James M. Kirshenbaum, MD, FACC

James M. Kirshenbaum, MD, FACC Associate Professor of Medicine Harvard Medical School Co-Director, Clinical Cardiology Director, Acute Interventional Cardiology Brigham and Women s Hospital Boston, MA Source (Photos): Davies MJ Heart 83:361,2000 Risk Reduction of Ischemic Events Objective Reduce the risk of recurrent cardiovascular events and/or mortality Control of risk factors to goal Smoking (cessation) Hyperlipidemia (LDL <70) Hypertension (BP <130/85) Diabetes (Hgb A1c <7) Diet/exercise/life style Pharmacologic therapy ASA Clopidogrel (post ACS/stent) ACE/ARB Beta-blocker Statin Treatment of Symptoms Objective Reduce symptoms to increase exercise tolerance, and functional capacity Anti-ischemic therapy Beta-blockers Nitrates Calcium antagonists Ranolazine Revascularization PCI or CABG 1

(<24hrs) (Discharge) 1. ASA 2. Clopidogrel/Prasugrel 3. Heparin/LMWH 4. Direct Thrombin Inhibitors 5. GP IIb/IIIa inhibitors 6. Factor Xa antagonists 7. Beta-blockers 8. Nitrates Libby P. Circ 2001;104:365, 1. ASA 2. Clopidogrel 3. Beta-blockers 4. ACE Inhibitors 5. Statins 6. Risk factor + Lifestyle Δ s 2007 ACC/AHA UA/NSTEMI Guideline Revision! Secondary Prevention BP control <140/90 mm Hg <130/80 mm Hg with diabetes or CKD Diabetes management: HbA 1c <7% Smoking cessation/no environmental smoke exposure Education, referral programs, drug therapy Physical activity (30-60 min, 7 d/wk; min 5 d/wk) Weight management BMI 18.5-24.9 kg/m 2 Waist circumference: men, <40 in; women, <35 in Discharge education/referral Stepped-care approach to musculoskeletal pain management Annual influenza immunization HRT, antioxidant vitamin supplements (C, E, beta carotene) and folic acid not recommended Anderson JL, et al. J Am Coll Cardiol. 2007;50:652-726. ACIP: Study design Angiographic CAD ( 50% stenosis in 1 major vessel or branch) suitable for revascularization + ischemia during exercise or pharmacologic stress testing and 1 asymptomatic episode during 48-hr AECG Angina-guided strategy (n = 183) Ischemia-guided strategy (n = 183) Revascularization strategy (n = 192) Primary outcome: Absence of ischemia at 12 weeks Secondary outcomes: Death, MI, recurrent hospitalization for cardiac disease, nonprotocol revascularization at 1 and 2 years Asymptomatic Cardiac Ischemia Pilot Pepine CJ et al. J Am Coll Cardiol. 1994:24:1-10. Davies RF et al. Circulation. 1997;95:2037-43. 2

ACIP: Two-year cumulative rates of death, MI, or cardiac hospitalization Davies, R. F. et al. Circulation 1997;95:2037-2043 Copyright 1997 American Heart Association ACIP: Two-year cumulative all-cause mortality rates for the treatment strategies 8 6.6% Angina guided Percent 6 4 2 4.4% Ischemia guided 1.1% Revascularization P = 0.34 P < 0.05 P < 0.005 0 0 4 8 12 15 20 Follow-up (months) 24 Davies RF et al. Circulation. 1997;95:2037-43. SWISSI II: Study design Recent first MI with asymptomatic myocardial ischemia on exercise testing and 1- or 2-vessel coronary disease suitable for PCI PCI (n = 96) Randomized, unblinded Anti-ischemic therapy* (n = 105) Primary outcomes: Cardiac death, nonfatal MI, symptom-driven revascularization Follow-up: 10.2 years (mean) *Nitrates, β-blockers, CCBs All patients also received aspirin and statin Swiss Interventional Study on Silent Ischemia Type II Erne P et al. JAMA. 2007;297:1985-91. 3

SWISSI II: Treatment effect on primary outcome Cardiac death, nonfatal MI, symptom-driven revascularization No. at risk PCI Anti-ischemic drug therapy *Log-rank Event-free survival 1.00 0.75 0.50 0.25 0 0 96 105 PCI Drug therapy P < 0.001* 5 10 15 Time from randomization (years) 77 54 64 37 Erne P et al. JAMA. 2007;297:1985-91. ACIP, SWISSI II: Summary and implications ACIP: In patients with documented CAD + symptomatic and asymptomatic ischemia, PCI compared with antiischemic or antianginal therapy reduced 2-year risk of major CV events SWISSI II extended these finding to post-mi patients with asymptomatic ischemia and a longer 10-year follow-up Davies RF et al. Circulation. 1997;95:2037-43. Erne P et al. JAMA. 2007;297:1985-91. Patient expectations about elective PCI for stable CAD N = 52 consecutive patients scheduled for first elective PCI; semi-structured questionnaire completed prospectively Do you think the angioplasty will prevent a heart attack? Yes 75% Do you think the angioplasty will help you live longer? Yes 71% Holmboe ES et al. J Gen Intern Med. 2000;15:632-7. 4

Perceived benefit of PTCA for coronary disease Rothberg. Ann Intern Med 2010;153:307 Conventional Wisdom Treatment Assumptions in CAD Management: Patients with symptomatic CAD and chronic angina who have significant coronary stenoses need revascularization Revascularization is required to improve prognosis PCI is less invasive than CABG surgery (i.e., is safer) and, therefore, should be selected Effects of Medical vs PCI Therapy on Angina Symptoms in Stable CAD 1018 stable CAD patients: 504 randomized to PTCA, 514 randomized to medical treatment Followup: 2.7 years Difference in Angina Class > II; Medical PTCA, 95% CI P<0.001 Angina better managed with PTCA, but difference attenuated over time (related to revasc in med group) (RITA-2 trial participants. Lancet 1997;350:461) 5

Effects of Medical vs PCI Therapy on ETT Performance in Stable CAD RITA-2, 1018 patients (504 PTCA, 514 medical management) ETT duration better in pts with PTCA, but difference attenuated over time (related to subsequent revascularization in medical group) (RITA-2 trial participants. Lancet 1997;350:461) Longterm Outcome in PCI vs Medical Management in RITA-2 RITA-2, 1018 patients (504 PTCA, 514 medical management) Death Death or MI P=NS P=NS No difference in outcome over median of 7 years (Henderson, et al. JACC 2003;42:1161) Effect of Medical Therapy vs. PTCA vs. CABG for Multivessel CAD (MASS-II) Multivessel CAD with obstruction > 70% Stable angina CCS II or III Baseline management: Beta blockers, Ca ++ blockers, nitrates, ACE, statins, ASA Randomization (n=611 patients): Ongoing medical management 203 patients PCI (bare metal stents) 205 patients CABG (92% with LIMA) 203 patients Medical management continued in all groups Minimal followup 1 year (Hueb, et al. JACC 2004;43:1743) 6

Effect of Medical Therapy vs. PTCA vs. CABG for Multivessel CAD (MASS-II) Persisting Anginal Symptoms at One Year P=0.0001 % with Persisting Angina P=0.16 (Hueb, et al. JACC 2004;43:1743; Favarato, et al Circ 2003;108:II-21) Effect of Medical Therapy vs. PTCA vs. CABG for Multivessel CAD (MASS-II) Freedom from additional revascularization within first year P=0.000015 (Hueb, et al. JACC 2004;43:1743) Effect of Medical Therapy vs. PTCA vs. CABG for Multivessel CAD (MASS-II) Incidence of cardiac mortality P=NS No difference in cardiac mortality (Hueb, et al. JACC 2004;43:1743) 7

Survival Curves from Major Randomized Clinical Trials Comparing Medical vs Surgical Therapy of CAD (Eager, et al. ACC/AHA guidelines for CABG JACC 1999;34:1262) Stable CAD: PCI vs Conservative Medical Management Meta-analysis of 11 randomized trials; N = 2,950 Favors Favors Medical PCI Management Death Cardiac death or MI Nonfatal MI CABG PCI 0 1 2 Risk ratio Katritsis DG et al. Circulation. 2005;111:2906-12. (95% Cl) P 0.68 0.28 0.12 0.82 0.34 Background More than 1 million PCI procedures are performed in the U.S. annually, the great majority of which are undertaken electively in patients with stable CAD Although successful PCI of flow-limiting stenoses might be expected to reduce the rate of death, MI or hospitalization for ACS, prior studies have shown only that PCI decreases the frequency of angina and improves short-term exercise performance 8

COURAGE: Defining optimal care Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation Intensive lifestyle intervention Reduce symptoms Treat underlying disease Intensive medical therapy Revascularization? Hypothesis PCI + Optimal Medical Therapy will be Superior to Optimal Medical Therapy Alone COURAGE: Study design AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + 70% stenosis in 1 proximal epicardial vessel + objective evidence of ischemia (or 80% stenosis + CCS class III angina without provocation testing) Optimal medical therapy* + PCI (n = 1149) Randomized Optimal medical therapy* (n = 1138) Primary outcomes: All-cause mortality, nonfatal MI Secondary outcomes: Death, MI, stroke; ACS hospitalization Follow-up: Median 4.6 years *Intensive pharmacologic therapy + lifestyle intervention CCS = Canadian Cardiovascular Society Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16. 9

COURAGE: Pharmacologic therapy Antiplatelet Aspirin Clopidogrel in accordance with established practice standards Dyslipidemia Simvastatin ± ezetimibe, ER niacin, or fibrates β-blocker ER metoprolol Calcium channel blocker Amlodipine Nitrate Isosorbide 5-mononitrate ACEI, ARB, or diuretic Lisinopril or losartan Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16. COURAGE: Lifestyle intervention and risk factor goals Smoking cessation Exercise program 30 min moderately intensive exercise 5x/week Nutrition counseling Total dietary fat <30% of calories Saturated fat <7% of calories Dietary cholesterol <200 mg/day Weight control BMI <25 kg/m 2 (if baseline BMI 25.0-27.5) 10% relative weight loss (if baseline BMI >27.5) LDL-C (mg/dl) 60-85 HDL-C (mg/dl) 40 Triglycerides (mg/dl) <150 BP (mm Hg) <130/85 <130/80 if diabetes or renal disease present A1C (%) <7.0 Boden WE et al. Am Heart J. 2006;151:1173-9. COURAGE: Treatment effect on primary outcome All-cause death, MI Survival free of primary outcome 1.0 0.9 0.8 0.7 0.6 0.5 0 0 1 2 3 4 5 6 7 Years Medical therapy No. at risk Medical therapy 1138 1017 959 834 638 408 192 30 PCI 1149 1013 952 833 637 417 200 35 HR 1.05 (0.87-1.27) P = 0.62* PCI + medical therapy *Unadjusted, log-rank Boden WE et al. N Engl J Med. 2007;356:1503-16. 10

Value of Optimal Medical Therapy: The COURAGE Trial Compared with Optimal Medical Therapy alone, PCI provided no incremental benefit on Death, MI, New ACS Death/MI Death New ACS New MI (Boden, et al. NEJM 2007;356:1503) Value of Optimal Medical Therapy: The COURAGE Trial Compared with Optimal Medical Therapy alone, PCI is associated with a reduction in angina, but not after 5 yrs 100 88 pns 87 PCI + Optimal Rx Optimal Rx alone 75 Percent With Angina 50 P<0.001 34 42 P=0.02 28 33 pns 26 28 25 Baseline 1 Year 3 Year 5 Year (Boden, et al. NEJM 2007;356:1503) COURAGE: Treatment effect in CV and diabetes subgroups Baseline characteristics Myocardial infarction Yes No Extent of CAD Multivessel disease Single-vessel disease Diabetes Yes No Angina CCS 0-I CCS II-III Ejection fraction 50% >50% Previous CABG No Yes PCI better Medical therapy better 0.25 0.50 1.00 1.50 1.75 2.00 Hazard ratio (95% CI) Boden WE et al. N Engl J Med. 2007;356:1503-16. 11

COURAGE QOL & Health Status Findings: 14 Aug. 2008 Freedom from Angina During Follow-up & NNT to Improve Sx Characteristic: CCS Class 0 PCI + OMT OMT NNT to improve angina in 1 pt with PCI CLINICAL Angina free no. Baseline 12% 13% --- 1 Yr *66% 58% 12.5 3 Yr *72% 67% 20 5 Yr 74% 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. Weintraub. NEJM 2008;359:677 Quality of Life Improvement with PCI? Weintraub. NEJM 2008;359:677 12

BARI 2D: Enrollment and Randomization The BARI 2D Study Group. N Engl J Med 2009;360:2503-2515 BARI 2D Trial design: Patients with type 2 diabetes and coronary artery disease were randomized (2x2 factorial design) to revascularization (n = 953) versus medical therapy (n = 991) and to insulin-sensitization (n = 977) versus insulin-provision (n = 967). Follow-up 5.3 years. % p = 0.97 p = 0.89 11.7 12.2 11.8 12.1 Results Mortality: 11.7% with revasc vs. 12.2% with medical therapy (p = 0.97); 11.8% with insulinsensitization vs. 12.1% with insulin-provision (p = 0.89) PCI stratum, MACE: 23.0% with revasc vs. 21.1% with medical therapy (p = 0.15) CABG stratum, MACE: 22.4% with revasc vs. 30.5% with medical therapy (p = 0.01) Mortality Revascularization Medical therapy Mortality Insulinsensitization! Insulin-provision! Conclusions Among patients with diabetes and stable coronary artery disease, revascularization by PCI or CABG failed to demonstrate superiority to medical therapy at 5.3 years There was also no notable benefit from insulin-sensitizing therapy versus insulinproviding therapy BARI 2D Study Group. N Engl J Med 2009; 360: 2503. BARI 2D: Rates of Survival and Freedom from Major Cardiovascular Events, According to PCI and CABG Strata The BARI 2D Study Group. N Engl J Med 2009;360:2503-2515 13

Hachamovitch, R. et al. Circulation 2003;107:2900-2907 Observed cardiac death rates over the follow-up period in patients undergoing revascularization (Revasc) vs medical therapy (Medical Rx) as a function of the amount of inducible ischemia Hachamovitch, R. et al. Circulation 2003;107:2900-2907 14

Mortality hazard for (Revasc) vs medical therapy (Medical Rx) as a function of % ischemic myocardium in 10,627 consecutive pts. Followed for 1.9 +/- 0.6 yrs. 6 5 4 3 2 1 0 Circulation 2008;117:1283-1291 Hypothesis: Reduction in Ischemia will be greater for patients Randomized to PCI+OMT than for those Randomized to OMT Source: Shaw et al. J Nucl Cardiol 2006;13:685-98. 15

33.3% with > 5% ischemia reduction 18.9% with > 5% ischemia reduction Shaw et al. J Nucl Cardiol 2006;13:685-98. Shaw LJ Circulation. 2008;117:1283. Shaw LJ Circulation. 2008;117:1283. 16

Shaw LJ Circulation. 2008;117:1283 Conclusions PCI as an initial management strategy in the setting of stable CAD has not been shown to reduce the incidence of Death or MI PCI has not been shown to prolong life expectancy PCI added to OMT was more effective in reducing ischemia and improving angina than OMT, particularly in patients with moderate-to-severe prerx ischemia Most patients will have improvement in anginal status whether treated initially with PCI+OMT or OMT alone Peterson NEJM 2008;359:7 Controversies remain Patients randomized after coronary angiograms preformed Patients excluded with severe LV dysfunction, clinical instability, or very early ST-segment depression or hypotension 33% of patients in medical group crossed over to revascularization 17

Medical Therapy vs PCI + Medical Therapy For Stable CAD Nishilgaki: J Am Coll Cardiol Intv 2008;1:469 Medical Therapy vs PCI + Medical Therapy For Stable CAD Nishilgaki: J Am Coll Cardiol Intv 2008;1:469 Summary Among patients with CAD, ample data indicate a direct relationship between the presence and magnitude of ischemia and the likelihood of death and MI. This relationship appears to be independent of the degree of symptoms. Revascularization coupled with medical therapy is more effective in relieving ischemia than medical therapy alone Whether routinely applied revascularization, as an adjunct to medical therapy, reduces the incidence of death or MI among CAD patients with significant ischemia remains unknown. 18

Questions to answered next: Among stable patients with moderate-tosevere provokable cardiac ischemia and preserved cardiac function would an initial strategy of cardiac catheterization followed by revascularization (PCI or CABG) and OMT be superior to a strategy of OMT alone for reducing the incidence of death or MI. Pharmacologic vs Revascularization Therapy for Stable CAD Critical Caveats in Interpreting Studies Field of PCI very rapidly evolving, with dramatic improvements in preventing restenosis: Balloon angioplasty (PTCA) Bare metal stents (BMS) Drug eluting stents (DES) Newer stent platforms Field of pharmacologic vascular protection and plaque stabilization also very rapidly evolving with dramatic improvements in medical outcomes A Comprehensive Approach to Managing Obstructive Coronary Artery Disease! Revascularization to relieve symptoms 19