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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