Evidence Based Secondary Prevention Christopher Cannon, M.D. TIMI

Evidence Based Secondary Prevention Christopher Cannon, M.D. TIMI

Evidence Based Secondary Prevention Christopher Cannon, M.D. TIMI Study Group Cardiovascular Division Brigham and Womens Hospital Boston, MA Presenter Disclosure Information Christopher P. Cannon, MD 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 2 Phases of ACS Treatment Acute (<24hrs) 1. 2. 3. 4. 5. 6. 7. ASA Clopidogrel Heparin/LMWH GP IIb/IIIa inhibitors Beta-blockers Nitrates ACE inhibitors Long-term

(Discharge) Libby P. Circ 2001;104:365, 1. 2. 3. 4. 5. 6. ASA Clopidogrel Beta-blockers ACE Inhibitors Statins Risk factor + Lifestyle ss Two Targets of Therapy in ACS: Culprit + Multiple Vulnerable Plaques Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarction Multiple vulnerable plaques detected in non-culprit segments 1-7 Culprit lesion (#8) detected with thrombus (red) ACS, acute coronary syndrome. Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288. Multiple vulnerable plaques detected in non-culprit segments 10-12

UA/NSTEMI 2002 ACC/AHA UA/NSTEMI Guidelines: Risk Factor Modification 1. 2. 3. 4. 5. 6. 7. 8. 9. Smoking cessation Achieve optimal weight Daily exercise AHA Diet HTN control BP < 130/85 Tight control of glucose in DM Statin for LDL > 130 mg/dL. Lipid-lowering LDL>100mg/dL A fibrate or niacin if HDL < 40 Medical 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 Braunwald E, et al. 2002. Available at: http://www.acc.org % of patients with death, MI or ,rehospitalization for ACS Death, MI or ACS Rehospitalization In First 30 days 5

Hazard ratio = 0.72 (CI 0.52,0.99) P=0.046 4 Pravastatin 40 mg 3 Atorvastatin 80 mg 2 1 0 0 5 10 15 20 25 Days following randomization KK Ray et al. JACC 2005 30 CHD Event Rates in Secondary Prevention and ACS Trials 30 y = 0.1629x 4.6776 R = 0.9029 p < 0.0001 CHD Events (%) 25

4S-P 20 HPS-P 4S-S 15 LIPID-P HPS-S A2Z 20 CARE-P A2Z 80 TNT 10 LIPID-S IDEAL S20/40 PROVE-IT-AT TNT 80 CARE-S IDEAL A80 PROVE-IT-PR 10 5 0 30 50 70 90 110 130 150 170 190 210 LDL Cholesterol (mg/dl) Updated from - OKeefe, J. et al., J Am Coll Cardiol 2004;43:2142-6. Meta-Analysis of Intensive Statin Therapy Event Rates Coronary Death or MI

Odds Reduction Odds Ratio (95% CI) No./Total (%) High Dose Std Dose PROVE IT-TIMI 22 -17% 147/2099 (7.0) 172/2063 (8.3) A-to-Z -15% 205/2265 (9.1) 235/2232 (10.5) TNT -21% 334/4995 (6.7) 418/5006 (8.3) IDEAL

-12% 411/4439 (9.3) 463/4449 (10.4) -16% 1097/13798 (8.0) 1288/13750 (9.4) OR, 0.84 95% CI, 0.77-0.91 p=0.00003 Total 0.658451 High-dose better Cannon CP, et al. submitted Cannon CP, et al. 1 1.51872 High-dose worse Meta-Analysis of Intensive Statin Therapy Event Rates All Endpoints Odds Ratio (95% CI) Odds Reduction No./Total (%) High Dose

Std Dose Coronary Death or Any Cardiovascular Event OR, 0.84 95% CI, 0.80-0.89 p<0.0001 -16% 3972/13798 (28.8) 4445/13750 (32.3) Coronary Death or MI OR, 0.84 95% CI, 0.77-0.91 p=0.00003 -16% 1097/13798 (8.0) 1288/13750 (9.4) Cardiovascular Death OR, 0.88 95% CI, 0.78-1.00 p=.054 -12% 462/13798 (3.3)

520/13750 (3.8) Non-Cardiovascular Death OR, 1.03 95% CI, 0.88-1.20 p=0.73 +3% 340/13798 (2.5) 331/13750 (2.4) Total Mortality OR, 0.94 95% CI, 0.85-1.04 P=0.20 -6% 808/13798 (5.9) 857/13750 (6.2) Stroke OR 0.82 95% CI, 0.71-0.96 p=0.012 -18% 316/13798 (2.3)

381/13750 (2.8) 0.5 1 High-dose statin better Cannon CP, et al. Cannon CP, et al. JACC 2006; 48: 438 - 445. 2.5 High-dose statin worse Lipids For LDL: Lower is better ATP III Update 2004: LDL-C Goals and Cutpoints for Therapy in Different Risk Categories Risk Category LDL-C Goal Initiate 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 100 mg/dL > 100 mg/dL (optional goal: (<100 mg/dL: <70 mg/dL) consider drug Rx) Goal <70 mg/dl 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 Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

CURE Major Bleeding at 1 year by ASA Dose ASA (N=6303) Clopidogrel + ASA (N=6259) P-Value ASA Dose: 75-100 mg (N=1927) 1.9% 3.0% 100-200 mg (N=7428) 2.8% 3.4% 200-325 mg (N=2301) 3.7% 4.9% Peters RJG, et al. Circulation 2003;108:1682-1687 0.53 CURE: Benefit of Clopidogrel Therapy at Over first year 31 days - 1 year 0

1 2 Weeks 0.98 0.96 0.94 Placebo + ASA RRR 18% 95% CI 0.700.95 P=0.009 0.90 RRR 21% 95% CI 0.670.92 P=0.003 Clopidogrel + ASA 0.92 0.92 0.94 Placebo + ASA Proportion Event-Free 0.96 Clopidogrel + ASA 0.90 Proportion Event-Free 0.98

1.00 1.00 MI, stroke, CV Death: 030 days 3 4 Yusuf, S. et al for THE CURE Trial Investigators. Circ. 2003;107:966-972. 1 4 6 8 Months 10 12 Benefit of Clopidogrel in PCI With and Without a Stent CV Death/MI NO STENT 0.20 0.06 0.08 0.10 0.12 0.14 CV Death/MI STENT Placebo Clopidogrel 0.10 0.15

Placebo RR: 0.56 (95% CI 0.34-0.95) P=0.03 0.0 0.0 RR: 0.73 (95% CI 0.56-0.95) p=0.02 0.05 0.02 0.04 Clopidogrel 0 100 200 300 Days of Follow up 0 100 200 300 Days of Follow up Mehta SR. ACC 2003 CHARISMA: Treatment Effect on Primary and Secondary Endpoints

Cumulative incidence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization;* N=15,603 Cumulative incidence of MI, stroke, CV death; N = 15,603 10 7% RRR RR 0.93 (0.831.05) P=0.22 15 6 4 Placebo Clopidogrel 2 Events (%) 8 Events (%) 8% RRR RR 0.92 (0.86-0.995) P=0.04 20 10 Placebo Clopidogrel 5 0 0 0

6 12 18 Months *Coronary, cerebral, or peripheral 24 30 0 6 12 18 Months 24 30 Bhatt DL, et al. N Engl J Med. 2006;354: Published online. CHARISMA: Bleeding Endpoints GUSTO criteria; N = 15,603 Event rate number of patients (%) Severe bleeding Fatal bleeding Intracranial hemorrhage Clopidogrel + ASA 130 (1.7) 26 (0.3) 26 (0.3)

Placebo + ASA 104 (1.3) 17 (0.2) 27 (0.3) P .09 .17 .89 164 (2.1) 101 (1.3) <.001 Moderate bleeding GUSTO = Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries. Bhatt DL, et al. N Engl J Med. 2006;354: Published Online. CHARISMA: Primary Endpoint Treatment Effect by Asymptomatic vs Symptomatic MI, stroke, CV death Hazard ratio RR (95% CI) Asymptomatic* n=3284 1.20 (0.911.59) Symptomatic n=12,153 0.88 (0.770.998) All patients N=15,603

0.93 (0.831.05) 0.5 Clopidogrel better 1.0 Placebo better 1.5 *Multiple atherothrombotic risk factors Documented coronary, cerebrovascular, or peripheral arterial disease P = 0.046 Bhatt DL, et al. N Engl J Med. 2006;354:. Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD CAPRIE-like Cohort Primary outcome event rate (%) 10 N=9478 Placebo + ASA 8.8 % 8 Clopidogrel + ASA 7.3 % 6 4

RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 2 0 0 6 12 18 24 Months since randomization Bhatt DL. Presented at ACC 2006. 30 Nordman AJ, et al. Hot Line Session. World Congress of Cardiology, September 3, 2006, Barcelona. Incidence of Late Stent Thrombosis: > 1 Year Per 1,000 pts 7 6 RR = 5.7 p = 0.049 RR = 5.0 p = 0.02 5 p = 0.22 4 3 2

1 0 DES/BMS SES/BMS Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006. In press PES/BMS Conclusions ACS is a manifestation of diffuse atherothrombosis Multiple plaques, inflammation + thrombosis Long-term medical Rx to prevent events: 5 drugs Athero + thrombosis Statins (high-dose) ASA (low-dose) ACE Inhibitor Clopidogrel Beta-blocker

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