This article has Open Peer Review reports available.
Assessment of dipyridamole stress echocardiography for risk stratification of diabetic patients
© Baroncini et al. 2015
Received: 12 May 2015
Accepted: 21 July 2015
Published: 25 July 2015
Despite advances in medical therapy, cardiovascular disease, mainly coronary artery disease (CAD), remains the leading cause of mortality among patients with diabetes mellitus (DM). The objective of the present study was to assess the effectiveness of dipyridamole stress echocardiography in identify diabetic patients at high risk for cardiovascular events.
Dipyridamole stress echocardiography was administered to 483 diabetic patients (294 women; mean age 63.41 ± 11.28 years) between July 2006 and December 2012.
Follow-up data were available for 264 patients (163 women; mean age 64.3 ± 10.5 years): 250 with a negative stress echocardiography and 14 with a positive stress echo. During a mean follow-up time of 18 ± 14 months, a cardiovascular event occurred in 18 (6.8 %) patients, 12 (4.8 %) in patients with a negative stress echo (n = 250) during a mean follow-up period of 20 ± 16 months and 6 (42 %) in patients with positive stress echo (n = 14) during a mean follow-up of 13 ± 13 months. The positive and negative predictive values of stress echocardiography were 42 % and 96 % respectively. The accuracy value was 92 %. A Cox regression model showed that CAD (hazard ratio [HR] 5.4, 95 % confidence interval [CI] 1.9-15.4; p = 0.002) and positive stress echocardiography (HR 7.1, 95 % CI 2.5-20.5; p < 0.001) were significant predictors of cardiovascular events.
For patients with diabetes, a negative dipyridamole stress echocardiogram predicts favorable outcome during the first year of follow-up. A new stress imaging test should be done after 12 months in diabetic patients.
Despite advances in medical therapy, cardiovascular disease, mainly coronary artery disease (CAD), remains the leading cause of mortality among patients with diabetes mellitus (DM). Indeed, DM has been classified as a coronary heart disease equivalent by both the American Heart Association and American College of Cardiology [1, 2]. In addition, diabetes is associated with a higher rate of progression of coronary lesions, coronary occlusion, plaque ulceration, thrombosis, and formation of new luminal narrowing, which suggests that the features of vascular disease are different in diabetic and nondiabetic patients . The challenge is to identify these high-risk patients early in their disease using noninvasive imaging methods. In a study assessing 1123 patients with type 2 diabetes and no symptoms of CAD , the participants were randomly assigned to be, or not to be, screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI). The authors concluded that the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years. However, the negative predictive value of stress echocardiography is thought to be lower in patients with DM. Diabetic patients with a normal stress echocardiogram have a higher risk for subsequent cardiovascular events than nondiabetic patients, especially in the second year after undergoing stress echocardiography [5, 6]. Unlike a normal or negative stress echocardiography, a positive echo stress test, or one which detects ischemia, enables the identification of patients at greater risk of cardiac events [7, 8]. Moreover, diabetic patients are more likely to have diffuse distal vascular disease. In these patients regional wall motion abnormalities of the left ventricle are harder to identify by stress echocardiography, because the reduced perfusion is global instead of regional [8–13]. Now there are new ultrasound imaging modalities that can identify early changes in the myocardium [13, 14]; however these modalities are not accessible to all patients and private clinics and routine screening of millions of asymptomatic diabetic patients would be prohibitively expensive. Most physicians use less expensive tests such as the electrocardiographic (EKG) exercise test and pharmacological stress echocardiography to stratify their patients’ risk. Therefore, the purpose of this study was to assess the effectiveness of dipyridamole stress echocardiography in identify diabetic patients at high risk for cardiovascular events.
Patients’ baseline characteristics
Age (y ± SD)
63.41 ± 11.28
64.3 ± 10.5
History of hypertension (N/%)
407 (84 %)
223 (84.5 %)
History of dyslipidemia (N/%)
329 (68 %)
181 (68.6 %)
Coronary artery disease (N/%)
68 (14 %)
37 (14 %)
Current smoking (N/%)
51 (10 %)
29 (11 %)
Altered/insufficient exercise stress testing (N/%)
132 (27 %)
70 (26 %)
1Altered EKG (N/%)
30 (6 %)
19 (7 %)
Indications for pharmacologic stress echo
264 - N(%)
Routine clinical and imaging follow-up
123 (25 %)
72 (27 %)
107 (22 %)
58 (22 %)
Perioperative risk stratification
76 (15 %)
41 (15 %)
Evaluation of known coronary artery disease
69 (14 %)
37 (14 %)
Altered resting EKG
30 (6 %)
19 (7 %)
18 (4 %)
12 (4 %)
Altered/insufficient exercise stress testing (N/%)
132 (27 %)
70 (26 %)
Follow-up data were obtained after a minimum of 6 months from telephone interviews with the patient or a close relative, or contact with the patient’s physician. The cardiovascular events recorded during the follow-up period were fatal and nonfatal myocardial infarction, unstable angina that required hospitalization, coronary revascularization procedures (surgery or angioplasty), and sudden death.
Stress echocardiography protocol
An accelerated high-dose dipyridamole protocol was used for all patients. Dipyridamole was infused intravenously at a dose of 0.84 mg/kg body weight over 6 min. Aminophylline was routinely administered to patients with negative findings 10 min after the initiation of the test. Two-dimensional echocardiography and 12-lead electrocardiography (EKG) were used for continuous monitoring during the test and the recovery phase. Blood pressure measurements using a cuff were recorded every minute. Echocardiographic images were semiquantitatively assessed using a 17 segments, 4-point scale model of the left ventricle. 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). Inotropic reserve was defined as any improvement of WMSI during stress in the absence of inducible ischemia. Necrotic pattern was akinetic or diskinetic myocardium with no thickening during stress. An hypokinetic segment that did not worsen during ischemic challenge was considered a rest wall motion abnormality (WMA). A test was normal in case of no rest and stress WMA. A test was considered positive for ischemia when at least 2 adjacent segments of the same vascular territory showed an increment of WMSI (worsening or regional function) of at least 1 point at peak stress . The following criteria were used for a premature interruption of the test: onset of obvious new wall motion abnormalities, severe chest pain, horizontal or downsloping ST-depression ≥ 2 mm, ST-segment elevation ≥ 1.5 mm, symptomatic hypotension and/or bradycardia, supra-ventricular or ventricular tachyarrythmias, and intolerable symptoms. Intravenous aminophylline (up to 240 mg) was immediately available to reverse the effects of dipyridamole. As recommended by Dal Porto et al. , each patient’s intravenous cannula remained in situ for 1 h after the stress test in the event of a late event occurring after the procedure. All the tests were performed by the same echocardiographer, who had more than 15 years of experience.
Quantitative variables were expressed as mean, median, and standard deviation, and qualitative variables as frequencies and percentages. Positive and negative predictive values and accuracy were calculated according to standard formulas. Kaplan-Meier survival estimations were performed for age, hypertension, smoking, CAD, and results of stress testing. The log-rank test was used to compare survival curves. An adjusted Cox regression model was used for multivariate analysis of variables, considering stress echo result and the presence of CAD as explanatory variables, with p-values <0.05. P-values <0.05 indicated statistical significance. Data were analyzed using the software program SPSS v. 20.0.
Stress echocardiography result
Two-hundred fifty patients had presented negative dipyridamole stress echocardiography results. Of the 14 patients (5 %, n = 264) with positive stress echocardiography, 7 had undergone the procedure as a routine clinical and imaging follow-up, 5 for chest pain, 1 for an inconclusive exercise EKG test, and 1 for heart failure. Of the 70 patients who had undergone an exercise EKG test before pharmacological stress echocardiography, only 1 presented positive dipyridamole stress test and 3 patients developed a cardiovascular event during the follow-up period.
Risk of cardiovascular events according to Cox regression model for multivariate analysis
HR (IC 95 %)
Age ≥ 65
Coronary artery disease
Positive stress echo
The utility of stress testing modalities for asymptomatic diabetic patients remains an area of active interest and study. Diabetic patients have significantly higher rates of silent ischemia than the general population, and that could in part explain the more advanced CAD seen on initial presentation and the worse outcomes in these patients . The absence of myocardial ischemia on noninvasive tests of patients with DM does not necessarily identify a lower-risk cohort. In the present study most of patients (250) had a negative stress echo and presented 4.8 % of cardiovascular event during the follow-up period. This may be related, at least in part, to the observation that diffuse coronary dysfunction in diabetic patients precedes overt atherosclerosis and regional wall motion abnormalities of the left ventricle are harder to identify by stress echocardiography, because the reduced perfusion is global instead of regional [1, 8–13]. Thus, the current guidelines recommend that all diabetic patients should be treated as if they have CAD with regard to blood pressure management, lipid-level goals, and other secondary preventive measures. Clinicians should make efforts to stratify the long-term risk of CAD-associated morbidity and mortality in diabetic patients in order to identify those patients who need more aggressive treatment strategies. The guidelines of the American College of Cardiology/American Heart Association and the American Diabetes Association recommend screening for CAD in diabetic patients with an abnormal resting EKG indicating myocardial infarction, with carotid or peripheral arterial disease, symptoms suggesting CAD, or 2 or more cardiovascular risk factors irrespective of the presence of CAD symptoms [21–22]. However, as seen in this study, these guidelines do not seem to satisfy physicians regarding the risk stratification of diabetic patients. Our results showed that 25 % of patients underwent pharmacological stress echocardiography with the only indication being that they had DM and stress echo is a safe procedure . The annual rate of hard events occurring in diabetic patients with a normal stress echocardiogram ranges from 1.6 % to 6 %, whereas the corresponding rate in nondiabetic patients ranges from 0.6 % to 2.7 %. In addition, in patients with DM the event rate increases sharply in the second year after the procedure . In our study, 4.8 % of patients had an event during a mean follow-up period of 18 ± 14 months in patients with a negative stress test, most occurring 1 year after the test. By contrast, among those patients with a positive stress test, there were about 4-fold more events during a mean follow-up of 13 ± 13 months. These findings are similar to other studies [12, 25–26]. Cortigiani et al.  compared the prognostic value of pharmacologic stress echocardiography in chest pain patients with and without DM, (mean age 60 ± 10 years) and positive exercise electrocardiography. During a median follow-up of 26 months, the results of stress echocardiography added prognostic value to the positive exercise electrocardiography results. Both diabetic and nondiabetic patients with nonischemic stress echocardiography results had lower annual rates of major events compared with the overall population of diabetic and nondiabetic patients with positive electrocardiography results. However, in our study, most patients did not undergo exercise stress testing before pharmacological stress echocardiography. Patients referred for pharmacological stress echocardiography have been found to have a higher risk for cardiovascular events than those referred for exercise testing, which likely reflects more severe underlying cardiovascular disease and comorbidities . When our patients were asked why they did not undergo an EKG exercise stress test before the pharmacological stress test, most answered that their private physician asked directly for a pharmacological test regardless of whether they could undergo an exercise test. Of the 70 patients who underwent exercise EKG testing before pharmacological echocardiography only 1 had a positive dipyridamole stress test and we found only three cardiovascular events during the follow-up period in these patients. It appears that physicians simply do not believe that an exercise test is adequate for stratifying their diabetic patients. In our study, the time to occurrence of cardiovascular events was significant shorter in patients with a positive echocardiography stress test compared to patients with a negative stress test (13.7 ± 13.2 versus 20.7 ± 16.6 months, respectively). However, most cardiovascular events, regardless of the results of stress testing, occurred around 18 months after the procedure, which suggests that patients with DM should undergo another imaging stress test 12 months after their first test. In a study assessing long-term outcomes of patients with diabetes (N = 230) and limited exercise capability, dobutamine stress echocardiography provided prognostic value for about 7 years after the initial test . However, in both that study and our study, the lack of data on the duration of diabetes is an important shortcoming. In addition, the socioeconomic background of the 2 study cohorts may be different, and that factor can affect the prognosis and evaluation of the disease.
The main limitations of this study include: (1) loss of > 50 % of patients in the follow-up period; (2) lack of information about each patients’ diabetes time course or renal function; (3) unknown exact number of subjects under anti-ischemic medical therapy; and (4) lack of data on patients’ blood pressure control and medication. These limitations could significantly influence our analysis and discussion and may have impacted the results of this study [28–34].
A negative dipyridamole echocardiography test in diabetic patients predicts favorable outcome for the first year of follow-up. A new stress imaging test should be done after 12 months in diabetic patients.
- Murthy VL, Naya M, Foster CR, Gaber M, Hainer J, Klein J, et al. Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus. Circulation. 2012;126:1858–68.View ArticlePubMedPubMed CentralGoogle Scholar
- Oliveira JLM, Barreto-Filho JAS, Oliveira CRP, Santana TA, Anjos-Andrade FD, Alves EO, et al. Prognostic value of exercise echocardiography in diabetic patients. Cardiovascular Ultrasound. 2009;7:24.Google Scholar
- Hung MJ, Wang CH, Cherng WJ. Can dobutamine stress echocardiography predict cardiac events in nonrevascularized diabetic patients following acute myocardial infarction? CHEST. 1999;116:1224–32.View ArticlePubMedGoogle Scholar
- Young LH, Wacker FJT, Chyun DA, Davey JA, Barrett EJ, Taillefer R, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes. The DIAD study: a randomized controlled trial. JAMA. 2009;301:1547–55.Google Scholar
- Cortigiani L, Bigi R, Sicari R, Landi P, Bovenzi F, Picano E. Prognostic value of pharmacological stress echocardiography in diabetic and nondiabetic patients with known or suspected coronary artery disease. JACC. 2006;47:605–10.View ArticlePubMedGoogle Scholar
- Kamalesh M, Matorin R, Sawada S. Prognostic value of a negative stress echocardiographic study in diabetic patients. Am Heart J. 2002;143:163–8.View ArticlePubMedGoogle Scholar
- Cortigiani L, Borelli L, Raciti M, Bovenzi F, Picano E, Molinaro S, et al. Prediction of mortality by stress echocardiography in 2835 diabetic and 11305 nondiabetic patients. Circ Cardiovasc Imaging. 2015;8(5):002757.View ArticleGoogle Scholar
- Chaowalit N, Arruda AL, McCully RB, Bailey KR, Pellikka P. Dobutamine stress echocardiography in patients with diabetes mellitus. J Am Coll Cardiol. 2006;47:1029–36.View ArticlePubMedGoogle Scholar
- Galderizi M, Raia R. Reduction of coronary flow reserve in a patient with type 2 diabetes mellitus without epicardial coronary stenosis. Heart Metab. 2009;45:30–3.Google Scholar
- Camici PG, Crea F. Medical progress: Coronary microvascular dysfunction. NEJM. 2007;356:830–40.View ArticlePubMedGoogle Scholar
- Pitkãnen OP, Nuutila P, Raitakari OT, Rönnemaa T, Koskinen PJ, Iida H, et al. Coronary flow reserve is reduced in young men with IDDM. Diabetes. 1998;47:248–54.View ArticlePubMedGoogle Scholar
- Albers AR, Krichavsky MZ, Balady GJ. Stress testing in patients with diabetes mellitus, Diagnostic and prognostic value. Circulation. 2006;113:583–92.View ArticlePubMedGoogle Scholar
- Cognet T, Vervueren PL, Dercle L, Bastié D, Richaud R, Berry M, et al. New concept of myocardial longitudinal strain reserve assessed by a dipyridamole infusion using 2D-strain echocardiography: the impact of diabetes and age, and the prognostic value. Cardiovasc Diabetol. 2013;12:84.View ArticlePubMedPubMed CentralGoogle Scholar
- Mohty D, Pibarot P, Echahidi N, Poirier P, Dagenais GR, Dumesnil JG. Reduced systemic arterial compliance measured by routine Doppler echocardiography: A new and independent predictor of mortality in patients with type 2 diabetes mellitus. Atherosclerosis. 2012;225:353–8.View ArticlePubMedGoogle Scholar
- Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology. J Hypertens. 2013;31:1281–357.View ArticlePubMedGoogle Scholar
- Jonas MA, Oates JA, Ockene JK, Hennekens CH. Statement on smoking and cardiovascular disease for health care professionals. Circulation. 1992;86:1664–9.View ArticlePubMedGoogle Scholar
- Stone NJ, Robinson JG, Lichtenstein AH, Merz CNB, Blum CB, Eckel RH, et al. 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129(suppl2):S1–S45.View ArticlePubMedGoogle Scholar
- Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, et al. Stress echocardiography expert consensus statement from European Association of Echocardiography. Eur J Echocardiogr. 2008;9:415–37.View ArticlePubMedGoogle Scholar
- Dal Porto R, Faletra F, Picano E, Pirelli S, Moreo A, Varga A. Safety, feasibility, and diagnostic accuracy of accelerated high-dose dipyridamole stress echocardiography. Am J Cardiol. 2001;87:520–4.View ArticlePubMedGoogle Scholar
- Albers AR, Krichavsky MZ, Balady GH. Contemporary reviews in Cardiovascular Medicine. Stress testing in patients with diabetes mellitus. Diagnostic and prognostic value. Ciculation. 2006;113:583–92.View ArticleGoogle Scholar
- Anand DV, Lim E, Lahiri A, Bax JJ. The role of non-invasive imaging in the risk stratification of asymptomatic diabetic subjects. Eur Hear J. 2006;27:905–12.View ArticleGoogle Scholar
- Chopra S, Peter S. Screening for coronary artery disease in patients with type 2 diabetes mellitus: An evidence-based review. Indian J Endocr Metab. 2012;16:94–101.View ArticleGoogle Scholar
- Elhendy A, van Domburg RT, Poldermans D, Bax JJ, Nierop PR, Geleijnse ML, et al. Safety and feasibility of dobutamine-atropine stress echocardiography for the diagnosis of coronary artery disease in diabetic patients unable to perform an exercise stress test. Diabetes Care. 1998;21:1797–802.View ArticlePubMedGoogle Scholar
- Bigi R, Desideri A, Cortigiani L, Baxx JJ, Celegon L, Fiorentini C. Stress echocardiography for risk stratification of diabetic patients with known or suspected coronary artery disease. Diabetes Care. 2001;24:1596–601.View ArticlePubMedGoogle Scholar
- D’Andrea A, Severino S, Caso P, De Simone L, Liccardo B, Forni A, et al. Prognostic value of pharmacological stress echocardiography in diabetic patients. Eur J Echocardiography. 2003;4:202–8.View ArticleGoogle Scholar
- van der Sijde JN, Boiten HJ, Sozzi FB, Elhendy A, van Domburg RT, Schinkel AFL. Long-term prognostic value of dobutamine stress echocardiography in diabetic patients with limited exercise capability, A 13-year follow-up study. Diabetes Care. 2012;35:634–9.View ArticlePubMedPubMed CentralGoogle Scholar
- UK Prospective. Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1999;318:29.Google Scholar
- Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–62.View ArticlePubMedGoogle Scholar
- Zanchetti A, Hansson L, Clement D, Elmfeldt D, Julius S, Rosenthal T, et al. HOT Study Group, Benefits and risks of more intensive blood pressure lowering in hypertensive patients of the HOT study with different risk profiles: does a J-shaped curve exist in smokers? J Hypertens. 2003;21:797–804.View ArticlePubMedGoogle Scholar
- Campbell NRC, Gilbert RE, Leiter LA, Larochelle P, Tobe S, Chockalingam A, et al. Hypertension in people with type 2 diabetes. Can Fam Physician. 2011;57:997–1002.PubMedPubMed CentralGoogle Scholar
- The ACCORD Study Group. Effects of intensive blood-pressure control in Type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.View ArticlePubMed CentralGoogle Scholar
- Schemthaner G, Drexel H, Rosenkranz AR, Schemthaner GH, Watschinger B. Austrian Diabetes Association. Antihypertensive therapy in diabetes mellitus – 2012 guidelines of the Austrian Diabetes Association. Wien Klin Wochenschr. 2012;124 suppl 2:23–7.View ArticleGoogle Scholar
- Authors/Task Force Members, Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34:3035–3087Google Scholar
- Stults B, Jones RE. Management of hypertension in diabetes. Diabetes Spectrum. 2006;19:25–31.View ArticleGoogle Scholar
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.