antiplatelet options for acs: the changing landscape dr harald vangerow medical advisor...

Antiplatelet Options for ACS: The Changing Landscape

Dr Harald Vangerow

Medical Advisor Cardiovascular

Eli Lilly

UKEFF00329Prescribing Information can be found at the end of this presentation

EFIENT : Review of current guidance of NICE and SMC

Disclosure:I am a full-time employee of Eli Lilly UK, presenting on behalf of the alliance between Lilly and Daiichi-Sankyo

UKEFF00329

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2.Adapted from Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Antithrombotic therapy for PCI

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

aIIbb3

aIIbb3

FibrinogenaIIbb3

Aggregation

AmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TPa

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x CLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x

GP IIb/IIIa ANTAGONISTS

xx

HEPARINSBIVALIRUDIN xThrombin

Background

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0

20

40

60

80

100

120

0

10

20

30

40

5 µM ADP induced plt agg Death/ACS/CVA by 6 m

Days1 2 3 4 5 6

Bas

elin

e (%

)

Quartiles of response

Q1

Q2

Q3

Q4

Clop resist 40

6.7

0 0

Per

cent

P = 0.007

Q1 Q2 Q3 Q4

1. Matetzky S, et al. Circulation 2004;109:3171-31752. Wiviott SD, Antman EM. Circulation 2004 109:3064-30673. Serebruany VL, J. Am Coll Cardiol 2005; 45: 246-514. O’Donoghue M et al. Circulation 2006; 114(22): e600-e606

Clopidogrel response variability and increasedrisk of ischaemic events (1,2)

Primary PCI for STEMI (N=60)

The range of variability to clopidogrel ranges from 4% to 56% of subjects showing some degree of non-responsiveness (3,4). There are many different definitions of poor-/nonresponse and various techniques to measure inhibition of platelet aggregation.

Is this clinically relevant?

N=15 N=15 N=15N=15

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TRITON-TIMI 38 Study Design

Wiviott SD et al. Am Heart J 2006;152:627-635

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, stroke2o endpoints: CV death, MI, stroke, rehosp, Rec Isch CV death, UTVR, Stent thrombosis (ARC definite/prob.)Safety endpoints: TIMI major bleeds, life-threatening bleedsKey sub-studies: Pharmacokinetic, genomic

Planned median duration of therapy - 12 months

N = 13,608

TRITON

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TRITON-TIMI 38: Rates of Key Study End Points (All ACS)

prasugrel + aspirin

clopidogrel + aspirin

5

10

15

00 30 60 90 180 270 360 450

Days After Randomisation

En

d P

oin

t (%

)

120

1.8 (111)

2.4(146)

Non-CABG TIMI Major Bleeds

CV Death, MI, Stroke

P=0.03

P<0.001↓138 events

↑ 35 events

12.1(781)

9.9 (643)

prasugrel + aspirin


Wiviott SD et al. New Engl J Med 2007;357:2001-2015

CABG = Coronary Artery Bypass Graft surgeryCV = CardiovascularMI = Myocardial Infarction TIMI = Thrombolysis In Myocardial Infarction

TRITON

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Eve

nts

(%

)

ARD 0.6%HR 1.32P = 0.03

NNH = 167

Clopidogrel Prasugrel

ARD 0.5%HR 1.52P = 0.01

ARD 0%P = 0.74

ARD 0.3%P = 0.002

ICH in patients with prior stroke/TIA (n = 518)

Clopidogrel 0 (0%) Prasugrel 6 (2.3%)(P = 0.02)

ARD 0.2%P = 0.23

n = 13,457

1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

0

2

4

Life-threatening

Non-fatal Fatal ICH

Bleeding Events: Safety Cohort

TIMI Major Non-CABG Bleeding

TRITON

Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FLhttp://www.clinicaltrialresults.org/Slides/TRITON%20TIMI%2038%20AHA%2007.pptUKEFF00329

Net Clinical Benefit: Bleeding Risk SubgroupsPost-hoc analysis

OVERALL

>60 kg

< 60 kg

< 75

>75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)+ 37

-16

-1

-16

+3

-14

-13

prasugrel better clopidogrel betterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FLhttp://www.clinicaltrialresults.org/Slides/TRITON%20TIMI%2038%20AHA%2007.ppt

TRITON

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Therapeutic Considerations

Significant Net Clinical Benefit

with Prasugrel80%

MD 10 mg

Recommend

Reduced MD

Guided PK

Wt < 60 kg

Age > 75 y16%

Avo

id

Prasu

grel

Prio

r

CVA

/TIA4%

TRITON

Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FLhttp://www.clinicaltrialresults.org/Slides/TRITON%20TIMI%2038%20AHA%2007.pptUKEFF00329

After Careful Risk-Benefit Evaluation

Appropriate Use of EFIENT

≥ 60kg and < 75 years

< 60kg

≥ 75 yearsGenerally not recommended

60mg

Loading Dose Maintenance Dose

10mg

60mg 5mg*

60mg 5mg*

ANY prior TIA/Stroke Contraindicated

European SmPC

* The evidence for a 5mg dose is based only on PK/PD analyses and no clinical data currently exist on the safety of this dose in the at risk sub groups.

Appropriate Use

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Prasugrel (Efient) co-administered with aspirin is accepted for restricted use within NHS Scotland for the prevention of athero-thrombotic events in patients with acute coronary syndrome under-going primary or delayed percutaneous coronary intervention. Use is restricted to patients who are eligible to receive the 10mg dose of prasugrel. (...)Alternative treatments are available at a lower drug acquisition cost.

Scottish Medicines Consortium

http://www.scottishmedicines.org.uk/files/prasugrel%205%20and%2010%20mg%20tablets%20(Efient)%20FINAL%20August%202009%20Revised%20Sept%202009.doc%20website.pdf

7th August 2009

SMC

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Balance of Efficacy and Safety in Patients <75 Yrs, ≥60 kg, and Without TIA/Stroke

En

dp

oin

t (%

)

0

2

4

6

8

1 0

1 2

1 4

1 6

0 30 90 180 270 360 450

Hazard Ratio, 1.240(95% CI, 0.91-1.69)P=0.17

Hazard Ratio, 0.75(95% CI, 0.66-0.84)P<0.001

Clopidogrel

Prasugrel

Clopidogrel

Prasugrel 1.95%

1.50%

11%

8.4%

CV Death / NF MI / NF Stroke

Non-CABG TIMI Major Bleeding

Days

NNT37

NNH222

FDA Briefing Document,http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm129219.pdf

n=10 804

TRITON

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NICE TA 182

Guidance

1.1 Prasugrel in combination with aspirin is recommended as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when:

• immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary

http://guidance.nice.org.uk/TA182/Guidance/pdf/English

Issued October 2009Review September 2010

NICE

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0

5

10

15

0 30 60 90 180 270 360 450

En

dp

oin

t (%

)

Days

9.5%

6.5%

HR 0.68(0.54 - 0.87)

P = 0.002

12.4%

10.0%

HR 0.79(0.65 - 0.97)

P = 0.02

Clopidogrel

Prasugrel

NNT = 42

CV death / MI / stroke

TIMI major non-CABG bleeds

Clopidogrel

Prasugrel 2.4%

2.1%

Montalescot G et al Lancet 2009, in press

N = 3534

STEMI Cohort (N= 3534)

TRITON-STEMI

UKEFF00329

[% P

atie

nts]

TRITON-TIMI 38: STEMI cohortMortality at 30 Days

Montalescot G et al. Lancet 2009;373:723_731

2.62.4

1.61.4

0

1

2

3

All Cause Death Cardiovascular Death

Clopidogrel Prasugrel

p=0.0445 p=0.0469

TRITON – STEMI

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NICE TA 182

Guidance


• stent thrombosis has occurred during clopidogrel treatment



NICE

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TRITON-TIMI 38: Stent thrombosis ratesat end of study

All Stents Bare-metal Stents

0

1

2

3

4

Ste

nt

Th

rom

bo

sis*

(%

)

Drug-eluting Stents

2.35 2.312.41

N=6,422 n=2,878 n=3,224

1.130.84

1.27

N=6,422 n=2,865 n=3,237

clopidogrelprasugrel

52% RRR(1.2% ARR)

64% RRR(1.5% ARR)

48% RRR(1.1% ARR)P=0.0009P<0.0001P<0.0001

*Stent thrombosis defined as Academic Research Consortium definite plus probable

ARC = Academic Research ConsortiumARR = Absolute Risk ReductionHR = Hazard Ratio NNT = Number Needed to TreatPCI = Percutaneous Coronary InterventionRRR = Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363

TRITON – Stent Thrombosis

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TRITON-TIMI 38: Intensive antiplatelet therapy withprasugrel resulted in fewer ischaemic outcomesincluding stent thrombosis than with clopidogrel

% o

f S

ub

ject

s

Days

Early Stent ThrombosisPras n=6,422; clop n=6,422

Late Stent Thrombosispras n=6,271; clop n=6,250

1.56%

0.64%

0.82%

0.49%


prasugrel + aspirin

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 30 30 90 150 210 270 330 390 450

HR 0.41 (0.29-0.59)P<0.0001RRR 59%

HR 0.60 (0.37-0.97)P=0.03RRR 40%


prasugrel + aspirin

ARC = Academic Research ConsortiumHR = Hazard ratioRRR = Relative risk reduction

Wiviott SD et al. Lancet 2008;371:1353-1363

TRITON – Stent Thrombosis

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NICE TA 182

Guidance


• the patient has diabetes mellitus.



NICE

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TRITON-TIMI 38: Diabetic SubgroupAnalysis (n=3,146)

CABG = Coronary Artery Bypass Graft surgeryCV = CardiovascularHR = Hazard RatioMI = Myocardial InfarctionNNT = Number Needed to TreatTIMI = Thrombolysis In Myocardial Infarction

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

d P

oin

t (%

)

CV Death, MI, Stroke

NNT=21

17.0

12.2

2.62.5

Non-CABG TIMI Major Bleeds

prasugrel + aspirin


Adapted from Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL

TRITON – Diabetes

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NICE TA 182

Guidance


• immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary or

• stent thrombosis has occurred during clopidogrel treatment or

• the patient has diabetes mellitus.

1.2 People currently receiving prasugrel for treatment of acute coronary syndromes whose circumstances do not meet the criteria in 1.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop.



NICE

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Conclusions

• Prasugrel is a more potent antiplatelet than clopidogrel

• This translates into fewer ischemic events in ACS patients undergoing PCI in TRITON

• A significant increase in bleeding events in Prasugrel treated patients was observed in this trial

• A post-hoc analysis was performed to define the population deriving net clinical benefit with prasugrel

• SMC and NICE have found EFIENT to be cost-effective in a subset of ACS patients undergoing PCI

Conclusions

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Thank You !

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Adverse Event Reporting

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk

Adverse events should also be reported to Eli Lilly and Company Limited (Tel No 0870 240 1125)

UKEFF00288 UKEFF00329

Prescribing Information (1/5)EFIENT*▼ (PRASUGREL) ABBREVIATED PRESCRIBING INFORMATION

Presentation

Film-coated tablet; 5mg or 10mg prasugrel hydrochloride.

Uses

Efient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in patients with acute coronary syndrome (ie, unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI], or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI).

Dosage and Administration Adults: Initiate with a single 60mg loading dose and then continue at 10mg daily. Patients should also take ASA daily (75mg to 325mg). In patients with ACS who are managed with PCI, premature discontinuation of any antiplatelet agent, including Efient, could result in an increased risk of thrombosis, myocardial infarction, or death due to the patient’s underlying disease. Treatment of up to 12 months is recommended unless the discontinuation is clinically indicated.

Patients ≥75 years old: Use in patients ≥75 years of age is generally not recommended. If, after a careful individual benefit/risk evaluation by the prescribing physician, treatment is deemed necessary, then following a 60mg loading dose a reduced maintenance dose of 5mg should be prescribed. Patients ≥75 years of age have greater sensitivity to bleeding and higher exposure to the active metabolite of prasugrel. The evidence for the 5mg dose is based only on pharmacodynamic/pharmacokinetic analyses and no clinical data currently exist on the safety of this dose in the age group ≥75 years.

Patients weighing <60kg: Give as a single 60mg loading dose and then continue at 5mg once daily. The 10mg maintenance dose is not recommended.

Renal impairment: No dose adjustment is necessary for patients with renal impairment, including patients with end stage renal disease.

Hepatic impairment: No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child-Pugh class A and B).

Children and adolescents: Not recommended.

Method of administration: For oral use. May be administered with or without food. Administration of the 60mg loading dose in the fasted state may provide most rapid onset of action. Do not crush or break the tablet.


Prescribing Information (2/5)Contra-indications

Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of stroke or transient ischaemic attack (TIA). Severe hepatic impairment (Child-Pugh class C).

Warnings and Special Precautions

Bleeding risk: Increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Use in patients at increased risk of bleeding should only be considered when the benefits in terms of prevention of ischaemic events are deemed to outweigh the risk of serious bleedings. This concern applies especially to patients:

• ≥75 years of age.

• with a propensity to bleed.

• with body weight <60kg. In these patients the 10mg maintenance dose is not recommended. A 5mg maintenance dose should be used.

• with concomitant administration of medicinal products that may increase the risk of bleeding, including oral

anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics.

For patients with active bleeding for whom reversal of the pharmacological effects of Efient is required, platelet

transfusion may be appropriate.

Use in patients ≥75 years of age is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk evaluation.

Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in these patients.

Use with caution in Asian patients as therapeutic experience is limited.

Patients should be told that it might take longer than usual to stop bleeding and that they should report any unusual bleeding (site or duration) to their physician.

Surgery: If a patient is to undergo elective surgery, and an antiplatelet effect is not desired, Efient should be discontinued at least 7 days prior to surgery. Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing CABG surgery within 7 days of discontinuation of prasugrel.

Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucosegalactose malabsorption should not take Efient.


Prescribing Information (3/5)Interactions

Warfarin: Warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution.

Non-steroidal anti-inflammatory drugs (NSAIDs): Chronic NSAIDs (including COX-2 inhibitors) and Efient should be co-administered with caution.

Effects of Other Medicinal Products on Efient

Acetylsalicylic acid: To be administered concomitantly with ASA. Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with ASA.

Effects of Efient on Other Medicinal Products

Medicinal products metabolised by CYP2B6: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be of clinical concern only when prasugrel is co-administered with medicinal products for which CYP2B6 is the only metabolic pathway and have a narrow therapeutic window (eg, cyclophosphamide, efavirenz).

Pregnancy and Lactation

Should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.

Driving, etc

Prasugrel is expected to have no or negligible influence on the ability to drive and use machines.

Undesirable Effects

Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel-controlled study (TRITON). Drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel).

Bleeding

Non-Coronary Artery Bypass Graft (CABG) related bleeding: In TRITON the incidence of non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel compared to clopidogrel in the UA/NSTEMI and all ACS populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastro-intestinal tract; the most frequent site of provoked bleeding was the arterial puncture site.


Prescribing Information (4/5)CABG-related bleeding: In the Phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those patients,

the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group and 4.5% in the clopidogrel group. The higher risk for bleeding events in subjects treated with prasugrel persisted up to 7 days from the most recent dose of study drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were 26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.3% (3 of 90 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups.

Adverse Reactions

The following is based on data from clinical trials:

Common (≥1-<10%): Anaemia, haematoma, epistaxis, gastro-intestinal haemorrhage, rash, ecchymosis, haematuria, vessel puncture site haematoma, puncture site haemorrhage, contusion.

Uncommon (≥1/1000-<1/100): Eye haemorrhage, retroperitoneal haemorrhage.

For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at http://emc.medicines.org.uk/.

Legal Category POM

Marketing Authorisation Numbers

EU/1/08/503/001, EU/1/08/503/002, EU/1/08/503/003, EU/1/08/503/004, EU/1/08/503/005, EU/1/08/503/006, EU/1/08/503/007, EU/1/08/503/008, EU/1/08/503/009, EU/1/08/503/010, EU/1/08/503/011, EU/1/08/503/012, EU/1/08/503/013, EU/1/08/503/014

Basic NHS Cost £ 47.56 per pack of 28 tablets

Date of Preparation or Last Review June 2009

Full Prescribing Information is Available From

Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL, Telephone: Basingstoke (01256) 315 999

*EFIENT (prasugrel) is a trademark of Eli Lilly and Company.


http://emc.medicines.org.uk/

Prescribing Information (5/5)

• Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk

• Adverse events should also be reported to Eli Lilly and Company Limited

• (Tel No 0870 240 1125)


http://www.yellowcard.gov.uk/

antiplatelet options for acs: the changing landscape dr harald vangerow medical advisor...

Documents

stemi n

request patients

range of variability

clopidogrel ranges

rec isch cv death

induced platelet aggregation

coll cardiol

study designwiviott