1. Evidence Based Secondary Prevention Christopher Cannon, M.D. TIMI Study Group Cardiovascular Division Brigham and Women’s Hospital Boston, MA

2. Presenter Disclosure Information DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Research grant support from Accumetrics, AstraZeneca, Merck, Merck/Schering-Plough, and Schering-Plough and has spoken at symposia sponsored by and served on scientific advisory boards for AstraZeneca, Bristol-Myers Squibb, Glaxo Smith Kline, Merck, Pfizer, Sanofi-Aventis, Merck/Schering-Plough, and Schering-Plough Christopher P. Cannon, MD

3. 2 Phases of ACS Treatment Libby P. Circ 2001;104:365, Acute Long-term (<24hrs) (Discharge) 1.ASA 2.Clopidogrel 3.Heparin/LMWH 4.GP IIb/IIIa inhibitors 5.Beta-blockers 6.Nitrates 7.ACE inhibitors 1.ASA 2.Clopidogrel 3.Beta-blockers 4.ACE Inhibitors 5.Statins 6.Risk factor + Lifestyle Δ’s

4. Two Targets of Therapy in ACS: Culprit + Multiple “Vulnerable” Plaques ACS, acute coronary syndrome. Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288. Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarction Multiple “vulnerable” plaques detected in non-culprit segments 10-12 Culprit lesion (#8) detected with thrombus (red) Multiple “vulnerable” plaques detected in non-culprit segments 1-7

5. 1.Smoking cessation 2.Achieve optimal weight 3.Daily exercise 4.AHA Diet 5.HTN control BP < 130/85 6.Tight control of glucose in DM 7.Statin for LDL > 130 mg/dL. 8.Lipid-lowering LDL>100mg/dL 9.A fibrate or niacin if HDL < 40 ACC/AHA UA/NSTEMI Guidelines: UA/NSTEMI 2002 Braunwald E, et al. 2002. Available at: http://www.acc.org Risk Factor ModificationMedical Therapy 1.Aspirin 75 to 325 mg/d 2.Clopidogrel (if ASA not tolerated) 3.ASA + clopidogrel for 9 months 4.  -Blocker 5.Statin and diet if LDL >130 mg/dL 6.Lipid-lowering Rx if LDL >100 p diet 7.ACEI if CHF, EF<0.40, HTN, DM

6. 051015202530 0 1 2 3 4 5 Pravastatin 40 mg Atorvastatin 80 mg Hazard ratio = 0.72 (CI 0.52,0.99) P=0.046 Days following randomization % of patients with death, MI or,rehospitalization for ACS Death, MI or ACS Rehospitalization In First 30 days KK Ray et al. JACC 2005

7. CHD Event Rates in Secondary Prevention and ACS Trials Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6. y = 0.1629x · 4.6776 R² = 0.9029 p < 0.0001 LDL Cholesterol (mg/dl) CHD Events (%) PROVE-IT-PR PROVE-IT-AT CARE-S LIPID-S HPS-S 4S-S HPS-P CARE-P LIPID-P 4S-P 0 5 10 15 20 25 30 507090110130150170190210 TNT 80 TNT 10A2Z 80 A2Z 20 IDEAL S20/40 IDEAL A80

8. High-dose betterHigh-dose worse Odds Reduction Event Rates No./Total (%) High DoseStd Dose -17% 147/2099 (7.0) 172/2063 (8.3) -15% 205/2265 (9.1) 235/2232 (10.5) -21% 334/4995 (6.7) 418/5006 (8.3) -12% 411/4439 (9.3) 463/4449 (10.4) -16% 1097/13798 (8.0) 1288/13750 (9.4) PROVE IT-TIMI 22 A-to-Z TNT IDEAL Total 0.65845111.51872 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 Odds Ratio (95% CI) Meta-Analysis of Intensive Statin Therapy Coronary Death or MI Cannon CP, et al. Cannon CP, et al. submitted

9. High-dose statin betterHigh-dose statin worse Odds Reduction Event Rates No./Total (%) High DoseStd Dose -16% 3972/13798 (28.8) 4445/13750 (32.3) -16% 1097/13798 (8.0) 1288/13750 (9.4) -12% 462/13798 (3.3) 520/13750 (3.8) +3% 340/13798 (2.5) 331/13750 (2.4) -6% 808/13798 (5.9) 857/13750 (6.2) -18% 316/13798 (2.3) 381/13750 (2.8) Coronary Death or Any Cardiovascular Event Coronary Death or MI Cardiovascular Death Non-Cardiovascular Death Total Mortality Stroke 0.512.5 OR 0.82 95% CI, 0.71-0.96 p=0.012 Odds Ratio (95% CI) Meta-Analysis of Intensive Statin Therapy All Endpoints Cannon CP, et al. OR, 0.94 95% CI, 0.85-1.04 P=0.20 OR, 1.03 95% CI, 0.88-1.20 p=0.73 OR, 0.88 95% CI, 0.78-1.00 p=.054 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 OR, 0.84 95% CI, 0.80-0.89 p<0.0001 Cannon CP, et al. JACC 2006; 48: 438 - 445.

10. Lipids “For LDL: Lower is better”

11. Risk CategoryLDL-C GoalInitiate TLC Consider Drug Therapy Very High risk: ACS, or CHD w/ DM,mult CRF <70 mg/dL  70 mg/dL > 70 mg/dL High risk: CHD or CHD risk equivalents (10-year risk >20%) If LDL <100 mg/dl <100 mg/dL (optional goal: <70 mg/dL) Goal <70 mg/dl  100 mg/dL > 100 mg/dL (<100 mg/dL: consider drug Rx) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) <100 mg/dL  130 mg/dL > 130 mg/dL (100-129 mg/dL: consider drug Rx) Moderate risk: 2+ risk factors ( risk <10%) <130 mg/dL  130 mg/dL > 160 mg/dL Lower risk: 0-1 risk factor <160 mg/dL  160 mg/dL >190 mg/dL ATP III Update 2004: LDL-C Goals and Cutpoints for Therapy in Different Risk Categories Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

12. Clopidogrel + ASA (N=6259) ASA (N=6303) ASA Dose: 75-100 mg (N=1927) 1.9% 3.0% 0.53 100-200 mg (N=7428) 2.8% 3.4% 200-325 mg (N=2301) 3.7% 4.9% Major Bleeding at 1 year by ASA Dose CURE P-Value Peters RJG, et al. Circulation 2003;108:1682-1687

13. Proportion Event-Free CURE: Benefit of Clopidogrel Therapy at Over first year Months 0.90 0.92 0.94 0.96 0.98 1.00 14681012 Weeks Proportion Event-Free 0.90 0.92 0.94 0.96 0.98 1.00 01234 RRR 21% 95% CI 0.67–0.92 P=0.003 Clopidogrel + ASA Placebo + ASA MI, stroke, CV Death: 0–30 days Yusuf, S. et al for THE CURE Trial Investigators. Circ. 2003;107:966-972. 31 days - 1 year RRR 18% 95% CI 0.70–0.95 P=0.009 Clopidogrel + ASA Placebo + ASA

14. Benefit of Clopidogrel in PCI With and Without a Stent Days of Follow up Placebo 300 100 200 0 0.0 0.02 0.04 0.06 0.08 0.10 0.12 Clopidogrel RR: 0.73 (95% CI 0.56-0.95) p=0.02 Clopidogrel Placebo RR: 0.56 (95% CI 0.34-0.95) P=0.03 300 100 200 0 0.0 0.05 0.10 0.15 0.20 Days of Follow up CV Death/MI STENT CV Death/MI NO STENT Mehta SR. ACC 2003 0.14

15. CHARISMA: Treatment Effect on Primary and Secondary Endpoints Bhatt DL, et al. N Engl J Med. 2006;354: Published online. Cumulative incidence of MI, stroke, CV death; N = 15,603 7% RRR RR 0.93 (0.83–1.05) P=0.22 Months 10 8 6 4 2 0 0612182430 Placebo Clopidogrel Events (%) 20 15 10 5 0 0612182430 Months Placebo Clopidogrel 8% RRR RR 0.92 (0.86-0.995) Events (%) P=0.04 Cumulative incidence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization ; * N=15,603 *Coronary, cerebral, or peripheral

16. CHARISMA: Bleeding Endpoints Event rate number of patients (%) Clopidogrel + ASA Placebo + ASAP Severe bleeding Fatal bleeding Intracranial hemorrhage 130 (1.7) 26 (0.3) 104 (1.3) 17 (0.2) 27 (0.3).09.17.89 Moderate bleeding164 (2.1)101 (1.3)<.001 Bhatt DL, et al. N Engl J Med. 2006;354: Published Online. GUSTO criteria; N = 15,603 GUSTO = Global Utilization of Streptokinase and t- PA for Occluded Coronary Arteries.

17. n=3284 n=12,153 N=15,603 CHARISMA: Primary Endpoint Treatment Effect by Asymptomatic vs Symptomatic MI, stroke, CV death *Multiple atherothrombotic risk factors † Documented coronary, cerebrovascular, or peripheral arterial disease ‡ P = 0.046 0.51.01.5 Placebo better Clopidogrel better Asymptomatic* Symptomatic † All patients Hazard ratioRR (95% CI) 1.20 (0.91–1.59) 0.88 (0.77–0.998) ‡ 0.93 (0.83–1.05) Bhatt DL, et al. N Engl J Med. 2006;354:.

18. Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort” RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 Primary outcome event rate (%) 0 2 4 6 8 10 Months since randomization 0 612182430 Clopidogrel + ASA 7.3 % Placebo + ASA 8.8 % Bhatt DL. Presented at ACC 2006. N=9478

19. Nordman AJ, et al. Hot Line Session. World Congress of Cardiology, September 3, 2006, Barcelona.

20. Incidence of Late Stent Thrombosis: > 1 Year RR = 5.7 p = 0.049 RR = 5.0 p = 0.02 p = 0.22 Per 1,000 pts 0 1 2 3 4 5 6 7 DES/BMSSES/BMSPES/BMS Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006. In press

21. Conclusions ACS is a manifestation of diffuse atherothrombosis ACS is a manifestation of diffuse atherothrombosis –Multiple plaques, inflammation + thrombosis Long-term medical Rx to prevent events: 5 drugs “Athero + thrombosis”Long-term medical Rx to prevent events: 5 drugs “Athero + thrombosis” Statins (high-dose) ASA (low-dose) ACE Inhibitor Clopidogrel Statins (high-dose) ASA (low-dose) ACE Inhibitor Clopidogrel Beta-blocker Beta-blocker