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Prevalence of Asymptomatic CAD in Diabetes Mellitus

Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic Patient Richard Nesto, MD. Prevalence of Asymptomatic CAD in Diabetes Mellitus. Positive ETT. Positive Angiography. Koistinen MJ . BMJ 1990;301:92-95 . Type 2 Type 1 Controls

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Prevalence of Asymptomatic CAD in Diabetes Mellitus

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  1. Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic PatientRichard Nesto, MD

  2. Prevalence of Asymptomatic CAD in Diabetes Mellitus Positive ETT Positive Angiography Koistinen MJ. BMJ 1990;301:92-95. Type 2 Type 1 Controls Naka Met al. Am Heart J 1992;123:46-53. Type 2 Controls MiSAD Group. Am J Cardiol 1997;79:134-139. Type 2 Rutter MK et al. Am J Cardiol 1999;83:27-31. Type 2 w microalb Type 2 w/o microalb Le A et al. Am J Kidney Dis 1994;24:65-71. Type 1 Renal Transplant Holley JL et al. Am J Med 1991;90:563-570. Type 1 & 2 Renal Transplant n = 64 n = 72 n = 80 n = 142 n = 149 n = 925 n = 43 n = 43 36% 24% 9% 31% 30% 12.1% 65% 40% 58% 55% 9% 11% 9% 12.1% 5.3% 6.4% — — 35% 43% (thal201)

  3. Indications for Cardiac Testing in Diabetic Patients • Typical or atypical cardiac symptoms • Resting ECG suggestive of ischemia or infarction • Peripheral or carotid occlusive arterial disease • Sedentary lifestyle or plan to begin a vigorous exercise program • Two or more of the risk factors listed below - Total cholesterol >240 mg/dL, LDL cholesterol >160 mg/dL, or HDL cholesterol <35 mg/dL - Blood pressure >140/90 mmHg - Smoking - Family history of premature CAD - Positive micro/macroalbuminuria

  4. Factors Limiting Accuracy of Noninvasive "Stress" Tests for CAD • Hypertensive Cardiomyopathy • Diabetic Cardiomyopathy • Autonomic Cardiomyopathy • Renal Insufficiency • Microvascular Dysfunction

  5. Benefits of Early Detection of CAD • Implement more aggressive CHD prevention regimen • Initiate anti-ischemic medications • Identify patients who would benefit from revascularization • Educate patients to recognize coronary symptoms

  6. Blood Pressure and CVD: Framingham Heart Study MEN WOMEN No Glucose Intolerance Glucose Intolerance No Glucose Intolerance Glucose Intolerance 174 119 113 Age-adjusted CV Event Rate/1,000 Age-adjusted CV Event Rate/1,000 90 77 74 59 56 50 48 38 36 31 23 24 15 105 135 165 195 105 135 165 195 Systolic BP (mmHg) Systolic BP (mmHg) Kannel WB et al. Am Heart J 1991;121:1268-1273.

  7. Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS) Intensive Conventional (rate/1000 pt yrs) (rate/1000 pt yrs) %Decrease Endpoints P Any diabetes related* MI Stroke PVD Microvascular 40.9 14.7 5.6 1.1 8.6 46 17.4 5 1.6 11.4 0.029 0.052 0.52 0.15 0.0099 11 16 – – 25 * Combined microvascular and macrovascular events UKPDS Group. Lancet 1998;352:837-853.

  8. N = 2729 (%) Fatal MI or SD Cancer Other Fatal Stroke Renal Disease Accidents PVD Hypo- or Hyperglycemia 231 120 74 43 16 5 2 1 (8.4%) (4.4%) (2.9%) (1.6%) (0.6%) (0.2%) (0.07%) (0.04%) Reasons for Death in UKPDS Intensive Treatment Arm: 10-Year Follow-up Accidents, PVD, Hypo-& Hyperglycemia Renal 2.5% 3.3% 15% Other 47% MI or SD 24% Cancer 8.7% Stroke UKPDS Group. Lancet 1998;352:837-853.

  9. Effect of Blood Pressure Control in the UKPDSTight vs. Less Tight Control • 1,148 Type 2 patients • Average BP lowered to 144/82 mmHg (controls: 154/87);9-year follow-up Tight Control Risk Reduction (%) P value Any diabetes-related endpoint Diabetes-related deaths Heart failure Stroke Myocardial infarction Microvascular disease 24 32 56 44 21 37 0.0046 0.019 0.0043 0.013 NS 0.0092 UKPDS Group. BMJ 1998;317:703-713.

  10. UKPDS: ACE Inhibitor vs. Beta-blocker for HTNAggregate Clinical Endpoints Relative Risk & 95% CI RR p 0.5 1 2 Any diabetes-related endpoint Diabetes-related deaths All-cause mortalityMyocardial infarction Stroke Microvascular 1.10 1.27 1.141.20 1.12 1.29 0.43 0.28 0.440.35 0.74 0.30 FavorsACE inhibitor FavorsBeta blocker UKPDS Group. BMJ 1998;317:713-720.

  11. Systolic Hypertension in Europe (Syst-Eur) Trial: Effect of Systolic BP Control on All Cardiovascular Events at 2 Years 57.6 25% RiskReduction 62% RiskReduction Events / 1000 Pt-Years 31.4 23.5 22.0 Placebo Active Rx Placebo Active Rx DiabeticPatients NondiabeticPatients N=492; P=0.002 N=4,203; P=0.02 Tuomilehto J et al. NEJM 1999;340: 677-684.

  12. Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup Diastolic Target p<0.005 <90 mmHg (N=501) <85 mmHg (N=501) <80 mmHg (N=499) Events / 1000 Pt-Years p<0.016 p<0.045 Major CV Events MI CV Mortality Hansson L et al. Lancet 1998;351: 1755-1762.

  13. HOT Trial:Cardiovascular Events in Diabetics and Nondiabetics—Effect of Diastolic Target at 4 Years 48% RiskReduction 24.4 18.6 Events / 1000 Pt-Years 11.9 9.9 10.0 9.3 <90 <85 <80 <90 <85 <80 Diabetic Patientsn=1,501; p=0.016 Nondiabetic Patientsn=18,790; p=NS Hansson L et al. Lancet 1998;351: 1755-1762.

  14. Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/Total Results on CVD SHEP GISSI-3 Syst-Eur HOT UKPDS CAPPP 583/4736 2790/18,131 492/4695 1501/18,790 1148 572/10,985 Beneficial Beneficial Beneficial Beneficial Beneficial Beneficial SHEP = Systolic Hypertension in the Elderly Program; GISSI = Grupo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico; Syst-Eur = Systolic Hypertension in Europe; HOT = Hypertension Optimal Treatment; CAPPP = Captopril Prevention Project Curb JD et al. JAMA 1996;276:1886-1892; Zuanetti G et al. Circulation 1997;96:4239-4245; Staessen JA et al. Am J Cardiol 1998;82:20R-22R; Hansson L et al. Lancet 1998;351:1755-1762;UK Prospective Diabetes Study Group. BMJ 1998;317:703-713; Hansson L et al. Lancet 1999;353:611-616.

  15. Heart Outcomes Prevention Evaluation (HOPE) StudyEffect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~ 4.5 Yrs 24% RiskReduction 21% RiskReduction 19.8 16.4 15.0 % of Patients 13.0 Placebo Ramipril Placebo Ramipril DiabeticPatients NondiabeticPatients N=3,578, P=<0.001 N=5,719, P=<0.001 Hope Study Investigators. NEJM 2000;342:145-153.

  16. Diabetes Increases Risk of Coronary PlaqueDisruption and ThrombosisCause of Myocardial Infarction Platelet Aggregation Fibrinogen vWF F VII F VIII Coronary Artery PAI-1 TPA PGI2 Thrombus PlaqueFormation PlaqueDisruption Sympathetic Tone

  17. Impact of Serum Fibrinogen and Total Cholesterol Levels on Risk of Coronary Events in ECAT 21/305 16/304 11/266 10/281 3/247 Total Cholesterol Risk of Coronary Events (%) 5/311 9/261 10/282 Higher 4/306 Middle Lower Lower Middle Higher Fibrinogen Thompson SG. N Engl J Med 1995;332:635-641.

  18. Effect of Aspirin on Mortality in Type 2 Patients with CHD: Bezafibrate Infarction Prevention Study OR=0.7 (0.6-0.8) Nodiabetes Survival (%) OR=0.8 (0.7-0.9) Type 2diabetes No aspirin Aspirin 0 1 2 3 4 5 6 Time (Years) Harpaz D et al. Am J Med 1998;105:494-499.

  19. Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists’ Collaboration P<0.002 Antiplatelet Therapy Control P<0.00001 CVD Events (%) Diabetes No Diabetes Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106.

  20. 0 0 1 1 2 2 3 3 4 4 5 5 Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Total Cohort No Insulin – Low Risk 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 p = .0111 p = .004 n=314 n=133 Control Mortality Mortality Control n=306 n=139 Insulin-glucoseInfusion Insulin-glucoseInfusion Years in Study Years in Study Malmberg K et al. BMJ 1997;314:1512-1515.

  21. Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE) Diabetics (n=237) Nondiabetics (n=1512) Placebo Placebo Event Rate Event Rate Trandolapril Trandolapril Relative risk, 0.38 P<0.001 Relative risk, 0.81 P = 0.1 0 1 2 3 4 0 1 2 3 4 Years Years Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.

  22. Effect of Trandolapril on Secondary Endpoints in TRACE Interaction P Diabetics RR (95% CI) P Nondiabetics RR (95% CI) P End Point 0.01 0.01 0.08 <0.001 Cardiovascular death Sudden death Reinfarction Progression in CHF 0.79 (0.66-0.96) 0.84 (0.63-1.12) 0.93 (0.69-1.26) 0.81 (0.63-1.04) 0.17 0.09 0.15 0.03 0.56 (0.37-0.85) 0.46 (0.25-0.85) 0.55 (0.29-1.07) 0.38 (0.21-0.67) 0.02 0.23 0.65 0.10 CI = confidence interval; RR = relative risk. Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89.

  23. Effect of Diabetes on 30-Day Mortality: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) 2.7 Diabetes vs no diabetes(unadjusted) Adjusted for clinical variables Adjusted for angiographicvariables Adjusted for clinical &angiographic variables 2.1 2.4 2.0 0 1 2 3 4 5 Odds Ratio for 30-Day Mortality Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669.

  24. Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1) DM-PTCA DM-CABG Non DM-CABG Non DM-PTCA Mortality 0.25 0.18 0.08 0.07 0 1 2 3 4 5 Follow-up (years) Detre KM et al. N Engl J Med 2000;342:989-997.

  25. 0 0 1 1 2 2 3 3 4 4 5 5 Impact of PTCA vs. CABG on Mortality in BARI-1 Mortality in Patientswithout Q-MI Mortality in PatientsAfter Q-MI DM-PTCA DM-CABG Non DM-CABG Non DM-PTCA 0.79 Mortality Mortality 0.29 0.27 0.22 0.17 0.16 0.07 0.06 Follow-up (years) Years after Q-MI Detre KM et al. N Engl J Med 2000;342:989-997.

  26. 0 0 0 1 1 1 2 2 2 3 3 3 4 4 4 5 5 5 6 6 6 7 7 7 Impact of Diabetes on 7-year Survival in BARI All Patients 84.4 80.9 % Survival CABG (n=914) PTCA (n=915) p = 0.0425 Patients with Treated Diabetes Patients without Treated Diabetes 86.8 86.4 76.4 % Survival 55.7 % Survival CABG (n=180) PTCA (n=173) CABG (n=734) PTCA (n=742) p = 0.0011 p = 0.7155 Years BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129.

  27. 0 0 0 1 1 1 2 2 2 3 3 3 4 4 4 5 5 5 6 6 6 7 7 7 8 8 8 Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST) All EAST Patients 82.7 79.3 % Survival CABG (n=194) PTCA (n=198) p = 0.40 Treated Diabetic Patients Patients without Diabetes % Survival % Survival CABG (n=30) PTCA (n=29) CABG (n=164) PTCA (n=169) p = 0.23 p = 0.71 Years after Randomization King SB III et al. J Am Coll Cardiol 2000;35:1116-1121.

  28. 6-Month Angiographic Outcome after PTCA in Diabetes (377 Patients with 476 Lesions) Overall Restenosis Rate Total Occlusion 62% Restenosis(n = 237) Total Occlusion(n = 60) Patients (%) Lesions (%) 37% 49% 25% 11% 13% 1 Site 2 Sites 3 Sites Angiographic FU = 6 months PTCA Site(s) Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.

  29. Impact of Restenosis and Total Occlusion on LV Function in Diabetes Restenosis (–)Total Occlusion (–) Restenosis (+)Total Occlusion (–) Total Occlusion (+) (n = 297) (n = 237) (n = 60)  in EF (%) +0.5+9.9 -1.5+9.5 -6.2+9.9 p = ns p = ns p = 0.0001 Van Belle E et al. J Am Coll Cardiol 1999;34:476-485.

  30. Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in Diabetes 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0 p = 0.021df = 3, Log-rank Test 1997 Proportion Free of TVR Year 1994 1995 1996 1997 N 305 425 480 288 % Stent 17.4 24.9 41.0 55.5 1996 1995 1994 0 2 4 6 8 10 12 Months Post PTCA Rankin JM et al. Circulation 1998;98:I-79.

  31. 0 0 30 30 60 60 90 90 120 120 150 150 180 180 Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Benefit of Abciximab and Stenting in Diabetes on Reducing TVR Patients with Diabetes(n = 491) Patients without Diabetes(n = 1908) 18.4% Stent + Placebo Stent + Abciximab Angioplasty + Abciximab Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 14.6% Incidence of repeated TVR at 6 mos. (%) Incidence of repeated TVR at 6 mos. (%) 16.6% 9.0% 8.8% 8.1% Days after Randomization Days after Randomization Lincoff AM et al. N Engl J Med 1999;341:319-327.

  32. EPISTENT: Optimization of PTCA/Stent Outcomes with Platelet IIb/IIIa Inhibition 6-Month Death, MI for Diabetics 12.7% p = 0.029 7.8% % of Patients 6.2% Stent + Placebo Stent + Abciximab PTCA + Abciximab 0 30 60 90 120 150 180 Days Marso SP et al. Circulation 1999;100:2477-2484.

  33. Conclusions In patients with diabetes mellitus, there are numerous opportunities to reduce morbidity and mortality from CAD: • identify diabetic patients with particularly high risk for CAD and perform appropriate screening • aggressively identify and modify coronary risk factors • explore and implement treatment to protect the left ventricle from ischemic injury • maintain tight but judicious glycemic control in acute coronary syndromes • use medications proven to dramatically improve outcomes in acute MI (beta blockers, ACE inhibitors, aspirin, IIb/IIIa platelet inhibitors, statins)

  34. Future Directions • Additional clinical trials are needed to evaluate cardiovascular therapeutic interventions in diabetic patients, because certain therapies may produce different results in the presence of diabetes

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