A Pharmacodynamic Evaluation
of Switching from Ticagrelor to
Prasugrel in Subjects with
Stable Coronary Artery Disease:
Results 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
Introduction
 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 oncedaily dosing regimen due to adherence issues
 However, the pharmacodynamic (PD) effects of
switching from ticagrelor to prasugrel are unknown
Introduction
 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
 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
 >50% PRI by the VASP assay
ASA= aspirin; BID=twice-daily; CAD= Coronary Artery Disease; HPR=high on-treatment platelet reactivity, MD=maintenance dose; PRI=platelet reactivity
index, PRU=P2Y12 reaction units, VASP-P=vasodilator stimulated phosphoprotein phosphorylation assay; QD= once-daily
Study Hypothesis
 Hypothesis
• 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
BID=twice-daily; MD=maintenance dose; PRU=P2Y12 reaction units; QD=once-daily
SWAP-2: Study design
Patients with stable CAD on low-dose ASA
not indicated for P2Y12 receptor antagonist
Baseline platelet function studies followed by
ticagrelor 180 mg LD/90 mg MD
every 12 h post LD
Run-in phase
3 – 5 days
Platelet function studies 12 h post last ticagrelor MD and prior
to randomized study drug (pre-randomization baseline)
Prasugrel 60 mg LD +
10 mg MD QD
Prasugrel 10 mg MD
QD
Ticagrelor 90 mg MD
BID
Platelet function studies at 2, 4, 24 and 48 hours and 7 days post first dose
of randomized study drug
ASA=aspirin, CAD=Coronary Artery Disease; BID=twice-daily, h=hours, LD=loading dose, MD=maintenance dose, QD=once-daily
SWAP-2: Subjects
Inclusion criteria
Exclusion criteria
 Male and female subjects aged
18-75 y, ≥60 kg, stable CAD,
low dose daily ASA (75-150 mg)
for ≥7 days prior to screening
 Need for P2Y12 receptor
antagonist therapy within 12
months of an ACS or PCI
 Stable CAD defined as
 Use of antiplatelet agents
except ASA (warfarin, NSAIDs,
or COX-2 inhibitors)
•
History of positive stress test
•
Previous coronary revascularization
•
Angiographic demonstration of CAD
 Strong inducers/inhibitors of
CYP3A4
•
At least moderate plaque by CT
angiography
 High doses of simvastatin or
lovastatin (>40 mg/d)
•
Electron beam CT coronary artery
calcification score ≥100 Agatston
units
 Active peptic ulcer
 History of TIA/stroke
ACS=Acute Coronary Syndrome, ASA=aspirin, CAD=Coronary Artery Disease; COX-2=cyclooxygenase-2, CYP=cytochrome P450, CT=computed tomography,
NSAIDs=nonsteroidal anti-inflammatory drugs, TIA=Transient ischemic attack
SWAP-2: Subject Disposition
Subjects screened (N=167)
Subjects enrolled in run-in period (N=120)
Subjects randomized (N=110)*
Prasugrel 60 mg LD +
10 mg MD QD
(Safety population) (n=34)
Prasugrel 10 mg MD QD
(Safety population)
(n=41)*
Ticagrelor 90 mg MD
BID (Safety population)
(n=35)
Primary analysis
population
(n=31)
Primary analysis
population
(n=34)
Primary analysis
population
(n=33)
*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.
SWAP-2: Baseline Demographics*
Treatment Group
Prasugrel
60 mg LD +
10 mg MD
(n=31)
Prasugrel
10 mg MD
(n=34)
Total
Prasugrel
(n=65)
Ticagrelor
(n=33)
P
value†
57.5 (10.1)
58.9 (8.5)
58.2 (9.3)
61.8 (7.0)
0.057
22 (71.0)
24 (70.6)
46 (70.8)
25 (75.8)
0.641
Weight, mean (SD), kg
96.9 (18.0)
95.1 (19.0)
96.0 (18.4)
88.3 (18.0)
0.054
BMI, mean (SD), kg/m2
32.9 (6.0)
32.5 (6.1)
32.7 (6.0)
29.2 (4.7)
0.004
Diabetes
14 (45.2)
11 (32.4)
26 (38.5)
5 (15.2)
0.021
HTN
24 (77.4)
25 (73.5)
49 (75.4)
22 (66.7)
0.473
Hyperlipidemia
30 (96.8)
29 (85.3)
59 (90.8)
29 (87.9)
0.729
2 (6.5)
1 (2.9)
3 (4.6)
2 (6.1)
1.00
Characteristic
Age, mean (SD), y
Male, n (%)
Medical History, n (%)
Peripheral arterial
disease
*primary population, †total prasugrel group vs ticagrelor
SWAP-2: Primary Endpoint
150
LS mean difference = 46.0
95% CI = 24.9, 67.2
p<0.001
PRU (mean ± SD)
125
100
75
50
25
0
Prasugrel total
Ticagrelor
After 7 days of randomized treatment
•
The upper 95% CI limit exceeded 45 PRU and did not reach the primary noninferiority endpoint
•
Sensitivity analysis correcting for imbalances in baseline characteristics did not
alter the results
SWAP-2: PRU Over Time
350
300
Prasugrel 60 mg LD/
10 mg MD
Prasugrel 10 mg MD
Prasugrel Total
Ticagrelor
PRU (mean ± SD)
250
200
230
208
150
100
50
0
Pre-Run-In
Baseline
Pre2 hrs Post 4 hrs Post 24 hrs Post 48 hrs Post 7 Days Post
Rand.
First
First
First
First
First
Baseline
Rand.
Rand.
Rand.
Rand.
Rand.
Dose
Dose
Dose
Dose
Dose
•
PRU increased at 24 and 48 hours in the prasugrel MD only group relative to pre-randomization values
•
Smaller 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 postrandomization
SWAP-2: PRI Over Time
Prasugrel 60 mg LD/
10 mg MD
Prasugrel 10 mg MD
Prasugrel Total
Ticagrelor
100
90
80
PRI (mean  SD)
70
60
50
50
40
30
20
10
0
Pre-Run-In
Baseline
PreRand.
Baseline
2 hrs Post
First
Rand.
Dose
4 hrs Post 24 hrs Post
First
First
Rand.
Rand.
Dose
Dose
48 hrs Post 7 Days Post
First
First
Rand.
Rand.
Dose
Dose
•
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
SWAP-2: HPR Status
PRU  230
Prasugrel 60 mg LD/
10 mg MD
Prasugrel 10 mg MD
Ticagrelor
100
Percent of Subjects
80
60
*p<0.01 vs. ticagrelor
40
*
*
20
0
Pre-Run-in
Pre-Rand.
2-Hr
4-Hr
24-Hr
48-Hr
7-Day
•
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
SWAP-2: HPR Status
PRI > 50%
Prasugrel 60 mg LD/
10 mg MD
Prasugrel 10 mg MD
Ticagrelor
100
Percent of Subjects
80
*
60
*p<0.01 vs. ticagrelor
†
p<0.05 vs. ticagrelor
†
40
†
20
0
•
Pre-Run-in
Pre-Rand.
2-Hr
4-Hr
24-Hr
48-Hr
7-Day
Rates of HPR were higher at 24 and 48 hours and at 7 days in both prasugrel groups
SWAP-2: Adverse Events
 Both prasugrel and ticagrelor were well tolerated
 Serious adverse events: only in 1 patient (ticagrelor group) and
were considered unrelated to study drug
 Incidence of dyspnea:
• Prasugrel: 0%
• Ticagrelor: 3.3% (n=4) during run-in phase; 2.9% (n=1) randomized
 Minor bleeding (mostly mild ecchymosis):
• Prasugrel: 10.7% (n= 8)
• Ticagrelor: 20.0% (n=7)
 No deaths or ischemic events observed during the course of the
study
SWAP-2 Conclusions
 SWAP-2 did not achieve the primary objective of
demonstrating non-inferiority of PD response after
switching from ticagrelor to prasugrel after 7 days of
treatment
 Results suggest a PD interaction when switching from
ticagrelor to prasugrel that is partially mitigated with
administration of a LD of prasugrel
 This is associated with higher rates of HPR in the first
24-48 hours after switching, which diminishes by 7 days
of treatment
 The optimal timing between the discontinuation of
ticagrelor and the administration of a LD of prasugrel
remains to be determined
Thank you to all the SWAP-2
investigators and study
coordinators
Investigators
Dr. Richard Anderson
Paul Gurbel, MD
University Hospital of Wales
Sinai Center for Thrombosis Research
Health Park, UK
Sinai Hospital of Baltimore, US
Dominick J. Angiolillo, MD, PhD
Dr. Thomas Johnson
University of Florida College of Medicine, US
Bristol Heart Institute, UK
Dr. James Cotton
Douglas K. Logan, MD
New Cross Hospital, UK
Medpace Clinical Pharmacology Unit, US
James Feldman, MD
Samuel Oberstein, MD
West Houston Area Clinical Trial
Clinical Pharmacology of Miami, Inc., US
Consultants, LLC, US
Randeep Suneja, MD
Professor Nicholas P. Curzen
Cardiology Center of Houston, US
Southampton General Hospital, UK
James Walder, MD
Professor Anthony H. Gershlick
Black Hills Cardiovascular Research, US
Department of Cardiovascular Science
University of Leicester, UK
Alexander White, MD
Progressive Medical Research, US