ΔΙΑΒΗΤΗΣ ΚΑΙ ΣΙΩΠΗΡΗ ΙΣΧΑΙΜΙΑ. Δρ. ΛΑΦΑΡΑΣ ΧΡΗΣΤΟΣ

Transcription

1 ΔΙΑΒΗΤΗΣ ΚΑΙ ΣΙΩΠΗΡΗ ΙΣΧΑΙΜΙΑ Δρ. ΛΑΦΑΡΑΣ ΧΡΗΣΤΟΣ Διευθυντής Καρδιολογικού Τμήματος, Α.Ν.Θ Θεαγένειο, Θεσσαλονίκη ΔΕΚΕΜΒΡΙΟΣ 2015

2 Introduction The incidence of diabetes mellitus is increasing globally. WHO estimated there were 30 million people who had diabetes worldwide in 1985, increased to 217 million in 2005, and by the year 2030, it is predicted to at least 366 million Rathmann W, Giani G. Diabetes Care 2004; 27: CVD is the leading cause of morbidity and mortality who have a risk of cardiovascular mortality two to four times greater than that of people without diabetes The National Cholesterol Education Programme Adult treatment Panel III (NCEP-ATPIII) has listed diabetes as a CAD equivalent, which would obviate the need for risk stratification There is a high prevalence of asymptomatic CAD, and higher incidences of silent ischaemia and of atypical symptoms Lam T., et al. World J. Diabetes 2015; 6(4):

3 Introduction

4 Introduction Despite the known association between diabetes and coronary artery disease (CAD), the prevalence of silent CAD in patients with diabetes is varied Characteristics of the patients who should be screened for CAD need to be better defined Answer the following questions: - What is the prevalence of myocardial ischemia in high-risk asymptomatic patients with diabetes? - What is the rate of a first manifestation of CAD in patients without evidence of CAD at baseline? - What is the rate of progression to major adverse cardiac events or to persistent, treatment-refractory silent CAD?

5 Silent Ischemia Is typically defined as objective evidence of myocardial ischemia in patients without symptoms related to that ischemia May be detected in patients who have no symptoms during an exercise or pharmaceutical stress test but who do have transient ST-segment changes, perfusion defects, or reversible regional wall motion abnormalities May be detected with the use the Holter and implanted ECG monitor The combination of an increasing demand and an altered supply secondary to abnormal microvascular and endothelial response is a possible explanation for the mechanism of silent ischemia. Conti R., et al.j Am Coll Cardiol. 2012;59(5):

6 The vulnerable patient with diabetes Katharina Hess, et al. Eur Heart J Suppl 2012;14:B4-B13

7 Vulnerable vessel Katharina Hess, et al. Eur Heart J Suppl 2012;14:B4-B13

8 Vulnerable blood Katharina Hess, et al. Eur Heart J Suppl 2012;14:B4-B13

9 Vulnerable myocardium Katharina Hess, et al. Eur Heart J Suppl 2012;14:B4-B13

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11 Sequence of Events Following myocardial Ischemia Conti R., et al. J Am Coll Cardiol. 2012;59(5):

12 Glycaemic continuum and cardiovascular disease Hyperglycaemia, insulin resistance, and cardiovascular disease Authors/Task Force Members et al. Eur Heart J 2013;34:

13 Diabetic cardiovascular autonomic neuropathy (CAN) resulting in damage to the neural fibres responsible for innervation of the heart include coronary vessels may lead to silent ischemia and/or atypical clinical manifestations Predictor of all cause and cardiovascular mortality Average prevalence in diabetics 30% Lam T, et al.world J Diabetes 2015 ; 6(4):

14 Factors Affecting Cardiac Autonomic Neuropathy poor glycemic control duration of diabetes diabetic retinopathy peripheral neuropathies diabetic nephropathy other diabetic complications

15 Clinical Manifestations Resting Tachycardia Exercise Intolerance Loss of Heart Rate Variability With Deep Breathing Orthostatic Hypotension Silent Myocardial Ischemia or Infarct QT Abnormalities Intraoperative Cardiovascular Instability Hypertension Sudden Death Syndrome

16 Prevalence of Asymptomatic CAD in Diabetes

17 Prevalence of Asymptomatic CAD in Diabetes Selection of patients Detection modalities Even with the wide range in prevalence of asymptomatic CAD (20-60%), asymptomatic CAD has a high prevalence in individuals with DMII

18 Risk Stratification Table 1. Clinical features suggesting diabetes patients at high risk Diabetes and age > 60 yr Diabetes and microalbuminuria (> 20 mcg/min or urine albumin to creatinine ratio > 2.5 mg/mmol for males, > 3.5 mg/mmol for females) Diabetes and moderate or severe chronic kidney disease (persistent proteinuria or egfr < 45 ml/min per 1.73 m2) Diabetes and a previous diagnosis of familial hypercholesterolaemia in the individual Diabetes and systolic blood pressure 180 mmhg or diastolic blood pressure 110 mmhg Diabetes and serum total cholesterol > 130mg/dl Albumin to creatinine ratio - confirmed on second test and not due to another cause (e.g., urinary tract infection). Table 2. Signs and symptoms of concern in an otherwise asymptomatic patient Symptoms suggestive of cardiovascular autonomic neuropathy Signs/symptoms suggestive of coexisting vascular disease - Erectile dysfunction - Claudication symptoms - Carotid bruit - Diminished/absent peripheral pulses - Inappropriate exercise tolerance

19 Choice of Investigation for Risk Stratification in Diabetics Depends on factors: - mobility - exercise tolerance - plans for future increases in exercise - gender Factors influencing selection of provocative testing are similar between diabetic and non-diabetic patients: - availability - sensitivity and specificity - risk. Specific differences in each modality performance accuracy in terms of sensitivity and specificity in patients with diabetes

20 Provocative Testing Gender effects - Pathophysiology of CAD can differ between males and females - Detection of disease in women more difficult given the lower likelihood of obstructive coronary disease and apparently lower levels of clinical suspicion - Provocative tests are both less sensitive and less specific in women - Ultimate decision may be limited by cost and local expertise Kohli P, et al. Circulation 2010; 122: Berman DS, et al. J Am Coll Cardiol 2003; 41:

21 Provocative Testing Sensitivity and specificity of provocative tests in patients with diabetes Diagnostic test Sensitivity (%) Specificity (%) Exercise stress test Stress echo Stress nuclear perfusion study CT coronary angiogram Coronary calcium score Sensitivity and specificity of provocative testing in women Diagnostic test Sensitivity (%) Specificity (%) Exercise electrocardiogram Exercise echo Pharmacological echo Nuclear perfusion study Computed tomography coronary angiogram

22 Provocative Testing Stress testing - Similar predictive value between diabetic and non-diabetics - Sensitivity is variable, and in some studies is less than 50% - A positive test will identify the majority of patients with left main or significant multi-vessel coronary artery disease - Many diabetic patients with obesity, peripheral neuropathy, decreased physical conditioning or other co-morbidities are unable to exercise long enough to determine low cardiovascular risk - Suboptimal for patients with diabetes who are unlikely to be able to reach an appropriate workload owing to co-morbidities and in women Lee DP, et al. Chest 2001; 119: Koistinen MJ, et al. Br Heart J 1990; 63: 7-11

23 Provocative Testing Stress contrast echocardiography - Greater diagnostic accuracy - Regional wall motion abnormalities - Asymptomatic ventricular dysfunction - Data regarding diagnostic accuracy of stress echo specifically in diabetic populations is relatively limited - Sensitivity of 82% but a specificity of only 54%, positive predictive value was 84% with a poor negative predictive value of 50% - Availability may be limited by cost and operator expertise Lam T, et al.world J Diabetes 2015 ; 6(4): Hennessy TG, et al. Coron Artery Dis 1997; 8:

24 Provocative Testing Nuclear perfusion scans - The most widely investigated modality for the detection of CAD in diabetic patients - Can be performed with exercise, or in subjects with limited exercise capacity with other modalities to increase coronary flow such as adenosine - Asymptomatic diabetic patients: SPECT imaging, positive test results for CAD in 22-58% - 41% of these patients with abnormal imaging findings no usual criteria for further investigation of CAD Kang X,et al. Am Heart J 1999; 137: Wackers FJ, et al. Diabetes Care 2004;27:

25 Provocative Testing the extent and severity of perfusion abnormalities exceeds that predicted by coronary angiography in diabetic patients (40% of the patients with high-risk MPI had mild angiographic CAD) Rajagopalan N, et al. J Am Coll Cardiol 2005;45:43-9 Normal stress SPECT is associated with higher risk in diabetic compared to nondiabetics Zellweger MJ, et al. Eur Heart J 2004;25: Hachamovitch R, et al. J Am Coll Cardiol 2003;41: Scans expose patients to ionizing radiation and should only be used in those whom the benefits outweigh the risks Greenland P,et al. J Am Coll Cardiol 2010;56:e50-103

26 Provocative Testing Computed tomography coronary angiogram (CTCA)/Coronary calcium score - Information on the vascular lumen and the arterial wall - Reduced sensitivity and specificity in diabetic due to differences in artifacts and calcification vs non-diabetic patients - Significant stenosis can occur in the absence of calcification, so coronary calcium score should not be used in isolation - Asymptomatic diabetic patients with high coronary artery calcium scores, high prevalence of inducible ischaemia on stress imaging (CAC score>400) Van Werkhoven JM, et al. Radiology 2010; 256: Andreini D, et al. Cardiovasc Diabetol 2010; 9: 80 Maffei E, et al. Eur Radiol 2011; 21:

27 Provocative Testing Proportions of patients with an event with increasing time since recruitment into the PREDICT study in successive coronary artery calcification score categories (Agatston units). Robert S. E., et al. Eur Heart J 2008;29:

28 Provocative Testing Coronary calcium score

29 Provocative Testing CAC score >400 should be further evaluated using other imaging modality to assess myocardial perfusion or wall motion abnormalities ACCF/AHA/ESC guidelines for assessment of cardiovascular risk in asymptomatic adults, CAC score measurement can be used for CV risk assessment in asymptomatic diabetics >40 years (class IIa, level of evidence B) Bax JJ,et al. Diabetes Care 2007;30: Greenland P, et al. J Am Coll Cardiol 2010;56:e Lam T, et al.world J Diabetes 2015 ; 6(4):

30 Provocative Testing Magnetic Resonance Imaging (MRI) - a non-invasive coronary angiogram - provide functional (myocardial perfusion) and anatomical (ventricular function, wall motion) information without radiation exposure Coupling of non-invasive imaging of coronary arteries with pharmacological stress test to assess the intensity and location of ischemia could make MRI the gold standard for CAD detection (stress MRI)

31 Provocative Testing Greenwood JP, et al. Lancet 2012;379:453-60

32 Studies on Screening for asymptomatic CAD in Diebetes

33 Studies on Screening for asymptomatic CAD in Diebetes Prevalence and characteristics of abnormal single-photon emission computed tomography scans in diabetic patients without evidence of coronary artery disease: data from the DIAD (Detection of Silent Myocardial Ischemia in Asymptomatic Diabetics) study.

34 Studies on Screening for asymptomatic CAD in Diebetes

35 Studies on Screening for asymptomatic CAD in Diebetes DIAD STUDY 22% had myocardial perfusion defects with 6% comprising moderate or large perfusion defects 79% of the 71 individuals (out of 358) with initial MPI abnormalities had resolution of ischemia at three-year (risk factor reduction with increased use of ACE inhibitors, statins and aspirin) 10% of the individuals with normal initial MPI had abnormal MPI Wackers FJ, et al. Diabetes Care 2004;27: Young H, et al. JAMA 2009;301: Bansal S, et al. Diabetes Care 2011;34:204-9

36 (A) Prevalence of one-, two-, or threevessel coronary artery disease (CAD) in type 2 diabetes mellitus (DM2) patients with myocardial perfusion abnormalities at stress myocardial contrast echocardiography and two or more associated risk factors (RF). Scognamiglio R, et al. Am Coll Cardiol 2007;47:65-71.

37 Studies on Screening for asymptomatic CAD in Diebetes Dhakshinamurthy A., et al. Eur Heart J 2006;27:

38 Studies on Screening for asymptomatic CAD in Diebetes Prospective study used coronary artery calcium (CAC) score and SPECT MPI to determine the rate of silent ischemia in DMII: - CAC score better predictor of silent ischemia and short-term cardiovascular events than established cardiovascular risk factors - CAC and MPI can be used synergistically to predict adverse cardiovascular events but the effect on clinical outcome of patients is unknown Anand DV, et al. Eur Heart J 2006;27: Do not make a strong argument for screening asymptomatic diabetics for CAD due to failure to show improved outcomes from screening for silent ischemia

39 Studies on Screening for asymptomatic CAD in Diebetes Zellweger M., et al. BARDOT Trial. JACC: Cardiovascular Imaging 2014:

40 Studies on Screening for asymptomatic CAD in Diebetes Zellweger M., et al. BARDOT Trial. JACC: Cardiovascular Imaging 2014:

41 Studies on Screening for asymptomatic CAD in Diebetes Zellweger M., et al. BARDOT Trial. JACC : Cardiovascular Imaging 2014:

42 Studies on Screening for asymptomatic CAD in Diebetes - If diabetics are clinically at high risk of CAD as in BARDOT, they should be considered for ischemia testing. - If there is no evidence of CAD as in about 80% of them, the 2-year outcome will be benign without further anti-ischemic therapy and no need for repeat testing within 4 to 5 years. - 20% of patients with abnormal MPS, antiischemic therapy should be advised because every third patient will experience MACE or therapy refractory silent CAD. - The optimal type of therapy is still open to debate. - An appropriately sized randomized controlled trial is needed to settle this question. Zellweger M., et al. BARDOT Trial. JACC : Cardiovascular Imaging 2014:

43 Should we screen asymptomatic patients? Studies have shown the prevalence of asymptomatic CAD to be 20-60% in diabetics Before screening can be recommended, certain criteria should be met: - prevalence of CAD in the population should be high - screening test should accurately differentiate between low and high risk patient - identification of individuals with disease should lead to treatment with better outcomes - the screening strategy must be cost-effective

44 Should we screen asymptomatic patients? Diabetes is already established as a CAD risk equivalent, screening for CAD will not alter optimal medical treatment The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial did not show a reduction in the risk of death, myocardial infarction, or other major cardiovascular events with PCI in addition to optimal medical therapy (33% diabetics, SCAD) The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study showed that compared to intensive medical therapy alone, prompt coronary revascularization in addition to intensive medical therapy did not reduce all-cause mortality A post hoc analysis of the high-risk participants in DIAD study found that annual cardiac event rate was not altered by routine screening for silent ischemia Bansal S, et al. Diabetes Care 2011;34:204-9 Boden WE, et al. N Engl J Med 2007;356: Group BDS, et al. N Engl J Med 2009;360:

45 Should we screen asymptomatic patients? - Lack of evidence of improved outcomes in asymptomatic diabetic patients to supports screening for silent ischemia - A stepwise screening with CAC score followed by SPECT, if necessary, is reasonable and may allow for optimal risk stratification of asymptomatic diabetics

46 Suggested algorithm for investigation of CVD in Diabetics Lam T et al. World J Diabetes 2015; 6(4):

47 Investigational algorithm outlining the principles for the diagnosis and management of CVD in DM patients with a primary diagnosis of DM or a primary diagnosis of CVD. Authors/Task Force Members et al. Eur Heart J 2013;34: The recommended investigations should be considered according to individual needs and clinical judgement and are not meant as a general recommendation to be undertaken by all patients

48 Management of Diabetics /SMI ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD Eur Heart J. 2013;34(39):

49 Management of Diabetics /SMI

50 Management of Diabetics /SMI

51 Management of Diabetics /SMI

52 Management of Diabetics /SMI

53 Management of Diabetics /SMI ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD Eur Heart J. 2013;34(39):

54 Management of Diabetics /SMI ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD Eur Heart J. 2013;34(39):

55 Management of Diabetics /SMI ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD Eur Heart J. 2013;34(39):

56 Take home messages Individualized approach Risk stratification is of great value patients with DM Routine screening for CAD is controversial Characteristics of the patients who should be screened for CAD need to be better defined Further evidence is needed to support screening for SMI in all high-risk patients with DM May be performed in patients at a particularly high risk, such as those with evidence of peripheral artery disease (PAD) or high CAC score or with proteinuria, and in people who wish to start a vigorous exercise program