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

2Ebrahimi et al, ACC 2007

Disclosures

► Sanofi-aventis: Consultant, speaker

► Bristol Myers: Consultant, speaker

► The Medicines Company: Consultant, speaker

► Abbott: Consultant

► Guerbett: Consultant

3Ebrahimi 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)

An

gio

gra

ph

y w

ith

in 7

2h

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Aspirin in allThienopyridine

dosing and timingper local practice

Medicalmanagement

PCI

CABG

BivalirudinAlone

UFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only

R

Bivalirudin

R

Routine upstream GPI in all ptsGPI started in

CCL for PCI only

4Ebrahimi 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

5Ebrahimi et al, ACC 2007

Primary Results by Treatment Arm (30 Day)

► Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.01 PSup = 0.32

PNI <0.001PSup <0.001

*Heparin=unfractionated or enoxaparinStone GW, et al. N Engl J Med 2006;335:2203-16

6Ebrahimi et al, ACC 2007

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.

7Ebrahimi 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)

8Ebrahimi 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 (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

9Ebrahimi et al, ACC 2007

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% 0.01

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% 0.10

GP IIb/IIIa 37.6% 36.4% 0.64

10Ebrahimi et al, ACC 2007

Overall Outcomes in CABG Patients

► Patients with and without a thienopyridine administered prior to CABG

54.2% 54.3%

12.8%15.5%

3.5% 3.1%

19.4%17.3%

Net clinicaloutcome

Compositeischemia

Major bleeding(non-CABG)

All MajorBleeding

Thieno (+) (N=806)

Thieno (–) (N=733)

P=0.046P=0.01

P=0.71

P=0.98

11Ebrahimi et al, ACC 2007

Composite Ischemic Outcomes in CABG Patients

► Patients with and without a thienopyridine administered prior to CABG

2.1%0.8%

4.0%

12.8%

8.7%

14.6%

17.3%

4.0%

CompositeIschemia

Death MI UnplannedRevasc

Thieno (+) (N=806)

Thieno (–) (N=733)

P=0.99

P=0.01

P=0.04

P<0.001

12Ebrahimi et al, ACC 2007

Composite Ischemia

Elevated CKMB/Troponin

1.51 (1.05-2.17) 0.027

Hypertension 1.75 (1.23-2.48) 0.002

Prior CABG 2.78 (1.57-4.91) <0.001

Thienopyridine prior to CABG

0.63 (0.46-0.86) 0.003

All Major Bleeding

CrCL < 60mL/min 1.37 (1.04-1.81) 0.025

Thienopyridine prior to CABG

1.01 (0.82-1.25) 0.897

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)

0 3 6

13Ebrahimi et al, ACC 2007

30 Day Outcomes – CABG Patients by Thienopyridine Status

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 <0.001

Post-CABG LOS, median 6.9 5.8 <0.001

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

► Patients with and without a thienopyridine administered prior to CABG

*CABG related bleeding was not CEC adjudicated

14Ebrahimi 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) 64 65 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 21.3% 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

15Ebrahimi et al, ACC 2007

11.2%7.8%

47.3%

17.1%19.0%

53.7%

59.3%

17.8%15.1%

Net clinical outcome Composite ischemia All Major Bleeding

Clop (-) (n=830)Clop (+) ≤ 5 days to CABG (n=450)

Clop (+) > 5 days to CABG (n=258)

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

16Ebrahimi et al, ACC 2007

1.2%2.7%

7.8%

2.3%

5.8%

0.4%

4.0%

17.1%

14.1%

10.0%

15.1%

4.9%

CompositeIschemia

Death MI Unplanned Revasc

Clop (-) (n=830)Clop (+) ≤ 5 days to CABG (n=450)

Clop (+) > 5 days to CABG (n=258)

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=0.054

p=0.36

p=0.004

17Ebrahimi et al, ACC 2007

30 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 9.0 10.8 <0.001 15.7 <0.001

Pre-CABG LOS, median 2.5 3.0 0.38 9.2 <0.001

Post-CABG LOS, median 5.8 7.0 <0.001 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 0.06 550.0 ml 0.15

► Comparison based on time to CABG

*CABG related bleeding was not CEC adjudicated

18Ebrahimi et al, ACC 2007

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

19Ebrahimi 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