Clopidogrel in ACS and CABG Surgery

1
Clopidogrel in ACS and CABG Surgery
Clopidogrel use and bleeding after coronary
artery bypass graft surgery John Hyung-Jun Kim,
MD, MBA, a,b L. Kristin Newby, MD, MHS, b,c
Robert M. Clare, MS, b Linda K. Shaw, MS, b
Andrew J. Lodge, MD, d Peter K. Smith, MD, d E.
Marc Jolicoeur, MD, MS, b Sunil V. Rao, MD, b,c
Richard C. Becker, MD, b,c Daniel B. Mark, MD,
MPH, b,c and Christopher B. Granger, MD b,c Palo
Alto, CA and Durham, NC Am Heart J. 2008
Nov156(5)886-92
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
2
Changing the Calculations for Assessing
Guidelines Adherence

• We need to invert the current equation to
  calculate an opportunity score for ACS patients
  rather than a risk score. Patients with higher
  baseline risks, such as the elderly, would have
  higher opportunity scores for benefit, even
  allowing for some of the greater risks from the
  treatment.

Anderson HV, Bach RG, J Am Coll Cardiol
2005461488-9.
3
Spectrum of Acute Coronary Syndromes
Ischemic Discomfort at Rest
Presentation
No ST-segment Elevation
ST-segment Elevation
Emergency Department




In-hospital 6-24hrs
NSTEMI
Non-Q-wave MI
Unstable Angina
Q-wave MI
(? positive cardiac biomarker)
4
Evolution of Guidelines for ACS
1990
1992
1994
1996
1998
2000
2002
2004
2007
1990 ACC/AHA AMI R. Gunnar
1994 AHCPR/NHLBI UA E.Braunwald
1996 1999 Rev Upd ACC/AHA AMI T.Ryan
5
Applying Classification of Recommendations
Class I Benefit gtgtgt Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit gtgt RiskAdditional studies with focused objectives needed IT IS REASONABLE to perform procedure/ administer treatment Class IIb Benefit RiskAdditional studies with broad objectives needed Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk BenefitNo additional studies needed Procedure/Treatment should NOT be performed/admini-stered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL
should is recommended is indicated is useful/effective/ beneficial is reasonable can be useful/effective/ beneficial is probably recommended or indicated may/might be considered may/might be reasonable usefulness/ effectiveness is unknown/unclear/ uncertain or not well established is not recommended is not indicated should not is not useful/effective/ beneficial may be harmful
6
The GuidelinesClasses of Recommendations

• Intervention is useful and effective
• Evidence supportive awaiting confirming data
• Evidence conflicts/opinions differ neutral
  statement
• Intervention is not useful/effective and may be
  harmful

7
Evidence-Based Approach to ACS Weighing the
Evidence

• Class I Benefit gt gt Risk
• Class IIa Benefit gt Risk
• Class IIb Benefit gt Risk
• Class III Risk gt Benefit

8
The GuidelinesWeighing the Evidence

• Weight of evidence grades
• Data from many large, randomized trials
• Data from fewer, smaller randomized trials,
  careful analyses of nonrandomized studies,
  observational registries
• Expert consensus

9
Antiplatelet Drug Targets
TRA
Platelet
Thrombin
PAR-1
Platelet
PAR - 1
PAR-4
Fibrinogen
Clopidogrel Prasugrel
P2Y1
GP IIIa
ADP
GP IIb
P2Y12
P2Y12
GP IIb
Thromboxane A2
Aspirin
TXA2-R
GP IIIa
Epinephrine
Serotonin
5HT2A
Gp IIb/IIIa inhibitors
Anionic phospholipid surfaces
GP VI
Collagen
GP Ia
10
Acute (lt 24 hrs) Antiplatelet Therapies for
High-Risk NSTE ACS
60
52
50
43
40
34
29
30
20
10
GP IIb/IIIa Clopidogrel GP
IIb/IIIa Neither
Clopidogrel
CRUSADE Q4 2003 data
11
Antiplatelet Tx 2007

• Clopidogrel with full loading dose in
  ASA-allergic patients
• EIS clopidogrel or IIb/IIIa administered
  upstream
• SIS clopidogrel initiated as soon as possible
  and continued for at least one month . . .
• . . . and preferably for one year

12
Antiplatelet Tx 2007

• ICS with recurrent ischemia on ASA, clopidogrel,
  and anticoag add IIb/IIIa upstream
• EIS it is reasonable to give both clopidogrel
  and IIb/IIIa upstream
• EIS can omit IIb/IIIa if bivalirudin is
  anticoagulant at least 300mg clopidogrel given
  gt 6h prior to cath

13
New Guidance on Thienopyridines

• Clopidogrel 75mg/d should be added to ASA in
  STEMI patients if lysed or if not reperfused
• If lt 75y/o and lysed or if not reperfused, add
  oral load of 300mg clopidogrel
• In PPCI, give 600mg clopidogrel as soon as
  possible

Antman et al, 2007 Focused Update to 2004 ACC/AHA
STEMI GLs King et al, 2008 Focused Update to 2005
ACC/AHA/SCAI PCI GLs
14
CLARITY-TIMI 28 Primary EndpointOccluded Artery
(or D/MI thru Angio/HD)
Odds Ratio 0.64(95 CI 0.53-0.76)
36 Odds Reduction
P0.00000036
Occluded Artery or Death/MI ()
1.0
0.4
0.6
0.8
1.2
1.6
LD 300 mgMD 75 mg
Clopidogrel better
Placebo better
STEMI, Age 18-75
Sabatine N Eng J Med 20053521179.
15
COMMIT Effect of Clopidogrel on Death In
Hospital
Placebo ASA 1,846 deaths (8.1)
Clopidogrel ASA 1,728 deaths (7.5)
0.6 ARD7 RRR P 0.03
Dead ()
N 45,852 No Age limit 26 gt 70 y Lytic Rx
50 No LD given
Days Since Randomization (up to 28 days)
Chen ZM, et al. Lancet. 20053661607.
16
CREDO 15 Hrs (Not 6 Hrs) Until Clinical Benefit
Seen with 300 mg Load
10 8 6 4 2 0
Death, MI, UTVR ()
Placebo Pretreatment (N915)
8.3
7.8
Clopidogrel Pretreatment lt 15 Hours (N645)
3.5
Clopidogrel Pretreatment gt 15 Hours (N202)
0 5 10 15 20 25
Days
Steinhubl S et al, J Am Coll Cardiol
200647939-943
17
Upstream Antiplatelet Therapy Bottom Line

• I-A recommendation for upstream advanced
  anti-platelet therapy in high-risk ACS
• Clopidogrel straightforward, well-supported
• What about bleeding risk and CABG surgery?
• New observational study

18
Clopidogrel in ASC and CABG Surgery

• Background Short-term use of clopidogrel plus
  aspirin among patients with acute coronary
  syndrome reduces ischemic events, but concerns
  about coronary artery bypass graft (CABG)
  surgeryrelated bleeding limit its early use.
  What does new data show?
• Methods Using data from 4,794 consecutive CABG
  procedures in the Duke Databank for
  Cardiovascular Disease , investigators developed
  multivariable models for associations with
  CABG-related bleeding defined as reoperation for
  bleeding, red cell transfusion, and a composite
  of reoperation/transfusion/ hematocrit drop 15.
  
• Study examined clopidogrel use 5 days versus no
  clopidogrel 5 days before CABG in each model.
  Models were adjusted for propensity for
  clopidogrel use 5 days.

Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
19
Clopidogrel in ACS and CABG Surgery

• Results Among the 4,794 CABG patients
• 332 (6.9) received clopidogrel 5 days before
  CABG
• 127 (2.6) had reoperation for bleeding
• 3,277 (68.4) received red cell transfusion
• 4,387 (91.5) had the composite outcome.
• After adjustment, clopidogrel use 5 days was not
  significantly associated with reoperation (odds
  ratio OR 1.24, 95 CI 0.63-2.41) or the
  composite bleeding end point (OR 1.23, 95 CI
  0.72-2.10).
• Clopidogrel 5 days was modestly associated with
  red cell transfusion (OR 1.40, 95 CI 1.04-1.89)
  but more weakly than other factors, including
  which surgeon performed the procedure.

Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
20
Bleeding End Point Rates by Timing of
Clopidogrel Use
No clopidogrel lt 5 days (n4462) Clopidogrel lt 5 days (n332)
Reoperation for bleeding () 2.6 3.3
Reoperation, transfusion, hematocrit drop gt 1.5 91.3 94.3
Packed red blood cell transfusion () 68.2 70.2
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
21
Multivariable Model of Reoperation for
Bleeding(Clopidogrel and Propensity for
Clopidogrel Forced In)
Parameter OR (95 CI) Wald X2 P
Weight (per kilogram increase) 0.98 (0.97-0.99) 10.63 .001
Heparin on day of surgery 1.71 (1.14-2.56) 6.68 .01
Myocardial infarction 1.57 (1.09-2.26) 5.97 .01
Clopidogrel lt5 days before surgery 1.24 (0.63-2.41) 0.39 .53
Propensity 0.07 (lt0.001-8.84) 1.10 .30
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
22
Multivariable Model of Composite Bleeding
Endpoint(Clopidogrel and Propensity for
Clopidogrel Forced In)
Parameter OR (95 CI) Wald X2 P
Baseline hematocrit (per unit up to 37) 1.33 (1.25-1.41) 87.13 lt.0001
Cardiopulmonary bypass used 2.69 (1.75-4.15) 20.07 lt.0001
Surgeon (10 degrees of freedom) 20.59 0.242
Female sex 1.83 (1.35-2.47) 15.29 lt.0001
Creatinine clearance (per unit gt67) 0.993 (0.989-0.997) 14.07 .0002
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
23
Multivariable Model of Composite Bleeding
Endpoint(continued)
Parameter OR (95 CI) Wald X2 P
Angina 1.86 (1.33-2.60) 13.32 .0003
Ever use of glycoprotein IIb/IIIa 2.26 (1.43-3.56) 12.22 .0004
No. of diseased vessels 1.44 (1.14-1.83) 9.06 .003
Clopidogrel lt 5 days before surgery 1.23 (0.72-2.10) 0.57 .45
Propensity 0.22 (0.007-7.09) 0.72 .38
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
24
Multivariable Model of Packed Red Blood Cell
Transfusion
Parameter OR (95 CI) Wald X2 P
Surgeon (10 degrees of freedom) 95.13 lt.0001
Baseline hematocrit (per unit gt 36) 0.92 (0.90-0.94) 54.52 lt.0001
Female sex 2.05 (1.70-2.49) 54.47 lt.0001
Creatinine clearance (per unit 30-130) 0.99 (0.985-0.997) 54.04 lt.0001
Cardiopulmonary bypass used 2.01 (1.54-2.63) 26.08 lt.0001
No. of diseased vessels 1.49 (1.28-1.74) 25.41 lt.0001
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
25
Multivariable Model of Packed Red Blood Cell
Transfusion (cont.)
Parameter OR (95 CI) Wald X2 P
Age (per 10 years) 1.22 (1.12-1.33) 20.64 lt.0001
Use of glycoprotein IIb/IIIa 1.51 (1.24-1.84) 16.99 lt.0001
Procedure status urgent 0.74 (0.62-0.87) 12.79 .0003
NYHA class 1.16 (1.02-1.31) 5.38 .02
Clopidogrel lt 5 days before surgery 1.40 (1.04-1.89) 4.91 .03
Propensity 0.31 (0.35-2.71) 1.13 .29
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
26
Multivariable Linear Model of Number of Units of
Packed Red Blood Cell Transfusion
Parameter Estimate F P
Age 0.60142 45.24 lt.0001
Cardiopulmonary bypass used 1.89740 35.95 lt.0001
Emergent procedure 2.33531 32.85 lt.0001
Surgeon (10 degrees of freedom) 9.58 lt.0001
Female sex 0.72614 13.41 .0003
Angina -0.87441 12.18 .0005
Hypercholesterolemia -0.64770 11.37 .0008
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
27
Multivariable Linear Model of Number of Units of
Packed Red Blood Cell Transfusion (cont.)
Parameter Estimate F P
Clopidogrel lt 5 days 1.18230 10.70 .0011
Number of diseased vessels 0.61893 9.30 .0023
Smoker -0.55180 8.22 .0042
Peripheral vascular disease 0.67225 7.12 .0077
Heart failure 0.69779 7.02 .0081
Propensity 3.40832 1.66 .198
Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
28
Study Conclusions

• Conclusion Clopidogrel administration 5 days
  before CABG was not significantly associated with
  reoperation for bleeding or a bleeding composite,
  and only weakly with red cell transfusion after
  surgery.
• Clinical Implication The impact of withholding
  clopidogrel acutely in those for whom clopidogrel
  has proven benefits and the impact of delaying
  CABG to prevent bleeding among patients treated
  with clopidogrel should be viewed in the context
  of other stronger determinants of bleeding.

Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
29
Study Conclusions

• Lack of a clear pattern of transfusion frequency
  with timing of CABG since the last clopidogrel
  dose suggests that factors other than a
  biological effect of clopidogrel contribute to
  transfusion use.
• Overall high rates of transfusion observed in our
  single- center study and the comparable high
  rates of transfusion in the CRUSADE registry and
  other reported experiences suggest that rather
  than focus on a single drug, a concerted,
  prospective effort should be undertaken to
  understand the general drivers of transfusion and
  ascertain what can be done to decrease rates of
  blood transfusion after heart surgery.

Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
30
Study Conclusions

• With careful analysis of baseline
  characteristics, concomitant medication use, type
  of procedure and surgeon, clopidogrel
  administration 5 days before CABG was not
  significantly associated with reoperation for
  bleeding or a composite measure of bleeding.
• Clopidogrel was more weakly associated with
  perioperative red cell transfusion than other
  factors.

Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92
31
Study Conclusions

• Impact of withholding clopidogrel acutely in ACS
  patients
• or of delaying CABG to prevent bleeding among
  
• clopidogrel-treated patients should be viewed
  in the
• context of managing other stronger
  determinants of
• bleeding.
• An aggressive effort to understand and limit high
  rates of
• transfusion use may be more important overall
  than
• continued focus on the effects of a single
  drug.

Kim JH, et al. Am Heart J. 2008 Nov156(5)886-92