1. Why I Prefer Ticagrelor
ANTIPLATELET CONTROVERSY FOR ACS:
HOW WILL THEY IMPACT OUR PRACTICE?
Why I Prefer Ticagrelor
Dominick J. Angiolillo, MD, PhD
Professor of Medicine
Director - Cardiovascular Research
Program Director – Interventional Cardiology Fellowship
University of Florida College of Medicine - Jacksonville

2. Presenter Disclosure Information
Name: Dominick J Angiolillo
Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below.
Received payment as an individual for:
a) Consulting fee or honorarium from Sanofi, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular and PLx Pharma;
b) Participation in review activities from CeloNova, and Johnson & Johnson, St. Jude.
Institutional payments for grants from:
Glaxo Smith Kline, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc., Novartis, CSL Behring, and Gilead.

3. (prasugrel vs clopidogrel) (ticagrelor vs clopidogrel)
TRITON TIMI 38
(prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)

4. WHY TICAGRELOR?
My Top 10 Reasons

5. WHY TICAGRELOR?
#1. Because I can safely pretreat or use for ad-hoc PCI in non pre-treated patients

6. Pretreatment with Ticagrelor in STEMI
ATLANTIC: 1862 patients with STEMI randomized to ticagrelor pretreatment or no pretreatment
Co-primary endpoints
Secondary endpoints
Pre-H
In-H P
Definite ST ≤24 h 0%
0.8%
0.008
30-d definite ST
0.2%
1.2%
0.02
Death
1.1%
0.08 MI
0.4%
0.53
Stroke
0.1%
0.39
Bleeding ≤48 h
2.6%
2.5%
0.87
Bleeding >48 h
2.0%
1.7%
0.63
P=0.63
P=0.82
Montalescot G, et al. N Engl J Med. 2014;371:

7. 1° Efficacy End Point at 7 + 30 days (All Patients)
Primary Efficacy and Safety Endpoints
1° Efficacy End Point at days (All Patients)
All TIMI (CABG or non-CABG)
Major Bleeding (All Treated patients)
Montalescot et al. N Engl J Med. 2013;369:

8. Angiolillo DJ et al JACC 2016 (in press)
Ad-Hoc PCI Trial
Time Course of PRU
350
300
250
200
150
100 50
Baseline
Mean PRU (95% CI)
0.5
End of PCI 2
Post LD (h) 8 T
icagrelor (n=45)
Clopidogrel (n=47)
p<0.05
p<0.001
Mean time to end of PCI 0.6 h
Angiolillo DJ et al JACC 2016 (in press)

9. switch from clopidogrel
WHY TICAGRELOR?
#2. Because I can safely
switch from clopidogrel

10. Wallentin L et al. N Engl J Med. 2009;361:1045-57
PLATO: Study design
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive
randomised within 24 hours of index event
(N=18,624)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
Wallentin L et al. N Engl J Med. 2009;361:

11. #3. Because of mortality benefit
WHY TICAGRELOR?
#3. Because of mortality benefit

12. Ticagrelor: The First and Only Oral Antiplatelet to Demonstrate Superior Reductions in CV Death vs Clopidogrel
Primary Endpoint (CV death, MI, Stroke)
HR 0.84
(0.77–0.92)
p= NNT = 54 12
Clopidogrel
11.7 11 10
N=18,624
9.8 9
Ticagrelor 8
CV death
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79
(0.69–0.91)
p= NNT = 90 7
Cumulative incidence (%) 6 5 4
Ticagrelor significantly reduced the rate of the composite endpoint of CV death, MI, and stroke v. clopidogrel (Relative Risk Reduction 16%, Absolute Risk Reduction 1.9%; p=0.0003), Number Needed to Treat (NNT)=54.
For every 54 ACS patients treated with ticagrelor for one year, one life will be saved, compared to patients treated with clopidogrel
These results support ticagrelor use to decrease the rate of clinically-important thrombotic events, those that represent major adverse cardiovascular events, in patients planned for invasive procedures and patients intended for medical management.
References
Wallentin L, et al.New Engl J Med. 2009;361. 3 2 1 60
120
180
360
Days after randomization
Wallentin L, et al. N Engl J Med. 2009;361: 14

13. WHY TICAGRELOR?
#4. Because of its unique pharmacology (not just like any other P2Y12 receptor antagonist!)

14. Cattaneo M, et al. J Am Coll Cardiol. 2014;63:2503-9
Tissue damage
Hypoxia
ATP
ATP
CD39
ADP
ADP
CD73
AMP
AMP
Adenosine kinase
Adenosine
Adenosine
Adenosine deaminase
ENT1
Inosine
Hypoxanthine A1 A3
A2A
A2B
Xanthine Gi Gi Gs Gs
Cell
Uric Acid
Adenylyl Cyclase
Ticagrelor
cAMP
Cattaneo M, et al. J Am Coll Cardiol. 2014;63:2503-9

15. Cattaneo M, et al. J Am Coll Cardiol. 2014;63:2503-9
Ticagrelor
Adenosine F
NH2 N HN F N HO N N O N HO N N O N N S HO OH OH OH
↑ Adenosine-induced increases in coronary blood flow (dogs and humans)
↑ Endothelial function (ACS patients)
↑ Vasodilation
↑ Endothelial progenitor cell migration
↓ Incidence of MACE (ACS patients)
↑ ST-segment resolution (ACS patients)
↓ CV and all cause mortality (ACS patients)
↑ Incidence of ventricular pauses (ACS patients)
↓ Infarct size (animal models)
↓ Ischemia/reperfusion injury
Induces pharmacological preconditioning
↓ Electrical conduction
↑ Adenosine-induced platelet inhibition (in vitro)
↓ Mortality (ACS patients with pulmonary infection)
↑ Platelet inhibition
Modulates inflammation
↑ Creatinine levels (ACS patients)
↓ Glomerular filtration
↑ Incidence of dyspnea (ACS patients)
↑ Adenosine-induced dyspnea (healthy subjects)
↑ Incidence of dyspnea
Cattaneo M, et al. J Am Coll Cardiol. 2014;63:2503-9

16. WHY TICAGRELOR?
#5. Because its benefits are across the ACS spectrum, irrespective of management (invasive vs non-invasive)

17. Mortality reduction in invasive and non-invasive treatment strategies10
Non-invasive HR, 0.75, 95% CI: (0.61–0.93)
6.1%
8.2%
N=5216 8 6
All-cause mortality (%)
5.0% 4
3.9% 2
N=13408
Invasive HR, 0.81, 95% CI: (0.68–0.95) 60
120
180
240
300
360
Number at risk
Invasive Ticagrelor Clopidogrel
Non-invasive Ticagrelor Clopidogrel
Days after randomization
James S et al. BMJ Jun 17;342:d3527

18. Primary Efficacy Endpoint to 30 Months (Age < 75 years)
HR (95% CI) ≤ 1 Year:
0.99 (0.84, 1.16)
HR (95% CI) > 1 Year:
0.72 (0.54, 0.97)
HR (95% CI):
0.91 (0.79, 1.05)
P = 0.21
Interaction P = 0.07
Roe MT et al. N Engl J Med ;367:

19. accrues over time (even >12 months)
WHY TICAGRELOR?
#6. Because its benefit
accrues over time (even >12 months)

20. Newer P2Y12 Inhibitors in STEMI
STEMI Cohorts in PLATO (N=7544) and TRITON-TIMI 38 (N=3534)
TRITON
PLATO
Primary Efficacy Endpoint
Time (Days) 5 10 15 50
100
150
200
250
300
350
400
450
Proportion of patients (%)
9.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=41
p=0.02
RRR=21%
p=0.002
RRR=32%
6.5
N=3534
P=0.02
N=7544
P=0.07
Primary Efficacy Endpoint 2 4 8 12 6 10
Clopidogrel
Ticagrelor
Cumulative incidence (%)
10.8
9.4
p=0.07
RRR=13%
Clopidogrel
Prasugrel
HR=0.87 (0.75 to 1.01) NNT=71
Time (Months)
Montalescot G et al., Lancet. 2009;373:723-31
Steg PG et al. Circulation. 2010;122:

21. Long-term secondary prevention with ticagrelor
PEGASUS: 21,162 patients with prior MI randomized to ticagrelor 90 mg bid, ticagrelor 60 mg bid, or placebo 3 6 9 12 15 18 21 24 27 30 33 36 1 2 4 5 7 8 10
Placebo
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
9.04% Placebo
7.85% 90 mg bid
7.77% 60 mg bid
Event rate (%)
Ticagrelor 90 mg vs placebo HR 0.85 (95% CI 0.75–0.96) P=0.008
By the way, this is consistent with a new trial in a dfferent population, but targeting a similar question
Ticagrelor 60 mg vs placebo HR 0.84 (95% CI 0.74–0.95) P=0.004
Months from randomisation
No. at risk
Placebo
90 mg bid
60 mg bid
7067
7050
7045
6979
6973
6969
6892
6899
6905
6823
6827
6842
6761
6769
6784
6681
6719
6733
6508
6550
6557
6236
6272
6270
5876
5921
5904
5157
5243
5222
4343
4401
4424
3360
3368
3392
2028
2038
2055
Bonaca MP, et al. N Engl J Med 2015;372:

22. WHY TICAGRELOR?
#7. Because I can crush the tablets without loss of platelet inhibition (or even better platelet inhibition)

23. Ticagrelor crushed tablets in STEMI
MOJITO: 82 STEMI patients randomized to crushed or integral ticagrelor 180-mg LD
P2Y12 Reactivity Units
P=0.006
Parodi G, et al. J Am Coll Cardiol. 2015;65:511-2

24. WHY TICAGRELOR?
#8. Because transition from cangrelor will be compatible and smooth (“cangrelor-friendly”)

25. Transition between Cangrelor and Ticagrelor
12 patients with stable CAD on aspirin and 180 mg of ticagrelor during infusion of cangrelor
Ticagrelor at 75 min
N=6
Ticagrelor at 30 min
N=6
300
250
Ticagrelor
Ticagrelor
200
VerifyNow (PRU)
150
Cangrelor infusion
Cangrelor infusion
100 50 1 2 3 4 5 1 2 3 4 5
Time (h)
Time (h)
Schneider DJ, et al. Am Coll Cardiol Intv 2014;7:435–42

26. WHY TICAGRELOR? #9. Because I can treat a
wide range of patients with less concerns of contraindications or warnings

27. Net Clinical Benefit Bleeding Risk Subgroups
Post-hoc analysis
Risk (%)
Yes
+ 54
Prior Stroke / TIA
-16 No
Pint = 0.006
TICAGRELOR: Benefits Consistent Across All Subgroups and No Subgroup Altered the Relative Risk of Bleeding Complications. -1
>=75
Age
Pint = 0.18
-16
< 75
As a result of the discordance between efficacy and safety with prasugrel –signficant reductions in events at the cost of a significant increase in bleeding we performed a series of post-hoc exploratory analyses to identify subgroups of patients that did not have a favorable net clinical benefit or who had net harm.
The group with a prior cerebrovascular event (shown in red) had more primary endpoint events and increased bleeding with prasugrel, resulting in a significant net clinical benefit favoring clopidogrel. Patients without a prior cerebrovascular event, shown in green, had a net clinical benefit favoring prasugrel. The P value for interaction was significant at
Elderly patients and those with a low body weight (shown in yellow) tended to have better efficacy but more bleeding with prasugrel, resulting in a net clinical benefit near unity. The younger patients and those with higher body weights (shown in green) had siginificant net clinical benefit favoring prasugrel. The interaction P values for the elderly and low weight patients did not reach statistical significance.
< 60 kg +3
Wgt
>=60 kg
Pint = 0.36
-14
-13
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better
Wiviott SD et al. NEJM 2007 HR 29

28. WHY TICAGRELOR?
#10. Because it is being studied across a wide range of patients with atherosclerosis

29. Pipeline of upcoming ticagrelor trials
Participants
Treatment
Primary endpoint
EUCLID
15,328 patients with symptomatic PAD
Ticagrelor 80 mg bid vs clopidogrel 75 mg od
Cardiovascular death, MI, or ischemic stroke at ≤35 months
GLOBAL LEADERS
16,000 patients undergoing PCI
Aspirin plus ticagrelor 90 mg bid for 1 month, then ticagrelor 90 mg twice
All-cause mortality or new Q-wave nonfatal MI at 2 years
HORIZONS AMI II
7,812 patients with STEMI undergoing primary PCI, receiving aspirin, bivalirudin, and cangrelor
Ticagrelor for 1 month, then clopidogrel for 18 months vs ticagrelor for whole study period
Death, MI, stroke, stent thrombosis, or TIMI major and minor bleeding
ISAR-REACT 5
4,000 patients with ACS and a planned invasive treatment strategy
Ticagrel 180 mg loading dose and 90 mg bid maintenance dose vs prasugrel 60 mg loading dose and 10 mg maintenance dose
Death, MI, or stroke at 12 months
SOCRATES
10,560 patients with acute ischaemic stroke or high-risk transiente ischaemic attack
Ticagrelor 180 mg loading dose and 90 mg bid maintenance dose vs aspirin 300 mg loading dose and 100 mg maintenance dose
Stroke, MI, or death at 90 days
THEMIS
19,000 patients with type 2 diabetes mellitus and stable CAD
Ticagrelor 90 mg twice daily vs placebo
Cardiovascular death, MI, or stroke at ≤35 months
TICAB
4,000 patients undergoing CABG
Ticagrelor 90 mg twice daily vs aspirin 100 mg once daily
Franchi F, Angiolillo DJ. Nat Rev Cardiol 2015;12:30-47