1. Controversies in Cardiology: Stable CAD & COURAGE Pro: Optimal Medical Therapy vs. PCI SYED ZAHID JAMAL MD ASSOC PROF NICVD

2. Ha ha ha ha !

3. Varying Degrees of CAD Lesion Severity in a Single Coronary Artery Highly variable degrees of: plaque formation luminal obstruction inflammation likelihood of rupture

4. Is this a benign lesion in a benign condition? Stable Angina

5. What are you lookin at?

6. Nature of the Problem: Severe Obstruction (Angina, No Rupture) vs Mild Obstruction (No Angina, Likely to Rupture) Revascularization; Anti-anginal Rx Exertional Angina, (+) ETT Severe Fibrotic Plaque Severe obstruction, No lipid, Fibrosis, Ca ++ Pharmacologic Stabilization; ? Early Identification of High-risk Plaque Rupture Acute MI, Unstable Angina, Sudden death Vulnerable Plaque Minor obstruction, Eccentric plaque, Lipid pool, Thin cap Courtesy of P. Stone, 2007

7. The Differing Fates of Coronary Stenoses of Varying Severity Clinical manifestations of coronary lesions behave differently based on the degree of luminal obstruction and morphology: –Lesions > 50-75% obstruction Angina; positive stress test; positive calcium score –Lesions < 50% obstruction Rupture, superimposed thrombus ACS/Death Both types of lesions are inevitably present within the same stable CAD patient at any point in time

8. Goals of Therapy in CAD Management 1.Improve anginal symptoms by optimizing myocardial O 2 supply:demand balance Medication: Reduce HR, BP, contractility, preload β-blockers Ca ++ blockers Nitrates Enhance myocardial O 2 supply Ca ++ blockers & ? Ranolazine Revascularization (PCI or CABG) 2.Reduce/stabilize atherosclerotic plaque, reducing likelihood of rupture ACS/Cardiac death –Aggressive statin therapy –ACE inhibitors –Aspirin ± Clopidogrel –β-blockers –Lifestyle modifications (Courtesy of P. Stone, 2007)

9. * Med Management (MM), Percutaneous Coronary Intervention (PCI), Coronary Artery Bypass Grafting (CABG) Increased Mortality with Medical Management for UA/NSTEMI Patients : Patients with Significant CAD on Cath in the SYNERGY Trial Chan M, JACC Cardiovasc Int 2008

10. A Different Story in Stable CAD: Contrasting 1 Year Death/MI Rates: ACS, Stable Angina, “Primary Prevention” Wallentin L et al. Lancet 2000;356:9–16 Juul-Moller S et al. Lancet 1992;340:1421–1425 Shepherd J et al. N Engl J Med 1995;333:1301–1307 Poole-Wilson et al ACTION Lancet 2004;364:849-57. Death/ MI (%) Months of follow up Unstable angina/non Q wave MI (FRISC II) 16 12 8 4 0 024681012 Stable angina (SAPAT) Primary Prevention (WOSCOPS) ACTION trial (stable CAD) Approx 1.5% Stable CAD COURAGE 3.8%

11. THE PROBLEM: Major Cardiac Events Occur in Non-Target Lesions Following Successful PCI Hazard Rate (%) (Cutlip, et al. Circulation 2004;110:1226) Substantial number of cardiac events could be prevented if we knew how to identify them 5 year Followup of 1228 Patients Treated with Bare Metal Stents 6.7 5.7 7.0 5.6 12.4 1.4 1.5 1.3 2.3 18.3 Non-Target Lesion Event Rates: 12.4% Year 1 37.4% Year 1-5

12. Classification of Natural History of Early Atherosclerotic Plaques Plaque Trajectory Histo- pathology Progression Rate Vascular Remodeling Proclivity to Rupture Clinical Manifestations Quiescent Plaque Small lipid core/thick cap Minimal Compensatory LowAsymptomatic High-risk vulnerable plaque Large lipid core/ thin,inflamed cap Increased Excessive expansive High Acute Coronary Syndrome Stenotic Plaque Small lipid core/very thick cap GradualConstrictiveLowStable Angina (Chatzizisis, et al. JACC 2007;49:2379)

13. Relative Risk of Recurrent Cardiac Events with PTCA vs Medical Therapy Meta-analysis of 6 randomized trials (n=1904) (Bucher, et al. BMJ 2000;321:73)

14. Stable CAD: PCI vs Conservative Medical Management Meta-analysis of 11 randomized trials; N = 2950 Death Cardiac death or MI Nonfatal MI CABG PCI Katritsis DG et al. Circulation. 2005;111:2906-12. 012 P 0.68 0.28 0.12 0.82 0.34 Risk ratio (95% Cl) Favors PCIFavors Medical Management

15. Long-Term Clinical Outcome: PTCA vs Medical Management in RITA-2 (Henderson, et al. JACC 2003;42:1161) P=NS No difference in outcome over median of 7 years RITA-2, 1018 patients (504 PTCA, 514 medical management) Death Death or MI

16. In Patients with Chronic Angina and Stable CAD: We know that PCI improves angina and short-term exercise capacity, so if we don’t “fix what we see”: 1.Will we expose patients to increased risk of death/MI? 2.Will angina and quality of life be worse? 3.Will residual ischemia be less well treated? 4.Will patients feel they did not receive “best care”? 5.What about high-risk patients—3V CAD; ↓ EF? What Is The Concern Of Leaving Coronary Stenoses Alone?

17. Evidence Prior to COURAGE of Leaving Coronary Stenoses Alone (Henderson, et al. JACC 2003;42:1161) P=NS No difference in outcome over median of 7 years RITA-2, 1018 patients (504 PTCA, 514 medical management) Death Death or MI

18. Stable CAD: PCI vs. Medical Management Pre-COURAGE Meta-analysis of 11 randomized trials; N = 2950 Death Cardiac death or MI Nonfatal MI CABG PCI Katritsis DG et al. Circulation. 2005;111:2906-12. 012 P 0.68 0.28 0.12 0.82 0.34 Risk ratio (95% Cl) Favors PCIFavors Medical Management

19. COURAGE Primary EP: Survival Free of Death or MI Years 0 123456 0.0 0.5 0.6 0.7 0.8 0.9 1.0 PCI + OMT Optimal Medical Therapy (OMT) Hazard ratio: 1.05 95% CI (0.87-1.27) P = 0.62 7 2,287 Pts. Randomized to PCI + OMT vs. OMT Intensive, Guideline-Driven Medical Therapy & Lifestyle Intervention In Both Groups Source: Boden et al. N Engl J Med. 2007; 356:1503-16.

20. Optimal Medical Therapy Pharmacologic Anti-platelet: aspirin; clopidogrel (c/w with established practice standards) Statin: simvastatin ± ezetimibe or extended-release niacin ACE Inhibitor or ARB: lisinopril or losartan Beta-blocker: long-acting metoprolol (Toprol XL®) Calcium channel blocker: amlodipine Nitrate: isosorbide 5-mononitrate Lifestyle Smoking cessation Exercise program Nutrition counseling Weight control Applied to Both Arms by Protocol and Case-Managed

21. Value of Optimal Medical Therapy: The COURAGE Trial Death/MIDeath New ACSNew MI Compared with Optimal Medical Therapy Alone, PCI provided no incremental benefit on Death, MI, New ACS (Boden, et al. NEJM 2007;356:1503)

22. Value of Optimal Medical Therapy: The COURAGE Trial (Boden, et al. NEJM 2007;356:1503) Percent With Angina 25 50 75 100 88 87 34 42 28 33 28 26 Baseline 1 Year 3 Year 5 Year Compared with Optimal Medical Therapy alone, PCI is associated with a reduction in angina, but not after 5 yrs pNS P<0.001 P=0.02 pNS PCI + Optimal Rx Optimal Rx alone

23. Tertiary Outcomes: Cardiac Death/MI/ACS Years 0 123456 PCI + OMT OMT Hazard ratio: 1.07 CI 95% (0.91, 1.27) P = 0.60 23.5% 22.6% 10% 20% 30%

24. “COURAGE Enrolled Low-Risk Patients”… Huh??? Diabetes: 34% Dyslipidemia: 71 % HTN: 67% Smokers: 29% Prior MI: 39% Prior Revasc: 26% Angina at BL: 88% Angina Duration: 26 mo Angina Freq.: 6 episodes/wk Multivessel CAD: 70% LAD disease: 68% Inducible Ischemia: 85% Stress MPI: Multiple defects 67% Death/MI Event Rate: 4.3%/year

25. COURAGE Patient Randomized to OMT Alone

27. Need for Subsequent Revascularization: 7 Years of F/U* PCI + OMTOMT Overall Need for Revascularization 21%33% Subsequent CABGN=77N=81 Median Time to Revascularization † 10 months; 10.5% 10.8 months; 16.5% *Median 4.6 years of follow-up † Median time to Repeat or 1 st Revascularization After ~ 11 mo, the avg. X-over from OMT to PCI was 2.8%/year over years 1-7

28. Freedom from CCS Angina During Follow-up & NNT to Improve Sx Characteristic: CCS Class 0 PCI + OMTOMT NNT to improve angina in 1 pt with PCI CLINICAL Angina free – no. Baseline12%13%--- 1 Yr*66%58%12.5 3 Yr*72%67%20 5 Yr74%72%50 * The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at baseline or 5 years.

29. SAQ Mean QOL Scores During Follow-up & NNT to Improve Sx CharacteristicPCI + OMTOMT NNT to improve SAQ QOL in 1 pt with PCI Mean SAQ QOL Score: 0-100 Scale Baseline51 --- 1 Mo*686216.7 6 Mo*757020 1 Yr*767333.3 2 Yr7776100 *P < 0.001 between groups

30. COURAGE QOL Editorial Commentary

31. Nuclear Substudy (n=314) Source: Shaw et al. J Nucl Cardiol 2006 Sep;13(5):685-98. Rest/Stress Myocardial Perfusion SPECT (MPS) Pre-Rx Pre-Rx Following 6-18m Randomized Rx (mean 374 ± 50 days) Following 6-18m Randomized Rx (mean 374 ± 50 days) Documented Pre-Rx Ischemia Pre-RxTc-99m sestamibi MPS Pre-RxTc-99m PCI + OMT (n=159) (n=159)OMT(n=155)OMT(n=155) Repeat MPS at 6-18m Repeat MPS at 6-18m Hypothesis: Reduction in Ischemia will be greater for Pts. Randomized to PCI+OMT than for those Randomized to OMT as Measured By Changes in Ischemic Burden by MPS at Baseline & 6- 18m after Randomization

32. Patient Expectations About Elective PCI for Stable CAD 52 consecutive patients scheduled for first elective PCI completed semi-structured questionnaire prospectively Holmboe et al. J Gen Intern Med 2000;15:632. Do you think the angioplasty will prevent a heart attack? Yes75% Do you think the angioplasty will help you live longer? Yes71%

33. Recent Mid-America Heart Institute Patient PCI Survey One million PCI procedures per year Majority elective Prospective survey of 350 elective PCI patients with stable CAD @ MAHI between 1/06-10/07 Focus: are pt. perspectives of PCI benefit aligned with current evidence? John H. Lee, MD et al: 2008 AHA Scientific Sessions, November 12, 2008

34. Patient Perceived Benefits of Elective PCI

35. Alternate Therapies Offered

36. Stenosis Severity prior to AMI: What Drives Late Events is CAD Progression in Non-Flow- Limiting Lesions → New Plaque Rupture

37. For Patients Undergoing Elective Coronary Angiography for Chronic Angina: 13 RCTs in 7,605 patients (including BARI-2D) show no difference in death, MI, stroke or other “hard” endpoints between PCI and OMT An initial course of OMT preserves the option for PCI if medical therapy fails (only 16.5% of COURAGE OMT patients “crossed over” to PCI within 1 year) Over a full 7-year follow-up period, 2/3 of all OMT patients never required even a 1 st PCI procedure Why The Evidence Supports OMT as the Initial Approach to Stable CAD Management

38. In Patients with Chronic Angina and Stable CAD: There is better angina relief with PCI over 1-3 years There is better QOL with PCI over 1-2 years The subsequent need for revascularization in the 1 st year is lower in PCI than OMT patients OMT is a safe & viable option for most patients, and for those who may not be good candidates for PCI (frailty; CKD; multiple co-morbidities; treacherous anatomy, etc.) OMT as an initial approach preserves PCI as a subsequent option for symptom/QOL relief, if needed Where Does COURAGE Give Us Clarity of Management?

39. In Patients with Chronic Angina and Stable CAD: Is OMT as good as PCI + OMT in patients with impaired LV systolic function (EF < 40%)? Do patients with high-grade 3-vessel CAD fare as well with OMT vs. PCI + OMT, esp. with EF < 40%? Does stenosis severity (≥ 90% vs. 70%-80%) alter PCI vs. OMT outcomes, and does defining coronary anatomy in all patients aid clinical decision-making? Is it important to delineate the presence or absence of high- risk inducible ischemia in all patients? Where Do the Results of COURAGE Still Leave Uncertainty?

40. CAD manifestations in an individual patient are due both to: –Flow-limiting obstructions (angina, + stress test, + Ca ++ score) –Minor obstructions with high-risk vulnerable plaque (ACS, death) –Catheter-based treatment directed only at flow-limiting obstructions will do little to reduce the burden of CAD events precipitated by olaque rupture of non-flow- limiting stenoses Selective Management Strategies Focusing on Obstructive and Non-Obstructive CAD Summary and Conclusions

41. Non-obstructive high-risk plaque: –Difficult to identify/predict natural history at this time –Aggressive systemic pharmacologic therapy stabilizes vulnerable plaque and thereby reduces mortality and morbidity Statins, ACE-inhibitors, ? Niacin –Ultimately, risk stratification (and local intervention) of individual lesions may be possible Selective Management Strategies Focusing on Obstructive and Non-Obstructive CAD Summary and Conclusions

42. Flow-limiting Obstructive CAD: –Optimal Medical Therapy is a viable & defendable initial management strategy and is supported by existing ACC/AHA Clinical Practice Guidelines –Revascularization is appropriate in patients with severe angina symptoms (or who have failed medical Rx), or in those who have substantial ischemic jeopardy –Revascularization may be more effective than medications to: reduce angina increase exercise capacity decrease subsequent revascularization procedures but not to improve mortality, reduce MI, or other CV events. Selective Management Strategies Focusing on Obstructive and Non-Obstructive CAD Summary and Conclusions

43. Occluded Artery Trial (OAT) Presented at The American Heart Association Scientific Session 2006 OAT Trial

44. OAT Trial: Background The goal of the trial was to evaluate percutaneous coronary intervention (PCI) compared with medical therapy among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-myocardial infarction (MI).The goal of the trial was to evaluate percutaneous coronary intervention (PCI) compared with medical therapy among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-myocardial infarction (MI). Presented at AHA 2006

45. OAT Trial: Hypothesis A strategy of routine PCI for total occlusion of the infarct-related artery 3-28 days after acute MI would reduce the occurrence of the composite of death, reinfarction, or New York Heart Association (NYHA) class IV heart failure.A strategy of routine PCI for total occlusion of the infarct-related artery 3-28 days after acute MI would reduce the occurrence of the composite of death, reinfarction, or New York Heart Association (NYHA) class IV heart failure. Presented at AHA 2006

46. OAT Trial: Study Design  Primary Endpoints: Death, MI, or NYHA class IV heart failure PCI with stenting n=1082 n=1082 Medical Therapy n=1084 n=1084 2166 patients with angiography on day 3-28 post-MI with evidence of total occlusion of the infarct- related artery with poor or absent antegrade flow (TIMI flow grade 0 or 1); and met a criterion for increased risk, defined as ejection fraction <50%, proximal occlusion of a major epicardial vessel with a large risk region, or both Exclusions: NYHA class III or IV heart failure, shock, serum creatinine concentration >2.5 mg/dl, angiographically significant left main or three-vessel coronary artery disease, angina at rest, or severe ischemia on stress testing. Randomized. 22% female, mean age 59 years, mean follow-up 3 years, mean EF 48% at baseline Concomitant medications: Aspirin, anticoagulation if indicated, ACE inhibitors, beta-blockers, and lipid-lowering therapy, unless contraindicated 2166 patients with angiography on day 3-28 post-MI with evidence of total occlusion of the infarct- related artery with poor or absent antegrade flow (TIMI flow grade 0 or 1); and met a criterion for increased risk, defined as ejection fraction <50%, proximal occlusion of a major epicardial vessel with a large risk region, or both Exclusions: NYHA class III or IV heart failure, shock, serum creatinine concentration >2.5 mg/dl, angiographically significant left main or three-vessel coronary artery disease, angina at rest, or severe ischemia on stress testing. Randomized. 22% female, mean age 59 years, mean follow-up 3 years, mean EF 48% at baseline Concomitant medications: Aspirin, anticoagulation if indicated, ACE inhibitors, beta-blockers, and lipid-lowering therapy, unless contraindicated Presented at AHA 2006

47. OAT Trial: Primary Endpoint The primary endpoint of death, reinfarction, or NYHA class IV heart failure occurred in 17.2% of the PCI group and 15.6% of the medical therapy group ([HR] 1.16, p=0.20).The primary endpoint of death, reinfarction, or NYHA class IV heart failure occurred in 17.2% of the PCI group and 15.6% of the medical therapy group ([HR] 1.16, p=0.20). Primary Endpoint of death, reinfarction, NYHA class IV heart failure (% patients) Hazard Ratio 1.16, p=0.20 Presented at AHA 2006

48. OAT Trial: Primary Component Endpoints Total reinfarction trended higher in the PCI group (7.0% vs. 5.3%, HR 1.36, p=0.13), as did nonfatal reinfarction (6.9% vs. 5.0%, HR 1.44, p=0.08).Total reinfarction trended higher in the PCI group (7.0% vs. 5.3%, HR 1.36, p=0.13), as did nonfatal reinfarction (6.9% vs. 5.0%, HR 1.44, p=0.08). Repeated elevation of cardiac biomarkers within 48 hours of randomization occurred significantly more frequently in the PCI group (10.0% vs. 3.3%, p<0.001).Repeated elevation of cardiac biomarkers within 48 hours of randomization occurred significantly more frequently in the PCI group (10.0% vs. 3.3%, p<0.001). There was no difference in the individual endpoints of death (9.1% for PCI vs. 9.4% for medical therapy, p=0.83) or NYHA class IV heart failure (4.4% vs. 4.5%, p=0.92) between the treatment groups.There was no difference in the individual endpoints of death (9.1% for PCI vs. 9.4% for medical therapy, p=0.83) or NYHA class IV heart failure (4.4% vs. 4.5%, p=0.92) between the treatment groups. Primary Component Endpoints (% patients) TotalReinfarction Presented at AHA 2006 % patients NonfatalReinfarctionDeath Repeated ↑ of Cardiac Biomarkers NYHA Class IV Heart Failure p=0.13p=0.13 p=0.08p=0.08 p<0.001p<0.001 p=0.83p=0.83 p=0.92p=0.92

49. OAT Trial: Summary Among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-MI, performance of PCI 3-28 days post-MI was not associated with a difference in the composite of death, reinfarction, or NYHA class IV heart failure through a mean follow-up of 3 years compared with medical therapy.Among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-MI, performance of PCI 3-28 days post-MI was not associated with a difference in the composite of death, reinfarction, or NYHA class IV heart failure through a mean follow-up of 3 years compared with medical therapy. Despite no reduction in the composite endpoint, PCI was associated with a trend toward higher rates of reinfarction compared with medication therapy.Despite no reduction in the composite endpoint, PCI was associated with a trend toward higher rates of reinfarction compared with medication therapy. Among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-MI, performance of PCI 3-28 days post-MI was not associated with a difference in the composite of death, reinfarction, or NYHA class IV heart failure through a mean follow-up of 3 years compared with medical therapy.Among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-MI, performance of PCI 3-28 days post-MI was not associated with a difference in the composite of death, reinfarction, or NYHA class IV heart failure through a mean follow-up of 3 years compared with medical therapy. Despite no reduction in the composite endpoint, PCI was associated with a trend toward higher rates of reinfarction compared with medication therapy.Despite no reduction in the composite endpoint, PCI was associated with a trend toward higher rates of reinfarction compared with medication therapy. Presented at AHA 2006

50. OAT Trial: Summary (cont.) The reinfarctions were not only procedural-related infarcts (i.e., early procedural enzymatic leaks), but true ST elevation reinfarctions that accumulated throughout follow-up.The reinfarctions were not only procedural-related infarcts (i.e., early procedural enzymatic leaks), but true ST elevation reinfarctions that accumulated throughout follow-up. One explanation for the trend toward an increase in reinfarctions with PCI may be embolization resulting in myocardial damage and impaired collateral flow.One explanation for the trend toward an increase in reinfarctions with PCI may be embolization resulting in myocardial damage and impaired collateral flow. Presence of persistent total occlusion remains a problem for a sizeable cohort of patients for whom suitable treatment is lacking.Presence of persistent total occlusion remains a problem for a sizeable cohort of patients for whom suitable treatment is lacking. The reinfarctions were not only procedural-related infarcts (i.e., early procedural enzymatic leaks), but true ST elevation reinfarctions that accumulated throughout follow-up.The reinfarctions were not only procedural-related infarcts (i.e., early procedural enzymatic leaks), but true ST elevation reinfarctions that accumulated throughout follow-up. One explanation for the trend toward an increase in reinfarctions with PCI may be embolization resulting in myocardial damage and impaired collateral flow.One explanation for the trend toward an increase in reinfarctions with PCI may be embolization resulting in myocardial damage and impaired collateral flow. Presence of persistent total occlusion remains a problem for a sizeable cohort of patients for whom suitable treatment is lacking.Presence of persistent total occlusion remains a problem for a sizeable cohort of patients for whom suitable treatment is lacking. Presented at AHA 2006

51. OAT Trial: Summary (cont.) Early reperfusion therapy, the goal of ST elevation MI treatment, with either primary PCI or thrombolysis, is not indicated for patients who present late, often with persistent total occlusion.Early reperfusion therapy, the goal of ST elevation MI treatment, with either primary PCI or thrombolysis, is not indicated for patients who present late, often with persistent total occlusion. The present study, the largest randomized trial to date in this population, does not support the use of late PCI for stable but persistent total occlusion.The present study, the largest randomized trial to date in this population, does not support the use of late PCI for stable but persistent total occlusion. Early reperfusion therapy, the goal of ST elevation MI treatment, with either primary PCI or thrombolysis, is not indicated for patients who present late, often with persistent total occlusion.Early reperfusion therapy, the goal of ST elevation MI treatment, with either primary PCI or thrombolysis, is not indicated for patients who present late, often with persistent total occlusion. The present study, the largest randomized trial to date in this population, does not support the use of late PCI for stable but persistent total occlusion.The present study, the largest randomized trial to date in this population, does not support the use of late PCI for stable but persistent total occlusion. Presented at AHA 2006

52. Dang, HE IS DRUNK