Evidence Based Secondary Prevention

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Evidence Based Secondary Prevention
Christopher Cannon, M.D. TIMI Study
Group Cardiovascular Division Brigham and
Womens Hospital Boston, MA
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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
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2 Phases of ACS Treatment
Acute Long-term
(lt24hrs) (Discharge)
Libby P. Circ 2001104365,

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 ?s

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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)
Multiple vulnerable plaques detected in
non-culprit segments 10-12
ACS, acute coronary syndrome. Asakura M, et al. J
Am Coll Cardiol. 2001371284-1288.
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ACC/AHA UA/NSTEMI Guidelines
Risk Factor Modification Medical Therapy

• Aspirin 75 to 325 mg/d
• Clopidogrel (if ASA not tolerated)
• ASA clopidogrel for 9 months
• ?-Blocker
• Statin and diet if LDL gt130 mg/dL
• Lipid-lowering Rx if LDL gt100 p diet
• ACEI if CHF, EFlt0.40, HTN, DM

1. Smoking cessation
2. Achieve optimal weight
3. Daily exercise
4. AHA Diet
5. HTN control BP lt 130/85
6. Tight control of glucose in DM
7. Statin for LDL gt 130 mg/dL.
8. Lipid-lowering LDLgt100mg/dL
9. A fibrate or niacin if HDL lt 40

Braunwald E, et al. 2002. Available at
http//www.acc.org
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Death, MI or ACS Rehospitalization In First 30
days
5
Hazard ratio 0.72 (CI 0.52,0.99) P0.046
Pravastatin 40 mg
4
3
of patients with death, MI or
,rehospitalization for ACS
Atorvastatin 80 mg
2
1
0
0
5
10
15
20
25
30
Days following randomization
KK Ray et al. JACC 2005
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CHD Event Rates in Secondary Prevention and ACS
Trials
30
y 0.1629x 4.6776R² 0.9029p lt 0.0001
4S-P
25
20
HPS-P
LIPID-P
CHD Events ()
4S-S
15
HPS-S
CARE-P
LIPID-S
10
PROVE-IT-AT
CARE-S
PROVE-IT-PR
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 2004432142-6.
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Meta-Analysis of Intensive Statin Therapy
Coronary Death or MI
Odds Reduction Event Rates No./Total () Event Rates No./Total ()
Odds Reduction 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)
Odds Ratio (95 CI)
PROVE IT-TIMI 22
A-to-Z
TNT
IDEAL
Total
OR, 0.84 95 CI, 0.77-0.91 p0.00003
0.658451
1
1.51872
High-dose better
High-dose worse
Cannon CP, et al. submitted
Cannon CP, et al.
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Meta-Analysis of Intensive Statin Therapy All
Endpoints
Odds Reduction Event Rates No./Total () Event Rates No./Total ()
Odds Reduction 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)
Odds Ratio (95 CI)
Coronary Death or Any Cardiovascular Event
Coronary Death or MI
Cardiovascular Death
Non-Cardiovascular Death
Total Mortality
Stroke
OR, 0.84 95 CI, 0.80-0.89 plt0.0001
OR, 0.84 95 CI, 0.77-0.91 p0.00003
OR, 0.88 95 CI, 0.78-1.00 p.054
OR, 1.03 95 CI, 0.88-1.20 p0.73
OR, 0.94 95 CI, 0.85-1.04 P0.20
OR 0.82 95 CI, 0.71-0.96 p0.012
0.5
1
2.5
High-dose statin better
High-dose statin worse
Cannon CP, et al.
Cannon CP, et al. JACC 2006 48 438 - 445.
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Lipids

• For LDL Lower is better

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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 lt70 mg/dL ?70 mg/dL gt 70 mg/dL
High risk CHD or CHD risk equivalents (10-year risk gt20) If LDL lt100 mg/dl lt100 mg/dL (optional goal lt70 mg/dL) Goal lt70 mg/dl ?100 mg/dL gt 100 mg/dL (lt100 mg/dL consider drug Rx)
Moderately high risk 2 risk factors (10-year risk 10 to 20) lt100 mg/dL ?130 mg/dL gt 130 mg/dL (100-129 mg/dL consider drug Rx)
Moderate risk 2 risk factors ( risk lt10) lt130 mg/dL ?130 mg/dL gt 160 mg/dL
Lower risk 0-1 risk factor lt160 mg/dL ?160 mg/dL gt190 mg/dL
Adapted from Grundy, S. et al., Circulation
2004110227-39.
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Major Bleeding at 1 year by ASA Dose
CURE
Clopidogrel ASA (N6259)
ASA (N6303)
P-Value

• ASA Dose
• 75-100 mg (N1927) 1.9 3.0
  0.53
• 100-200 mg (N7428) 2.8
  3.4200-325 mg (N2301) 3.7 4.9
  

Peters RJG, et al. Circulation 20031081682-1687
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CURE Benefit of Clopidogrel Therapy at Over
first year
31 days - 1 year
MI, stroke, CV Death 030 days
1.00
1.00
Clopidogrel ASA
0.98
0.98
Clopidogrel ASA
0.96
0.96
Proportion Event-Free
Proportion Event-Free
Placebo ASA
Placebo ASA
0.94
0.94
RRR 21 95 CI 0.670.92 P0.003
0.92
0.92
RRR 18 95 CI 0.700.95 P0.009
0.90
0.90
1
4
6
8
10
12
0
1
2
3
4
Months
Weeks
Yusuf, S. et al for THE CURE Trial
Investigators. Circ. 2003107966-972.
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Benefit of Clopidogrel in PCI With and Without a
Stent
CV Death/MI NO STENT
CV Death/MI STENT
0.14
0.20
0.12
Placebo
Placebo
0.15
0.10
0.08
0.10
Clopidogrel
0.06
Clopidogrel
0.04
0.05
RR 0.73 (95 CI 0.56-0.95) p0.02
RR 0.56 (95 CI 0.34-0.95) P0.03
0.02
0.0
0.0
300
100
200
0
100
200
0
Days of Follow up
Days of Follow up
Mehta SR. ACC 2003
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CHARISMA Treatment Effect on Primary and
Secondary Endpoints
Cumulative incidence of MI, stroke, CV death,
hospitalization for UA, TIA, revascularization
N15,603
Cumulative incidence of MI, stroke, CV death N
15,603
8 RRR
10
20
RR 0.92 (0.86-0.995)
7 RRR
P0.04
8
RR 0.93 (0.831.05)
15
P0.22
6
Events ()
10
Events ()
4
Placebo
Placebo
5
Clopidogrel
Clopidogrel
2
0
0
0
6
12
18
24
30
0
6
12
18
24
30
Months
Months
Bhatt DL, et al. N Engl J Med. 2006354
Published online.
Coronary, cerebral, or peripheral
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CHARISMA Bleeding Endpoints
GUSTO criteria N 15,603
Event ratenumber of patients () 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) lt.001
GUSTO Global Utilization of Streptokinase and
t-PA for Occluded Coronary Arteries.
Bhatt DL, et al. N Engl J Med. 2006354
Published Online.
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CHARISMA Primary EndpointTreatment Effect by
Asymptomatic vs Symptomatic
MI, stroke, CV death
Hazard ratio
RR (95 CI)
n3284
Asymptomatic
1.20 (0.911.59)
n12,153
Symptomatic
0.88 (0.770.998)
N15,603
All patients
0.93 (0.831.05)
0.5
1.0
1.5
Placebo
Clopidogrel
better
better
Multiple atherothrombotic risk
factors Documented coronary, cerebrovascular, or
peripheral arterial disease P 0.046
Bhatt DL, et al. N Engl J Med. 2006354.
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Primary Endpoint (MI/Stroke/CV Death) in Patients
with Previous MI, IS, or PADCAPRIE-like Cohort
N9478
Bhatt DL. Presented at ACC 2006.
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Nordman AJ, et al. Hot Line Session. World
Congress of Cardiology, September 3, 2006,
Barcelona.
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Incidence of Late Stent Thrombosis gt 1 Year
Per 1,000 pts
RR 5.7 p 0.049
RR 5.0 p 0.02
p 0.22
Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM
2006. In press
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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