evidence based secondary prevention christopher cannon, m.d. timi study group cardiovascular...

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