optimal acs management with antiplatelet...

Sanjay Kaul, MD

Division of Cardiology

Cedars-Sinai Medical Center

Professor, Geffen School of Medicine at UCLA

Los Angeles, California, USA

Optimal ACS Management

with Antiplatelet Agents

Optimal ACS Management

with Antiplatelet Agents

The 3 Most Important Advances in

Antiplatelet Therapy for ACS

The 3 Most Important Advances in

Antiplatelet Therapy for ACS

• Aspirin

• ADP antagonists

• Platelet GP IIb/IIIa receptor antagonists

2007 ACC/AHA Guideline Recommendations Antithrombotic Therapy for Acute Coronary Syndromes

2007 ACC/AHA Guideline Recommendations Antithrombotic Therapy for Acute Coronary Syndromes

Level C(Consensus opinion,

case studies, or standard of care)

1. GPI + clopidogrel during early PCI in high-risk pts

2. GPI (eptifibatide or tirofiban) during medical Rx

1. Early invasive Rx inunstable high-risk pts

2. Fondaparinux(medical Rx)

3. Bivalirudin (early PCI)

Level B(Single randomized

trial or nonrandomized

studies

1.Fibrinolytic therapy2.GPI (abciximab) during medical Rx

1. Aspirin2. UFH or Enoxaparin3. Clopidogrel4. GPI during early PCI5. Early invasive Rx in stabilized high-risk pts

6. Statins at any LDL level

Level A(Multiple randomized

clinical trials)

IIb(Benefit ? risk)

(May be considered)

IIa(Benefit >>risk)(Reasonably

recommended)

Class III(Risk ? Benefit)

(Not recommended)

Class IIClass I(Benefit >>> risk)

(Highly recommended)

J Am Coll Cardiol 2007; DOI:10.1016/j.jacc.2007.02.028

Antiplatelet AgentsDifferent Mechanisms of Action

Antiplatelet AgentsDifferent Mechanisms of Action

Ticlopidine

Clopidogrel

Prasugrel

Cangrelor

(P2Y receptor)

Platelet Aggregation

GPIIb/IIIa

Receptor

Heparin

LMWH

Hirudin

ADP

EpinephrineCollagen

Thrombin

ArachadonicAcid

TxA2PGI2

CyclooxygenasePGG2

Aspirin

GP 2b/3a

antagonists

Effect of ASA in Non-ST Elevation MI and Unstable Angina

Effect of ASA in Non-ST Elevation MI and Unstable Angina Incidence of Death or Subsequent MI

% of Patients

0

4

8

12

Lewis

P=0.0005

10.110.1 5550%

RRR

0

5

10

15

Cairns

P=0.012

12.912.9 6.26.252%

RRR

0

5

10

15

Theroux

P=0.008

11.911.9 3.33.372%

RRR

0

4

8

12

RISC

P<0.0001

17.117.1 6.56.562%

RRR

N = 155 178 279 276 118 121 397 399

Time 3m 24m 3-9d 3m

Dose 324mg 1300mg 650mg 75mg

Placebo ASA

Limitations of AspirinLimitations of Aspirin

Multiple pathways of platelet activation in vivoThrombin, collagen, high shear stress activate

platelets via non-cyclooxygenase pathways

Catecholamines can overcome antiplatelet effect

Platelet adhesion and thrombus formation notblocked

Prothrombotic effect at higher dosesInhibition of vascular prostacyclin generation

Inhibition of tPA (at doses >300 mg)

New ACC/AHA Guidelines for Management

of Unstable Angina/NSTEMI (2007)


of Unstable Angina/NSTEMI (2007)

• Early invasive strategy for high-risk patients (Class I, Level B)

• Add clopidogrel to aspirin and heparin (Class I, Level A)

• Add GP 2b/3a inhibitor (Class I, Level A) to clopidogrel (Class IIa, Level B) prior to angiography

• Add UFH or Enoxaparin (Class I, Level A) or bivalirudin or fondaparinux (Class I, Level B) to antiplatelet therapy with ASA and clopidogrel

• Statin Rx regardless of LDL-C (Class I, Level A)

ACC/AHA Guidelines. August 14, 2007

J Am Coll Cardiol. 2007;50:652-726

3 months ≤≤≤≤ double-blind treatment ≤≤≤≤ 12 months

Aspirin 75-325mg

Clopidogrel(6,259 patients)

Placebo(6,303 patients)

Aspirin 75-325mg

Day 1

6 m. Visit

9 m. Visit

12 m.

or Final Visit

Clopidogrel 300mg loading +75mg qd dose

3 m. Visit

Discharge Visit

1 m. Visit

Patients withAcute Coronary

Syndrome

(UA or MI Without STelevation)

R

Placebo loading dose

R=Randomization

The CURE Trial InvestigatorsThe CURE Trial InvestigatorsThe CURE Trial InvestigatorsThe CURE Trial Investigators. . N Engl J Med.N Engl J Med. 2001;345:4942001;345:494--502.502.

CURE ProtocolCURE Protocol

CURE: ResultsPrimary End-Point

CURE: ResultsPrimary End-Point

581

723

0

200

400

600

800

1000

Number of events RRR = 20%; p=0.00005

CV Death, MI, Stroke

9.28% 11.47%

Clopidogrel + ASA

(n=6259)

Aspirin

(n=6303)

ARR = 2.19

NNT = 46

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CURETreatment Effect by Individual Endpoint

CURETreatment Effect by Individual Endpoint

317 340

0

250

500

CV Death

p=ns

5.06

%

5.4%

8

%

RRR

Clopidogrel + ASA

(n=6259)Aspirin

(n=6303)

ARR = 0.34%

NNT = 294

MI

325

421

0

250

500P<0.001

5.19

%

6.68

%

23

%

RRR

ARR = 1.49%

NNT = 67

75

88

0

75

150

Stroke

p=ns

1.4

%

1.2

%

15

%

RRR

ARR = 0.2%

NNT = 500

Bleeding Complications in CURE

p valueRelative

riskAspirin

(n=6303)

Endpoint

0.13

8.6%Minor bleeding

2.2%

Major bleeding

Transfusions

Aspirin +

clopidogrel

(n=6259)

2.8%

<0.001

Life-threatening

bleeding

2.2%

1.8%

2.7% 3.7%

15.3%

1.34

1.15

1.78

1.28

0.003

0.03

The CURE Trial InvestigatorsThe CURE Trial InvestigatorsThe CURE Trial InvestigatorsThe CURE Trial Investigators. . N Engl J Med.N Engl J Med. 2001;345:4942001;345:494--502.502.

5.7

11.4

20.7

4.1

9.8

15.9

0

5

10

15

20

25

CURE Trial: Who Are Most Likely to Benefit?Clopidogrel+ASA vs ASA Stratified by TIMI-Risk Score

CURE Trial: Who Are Most Likely to Benefit?Clopidogrel+ASA vs ASA Stratified by TIMI-Risk Score

ASA (n=6303)

Clopidogrel + ASA (n=6259)

No. of pts. 26% 58% 16%

ARD 1.6 1.6 4.8

NNT 63 63 21

Rate of Composite

Endpoints (CVD/MI/stroke)

(%)

Budaj A et al, Circulation.2002;106:1622-1626

Risk Profile Low Intermediate High

P<0.04

P<0.03

P<0.004

Key Issues Regarding Clopidogrel UseKey Issues Regarding Clopidogrel Use

• How long to give it for optimum benefit?

• Is it necessary to pre-treat?

• When to stop prior to CABG?

• Should it be used with GP 2b/3a antagonists?

• What about clopidogrel resistance?

Role of ADP Antagonists in AtherothrombosisKey Issues Regarding Clopidogrel Use in Clinical Practice


Duration of treatment

• Stable CVD: No long-term benefit in patients with stable CVD or CV risk factors

• UA/NSTEMI: < 1 month (IA), < 12 months (IB) in high-risk pts at low-risk for bleeding

• STEMI: At least 1 month with fibrinolytic Rx; no direct studies with primary PCI

• PCI: At least 1 month (IA) and up to 12m (IB) with BMS; at least 12m (IB) with DES

• Stroke: Not recommended as first-line Rx unless a clear indication is also present

Management of Atherothrombosis with Clopidogrel in

High Risk Patients with Recent TIA or Ischemic Stroke

MATCH Trial (N=7,599)MI, ischemic stroke, vascular death, or rehospitalization

for an acute ischemic event at 18 months

Management of Atherothrombosis with Clopidogrel in

High Risk Patients with Recent TIA or Ischemic Stroke

MATCH Trial (N=7,599)MI, ischemic stroke, vascular death, or rehospitalization

for an acute ischemic event at 18 months

15.716.73

0

5

10

15

20

25

Clop + ASA Clop

Number of People

(%)

2.54

1.3

0

2

4

6

8

Clop + ASA Clop

596 636 96 49

(N=3797) (N=3802)

OR 0.93

95%CI 0.82, 1.05

(N=3759) (N=3781)

Ischemic Events Life Threatening Hemorrhage

OR 2.0

95%CI 1.41, 2.82

Diener HC et al, Lancet 2004;364:331-337.

Antiplatelet Therapy Following StentingAHA/ACC/SCAI/ACS/ADA Science Advisory 2007

Antiplatelet Therapy Following StentingAHA/ACC/SCAI/ACS/ADA Science Advisory 2007

100%31%4yAngiogram

plus clinical

DESMauri, 2007

(N=4545)

NA31%6 mAngiogramDESKuchulakanti, 2006

(N=2974)

100%25%1 mAngiogram

plus clinical

DESOng, 2005

(N=2016)

93%45%9 mAngiogram

or clinical

DESIakovou, 2005

(N=2229)

100%17%9mAngiogram plus

acute MI

BMSHeller, 2001

(N=1855)

70%21%6 mAngiogram or

clinical

BMSCutlip, 2001

(N=6186)

Death

or MI

DeathDurationConfirmation

of stent

thrombosis

Stent

type

Study

Clinical Importance of Stent Thrombosis“Real-World” and RCT Experience

Clinical Importance of Stent Thrombosis“Real-World” and RCT Experience

Cutlip D, et al. Circulation 2001;103:1967; Iakovou I, et al. JAMA 2005;293:2196Kuchulakanti PK et al. Circulation. 2006;113:1108-1113; Ong, et al. JACC 2005:45;2088-2092; Mauri L et al. NEJM 2007;356:1020-9

Longer period of anti-platelet therapy is needed after DES

0

25

50

75

100

0

25

50

75

100

Incomplete coverage Complete coverage

Grade 0 Grade 1 Grade 2 Grade 3

Percent

Percent

Sirolimus-eluting stent

Bare metal stent

Angioscopy at 8 months post SES implantation

Kotani J et al. JACC. 2006,47:2108

Virmani autopsy dataPercentage

Endothelialization

Duration in months

1 2 3 4 5 6 7 8 9 11 15 16 17 20>40

0

10

20

30

40

50

60

70

80

90

100

BMS

DES

Joner M et al. JACC. 2006;48:193.

Incomplete Strut Endothelialization With DES?Incomplete Strut Endothelialization With DES?

Eisenstein E et al. JAMA. 2007;297:159-168

The PREMIER Registry Prevalence, Predictors, and Outcomes of Premature

Discontinuation of Clopidogrel Therapy After DES

The PREMIER Registry The PREMIER Registry Prevalence, Predictors, and Outcomes of PrematurePrevalence, Predictors, and Outcomes of Premature

Discontinuation of Clopidogrel Therapy After DESDiscontinuation of Clopidogrel Therapy After DES

Spertus J et al, Circulation 2006;113:2803-2809

• 500 patients post MI• 68 (13.6%) stopped Rx <30d• Predictors of nonadherence:- Age

- Socioeconomic, educational

and marital status

- Discharge instructionsMortality (%)

Compliant

(>30d)

Noncompliant

(>30d)

0.7

7.5

0

5

10

15

Adjusted hazard ratio

9.0 (95% CI, 1.3 to 60.6)

Long-Term Clopidogrel Plus Aspirin Treatment

Results of The CHARISMA Trial (28m)

LongLong--Term Clopidogrel Plus Aspirin Treatment Term Clopidogrel Plus Aspirin Treatment

Results of The CHARISMA Trial (28m)Results of The CHARISMA Trial (28m)

(%)

ASA+Clop

N=7802

ASA

N=7801

6.807.30

0.00

5.00

10.00OR = 0.93 (0.83-1.05)

CV death, MI or stroke

Bhatt DL et al, NEJM 2006

(%)

ASA+Clop

N=7802

ASA

N=7801

2.10

1.30

0.00

1.00

2.00

3.00

Major bleeding (TIMI)

OR = 1.64 (1.27-2.10)

Fatal bleeding

0.3%

Timing of Surgery/Invasive Procedures Post-DES

Special Considerations

Timing of Surgery/Invasive Procedures Post-DES

Special Considerations

• Elective procedures: Postpone• Emergencies/urgencies

- Do not hold aspirin and

clopidogrel unless bleeding

risk is prohibitive

- Cardiology consultation for

“bridging” therapy

- “Code white” for peri-op

CP or ECG changes

(stent thrombosis)

0 1 y ? 2-3 y

• Elective procedures - May be safe

- Do not hold aspirin

unless bleeding risk

outweighs stent thrombosis

risk

• Emergencies/urgencies- Do not hold aspirin unless

prohibitive bleeding risk

“Bridging” Therapy Post-DES(Multidisciplinary Approach)

“Bridging” Therapy Post-DES(Multidisciplinary Approach)

• Formal pre-op evaluation 1 wk prior• Communication between surgeon, anesthesiologist & cardiologist is key

• Hold clopidogrel 5-7d prior• Do not hold aspirin unless prohibitive bleeding risk (increase to 325mg)

• Admit in-patient 3-4 days prior• Initiate IV short-acting GP 2b/3a (eptifibatide or tirofiban) without

loading dose

• Monitor CBC daily for plt count• Stop GP 2b/3a 10-12h prior to procedure (5-6 half-lives)

• Check plt count &/or function 2h prior• Restart clopidogrel (300-600 mg loading dose) >24h post-op

Do’s

• Don’t use abciximab (long half-life)• Heparin, including LMWH, unlikely to be effective

• Antiplatelet agents such as dipyrimadole or aggrenox should

be avoided

• Platelet transfusions not helpful

Dont’s

• Platelet function assay• Random donor plts (apharesis)• Investigational ADP antagonist, IV cangrelor (phase III trials)

Don’t know’s

Clopidogrel Pre-treatmentFact or Fashion

Clopidogrel Pre-treatmentFact or Fashion

No definite benefit with pretreatment, but a potential risk for

increased bleeding associated with PCI and CABG

TrialPre-Rx

duration Clopidogrel Control Risk ratio

PCI-CURE

(300 mg)59/1313 86/1345 0.70 (0.51 to 0.97)

PCI-CLARITY

(300 mg)

70/933 112/930 0.62 (0.47 to 0.83)

CREDO

(300 mg)

61/900 76/915 0.82 (0.59 to 1.13)

PRAGUE-8*(600 mg)

4/513 4/515 1.00 (0.25 to 4.00)

0 0.5 1 1.5 2

3-120d (10d)

48-192h

3-24h

>6h

Indication

UA/NSTEMI

STEMI

Non-urgent

PCI

Elective

angiography

Endpoint

D, MI, TVR

(30d)

D, MI, CVA

(30d)

D, MI, TVR

(28d)

D, MI, TVR,

CVA (7d)

*Increased bleeding

3.5 vs 1.2% (P=0.02) angio

7.2 vs 0.7% (P=0.006) PCI

Risk ratio

Optimal Timing of Clopidogrel Pre-Treatment

(300mg): CREDO Post hoc Analysis

Results at 28 days


(300mg): CREDO Post hoc Analysis

Results at 28 days

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

Pretreatment with 300mg loading for at least 15h and ideally 24h

Kandzari D. et al. J Am Coll Cardiol, 2004; 44:2133-2136

2-3h

N=367

>12h

N=746

4.4%

3.5%

D, MI or uTVR

2-3h

N=367

12h

N=746

4.1%3.4%

MI

2-3h

N=36712h

N=746

1.6%1.2%

Major bleeding

16 26 15 256 9

OR = 0.82 (0.44-1.54) OR = 0.74 (0.26-2.06)OR = 0.80 (0.43-1.47)

No time-dependence with 600mg loading dose + GP2b/3a


(600mg): ISAR-REACT Post hoc Analysis

Results at 30 days


(600mg): ISAR-REACT Post hoc Analysis

Results at 30 days



Pre-treatment ?

• Favorable data in retrospective analysis (EPISTENT, ESPRIT, TARGET)

• Pretreatment hypothesis not validated in the only prospective assessment (CREDO)

• Guideline recommendations:

- ESC: 600 mg loading 2-6h pre-PCI (IC)

- ACC/AHA: 300 mg loading dose 6h pre-PCI without (IA) or with (IIa, B) GP IIb/IIIa in ACS

- ACCP: 300 mg loading dose 6h pre-PCI without (IA)

• Prudent to rule out surgical CAD before pretreatment to avoid bleeding risk

• A properly designed clinical trial is warranted to provide unequivocal support

0

5

10

Number of events

(%)

4.4% 9.6%

>5 days

(n=456)

<5 days

(n=436)

ARI = 5.2%

NNH = 18

P=0.003

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Key Issues Regarding Clopidogrel Use in ACSWhen Should Clopidogrel be Stopped Prior to CABG?

Key Issues Regarding Clopidogrel Use in ACSWhen Should Clopidogrel be Stopped Prior to CABG?

Major Bleeding

N=20

N=42

At least 5 days and preferably 7 days (I, B)

ISAR-REACT 2 Trial: Study DesignISAR-REACT 2 Trial: Study Design

• Primary Endpoint: Composite of death, MI, and urgent target vessel

revascularization (TVR) due to myocardial ischemia within 30 days

• Secondary Endpoint: In-hospital major and minor bleeding

2022 patients with an episode of angina within the preceding 48 hours and an elevated

troponin T level or new ST-segment depression of ≥≥≥≥0.1 mV or transient (<20 minutes)

ST-segment elevation of ≥≥≥≥0.1 mV or new or presumed new bundle-branch block;

significant angiographic lesions in a native coronary vessel or venous bypass graft

amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded.

24% female, mean age 66 years, mean follow-up 30 days

Abciximab

(usual bolus or infusion dose)

n=1012

Placebo

n=1010

Pre-treatment with high dose (600mg) clopidogrel at least 2 hours pre-procedure

Kastrati, A. et al. JAMA 2006;295:1531-1538

ISAR-REACT 2Results at 30 days

ISAR-REACT 2Results at 30 days


Placebo

N=1,010

Abciximab

N=1,012

11.9%

8.9%

D, MI or uTVR

Placebo

N=1,010

Abciximab

N=1,012

11.5%

8.6%

Death or MI

Placebo

N=1,010Abciximab

N=1,012

1.4% 1.4%

Major bleeeding

0.75 (0.58-0.97)

120 90

0.75 (0.57-0.97) 1.00 (0.50-2.08)

116 8714 14

ISAR-REACT 2Results Stratified by Baseline Troponin

ISAR-REACT 2Results Stratified by Baseline Troponin


Placebo

N=536

Abciximab

N=513

18.3%

13.1%

30 day

D, MI or uTVR

Placebo

N=474

Abciximab

N=499

4.6% 4.6%

Troponin <0.03µg/L

0.71 (0.54-0.95)

98 67

0.99 (0.56-1.76)

22 23

Troponin >0.03µg/L

Impact of Triple Antiplatelet Rx in Non-urgent PCI(ASA, Clopidogrel, Abciximab)

Death, MI or Urgent TVR at 30 days

Impact of Triple Antiplatelet Rx in Non-urgent PCI(ASA, Clopidogrel, Abciximab)

Death, MI or Urgent TVR at 30 days

Abciximab Control Risk ratio

(95% CI)Trial

ISAR REACT 45/1079 43/1080 1.05 (0.7 to 1.58)

ISAR REACT-2* 22/474 23/499 1.01 (0.57 to 1.78)

ISAR SWEET 20/351 15/350 1.33 (0.69 to 2.55)

ISAR SMART-2 13/251 8/251 1.63 (0.69 to 3.85)

Combined 100/2155 89/2180 1.14 (0.86 to 1.50)0 1 2 3 4

* Troponin negative pts Abciximab

betterAbciximab

worse

Adjunctive therapy with GP 2b/3a not effective and safe in stable pts

Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.

Individual Response Variability to Dual Antiplatelet Rx in the Steady State PhaseIndividual Response Variability to Dual Antiplatelet Rx in the Steady State Phase

% Platelet Aggregation (LTA-ADP 20µmol/L)

97.5

92.5

87.5

82.5

77.5

72.5

67.5

62.5

57.5

52.5

47.5

42.5

37.5

32.5

27.5

22.5

17.5

12.5

7.5

2.5

20

15

10

5

0

Numberof Patients Bleeding risk Ischemic risk

~ 5-30% incidence of ‘hyporesponsiveness’ to clopidogrel

Cellular FactorsCellular Factors• Accelerated platelet turnoverAccelerated platelet turnover

•• Reduced CYP3A metabolic activityReduced CYP3A metabolic activity

•• Increased ADP exposure Increased ADP exposure

•• UpUp--regulation of the P2Yregulation of the P2Y1212 pathwaypathway

•• UpUp--regulation of the P2Yregulation of the P2Y11 pathway pathway

•• UpUp--regulation of P2Yregulation of P2Y––independent independent

pathwayspathways

(collagen, epinephrine, TXA(collagen, epinephrine, TXA22, thrombin), thrombin)

Clinical FactorsClinical Factors• Failure to prescribe/poor complianceFailure to prescribe/poor compliance

•• UnderUnder--dosing dosing

•• Poor absorptionPoor absorption

•• DrugDrug--drug interactions involving CYP3A4drug interactions involving CYP3A4

•• Acute coronary syndromeAcute coronary syndrome

•• Diabetes mellitus/insulin resistanceDiabetes mellitus/insulin resistance

•• Elevated body mass indexElevated body mass index

Genetic FactorsGenetic Factors• Polymorphisms of CYPPolymorphisms of CYP

•• Polymorphisms of Polymorphisms of GPIaGPIa

•• Polymorphisms of P2YPolymorphisms of P2Y1212

•• Polymorphisms of Polymorphisms of GPIIIaGPIIIa

Clopidogrel Response Variability

Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .

Clinical RelevanceFunctional ParameterN

Post-PCI ischemic events

(30 days)↑↑↑↑ platelet aggregation292Cuisset et al.

JACC 2006


(30 days)


(3 months)


(12 months)

↑↑↑↑ platelet aggregation (3rd & 4th quartiles)

↓↓↓↓ platelet inhibition

↑↑↑↑ platelet aggregation

802

379

100

Hocholzer et al.

JACC 2006

Geisler et al.

Eur Heart J 2006

Bliden et al.

JACC 2007

Post PCI-myonecrosis↑↑↑↑ clopidogrel/aspirin-resistant patients120Lev et al.

JACC 2006


(30 days)↑↑↑↑ platelet aggregation106Cuisset et al.

J Thromb Haemost 2006

Myonecrosis and inflammation marker release

↑↑↑↑ periprocedrual platelet aggregation 120Gurbel et al.

Circulation 2005


(6 months) ↑↑↑↑ periprocedrual platelet aggregation 192Gurbel et al.

JACC 2005

Post-primary PCI ischemic events (6 months)

↑↑↑↑ platelet aggregation (4th quartile)60Matezky et al.

Circulation 2004

Angiolillo DJ et al. Am J Cardiol Drugs. 2007.

Post-Stent Ischemic Events and Periprocedural Infarction

Clinical Relevance of Clopidogrel Non-responsiveness

Clinical Relevance of Clopidogrel Non-responsiveness

Inhibition of ADP-induced

Aggregation @ 6 days (%)

Ist Qrt

(n=15)

• 60 patients with STEMI undergoing primary PCI <6h• Aspirin, heparin, eptifibatide during PCI• Clopidogrel 300 mg load post-PCI, 75 mg daily x3 months

Matetzky S et al, Circulation. 2004;109:3171-3175

Clopidogrel ResistanceClopidogrel Resistance

40

0.7

0

0

0 10 20 30 40 50

-9

-22

-28

-45

-50 -40 -30 -20 -10 0

Recurrent CVS Events

@ 6 months (%)

2nd Qrt

(n=15)

3rd Qrt

(n=15)

4th Qrt

(n=15)

P<0.01 P<0.007

Total # of events = 8

(7/15)

(1/15)



Clopidogrel resistance

• Unclear entity with unclear definition (variable “responsiveness” or true “resistance”)

• Unclear diagnosis (? optimum test)

• Unclear mechanism

• Unclear clinical relevance (? prediction of clinical outcomes; ? titration of drug Rx)

• Not recommended by ISTH, ACCP, ESC

• A thorough assessment of the phenomenon is indicated

≈≈≈≈ 95%

(few minutes)

≈≈≈≈ 95%

(2-4 hours)

≈≈≈≈ 70%

(<1 hour)

Mean

Platelet

Inhibition

(Time

Required)

CHAMPION

PLATO

TRITON

Trials

(Phase III)DoseActionRouteTypeDrug

4 µg/kg/minCompetitive

bindingParenteral

ATP analogue –

Direct inhibition

Cangrelor

(ARC-669931MX)

90 mg bidCompetitive

bindingOral

Cyclopetyl-

triazolopy-

rimidine –

Direct inhibitionAZD6140

60 mg

loading

dose, 10 mg

maintenance

dose

Irreversible

bindingOral

Thienopyridine

(3rd gen) –

requires hepatic

conversion to

active

metabolite

Prasugrel

(CS-747)

Novel P2Y12 ADP Receptor AntagonistNovel P2Y12 ADP Receptor Antagonist

More potent and less variability!!More potent and less variability!!Angiolillo DJ et al. J Am Coll Cardiol. 2007; 49: 1505-1516 .


of Unstable Angina/NSTEMI


of Unstable Angina/NSTEMI

• Early invasive strategy for high-risk patients (Class I, Level B)

• Add clopidogrel to aspirin and heparin (Class I, Level A)

• Add GP 2b/3a inhibitor (Class I, Level A) to clopidogrel (Class IIa, Level B) prior to angiography

• Add UFH or Enoxaparin (Class I, Level A) or bivalirudin or fondaparinux (Class I, Level B) to antiplatelet therapy with ASA and clopidogrel

• Statin Rx regardless of LDL-C (Class I, Level A)

ACC/AHA Guidelines. August 14, 2007

J Am Coll Cardiol. 2007;50:652-726

Boersma et al, Lancet 2002;359:189-1198.

GUSTO IV

PRISM

PRISM-Plus

PURSUIT

PARAGON A

PARAGON B

POOLED

Trial (IIb/IIIa) Placebo 2b/3a

7800

3232

1570

9461

1513

5169

28,745

N

8.0

7.0

11.9

15.7

11.7

11.4

12.5

8.7

5.7

8.7

14.2

10.3

10.5

11.3

Better Worse0.1 1 10

Death / MI at 30 days

Risk Ratio & 95% CI (%) (%)

0.91 (0.86, 0.99)

P=0.015

P=0.339

Breslow-Day

Homogeneity

ARR = 1.2%

RRR = 9%

Clinical Importance vs Statistical SignificanceImpact of GP IIb/IIIa Inhibitor on Death or MI

Clinical Importance vs Statistical SignificanceImpact of GP IIb/IIIa Inhibitor on Death or MI

GP 2b/3a Inhibitors in ACS (N=31,402)30-Day Death/MI and Bleeding Complications

GP 2b/3a Inhibitors in ACS (N=31,402)30-Day Death/MI and Bleeding Complications

11.810.8

0

5

10

15

20

25

Placebo GPI

Number of People

(%)

(N=13105) (N=18297)

OR 0.91

95%CI 0.84, 0.98

P=0.015

1550 1980

Death/MI

1.4

2.4

0

1

2

3

4

Placebo GPI

(N=13105) (N=18297)

OR 1.62

95%CI 1.36, 1.97

P<0.0001

180 445

Major Bleeding


GP 2b/3a Inhibitors in ACS (N=32,402)30-Day Death/MI According to PCI Within 5d (14%)

GP 2b/3a Inhibitors in ACS (N=32,402)30-Day Death/MI According to PCI Within 5d (14%)

11.4 10.7

0

5

10

15

20

25

Placebo GPI

1266 1695

(N=11148) (N=15876)

OR 0.95

95%CI 0.87, 1.02

NNT=143

- PCI

Number of People

(%)

14.5

11.8

0

5

10

15

20

25

Placebo GPI

284 285

(N=1957) (N=2421)

+ PCIOR 0.77

95%CI 0.64, 0.92

NNT=37


GP 2b/3a Inhibitors in ACS (N=32,402)30-Day Death/MI According to Troponin Status (35%)

GP 2b/3a Inhibitors in ACS (N=32,402)30-Day Death/MI According to Troponin Status (35%)

6.2 7

0

5

10

15

20

Placebo GPI

153 255

(N=2452) (N=3653)

OR 1.17

95%CI 0.94, 1.44

Troponin -


Number of People

(%)

1210.3

0

5

10

15

20

Placebo GPI

222 321

(N=1851) (N=3113)

Troponin +

OR 0.85

95%CI 0.70, 1.03

GUSTO IV-ACS: 48-hour OutcomesGUSTO IV-ACS: 48-hour Outcomes

1.8

0.3

2.6

0.7

3.1

0.9

0

1

2

3

4

Death/MI Death

Placebo

Abciximab 24 hours

Abciximab 48 hours

P = 0.006

% Patients

Lancet 2001

Key Points Regarding GP IIb/IIIa Inhibitors in ACSKey Points Regarding GP IIb/IIIa Inhibitors in ACS

• Should be considered in high-risk patients oriented to an

early invasive strategy (I, A); abciximab for upstream Rx if

no appreciable delay in angiography (I, B)

• Small molecules (tirofiban & eptifibatide) approved

for medical stabilization therapy (IIa, B)

• Combination Rx with ASA, heparin and clopidogrel may have

a favorable risk-benefit in high-risk pts - � TnI (IIa, B)

• Abciximab is contraindicated for medical therapy (Class III)

Optimal ACS Management with Antiplatelet Agents

Conclusion

Optimal ACS Management with Antiplatelet Agents

Conclusion

• Aspirin and clopidogrel are the most used, effective, safe and

cost-effective therapies

• GP IIb/IIIa inhibitors offer significant benefits with potential of

cost-effectiveness in high-risk patients

• Newer therapies look promising (prasugrel, cangrelor, AZD6140)

• Strategies for risk stratification and optimization of cost-benefit-

risk profile are worthwhile goals

“The aim of science is not only to

open the door to endless wisdom

but also to put a limit to endless error”

Galileo

Given our limited understanding of the exact mechanism and

incidence of stent thrombosis, our inability to accurately identify

at-risk patients and the lack of effective and safe therapies

to mitigate this risk, the most prudent strategy to limit this rare

but potentially life-threatening complication at the current time

is a selective, thoughtful and evidence-based application of

drug-eluting stents in clinical practice

0%

use

100%

use

~60% “off-label”(TAXUS ARRIVE 1, BASKET-LATE)

(� stent thrombosis = 2-3%)

Balancing Risk and BenefitDES Utilization: 2006


Evidence-based

threshold

0%

use

100%

use



2007

Role of Clopidogrel in CHDRole of Clopidogrel in CHD

Stable CVDMI

Stroke

PAD

CHARISMA CURE

ACSUA/NSTEMI

CREDO

PCI-CURE

PCI-CLARITY

PCIStable CAD

UA/NSTEMI

STEMI

CLARITY

COMMIT

STEMI

Trial

Indication

Duration 28 months 9 months 1-12 months 8-28 days

Role of Clopidogrel in CHDRole of Clopidogrel in CHD

0 0.5 1 1.5

CV Death, MI or Stroke

CURE (9m)

CHARISMA (28m)

CLARITY (30d)

COMMIT (28d)

2

CREDO (12m)

Odds ratio

Major Bleeding

0 0.5 1 1.5 2

Odds ratio

Eshaghian, Kaul et al. Ann Int Med 2007

Role of Clopidogrel in CHD

Benefit-Risk Profile

Role of Clopidogrel in CHD

Benefit-Risk Profile

0

5

10

15

20

25

30

35

6 7 8 9 10 11 12

Control Event Rate (%)

0

5

10

15

20

25

30

35

Treatment benefit

Bleeding hazard

Bleeding hazard

(number per 1000)T

reatment benefit

(number per 1000)

CHARISMACOMMIT

CLARITY

CURE

CREDO

Eshaghian, Kaul et al. Ann Int Med 2007

Therapeutic Options in ACS (2007 Update)Therapeutic Options in ACS (2007 Update)

PCI eligible

Yes

PTCA/Stent

No

CABG or

Medical Rx

UFH or

LMWH or

Fondaparinux

(FRICESSENCE

TIMI-11B

FRAXIS

OASIS-5)

Convenient, reliable, safe,

as good as UFH

GP IIb/IIIa + heparin

(SYNERGY, A-to-Z)

Bivalirudin(ACUITY)

↓ Safety= efficacy

LMWH (dalteparin)

(FRISC-II)

Safe, effective,

‘Bridge’-Rx

+ GP IIb/IIIa +

(GUSTO IV-ACS

ACUTE-2)

Safe

? efficacy

USAP/NSTEMIASA + Clopidogrel (CURE)

UFH or

LMWH (enoxaparin)

(SYNERGY, A-to-Z)

GP IIb/IIIa

(Abciximab if no delay)

↓ Safety= efficacy

Aggressive strategy

Cor angio within 24-48h

Yes (FRISC II, TIMI 18-TACTICS, ICTUS)

Medical

stabilization Rx

No

High-risk

(don’t switch to UFH)

Cath Lab

+ _

Medical Rx

Stress test

(LVEF >40%)

>12-24h minimum

optimal acs management with antiplatelet...

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