Implications of Preoperative Thienopyridine Use Prior to Coronary Bypass Graft Surgery: A Report from the ACUITY Trial Ramin Ebrahimi, MD University of California Los Angeles/ Greater Los Angeles VA Medical Center

2 Ebrahimi et al, TCT 2006 Disclosures ►Sanofi: Consultant, speaker ►Bristol: Consultant, speaker ►TMC: Consultant, speaker ►Abbott: Consultant ►Guerbett: Consultant

3 Ebrahimi et al, TCT 2006 Bivalirudin in ACS: ACUITY Hypotheses ►In moderate and high risk patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors:  Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding  Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding

4 Ebrahimi et al, TCT 2006 Major Entry Criteria ►Moderate and high risk unstable angina or NSTEMI ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Inclusion Criteria  Age ≥18 years  Chest pain ≥10’ within 24h  At least one of:  New ST depression or transient ST elevation ≥1 mm  Troponin I, T, or CKMB   Documented CAD  All other 4 TIMI risk criteria - Age ≥65 years - Aspirin within 7 days - ≥2 angina episodes w/i 24h - ≥3 cardiac risk factors  Written informed consent Exclusion Criteria  No angiography within 72h  Acute STEMI or shock  Bleeding diathesis or major bleed within 2 weeks  Platelet count ≤100,000/mm 3  INR >1.5 control  CrCl ≤30 ml/min  Abcx or ≥2 prior LMWH doses  Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed  Allergy to drugs, contrast

5 Ebrahimi et al, TCT 2006 Moderate- high risk ACS Study Design – First Randomization ►Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Medical management PCI CABG

6 Ebrahimi et al, TCT 2006 Moderate- high risk ACS Study Design – Second Randomization ►Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72h ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Aspirin in all Clopidogrel dosing and timing per local practice Medical management PCI CABG Bivalirudin Alone UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only R Bivalirudin R Routine upstream GPI in all pts GPI started in CCL for PCI only

7 Ebrahimi et al, TCT 2006 UF HeparinEnoxaparinBivalirudin U/Kgmg/Kgmg/kg Bolus601.0 sc bid0.1 iv Infusion/h iv PCI ACT s 0.30 iv bolus iv bolus bolus iv 1.75/h infusion iv 4 CABGPer institution Per institution 5 Medical mgtNone 6 Study Medications ►Anti-thrombin agents (started pre angiography) 1 Target aPTT seconds 2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

8 Ebrahimi et al, TCT 2006 Primary Endpoints (30 day) ►Net Clinical Outcomes  Death, MI, unplanned revascularization for ischemia or non-CABG major bleeding ►Composite Ischemia  Death, MI or unplanned revascularization for ischemia ►Major Bleeding (Non-CABG)  Intracranial, intraocular, or retroperitoneal bleeding  Access site bleed requiring intervention/surgery  Hematoma ≥5 cm  Hgb  ≥4g/dL w/o overt source  Hgb  ≥3g/dL with an overt source  Reoperation for bleeding  Any blood transfusion

9 Ebrahimi et al, TCT 2006 Invasive Management UFH/Enoxaparin + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin alone (N=4,612) Angiography99.2%98.8%98.9% Actual procedure PCI55.6%56.7%56.8% CABG11.9%10.8%10.6% Medical therapy32.4%32.5%32.6%

10 Ebrahimi et al, TCT 2006 Primary Results by Treatment Arm ►Total of 13,819 total patients (11.1% CABG, n=1539) UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone Endpoint Rate P ValueRateP Value Net clinical outcome 11.7%11.8%<0.001 NI10.1%0.015 Sup Ischemic events 7.3%7.7%0.007 NI7.8%0.011 NI Major bleeding 5.7%5.3%0.001 NI3.0%<0.001 Sup NI = non-inferiority; Sup = superiority Gregg Stone, ACC 2006 Presentation

11 Ebrahimi et al, TCT 2006 Thienopyridines in NSTE-ACS ►ACC/AHA guidelines  Class IA recommendation if aspirin is contraindicated  Class IA recommendation in PCI patients for one month, Class IB recommendation for up to nine months  Class IA recommendation in patients managed conservatively for one month, Class IB recommendation for up to nine months  Class IA recommendation to withhold Clopidogrel for 5-7 days if elective CABG is planned.

12 Ebrahimi et al, TCT 2006 Background of Thienopyridines in CABG ►Clopidogrel before elective CABG: Insights from prior studies Clopidogrel (n=59) No Clopidogrel (n=165) P-value CT output 1st 24º Transfusions any85%61%0.001 RBC any79%58%0.004 RBC mean U Platelet any51%18%0.001 Plat mean U Reop for bleed6.8%0.6%0.02 Extubate <8º54%76%0.002 LOS <5 days34%47%0.09 Hongo RH, et al. JACC 2002;40:231-7

13 Ebrahimi et al, TCT 2006 P=0.07P=0.53 K.Fox et al, ESC 2002 Clopidogrel stopped <5 days prior to CABG prior to CABG Clopidogrel stopped >5 days prior to CABG prior to CABG CURE: Major Bleeding in CABG Patients ►Major or life-threatening bleeding w/in 7 days of CABG

14 Ebrahimi et al, TCT 2006 Background of Thienopyridines in CABG ►OPCAB series 1  No difference in mortality  Increased: – Reoperation for bleeding – Need for blood product transfusion ►CRUSADE registry 2  30% of patients received Plavix before surgery  Most NSTE/ACS patients have CABG within 5 days of last treatment (87%)  Surgery on Plavix associated with increase in % and amount of blood transfusions 1 Kapetanakis EI, Medlam DA, Petro KR, et al. Effect of clopidogrel premedication in off-pump cardiac surgery: are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation 2006;113: Mehta RH, Roe MT, Mulgund J, et al. Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. JACC 2006; 48(2):

15 Ebrahimi et al, TCT 2006 Background information ►Early benefits of thienopyridine administration in NSTE-ACS have been established 1,2 ►Many clinicians restrict administration until after angiography ►Reluctance usually driven by concern over minority of patients that will require CABG ►Limited data are available on the role of thienopyridines in NSTE-ACS patients undergoing CABG. 1 Yusuf S, Zhao F, Mehta SR, et al. Effects Of Clopidogrel In Addition To Aspirin In Patients With Acute Coronary Syndromes Without St-Segment Elevation. NEJM 2001;345(7): Steinhubl S, Berger PB, Mann III JT, et al. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention-A Randomized Controlled Trial. JAMA 2002;288:

16 Ebrahimi et al, TCT 2006 Statistical Analyses ►Summary of baseline characteristics are based on data observed ►Efficacy endpoints are based on ITT ►Chi-square test used to test categorical variables ►Wilcoxon rank sum test was used to test continuous variables ►Multivariate logistic regression was performed to adjust for differences in baseline characteristics

17 Ebrahimi et al, TCT 2006 Goals of the current analysis ►Examine prevalence of early thienopyridine use in NSTE-ACS patients during index hospitalization prior to CABG ►Compare resource utilization (LOS) ►Report on safety and efficacy of thienopyridine use prior to CABG ►Examine the effect CABG-related outcomes (chest tube output, rate of transfusion, bleeding)

18 Ebrahimi et al, TCT 2006 Breakdown of Thienopyridine Use ►Of 13,819 pts enrolled in ACUITY, CABG was performed in 1539 (11%)  46.7% received a thienopyridine, in-hospital, prior to CABG (Thieno+ pts)  Clopidogrel was used 98.6% of the time ►In Thieno+ pts, median time between last dose of thienopyridine and CABG was 3.0 days ( )  258 (36.4%) of Thieno+ patients went to surgery >5 days after last thieno exposure ►Median time from angiogram to CABG was 3.3 days ( ) in Thieno + pts vs. 1.8 days ( ) in Thieno- pts ►All patients, regardless of randomized arm, received UFH during CABG

19 Ebrahimi et al, TCT 2006 Baseline Characteristics of CABG Pts ►Patients with and without a thienopyridine administered in-hospital prior to CABG Thieno (+)Thieno (-)P-value N Age (median) Female22.8%23.3%0.83 Diabetes34.4%34.2%0.94 CrCl <6018.8% 0.99 Hypertension68.7%65.1%0.14 Current Smoker28.8%27.6%0.59 Prior MI25.6%23.4%0.32 Prior PCI22.8%21.6%0.58 Prior CABG5.9%3.8%0.06 Elevated CK-MB/Troponin73.5% 0.99 ECG Changes51.8%47.6%0.10 ASA99.3%97.6%0.007 GP IIb/IIIa37.6%36.6%0.68 OUS60.6%28.3%<.001

20 Ebrahimi et al, TCT 2006*Heparin=unfractionated or enoxaparin Primary Outcomes in CABG Patients P=0.066P=0.013 ►Patients with and without a thienopyridine administered in-hospital prior to CABG P=0.362

21 Ebrahimi et al, TCT Day Outcomes – CABG Patients by Thienopyridine Status Thieno (+) n=718 Thieno (-) n=820 P-value Resource Utilization Total LOS, median <0.001 Pre-CABG LOS, median4.62.5<0.001 Post-CABG LOS, median6.95.8<0.001 Bleeding Endpoints Post CABG Major Bleeding50.0%50.5%0.85 Post CABG Blood transfusions 38.2%38.0% hr Chest Tube Output (median) ml550.0 ml0.22 ►Patients with and without a thienopyridine administered in-hospital prior to CABG

22 Ebrahimi et al, TCT 2006 Multivariate Model – Composite Ischemia ►In patients undergoing CABG VariableEstimateRangep-value Thienopyridine in-hospital Prior CABG <0.001 Hypertension (on meds) Elevated cardiac markers Baseline CrCl < Family history CAD

23 Ebrahimi et al, TCT 2006 Baseline Characteristics of CABG Pts Clop (-) “A” Clop (+), ≤ 5 Days to CABG “B” P-value A vs B Clop (+), > 5 Days to CABG “C” P-value B vs C N=830N=450N=258 Age (median) Female23.3%24.0% %0.41 Diabetes34.2%33.8% %0.66 CrCl <6018.7%20.7% %0.12 Hypertension65.1%69.3% %0.60 Current Smoker27.5%29.2% %0.83 Prior MI23.3%25.1% %0.67 Prior PCI21.3%22.7% %0.73 Prior CABG3.7%6.2% %0.66 Elevated CM73.5%74.4% %0.53 ECG Changes47.7%50.9% %0.57 OUS pts28.2%50.7%< %<0.001 ►Comparison based on time to CABG

24 Ebrahimi et al, TCT 2006*Heparin=unfractionated or enoxaparin ►Comparison based on time to CABG Unadjusted Primary Outcomes

25 Ebrahimi et al, TCT Day Outcomes – CABG Patients by Clopidogrel Status Clop (-) “A” N=830 Clop (+), ≤ 5 Days to CABG “B” N=450 p-value A vs B Clop (+), > 5 Days to CABG “C” N=258 p-value B vs C Resource Utilization Total LOS, median < <0.001 Pre-CABG LOS, median <0.001 Post-CABG LOS, median5.87.0< Bleeding Endpoints Post CABG Major Bleeding50.2%54.0% %0.009 Post CABG Blood transfusions 37.8%42.7% % hr Chest Tube Output (median) ml600.0 ml ml0.15 ►Comparison based on time to CABG

26 Ebrahimi et al, TCT 2006 Study Limitations ►Unblinded, non-randomized subgroup analysis ►Operators, aware of thienopyridine status, may have altered clinical decisions ►Current study does not take into account the exact timing of last dose of thienopyridine in relation to CABG ►CABG-related bleeding, CT output were not CEC adjudicated

27 Ebrahimi et al, TCT 2006 Conclusions ►In NSTE-ACS patients undergoing CABG in the ACUITY trial, thienopyridine use prior to CABG was associated with a prolonged duration of hospitalization primarily because of the delays to surgery ►However, in the entire CABG cohort, thienopyridine exposure prior to surgery was associated with improved ischemic outcomes at one month, and was not associated with increased post surgical bleeding with appropriate delays to CABG in 36.4% of pts ►Since surgery is only required in approximately 10% of NSTE-ACS pts, and since thienopyridine use prior to PCI (56% of pts) is known to significantly improve outcomes, these data support a routine strategy of thienopyridine administration prior to angiography from a clinical standpoint