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

>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 HypothesisStudy 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 designSWAP-2: Study design

ASA=aspirin, CAD=Coronary Artery Disease; BID=twice-daily, h=hours, LD=loading dose, MD=maintenance dose, QD=once-daily

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

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

3 – 5 daysRun-in phase

SWAP-2: SubjectsSWAP-2: SubjectsInclusion 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

Stable CAD defined as

• History of positive stress test

• Previous coronary revascularization

• Angiographic demonstration of CAD

• At least moderate plaque by CT angiography

• Electron beam CT coronary artery calcification score ≥100 Agatston units

Exclusion criteria

Need for P2Y12 receptor antagonist therapy within 12 months of an ACS or PCI

Use of antiplatelet agents except ASA (warfarin, NSAIDs, or COX-2 inhibitors)

Strong inducers/inhibitors of CYP3A4

High doses of simvastatin or lovastatin (>40 mg/d)

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 DispositionSWAP-2: Subject DispositionSubjects 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)

*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

Male, n (%) 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

Medical History, n (%)

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

Peripheral arterial disease 2 (6.5) 1 (2.9) 3 (4.6) 2 (6.1) 1.00

*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

Pre-Run-in Pre-Rand. 2-Hr 4-Hr 24-Hr 48-Hr 7-Day0

20

40

60

80

100

Prasugrel 60 mg LD/10 mg MDPrasugrel 10 mg MDTicagrelor

*

†

*p<0.01 vs. ticagrelor†p<0.05 vs. ticagrelor

†

PRI > 50%

Per

cen

t o

f S

ub

ject

s

SWAP-2: Adverse EventsSWAP-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 ConclusionsSWAP-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 Thank you to all the SWAP-2 investigators and study investigators and study

coordinatorscoordinators

InvestigatorsInvestigatorsDr. Richard Anderson

University Hospital of Wales

Health Park, UK

 

Dominick J. Angiolillo, MD, PhD

University of Florida College of Medicine, US

 

Dr. James Cotton

New Cross Hospital, UK

 

James Feldman, MD

West Houston Area Clinical Trial

Consultants, LLC, US

 

Professor Nicholas P. Curzen

Southampton General Hospital, UK

 

Professor Anthony H. Gershlick

Department of Cardiovascular Science

University of Leicester, UK

Paul Gurbel, MD

Sinai Center for Thrombosis Research

Sinai Hospital of Baltimore, US

 

Dr. Thomas Johnson

Bristol Heart Institute, UK

 

Douglas K. Logan, MD

Medpace Clinical Pharmacology Unit, US

 

Samuel Oberstein, MD

Clinical Pharmacology of Miami, Inc., US

 

Randeep Suneja, MD

Cardiology Center of Houston, US

 

James Walder, MD

Black Hills Cardiovascular Research, US

 

Alexander White, MD

Progressive Medical Research, US