Clopidogrel Pretreatment Versus Clopidogrel Exposure

Prior to PCI in the ACUITY Trial: Does it Really Matter?

Clopidogrel Pretreatment Versus Clopidogrel Exposure

Prior to PCI in the ACUITY Trial: Does it Really Matter?

Steven R. Steinhubl, Frederick Feit, Antonio Colombo, Ramin Ebrahimi, David A. Cox, Brent T. McLaurin,

Roxana Mehran, George D. Dangas, Steven V. Manoukian, Harvey D. White, A. Michael Lincoff, Jeffery

W. Moses,Michel E. Bertrand, E. Magnus Ohman, Walter Desmet, Gregg W. Stone,

for the ACUITY Investigators

Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest

Within the past 12 months, I or my spouse/partner have had a financial Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Grant/Research SupportGrant/Research Support The Medicines CompanyThe Medicines Company

Eli Lilly / Daiichi-SankyoEli Lilly / Daiichi-Sankyo

Consulting Fees/HonorariaConsulting Fees/Honoraria AstrazenecaAstrazeneca

Bristol-Myers SquibbBristol-Myers Squibb

Sanofi aventisSanofi aventis

The Medicines CompanyThe Medicines Company

Eli Lilly / Daiichi-SankyoEli Lilly / Daiichi-Sankyo

Portola PharmaceuticialsPortola Pharmaceuticials

CogentusCogentus

CardaxCardax

PlaCorPlaCor

28-Day Endpoint Per Protocol

0

5

10

0 7 14 21 28

Days Post-Randomization

Death, MI, or UTVR

8.3%

6.8%

18.5 % RRR18.5 % RRR

p = 0.23

Pretreatment

No Pretreatment

TCT 2002

Clopidogrel Loading Dose Timing and Risk of MACE

- 6

- 5

- 4

- 3

- 2

0 5 10 15 20 25 30Hours Prior to PCI of Study Drug Loading Dose

Log Odds of Death, MI or UTVR at 28 Days

Placebo

Clopidogrel

P = 0.020for treatment / timing

interaction

J Am Coll Cardiol 2006

Hochholzer W. Circulation 2005;111:

Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 Patients

Potential Limitations of Clopidogrel

1. Several hour delay in onset, even with loading dose.2. Irreversible.3. Wide variability in response.

0

2

4

6

8

10

<3 h 3-6 h 6-12 h >12 h

% Death, MI or revascularization

Pinteraction=0.27

Abciximab

Placebo

ISAR REACT: Relationship Between ISAR REACT: Relationship Between Time of Loading Dose and OutcomesTime of Loading Dose and Outcomes

Berger PB. AHA 2003

P=0.7P=0.5P=0.4

P=0.7

9.0%

6.7% 6.6%7.3%

9.8%

7.3% 7.2% 7.8%

0%

4%

8%

Noclopidogrel

Clopidogrelpretreatment

<6 hours ≥6 hours

UFH + GP IIb/IIIaBivalirudin

435† 396† 2,499† 2,526† 1,828†1,807† 632† 642†

Clopidogrel Treatment – No Differential in Benefit

Saw J J Am Coll Cardiol. 2004;44:1194-1199.

Dea

th,

MI,

UT

VR

(%

)

~85% of patients in each arm received clopidogrel pre-PCI.

~20% were pretreated > 6 hours prior to PCI.

Moderateand highrisk ACS

(n=13,819)

Study Design – First RandomizationStudy Design – First Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

Aspirin in allClopidogrel

dosing and timingper local practice

UFH/Enox+ GP IIb/IIIa(n=4,603)

Bivalirudin+ GP IIb/IIIa(n=4,604)

BivalirudinAlone

(n=4,612)

R*

*Stratified by pre-angiography thienopyridine use or administration*Stratified by pre-angiography thienopyridine use or administration

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

Medicalmanagement

PCI

CABG

Management Strategy (N=13,819)Management Strategy (N=13,819)

56.4%

11.4%32.2%CABG (n=1,539)CABG (n=1,539)

Medical Rx (n=4,491)Medical Rx (n=4,491)

PCI (n=7,789)PCI (n=7,789)

Heparin + IIb/IIIaN = 2,561

Bivalirudin + IIb/IIIaN = 2,609

Bivalirudin aloneN = 2,619

Composite Ischemia – PCI ptsComposite Ischemia – PCI pts

0

5

10

15

0 5 10 15 20 25 30 35

Eve

nt

Rat

e (%

)

Days from Randomization

*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin

Estimate P(log rank)

8.4%Heparin* + IIb/IIIa (N=2561)

Bivalirudin + IIb/IIIa (N=2609) 0.159.4%

Bivalirudin alone (N=2619) 0.458.9%

Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

P=0.36

13.8%

8.4%7.2%

8.1%

11.1%

3.6%

Net clinicaloutcomes

Ischemiccomposite

Major bleeding

UFH/Enoxaparin + IIb/IIIa (N=1722)

Bivalirudin Alone (N=1789)

11.8%

7.5%

5.7%

10.3%

12.7%

3.5%

Net clinicaloutcomes

Ischemiccomposite

Major bleeding

UFH/Enoxaparin + IIb/IIIa (N=811)

Bivalirudin Alone (N=804)

Thienopyridine Exposed* Not Thienopyridine Exposed

Influence of Thienopyridine Exposure – PCI ptsInfluence of Thienopyridine Exposure – PCI pts

RR [95%CI]

0.81 (0.68-0.96)

RR [95%CI]

0.96 (0.77-1.20)

RR [95%CI]

0.50 (0.37-0.67)

RR [95%CI]

1.07 (0.83-1.39)

RR [95%CI]

1.37 (1.00-1.88)

RR [95%CI]

0.61 (0.39-0.97)

Interaction P values = 0.17, 0.19 and 0.65 respectivelyInteraction P values = 0.17, 0.19 and 0.65 respectively

30 Day Primary Endpoint Adverse Events30 Day Primary Endpoint Adverse Events

*Thienopyridine at any time, any dose, up to time of PCI

Editorial: Do High-Risk Patients Need More Antiplatelet Therapy in Addition to

Bivalirudin?

Waksman R. Lancet 2007;369:881-2

IIa RecommendationFor UA/NSTEMI patients in whom an initial invasive strategy isselected, it is reasonable to omit upstream administration of anintravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than plannedcatheterization or PCI. (Level of Evidence: B)

Method of Analysis of Timing of Clopidogrel

• Timing for the initiation of clopidogrel was a priori designated as:– pre-PCI if it was initiated at any time

prior to the PCI.– Peri-PCI if it was initiated after

angiography and within 30 minutes of the end of PCI.

– Post-PCI if it was initiated > 30 minutes after PCI

Underwent PCI and received clopidogrel at some time prior to or during hospitalization

N= 7517

Clopidogrel pre-hospital

N=1820 (24%)

Clopidogrel at hospital but

pre- randomizationN= 2383 (32%)

Clopidogrel after

randomizationN= 3314 (44%)

Clopidogrel Pre-angiography N = 928

Clopidogrel Peri- PCI N =1572

Clopidogrel Post-PCI N = 814

No clopidogrel

N= 129

Known dose and duration

What is known About Clopidogrel Exposure in ACUITY Patients Pre-PCI

GPIIb/IIIa plus heparin

GPIIb/IIIa plus bivalirudin

Bivalirudin alone

8.6

6.8

8.7

6.9

8.8 9.410.7

19.1

8.0 8.4

12.7

22.0

0

10

20

Pre-procedure

Procedural Post-PCI None

Timing of Clopidogrel Exposure

Percent Composite Ischemic Endpoint

Timing of Clopidogrel and 30-Day Ischemic Outcomes

Timing of Clopidogrel Exposure

Composite Ischemia %

8.89.7

14.0

8.18.6

12.6

23.3

8.2

0

10

20

Pre-PCIN=5131

Peri-PCIN=1572

Post-PCIN=814

NoneN=129

GPIIb/IIIa antagonist + any anticoagulant

Bivalirudin alone

P=0.36 P=0.77

P=0.22

P=0.18

30-Day Ischemic Outcomes Based on Antiplatelet Therapy

Risk ratio (RR) ±95% CI for the triple ischemic endpoint(death, MI, unplanned revascularization)

Bivalirudin alone better Heparin + GPIIb/IIIa better

Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92]

Post-PCI Clopidgrel N=519 RR 1.48 [95% CI 0.89, 2.47]

Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15]

No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72]

pinteraction =0.35

0 1 2 3 4 5 6 7 8

Timing of Clopidogrel and 30-Day Risk of Ischemic Outcomes

Estimated Spline Transformation and 95% C.I. Log Odds for Composite Ischemia (30-Days)

Duration of Clopidogrel Treatment Prior to PCI (hours)

-4

-3

-2

-1

0

1

2

0 2 4 6 8 10 12 14 16 18 20 22 24

GPIIb/IIIa antagonist + any anticoagulant

Bivalirudin alone

Timing of Clopidogrel Pretreatment and Ischemic Outcomes in Patients with

Known Dose and Duration

9.0 9.1

19.6

8.4 8.3

13.7

23.1

8.2

0

10

20

Timing of Clopidogrel Exposure

Composite Ischemia %

Pre-PCIN=2824

Peri-PCIN=950

Post-PCIN=471

NoneN=77

GPIIb/IIIa antagonist + any anticoagulant

Bivalirudin alone

P=0.60

P=0.72

P=0.13

P=0.97

30-Day Ischemic Outcomes in Troponin + Patients Only

Risk ratio ±95% CI for major bleeding endpoint

Bivalirudin alone better Heparin(s) + GP IIb/IIIa better

pinteraction = 0.32

Peri-PCI ClopidogrelN=1044, RR 0.80 [95% CI 0.45, 1.42]

Post-PCI ClopidogrelN=519 RR 0.58 [95% CI 0.27, 1.22]

Pre-PCI clopidogrel N=3429, RR 0.48 [95% CI 0.35, 0.64]

No ClopidogrelN=88 RR 0.0

0 1 2

Timing of Clopidogrel and 30-Day Risk of Major Bleeding

• In ACUITY, patients who received clopidogrel either prior to, or at the time of PCI achieved similar ischemic event rates and significantly less bleeding when randomization to bivalirudin alone versus a GPIIb/IIIa antagonist, irrespective of troponin status.

• There was a non-significant trend towards worse ischemic outcomes among patients receiving clopidogrel after PCI or no clopidogrel at all.

• The desire or ability to pretreat an ACS patient with clopidogrel prior to PCI should not influence the choice of antithrombotic therapy.

Clopidogrel Pretreatment Versus Clopidogrel Exposure Prior to PCI in the

ACUITY Trial: Does it Really Matter?