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Clinical Evaluation and Nonlipid Treatment of Coronary Artery Disease in the Diabetic Patient Richard Nesto, MD Prevalence of Asymptomatic CAD in Diabetes Mellitus Positive Positive Koistinen MJ. BMJ 1990;301:92-95. Type 2 Type 1 Controls Naka M et 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 ETT Angiography n = 64 n = 72 n = 80 36% 24% 9% 9% 11% 9% n = 142 n = 149 31% 30% 12.1% 5.3% n = 925 12.1% n = 43 n = 43 65% 40% 6.4% (thal201) — — 58% 35% 55% 43% 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 Factors Limiting Accuracy of Noninvasive "Stress" Tests for CAD Hypertensive Cardiomyopathy Diabetic Cardiomyopathy Autonomic Cardiomyopathy Renal Insufficiency Microvascular Dysfunction 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 MEN 180 No Glucose Intolerance 160 140 174 Glucose Intolerance 120 119 100 90 80 77 60 40 20 0 59 50 38 24 105 135 165 Age-adjusted CV Event Rate/1,000 Age-adjusted CV Event Rate/1,000 Blood Pressure and CVD: Framingham Heart Study WOMEN 180 No Glucose Intolerance 160 140 Glucose Intolerance 120 113 100 80 74 60 40 20 195 Systolic BP (mmHg) Kannel WB et al. Am Heart J 1991;121:1268-1273. 0 56 48 31 15 105 36 23 135 165 195 Systolic BP (mmHg) Effect of Glycemic Control in the UK Prospective Diabetes Study (UKPDS) Endpoints Intensive Conventional (rate/1000 (rate/1000 P pt yrs) pt yrs) % Decrease Any diabetes related* 40.9 46 0.029 11 MI 17.4 0.052 16 14.7 Stroke 5.6 5 0.52 – PVD 1.1 1.6 0.15 – Microvascular 8.6 11.4 * Combined microvascular and macrovascular events UKPDS Group. Lancet 1998;352:837-853. 0.0099 25 Reasons for Death in UKPDS Intensive Treatment Arm: 10-Year Follow-up N= 2729 (%) Fatal MI or SD 231 (8.4%) Cancer 120 (4.4%) Other 74 (2.9%) Fatal Stroke 43 (1.6%) Renal Disease 16 (0.6%) Accidents 5 (0.2%) PVD 2 (0.07%) Hypo- or Hyperglycemia 1 (0.04%) Accidents, PVD, Hypo& Hyperglycemia Renal 3.3% 2.5% 15% Other 24% Cancer 47% MI or SD 8.7% Stroke UKPDS Group. Lancet 1998;352:837-853. Effect of Blood Pressure Control in the UKPDS Tight 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 24 32 0.0046 0.019 Heart failure Stroke Myocardial infarction Microvascular disease 56 44 21 37 0.0043 0.013 NS 0.0092 UKPDS Group. BMJ 1998;317:703-713. UKPDS: ACE Inhibitor vs. Beta-blocker for HTN Aggregate Clinical Endpoints Relative Risk & 95% CI RR p Any diabetes-related endpoint 1.10 0.43 Diabetes-related deaths 1.27 0.28 All-cause mortality 1.14 0.44 Myocardial infarction 1.20 0.35 Stroke 1.12 0.74 Microvascular 1.29 0.30 0.5 Favors ACE inhibitor UKPDS Group. BMJ 1998;317:713-720. 1 2 Favors Beta blocker Systolic Hypertension in Europe (Syst-Eur) Trial: Events / 1000 Pt-Years Effect of Systolic BP Control on All Cardiovascular Events at 2 Years 70 60 50 40 30 20 10 0 57.6 25% 62% Risk Reduction 22.0 Placebo Active Rx Diabetic Patients N=492; P=0.002 Tuomilehto J et al. NEJM 1999;340: 677-684. 31.4 Risk Reduction 23.5 Placebo Active Rx Nondiabetic Patients N=4,203; P=0.02 Major Outcomes of the Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup Events / 1000 Pt-Years 30 25 Diastolic Target p<0.005 <90 mmHg (N=501) <85 mmHg (N=501) 20 <80 mmHg (N=499) 15 p<0.045 10 p<0.016 5 0 Major CV Events Hansson L et al. Lancet 1998;351: 1755-1762. MI CV Mortality Events / 1000 Pt-Years HOT Trial:Cardiovascular Events in Diabetics and Nondiabetics—Effect of Diastolic Target at 4 Years 30 25 20 15 10 24.4 48% Risk 18.6 Reduction 11.9 5 0 <90 <85 <80 Diabetic Patients n=1,501; p=0.016 Hansson L et al. Lancet 1998;351: 1755-1762. 9.9 10.0 9.3 <90 <85 <80 Nondiabetic Patients n=18,790; p=NS Completed Clinical Trials with Antihypertensive Agents in Diabetes Trial Diabetic/Total SHEP 583/4736 Beneficial GISSI-3 2790/18,131 Beneficial Syst-Eur 492/4695 Beneficial 1501/18,790 Beneficial UKPDS 1148 Beneficial CAPPP 572/10,985 Beneficial HOT Results on CVD 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. Heart Outcomes Prevention Evaluation (HOPE) Study Effect of Ramipril on Cardiovascular Events (Myocardial Infarction, Stroke, or CVD Death) ~ 4.5 Yrs % of Patients 25 20 15 24% 19.8 Risk Reduction 15.0 10 21% 16.4 Risk Reduction 13.0 5 0 Placebo Ramipril Diabetic Patients N=3,578, P=<0.001 Hope Study Investigators. NEJM 2000;342:145-153. Placebo Ramipril Nondiabetic Patients N=5,719, P=<0.001 Diabetes Increases Risk of Coronary Plaque Disruption and Thrombosis Cause of Myocardial Infarction Platelet Aggregation F VII Fibrinogen F VIII vWF Coronary Artery Thrombus Plaque Formation Plaque Disruption Sympathetic Tone PAI-1 TPA PGI2 Impact of Serum Fibrinogen and Total Cholesterol Levels on Risk of Coronary Events in ECAT 7 6 Risk of Coronary Events (%) Total Cholesterol 5 4 3 Higher 2 1 Middle 0 Lower Middle Fibrinogen Thompson SG. N Engl J Med 1995;332:635-641. Lower Higher Effect of Aspirin on Mortality in Type 2 Patients with CHD: Bezafibrate Infarction Prevention Study Survival (%) 100 OR=0.7 (0.6-0.8) No diabetes 90 OR=0.8 (0.7-0.9) 80 Type 2 diabetes No aspirin Aspirin 70 0 1 2 3 4 Time (Years) Harpaz D et al. Am J Med 1998;105:494-499. 5 6 Antiplatelet Agents Reduce CVD Events in Patients with Diabetes: Antiplatelet Trialists’ Collaboration CVD Events (%) 25 P<0.002 Antiplatelet Therapy Control 20 P<0.00001 15 10 5 0 Diabetes Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81-106. No Diabetes Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI): Benefit of Tight Glycemic Control in No Insulin – Low Risk Cohort Total Cohort p = .0111 Mortality 0.6 0.7 0.5 Control 0.4 n=306 0.3 0.2 Insulin-glucose Infusion 0.1 0 0 1 2 3 4 Years in Study p = .004 0.6 n=314 Mortality 0.7 No Insulin – Low Risk 0.5 n=133 0.4 Control 0.3 0.2 n=139 0.1 5 Malmberg K et al. BMJ 1997;314:1512-1515. 0 0 Insulin-glucose Infusion 1 2 3 4 Years in Study 5 Effect of Trandolapril on Post-MI CHF Progression: Trandolapril Cardiac Evaluation (TRACE) Diabetics (n=237) 0.5 0.5 Placebo 0.4 Event Rate Event Rate 0.4 0.3 Trandolapril 0.2 0.1 0.0 Nondiabetics (n=1512) 1 2 Years 3 Placebo 0.2 Trandolapril 0.1 Relative risk, 0.38 P<0.001 0 0.3 4 0.0 Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89. Relative risk, 0.81 P = 0.1 0 1 2 Years 3 4 Effect of Trandolapril on Secondary Endpoints in TRACE Diabetics End Point RR (95% CI) Interaction Nondiabetics P RR (95% CI) P P Cardiovascular death 0.56 (0.37-0.85) 0.01 0.79 (0.66-0.96) 0.02 0.17 Sudden death 0.46 (0.25-0.85) 0.01 0.84 (0.63-1.12) 0.23 0.09 Reinfarction 0.55 (0.29-1.07) 0.08 0.93 (0.69-1.26) 0.65 0.15 Progression in CHF 0.38 (0.21-0.67) <0.001 0.81 (0.63-1.04) 0.10 0.03 CI = confidence interval; RR = relative risk. Gustafsson I et al. J Am Coll Cardiol 1999;34:83-89. 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) 2.1 Adjusted for clinical variables 2.4 Adjusted for angiographic variables 2.0 Adjusted for clinical & angiographic variables 0 1 2 3 4 Odds Ratio for 30-Day Mortality Woodfield SL et al. J Am Coll Cardiol 1996;28:1661-1669. 5 Overall 5-Year Mortality in the Bypass Angioplasty Revascularization Investigation (BARI-1) 1.0 DM-PTCA Mortality 0.8 DM-CABG Non DM-CABG 0.6 Non DM-PTCA 0.4 0.25 0.18 0.08 0.07 0.2 0.0 0 1 2 3 Follow-up (years) Detre KM et al. N Engl J Med 2000;342:989-997. 4 5 Impact of PTCA vs. CABG on Mortality in BARI-1 Mortality in Patients without Q-MI 1.0 DM-CABG 0.8 Non DM-CABG Non DM-PTCA 0.6 Mortality Mortality 1.0 DM-PTCA 0.8 0.4 0.79 0.6 0.4 0.29 0.27 0.22 0.2 0.16 0.07 0.06 0.2 0.0 Mortality in Patients After Q-MI 0 1 2 3 4 Follow-up (years) 5 0.0 Detre KM et al. N Engl J Med 2000;342:989-997. 0.17 0 1 2 3 4 Years after Q-MI 5 Impact of Diabetes on 7-year Survival in BARI All Patients 60 40 CABG (n=914) 20 PTCA (n=915) 0 0 1 2 3 Patients with Treated Diabetes 100 % Survival 84.4 80.9 80 76.4 60 55.7 CABG (n=180) 20 PTCA (n=173) 0 0 1 2 3 4 p = 0.0011 4 5 6 5 6 7 Years 7 Patients without Treated Diabetes 100 80 40 p = 0.0425 % Survival % Survival 100 86.8 86.4 80 60 40 CABG (n=734) 20 PTCA (n=742) 0 0 1 BARI Investigators. J Am Coll Cardiol 2000;35:1122-1129. 2 3 p = 0.7155 4 5 6 7 Eight-Year Mortality in Emory Angioplasty vs Surgery Trial (EAST) All EAST Patients % Survival 100 80 60 40 CABG (n=194) 20 PTCA (n=198) 0 0 1 2 4 5 60 40 CABG (n=30) 20 PTCA (n=29) p = 0.23 6 100 % Survival 80 0 3 p = 0.40 Treated Diabetic Patients 100 % Survival 82.7 79.3 7 8 Patients without Diabetes 80 60 40 CABG (n=164) 20 PTCA (n=169) 0 7 8 0 1 2 Years after Randomization King SB III et al. J Am Coll Cardiol 2000;35:1116-1121. 0 1 2 3 4 5 6 3 4 p = 0.71 5 6 7 8 6-Month Angiographic Outcome after PTCA in Diabetes (377 Patients with 476 Lesions) Total Occlusion 100 100 75 75 62% 50 49% 25 Restenosis (n = 237) Total Occlusion (n = 60) Patients (%) Lesions (%) Overall Restenosis Rate 50 37% 25% 25 11% 0 13% 0 Angiographic FU = 6 months Van Belle E et al. J Am Coll Cardiol 1999;34:476-485. 1 Site 2 Sites 3 Sites PTCA Site(s) Impact of Restenosis and Total Occlusion on LV Function in Diabetes 15 Restenosis (–) Restenosis (+) Total Occlusion (–) Total Occlusion (–) (n = 297) (n = 237) Total Occlusion (+) (n = 60) in EF (%) 10 5 0 -5 -1.5+9.5 +0.5+9.9 -6.2+9.9 -10 -15 -20 p = ns p = ns Van Belle E et al. J Am Coll Cardiol 1999;34:476-485. p = 0.0001 Effect of Stents on Target Vessel Revascularization (TVR) after PTCA in Diabetes Proportion Free of TVR 1.00 p = 0.021 df = 3, Log-rank Test 0.95 0.90 0.85 1997 0.80 0.75 0.70 0 0 Year N % Stent 1994 305 17.4 1995 425 24.9 1996 480 41.0 1997 288 55.5 2 1996 1995 1994 4 6 8 Months Post PTCA Rankin JM et al. Circulation 1998;98:I-79. 10 12 Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT): Benefit of Abciximab and Stenting in Diabetes on Reducing TVR 20 Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 15 18.4% 16.6% 10 8.1% 5 0 0 30 60 90 120 150 180 Patients without Diabetes (n = 1908) Incidence of repeated TVR at 6 mos. (%) Incidence of repeated TVR at 6 mos. (%) Patients with Diabetes (n = 491) Days after Randomization Lincoff AM et al. N Engl J Med 1999;341:319-327. 20 Stent + Placebo Stent + Abciximab Angioplasty + Abciximab 15 14.6% 9.0% 10 8.8% 5 0 0 30 60 90 120 150 180 Days after Randomization EPISTENT: Optimization of PTCA/Stent Outcomes with Platelet IIb/IIIa Inhibition 6-Month Death, MI for Diabetics 15 % of Patients 12.7% p = 0.029 10 7.8% 6.2% 5 0 Stent + Placebo Stent + Abciximab PTCA + Abciximab 0 30 60 90 Days Marso SP et al. Circulation 1999;100:2477-2484. 120 150 180 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) 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