Does The Efficacy of Bivalirudin During PCI Depend on Pre-treatment? Matthew J. Price MD, FACC Director, Cardiac Catheterization Laboratory Scripps Clinic La Jolla, CA

SCRIPPS CLINIC IIa Recommendation For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit upstream administration of an intravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the and at least 300 mg of clopidogrel was administered at least 6 h earlier than planned catheterization or PCI. (Level of Evidence: B) REPLACE-2 Trial Design

Randomized, double-blind, active-controlled trial

Primary Endpoints Bivalirudin 6,002 2,994 0.75 mg/kg bolus 30-Day: 1.75 mg/kg/h procedure Death Urgent with provisional GP IIb/IIIa MI Revascularization or clopidogrel Major bleeding elective stent Planned PCI Economics 3,008 patients 65 units/kg or 6-Month ischemia 1-Year mortality

Secondary composite end point=death, MI, or urgent revascularization.

Clopidogrel 300-mg encouraged 2 to 12 hrs before PCI

Lincoff AM et al. JAMA. 2003;289:853-863. SCRIPPS CLINIC REPLACE 2: Results Stratified By Clopidogrel Tx No Differential Benefit Between Heparin/GPI and Bival

P=0.7 9.8% P=0.7 9.0% P=0.4 P=0.5 7.8% 7.3% 7.2% 7.3% 8% 6.7% 6.6% UFH + GP IIb/IIIa Bivalirudin 4%

Death, MI, UTVR (%) Death, MI, UTVR 0% 435† 396† 2,499† 2,526† 1,807† 1,828† 632† 642† No Clopidogrel <6 hours ≥6 hours clopidogrel pretreatment

~85% of patients in each arm received clopidogrel pre-PCI. ~20% were pretreated > 6 hours prior to PCI.

Saw J, J Am Coll Cardiol. 2004;44:1194-1199. SCRIPPS CLINIC REPLACE 2: Results Stratified By Clopidogrel Tx No Differential Benefit On Net Clinical Events

Saw J, J Am Coll Cardiol. 2004;44:1194-1199. SCRIPPS CLINIC ACUITY Study Design First Randomization

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

Moderate Bivalirudin and high R* + GP IIb/IIIa risk ACS (n=4,604) PCI (n=13,819)

AspirinAspirin inin allall Bivalirudin ClopidogrelClopidogrel Alone Angiography within 72h dosingdosing andand timingtiming (n=4,612) CABG perper locallocal practicepractice

SCRIPPS CLINIC ACUITY: Influence of Exposure 30 Day Primary Endpoint Adverse Events

RR [95%CI] RR [95%CI] RR [95%CI] RR [95%CI] RR [95%CI] RR [95%CI] 0.81 (0.68-0.96) 0.96 (0.77-1.20) 0.50 (0.37-0.67) 1.07 (0.83-1.39) 1.37 (1.00-1.88) 0.61 (0.39-0.97)

Thienopyridine Exposed* Not Thienopyridine Exposed Interaction P values = 0.17, 0.19 and 0.65 respectively *Thienopyridine at any time, any dose, up to time of PCI SCRIPPS CLINIC What is known About Clopidogrel Exposure in ACUITY Patients Pre-PCI

Underwent PCI and received clopidogrel at No some time prior to or during hospitalization clopidogrel N= 7517 N= 129

Clopidogrel Clopidogrel at Clopidogrel after pre-hospital hospital but pre- randomization N=1820 (24%) randomization N= 3314 (44%) N= 2383 (32%) Known dose and duration

Clopidogrel Pre-angiography N = 928 Clopidogrel Peri- PCI N =1572 Clopidogrel Post-PCI N = 814 Steinhubl, TCT 2007 ACUITY and Clopidogrel Preloading 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 angiogram. – 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

Steinhubl, TCT 2007 SCRIPPS CLINIC 30-Day Ischemic Outcomes Based on Antiplatelet Therapy

Composite Ischemia % P=0.18

GPIIb/IIIa antagonist + any anticoagulant 23.3 20 Bivalirudin alone

P=0.22 14.0 P=0.77 12.6 10 P=0.36 9.7 8.8 8.6 8.1 8.2

0 Pre-PCI Peri-PCI Post-PCI None N=5131 N=1572 N=814 N=129 Timing of Clopidogrel Exposure Steinhubl, TCT 2007 30-Day Ischemic Outcomes in Troponin Positive Patients Only

Composite Ischemia %

P=0.72

23.1 20 GPIIb/IIIa antagonist + any anticoagulant Bivalirudin alone P=0.13 19.6

P=0.60 P=0.97 13.7 10 9.0 9.1 8.4 8.2 8.3

0 Pre-PCI Peri-PCI Post-PCI None N=2824 N=950 N=471 N=77 Timing of Clopidogrel Exposure Steinhubl, TCT 2007 ACUITY PCI: Impact of Timing of Clopidogrel Administration on 1 Yr Mortality (Tn + patients)

1-year Mortality PCI troponin+ patients HR (95% CI) PCI troponin+ patients Hazard Ratio ±95% CI

ClopidogrelClopidogrelat any time prior to hospitalization,hospitalization, randomizationrandomization oror endend 1.07 (0.66-1.73) ofof angiographyangiography (n=1,891)(n=1,891)

ClopidogrelClopidogrelafter end ofof angioangio-- 1.09 (0.46-2.58) graphygraphyto 3030’’ post PCI (n=649)(n=649)

ClopidogrelClopidogrelafter after 3030’’ 0.56 (0.17-1.93) postpost PCIPCI (n=307)(n=307)

NoNo clopidogrel (n=51)(n=51) 3.07 (0.32-29.49)

0.1 1 10 Bivalirudin Alone Better UFH/Enox + IIb/IIIa Better

White et al, JACC 2008 What dose and duration is an adequate preload? Analysis of the CREDO trial

Log Odds of Death, MI CREDO or UTVR at 28 Days -2 Placebo

-3 P = 0.020 for treatment / timing interaction -4 Clopidogrel

-5

-6 0 5 10 15 20 25 30 Hours Prior to PCI of Study Drug Loading Dose

Steinhubl et al, Am. Coll. Cardiol. 2006;47;939-943 SCRIPPS CLINIC What dose and duration is an adequate preload? Time to inhibition for different clopidogrel loading doses

* p < 0.01 (600- or 900-mg vs. 300-mg)

300 m g 10 0 ** 600 m g * * 900 m g * 80 *

60

40 Percent Inhibition Percent

20

0 Baseline Hour 1 Hour 2 Hour 3 Hour 4 Hour 5 Hour 6 Hour 7 Tim e Point

Price MJ, Am J Cardiol 2006;98(5):681-4 SCRIPPS CLINIC 11--YearYear StentStent ThrombosisThrombosis:: ImpactImpact ofof ClopidogrelClopidogrel LoadingLoading DoseDose (all(all pts)pts)

600mg Clopidogrel 300mg Clopidogrel 5

4 3.8%

3 3.0%

2 HR [95%CI] = Stent Thrombosis (%) Stent Thrombosis Stent Thrombosis (%) Stent Thrombosis 1.30 [0.86-1.95] 1 Prob Prob P = 0.10 Def/ Def/ 0 0 30 60 90 120 150 180 210 240 270 300 330 365 Time in days Number at risk 600 mg 1983 1906 1881 1858 1832 1653 300 mg 1034 983 974 965 952 871 StentStent ThrombosisThrombosis 11--DayDay LandmarkLandmark Analysis:Analysis: ImpactImpact ofof ClopidogrelClopidogrel LoadingLoading ((BivalirudinBivalirudin))

600mg Clopidogrel 5 300mg Clopidogrel HR [95%CI] =2.11

HR [95%CI] = [1.07,4.17] 4 1.30 [0.54-3.16] P = 0.03 P = 0.56 3.4% 3

2 Stent Thrombosis (%) Stent Thrombosis

Stent Thrombosis (%) Stent Thrombosis 1.6% 1.5% 1.6% 1 Prob Prob 1.2% Def/ Def/ 0 0 1 30 90 180 270 365 Time in Days Number at risk 600 mg 1013 1009 990 969 957 943 863 300 mg 519 514 497 486 480 474 430 Efficacy of Clopidogrel Pre-treatment in Patients Receiving GpIs: Combined Analysis PCI-CURE, CREDO and PCI-CLARITY CV Death, MI, or Stroke Following PCI

Without GPI Favors Favors Trial Clop PreRx No PreRx PreRx No PreRx PCI-CURE 27/1039 (2.6) 39/988 (3.9) CREDO 26/473 (5.5) 34/519 (6.6) PCI-CLARITY 22/639 (3.4) 30/615 (4.9) OR 0.72 (0.53-0.98) OVERALL 75/2151 (3.5) 103/2122 (4.9) P=0.03

0.250.5 1.0 2.0 With GPI OR (95% CI) P=0.85 for Trial Clop PreRx No PreRx heterogeneity by GPI use PCI-CURE 14/274 (5.1) 23/357 (6.4) CREDO 29/427 (6.8) 32/396 (8.1) PCI-CLARITY 12/288 (4.2) 28/310 (9.0) OVERALL 55/989 (5.6) 83/1063 (7.8) OR 0.69 (0.47-1.00) P=0.05

0.250.5 1.0 2.0 Sabatine MS Am Heart J 2008;155(5):910-917 OR (95% CI) The Response To A Uniform Dose Of Clopidogrel Is Not Uniform

100

80

60 n = 1001, clopidogrel 600-mg

40

5 µmol/L ADP (%) 20 Maximal Aggregation

0 0246810 Time from Loading Dose to Catheterization (hr)

Hochholzer W et al. Circulation. 2005;111:2560-2564. SCRIPPS CLINIC PRINCIPLE TIMI 44: Time and Magnitude of Onset of Inhibition of Compared with 600-mg Clopidogrel

IPA (20 mM ADP) N = 201

100 P<0.0001 for each

Prasugrel 60 mg 80 74.8 64.5

60 69.3

% 40 Clopidogrel 600 mg 32.6

30.8 31.8 20 20.3

4.9 0 0481216202428 Hours IPA = inhibition of platelet aggregation.

Wiviott SD et al. Circulation. 2007;116:2923-2932. SCRIPPS CLINIC TRITON-TIMI 38: Primary Endpoint

15

Clopidogrel 12.1 HR 0.81 CV Death/MI/Stroke (95% CI, 0.73–0.90) 10 9.9 P<0.001) Prasugrel* NNT=46

Endpoint (%) 5 TIMI Major Non-CABG HR 1.32 Prasugrel Bleeds 2.4 (95% CI, 1.8 1.03–1.68) Clopidogrel P=0.03 0 0 30 60 90 180 270 360 450 NNH=167 Days After Randomization

Wiviott SD et al. N Engl J Med. 2007;357(20):2001-2015. SCRIPPS CLINIC Conclusions

• In REPLACE 2, clopidogrel pretreatment did not influence the relative efficacy of bivalirudin versus heparin plus a GPI. However, pretreatment was associated with a trend towards lower clinical events overall.

• 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 randomized to bivalirudin alone versus a GPI, irrespective of troponin status.

• There was a trend in ACUITY towards worse ischemic outcomes among patients receiving clopidogrel > 30 min after PCI or no clopidogrel at all.

SCRIPPS CLINIC Conclusions (2)

• Clopidogrel pre-treatment is beneficial whether or not a GPI is used at the time of PCI.

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

• In the case of ACS, the availability of prasugrel, which provides greater, more consistent, and quicker onset of inhibition then clopidogrel, may make the question of clopidogrel pretreatment moot.

SCRIPPS CLINIC