CHARISMA: CHARISMA: The “CAPRIE-like” CohortThe “CAPRIE-like” Cohort

Deepak L. Bhatt MD, FACC, FSCAI, FESC, FACP

Associate Director, Cleveland Clinic Cardiovascular Coordinating Center

Staff, Cardiac, Peripheral, and Carotid Intervention

Associate Professor of Medicine

Disclosure

Dr. Bhatt has served as a consultant to: Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, sanofi aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex.

Honoraria are donated to NPOs.

Principal Investigator for CHARISMA, co-PI of CHAMPION, and co-chair of REACH, as well as other potentially related studies – no personal compensation, though the Cleveland Clinic does receive research funding.

This presentation discusses off-label and/or investigational uses of aspirin, AZD6140, cangrelor, clopidogrel, prasugrel, drug-eluting stents.

Sponsors – C5Sponsors – C5

• Abraxis

• Alexion Pharma

• AstraZeneca

• Atherogenics

• Aventis

• Biosense Webster

• Biosite

• Boehringer Ingelheim

• Boston Scientific

• Bristol-Myers Squibb (BMS)

• Cardionet

• Centocor

• Converge Medical Inc.

• Cordis

• Dr. Reddy’s

• Abraxis

• Alexion Pharma

• AstraZeneca

• Atherogenics

• Aventis

• Biosense Webster

• Biosite

• Boehringer Ingelheim

• Boston Scientific

• Bristol-Myers Squibb (BMS)

• Cardionet

• Centocor

• Converge Medical Inc.

• Cordis

• Dr. Reddy’s

• Edwards Lifesciences

• Esperion

• GE Medical

• Genentech

• Gilford

• GSK

• Guidant

• J&J

• Kensey-Nash

• Lilly

• Medtronic

• Merck

• Mytogen

• Novartis

• Edwards Lifesciences

• Esperion

• GE Medical

• Genentech

• Gilford

• GSK

• Guidant

• J&J

• Kensey-Nash

• Lilly

• Medtronic

• Merck

• Mytogen

• Novartis

• Novo Nordisk

• Orphan Therapeutics

• P&G Pharma

• Pfizer

• Roche

• Sankyo

• Sanofi-Aventis

• Schering-Plough

• Scios

• St. Jude Medical

• Takeda

• TMC

• VasoGenix

• Viacor

• Novo Nordisk

• Orphan Therapeutics

• P&G Pharma

• Pfizer

• Roche

• Sankyo

• Sanofi-Aventis

• Schering-Plough

• Scios

• St. Jude Medical

• Takeda

• TMC

• VasoGenix

• Viacor

CAPRIE: Superior Efficacy of Clopidogrel versus ASA

*MI, ischemic stroke or vascular death†Intent-to-treat analysis (n=19,185)

CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

Months of follow-up

Cu

mu

lati

ve e

ven

t ra

te*

(%)

ASA

Clopidogrel

8.7%† RRR (p=0.043)

20

Patients with recent ischemic stroke, recent MI or symptomatic PAD

CAPRIE: Clopidogrel Provides Amplified Benefit in Patients with High Vascular Risk

Ringleb PA, Bhatt DL, Hirsch AT, et al. Stroke 2004; 35: 528–532.

*MI, ischemic stroke or vascular death;mean duration of treatment was 1.6 years

5.8%

10.2%

5.3%

8.8%

0

2

4

6

8

10

All CAPRIE patients

(n=19,099)

Prior history of major acute event

(MI or stroke; n=4496)

Eve

nt

rate

/yea

r* (

%)

ASA

Clopidogrel

12

p=0.043

RRR 8.7%

RRR 14.9%

p=0.045

Months of Follow-up

Yusuf S, et al. N Engl J Med. 2001;345:494-502.

CURE Study: Primary End Point: MI/Stroke/CV Death

Clopidogrel + Aspirin(n=6259)

Placebo + Aspirin(n=6303)

P <.001N=12,562

3 6 90 12

20%Relative RiskReduction

0.12

0.14

0.10

0.06

0.08

0.00

0.04

0.02

Cu

mu

lati

ve H

aza

rd R

ate

Mehta SR, et al. Lancet. 2001;358:527-533.

.00

.05

.10

.15

0 10 100 300 400200

Cu

mu

lati

ve H

aza

rd R

ate

Clopidogrel + Aspirin(n=1313)

31% RelativeRisk Reduction

Placebo + Aspirin(n=1345)Median

time to PCI

Days of Follow-up

12.6%

8.8%

P=.002

PCI-CURE Study: CV Death or MIFrom Randomization

CLARITY: Incidence of CV Death, MI, RI Urgent Revascularization

Sabatine MS, Cannon CP, Gibson CM, et al. N Engl J Med. 2005;352:1179-89.

Days

En

d p

oin

t (%

)

0

5

10

15

0 5 10 15 20 25 30

Placebo + ASA

Clopidogrel + ASA

Odds ratio 0.80(95% CI, 0.65-0.97)

P=0.026

20%

Days since randomization

Eve

nt

(%) 9% relative risk reduction

(P=0.002)

Placebo: 2310 events (10.1%)

Clopidogrel: 2121 events (9.2%)

COMMIT: Incidence of Death, Re-MI, or Stroke at 28 Days

07 14 2821

1

2

3

4

5

6

7

9

8

0

COMMIT Collaborative Group. Lancet. 2005;366:1607.

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 E

ven

t R

ate

(%)

0

2

4

6

8

10

Months Since Randomization

0 6 12 18 24 30

Clopidogrel + ASAPlacebo + ASA

N=9,478

* Post hoc analysis.

Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

8.8%8.8%

7.3%7.3%

Primary Endpoint (MI/Stroke/CV Death) in Patients With Previous MI, IS, or PAD*

“CAPRIE-like Cohort”

*Post hoc analysis.

Cardiovascular Death/MI/StrokePlacebo Clopidogrel HR (95% CI) P value

Prior MI 8.3% 6.6% 0.774 (0.613, 0.978)

0.031

Prior IS 10.7% 8.4% 0.780 (0.624, 0.976)

0.029

Prior PAD 8.7% 7.6% 0.869 (0.671, 1.125)

0.085

Entire Cohort 8.8% 7.3% 0.829 (0.719, 0.956)

0.010

0.5 1 2

Placebo Clopidogrel P value

Prior MI 8.3% 6.6% 0.774 (0.613, 0.978)

0.031

Prior IS 10.7% 8.4% 0.780 (0.624, 0.976)

0.029

Prior PAD 8.7% 7.6% 0.869 (0.671, 1.125)

0.085

Entire Cohort 8.8% 7.3% 0.829 (0.719, 0.956)

0.010

0.5 1 2

Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

10

8

6

4

2

0

CHARISMA―Prior MI

0 6 12 18 24 30

HR=0.774 (95% CI [0.613–0.978])

P=0.031

N=3,846

Pri

mar

y O

utc

om

e E

ven

t R

ate

(%)

Months Since Randomization

8.3%

6.6%

Placebo + ASA

Clopidogrel + ASA

Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

CHARISMA―CAD Without Prior MI

10

8

6

4

2

00 6 12 18 24 30

HR=1.103 (95% CI (0.770–1.580])

P=0.593

N=1,989

Pri

mar

y O

utc

om

e E

ven

t R

ate

(%)

Months Since Randomization

6.3%

5.7%

Placebo + ASA

Clopidogrel + ASA

Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Timing of Severe or Moderate Bleeding

Placebo + ASA

Clopidogrel + ASA

Days Since Randomization

15 60 135 270 450 630 810

0.00008

0.00007

0.00006

0.00005

0.00004

0.00003

0.00002

0.00001

0

Haz

ard

Fu

nct

ion

/d

Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Median Time of Late Stent Thrombosis

p = 0.04p = 0.0003 p = 0.0052

Months

Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006.

0

4

8

12

16

20

DES/BMS SES/BMS PES/BMS

Clinical Presentation of Bare Metal In-stent Restenosis

Clinical Presentation of Bare Metal In-stent Restenosis

Chen MS, John JM, Chew DP, Lee DS, Ellis SG, Bhatt DL. Am Heart J. 2006;151:1260-1264.

Clopidogrel Use and Long-term Clinical Outcomes after DES - Duke Registry

3.1%

7.2%

5.5%6.0%

0%

2%

4%

6%

8%

10%

DES + Clop DES - Clop BMS + Clop BMS - Clop

En

dp

oin

t (

%)

• Adjusted outcomes were analyzed at 24 months

• Patients in the DES with clop. group had significantly lower rates of death or MI than did patients in the DES without clopidogrel group

• Among BMS patients, there were no differences in death or MI

Adjusted rates of death or MI starting at 6 months

Difference = -4.1 ± 3.5

P=.02

Difference = -0.5 ± 2 .7

P=.70

Eisenstein EL, et al. JAMA. 2007;10;297(2):159-168.

Conclusions

• Dual antiplatelet therapy indicated for at least 1 year

after ACS and/or PCI – CURE, PCI CURE, CREDO

• Potential benefit beyond 1 year in patients with prior

ischemic events – CHARISMA subgroup

• Potential benefit beyond 1 year in patients with DES –

registry data