A Pharmacodynamic A Pharmacodynamic Evaluation of Switching Evaluation of Switching from Ticagrelor to from Ticagrelor to Prasugrel in Subjects with Prasugrel in Subjects with Stable Coronary Artery Stable Coronary Artery Disease: Results of the Disease: Results of the SWAP-2 Study SWAP-2 Study Dominick J. Angiolillo, MD, PhD; Nicholas Curzen, BM (Hons), PhD; Paul Gurbel, MD; Paul Vaitkus, MD, MBA; Fred Lipkin, PharmD; Wei Li, PhD; Joseph A. Jakubowski, PhD; Marjorie Zettler, PhD, MPH; Mark B. Effron, MD; and Dietmar Trenk, PhD Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2013.11.032
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A Pharmacodynamic Evaluation of Switching from Ticagrelor to Prasugrel in Subjects with Stable Coronary Artery Disease: Results of the SWAP-2 Study A Pharmacodynamic.
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A Pharmacodynamic Evaluation A Pharmacodynamic Evaluation of Switching from Ticagrelor to of Switching from Ticagrelor to
Prasugrel in Subjects with Prasugrel in Subjects with Stable Coronary Artery Disease: Stable Coronary Artery Disease:
Results of the SWAP-2 StudyResults of the SWAP-2 Study
Dominick J. Angiolillo, MD, PhD; Nicholas Curzen, BM (Hons), PhD; Paul Gurbel, MD; Paul Vaitkus, MD, MBA; Fred Lipkin, PharmD; Wei Li, PhD; Joseph A. Jakubowski, PhD; Marjorie
Zettler, PhD, MPH; Mark B. Effron, MD; and Dietmar Trenk, PhD
Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2013.11.032
Disclosures
Dominick J. Angiolillo: Received payment as an individual for: a) Consulting fee or honorarium from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, Inc., The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular, and PLx Pharma; b) Participation in review activities from Johnson & Johnson, St. Jude, and Sunovion; c) he has received institutional payments for grants from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmith Kline, Otsuka, Eli Lilly, Daiichi Sankyo, Inc., The Medicines Company, AstraZeneca, Evolva; Gilead; and has other financial relationships with Esther and King Biomedical Research Grant
Funding/Support: This study was sponsored by Daiichi Sankyo, Inc., and Eli Lilly and Company
IntroductionIntroduction
More potent platelet P2Y12 receptor inhibitors (prasugrel and ticagrelor) have been developed with improved efficacy, albeit increased bleeding, compared with clopidogrel
In certain clinical situations, switching from ticagrelor to prasugrel may be considered
• e.g. patients who experience dyspnea or use of a once-daily dosing regimen due to adherence issues
However, the pharmacodynamic (PD) effects of switching from ticagrelor to prasugrel are unknown
IntroductionIntroduction
The dissociation rate of ticagrelor and its active metabolite from the P2Y12 receptor would determine if, when switching to prasugrel, there is:
• no change in level of platelet inhibition
• additive platelet inhibition
• blunted/delayed platelet inhibition
The aim of the study was to compare the PD effects of switching from ticagrelor to prasugrel in subjects with stable CAD
Methods Methods Prospective, randomized, multicenter, international (12 sites), open-
label study in subjects with stable CAD on ASA therapy
• Blinded platelet function assessment (VerifyNow® P2Y12 assay and VASP)
Primary endpoint
• PRU by VerifyNow® for prasugrel 10 mg QD MD and ticagrelor 90 mg BID MD after 7 days of randomized treatment
Secondary endpoints
• PRI by VASP assay 2, 4, 24, and 48 hours and 7 days
• PRU by VerifyNow® P2Y12 assay 2, 4, 24, and 48 hours
• Percentage of subjects with HPR, defined as
≥230 PRU and ≥208 PRU by the VerifyNow® P2Y12 assay, and
• Platelet reactivity (PRU) after 7 days of randomized treatment would be non-inferior in subjects who switched from ticagrelor to prasugrel compared with subjects treated continuously with ticagrelor using 45 PRU as the non-inferiority margin for the upper 95% CI limit of the difference
Sample size• Based on the objective of establishing non-inferiority of prasugrel 10 mg
QD MD (based on combined prasugrel-treated subjects) compared with ticagrelor 90 mg BID MD
• Assuming a zero difference in mean PRU between treatment groups, a common standard deviation of 60 PRU, and a drop-out rate not exceeding 15%, a sample size of 105 allows for the 95% CI of the treatment difference to stay within 45 PRU with a probability of 0.90
*4 subjects randomized to Prasugrel 60 mg LD/10 mg MD group inadvertently only received MD and were included in the Prasugrel 10 MD group for analyses. BID=twice-daily, LD=loading dose, MD=maintenance dose, QD=once-daily.
Primary analysis population
(n=31)
Primary analysis population
(n=34)
Primary analysis population
(n=33)
SWAP-2: Baseline Demographics*SWAP-2: Baseline Demographics*Treatment Group
Characteristic
Prasugrel 60 mg LD + 10 mg MD
(n=31)
Prasugrel 10 mg MD
(n=34)
Total Prasugrel
(n=65)
Ticagrelor (n=33)
P value†
Age, mean (SD), y 57.5 (10.1) 58.9 (8.5) 58.2 (9.3) 61.8 (7.0) 0.057
*primary population, †total prasugrel group vs ticagrelor
SWAP-2: Primary EndpointSWAP-2: Primary Endpoint
• The upper 95% CI limit exceeded 45 PRU and did not reach the primary non-inferiority endpoint
• Sensitivity analysis correcting for imbalances in baseline characteristics did not Sensitivity analysis correcting for imbalances in baseline characteristics did not alter the resultsalter the results
Prasugrel total Ticagrelor0
25
50
75
100
125
150
LS mean difference = 46.095% CI = 24.9, 67.2p<0.001
After 7 days of randomized treatment
PR
U (
me
an
± S
D)
SWAP-2: PRU Over TimeSWAP-2: PRU Over Time
• PRU increased at 24 and 48 hours in the prasugrel MD only group relative to pre-randomization values
0
50
100
150
200
250
300
350
Prasugrel 60 mg LD/10 mg MDPrasugrel 10 mg MD
Prasugrel TotalTicagrelor
Pre-Run-In Baseline
Pre-Rand.
Baseline
2 hrs PostFirst
Rand.Dose
4 hrs PostFirst
Rand.Dose
24 hrs PostFirst
Rand.Dose
48 hrs PostFirst
Rand.Dose
7 Days PostFirst
Rand. Dose
230208
PR
U (
mea
n
SD
)
• Smaller increase in the prasugrel LD group compared with the prasugrel MD only groupSmaller increase in the prasugrel LD group compared with the prasugrel MD only group
• PRU was higher in the prasugrel total group compared with the ticagrelor group at 7 days post-randomization
SWAP-2: PRI Over TimeSWAP-2: PRI Over Time
• Results for PRI over time paralleled those of PRU
• PRI was higher in the prasugrel total group compared with the ticagrelor group at 7 days post-randomization
0
10
20
30
40
50
60
70
80
90
100
Prasugrel 60 mg LD/10 mg MDPrasugrel 10 mg MD
Prasugrel TotalTicagrelor
Pre-Run-In Baseline
Pre-Rand.
Baseline
2 hrs PostFirst
Rand.Dose
4 hrs PostFirst
Rand.Dose
24 hrs PostFirst
Rand.Dose
48 hrs PostFirst
Rand.Dose
7 Days PostFirst
Rand. Dose
50
PR
I (m
ean
S
D)
SWAP-2: HPR StatusSWAP-2: HPR Status
• Rates of HPR were higher at 24 and 48 hours in both prasugrel groups. No differences in PRU were observed at 7 days
• Similar findings were observed for PRU ≥208
Pre-Run-in Pre-Rand. 2-Hr 4-Hr 24-Hr 48-Hr 7-Day0
20
40
60
80
100Prasugrel 60 mg LD/10 mg MD
Prasugrel 10 mg MDTicagrelor
*
*
*p<0.01 vs. ticagrelor
PRU 230
Per
cen
t o
f S
ub
ject
s
SWAP-2: HPR StatusSWAP-2: HPR Status
• Rates of HPR were higher at 24 and 48 hours and at 7 days in both prasugrel groups