implications of preoperative thienopyridine use prior to coronary bypass graft surgery: a report...

Implications of Preoperative Thienopyridine Use Prior to Coronary Bypass Graft Surgery: A Report

from the ACUITY Trial

Ramin Ebrahimi, MDUniversity of California Los Angeles/ Greater Los Angeles VA

Medical Center

2Ebrahimi et al, TCT 2006

Disclosures► Sanofi: Consultant, speaker► Bristol: Consultant, speaker► TMC: Consultant, speaker► Abbott: Consultant► Guerbett: Consultant


Bivalirudin in ACS: ACUITY Hypotheses► In moderate and high risk patients with ACS undergoing an

invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors: Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse

ischemic events and less bleeding Bivalirudin alone will result in similar rates of ischemic events and

markedly reduced bleeding


Major Entry Criteria► Moderate and high risk unstable angina or NSTEMI

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

Inclusion CriteriaAge ≥18 yearsChest pain ≥10’ within 24hAt least one of:

New ST depression or transient ST elevation ≥1 mmTroponin I, T, or CKMBDocumented CADAll other 4 TIMI risk criteria

- Age ≥65 years- Aspirin within 7 days- ≥2 angina episodes w/i 24h- ≥3 cardiac risk factors

Written informed consent

Exclusion CriteriaNo angiography within 72hAcute STEMI or shockBleeding diathesis or major bleed within 2 weeksPlatelet count ≤100,000/mm3

INR >1.5 controlCrCl ≤30 ml/minAbcx or ≥2 prior LMWH doses

Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed

Allergy to drugs, contrast


Moderate-high risk

ACS

Study Design – First Randomization► Moderate and high risk unstable angina or NSTEMI

undergoing an invasive strategy (N = 13,819)

Ang

iogr

aphy

with

in 7

2h

Aspirin in allAspirin in allClopidogrelClopidogrel

dosing and timingdosing and timingper local practiceper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

*Stratified by pre-angiography thienopyridine use or administration


Medicalmanagement

PCI

CABG


Moderate-high risk

ACS

Study Design – Second Randomization► Moderate and high risk unstable angina or NSTEMI

undergoing an invasive strategy (N = 13,819)

Ang

iogr

aphy

with

in 7

2h


Aspirin in allClopidogrel

dosing and timingper local practice

Medicalmanagement

PCI

CABGBivalirudin

Alone

UFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI onlyR

Bivalirudin

RRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only


UF Heparin Enoxaparin BivalirudinU/Kg mg/Kg mg/kg

Bolus 60 1.0 sc bid 0.1 ivInfusion/h 121 0.25 iv

PCIACT

200-250s0.30 iv bolus2

0.75 iv bolus3

0.50 bolus iv1.75/h infusion iv4

CABG Per institution Per institution Per institution5

Medical mgt None6 None6 None6

Study Medications► Anti-thrombin agents (started pre angiography)

1 Target aPTT 50-75 seconds2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion


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


Primary Results by Treatment Arm► Total of 13,819 total patients (11.1% CABG, n=1539)

UFH/Enox + GP IIb/IIIa

Bivalirudin +GP IIb/IIIa

Bivalirudinalone

Endpoint Rate Rate P Value Rate P Value

Net clinical outcome 11.7% 11.8% <0.001 NI 10.1% 0.015 Sup

Ischemic events 7.3% 7.7% 0.007 NI 7.8% 0.011 NI

Major bleeding 5.7% 5.3% 0.001 NI 3.0% <0.001 Sup

NI = non-inferiority; Sup = superiority

Gregg Stone, ACC 2006 Presentation


Thienopyridines in NSTE-ACS► ACC/AHA guidelines

Class IA recommendation if aspirin is contraindicated Class IA recommendation in PCI patients for one month, Class IB

recommendation for up to nine months Class IA recommendation in patients managed conservatively for

one month, Class IB recommendation for up to nine months Class IA recommendation to withhold Clopidogrel for 5-7 days if

elective CABG is planned.


Background of Thienopyridines in CABG► Clopidogrel before elective CABG: Insights from prior

studiesClopidogrel

(n=59)No Clopidogrel

(n=165) P-value

CT output 1st 24º 1224 840 0.001Transfusions any 85% 61% 0.001 RBC any 79% 58% 0.004 RBC mean U 2.51 1.74 0.036 Platelet any 51% 18% 0.001 Plat mean U 0.86 0.24 0.001Reop for bleed 6.8% 0.6% 0.02Extubate <8º 54% 76% 0.002LOS <5 days 34% 47% 0.09

Hongo RH, et al. JACC 2002;40:231-7Hongo RH, et al. JACC 2002;40:231-7


5.3%5.7%4.4%

8.5%

0

2

4

6

8

10 PlaceboClopidogrel

P=0.07 P=0.53

K.Fox et al, ESC 2002K.Fox et al, ESC 2002

Clopidogrel stoppedClopidogrel stopped<5 days<5 days

prior to CABGprior to CABG

Clopidogrel stoppedClopidogrel stopped>5 days>5 days

prior to CABGprior to CABG

CURE: Major Bleeding in CABG Patients► Major or life-threatening bleeding w/in 7 days of CABG


Background of Thienopyridines in CABG► OPCAB series1

No difference in mortality Increased:– Reoperation for bleeding– Need for blood product transfusion

► CRUSADE registry2

30% of patients received Plavix before surgery Most NSTE/ACS patients have CABG within 5 days of last

treatment (87%) Surgery on Plavix associated with increase in % and amount of

blood transfusions

1 Kapetanakis EI, Medlam DA, Petro KR, et al. Effect of clopidogrel premedication in off-pump cardiac surgery: are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation 2006;113:1667-1674.

2 Mehta RH, Roe MT, Mulgund J, et al. Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. JACC 2006; 48(2):281-286.


Background information► Early benefits of thienopyridine administration in NSTE-ACS

have been established1,2

► Many clinicians restrict administration until after angiography

► Reluctance usually driven by concern over minority of patients that will require CABG

► 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.

2 Steinhubl S, Berger PB, Mann III JT, et al. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention-A Randomized Controlled Trial. JAMA 2002;288:2411-2420.


Statistical Analyses► Summary of baseline characteristics are based on data

observed► Efficacy endpoints are based on ITT► Chi-square test used to test categorical variables► Wilcoxon rank sum test was used to test continuous

variables► Multivariate logistic regression was performed to adjust for

differences in baseline characteristics


Goals of the current analysis► Examine prevalence of early thienopyridine use in NSTE-

ACS patients during index hospitalization prior to CABG► Compare resource utilization (LOS) ► Report on safety and efficacy of thienopyridine use prior to

CABG► Examine the effect CABG-related outcomes (chest tube

output, rate of transfusion, bleeding)


Breakdown of Thienopyridine Use► Of 13,819 pts enrolled in ACUITY, CABG was performed in

1539 (11%) 46.7% received a thienopyridine, in-hospital, prior to

CABG (Thieno+ pts) Clopidogrel was used 98.6% of the time

► In Thieno+ pts, median time between last dose of thienopyridine and CABG was 3.0 days (1.1-6.2) 258 (36.4%) of Thieno+ patients went to surgery >5

days after last thieno exposure► Median time from angiogram to CABG was 3.3 days (1.3-

6.8) in Thieno + pts vs. 1.8 days (0.9-3.8) in Thieno- pts ► All patients, regardless of randomized arm, received UFH

during CABG


Baseline Characteristics of CABG Pts► Patients with and without a thienopyridine administered in-

hospital prior to CABGThieno (+) Thieno (-) P-value

N 718 820Age (median) 65 64 0.27Female 22.8% 23.3% 0.83Diabetes 34.4% 34.2% 0.94CrCl <60 18.8% 18.8% 0.99Hypertension 68.7% 65.1% 0.14Current Smoker 28.8% 27.6% 0.59Prior MI 25.6% 23.4% 0.32Prior PCI 22.8% 21.6% 0.58Prior CABG 5.9% 3.8% 0.06Elevated CK-MB/Troponin 73.5% 73.5% 0.99ECG Changes 51.8% 47.6% 0.10ASA 99.3% 97.6% 0.007GP IIb/IIIa 37.6% 36.6% 0.68OUS 60.6% 28.3% <.001


12.5%

15.5%

3.8% 2.9%

19.0%17.1%

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

Thieno (+)Thieno (–)

*Heparin=unfractionated or enoxaparin

Primary Outcomes in CABG Patients

P=0.066 P=0.013

► Patients with and without a thienopyridine administered in-hospital prior to CABG

P=0.362


30 Day Outcomes – CABG Patients by Thienopyridine Status

Thieno (+) n=718

Thieno (-) n=820 P-value

Resource UtilizationTotal LOS, median 12.1 9.0 <0.001Pre-CABG LOS, median 4.6 2.5 <0.001Post-CABG LOS, median 6.9 5.8 <0.001

Bleeding EndpointsPost CABG Major Bleeding 50.0% 50.5% 0.85Post CABG Blood transfusions 38.2% 38.0% 0.96

24hr Chest Tube Output (median) 600.0 ml 550.0 ml 0.22

► Patients with and without a thienopyridine administered in-hospital prior to CABG


Multivariate Model – Composite Ischemia► In patients undergoing CABG

Variable Estimate Range p-valueThienopyridine in-hospital 0.60 0.43- 0.83 0.002Prior CABG 3.45 1.89- 6.28 <0.001Hypertension (on meds) 1.84 1.27- 2.67 0.001Elevated cardiac markers 1.69 1.14- 2.48 0.009Baseline CrCl <60 1.49 1.01- 2.20 0.05Family history CAD 1.44 1.04- 2.00 0.03


Baseline Characteristics of CABG Pts

Clop (-)“A”

Clop (+), ≤ 5 Days to CABG “B”

P-valueA vs B

Clop (+), > 5 Days toCABG “C”

P-valueB vs C

N=830 N=450 N=258Age (median) 64 65 65 0.99Female 23.3% 24.0% 0.73 21.3% 0.41Diabetes 34.2% 33.8% 0.89 35.4% 0.66CrCl <60 18.7% 20.7% 0.39 15.9% 0.12Hypertension 65.1% 69.3% 0.13 67.4% 0.60Current Smoker 27.5% 29.2% 0.51 28.5% 0.83Prior MI 23.3% 25.1% 0.48 26.6% 0.67Prior PCI 21.3% 22.7% 0.57 23.8% 0.73Prior CABG 3.7% 6.2% 0.04 5.4% 0.66Elevated CM 73.5% 74.4% 0.74 72.1% 0.53ECG Changes 47.7% 50.9% 0.28 53.1% 0.57OUS pts 28.2% 50.7% <0.001 79.5% <0.001

► Comparison based on time to CABG


11.2%

7.8%

3.9%

17.1%19.0%

3.0% 3.6%

17.8%

15.1%

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

Clop (-)Clop (+) ≤ days to CABGClop (+) > 5 days to CABG

*Heparin=unfractionated or enoxaparin


Unadjusted Primary Outcomes


30 Day Outcomes – CABG Patients by Clopidogrel Status

Clop (-) “A”

N=830

Clop (+), ≤ 5 Days to CABG

“B”N=450

p-valueA vs B

Clop (+), > 5 Days to CABG

“C”N=258

p-valueB vs C

Resource UtilizationTotal LOS, median 9.0 10.8 <0.001 15.7 <0.001Pre-CABG LOS, median 2.5 3.0 0.38 9.2 <0.001Post-CABG LOS, median 5.8 7.0 <0.001 6.8 0.006

Bleeding EndpointsPost CABG Major Bleeding 50.2% 54.0% 0.20 43.8% 0.009Post 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



Study Limitations► Unblinded, non-randomized subgroup analysis► Operators, aware of thienopyridine status, may have

altered clinical decisions► Current study does not take into account the exact timing

of last dose of thienopyridine in relation to CABG► CABG-related bleeding, CT output were not CEC

adjudicated


Conclusions► In NSTE-ACS patients undergoing CABG in the ACUITY trial,

thienopyridine use prior to CABG was associated with a prolonged duration of hospitalization primarily because of the delays to surgery

► However, in the entire CABG cohort, thienopyridine exposure prior to surgery was associated with improved ischemic outcomes at one month, and was not associated with increased post surgical bleeding with appropriate delays to CABG in 36.4% of pts

► Since surgery is only required in approximately 10% of NSTE-ACS pts, and since thienopyridine use prior to PCI (56% of pts) is known to significantly improve outcomes, these data support a routine strategy of thienopyridine administration prior to angiography from a clinical standpoint

implications of preoperative thienopyridine use prior to coronary bypass graft surgery: a report...

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