1. Consistent Reduction in MI with Cangrelor Deepak L
Consistent Reduction in MI with Cangrelor Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, BWH Heart and Vascular Center Professor of Medicine, Harvard Medical School

2. Disclosures for Dr. Bhatt
Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda.
This presentation discusses off-label and/or investigational uses of various drugs and devices.

3. Cangrelor Direct platelet P2Y12 receptor antagonist
ATP analogue MW=800 Daltons
Parenteral administration
T1/2 = 3 to 6 minutes
Offset = 60 minutes N H S C F 3 O P Cl
4Na +
Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.

4. CHAMPION PHOENIX Study DesignOR
Placebo3 oral (right before PCI or right after, per physician)
CHAMPION PHOENIX
N = 10,900 MITT
SA/ NSTE-ACS/ STEMI
Patients requiring PCI1
P2Y12 inhibitor naïve
Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min)
Clopidogrel
600 mg oral
Rand
PCI ~30’
Placebo2 bolus & infusion
Placebo oral OR
Clopidogrel3 (600 mg or 300 mg oral, per physician) 1
2 to 4 hours
1Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis.
Double blind study medication was administered as soon as possible following randomization.
2Study drug Infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of the treating physician. At the end of the infusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy.
3Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time of patient randomization, a clopidogrel loading dose of 600 mg or 300 mg was specified by the investigator.
MITT=modified intent-to-treat; NSTE-ACS=non-ST-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI.

5. Death/ MI/ IDR/ Stent Thrombosis within 48 Hours
cangrelor
clopidogrel
5.9%
4.7%
Event Rate (%)
Log Rank P Value = 0.006
Patient at Risk
Hours from Randomization
Cangrelor:
5472
5233
5229
5225
5223
5221
5220
5217
5213
Clopidogrel:
5470
5162
5159
5155
5152
5151
5147
Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013.

6. Stent Thrombosis within 48 Hours
cangrelor
clopidogrel
1.4%
0.8%
Event Rate (%)
Log Rank P Value = 0.01
Patient at Risk
Hours from Randomization
Cangrelor:
5472
5426
5421
5419
5418
5417
5416
5414
Clopidogrel:
5470
5392
5389
5388
5386
5385
5383
Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013.

7. Non-CABG Bleeding at 48 Hours, Safety
Bleeding Scale
Cangrelor
(N=5529)
Clopidogrel
(N=5527)
OR (95% CI)
P Value
GUSTO Severe
9 (0.16%)
6 (0.11%)
1.50 (0.53,4.22)
0.44
GUSTO Moderate
22 (0.4%)
13 (0.2%)
1.69 (0.85,3.37)
0.13
GUSTO Severe + Moderate
31 (0.6%)
19 (0.3%)
1.63 (0.92,2.90)
0.09
TIMI Major
5 (0.1%)
1.00 (0.29,3.45)
>0.999
TIMI Minor
9 (0.2%)
3 (0.1%)
3.00 (0.81,11.10)
0.08
TIMI Major + Minor
14 (0.3%)
8 (0.1%)
1.75 (0.73,4.18)
0.2
Any Blood Transfusion
25 (0.5%)
16 (0.3%)
1.56 (0.83,2.93)
0.16
ACUITY Major
235 (4.3%)
139 (2.5%)
1.72 (1.39,2.13)
<0.001
ACUITY w/out hematoma
42 (0.8%)
26 (0.5%)
1.62 (0.99,2.64)
0.05
Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013 at

8. IPST in CHAMPION PHOENIX
10,939 pts assessed by a blinded core lab
Reduction of IPST with cangrelor
P Int = 0.77
OR [0.34,1.73]
p=0.52
OR [0.38,1.50]
p=0.42
OR [0.42,0.99]
p=0.04
IPST (%)
OR [0.24,1.05] p=0.06
Généreux P et al. JACC 2013.

9. Effect of Cangrelor on Type 4a MI at 48 hrs Stratified by Peak CK-MB
Peak CK-MB of Incident MI
in CHAMPION-PHOENIX
Cangrelor
n=5470
Clopidogrel
n=5469
OR (95% CI)
3.5% (194)
4.4% (239)
0.80 ( )
≥ 3x ULN
1.2% (106)
1.7% (129)
0.82 ( )
≥ 5x ULN
0.6% (37)
1.1% (62)
0.59 ( )
≥ 10x ULN
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Hazard Ratio
Cangrelor Better
Cavender M, Bhatt, DL, Stone GW, et al and Harrington RA. Circulation 2016.

10. Results: Sensitivity analyses for composite endpoints
Cangrelor (N=5472)
Clopidogrel (N=5470)
Odds Ratio
(95% CI)
Protocol-defined primary endpoint
  4.7%
(257/5470)
  5.9% (322/5469)
0.79 (0.67, 0.93)
Death/MI/IDR/ST
Sensitivity Analyses
Removal of IPST
Death/MI/IDR/ARC-ST
  4.2% (230/5470)
  5.2% (286/5469)
0.80 (0.67, 0.95)
Removal of IPST and MIs solely identified
by CK-MB >3xULN but <10xULN
Death/MI≥10xULN or
Symptoms or ECG/IDR/ARC-ST
  1.9%
(106/5470)
  2.9%
(161/5469)
0.65 (0.51, 0.83)
Removal of IPST and all MIs
solely identified by biomarkers
Death/MI with Symptom or
ECG/IDR/ARC-ST
   1.6% (86/5470)
  2.4% (130/5469)
0.66 (0.50, 0.86)
Favors Cangrelor
Favors Clopidogrel
Cavender M et al. Circulation 2016.

11. Effect of Cangrelor on MI at 48 hrs by SCAI Consensus Defintion
Endpoints with SCAI Criteria for MI*
Cangrelor (N=5472)
Clopidogrel (N=5470
Odds Ratio
(95% CI)
P value
CK-MB ≥10xULN or
MI ≥5xULN + QWAVE
or LBBB
1.0%
(52/5470)
1.4%
(79/5469) 
0.65
(0.46, 0.93)
0.0176 
Death/MI ≥10xULN
or LBBB/IDR/ARC-ST
(79/5470)
2.0%
(112/5469)
0.70
(0.52, 0.94)
0.0159
*Moussa J, et al. J Am Coll Cardiol 2013;62:1563–70)
Cavender M, Bhatt, DL, Stone GW, et al and Harrington RA. Circulation 2016.

12. CHAMPION Trials Study Designs
Randomised, Double Blind, Controlled Trials of patients undergoing PCI
CHAMPION PHOENIX
n=10,942 mITT
SA / NSTE-ACS / STEMI
P2Y12 naïve
Placebo or clopidogrel before or after PCI
Cangrelor bolus then infusion
Clopidogrel
600 mg oral OR
Clopidogrel 600 mg or 300 mg oral
CHAMPION PCI
n=8,667 mITT
SA / NSTE-ACS / STEMI
Placebo or clopidogrel before PCI
Cangrelor bolus then infusion
Clopidogrel
600 mg oral
Clopidogrel
600 mg oral
CHAMPION PLATFORM
n=5,301 mITT
SA / NSTE-ACS
P2Y12 naïve
Placebo or clopidogrel after PCI
Cangrelor bolus then infusion
Clopidogrel
600 mg oral
Clopidogrel
600 mg oral 1
2 hours
Harrington RA, et al. NEJM 2009
Bhatt DL, et al. NEJM 2009
Bhatt DL, et al. NEJM 2013
PCI ~30’

13. Summary of Clinical Efficacy: Pooled Analysis
Death / MI / IDR / ST
OR (95% CI)
p value
p for interaction
PLATFORM
0.72 (0.53, 0.97)
0.0330
PCI
0.90 (0.72, 1.14)
0.3859
PHOENIX
0.79 (0.67, 0.93)
0.0055
Pooled
0.81 (0.71, 0.91)
0.0007
0.4537 ST
0.31 (0.11, 0.85)
0.0157
0.73 (0.33, 1.59)
0.4242
0.62 (0.43, 0.90)
0.0101
0.59 (0.43, 0.80)
0.0008
0.3716
Death / MI / IDR
0.80 (0.67, 0.95)
0.0115
0.81 (0.71, 0.92)
0.0014
0.4681
Death / QMI / IDR
   PLATFORM
0.55 (0.33, 0.93)
0.0224
   PCI
0.66 (0.42, 1.05)
0.0779
   PHOENIX
0.76 (0.53, 1.11)
0.1558
   Pooled
0.68 (0.52, 0.87)
0.0022
0.6093
Cangrelor better
Comparator better
Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet

14. Cangrelor
Mehta SR. Lancet 2013.

15. Alexopolous D, Bhatt DL, Hamm CW, Steg PG, Stone GW
Alexopolous D, Bhatt DL, Hamm CW, Steg PG, Stone GW. Am Heart J 2015;170:3-12

16. CHAMPION PHOENIX Overall and STEMI outcomes, 48 h
Primary Endpoint
Cangrelor
Clopidogrel OR
Overall mITT (N=10,942)
257/5470 (4.7%)
322/5469 (5.9%)
0.78 ( )
STEMI (n=1,991)
27/961 (2.8%)
38/1030 (3.7%)
0.75 ( )
Stent Thrombosis
Overall mITT (N=10,942)
46/5470 (0.8%)
74/5469 (1.4%)
0.62 ( )
STEMI (n=1,991)
12/961 (1.2%)
20/1030 (1.9%)
0.64 ( )
GUSTO sev/mod bleeding
Overall safety (N=11,056)
31/5529 (0.6%)
19/5527 (0.3%)
1.63 ( )
STEMI (n=2,070)
12/1000 (1.2%)
7/1070 (0.7%)
1.84 ( )
Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013;68: and online appendix.

17. Pooled CHAMPION Trials Overall and STEMI outcomes, 48 h
Primary Endpoint
Cangrelor
Clopidogrel OR
Overall mITT* (N=24,910)
473/12,459 (3.8%)
579/12,422 (4.7%)
0·81 ( )
STEMI† (n=2884)
41/1407 (2.9%)
51/1477 (3.5%)
0·84 ( )
Stent Thrombosis
Overall mITT* (N=24,881)
62/12,459 (0.5%)
105/12,422 (0.8%)
0·59 ( )
STEMI (n=2,884)
16/1407 (1.1%)
24/1477 (1.6%)
0.70 ( )
GUSTO sev/mod bleeding
Overall safety* (N=25,107)
103 (0.8%)
79 (0.6%)
1·30 ( )
STEMI (n=3008)
17/1463 (1.2%)
15/1545 (1.0%)
1.20 ( )
* Overall population includes CHAMPION PHOENIX, PCI, and PLATFORM; †STEMI population from PHOENIX and PCI
* Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet 2013; 82:1981–92.

18. Oral Pretreatment in STEMI
Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.

19. Oral Pretreatment in STEMI
Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.

20. Summary
There was a consistent risk reduction with cangrelor irrespective of the exact composite outcome examined.
Specifically for MI, even when all biomarker defined MI were excluded, the treatment effect of cangrelor remained significant.
Compared with clopidogrel, cangrelor reduces important ischemic events, even using the most restrictive definitions of MI and ST.

21. Conclusions In CHAMPION PHOENIX, cangrelor during PCI:
Significantly reduced the primary endpoint (death/MI/IDR/ST)
Significantly reduced the secondary endpoint (ST)
Significantly reduced IPST as assessed by a blinded core lab
Consistently reduced important ischemic events, irrespective of the MI definitions used and including “hard” events
Cangrelor is superior to clopidogrel across the full spectrum of PCI in reducing important clinical events

22. Thank You! Deepak L. Bhatt, MD, MPH
Executive Director of Interventional Cardiovascular Programs,
BWH Heart & Vascular Center Professor of Medicine,
Harvard Medical School
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