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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
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.
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)
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.
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.
SWAP
Study Design
Patient eligible for enrollment 30-330 days post ACS
(Must be prescribed clopidogrel 75 mg)
Daily aspirin 81-325 mg to continue throughout study
Clopidogrel 75 mg MD x 13-15 days
Baseline platelet function studies at end of clopidogrel run-in
(139 patients randomized)
Clopidogrel 75 mg MD
x 13-15 days
N=33
Prasugrel 10 mg MD
x 13-15 days
N=36
Prasugrel 60 mg LD,
10 mg MD x 13-15 days
N=31
Platelet function studies at 2 hours, 24 hours, 7 and 14 days
SWAP
Maximum Platelet Aggregation (%)
Maximum Platelet Aggregation (20 µM ADP)
100
Placebo LD/Clopidogrel 75 mg MD (n=33)
Placebo LD/Prasugrel 10 mg MD (n=36)
Prasugrel 60 mg LD/10 mg MD (n=31)
80
60
*
*
40
*†
*†
**
20
* p<0.0001 vs clopidogrel 75 mg MD
† p<0.0001 vs prasugrel 10 mg MD
Mean±SE
0
02
12
Time, hours
24
4
6
8 10 12 14
Time, days
Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU
SWAP
Thienopyridine Poor Responders
Poor Responder Rate at Baseline and 7 Days by
Multiple Platelet Function Assays.
100
Poor Responder Rate (%)
80
60
40
20
*
†
†
0
Baseline 7 days Baseline 7 days Baseline 7 days Baseline 7 days
MPA >65%
MPA >50%
PRU >235
PRI >=50%
Clopidogrel 75 mg
Combined Prasugrel Groups
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
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.
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
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.
OPTIMUS-3
Primary Objective
• 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.
OPTIMUS-3
Study Design
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
OPTIMUS-3
Verify Now®-P2Y12 % Inhibition
350
VN-P2Y12 %
Inhibition
PRU
100
300
250
80
200
60
150
B
A
LD
LD
***
MD
MD
Washout
Washout
***
***
***
***
***
40
100
20
50
0
0
***
***
Mean±SE
0 4
24
0 4 Hours post LD 24
Hours post LD
***p<0.0001
7 days
7 days
No study drug
No(7
study
drug
days)
(7 days)
prasugrel 60 mg LD/10 mg MD
clopidogrel 600 mg LD/150 mg MD
Similar findings obtained with MPA to 5 and 20 µM ADP, VASP PRI, and Verify Now® PRU
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.
New pharmacodynamic studies
on Ticagrelor
PLATO PLATELET
ONSET/OFFSET
RESPOND
Presented at American Heart Association Orlando, Fl - Nov 2009
PLATELET REACTION UNITS (PRU)
PLATO PLATELET – VerifyNow P2Y12 assay Maintenance
therapy with clopidogrel (C) vs ticagrelor (T)
500
****
****
400
300
235
PRU
200
100
0
C
T
Trough
Storey RF, Angiolillo DJ, et al. Presented at American Heart Association Nov 2009
C
T
Peak
ONSET/OFFSET Study
100
Loading
Dose
Last
Maintenance
Dose *
* * *
90
*
Ticagrelor (n=54)
*
Clopidogrel (n=50)
Placebo (n=12)
*
80
†

20 µM ADP- Final Extent
*
70
IPA %
60
50

*
40
‡
30
†
20
10
0
0
.5
1
2
Onset
Gurbel PA et al. Circulation 2010
4
8
24
6 weeks


0
2
4
8
Maintenance
24 48 72 120 168 240
Offset
Time (hours)
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 2010 (in press)