Clopidogrel in ACS and CABG Surgery Kim JH, et al. Am Heart J. 2008 Nov;156(5):886-92 Clopidogrel...

Clopidogrel in ACS and CABG SurgeryClopidogrel in ACS and CABG Surgery

Kim JH, et alKim JH, et al. Am Heart J. . Am Heart J. 2008 Nov;156(5):886-922008 Nov;156(5):886-92

Clopidogrel use and bleeding after Clopidogrel use and bleeding after coronary artery bypass graft surgery 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 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 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. 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, NCGranger, MD b,c Palo Alto, CA; and Durham, NC

Am Heart J. Am Heart J. 2008 Nov;156(5):886-922008 Nov;156(5):886-92

Changing the Calculations for Assessing Guidelines Adherence

Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9.Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9. Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9.Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9.

“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.”

“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.”

++++

Ischemic Discomfort at Rest

No ST-segment Elevation

Non-Q-wave MIUnstable Angina

Q-wave MI

ST-segment Elevation

++ ++

( : positive cardiac biomarker)

EmergencyEmergencyDepartmentDepartment

In-hospitalIn-hospital6-24hrs6-24hrs

PresentationPresentation

Spectrum of Acute Coronary Syndromes

NSTEMINSTEMI

1990 1992 1994 1996 1998 2000 2002 2004 2007

Evolution of Guidelines for ACS

19901990ACC/AHAACC/AHA

AMIAMIR. GunnarR. Gunnar

19941994AHCPR/NHLBIAHCPR/NHLBI

UAUAE.BraunwaldE.Braunwald

19961996

19991999 RevRev

UpdUpdACC/AHA AMIACC/AHA AMI

T.RyanT.Ryan 2000 2002 2007 2000 2002 2007 Rev UpdRev Upd RevRev

ACC/AHA UA/NSTEMI ACC/AHA UA/NSTEMI E. Braunwald J. AndersonE. Braunwald J. Anderson

2004 20072004 2007 Rev Upd Rev Upd

ACC/AHA STEMI ACC/AHA STEMI E. AntmanE. Antman

Class I Benefit >>> Risk

Procedure/ Treatment SHOULD be performed/ administered

Class IIa Benefit >> 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

shouldis recommendedis indicatedis useful/effective/

beneficial

is reasonablecan 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 recommendedis not indicatedshould notis not useful/effective/

beneficialmay be harmful

Applying Classification of RecommendationsApplying Classification of Recommendations

II IIaIIa IIbIIb IIIIII

“The Guidelines”Classes 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

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

Evidence-Based Approach to ACS Weighing the Evidence

► Class I: Benefit > > Risk

► Class IIa: Benefit > Risk

► Class IIb: Benefit > Risk

► Class III: Risk > Benefit

► Class I: Benefit > > Risk

► Class IIa: Benefit > Risk

► Class IIb: Benefit > Risk

► Class III: Risk > Benefit

“The Guidelines”Weighing 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

► 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

Antiplatelet Drug Targets

PlateletPlateletThrombinThrombin

ADPADP

Thromboxane Thromboxane AA22

EpinephrineEpinephrine

SerotoninSerotonin

CollagenCollagen

PAR-1PAR-1

PAR-4PAR-4

P2YP2Y11

P2YP2Y1212

TXA2-RTXA2-R

5HT5HT22AA

AnionicAnionicphospholipidphospholipidsurfacessurfaces

GP IIbGP IIbGP IIIaGP IIIa

GP VIGP VI

PlateletPlatelet

GP IIIaGP IIIaGP IIbGP IIb

FibrinogenFibrinogen

GP IaGP Ia

TRATRA

Clopidogrel Clopidogrel PrasugrelPrasugrel

AspirinAspirin

Gp IIb/IIIa Gp IIb/IIIa inhibitorsinhibitors

PAR - 1PAR - 1

P2YP2Y1212

Acute (< 24 hrs) Antiplatelet Therapies for High-Risk NSTE ACS

43%43%

10%10%

20%20%

30%30%

40%40%

50%50%

60% 60% 52%52%

34%34%

GP IIb/IIIa Clopidogrel GP IIb/IIIa + NeitherGP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither ClopidogrelClopidogrel

CRUSADE Q4 2003 dataCRUSADE Q4 2003 dataCRUSADE Q4 2003 dataCRUSADE Q4 2003 data

29%29%

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

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

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 > 6h prior to cath

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 > 6h prior to cath

New Guidance on Thienopyridines


Clopidogrel 75mg/d should be added to ASA in STEMI patients if lysed or if not reperfused

If < 75y/o and lysed or if not reperfused, add oral load of 300mg clopidogrel

In PPCI, give 600mg clopidogrel as soon as possible

Clopidogrel 75mg/d should be added to ASA in STEMI patients if lysed or if not reperfused

If < 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 GLsAntman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLsAntman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsAntman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLs

0.0

5.0

10.0

15.0

20.0

25.0

Clopidogrel Placebo

CLARITY-TIMI 28 Primary Endpoint:Occluded Artery (or D/MI thru Angio/HD)

LD 300 mgMD 75 mg

P=0.00000036P=0.00000036

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

Clopidogrelbetter

Placebobetter

Sabatine N Eng J Med 2005;352:1179.Sabatine N Eng J Med 2005;352:1179.

STEMI, Age 18-75

Occ

lude

d A

rter

y or

Dea

th/M

I (%

)

1.00.4 0.6 0.8 1.2 1.6

36%36%Odds ReductionOdds Reduction

De

ad

De

ad

(%)

(%)

Days Since Randomization (up to 28 days)

Placebo + ASA: Placebo + ASA: 1,846 deaths (8.1%)1,846 deaths (8.1%)

Clopidogrel + ASA:Clopidogrel + ASA:1,728 deaths (7.5%)1,728 deaths (7.5%)

0.6% ARD0.6% ARD7% RRR 7% RRR PP = 0.03 = 0.03

N = 45,852 N = 45,852 No Age limit ; 26% No Age limit ; 26% >> 70 y 70 y

Lytic Rx 50%Lytic Rx 50%

No LD givenNo LD given

COMMIT: Effect of Clopidogrel on Death In Hospital

Chen ZM, et al. Lancet. 2005;366:1607.

CREDO: 15 Hrs (Not 6 Hrs) Until Clinical Benefit Seen with 300 mg Load

Steinhubl S et al, J Am Coll Cardiol 2006;47:939-943Steinhubl S et al, J Am Coll Cardiol 2006;47:939-943

Placebo Pretreatment (N=915)Placebo Pretreatment (N=915)Death, MI, UTVR (%)Death, MI, UTVR (%)

Clopidogrel Pretreatment < 15 Hours (N=645)Clopidogrel Pretreatment < 15 Hours (N=645)

Clopidogrel Pretreatment Clopidogrel Pretreatment >> 15 Hours (N=202) 15 Hours (N=202)

3.5%3.5%

7.8%7.8%

8.3%8.3%

DaysDays

00 5 5 1010 15 15 20 20 2525

1010

88

66

44

22

00

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

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

Upstream Antiplatelet Therapy: Bottom Line

Clopidogrel in ASC and CABG SurgeryClopidogrel in ASC and CABG Surgery


► Background: Background: Short-term use of clopidogrel plus aspirin among Short-term use of clopidogrel plus aspirin among patients with acute coronary syndrome reduces ischemic events, patients with acute coronary syndrome reduces ischemic events, but concerns about coronary artery bypass graft (CABG) surgery–but concerns about coronary artery bypass graft (CABG) surgery–related bleeding limit its early use. What does new data show?related bleeding limit its early use. What does new data show?

► Methods: Methods: Using data from 4,794 consecutive CABG procedures in Using data from 4,794 consecutive CABG procedures in the Duke Databank for Cardiovascular Disease , investigators the Duke Databank for Cardiovascular Disease , investigators developed multivariable models for associations with CABG-related developed multivariable models for associations with CABG-related bleeding defined as reoperation for bleeding, red cell transfusion, bleeding defined as reoperation for bleeding, red cell transfusion, and a composite of reoperation/transfusion/ hematocrit drop ≥15%. and a composite of reoperation/transfusion/ hematocrit drop ≥15%.

► Study examined clopidogrel use ≤5 days versus no clopidogrel ≤5 Study examined clopidogrel use ≤5 days versus no clopidogrel ≤5 days before CABG in each model. Models were adjusted for days before CABG in each model. Models were adjusted for propensity for clopidogrel use ≤5 days. propensity for clopidogrel use ≤5 days.

Clopidogrel in ACS and CABG SurgeryClopidogrel in ACS and CABG Surgery


► Results: Results: Among the 4,794 CABG patients:Among the 4,794 CABG patients:

● 332 (6.9%) received clopidogrel ≤5 days before CABG332 (6.9%) received clopidogrel ≤5 days before CABG● 127 (2.6%) had reoperation for bleeding127 (2.6%) had reoperation for bleeding● 3,277 (68.4%) received red cell transfusion3,277 (68.4%) received red cell transfusion● 4,387 (91.5%) had the composite outcome. 4,387 (91.5%) had the composite outcome.

► After adjustment, clopidogrel use ≤5 days was not significantly After adjustment, clopidogrel use ≤5 days was not significantly associated with reoperation (odds ratio [OR] 1.24, 95% CI 0.63-2.41) 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). or the composite bleeding end point (OR 1.23, 95% CI 0.72-2.10).

► Clopidogrel ≤5 days was modestly associated with red cell Clopidogrel ≤5 days was modestly associated with red cell transfusion (OR 1.40, 95% CI 1.04-1.89) but more weakly than transfusion (OR 1.40, 95% CI 1.04-1.89) but more weakly than other factors, including which surgeon performed the procedure. other factors, including which surgeon performed the procedure.

Bleeding End Point Rates by Bleeding End Point Rates by Timing of Clopidogrel UseTiming of Clopidogrel Use


Multivariable Model of Reoperation for BleedingMultivariable Model of Reoperation for Bleeding(Clopidogrel and Propensity for Clopidogrel Forced In)(Clopidogrel and Propensity for Clopidogrel Forced In)


Multivariable Model of Composite Bleeding EndpointMultivariable Model of Composite Bleeding Endpoint(Clopidogrel and Propensity for Clopidogrel Forced In)(Clopidogrel and Propensity for Clopidogrel Forced In)


Multivariable Model of Composite Bleeding EndpointMultivariable Model of Composite Bleeding Endpoint(continued)(continued)


Multivariable Model of Packed Multivariable Model of Packed Red Blood Cell TransfusionRed Blood Cell Transfusion


Multivariable Model of Packed Multivariable Model of Packed Red Blood Cell Transfusion (cont.)Red Blood Cell Transfusion (cont.)


Multivariable Linear Model of Number of Units Multivariable Linear Model of Number of Units of Packed Red Blood Cell Transfusionof Packed Red Blood Cell Transfusion


Multivariable Linear Model of Number of Units Multivariable Linear Model of Number of Units of Packed Red Blood Cell Transfusion (cont.)of Packed Red Blood Cell Transfusion (cont.)


Study ConclusionsStudy Conclusions


► Conclusion: Conclusion: Clopidogrel administration ≤5 days before Clopidogrel administration ≤5 days before CABG was not significantly associated with reoperation CABG was not significantly associated with reoperation for bleeding or a bleeding composite, and only weakly for bleeding or a bleeding composite, and only weakly with red cell transfusion after surgery. with red cell transfusion after surgery.

► Clinical Implication:Clinical Implication: The impact of withholding The impact of withholding clopidogrel acutely in those for whom clopidogrel has clopidogrel acutely in those for whom clopidogrel has proven benefits and the impact of delaying CABG to proven benefits and the impact of delaying CABG to prevent bleeding among patients treated with clopidogrel prevent bleeding among patients treated with clopidogrel should be viewed in the context of other stronger should be viewed in the context of other stronger determinants of bleeding. determinants of bleeding.


► Lack of a clear pattern of transfusion frequency with Lack of a clear pattern of transfusion frequency with timing of CABG since the last clopidogrel dose suggests timing of CABG since the last clopidogrel dose suggests that factors other than a biological effect of clopidogrel that factors other than a biological effect of clopidogrel contribute to transfusion use. contribute to transfusion use.

► Overall high rates of transfusion observed in our single- Overall high rates of transfusion observed in our single- center study and the comparable high rates of center study and the comparable high rates of transfusion in the CRUSADE registry and other reported transfusion in the CRUSADE registry and other reported experiences suggest that rather than focus on a single experiences suggest that rather than focus on a single drug, a concerted, prospective effort should be drug, a concerted, prospective effort should be undertaken to understand the general drivers of undertaken to understand the general drivers of transfusion and ascertain what can be done to decrease transfusion and ascertain what can be done to decrease rates of blood transfusion after heart surgery.rates of blood transfusion after heart surgery.



► With careful analysis of baseline characteristics, With careful analysis of baseline characteristics, concomitant medication use, type of procedure and concomitant medication use, type of procedure and surgeon, surgeon, clopidogrel administration ≤5 days before CABG clopidogrel administration ≤5 days before CABG was not significantly associated with reoperation for was not significantly associated with reoperation for bleeding or a composite measure of bleeding.bleeding or a composite measure of bleeding.

► Clopidogrel was more weakly associated with Clopidogrel was more weakly associated with perioperative red cell transfusion than other factors. perioperative red cell transfusion than other factors.



►Impact of withholding clopidogrel acutely in ACS patients Impact of withholding clopidogrel acutely in ACS patients or of delaying CABG to prevent bleeding among or of delaying CABG to prevent bleeding among clopidogrel-treated patients should be viewed in the clopidogrel-treated patients should be viewed in the context of managing other stronger determinants of context of managing other stronger determinants of bleeding.bleeding.

►An aggressive effort to understand and limit high rates of An aggressive effort to understand and limit high rates of transfusion use may be more important overall than transfusion use may be more important overall than continued focus on the effects of a single drug. continued focus on the effects of a single drug.


Clopidogrel in ACS and CABG Surgery Kim JH, et al. Am Heart J. 2008 Nov;156(5):886-92 Clopidogrel...

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