPI using single-photon emission computed tomography (SPECT) with technetium-99 m sestamibi to detect perfusion defects and predict cardiac events in asymptomatic patients with diabetes. A total of 180 patients without known CAD were evaluated using a two-day SPECT protocol with technetium-99 m sestamibi imaging and followed for 36±18 months. The hard end points were defined as myocardial infarction or cardiac death. Perfusion defects were found in 26% of the patients. The results showed that an abnormal MPI study correlated with an increased annual incidence of hard CV events (9%) when compared with patients who had a normal study (2%). In addition, in this study, the extent of disease identified those patients at the highest risk for having hard events, and a normal study isolated patients with the overall lowest risk. The investigators concluded that MPI with technetium-99 m sestamibi SPECT is useful in evaluating asymptomatic diabetic patients for CAD and risk-stratifying them for hard cardiac events. In a larger retrospective multicenter trial, Giri and colleagues12 evaluated 4755 patients, 929 of whom were diabetic, for suspected CAD using adenosine or exercise nuclear MPI. Patients were followed for a mean of 2.5 years for cardiac death, myocardial infarction, and revascularization. Diabetics had a higher cardiac event rate than nondiabetics (8.6% vs 4.5%), and abnormal MPI studies prognosticated an increased risk of cardiac events in both groups.

The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, designed by Wackers and colleagues,13 was a prospectively designed multicenter study that sought to assess both the prevalence and clinical predictors associated with silent myocardial ischemia and the ability of the current ADA screening guidelines to adequately select asymptomatic diabetic patients with silent ischemia. The study enrolled 1123 type 2 diabetic patients, aged 50 to 75, who did not have a known or suspected history of CAD. Of these patients, half were randomized to either adenosine stress perfusion imaging with follow-up or to follow-up alone. Exclusion criteria included prior stress testing or coronary angiography in the past three years, heart failure, prior coronary event or intervention, and Q waves ± ST-segment or T-wave changes on resting baseline electrocardiography. Ultimately, 522 patients underwent adenosine perfusion imaging, with or without low-level exercise. In this relatively low-risk group of patients, 22% had an abnormal MPI study, with 6% having marked perfusion abnormalities. The investigators determined that the strongest predictors for an abnormal MPI study were cardiac autonomic dysfunction (assessed by heart response to the Valsalva maneuver), male sex, and duration of diabetes. Surprisingly, the findings from the DIAD study also showed that traditional risk factors did not accurately identify patients with perfusion abnormalities. In fact, markedly abnormal perfusion defects occurred with equal frequency in patients with ≥2 and <2 risk factors.

Wackers and colleagues recently published outcomes of their follow-up analysis, which aimed to assess whether MPI in asymptomatic diabetics could adequately identify patients at higher risk for adverse cardiac events (eg, cardiac death and nonfatal myocardial infarction).14 Their mean follow-up period was 4.8 years, and the cumulative cardiac event rate was strikingly low (2.9%). Of those screened, patients with normal results or small MPI perfusion defects had a yearly cardiac event rate of 0.4%, compared with 2.4% in patients with moderate to large MPI defects. While this was statistically significant, the overall positive predictive value of moderate-large perfusion defects was only 12%. The authors concluded that screening MPI, at least in the subset of diabetic patients they studied, did not significantly reduce cardiac event rates. It is possible that the low cumulative cardiac event rate and poor positive predictive value of abnormal MPI studies reflects the relatively low-risk diabetic population that was included in the DIAD study.

In a retrospective study of 1427 asymptomatic patients who were referred to the Mayo Clinic for stress testing, Rajagopalan and colleagues14 aimed to define the variables that would characterize which asymptomatic diabetic patients are most suitable for screening with stress MPI. The patients in this study were higher risk than those in the DIAD study, and this was reflected in the results, which showed abnormal stress MPI studies in 58% of the patients and high-risk scans in 18% of those studied. They conducted multivariate analysis and found that high-risk scans were most strongly associated with seven independent variables, the most notable being electrocardiographic Q waves and peripheral arterial disease. Nearly half of the patients with high-risk MPI studies were angiographically studied, 61% of whom had high-risk CAD (left main, 3-vessel, and/or proximal left anterior descending involvement). Annual mortality rates varied by the degree of MPI study severity: 5.9%, 5.0%, and 3.6% in the high-, intermediate-, and low-risk scans, respectively. Although this was a retrospective study and many have been influenced by verification bias, it provides additional support that high-risk asymptomatic diabetic patients with electrocardiographic abnormalities, peripheral arterial disease, among other clinical variables, may benefit from screening with stress MPI.

DM is becoming increasingly more common in the United States and abroad, with the worldwide prevalence estimated to exceed 360 million patients by 2030.15 Patients with type 2 diabetes have a two- to four-fold higher risk of CV events than nondiabetic patients, with higher associated mortality rates and more severe and debilitating CAD that often manifests at an earlier age.17 Early diagnosis, risk stratification, and treatment of these patients are imperative. Although not uniform across all studies, there appears to be a role of screening stress MPI in a select group of asymptomatic patients. Additional large-scale prospective trials are needed to elucidate which asymptomatic diabetic patients would most benefit from the diagnostic and prognostic capabilities of stress MPI. In addition, we need to assess whether the information we gain from stress MPI is able to affect treatment with risk factor modification or coronary artery revascularization in a way that alters the natural history of CV disease in these patients.


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