Emerging Approaches to Antiplatelet Therapy for PCI: Prasugrel

Emerging Approaches to Emerging Approaches to AntiplateletAntiplatelet Therapy for PCI:Therapy for PCI:

PrasugrelPrasugrel

David J. Cohen, M.D., M.Sc.David J. Cohen, M.D., M.Sc.

Director, Cardiovascular ResearchDirector, Cardiovascular ResearchSaintSaint--LukeLuke’’s Mid America Heart Institutes Mid America Heart Institute

Professor of MedicineProfessor of MedicineUniversity of MissouriUniversity of Missouri--Kansas CityKansas City

DisclosuresDisclosures

Grant Support/DrugsGrant Support/Drugs−− Eli Lilly/DaiichiEli Lilly/Daiichi--SankyoSankyo -- Merck/Schering PloughMerck/Schering Plough−− Eisai PharmaceuticalsEisai Pharmaceuticals

Grant Support/DevicesGrant Support/Devices−− MedRADMedRAD -- Boston ScientificBoston Scientific−− Edwards Edwards LifesciencesLifesciences -- Abbott VascularAbbott Vascular−− MedtronicMedtronic

Consulting/Advisory BoardsConsulting/Advisory Boards−− MedtronicMedtronic -- Eli Lilly/DaiichiEli Lilly/Daiichi--SankyoSankyo−− CordisCordis -- BoehringerBoehringer--IngelheimIngelheim

DJC: 4/11

AspirinAspirin

TiclopidineClopidogrelTiclopidineClopidogrel

AbciximabEptifibatide

Tirofiban

AbciximabEptifibatide

Tirofiban

PrasugrelPrasugrelPrasugrel

PrasugrelPrasugrelPrasugrel

Prasugrel: Key Properties• Novel thienopyridine• Prodrug more efficient generation of active

metabolite than clopidogrel No meaningful genetic heterogeneity in

pharmacokinetics or pharmacodynamics• Achieves high levels of IPA rapidly and reliably• 1x/day dosing

Prasugrel: Key Properties• Novel thienopyridine• Prodrug more efficient generation of active

metabolite than clopidogrel No meaningful genetic heterogeneity in

pharmacokinetics or pharmacodynamics• Achieves high levels of IPA rapidly and reliably• 1x/day dosing

Prasugrel vs. Clopidogrel: Active Metabolite Formation

Clopidogrel4-8

85% Inactive Metabolite8

hCE1

2nd Oxidation

CYP1A22B6

2C19CYP3A2B62C9

2C19

Active MetaboliteGenetic variation in CYP2C19 can impair metabolism

1st Oxidation

Hydrolysis

*Prasugrel is not 100% converted to the active metabolite; a portion of the dose is metabolized to inactive metabolites.

Hydrolysis 1st OxidationPrasugrel1-3

hCE2 Active Metabolite*No relevant effect of genetic variation in CYP2C19CYP3A

2B62C92C19

Prasugrel vs. Clopidogrel: Prasugrel vs. Clopidogrel: Healthy Volunteer Crossover StudyHealthy Volunteer Crossover Study

--2020

00

2020

4040

6060

8080

100100IP

A a

t 24

hour

s (%

)IP

A a

t 24

hour

s (%

)

Response to Response to Prasugrel 60 mgPrasugrel 60 mg

Response to Response to Clopidogrel 300 mgClopidogrel 300 mg

Clopidogrel ResponderClopidogrel Responder

Clopidogrel NonClopidogrel Non--responderresponder

Inte

rpat

ient

Inte

rpat

ient

Varia

bilit

yVa

riabi

lity

InterpatientInterpatientVariabilityVariability

From Brandt JT AHJ 153: 66e9,2007

N=66

Inhibition of Platelet Aggregation (IPA):Prasugrel and Clopidogrel Loading Dose

80

60

40

20

0

100

0 4 8 12 16

Time After Administration (h)

Inhi

bitio

n of

Pla

tele

t A

ggre

gatio

n (%

) 20 μM Adenosine Diphosphate*

The relationship between IPA and clinical activity has not been established.

20 24

†P<0.01Mean ± SD

Prasugrel 60 mg Clopidogrel 300 mg

† †††

†

†† †

1. Brandt et al. Am Heart J. 2007;153:66.e9-16.2. Effient Full Prescribing Information.

1 2 6

*Represents healthy subjects in a crossover study who were not on concurrent ASA therapy (n=64).

TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioNWith Prasugrel (TRITON)-TIMI 38

TRITON-TIMI 38

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke

Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy = 14.5 months

N= 13,608

12

10

8

6

4

2

0

Primary Composite Endpoint* Through End of Study

UA/NSTEMI STEMI

Days After Randomization

12

10

0 90 180 450

8

6

4

2

0

HR=0.82 (95% CI, 0.7–0.9)P=0.002

0 90 180 450

HR=0.79 (95% CI, 0.6–1.0)P=0.02

% (n/N)†

Prasugrel 9.3 (469/5044) Clopidogrel 11.2 (565/5030)

% (n/N)†


1. Effient Full Prescribing Information.2. Data on file: #EFF20091204a: DSI/Lilly.

*Composite of CV death, nonfatal MI, or nonfatal stroke.†Observed data.

CV

Dea

th, N

onfa

tal M

I,or

Non

fata

l Str

oke

(%)

TRITON-TIMI 38

CV

Dea

th, N

onfa

tal M

I,or

Non

fata

l Str

oke

(%)

UA/NSTEMI1

3.3

2.4

12.2

9.8†

8.8

6.7†

1.8

1.8

0.8

0.8

7.1*

9.2

9.3*

11.2

2.0

2.2

0.9

0.9

7.0‡

9.1

9.4‡

11.5

CV Death, Nonfatal MI, or Nonfatal

Stroke

Nonfatal MI

NonfatalStroke

CV Death

1240 8

STEMI1 All-ACS2,3

Endpoint (%)

PrasugrelClopidogrel

1.1

1.2

1240 8 1240 8

*P<0.003 vs clopidogrel †P<0.02 vs clopidogrel ‡P<0.001 vs clopidogrel

In the overall study, approximately 40% of MIs occurred periprocedurally and were detected solely by changes in CK-MB.

1. Effient Full Prescribing Information. 2. Data on file: #EFF20091204a: DSI/Lilly. 3. Data on file: #EFF20091204e: DSI/Lilly.

Primary Composite Endpoint* and Components

TRITON-TIMI 38

*Composite of CV death, nonfatal MI, or nonfatal stroke.

Non-CABG TIMI Bleeding

5

Patie

nts

(%)

4.5

3.4

2.2

1.7

2.4

1.9

P=0.002

P=0.029P=0.022

Prasugrel (n=6741)Clopidogrel (n=6716)

Non-CABG TIMI Major or Minor Bleeding

Non-CABG TIMI MajorBleeding

Non-CABG TIMI Minor Bleeding

0

1

2

3

4

Observed rates of fatal bleeding were 0.3% with prasugrel + ASA vs 0.1% with clopidogrel + ASA

TRITON-TIMI 38

The trial only used a 300 mg loading The trial only used a 300 mg loading dose of clopidogreldose of clopidogrel–– we generally use we generally use

600 mg these days600 mg these days

Issues with Prasugrel/TRITONIssues with Prasugrel/TRITON--TIMI 38TIMI 38

PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel

P<0.0001 for each

IPA (%; 20 M ADP)

Hours 14 Days

IPA (%; 20 M ADP)P<0.0001

Prasugrel 10 mg

Clopidogrel 150 mg

N=201

Prasugrel 60 mg

Clopidogrel 600 mg

Wiviott S, et al. Circulation 2007

0

2

4

6

8

0 1 2 3

1

0 306090 180 270 360 450

HR 0.82P=0.01

HR 0.80P=0.003

5.6

4.7

6.9

5.6

Days

Prim

ary

Endp

oint

(%)

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel

Loading Dose Maintenance Dose

Timing of BenefitTiming of Benefit(Landmark Analysis)(Landmark Analysis)

Wiviott SD et al. NEJM 2007;357:2001-15

The benefit of prasugrel was driven The benefit of prasugrel was driven entirely by a reduction in nonentirely by a reduction in non--fatal MIfatal MI



Cum

ulat

ive

Inci

denc

e (%

)

Type 1Spontaneous

Type 2Secondary

Type 3Sudden

Cardiac Death

Type 4PCI-Related

Type 5Peri-CABG

1

0

2

3

4

5

6

7

2.5

n=150

3.4

n=209

0.3

n=19

0.4

n=230.0n=1

0.1n=4

0.1n=4

0.0n=3

Morrow et al. Circulation. 2009;119:2758-2764.

In the TRITON-TIMI 38 trial, there were a total of 1218 MIs. This retrospective analysis classified these MIs using the newly developed classification system from the universal definition of MI, which was developed after the study protocol was complete.

Application of Universal MI Classification to TRITON-TIMI 38 MI Events

4a4.7

6.4

n=424

4a4.1

4.8

n=324

4b0.8

4b1.7

TRITON-TIMI 38

Type of MI

Cum

ulat

ive

Inci

denc

e (%

)

0.90.7

0.60.5

1.81.4

2.8

2.1

3.8

2.8

1

0

2

3

4

1–<2 x ULN 2–<3 x ULN 3–<5 x ULN 5–<10 x ULN ≥10 x ULN


n=109

n=70

n=212

n=331

n=441

Morrow et al. Circulation. 2009;119:2758-2764.

Application of Universal MI Classification to TRITON-TIMI 38 MI Events

TRITON-TIMI 38

Level of CK Elevation

In the TRITON-TIMI 38 trial, there were a total of 1218 MIs. This retrospective analysis classified these MIs using the newly developed classification system from the universal definition of MI, which was developed after the study protocol was complete.

The stent thrombosis rates in TRITON The stent thrombosis rates in TRITON seem very highseem very high–– we donwe don’’t see anything t see anything

like this in our practicelike this in our practice


Stent Thrombosis: All ACS

Days After Randomization

Sten

t Thr

ombo

sis*

(%)

Any Stent PostAny Stent Post--RandomizationRandomization

0

1

2

3

0 50 100 200 300 400 450

HR=0.48 (95% CI, 0.4–0.6)P<0.0001

350250150

% (n/N)†


1. Wiviott et al. Lancet. 2008;371:1353-1363. 2. Data on file: #EFF20091204b: DSI/Lilly.

*Stent thrombosis defined as Academic Research Consortium definite or probable.†Observed data.

TRITON-TIMI 38

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

5

Sten

t Thr

ombo

sis

(%)

Days from Randomization

2

1

Stent Thrombosis (Protocol Defn.)Stent Thrombosis (Protocol Defn.)Drug-eluting Stents (DES) vs. Bare Metal Stents (BMS)Drug-eluting Stents (DES) vs. Bare Metal Stents (BMS)

EstimateP

(log rank)

≥1 DES (N=4630)0.38

2.2%

1 year

All BMS (N=2528) 2.3%

All (N=7158) 2.2%

11--Year Stent Thrombosis: Year Stent Thrombosis: Impact of Impact of Implanted Stent TypeImplanted Stent Type

3.3% 3.3% 3.4% 3.4%

HR [95%CI] =HR [95%CI] =0.98 [0.640.98 [0.64--1.51]1.51]

P = 0.93P = 0.93

22612261 21712171 21472147 21232123 20972097 19001900872872 832832 818818 805805 791791 720720

Number at riskNumber at riskAny DESAny DESBMS onlyBMS only

Def

/Pro

b St

ent T

hrom

bosi

s (%

)D

ef/P

rob

Sten

t Thr

ombo

sis

(%)

00

11

22

33

44

Time in daysTime in days00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300 330330 365365

Any DESAny DESBMS OnlyBMS Only

InvasiveStent thrombosis

Ticagrelor(n=6,732)

Clopidogrel(n=6,676)

HR for ticagrelor(95% CI)

p value*

Stent thrombosis, %

Definite

Probable or definite

Possible, probable, or definite

1.0

1.7

2.2

1.6

2.3

3.1

0.62 (0.45–0.85)

0.72 (0.56–0.93)

0.72 (0.58–0.90)

0.003

0.01

0.003

¶ Evaluated in patients with any stent during the studyTime-at-risk is calculated from the date of first stent insertion in the study or date of randomization* By univariate Cox model

The increased risk of bleeding outweighs The increased risk of bleeding outweighs any benefit in reduced MI and stent any benefit in reduced MI and stent

thrombosisthrombosis


Antiplatelet Therapy in ACSAntiplatelet Therapy in ACS

0

1 08

Placebo APTC CURE TRITON-TIMI 38Single

Antiplatelet RxDual

Antiplatelet RxHigher

IPA

ASA ASA +Clopidogrel ASA +

Prasugrel- 22%

- 20%

- 19%

+ 60% + 38% + 32%

ReducedIschemicEvents

Increased Major

Bleeds

Major or Minor Bleeding in UA/NSTEMI and STEMI Populations

Non-CABG TIMI Major or Minor Bleeding by Age, Weight, and History of TIA/Stroke

10

6

8

Prasugrel Clopidogrel

All-ACS Patients <75 Years, ≥60 kg, and No

History of TIA/Stroke

Patie

nts

(%)

4

2

0Patients ≥75 Years,

<60 kg, or With a History of TIA/Stroke

4.5(21)*

n=6741

3.4(6)*

n=6716

3.5(9)*

n=5390

2.8(4)*

n=5337

8.6(10)*

n=1291

6.2(2)*

n=1318

P=0.002

1. Wiviott et al N Engl J Med. 2007;357:2001-2015.2. Data on file: #EFF20091204h: DSI/Lilly.

*Number of patients with a fatal bleed.

The TRITON-TIMI 38 trial was not designed or powered to demonstrate independent efficacy or safety in patients <75 or ≥75 years, and <60 or ≥ 60 kg and with or without a history of TIA/stroke.

TRITON-TIMI 38

•• While current antiplatelet therapies are efficacious, While current antiplatelet therapies are efficacious, there is substantial room for improvementthere is substantial room for improvement–– particularly particularly in the ACS settingin the ACS setting

•• Prasugrel is the first agent to demonstrate that greater, Prasugrel is the first agent to demonstrate that greater, more rapid, and more uniform platelet inhibition can more rapid, and more uniform platelet inhibition can further reduce ischemic events, but it does come at further reduce ischemic events, but it does come at the price of greater major bleeding. the price of greater major bleeding.

•• Careful patient selection is critical to optimizing the Careful patient selection is critical to optimizing the riskrisk--benefit profile of prasugrelbenefit profile of prasugrel

–– Clinical Factors: Age, Weight, ACS type, diabetesClinical Factors: Age, Weight, ACS type, diabetes–– Novel Factors: Genetics, Platelet function testingNovel Factors: Genetics, Platelet function testing

Conclusions: Emerging Platelet InhibitorsConclusions: Emerging Platelet Inhibitors

Prasugrel is just too expensivePrasugrel is just too expensive–– especially especially compared with generic clopidogrelcompared with generic clopidogrel


Incremental Costs/Cost Offsets with Prasugrel* Incremental Costs/Cost Offsets with Prasugrel*

-800

-600

-400

-200

0

200

400

PCI-$621

CABG-$21

Other Vasc.Interventions

$12

Other$82

Total-$517

Bleeding$69Angina

$20

MI (no PCI)-$57

Prasugrel Clopidogrel Difference (P-C)

Index Hospitalization Costs $19,740 $19,752 -$12

Rehospitalization Costs $4,465 $4,982 -$517

Study Drug Costs $1,862 $1,554 $308

TOTAL COSTS $26,067 $26,288 -$221

CostCost--Effectiveness: Effectiveness: Base Case Base Case

-$3,000

-$2,000

-$1,000

$0

$1,000

$2,000

$3,000

-0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4

Life Years (Prasugrel – Clopidogrel)

C

ost

(Pra

sugr

el –

Clo

pido

grel

)

Cost = -$221 Life Exp. = 0.102 yrsICER = Dominant

% Dominant: 79.7%

Cost = -$221 Life Exp. = 0.102 yrsICER = Dominant

% Dominant: 79.7%

% <$50,000/LYG: 99.8%% <$50,000/LYG: 99.8%

Impact of Generic ClopidogrelImpact of Generic Clopidogrel

Treatment Over Full Trial DurationTreatment Over Full Trial DurationCost of Generic Clopidogrel = $1/dayCost of Generic Clopidogrel = $1/day

-$3,000

-$2,000

-$1,000

$0

$1,000

$2,000

$3,000

-0.4 -0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4

Life Years (Prasugrel – Clopidogrel)

C

ost

(Pra

sugr

el –

Clo

pido

grel

)

Cost = +$996 Life-years= 0.102ICER = $9,727/LYG

% Dominant: 0%

Cost = +$996 Life-years= 0.102ICER = $9,727/LYG

% Dominant: 0%

% <$50,000/LYG: 98.2%% <$50,000/LYG: 98.2%

Emerging Approaches to Antiplatelet Therapy for PCI: Prasugrel

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