.: Detection of Silent Coronary Artery Disease in Asymptomatic Patients with Type 2 Diabetes Mellitus

Frans J. Th. Wackers, MD
and
Janice A. Davey, APRN

Frans J. Th. Wackers, MD, PHD
Cardiovascular Nuclear Imaging Laboratory
Yale University School of Medicine
333 Cedar Street F-3
email: frans.wackers@yale.edu

Dr Wackers is Professor of Diagnostic
Radiology and Medicine and the Principal
Investigator of the Detection of Asymptomatic
Ischemia in Diabetics (DIAD) Study

Diabetes, a coronary artery disease equivalent

Diabetes mellitus is an important risk factor for cardiovascular disease. Moreover, cardiovascular diseases are the leading causes for morbidity and mortality in patients with type 2 diabetes mellitus. The high mortality rate is in part due to the diabetic state per se, above and beyond the clustering of other risk factors such as hypertension, dyslipidemia and obesity. Over the last decade the overall mortality from cardiovascular disease in the general population has decreased by about 20%. In contrast, mortality in patients with diabetes has increased with a similar percentage.1 As mentioned above cardiovascular events account for the majority of the deaths.
Diabetes is considered a “coronary artery disease equivalent” since patient with diabetes without known coronary artery disease (CAD) have a similar cardiac event rate as patients without diabetes who had a prior myocardial infarction.2 In the USA the direct medical cost of diabetes mellitus to society is about $ 92 billion per year. Most of these costs are due to cardiovascular complications of diabetes.
The conundrum of coronary artery disease in conjunction with type 2 diabetes is that it is often silent and when it becomes clinically manifest the disease is often in an advanced stage.3,4 Thus, there is good justification to consider appropriate means of screening for coronary artery disease in asymptomatic patients with diabetes in order to detect the disease before it strikes.


Prevalence of silent coronary artery disease

In 1998 the American Diabetes Association proposed guidelines for screening of asymptomatic patients with diabetes.5 (Box 1) It should be realized that these guidelines represented the best medical judgment of an expert panel and were not based on evidence in the literature.
For example, no credible data existed on the prevalence of silent CAD in asymptomatic diabetic patients. The prevalence of silent myocardial ischemia, as evidenced by abnormal stress myocardial perfusion imaging, was reported to be as high as 58% and as low as 7 %. Most studies in the literature were flawed by selection bias. Three types of studies existed. 1. Retrospective data base analyses of patients who were referred for stress testing because of typical or atypical symptoms.6,7 In general these studies had no reliable data about clinical aspects of diabetes, such as duration and treatment. These analyses usually revealed a high (~58%) prevalence of myocardial ischemia. 2. Retrospective data base analyses of patients who were likely asymptomatic and mostly referred for preoperative risk stratification. This category in general showed a lower prevalence of ischemia, in the range of 26% to 36%.8-10 3. Prospectively designed studies in truly asymptomatic patients with diabetes. 11-13 These studies revealed the lowest prevalence of silent ischemia but with a relatively wide range from 21% to 7%. The latter studies often were open to critique because of inconsistencies in stress testing methodology, which potentially resulted in underestimation of disease.


The DIAD Study

The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study was designed to determine prospectively the prevalence of silent myocardial ischemia in truly asymptomatic patients.14 Precise determination of the prevalence of silent ischemia in asymptomatic diabetics is of clinical relevance. It is generally agreed that screening is not justified in patient cohorts with low (e.g. < 10%) prevalence of disease. If the overall prevalence of disease is low, a relatively high number of false-positive results can be anticipated. Screening yields optimal results in populations with an intermediate pretest likelihood of disease, ranging from 20-80%. In DIAD study special attention was given in ensuring that enrolled patients were truly asymptomatic. (Box 2) All patients completed the Rose Questionaire to exclude angina or angina-like symptoms. A total of 1,123 patients were enrolled in the DIAD study between 2000 and 2002 in 14 clinical centers in the USA and Canada. Patients were randomized to testing (n=561) or no-testing (n=562). Testing consisted of adenosine pharmacologic vasodilator stress in conjunction with Tc-99m Sestamibi SPECT imaging, which was ultimately performed in 522 of randomized patients. Pharmacological stress was chosen since it could be anticipated that many patients with diabetes would not be able to perform adequate physical exercise. Indeed, only about one-half of the patients in the DIAD study could not even perform low-level exercise in conjunction with adenosine infusion. As mentioned, enrolment was completed in 2002, and all 1,1,23 patients will be followed for 5 years for the occurrence of cardiac events. Follow-up will be complete in September 2007. Patients who were randomized to “no-testing” will also have 5- year follow-up and represent a “natural history” arm.

One hundred thirteen (22%) of 522 patients randomized to testing with adenosine-Tc-99m Sestamibi SPECT had abnormal results suggestive of silent CAD. Of these, 73 patients (16% of the entire cohort) had regional myocardial perfusion abnormalities on SPECT imaging. The remaining patients (6%) had non-perfusion abnormalities, predominantly consisting of ischemic ST segment changes during the adenosine infusion. Of the patients with regional myocardial perfusion defects, 44% (6% of the screened cohort) were moderate-large in size, abnormalities that would warrant further evaluation by a cardiologist and consideration of coronary angiography.


Predictors of silent CAD

Thus, the DIAD study, which is the first large prospective study in asymptomatic patients with diabetes, revealed a prevalence of silent myocardial ischemia of 22%. This intermediate prevalence would justify systematic screening of asymptomatic patients with diabetes. However, since there are more than 18 million persons with diabetes in the USA alone, the costs of such screening would be prohibitive. It was therefore important to explore multivariate predictors for abnormal SPECT imaging. In multivariate logistic regression, the main predictors for moderate-large myocardial perfusion abnormalities were evidence of cardiac autonomic dysfunction (blunted heart rate response to the Valsalva maneuver) (OR 5.6), diabetes duration (OR 5.2), and male gender (OR 2.5). Traditional risk factors for CAD, such as hypertension, dyslipidemia, smoking, and family history for CAD were not predictive for myocardial perfusion abnormalities. In fact, if the ADA consensus statement guidelines for testing had been followed, i.e. testing only asymptomatic diabetic patients with > 2 additional risk factors, 41% of abnormal SPECT studies would have been missed. Other demographic characteristics, diabetes complications, clinical and laboratory values were not predictive of abnormal studies. Specifically, C-reactive protein, hyperhomocysteinemia, plasminogen activator inhibitor -1, hemoglobin A1C and retinopathy were not statistically associated with evidence for silent CAD. Of note, the strongest statistical predictor, blunted heart rate response to Valsalva maneuver, had a positive predictive value of only 19%, which makes it of limited practical value (even though the negative predictive value was high at 95%). Ischemic ST-segment depression during adenosine infusion was significantly associated with female gender (OR 3.4).

The key conclusions of the DIAD study are the following: 1. More than one in 5 of asymptomatic patients with type 2 diabetes have evidence of silent myocardial ischemia; 2. In approximately one in 16 patients, perfusion defects are sufficiently large to warrant further cardiologic evaluation; 3. Emerging and traditional risk factors do not help the clinician in determining which patients are at greatest risk for an abnormal SPECT study; 4. The presence of cardiac autonomic dysfunction increases the risk of silent ischemia.

It is important to consider the general applicability of the findings of the DIAD study. The DIAD findings apply to truly asymptomatic patients. Patients with abnormal resting electrocardiogram were excluded from the DIAD study. As in any larger randomized trial unintended selection bias may occur: because of the process of targeted recruitment and informed consent, generally “healthier” patients are enrolled and their outcome may be better than that of not enrolled patients. In the “real world” of clinical practice the prevalence of silent ischemia may be somewhat higher.

Coronary artery calcium scoring for detecting patients at higher risk
The true practical implications of the findings of the DIAD will become apparent when 5-year follow-up is complete in 2007. Nevertheless, it will be important to explore other ways for identifying higher risk asymptomatic diabetic patients in whom the yield of screening (i.e. number of abnormal test results) will be more (cost-) effective. One of such ways was recently proposed by Anand et al. 15 These investigators also evaluated the presence of silent myocardial ischemia in asymptomatic patients with type 2 diabetes. However they applied a prescreening step involving coronary calcium scoring (CAC) with electron beam CT scanners. Previous studies have shown that if CAC is < 100 Agatston units (AU) the likelihood of abnormal myocardial perfusion imaging is low. Accordingly Anand et al performed stress myocardial perfusion imaging SPECT only in asymptomatic diabetic patients with CAC > 100 AU. The overall prevalence of silent myocardial ischemia in this selected cohort was 39%. (Extrapolated to their total initial population the overall prevalence would amount to about 13%). Importantly, they observed an increasing incidence of abnormal myocardial perfusion images (i.e. silent ischemia) with increasing CAC scores: 60% in patients with > 400 AU and 71% in patients with > 1000 AU. Whereas in DIAD only 6% of the cohort had moderate-large myocardial perfusion abnormalities, this occurred in 31.5% of the patients in Anand et al’s study after prescreening with EBCT.


Summary

The literature until recently was ambiguous concerning the true prevalence of silent CAD in asymptomatic patients with type 2 diabetes mellitus. Recent prospective studies suggested that the overall prevalence is about 20% in patients aged 50-75 years. Abnormal SPECT studies were not reliably predicted by clinical and biochemical variables, nor traditional clinical risk factors. The observed prevalence was not as high as initially reported, but high enough to justify systematic screening for CAD. Because of the large number of patients with diabetes it is important to identify patients at greatest risk. Prescreening for CAC by CT scanning, followed by stress myocardial perfusion imaging has the promise for effectively detection silent CAD before it strikes patients with diabetes. (Box 3)


References:

1. Center of disease control and prevention mortality database: http://www.cdc.gov

2. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N.Engl.J.Med. 1998;339:229-234.

3. Nesto RW, Watson FS, Kowalchuk GJ, Zarich SW, Hill T, Lewis SM et al. Silent myocardial ischemia and infarction in diabetics with peripheral vascular disease: assessment by dipyridamole thallium-201 scintigraphy. Am.Heart J. 1990;120:1073-1077.

4. Langer A, Freeman MR, Josse RG, Steiner G, Armstrong PW. Detection of silent myocardial ischemia in diabetes mellitus. Am.J.Cardiol. 1991;67:1073-1078.

5. ADA consensus statement American Diabetes Association. Consensus development conference on the diagnosis of coronary heart disease in people with diabetes: 10-11 February 1998, Miami, Florida. American Diabetes Association. Diabetes Care 1998;21:1551-1559.

6. Kang X, Berman DS, Lewin HC, Cohen I, Friedman JD, Germano G et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography in patients with diabetes mellitus. Am.Heart J. 1999;138:1025-1032.

7. Giri S, Shaw LJ, Murthy DR, Travin MI, Miller DD, Hachamovitch R et al. Impact of diabetes on the risk stratification using stress single-photon emission computed tomography myocardial perfusion imaging in patients with symptoms suggestive of coronary artery disease. Circulation 2002;105:32-40.

8. De Lorenzo A, Lima RS, Siqueira-Filho AG, Pantoja MR. Prevalence and prognostic value of perfusion defects detected by stress technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography in asymptomatic patients with diabetes mellitus and no known coronary artery disease. Am.J.Cardiol. 2002;90:827-32.

9. Prior JO, Monbaron D, Koehli M, Calcagni ML, Ruiz J, Bischof DA. Prevalence of symptomatic and silent stress-induced perfusion defects in diabetic patients with suspected coronary artery disease referred for myocardial perfusion scintigraphy. Eur.J.Nucl.Med.Mol.Imaging 2005;32:60-69.

10. Miller TD, Rajagopalan N, Hodge DO, Frye RL, Gibbons RJ. Yield of stress single-photon emission computed tomography in asymptomatic patients with diabetes. Am.Heart J. 2004;147:890-896.

11. Janand-Delenne B, Savin B, Habib G, Bory M, Vague P, Lassmann-Vague V. Silent myocardial ischemia in patients with diabetes: who to screen. Diabetes Care 1999;22:1396-1400.

12. Penfornis A, Zimmerman C, Boumal D, Sabbah, Meneveau N, Gaultier-Bourgeois S, Bassand JP, Bernard Y. Use of dobutamine stress echocardiography in detecting silent myocardial ischaemia in asymptomatic diabetic patients: a comparison with thallium scintigraphy and exercise testing. Diabet Med 2001; 18:900-905.

13, Faglia E, Favales F, Calia P, Paleari F, Segalini G, Gamba PL et al. Cardiac events in 735 type 2 diabetic patients who underwent screening for unknown asymptomatic coronary heart disease: 5-year follow-up report from the Milan Study on Atherosclerosis and Diabetes (MiSAD). Diabetes Care 2002;25:2032-2036.

14. Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004;27:1954-1961.

15. Anand DV, Lim ETS, Hopkins D, Corder R, Sharp P, Lipkin DP, Lahiri A. Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion imaging. Eur H J 2006 (in press).



Box 1

ADA consensus guidelines for cardiac stress testing in diabetic patients
Modified from Diabetes Care 1998;21:1551-1559

Testing for CAD is warranted in patients with the following:

     1. Typical or atypical cardiac symptoms
     2. Resting electrocardiogram suggestive of ischemia or infarction
     3. Peripheral or carotid occlusive arterial disease
     4. sedentary lifestyle, age > 35 years, and plans to begin vigorous exercise program
     Asymptomatic individuals:
     5. Two or more of the risk factors listed below (a-e) in addition to diabetes
         a) Total cholestrol > 240 mg/dl, LDL cholesterol > 160 mg/dl, or HDL cholesterol
         < 35 mg/dl
         b) Blood pressure > 140/90 mmHg
         c) Smoking
         d) Family history of premature CAD
         e) Positive micro/macroalbuminura


Box 2

Inclusion criteria for the DIAD Study
From Diabetes Care 2004; 27: 1954-1961

     1. Type 2 diabetes mellitus, onset > 30 yrs, no history of ketoacidosis
     2. Age 50-75 years
     3. No history of coronary artery disease, no angina pectoris
     4. No history of congestive heart failure
     5. No clinical indication for stress testing
     6. No cardiac stress testing or coronary angiography in 3 yrs before enrolment
     7. Normal resting electrocardiogram


Box 3

Proposed screening algorithm for detecting silent CAD in symptomatic patients with type 2 diabetes mellitus

abbreviations: CAD=coronary artery disease, CT= computerized tomography, SPECT= single photon emission computerized tomography, Tc-99m= technetium-99m