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

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

3. Routine upstream GPI in all pts GPI started in CCL for PCI only
Study Design
Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)
Bivalirudin
Alone
UFH or Enoxaparin
Routine upstream GPI in all pts
GPI started in CCL for PCI only R
Medical
management
PCI
CABG
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. Primary Results by Treatment Arm (30 Day)
Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone
PNI <0.001
PSup = 0.015
PNI = 0.01
PSup = 0.32
PSup <0.001
*Heparin=unfractionated or enoxaparin
Stone GW, et al. N Engl J Med 2006;335:

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):

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 ( )
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. Baseline Characteristics: CABG Patients
Patients with and without a thienopyridine administered prior to CABG
Thieno (+)
Thieno (-)
P-value N
806
733
Age (median) 65 64
0.63
Female
23.4%
22.6%
0.71
Diabetes
34.7%
33.7%
0.69
CrCl <60
18.1%
19.6%
0.47
Hypertension
69.7%
63.4%
0.01
Current Smoker
28.0%
28.3%
0.90
Prior MI
26.2%
22.5%
0.10
Prior PCI
24.8%
19.3%
Prior CABG
5.7%
3.7%
0.06
Elevated CK-MB/Troponin
73.0%
74.1%
0.65
ECG Changes
51.4%
47.5%
0.13
ASA
98.9%
97.8%
GP IIb/IIIa
37.6%
36.4%
0.64

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
Composite Ischemia
Elevated CKMB/Troponin
1.51 ( )
0.027
Hypertension
1.75 ( )
0.002
Prior CABG
2.78 ( )
<0.001
Thienopyridine prior to CABG
0.63 ( )
0.003
All Major Bleeding
CrCL < 60mL/min
1.37 ( )
0.025
1.01 ( )
0.897

13. 30 Day Outcomes – CABG Patients by Thienopyridine Status
Patients with and without a thienopyridine administered prior to CABG
Thieno (+) n=806
Thieno (-) n=733
P-value
Resource Utilization
Total LOS, median
11.9
8.9
<0.001
Pre-CABG LOS, median
4.2
2.5
Post-CABG LOS, median
6.9
5.8
Bleeding Endpoints*
Post CABG Major Bleeding
50.0%
50.5%
0.85
Post CABG Blood transfusions
38.3%
37.8%
0.83
24hr Chest Tube Output (median)
590.0 ml
553.0 ml
0.74
*CABG related bleeding was not CEC adjudicated

14. 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) 64 65
Age ≥75 years
18%
20.9%
16.7%
Female
23.1%
24%
21.3%
Diabetes
34.2%
33.8%
35.4%
CrCl < 60
18.7%
20.7%
15.9%
Hypertension
65.1%
69.3%
67.4%
Current Smoker
27.5%
29.2%
28.5%
Prior MI
23.3%
25.1%
26.6%
Prior PCI
22.7%
23.8%
Prior CABG
3.7%*
6.2%
5.4%
Elevated CK-MB/Troponin
73.5%
74.4%
72.1%
ECG Changes
47.7%
50.9%
53.1%
*P=0.04 vs Thienopyridine <120 hrs

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

16. Unadjusted 30 Day Composite Ischemia Based on time to CABG

17. 30 Day Outcomes – CABG Patients by Clopidogrel Status
Comparison based on time to CABG
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
B vs C
Resource Utilization (days)
Total LOS, median
9.0
10.8
<0.001
15.7
Pre-CABG LOS, median
2.5
3.0
0.38
9.2
Post-CABG LOS, median
5.8
7.0
6.8
0.006
Bleeding Endpoints*
Post CABG Major Bleeding
50.2%
54.0%
0.20
43.8%
0.009
Post CABG Blood transfusions
37.8%
42.7%
0.09
30.6%
0.002
24hr Chest Tube Output (median)
550.0 ml
600.0 ml
0.06
0.15
*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

20. Question
&
Answer