expectation of prasugrel use in japanese pci patients · 2016-10-12 · mace：cardiovascular(cv)...

Expectation of Prasugrel Use in Japanese PCI Patients

Sendai Kousei Hospital/Tokyo Kamata Hospital Naoto Inoue, MD, FSCAI, FAHA, FJCC

M Nakamura, T Isshiki, H Ogawa, T Kimura,

H Yokoi, S Nanto, M Takayama, K Kitagawa,

M Nishikawa, S Miyazaki, Y Ikeda, and S Saito

On behalf of PRASFIT Study Investigators Study funded by Daiichi Sankyo Company, Limited

PRASFIT-ACS*:JapicCTI-No: JapicCTI-111550

PRASFIT-Elective**:JapicCTI-No: JapicCTI-101339 * PRASugrel compared to clopidogrel For Japanese PatIenTs with ACS Undergoing PCI

** PRASugrel For Japanese PatIenTs with Coronary Artery Disease Undergoing Elective PCI

Speaker’s name: Naoto Inoue

☑ I have the following potential conflicts of interest to report:

Research contracts ☑ Consulting-Kaneka, Medicon, Fukuda

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

I do not have any potential conflict of interest

66 y.o. Male

NOBORI stent was implanted in LMT in Oct. 2013

Antiplatlet regiemen

Aspirin 100mg, Clopidogrel 75mg

Chest pain and ST elevation in V1-V6 in June 8 2014

Emergent CAG was performed

66 y.o. Male

IABP

DCB 3.5/15mm

66 y.o. Male

Platelet Aggregation Analysis Methods

• VerifyNow® P2Y12 assay

– PRU (P2Y12 reaction unit)

– % Inhibition

P2Y12 PRU 264

Stone G et al

Our case: P2Y12 PRU 264

EM=extensive metabolizer; IM=intermediate metabolizer; PM=poor metabolizer

Frequency of CYP2C19 Genetic Polymorphisms

in the Japanese Population

2-3% 3.5%

4.8%

13-20%

13%

18-23%

Proportion of CYP2C19 PM

across the world

The proportion of CYP2C19 PM is high in

Asia. Prepared from Furuta T. et al: Drug Metab. Pharmacokinet. 20(3), 153-167, 2005

Ratio of CYP2C19 genetic

polymorphism phenotypes among

the Japanese population

One in every 2 Japanese people

have abnormal CYP2C19

metabolism.

EM (extensive metabolizer): Normal CYP2C19 metabolism type

IM (intermediate metabolizer): Underactive CYP2C19 metabolism type

PM (poor metabolizer): Inactive CYP2C19 metabolism type

Yamamoto K. et al: J. cardiol. 57(2), 194-201, 2011 (partly adapted)

n＝201

EM 37 %

I M 44%

P M 19%

Comparison of the on-treatment platelet reactivity

according to CYP2C19 genotype in Japanese patients for DAPT

PM (*2/*2, *2/*3, *3/*3)

n=25

IM (*1/*2, *1/*3)

n=51

EM (CYP2C19 *1/*1)

n=47

8000

6000

4000

2000

0

P<0.05

P<0.05 7000

5000

3000

1000

AU*min

Mann-Whitney U test Mean±SD

*AU:aggregation units. Platelet aggregation (AU min)induced by 20 μmol/L adenosine diphosphate was measured using a light transmission aggregometer.

Yamamoto K. et al. J cardiol. 2011;57:194-201.

EM=extensive metabolizer; IM=intermediate metabolizer; PM=poor metabolizer

Effect of Cytochrome P450 2C19 Polymorphism on Target Lesion Outcome After Drug-Eluting Stent Implantation in Japanese Patients Receiving clopidogrel

Nishio R. et al. Circ J. 2012;76:2348-2355.

MACE free survival curve

EM

IM

MA

CE

fre

e su

rviv

al r

ate

100

80

60

40

20

0

1200 1000 800 600 400 200 0

PM

Time after PCI (days)

*** *

**

(%)

* P=0.007

** P=0.44

***P=0.002

Log-rank test

EM=extensive metabolizer; IM=intermediate metabolizer; PM=poor metabolizer; MACE=major

adverse cardiac event; TLR=target lesion revascularization;

PCI=percutaneous coronary intervention

Difference of drug metabolism

CYP=Cytochrome P450

Clopidogrel Prasugrel

Pro-drug

Inactive metabolite

1st CYP450 oxidation

CYP 1A2 2B6

2C19

CYP 3A 2B6 2C9

2C19

Active metabolite

1st CYP450 oxidation

Intermediate metabolite

esterase

85%

Binding P2Y12

Binding P2Y12

2nd CYP450 oxidation

Active Metabolite

CYP 3A 2B6 2C9

2C19

esterase

Intermediate metabolite

Unchanged

Adapted from N.A.Farid et al. J.Clin.Pharmacol. 50, 126-142, 2010

Results of TRITON-TIMI 38

• Prasugrel 60 mg LD/10 mg MD

• Rapid onset compared to clopidogrel1

• Greater efficacy compared to clopidogrel2

• Increased TIMI Major bleeding2

1 Brandt et al. Am Heart J. 2007 2 Wiviott S et al. NEJM 2007;357:2001-2015

0

5

10

15

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

) 12.1

9.9

Prasugrel

Clopidogrel 1.8

2.4

CV Death / MI / Stroke

TIMI Major

Non-CABG Bleeds

LD: Loading Dose

MD: Maintenance Dose

HR 0.81

(0.73-0.90)

P=0.0004

HR 1.32

(1.03-1.68)

P=0.03

Different Characteristic in Japan and Caucasian of PCI Patients

Japanese Caucasian

Age Higher

(68years) 4

Lower (61years)2

BMI Lower (23.9) 4

Higher (28.5) 2

Body weight Lower Higher

CYP 2C19 IM+PM 3 60-70% 25%

Bleeding risk

for antiplatelet Higher ? Lower?

2 Wiviott S et al. NEJM 2007;357:2001-2015 3 Furuta T et al. Drug Metab. Pharmacokinet. 2005 20(3) 153-167 4 Kimura T et al. Circulation. 2009;119:987-995 5 Hori M APSC2012

2.2

1.1

1.4

1.8

0.7

1.0

0.0

0.5

1.0

1.5

2.0

2.5

Life threatening bleeding

Intracranial bleeding GI major bleeding

Asia

Non-Asia

Bleeding in RE-LY sub analyses Warfarin arm ( Asia vs. non-Asia ) 5

%/y

ear

Phase 1 Single-dose Study Study Design

Ran

do

miz

atio

n

Placebo

(n＝2)

Placebo

(n＝2)

Placebo

(n＝2)

Placebo

(n＝2)

Placebo

(n＝2)

Step 1 Step 2 Step 3 Step 4 Step 5

<Endpoints>

IPA (ADP 20μM induced), bleeding time (Ivy method)

Efient

2 mg (n＝8)

Efient

5 mg (n＝8)

Efient

10 mg (n＝7)

Efient

20 mg (n＝8)

Efient

30 mg (n＝8)

Data for approval review (Phase 1 single-dose study)

Healthy

adult

males

n=49

Japanese Phase I trial: IPA for single ascending dose

time（hr）

（％）

0 1 2 4 8 24

100

50

0

40

30

20

10

60

70

80

90

Prasugrel 30mg（n=8）



Prasugrel 5mg （n=8）

Prasugrel 2mg （n=8）

Placebo （n=10）

Mean± SD

ＩＰＡ

Japanese Healthy volunteers n=49 IPA = Inhibition Platelet Aggregation at ADP20μM

Pla

tele

t inhib

itio

n

Strong

Weak

Phase 2 Dose-finding Study in Patients Undergoing Elective PCI Study Design

<Primary safety endpoint>

Non-CABG-related major bleeding and minor bleeding

<Secondary safety endpoint>

Non-CABG-related major bleeding, minor bleeding, and other clinically relevant bleeding

Prasugrel LD 20 mg, MD 5 mg/day

Clopidogrel LD 300 mg, MD 75 mg/day

PCI performed

(From >6 hours, but within 4 days

after LD administration)

Start day of treatment Day 4 Week 12

3.75 mg in elderly/low-weight patients

Non-elderly/non-low weight patients: Aged <75 years and weighing >50 kg

Elderly/low-weight patients: Aged 75≤ to <85 years and weighing ≤50 but >40 kg

Data for approval review (Phase 2 dose-finding study in patients undergoing elective PC)

n=422

LD : Loading dose

MD : Maintenance dose

Concomitant drug: Aspirin (81 to 100 mg/day)

Prasugrel LD 20 mg, MD 3.75 mg/day

n=141

n=141

n=140

Enrollment

Stenosis confirmed

(CAG or coronary artery CT

2.5 mg in elderly/low-weight patients

Day 1

Coronary

artery

disease

patients

undergoing

elective

PCI Ra

nd

om

iza

tio

n

*** p<0.0001 by paired t test, compared to Pre value

PD analysis set

Platelet aggregation profile of Japanese Phase II dose finding study

(Elective PCI patients)

Low BW：BW ≤50 but >40 kg Elderly：Aged 75≤ to <85 Subjects：CAD patients undergoing PCI (n=370

Method：LDとして、ﾌﾟﾗｽｸﾞﾚﾙ20mgまたはｸﾛﾋﾟﾄﾞｸﾞﾚﾙ300mgをPCI前に投与した。LD投与翌日以降、MDとしてﾌﾟﾗｽｸﾞﾚﾙを 5.0mg/日(低体重または高齢患者では3.75mg)、3.75mg/日(低体重または高齢患者では2.5mg)、ｸﾛﾋﾟﾄﾞｸﾞﾚﾙ75mg/日なお、ｱｽﾋﾟﾘﾝ81～100mg/日を5日間以上反復投与した上で、ﾌﾟﾗｽｸﾞﾚﾙあるいはｸﾛﾋﾟﾄﾞｸﾞﾚﾙと併用投与した。

*** ***

***

*** ***

***

arithmetic mean SD

***

***

***

***

*** ***

arithmetic mean SD

Elderly / Low BW population

Non-Elderly/ Normal BW population

0

100

200

300

400

500

0

100

200

300

400

500

Ｐｒｅ 4W 12W Ｐｒｅ 4W 12W

Prasugrel 20/2.5 mg （n=31） Prasugrel 20/3.75 mg （n=93） Prasugrel 20/5 mg （n=87）

Clopidogrel 300/75 mg （n=91）

Prasugrel 20/3.75 mg （n=34）

Clopidogrel 300/75 mg （n=27） Pla

tele

t aggre

gatio

n

Strong

Weak

PRU

T Isshiki. et al. CVIT 2011

Bleeding profile of Japanese Phase II dose finding study

(Elective PCI patients)

Group （LD/MD mg）

Non-Elderly/ Normal BW population

**Elderly / Low BW population

Prasugrel Clopidogrel

300/75

n = 104


300/75

n = 36 20/3.75 n = 104

20/5 n = 103

20/2.5 n = 37

20/3.75 n = 37

TIMI Major bleeding 0 0 2 （1.9%） 0 0 0

TIMI Minor bleeding 4 （3.8%） 0 1 （1.0%） 0 1 （2.7%） 1 （2.8%）

Clinically relevant bleeding

2 （1.9%） 5 （4.9%） 3 （2.9%） 1 （2.7%） 0 0

Major, minor, and clinically relevant bleeding

6 （5.8%） 5 （4.9%） 6 （5.8%） 1 （2.7%） 1 （2.7%） 1 （2.8%）

*: number of patients （%）

Safety analysis set

**Elderly / Low BW : ≥75year / ≤50kg

Isshiki T. et al. CVIT 2011

• Prasugrel dose for Phase III trial in Japan was set up at 20 mg

LD/3.75 mg MD, regardless of age and body weight.

– Clinically important bleeding events were similar in both the

prasugrel and clopidogrel groups.

– Prasugrel groups provided more potent and consistent inhibition

of platelet aggregation compared with clopidogrel groups.

Results of Japanese Phase II Trial : Confirmed Appropriate Prasugrel Dosage

(n = 104) (n = 103) (n = 104)

Eve

nt

Ra

te(%

)

Non-CABG TIMI Major, Minor bleeding,

Clinically relevant bleeding Bleeding in Phase II Pre Week 4 Week 12

0

50

100

150

200

250

300

350

400

PR

U

arithmetic mean

Prasugrel 20/3.75mg (n=93)

Clopidogrel 300/75mg (n=91)

20/5mg (n=87)

PRU: P2Y12 Reaction Unit

Prasugrel

0%

5%

10%Prasugrel 20/3.75 mg

Clopidogrel 300/75 mg

Prasugrel 20/5 mg

5.8% 4.9% 5.8%

Study Design

Clopidogrel

300 mg LD/ 75 mg MD

Prasugrel

20 mg LD/ 3.75 mg MD

Treatment duration: 24 to 48 weeks

N=1,363

LD: Loading Dose MD: Maintenance Dose

Primary Efficacy Endpoint:

MACE：Cardiovascular(CV) death, Nonfatal MI and Nonfatal ischemic stroke

Safety Endpoints: Non-CABG TIMI major bleed

Inclusion criteria

・chest discomfort or ischemic symptoms

lasting 10 min or more within 72 hours

before randomization

・ST-segment deviation of 1 mm or more,

or T-wave inversion of 3 mm or more,

or elevated levels of a cardiac biomarker of

necrosis

ACS (STEMI, NSTEMI, UA) patients undergoing PCI

Major exclusion criteria

・History of intracranial bleeding or

increased bleeding risk

・Stroke/TIA

・Thienopyridine use within 5 days

before enrollment

Randomized

Preoperative Examination† Randomized

Study Design

PCI

LD: loading dose, MD: maintenance dose †：after preoperative examination, LD(+)/LD(-) selection was determined by investigators

CAD patients (Stable angina, Previous myocardial infarction,

Silent myocardial ischemia) undergoing elective PCI

Treatment duration: 24 to 48 weeks

Clopidogrel 75 mg MD Prasugrel 3.75 mg MD

Clopidogrel

LD 300mg 【before PCI】 or

MD 75mg 14-21days

Prasugrel

LD 20mg 【before PCI】 or

MD 3.75mg 14-21days

Major exclusion criteria

・Unstable angina (within 72 hours after the onset), or acute MI

・ History of intracranial bleeding or increased bleeding risk

・Ischemic stroke with one or more of the following conditions,

1) Required to receive anticoagulation therapy

2) Age 75 years or older

3) Within 6 months after the onset of cerebral infarction

Platelet Aggregation (PRU) at 4w:

Impact of CYP2C19 phenotype

mean

SD

181.2

68.63

195.0

69.98

205.2

74.95

212.7

79.41

247.5

65.13

303.9

41.43 Based on Pharmacodynamics Analysis Set

PRU: P2Y12 Reaction Unit

500

400

300

200

100

0

n=78 n=116 n=46 n=76 n=118 n=42

N.S

PR

U b

y V

eri

fyN

ow

®

*P<0.005

*

*


EM IM PM EM IM PM

Efficacy

Results

Primary Efficacy Endpoint

of TRITON-TIMI 38 and PRASFIT-ACS

30 60 90 180 270 360 450

Prasugrel 60/10mg

Clopidogrel 300/75mg

Days

CV Death / MI / Stroke

Risk

reduction

19%

TRITON-TIMI 38

15

10

5

0

Cu

mu

lati

ve

In

cid

en

ce

of

MA

CE

(%

)

12.1

9.9

11.8 Clopidogrel 300/75 mg

CV Death / MI / Ischemic Stroke

Prasugrel 20/3.75mg

9.4

15

10

5

0

0 30 60 90 120 150 168

Days

Risk

reduction

23%

PRASFIT-ACS

Cu

mu

lati

ve

In

cid

en

ce

of

MA

CE

(%

) Hazard ratio, 0.77

95% CI, 0.56-1.07

Hazard ratio, 0.81

95% CI, 0.73-0.90

2 Wiviott S et al. NEJM 2007;357:2001-2015

Primary Endpoint of

TRITON-TIMI 38 and PRASFIT-ACS

PRASFIT-ACS HR: 0.77, 95% CI [0.56- 1.07]

P-value: 0.12

Follow-up: 24 weeks

Prasugrel

20/3.75 mg

(n = 685)

Clopidogrel

300/75 mg

(n = 678)

0

5

10

15

9.4% 11.8%

Cu

mu

lati

ve i

ncid

en

ce o

f M

AC

E (

%)

HR: 0.81, 95% CI [0.73- 0.90]

P-value: < 0.001

Follow-up: 15 months

TRITON-TIMI 38

Prasugrel

60/10 mg

(n = 6813)

Clopidogrel

300/75 mg

(n = 6795)

0

5

10

15

9.9% 12.1%

Cu

mu

lati

ve i

ncid

en

ce o

f M

AC

E (

%)


TRITON-TIMI 38 / PRASFIT-ACS

Consistency of Primary Endpoint

Hazard Ratio PRASFIT-ACS N Prasugrel Clopidogrel

Japan 1363 9.4 11.8

Prasugrel Better Clopidogrel Better

1 2 0.5

Based on Full Analysis Set

PRASFIT-Elective * ：Test for statistical significance was not conducted

PRASFIT-Elective*

Eve

nt

rate

（%

）

0

5

10

15

4.1%

6.7%

Prasugrel

20/3.75mg

(n = 370)

Clopidogrel

300/75mg

(n = 372)

Follow-up: 24 weeks

PRASFIT-ACS HR: 0.77

95% CI [0.56- 1.07]

Follow-up: 24 weeks

0

5

10

15

9.4%

11.8%

Prasugrel 20/3.75 mg (n = 685)

Clopidogrel 300/75 mg (n = 678)

Even

t ra

te

（%

） Primary Endpoint of PRASFIT-ACS and PRASFIT-Elective


No. at Risk

0.0

2.0

4.0

6.0

8.0

10.0

Cu

mu

lati

ve In

cid

en

ce (

%)

Prasugrel

Clopidogrel

Days after first treatment

370 356 356 356 355 355

372 351 350 350 349 346

0 30 60 90 120 168

Primary Efficacy Endpoint MACE at 24 weeks: Overall


Test for statistical significance was not conducted

Prasugrel 4.1%

Clopidogrel 6.7%

150

353

345

Primary Efficacy Endpoint MACE at 24 weeks: LD (+)/(-)

No. at Risk

0.0

2.0

4.0

6.0

8.0

10.0

Cu

mu

lati

ve

In

cid

en

ce

(%

)

0 30 60 90 120 150

Prasugrel

Clopidogrel

4.1%

6.8%


LD (+) LD (-)

4.0%

6.6%

Prasugrel

Clopidogrel

0 30 60 90 120 168


0.0

2.0

4.0

6.0

8.0

10.0

Cu

mu

lati

ve

In

cid

en

ce

(%

)



150 168

Clopidogrel 266 251 251 251 250 247 246

Prasugrel 269 259 259 259 258 258 257 101 97 97 97 97 97 96

106 100 99 99 99 99 99

Endpoints

Prasugrel

N=370

Clopidogrel

N=372

n (%) n (%)

MACE 15 (4.1) 25 (6.7)

CV death 0 (0.0) 0 (0.0)

Nonfatal MI 12 (3.2) 24 (6.5)

Nonfatal ischemic stroke 3 (0.8) 1 (0.3)

All cause death 0 (0.0) 0 (0.0)

Nonfatal stroke 3 (0.8) 2 (0.5)

Hospitalization for angina 0 (0.0) 1 (0.3)

Revascularization 8 (2.2) 9 (2.4)

Stent thrombosis 0 (0.0) 1 (0.3)

Efficacy Component Endpoints Through 24 weeks



Percentage: (n / n) x 100%

Nonfatal MI 12 (3.2) 24 (6.5)

Nonfatal myocardial infarction Characteristics

Endpoints

Prasugrel

N=370

Clopidogrel

N=372

n (%) n (%)

Nonfatal MI 12 (3.2) 24 (6.5)

Periprocedural (P-MI) 11 (3.0) 19 (5.1)

Spontaneous 1 (0.3) 5 (1.3)




Incid

en

ce o

f P

-MI

(%)

P-MIs were adjudicated according to 3rd universal

definition of myocardial infarction.

P-MI by Peak CK-MB Concentration

3.0

0.5 0.8

1.6

5.1

0.5

1.3

3.2

0

2

4

6


Total P-MI 3-<5*URL 10*URL 5-<10*URL

Periprocedural (P-MI) 11 (3.0) 19 (5.1)

Safety

Results

Non-CABG TIMI-Major Bleeding Events of

TRITON-TIMI 38 and PRASFIT-ACS

PRASFIT-ACS



1.9 % 2.2 %

HR: 0.82, 95% CI [0.39-1.73]

P-value: 0.38

Follow-up: 48 weeks

0

1

2

3

Inc

ide

nc

e (

%)

TRITON-TIMI 38

Prasugrel 60/10 mg (n = 6813)


HR: 1.32, 95% CI [1.03- 1.68]

P-value: 0.03

Follow-up: 15 months

1.7 % 2.2 %

0

1

2

3

Inc

ide

nc

e (

%)

Based on Safety Analysis Set

Incidence: (n / n) x 100%


Non-CABG TIMI Major Bleeding

Subgroup Analysis in PRASFIT-ACS

Incid

en

ce (

%)

Hazard Ratio

P-value

0.77 0.89 0.88 0.65

0.30 0.73 0.55 0.32

1.3

3.6 3.4

1.0

1.7

4.1 3.8

1.4

0

1

2

3

4

5

< 75 years ≥ 75 years =< 60 kg > 60 kg



Incidence: (n / n) x 100

n=520 n=530 n=165 n=148 n=266 n=240 n=418 n=438

≤ 60kg > 60kg < 75 years ≥ 75 years

Age Body Weight



PRASFIT-ACS



0

2

Incid

en

ce

(%

)

1.9 % 2.2 %

1

HR: 0.82, 95% CI [0.39-1.73]

P-value: 0.38

Follow-up: 48 weeks

3

Non-CABG TIMI-Major Bleeding Events of

PRASFIT-ACS and PRASFIT-Elective

PRASFIT-Elective

Prasugrel

20/3.75mg

(n = 370)

Clopidogrel

300/75mg

(n = 372)

0

2

3

0.0 %

Incid

en

ce

(%

)

2.2 %

1


Summary of Efficacy and Safety

Ph III trials for Japanese ACS and elective-PCI patients with 20mg

LD/ 3.75 mg MD of prasugrel were conducted.

Efficacy

• In PRASFIT-ACS, the incidence of MACE at 24 weeks in Prasugrel 20 mg

LD/3.75 mg MD group was 9.4%, while 11.8% in Clopidogrel group.

(Risk reduction*: 23%)

• In PRASFIT-Elective, the incidence of MACE at 24 weeks was 4.1% in the

prasugrel group, and 6.7 % in the clopidogrel group.

Safety

• In PRASFIT-ACS, the incidence of Non-CABG TIMI major bleeding, and the

incidence of TIMI major or minor bleeding or clinically relevant bleeding,

were similar in the prasugrel and clopidogrel groups.

• PRASFIT-Elective study provided efficacy and safety results in CAD with PCI consistent with the results seen in the PRASFIT-ACS study in ACS-PCI.

LD: Loading Dose MD: Maintenance Dose

MACE: Major adverse cardiovascular event

*Risk reduction: 1- HR (Hazard Ratio)

Conclusions

Prasugrel (20mg/3.75mg) demonstrated

a favorable clinical benefit in Japanese patients

with ACS or stable CAD treated with PCI.

Thank you very much!

expectation of prasugrel use in japanese pci patients · 2016-10-12 · mace：cardiovascular(cv)...

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