Abstract


Diabetes is a major worldwide healthcare problem and cardiovascular diseases are the most common causes of mortality and morbidity in the type 2 diabetic population with Coronary artery disease (CAD) accounting for 65% to 80% of deaths in diabetic patients. It has been suggested that screening asymptomatic diabetics could identify early coronary artery disease which may improve their outcomes. In this review, we summarize the data regarding screening asymptomatic diabetics and provide recommendations based on the evidence. Heart Views 2009;10(3)121-127. © Gulf Heart Association 2009.

Keywords: ¨ diabetes ¨ coronary artery disease



Introduction


Diabetes is a major worldwide healthcare problem, with 200 million people currently having diabetes. It is estimated that the prevalence worldwide will exceed will exceed 300 million by 2025 and 360 million by 2030. The majority of these patients will have type 2 diabetes1. A study in the United Arab Emirates showed that nearly one fifth of the population had high Framingham risk score and nearly one fourth had diabetes2. Cardiovascular diseases are the most common causes of mortality and morbidity in the type 2 diabetic population with Coronary artery disease (CAD) accounting for 65% to 80% of deaths in diabetic patients. Haffner and colleagues have shown that diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction3. In addition, data from the GULF RACE registry suggest that diabetic patients with ACS have worse clinical outcomes than non diabetics4,5. The current NCEP III guidelines recommend treating diabetic patients as a CAD equivalent6.

However, we do not know if all diabetics have CAD? It is also unclear if identifying patients with coronary disease impact on the outcomes of these patients. Thus, accurate cardiovascular risk stratification in diabetics is needed. This could be difficult since the clinical presentation and progression of CAD differs between diabetic and nondiabetic patients7. The Framingham risk score is one of the tools that can be used to determine 10-year (short-term) and long-term (30 year) risk for developing CAD8. However, the Framingham risk score may provide imprecise estimates of future risk of cardiovascular (CV) events in diabetics9,10. Other indicators include exercise capacity and metabolic activity. While these measures provide important prognostic information, their utility alone in the diagnosis of CAD is limited. Thus, there is a need for other modalities to supplement the clinical criteria used in the risk stratification of diabetic patients. Multiple screening tests have been proposed to be used to diagnose CAD in diabetic patients. In this article, we review the evidence behind the use of myocardial perfusion imaging in asymptomatic diabetics.


What is the prevalence of CAD in asymptomatic diabetics?


Myocardial perfusion imaging (MPI) is a widely used imaging modality to detect coronary disease that has high diagnostic accuracy in evaluating CAD. Kang et al11 evaluated 138 patients with  diabetes who also underwent invasive angiography and reported a sensitivity of 86% with a lower specificity of 56%. Other Studies that evaluated the prevalence of CAD in asymptomatic patients with DM are summarized in Table 1. The incidence of abnormal Single photon emission computed tomography myocardial perfusion imaging SPECT-MPI in this patient population ranged between 16-58%. In addition, the incidence of abnormal SPECT MPI was the same in symptomatic and asymptomatic patients with DM (59% vs 60%)12. In multivariate analysis, Q waves on echocardiogram and peripheral arterial disease were independently associated with a high-risk scan and high annual mortality rate13,14.

However, most of the above mentioned studies were retrospective in nature and included different patient populations that had different pretest likelihood of CAD. To date, there is only one study that has prospectively evaluated the prevalence of silent CAD in diabetic patients. The Detection of silent myocardial Ischemia in Asymptomatic Diabetic subjects (DIAD) 15 study enrolled 522 patients who were screened for the presence of CAD by MPI. Of these, 22% had an abnormal stress test result. The number of atherosclerotic risk factor was not associated with the presence of a perfusion defect. Cardiac autonomic neuropathy appeared to be the only independent predictor of abnormal MPI; none of the well-known CAD risk factors were.

Given the high prevalence of CAD in asymptomatic diabetes, the current American Diabetes Association (ADA) guidelines recommend stress testing for diabetic patients who have two other risk factors for CAD16. Scognamiglio and colleagues17 evaluated the effectiveness of the current American Diabetes Association screening guidelines in identifying asymptomatic patients with CAD in type 2 diabetes in 1899 asymptomatic patients (age £ 60 years) who underwent dipyridamole myocardial contrast echocardiography (MCE). In those with myocardial perfusion defects, the anatomy of coronary vessels was evaluated by selective coronary angiography. The prevalence of abnormal MCE was 60% irrespective of risk factor profile. On catheterization, there was higher prevalence of diffuse disease (18% vs 55%, p < 0.001), and of vessel occlusion (4% vs 31%, p < 0.001) in patients with multiple risk factors.

In addition, earlier studies suggested that screening for asymptomatic CAD in diabetic patients may be cost effective if exercise echocardiography was used. Compared with no screening, incremental cost-effectiveness ratio of exercise electrocardiography was $41,600/QALY in 60-year-old asymptomatic diabetic men with hypertension and smoking, but was weakly dominated by exercise echocardiography18.

 

Table 1: Prevalence of Abnormal of MPI in asymptomatic diabetics

 

Fig.1: Changes in Medications in the DIAD study after the NCEPIII guidelines publications.

Prognostic value of SPECT MPI in diabetics


There is limited data evaluating the prognosis of asymptomatic diabetic patients with silent CAD. To date, reports have consistently shown that normal MPI in diabetic populations is not associated with a low level of risk regardless of the presence of symptoms. Moreover, the cardiovascular mortality rate is more than doubled in symptomatic diabetic patients, especially if they had abnormal imaging scans19. As shown in Table 2, the annual event rate could be as high as 12 in symptomatic diabetic patients. Rajagopalan et al13 examined mortality rates in 826 asymptomatic diabetic patients. The mortality rate in high-risk patients was 5.9%, in intermediate-risk patients 5.0%, and in low-risk patients 3.6% (p < 0.001 for differences between groups). Post hoc analyses were performed to determine if a truly low-risk (annual mortality < 1%) subset of patients could be identified. Annual mortality in patients without ECG Q-waves or peripheral arterial disease and with a completely normal SPECT imaging scan (n = 443) was lower but was still 2.9%.

The DIAD study is the first large prospective study addressing the issue of whether a strategy of systematic screening for silent coronary artery disease alters cardiac outcome. It enrolled 1,123 diabetic patients without symptomatic or previously diagnosed CAD who were randomized to either screening with myocardial perfusion imaging or standard care without screening. After an average five-year follow-up, there was a low overall cardiac event rate and no difference between the two groups. This could have been mediated by a high use of anti-atherosclerotic therapies in this cohort. Unexpectedly, diabetic patients without known CAD have an overall highly favorable five-year prognosis with contemporary therapy, such as aspirin, statins, and ACE-inhibitors. (Figure 1) However, in the group that was screened for CAD, MPI provided incremental prognostic information. Asymptomatic diabetic patients with high risk scans had worse outcomes than asymptomatic diabetic patients with normal or low risk scans20.

The DIAD outcomes study suggests that systematic screening cannot be recommended in all asymptomatic patients with diabetes. However, whether targeted screening results in higher yield and improved outcomes is a question that is still looking for an answer. It appears that screening every diabetic may not be cost effective and may not alter long-term clinical outcomes. Whether the value of screening a targeted population of higher risk diabetics is not known. These observations reflect the heterogeneity of cardiovascular risk in patients with diabetes (i.e. diabetics are not equal). This heterogeneity may reflect heterogeneity of the disease itself, concomitant risk factors, or therapeutic strategies used to control the underlying metabolic derangement and associated risk factors. The dilemma lies in how to identify the high risk asymptomatic diabetic population that may benefit from treated screening by MPI. The DIAD study suggests that the number of risk factors do not identify this population. It is unclear whether there is a biochemical marker that could make this distinction. We believe that using another imaging modality as a gate keeper to screening by MPI may be the way to go. Using biomarkers may not work. A study of 44 individual with normal SPECT did not show any role for the inflammatory markers in predicating the presence of coronary artery disease in participants with DM, without medium size artery disease21.
 

Table 2: Prognostic Value of SPECT MPI in diabetics

 

Fig.2: Relation between perfusion defects and Coronary Calcium Scores.

Do we need other imaging modalities in asymptomatic diabetics?


While not every diabetic patient has obstructive coronary disease detectable by a stress test, coronary calcium scoring (CCS) provides a tool to identify early atherosclerosis. It has been shown that CCS has an excellent prognostic value for subsequent cardiac events in asymptomatic individuals22,23. High CCS can modify predicted risk obtained from Framingham risk score alone, especially among patients in the intermediate risk category in whom clinical decision making is most uncertain24. A very low rate of cardiac death and myocardial infarction (0.4%) over 3 to 5 years has been reported for individuals without detectable calcium. In contrast, annual event rates as high as 7.1% have been reported for individuals a CCS > 1,000. The positive relationship between a high CCS and an elevated cardiac event rate may be explained by the fact that an increase in coronary calcium reflects an increase in overall coronary plaque burden. More importantly, the absence of coronary atherosclerosis on CCS or CCTA may ameliorate the need for further testing within a 3-5 year period.

Lahiri and colleagues prospectively evaluated 510 asymptomatic type 2 diabetic subjects without prior cardiovascular disease using a strategy that involved CCS in everyone and MPI in patients with a CCS more than 10 Agatston units (AU). CCS > 10 AU was found in 46% and CAC > 100 was seen in 25% of patients. In the subset of patients with CCS > 1000, 70% of the patient had an abnormal MPI compared to 48% of patients with CCS between 400-1000 (Figure 2). Age, systolic blood pressure, the duration of diabetes, United Kingdom Prospective Diabetes Study risk score, CAC score, and extent of MPI abnormality were significant predictors of time to cardiovascular events. This early data suggests that using a hybrid screening strategy may be beneficial and increases the diagnostic yield of a screening strategy. Such a strategy need to be evaluated in a large multicenter randomized trial before it is recommended widely.


What about Cardiac MRI?


Cardiovascular magnetic resonance imaging (CMR) plays an increasing role in the assessment of patients with various cardiovascular disorders. Given its enhanced spatial and temporal resolution, improved tissue characterization and lack of ionizing radiation, it has often become the test of choice in the evaluation of patients with various clinical scenarios including pericardial diseases, myocarditis, heart failure and coronary artery disease. Contrast-enhanced cardiac magnetic resonance imaging (CMR) can determine the extent of myocardial scar from infarction (MI). Among patients with a clinical suspicion of coronary artery disease but without a history of MI, LGE involving a small amount of myocardium carries a high cardiac risk25.

In a study of clinically indicated CMR imaging in 187 diabetic patients, late gadolinium enhancement (LGE by CMR was present in 30 of 107 patients (28%) without known prior CAD. At a median follow-up of 17 months, 38 of 107 patients (36%) experienced MACE, which included 18 deaths. Presence of LGE was associated with a > 3-fold hazards increase for MACE and for death (hazard ratio, 3.71 and 3.61; P < 0.001 and P = 0.007, respectively)26. Thus, CMR imaging can characterize occult myocardial scar consistent with MI in diabetic patients without clinical evidence of MI. This imaging finding demonstrates strong association with MACE and mortality hazards that is incremental to clinical, ECG, and left ventricular function combined.


Questions yet to be answered:


Recently, Coronary CT Angiography (CCTA) has become a widely accepted for noninvasive evaluation of the coronary arteries. CCTA has a very high negative predictive value to rule out CAD27,28. A particular advantage of CCTA over CCS is the fact that noncalcified plaques are also identified, thus providing a more accurate evaluation of the underlying atherosclerotic plaque burden. However, intravenous contrast media has to be used. At present, it is unclear whether identifying the noncalcified plaque adds prognostic information. These questions are currently being evaluated in the prospective cardiac imaging in asymptomatic diabetics Study (CASCAD) which is evaluating the role of biomarkers, exercise capacity, stress echocardiography, CCS and CCTA in asymptomatic diabetics.


Summary


In summary, the current data suggests that CAD systematic screening of asymptomatic diabetic patients by MPI will not alter clinical outcomes of adequately treated patients. However, whether using a directed hybrid screening strategy with CCS and MPI will improve the outcomes of asymptomatic diabetics remains a question looking for an answer.¨
 
 

References:


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