1. Prasugrel - New Pharmacodynamic Data: SWAP and OPTIMUS-3 Trials, and Ticagrelor on Platelet Function
Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI
Director of Cardiovascular Research
Assistant Professor of Medicine
University of Florida College of Medicine-Jacksonville

2. Dominick J. Angiolillo, MD, PhD
DISCLOSURES
Dominick J. Angiolillo, MD, PhD
Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below.
Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc.,
Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure
Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson & Johnson
I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation.
I intend to reference Ticagrelor, Elinogrel, Cangrelor, and TRA.

3. The SWitching Anti Platelet (SWAP) Study
Angiolillo DJ et al. Presented at American Heart Association Nov 2009
Angiolillo DJ et al. J Am Coll Cardiol 2010 (in press)

4. SWAP
Background
Prasugrel is associated with greater P2Y12 receptor blockade, greater platelet inhibition, and reduction of ischemic complications compared to clopidogrel in ACS patients undergoing PCI.
Pharmacodynamic studies have shown that treatment with prasugrel results in higher and more consistent levels of platelet inhibition than clopidogrel, even when higher than approved loading or maintenance clopidogrel doses are used.
The effects of switching ACS patients during maintenance phase clopidogrel therapy to prasugrel on platelet function are unknown.

5. SWAP
Objectives
PRIMARY
Evaluate the pharmacodynamic consequence of switching patients on clopidogrel 75 mg maintenance dose (MD) following an ACS event to prasugrel 10 mg MD therapy with or without a loading dose (LD).
SECONDARY
Evaluate the effect of switching from clopidogrel to prasugrel on thienopyridine pharmacodynamic poor responder rates.

6. Study Design SWAP Patient eligible for enrollment 30-330 days post ACS
(Must be prescribed clopidogrel 75 mg)
Daily aspirin mg to continue throughout study
Clopidogrel 75 mg MD x days
Baseline platelet function studies at end of clopidogrel run-in
(139 patients randomized)
Platelet function studies at 2 hours, 24 hours, 7 and 14 days
Prasugrel 60 mg LD,
10 mg MD x days
N=31
Clopidogrel 75 mg MD
x days
N=33
Prasugrel 10 mg MD
N=36

7. Maximum Platelet Aggregation (20 µM ADP)
SWAP
Maximum Platelet Aggregation (20 µM ADP)
Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU

8. Thienopyridine Poor Responders
SWAP
Thienopyridine Poor Responders
Poor Responder Rate at Baseline and 7 Days by Multiple Platelet Function Assays.
Poor responders were defined at baseline (prior to randomization) and at 7 days following start of study drug.
*p<0.05; †p≤0.001;
MPA= Maximal platelet aggregation to 20 mM ADP by LTA; PRU=P2Y12 reaction units; PRI=platelet reactivity index

9. SWAP
Conclusions
Switching ACS patients during maintenance phase clopidogrel therapy to prasugrel:
resulted in significantly lower platelet aggregation by one week, regardless of the platelet function test used.
achieved more rapid platelet inhibition within 2 hours using a LD of prasugrel than without a LD.
associated with reduced poor responder rates.

10. Comparison of the Effects of Prasugrel with Clopidogrel on Platelet Function in Coronary Artery Disease Patients with Type 2 Diabetes Mellitus — Third Optimizing Anti-Platelet Therapy In Diabetes MellitUS (OPTIMUS-3)
Angiolillo DJ et al. Presented at American Heart Association Nov 2009

11. OPTIMUS-3
Background
Patients with diabetes are characterized by enhanced platelet reactivity and decreased response to clopidogrel compared to patients without diabetes.
In TRITON-TIMI-38, the subset of patients with diabetes showed a 30% reduction in the primary composite endpoint of cardiovascular death, MI, or stroke with prasugrel compared with clopidogrel
Specifically designed, randomized studies of pharmacodynamic effects of prasugrel in patients with diabetes and coronary artery disease (CAD) have not been previously performed.

12. Primary Objective OPTIMUS-3
Compare the pharmacodynamic effects of a 60-mg loading dose (LD) of prasugrel vs. clopidogrel 600 mg LD in subjects with diabetes mellitus and CAD using inhibition of platelet aggregation (IPA), as measured by the VerifyNow® P2Y12 assay at 4 hours post-LD.

13. Study Design
OPTIMUS-3
Randomized, two-way, crossover, double-blind study in patients with diabetes and CAD
Enrollment (n=35)
Randomization
Prasugrel 60 mg LD/10 mg MD
Clopidogrel 600 mg LD/150 mg MD
Platelet function studies drawn at
baseline, 1 hr post-LD, 4 hrs post-LD, 24 hrs post-LD, 1 week post-LD
Platelet function studies drawn 1 week post-drug discontinuation
Platelet function studies drawn 1 week post-drug discontinuation
2 Week Washout
Prasugrel 60 mg LD/10 mg MD
Clopidogrel 600 mg LD/150 mg MD
Repeat platelet function studies as above
Including 1 week post-discontinuation
MD= maintenance dose

14. Verify Now®-P2Y12 % Inhibition
OPTIMUS-3
Verify Now®-P2Y12 % Inhibition
***p<0.0001
Mean±SE
Similar findings obtained with MPA to 5 and 20 µM ADP, VASP PRI, and Verify Now® PRU

15. OPTIMUS-3
Conclusions
In patients with diabetes mellitus and CAD, standard dose prasugrel is associated with significantly greater inhibition of platelet function than double-dose regimens of clopidogrel in the acute and maintenance phases of treatment.

16. New pharmacodynamic studies on Ticagrelor
PLATO PLATELET
ONSET/OFFSET
RESPOND
Presented at American Heart Association Orlando, Fl - Nov 2009

17. PLATO PLATELET – VerifyNow P2Y12 assay Maintenance therapy with clopidogrel (C) vs ticagrelor (T)
Storey RF, Angiolillo DJ, et al. Presented at American Heart Association Nov 2009

18. ONSET/OFFSET Study     * * IPA % 20 µM ADP- Final Extent † ‡
Last
Maintenance Dose
100
Loading Dose
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12) * * ‡ † 90
20 µM ADP- Final Extent 80  70 60
IPA % 50  40 30 20 10 
weeks
Onset Maintenance Offset
Time (hours)
Gurbel PA et al. Circulation 2010 18

19. RESPOND
Patients with stable CAD on aspirin (n=98) were administered a 300 mg Clopiogrel load and Non-responders (NR) identified (10% absolute change from baseline in MPA by LTA (20 µM ADP) at 6 – 8 h).
Two-way crossover design (Phase I and Phase II): NR (n=41) and responders (R) (n=57) were randomized to receive either Clopidogrel 600 mg load/75 mg qd for 14 days or Ticagrelor 180 mg load/90 mg bid for 14 days.
Ticagrelor was associated with significantly greater platelet inhibition in both clopidogrel responders and nonresponders (effect not influenced by clopidogrel response status).
Clopidogrel nonresponse was uniformly overcome by ticagrelor.
During switching of therapies, ticagrelor produced a rapid enhancement in platelet inhibition in both clopidogrel responders and nonresponders.
Gurbel PA et al. Circulation (in press)