Evidence Based Secondary Prevention

Christopher Cannon, M.D.TIMI Study Group

Cardiovascular Division Brigham and Women’s Hospital

Boston, MA

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

2 Phases of ACS Treatment2 Phases of ACS Treatment

Libby P. Circ 2001;104:365,

AcuteAcute Long-term Long-termAcuteAcute Long-term Long-term(<24hrs) (Discharge)

1. ASA2. Clopidogrel3. Heparin/LMWH4. GP IIb/IIIa inhibitors 5. Beta-blockers6. Nitrates7. ACE inhibitors

1. ASA2. Clopidogrel 3. Beta-blockers4. ACE Inhibitors5. Statins6. Risk factor + Lifestyle Δ’s

Two Targets of Therapy in ACS: Two Targets of Therapy in ACS: Culprit + Multiple “Vulnerable” Culprit + Multiple “Vulnerable”

Plaques 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

1.1. Smoking cessation Smoking cessation 2.2. Achieve optimal weight Achieve optimal weight 3.3. Daily exerciseDaily exercise4.4. AHA Diet AHA Diet 5.5. HTN control BP < 130/85HTN control BP < 130/856.6. Tight control of glucose in DMTight control of glucose in DM7.7. Statin for LDL > 130 mg/dL. Statin for LDL > 130 mg/dL. 8.8. Lipid-lowering LDL>100mg/dL Lipid-lowering LDL>100mg/dL 9.9. A fibrate or niacin if HDL < 40 A fibrate or niacin if HDL < 40

ACC/AHA UA/NSTEMI ACC/AHA UA/NSTEMI Guidelines:Guidelines:UA/NSTEMI 2002

Braunwald E, et al. 2002. Available at: http://www.acc.org

Risk Factor Modification 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

0 5 10 15 20 25 300

1

2

3

4

5Pravastatin 40 mg

Atorvastatin 80 mg

Hazard ratio = 0.72 (CI 0.52,0.99)

P=0.046

Days following randomization

% o

f p

atie

nts

wit

h d

eath

, MI o

r ,r

eho

spit

aliz

atio

n

for

AC

SDeath, MI or ACS Rehospitalization

In First 30 days

KK Ray et al. JACC 2005

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 · 4.6776R² = 0.9029p < 0.0001

LDL Cholesterol (mg/dl)

CH

D E

ven

ts (

%)

PROVE-IT-PR

PROVE-IT-AT CARE-S

LIPID-S

HPS-S4S-S

HPS-P

CARE-P

LIPID-P

4S-P

0

5

10

15

20

25

30

30 50 70 90 110 130 150 170 190 210

TNT 80TNT 10A2Z 80

A2Z 20

IDEAL S20/40IDEAL A80

High-dose better High-dose worse

Odds Reduction

Event Rates

No./Total (%)

High Dose Std 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

0.658451 1 1.51872

OR, 0.8495% CI, 0.77-0.91p=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

High-dose statin better High-dose statin worse

Odds Reduction

Event Rates

No./Total (%)

High Dose Std 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

0.5 1 2.5

OR 0.8295% CI, 0.71-0.96p=0.012

Odds Ratio (95% CI)

Meta-Analysis of Intensive Statin Therapy All Endpoints

Cannon CP, et al.

OR, 0.9495% CI, 0.85-1.04P=0.20

OR, 1.0395% CI, 0.88-1.20p=0.73

OR, 0.8895% CI, 0.78-1.00p=.054

OR, 0.8495% CI, 0.77-0.91p=0.00003

OR, 0.8495% CI, 0.80-0.89p<0.0001

Cannon CP, et al. JACC 2006; 48: 438 - 445.

LipidsLipids

““For LDL: For LDL: Lower is Lower is better”better”

Risk Category LDL-C Goal Initiate TLCConsider

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.

Clopidogrel+ ASA

(N=6259)

ASA

(N=6303)

ASA Dose:ASA Dose:

75-100 mg (N=1927)75-100 mg (N=1927) 1.9% 1.9% 3.0% 3.0% 0.53 0.53

100-200 mg (N=7428) 2.8%100-200 mg (N=7428) 2.8% 3.4% 3.4%

200-325 mg (N=2301) 200-325 mg (N=2301) 3.7%3.7% 4.9% 4.9%

Major Bleeding at 1 year by Major Bleeding at 1 year by ASA DoseASA Dose

CURECURE

P-Value

Peters RJG, et al. Circulation 2003;108:1682-1687

Pro

po

rtio

n E

ven

t-F

ree

CURE: Benefit of Clopidogrel Therapy at Over first year

Months

0.90

0.92

0.94

0.96

0.98

1.00

1 4 6 8 10 12

Weeks

Pro

po

rtio

n E

ven

t-F

ree

0.90

0.92

0.94

0.96

0.98

1.00

0 1 2 3 4

RRR 21%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.Yusuf, S. et al for THE CURE Trial Investigators. Circ. 2003;107:966-972.

31 days - 1 year

RRR 18%RRR 18%95% CI 0.70–0.95 P=0.009

Clopidogrel + ASA

Placebo + ASA

Benefit of Clopidogrel in PCI Benefit of Clopidogrel in PCI With and Without a StentWith and Without a Stent

Days of Follow upDays of Follow up

PlaceboPlacebo

300300100100 20020000

0.0

0.0

0.02

0.02

0.04

0.04

0.06

0.06

0.08

0.08

0.10

0.10

0.12

0.12

ClopidogrelClopidogrel

RR: 0.73 RR: 0.73 (95% CI 0.56-0.95)(95% CI 0.56-0.95)

p=0.02p=0.02

ClopidogrelClopidogrel

PlaceboPlacebo

RR: 0.56 RR: 0.56 (95% CI 0.34-0.95)(95% CI 0.34-0.95)

P=0.03P=0.03

300300100100 20020000

0.0

0.0

0.05

0.05

0.10

0.10

0.15

0.15

0.20

0.20

Days of Follow upDays of Follow up

CV Death/MI STENT CV Death/MI NO STENT

Mehta SR. ACC 2003

0.14

0.14

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% RRRRR 0.93 (0.83–1.05)P=0.22

Months

10

8

6

4

2

00 6 12 18 24 30

PlaceboClopidogrel

Eve

nts

(%

)

20

15

10

5

00 6 12 18 24 30

Months

PlaceboClopidogrel

8% RRRRR 0.92 (0.86-0.995)

Eve

nts

(%

)

P=0.04

Cumulative incidence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization;* N=15,603

*Coronary, cerebral, or peripheral

CHARISMA: Bleeding Endpoints

Event ratenumber of patients (%)

Clopidogrel + ASA

Placebo + ASA P

Severe bleeding

Fatal bleeding

Intracranial hemorrhage

130 (1.7)

26 (0.3)

26 (0.3)

104 (1.3)

17 (0.2)

27 (0.3)

.09

.17

.89

Moderate bleeding 164 (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.

n=3284

n=12,153

N=15,603

CHARISMA: Primary EndpointTreatment Effect by Asymptomatic vs Symptomatic

MI, stroke, CV death

*Multiple atherothrombotic risk factors†Documented coronary, cerebrovascular, or peripheral arterial disease‡P = 0.046

0.5 1.0 1.5Placebobetter

Clopidogrelbetter

Asymptomatic*

Symptomatic†

All patients

Hazard ratio RR (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:.

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

Pri

mar

y o

utc

om

e ev

ent

rate

(%

)

0

2

4

6

8

10

Months since randomization

0 6 12 18 24 30

Clopidogrel + ASA7.3 %

Placebo + ASA8.8 %

Bhatt DL. Presented at ACC 2006.

N=9478

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

Incidence of Late Stent Thrombosis: > 1 Year

RR = 5.7

p = 0.049RR = 5.0

p = 0.02

p = 0.22

Per 1,000 pts

0

1

2

3

4

5

6

7

DES/BMS SES/BMS PES/BMSBavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006. In press

ConclusionsConclusions

• ACS is a manifestation of diffuse ACS is a manifestation of diffuse atherothrombosisatherothrombosis– Multiple plaques, inflammation + Multiple plaques, inflammation +

thrombosisthrombosis

• Long-term medical Rx to prevent events: 5 Long-term medical Rx to prevent events: 5 drugs drugs “ “AtheroAthero + + thrombosisthrombosis””

Statins (high-dose) ASA (low-dose)Statins (high-dose) ASA (low-dose)ACE InhibitorACE Inhibitor Clopidogrel Clopidogrel Beta-blockerBeta-blocker