CHAMPION PLATFORM

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CHAMPION PLATFORM Deepak L. Bhatt, MD, MPH, A.
Michael Lincoff, MD, C. Michael Gibson, MS,
MD, Gregg W. Stone, MD, Steven McNulty, MS,
Gilles Montalescot, MD, PhD, Neal S. Kleiman,
MD, Shaun G. Goodman, MD, Harvey D. White, DSc,
Kenneth W. Mahaffey, MD, Charles V. Pollack, Jr,
MA, MD, Steven V. Manoukian, MD, Petr Widimsky,
MD, DrSc, Derek P. Chew, MBBS, MPH, Fernando
Cura, MD, Ivan Manukov, MD, Frantisek Tousek, MD,
M. Zubair Jafar, MD, Jaspal Arneja, MD, Simona
Skerjanec, PharmD, Robert A. Harrington, MD, on
behalf of the CHAMPION PLATFORM Investigators
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The CHAMPION trial was funded by The Medicines
Company. Statistical analyses were performed by
Duke Clinical Research Institute. Graphical
support was provided by The Medicines
Company. Dr. Bhatt has received (significant)
institutional research support from Astra
Zeneca, Bristol-Myers Squibb, Eisai, Ethicon,
Heartscape, sanofi aventis, The Medicines
Company. This presentation includes off label
and/or investigational uses of drugs.
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Background

• Observational and subgroup analyses have shown
  that pretreatment with oral ADP receptor blockers
  prior to PCI reduces ischemic events
• If there is a need for emergent CABG, however,
  bleeding is increased with currently available
  oral agents
• Furthermore, it is not clear what the optimal
  timing of pretreatment with oral agents may be
  around the time of PCI

Mehta SR, et al Lancet 200135852733. Sabatine
MS, et al JAMA. 20052941224-32.
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CREDO 28-Day Endpoint
Death, MI, or UTVR
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No Pretreatment
8.3
6.8
Pretreatment
18.5 RRR p 0.23
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0
0
7
14
21
28
Days Post-Randomization
Steinhubl SR, et al. JAMA 2002 2882411-20.
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Timing of Loading Dose and 28-Day Endpoint
N Pretreat No Pretreat lt 6 hrs
893 7.9 7.0 6 to 24 hr
851 5.8 9.4
RRR -13.4 P0.56
RRR 38.6 P0.05
RRR 18.5 P0.23
CREDO Per Protocol Overall
Hazard ratio (95 CI)
Steinhubl SR, et al JAMA 2002 2882411-20.
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CREDO Clopidogrel Loading Dose Timing vs Risk of
MACE
Steinhubl SR, et al. JACC 20064793943.
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Cangrelor

• Intravenous ADPP2Y12 receptor antagonist
• Rapid acting quick onset, quick offset
• Plasma half-life of 3 6 minutes
• 60 minutes for return to normal platelet function

Meadows TA and Bhatt DL. Circulation Research
20071001261-1275.
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PLATFORM Study Design
Primary 48 hours Death/MI/IDR Secondary 30
days Death/MI/IDR 1 year Death
Dummy
Placebo infusion

• N 6400
• SA/UA/NSTEMI
• No clopidogrel
• Angiogram and PCI

PCI
R
Cangrelor infusion
Dummy
Randomization
Screening
2 - 4 hr Treatment
Follow-up
Study stopped by IARC, ITT population 5362
SA stable angina , UA unstable angina, NSTEMI
non-ST segment elevation myocardial infarction,
MI myocardial infarction, IDR ischemic-driven
revascularization
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Endpoint Definitions in CHAMPION

• Death - All cause mortality
• Myocardial Infarction (MI)
• Data collection
• 1 baseline, sampling at 2h, 10h, 18h, 24h
• Baseline troponin and CKMB
• Post-baseline CKMB troponin if available
• CEC adjudication
• Followed generally accepted criteria for post-PCI
  MI in 2006
• 3X ULN
• Required 50 increase if baseline CKMB/troponin
  positive
• CKMB primary marker
• CEC rule to exclude elevations lt 6 hrs post
  randomization

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Endpoint Definitions in CHAMPION

• Myocardial Infarction (MI) Continued
• Q-wave-MI
• New Q waves w/duration of gt 0.03 sec in 2
  contiguous leads
• CEC adjudicated
• Ischemia Driven Revascularization (IDR)
• Requires clinical signs or ST changes
• Within 24 hours
• Definite Stent Thrombosis
• Adjudicated as part of IDR
• Angiographically documented re-study for
  documented ischemia
• Acute Within 24 hours
• Subacute Between 24 hours and 30 days

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Statistical Analysis
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CHAMPION PLATFORM Top 10 Enrollers
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Demographics and History
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PLATFORM Presentation
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Presentation and Procedural Characteristics
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Efficacy Endpoints at 48 Hours
5.0
2.0
1.0
0.2
0.5
Cangrelor Better
Comparator (placebo) Better
Primary Analysis
mITT modified intent to treat population
(patients with PCI and study drug), QMI Q-wave
myocardial infarction
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30-Day Time-to-Event AnalysisEndpoint
Death/MI/IDR
P 0.25
Estimated Event Rate ()
Days from Randomization
Patients at risk
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Landmark Analysis 48-Hour/30-Day Stent Thrombosis
0.6
0.5
Estimated Event Rate ()
P0.02
P0.65
0.4
0.2
Days from Randomization
Hours from Randomization
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Landmark Analysis 48-Hour/30-Day Mortality
1.1
1.1
P0.97
0.7
P0.02
Estimated Event Rate ()
0.2
Days from Randomization
Hours from Randomization
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PLATFORM 48-Hour Efficacy Subgroup Analyses, mITT
5.0
2.0
1.0
0.2
0.5
Cangrelor Better
Comparator (placebo) Better
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Bleeding Results at 48 Hours
5.0
2.0
1.0
0.2
0.5
Cangrelor Better
Comparator (placebo) Better
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Transfusions (48 Hours, Non-CABG)High-Risk
Subgroups
5.0
2.0
1.0
0.2
0.5
Cangrelor Better
Comparator (placebo) Better
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Limitations

• Power somewhat limited due to IARC ending trial
  early
• Short time to PCI increases difficulty of
  discerning peri-procedural MI, particularly in
  troponin positive patients
• Primary endpoint negative
• Secondary/prespecified endpoints hypothesis
  generating

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Conclusions

• Difference in primary endpoint not statistically
  significant
• Lower rates of stent thrombosis, mortality
  biologically plausible
• Effect on harder endpoints but not
  periprocedural MI intriguing
• Calls into question the definition of
  periprocedural MI used
• No significant effect on transfusions, even in
  high risk subgroups
• Groin hematomas increased, not unexpected versus
  placebo
• Given these results, further study of cangrelor
  warranted

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For Full Details, See NEJM Online
Bhatt DL, Lincoff AM, Gibson CM, . Harrington
RA. NEJM 2009 361 at www.nejm.org
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Backup Slides
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Summary of Clinical Efficacy
5.0
2.0
1.0
0.2
0.5
Cangrelor Better
Comparator Better
Primary Analysis
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Time to Cath Lab is Decreasing

• Hospitalization to cath lab

FRISC (Lancet 1999) 4 Days
RITA-3(Fox Lancet 2002) 3 Days
CRUSADE(Ryan Circ 2003) 23.4h
ACUITY (Stone NEJM 2006) 19.7h
CHAMPION(PLATFORM) 6.3h
2000
2005
2009
1998
1999
2001
2002
2003
2004
2006
2007
2008
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Benefit of Clopidogrel Pretreatment
Odds ratio 95 CI
Mehta SR, et al Lancet 200135852733.
Sabatine MS, et al JAMA. 20052941224-32.
Mehta SR ESC 2009
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Clopidogrel Response in AMI Patients Stable
Versus Unstable
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20
0
0
from baseline
-20
-20
-40
-40
baseline
4h
24h
2d
Significance between groups P lt 0.01.
Osmancik P et al, Widimsky P. Catheter Cardiovasc
Interv 2009 Aug 7 epub
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30-Day Time-to-Event AnalysisStent Thrombosis
Estimated Event Rate ()
P0.04
Days from Randomization
Patients at risk
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30-Day Time-to-Event AnalysisMortality
P 0.16
Estimated Event Rate ()
Days from Randomization
Patients at risk
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Trial Design PCI and PLATFORM
CHAMPION PCI
600 mg Clopidogrel
Cangrelor infusion

N 9000

R
SA/UA/NSTEMI/STEMI Not Thienopyridine Naive

600 mg Clopidogrel
Enrollment stopped early by IARC Actual
N8885 (98 of planned)
End of PCI procedure
CHAMPION PLATFORM
600 mg Clopidogrel
Cangrelor infusion

N 6400
R

SA/UA/NSTEMI
600 mg Clopidogrel

Thienopyridine Naive
Enrollment stopped early by IARC Actual
N5362 (84 of planned)
End of PCI procedure
Screening
Randomization
Follow
-
up
Drug Infusion
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(No Transcript)
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Global Enrollment - PLATFORM
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CHAMPION PLATFORM Top 15 USA
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CHAMPION PCI PLATFORM Top 10 Enrollers
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Trial Committees
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Trial Committees