Ramin Ebrahimi, MD University of California Los Angeles/ Greater Los Angeles VA Medical Center

1. Ramin Ebrahimi, MDUniversity of California Los Angeles/ Greater Los Angeles VA Medical Center Implications of Preoperative Thienopyridine Use Prior to Coronary Bypass Graft Surgery in Patients with ACS: A Report from the ACUITY Trial

2. Disclosures • Sanofi-aventis: Consultant, speaker • Bristol Myers: Consultant, speaker • The Medicines Company: Consultant, speaker • Abbott: Consultant • Guerbett: Consultant

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

4. 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

5. PNI <0.001 PSup = 0.015 PNI = 0.01 PSup = 0.32 PNI <0.001 PSup <0.001 Primary Results by Treatment Arm (30 Day) • Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin Stone GW, et al. N Engl J Med 2006;335:2203-16

6. Background information • Early benefits of thienopyridine administration in NSTE-ACS have been established1 • Many clinicians restrict administration until after angiography • Reluctance is usually driven by concern over minority of patients that will require CABG • Although guidelines recommend a five day delay to surgery, many patients undergo surgery within five days • 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):494-502.

7. Goals of the current analysis • Examine prevalence of thienopyridine use in NSTE-ACS patients prior to CABG. • Examine treatment patterns associated with thienopyridine use including timing of CABG • Report on safety and efficacy of thienopyridine use prior to CABG based on 30 day ACUITY outcomes and time delay to CABG (≤5, >5 days) • Examine the effect of delay to CABG on CABG-related outcomes (chest tube output, frequency of transfusion, bleeding) • Compare resource utilization (LOS)

8. Breakdown of Thienopyridine Use • Of 13,819 pts enrolled in ACUITY, CABG was performed in 1539 (11.1%) • Exposure was defined as any thienopyridine use from 7 days prior to hospitalization up to CABG • 806 (52.3%) received a thienopyridine prior to CABG (Thieno + pts) • Clopidogrel was used 99.0% of the time • In Thieno (+) pts, median time between last dose of thienopyridine and CABG was 2.9 days (1.1-6.0) • 258 (36.4%) of Thieno (+) patients went to surgery >5 days after last thieno exposure • Median time from angiogram to CABG was 3.1 days (1.1-6.7) in Thieno (+) pts vs. 1.8 days (0.9-3.7) in Thieno (-) pts • All patients, regardless of randomized arm, received UFH during CABG

9. Baseline Characteristics:CABG Patients • Patients with and without a thienopyridine administered prior to CABG

10. Overall Outcomes in CABG Patients • Patients with and without a thienopyridine administered prior to CABG P=0.98 P=0.046 P=0.01 P=0.71

11. Composite Ischemic Outcomes in CABG Patients • Patients with and without a thienopyridine administered prior to CABG P=0.01 P<0.001 P=0.99 P=0.04

12. Multivariate Model - Composite Ischemia and All Major Bleeding • Adjusted analysis in patients Undergoing CABG Odds ratio ±95% CI OR (95% CI) P-value

13. 30 Day Outcomes – CABG Patients by Thienopyridine Status • Patients with and without a thienopyridine administered prior to CABG *CABG related bleeding was not CEC adjudicated

14. Baseline Characteristics: CABG Patients • Timing based on clopidogrel administration during index hospitalization *P=0.04 vs Thienopyridine <120 hrs

15. P=0.36 p=0.02 p=0.59 p=0.004 Unadjusted 30 Day Outcomes Based on time to CABG p=0.052 p=0.002

16. p=0.09 p=0.44 p=0.36 Unadjusted 30 Day Composite Ischemia Based on time to CABG p=0.004 P=0.04 p=0.054 p=0.054 p=0.03

17. 30 Day Outcomes – CABG Patients by Clopidogrel Status • Comparison based on time to CABG *CABG related bleeding was not CEC adjudicated

18. Study Limitations • Comparison of thienopyridine < 5 days vs > 5 days was an unblinded, non-randomized subgroup analysis • Known thienopyridine status or the degree of patient acuity may have influenced time to CABG • CABG-related bleeding, chest tube output were not CEC adjudicated • Current study does not take into account the exact timing of last dose of thienopyridine in relation to CABG for the entire population

19. Conclusions • Thienopyridine administration with subsequent delays prior to CABG are associated with significant increases in resource utilization • In the entire CABG cohort, thienopyridine exposure prior to surgery was: • Associated similar mortality and reduction in myocardial infarction • Not associated with increased post surgical bleeding • While post-surgical bleeding was increased in patients unable to wait 5 days for CABG, pre-procedural thienopyridine use was an independent predictor of freedom from adverse ischemic events • These data, in concert with the known benefit of thienopyridine use in NSTE-ACS patients undergoing PCI, suggest that all patients with NSTE-ACS should receive theinopyridines upon admission