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
