Ramin Ebrahimi, MD University 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 Ebrahimi et al, ACC 2007 Disclosures ►Sanofi-aventis: Consultant, speaker ►Bristol Myers: Consultant, speaker ►The Medicines Company: Consultant, speaker ►Abbott: Consultant ►Guerbett: Consultant

3 Ebrahimi et al, ACC 2007 Moderate- high risk ACS Study Design ►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 Thienopyridine 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

4 Ebrahimi et al, ACC 2007 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 Ebrahimi et al, ACC 2007 Primary Results by Treatment Arm (30 Day) ►Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = P NI = 0.01 P Sup = 0.32 P NI <0.001 P Sup <0.001 *Heparin=unfractionated or enoxaparin Stone GW, et al. N Engl J Med 2006;335:

6 Ebrahimi et al, ACC 2007 Background information ►Early benefits of thienopyridine administration in NSTE-ACS have been established 1 ►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):

7 Ebrahimi et al, ACC 2007 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 Ebrahimi et al, ACC 2007 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 ( )  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 ( ) in Thieno (+) pts vs. 1.8 days ( ) in Thieno (-) pts ►All patients, regardless of randomized arm, received UFH during CABG

9 Ebrahimi et al, ACC 2007 Baseline Characteristics: CABG Patients ►Patients with and without a thienopyridine administered prior to CABG Thieno (+)Thieno (-)P-value N Age (median) Female23.4%22.6%0.71 Diabetes34.7%33.7%0.69 CrCl <6018.1%19.6%0.47 Hypertension69.7%63.4%0.01 Current Smoker28.0%28.3%0.90 Prior MI26.2%22.5%0.10 Prior PCI24.8%19.3%0.01 Prior CABG5.7%3.7%0.06 Elevated CK-MB/Troponin73.0%74.1%0.65 ECG Changes51.4%47.5%0.13 ASA98.9%97.8%0.10 GP IIb/IIIa37.6%36.4%0.64

10 Ebrahimi et al, ACC 2007 Overall Outcomes in CABG Patients ►Patients with and without a thienopyridine administered prior to CABG P=0.046 P=0.01 P=0.71 P=0.98

11 Ebrahimi et al, ACC 2007 Composite Ischemic Outcomes in CABG Patients ►Patients with and without a thienopyridine administered prior to CABG P=0.99 P=0.01 P=0.04 P<0.001

12 Ebrahimi et al, ACC 2007 Composite Ischemia Elevated CKMB/Troponin1.51 ( ) Hypertension 1.75 ( )0.002 Prior CABG2.78 ( ) <0.001 Thienopyridine prior to CABG 0.63 ( ) All Major Bleeding CrCL < 60mL/min1.37 ( ) Thienopyridine prior to CABG 1.01 ( ) Multivariate Model - Composite Ischemia and All Major Bleeding ►Adjusted analysis in patients Undergoing CABG Odds ratio ±95% CI Odds ratio ±95% CI P-valueOR (95% CI)

13 Ebrahimi et al, ACC Day Outcomes – CABG Patients by Thienopyridine Status Thieno (+) n=806 Thieno (-) n=733 P-value Resource Utilization Total LOS, median <0.001 Pre-CABG LOS, median4.22.5<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 38.3%37.8% hr Chest Tube Output (median) ml553.0 ml0.74 ►Patients with and without a thienopyridine administered prior to CABG *CABG related bleeding was not CEC adjudicated

14 Ebrahimi et al, ACC 2007 Baseline Characteristics: CABG Patients ►Timing based on clopidogrel administration during index hospitalization No clopidogrel N=830 Clopidogrel <5 days N=450 Clopidogrel >5 days N=258 Age (median, years)6465 Age ≥75 years18%20.9%16.7% Female23.1%24%21.3% Diabetes34.2%33.8%35.4% CrCl < %20.7%15.9% Hypertension65.1%69.3%67.4% Current Smoker27.5%29.2%28.5% Prior MI23.3%25.1%26.6% Prior PCI21.3%22.7%23.8% Prior CABG3.7%*6.2%5.4% Elevated CK-MB/Troponin73.5%74.4%72.1% ECG Changes47.7%50.9%53.1% *P=0.04 vs Thienopyridine <120 hrs

15 Ebrahimi et al, ACC 2007 Unadjusted 30 Day Outcomes Based on time to CABG P=0.36 p=0.002 p=0.02p=0.59 p=0.004 p=0.052

16 Ebrahimi et al, ACC 2007 Unadjusted 30 Day Composite Ischemia Based on time to CABG P=0.04 p=0.03 p=0.44 p=0.09 p=0.054 p=0.36 p=0.004

17 Ebrahimi et al, ACC 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 (days) 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 *CABG related bleeding was not CEC adjudicated

18 Ebrahimi et al, ACC 2007 Study Limitations ►Comparison of thienopyridine 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 Ebrahimi et al, ACC 2007 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