New Option and Controversies

in ACS Treatment

Evolving landscape of antithrombotic treatment in A CS

Aspirin dose

Heparin

LMWH

GP IIb/IIIa timing

Direct thrombin inhib

Clopidogrel dose

Fonda

Prasugrel

Ticagrelor

ANTI PLATELET

ASPIRIN

TICLOPIDINE

Clopidogrel standard Dose

PRASUGREL

TICAGLEROL

CLOPIDOGREL High Dose

PLATO

TRITON

TRILOGI ACS

GRAVITAS

CURRENT

CURE, CALRITY

CREDO, COMMIT

Atherothrombosis: A Generalized and Progressive Disease

Unstable angina MI

Ischemic stroke/TIA

Critical leg ischemiaIntermittentclaudication

CV death

ACS

Atherosclerosis

Stable angina/Intermittent claudication

Atherothrombosis

MI = Myocardial infarctionACS = Acute coronary syndromesCV = Cardiovascular

Adapted from Libby P. Circulation 2001; 104: 365–372

CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of

Optimal Clopidogrel and Aspirin Dosing in Patients with

ACS Undergoing an Early Invasive Strategy with Intent

For PCI

OASIS-7

Shamir R. Mehta on behalf of the CURRENT Investigat ors

Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.

Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)

� Planned Early (<24 h) Invasive Management with intended PCI� Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)� Planned Early (<24 h) Invasive Management with intended PCI� Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232(70%)

Angio 24,769(99%)

Angio 24,769(99%)

No PCI 7,855 (30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Randomized to receive (2 X 2 factorial):

CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)

ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Clop in 1st 7d (median) 7d 7 d 2 d 7d

Complete Followup

99.8%

Compliance:

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR

CV Death, MI or Stroke

Days

Cum

ulat

ive

Haz

ard

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Dose

Clopidogrel Double Dose

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)

CLOPIDOGREL vs. PRASUGREL

TRITON: Primary Efficacy Results in Entire ACS Cohort at 15 Months

Wiviott SD, et al. N Engl J Med 2007;357:2001-15

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)

P<0.001

Prasugrel

Clopidogrel

HR 0.80P=0.0003

HR 0.77P=0.0001

Days

Prim

ary

End

poin

t %

(N

) 12.1%(781)

9.9% (643)

NNT= 46

ITT= 13,608 LTFU = 14 (0.1%)

LTFU = Lost to follow-upITT = Intention to treat

TRITON: Primary Efficacy and Safety Endpoints in Entire ACS Cohort at 15 Months

Wiviott SD, et al. N Engl J Med 2007;357:2001-15

0

5

10

15

0 30 60 90 180 270 360 450

Prasugrel

Clopidogrel

Days

End

poin

t (%

)

12.1

9.9

Prasugrel

Clopidogrel1.82.4

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

HR 0.81(0.73-0.90)

P<0.001

138events

NNT = 46

HR 1.32(1.03-1.68)

P=0.03

35events

NNH = 167

% E

vent

s

TIMI MajorBleeds

ARR 0.6%HR 1.32P=0.03

Clopidogrel

Prasugrel

LifeThreateningARR 0.5%HR 1.52P=0.01

NonfatalARR 0.2%

P=0.23

ICHARR 0%P=0.74

FatalARR 0.3%P=0.002

ICH in Pts w Prior Stroke/TIA

(N=518)

Clop 0 (0) %Pras 6 (2.3)%

(P=0.02)1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

0

2

4

TRITON: Prasugrel increase Significant Major & Life Threatening Bleeding Results in Entire ACS Cohort a t 15 Months

Adapted Wiviott SD, et al. N Engl J Med 2007;357:2001-15

NNH=167

NNH = Number needed to harmARR = Absolute risk reductionHR = hazard ratioICH = intracranial hemorrhage

CURRENT PCI

N=17,232

TRITON

N=13,608

CV Death, MI or Stroke ↓ 15%

↓ 21% (w high dose ASA)

↓ 19%

Definite Stent Thrombosis ↓ 42%

↓ 51% (w high dose ASA)

↓ 58%

TIMI Major Bleed No increase ↑ 32%

CABG-related Bleeding No increase ↑ 4-fold

Fatal bleeding No increase ↑ 4-fold

Comparison of CURRENT and TRITON

CLOPIDOGREL Vs. TICAGLEROL

Primary efficacy endpoint: Death from vascular caus es/MI/strokeSecondary efficacy endpoints: Primary endpoint in patients undergoing PCI; all cause mortality/MI/stroke,vascular death/MI/stroke/severe recurrent ischemia/TIA/arterial thrombotic event; stent thrombosis; all-cause mortalityPrimary safety endpoint: PLATO-defined major bleedi ng

12-month maximum exposure(Min = 6 mo, Max = 12 mo, Mean = 11 mo)

(N>18,000)

ASA* + Clopidogrel300-mg LD/75 mg qd †

Additional 300-mg LD allowed in PCI

ASA* + AZD6140180-mg LD/90 mg bid †

Additional 90 mg LD allowed in PCI >24 h after randomization

ACS patients (UA/NSTEMI/STEMI, PCI,

medically managed, or CABG)

*All patients received ASA 75-100 mg qd unless intolerant.

ASA = acetylsalicylic acid; LD = loading dose; PLATO = PLATelet inhibition and patient Outcomes trial.

James S et al. Am Heart J. 2009;157:599-605.

PLATO Study Design

Dose of study drug assigned as soon as possible ( ≤ 24 h) after index event

4

8

2

6

Primary efficacy endpoint over time (composite of CV death, MI or stroke)

*Excludes patients with any primary event during the first 30 days

0

Clopidogrel

Cum

ulat

ive

inci

denc

e (%

)

Ticagrelor

HR 0.88 (95% CI 0.77–1.00), p=0.045

0 10 20 30

Days after randomisation

5,43

4.77

No. at riskTicagrelor 9,333 8,942 8,827 8,763Clopidogrel 9,291 8,875 8,763 8,688

8

0

Clopidogrel

2

4

6

Cum

ulat

ive

inci

denc

e (%

)

Ticagrelor

0 90 150 330

Days after randomisation

8,673 8,543 8,397 7,028 6,480 4,8228,688 8,437 8,286 6,945 6,379 4,751

210 270

6.60

5.28

HR 0.80 (95% CI 0.70–0.91), p<0.001

Wallentin L et al. New Engl J Med.2009;361:DOI:10.1056/NEJMoa0904327. http://www.clinicaltrialresults.org/

PLATO : No Significant different in Sub Analysis fo r UA

US PLATO: Clopidogrel Better than Ticagrelor

Ticaglerol Better Vs. Clopi Ticaglerol Non Significant and Clopi better

PLATO : Ticaglerol significantly increase Non-CABG Bleeding

7

0

K-M

est

imat

ed r

ate

(% p

er y

ear)

9

8

6

5

4

3

2

1

Non-CABGPLATO major

bleeding

4.5

3.8

P=0.03 HR 1.19 (1.02-

1.38)

2.8

2.2

P=0.03 HR 1.25 (1.03-

1.53)

7.47.9

NS

5.35.8

NS

Ticagrelor

Clopidogrel

Non-CABGTIMI majorbleeding

CABGPLATO major

bleeding

CABGTIMI major bleeding

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.

NNH = 143

PLATO : Ticaglerol Increase Intracranial bleeding & Fatal ICH

P=0.06 HR 1.87

P=0.02 HR=5.47

K-M

est

imat

ed r

ate

(%

per

yea

r)

ICH

0.35

0.3

0.25

0.2

0.15

0.1

0.05

0Fatal ICH

0.28

0.15

0.12

0.01

TicagrelorClopidogrel

Ticagrelor (N=9235) 26 11

Clopidogrel (N=9186) 14 1

Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57.FDA website CardiovascularandRenalDrugsAdvisoryCommittee/ucm192863.htm. Accessed on August 23rd, 2010.

Bleeding is a serious event

Moscucci et al, Eur Heart J 2003

*

* p<0.01

Bleeding associated with higher mortality after ACS

Ndrepepa et al, J Am Coll Cardiol 2008

5384 patients from 4 RCT’s, PCI studies, Stable CAD and ACS

Bleeding is a serious event

Same impact on long term mortality than new MI

Verheugt et al, JACC Cardiovasc Interv 2011

Recurrent events and Mortality

17393 PCI patients from 3 RCT’s (REPLACE 2, ACUITY an d HORIZON)

Bleeding is a serious event

Greater impact on prognosis of non access site bleedings

All Access-site bleeding impact mortality ?

Access-site bleeding impact mortality only if associat ed with Ht decrease

Romaguera et al, Am J Cardiol 2012

7718 PCI patients, single center registry, femoral a ccess

Two Types of Bleedings

In Hospital Bleedings (Procedure/Antithrombotic therapy)

Post Discharge Bleedings (Oral Antiplatelet Therapy)

After Discharge

Low dose aspirin

Individualized P2Y12 inhibitors

Use of PPI

Monitoring ?

In Hospital

- Radial Access +++

- Careful use of anticoagulant

- Shorten Duration of Therapy

- Selective use of GPIIbIIIa

How to prevent bleedings in ACS/PCI patients ?

0

108

Placebo APTC CURE

Antiplatelet Therapy in ACS

Single

Antiplatelet Rx

Dual

Antiplatelet RxHigher IPA

ASA

ASA + Clopidogrel ASA +

New P2Y12 blockers

- 22%

- 20%

- 19%

+ 60% + 38%+ 32%

Reduction in

Ischemic Events

Increase in

Major Bleeds

Placebo

0 30 60 90 180 270 360 450 days

5

10

En

dp

oin

t (%

)

0

9.8

11.7

Ticagrelor 90mg x2

HR 0.84 (0.77–0.92) p=0.0003*

12.1

9.9

Prasugrel 10mg

Clopidogrel 75mg

HR 0.81 (0.73-0.90) p=0.0004*

TRITON and PLATO

Primary endpoint = CV Death / MI / Stroke 12-15 months

Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010

p=0.03* p=0.025*

7

6

5

4

3

2

1

0

2.8

2.2

Safety = Non-CABG related TIMI major bleedings

1.8

2.4

p=0.001*

2.7

3.7

450 days

AS

A o

nly

360 days360 days

+38% +32% +27%

TicagrelorClopidogrel 75

Prasugrel

TRITON PLATOCURE

Same Platelet InhibiCon → Same Bleeding Risk

NNH=167 NNH=167

Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010

High risk

STEMI

Diabetes mellitus, CKD

High-risk NSTE ACS

(Tn + and/or ST changes)

Recurrent event on clopidogrel

Stent Thrombosis

Low risk

No ST changes

No Troponin elevation

(Patients not in Triton / Plato)

High risk:

Prior stroke/TIA*

Age > 75 y.o

Weight < 60 kg

Chronic OAC, Prior Bleeding

Low risk

No prior stroke/TIA/Bleeding

Age < 75 y.o

Weight > 60 kg

No Chronic OAC

Ischemic Risk

Bleeding Risk

P2Y12 Blockers

Individual Decision Clopidogrel

Clopidogrel

ACS patients

* CI Prasugrel

Prevention of Post discharge Bleedings

STEMI: Oral antiplateletsWhat, when and how?

WHAT?

WHEN?

HOW?

AspirinClopidogrel / Prasugrel* / Ticagrelor*

AspirinClopidogrel

ASAP

Aspirin: started at a dose of 150–300mg per os or 250–500mg bolus iv followed by 75-100mg daily

Prasugrel: 60mg LD followed by 10mg daily, or

Ticagrelor: 180mg LD followed by 90mg twice daily, or

Clopidogrel: 600mg LD followed by 75mg daily

Aspirin: oral dose of 150-325mg or i.v. dose of 250 mg if oral ingestion is not possible.

Clopidogrel: loading dose of 300mg if age ≤75 years; 75mg if age >75 years

1. Wijns W et al Eur Heart J 2010;31:2501-55

2. Van de Werf F et al Eur Heart J 2008;29:2909-45

Primary PCI 1 Thrombolysis 2

Invasive 1,2 Conservative 2

WHAT?

WHEN?

HOW?

AspirinTicagrelor* / Clopidogrel‡

AspirinTicagrelor* / Clopidogrel‡

Loading dose ASAP

Aspirin: started at a dose of 150–300 mg and at a maintenance dose of 75–100 mg, plus

Ticagrelor: 180 mg LD, 90 mg twice daily, or

Clopidogrel: 300 or 600 mg LD, 75 mg daily

Upstream GPIIbIIIa are not recommended in patients with high ischaemic risk

Aspirin: started at 150–300 mg and at a maintenance dose of 75–100 mg, plus

Ticagrelor 180 mg LD, 90 mg twice daily, or

Clopidogrel: an immediate 300 mg LD, 75 mg daily dose

1. Wijns W et al Eur Heart J 2010;31:2501-55

2. Hamm CW et al ESC NSTE-ACS Guidelines EHJ 2011; doi:10.1093/eurheartj/ehr236

3. Anderson JL et al Circulation 2007;116:148-304

‡All patient received clopidogrel LD before PCI in CURRENT* Ticagrelor has limited experience for prePCI load ing

Patients with low-likelihood of ACS, and lowest-risk ACS were excluded from clinical trials=> Recommendations apply to NSTEMI for which the diagnosis is likely or definite 3 and should be adapted

to patient risk level for thrombosis and bleeding 2,3

NSTE-ACS : AntiplateletsWhat, when and how?

New ESC and ACC Guidelines

ESC Guidelines

ACC AHA - PCI

- Loading dose for all P2Y12 inhibitors is recommended (Class I-A)

- 600 mg loading recommended for clopidogrel

- Limitations imposed on prasugrel

- Issue of compliance posed against ticagrelor

Plavix 300 mg = Improve Compliance

Loading Dose 4 tabs 75 mg = 1 tab Plavix 300 mg

Loading Dose 8 tabs 75 mg = 2 tabs Plavix 300 mg

Summary

Clopidogrel Prasugrel TicagrelorMajor study CURE TRITON-TIMI 38 PLATO

Population NSTEACS ACS - PCI ACS

Loading dose 300 mg 60 mg 180 mg

Maintenance dose 75 mg 10 mg 90 mg

Maintenance schedule Daily Daily Twice daily

Treatment arms Clopidogrel vs placebo Prasugrel vs clopidogrel

Ticagrelor vs clopidogrel

Duration of follow-up 9 months 14.5 months 9 months

CV death, MI, stroke9.3 vs 11.4%

RR 0.80, p < 0.0019.9 vs 12.1%

HR 0.81, p < 0.0019.8 vs 11.7%

HR 0.84, p < 0.001

TIMI non-CABG major bleeding1.1 vs 1.2%*

RR 0.94, p = 0.72.4 vs 1.8%

HR 1.32, p = 0.032.8 vs 2.2%

HR 1.25, p = 0.03

Major bleeding per study definition3.7 vs 2.7%

RR 1.38, p = 0.0012.4 vs 1.8%

HR 1.32, p = 0.0311.6 vs 11.2%

HR 1.04, p = 0.43

Yusuf S et al. N Engl J Med. 2001;345:494-502.Wiviott SD et al. N Engl J Med 2007;357:2001-15Wallentin L et al. N Engl J Med. 2009;361(11):1045-57.

*TIMI major bleeding