October 18, 2004

How Long Should We Prescribe How Long Should We Prescribe Plavix??? Plavix???

Resistance and RespondersResistance and Responders

Ron Waksman, MD, FACCRon Waksman, MD, FACCProfessor of Medicine (Cardiology) Georgetown Professor of Medicine (Cardiology) Georgetown

UniversityUniversityAssociate Director, Division of Cardiology, Washington Associate Director, Division of Cardiology, Washington

Hospital CenterHospital Center

Disclosure• Consultant and speaker or research grant Support from

Medtronic, Boston Scientific, Biotronik, GSK, Sanofi, BMS

• Educational Grant Support for CRT from variety of device and drug companies

• You will find this presentation on

• Premature discontinuation (before labeled duration) of dual anti-platelet therapy is associated with increased risk of ST

• Dual antiplatelet therapy is recommended for at least 12 months post DES implant

• Ideal duration of dual antiplatlet therapy is uncertain

• Cypher and Taxus labels should carry AHA/ACC/SCAI recommendation re: APT 12 months for patients that can tolerate DAP

Antiplatelet TherapyAntiplatelet TherapySummary of FDA Circulatory Panel FindingsSummary of FDA Circulatory Panel Findings

Despite animal data showing complete coverage at 30 days, DES stDespite animal data showing complete coverage at 30 days, DES strut rut endothelialization is reduced in humans with CADendothelialization is reduced in humans with CAD

0

25

50

75

100

0

25

50

75

100

Incomplete coverage Complete coverage

Grade 0 Grade 1 Grade 2 Grade 3

Perc

ent

Perc

ent

SirolimusSirolimus--eluting stenteluting stent

Bare metal stent

Angioscopy at 3-6 months post SES implantation Virmani autopsy data

Longer period of anti-platelet therapy is indicated with DES vs. BMS

Perc

enta

geEn

doth

elia

lizat

ion

Duration in months1 2 3 4 5 6 7 8 9 1115161720>40

0102030405060708090

100

BMSDES

Kotani J et al. JACC. 2006,47:2108. Joner M et al. JACC. 2006;48:193.

Discontinuation of Anti-platelet Therapy and Risk for STIn

cide

nce

(%)

Iakovou et al. JAMA. 2005;293:2126.

Overall stent thrombosis = 1.3% (P=0.09, N=2229)

1.4% 2.0% 2.5% 3.3% 3.6%6.2%

8.7%

29.0%

Unstable angina

Thrombus Diabetes Unprotected left main

Bifurcation Renal failure

Prior brachy Rx

Premature antiplateletdiscont’d

How long should dual antiplatelet therapy continue?Is there a rebound phenomenon?

How long should dual antiplatelet therapy continue?Is there a rebound phenomenon?

Clopidogrel Cessation:Is it due to lack of antiplatelet therapy or to rebound?

Conclusions

• First study to evaluate patterns of adverse events after clopidogrel cessation in national cohort of pts w/ ACS

• A clustering of significantly higher risk of death or AMI was found in the initial 90 day period after stopping treatment with clopidogrel compared w/ later follow-up intervals

• These findings were consistent among patients subgroups including those who took shorter versus longer durations of clopidogrel therapy, among patients with and without diabetes, as well as among PCI treated ACS patients.

• In addition the rate of adverse events in the initial 90 days interval after stopping treatment with clopidogrel was higher than the rate of adverse events following hospital discharge while patients still taking clopidogrel.

Definite Stent Thrombosis With DES:Bern - Rotterdam Cohort Study

0.6% / yearEarly ST 91 pts(60%)

Late ST 61 pts (40%)

Incidence density:

1.3 / 100 patient years

N=8146

0102030405060708090

100

4 Months 6 Months 9 Months 12 Months 24 Months 36 Months 48 Months

LimitationsNo formal medication logIncomplete data collection between trials at various time points

DFU compliance Physician Discretion

93.6% 83.2%53.9%

39.8%31.2%

18.2% 15.1%2,312/2,470

272/327

1,332/2,470

1,088/2,736

771/2,470

239/1,314

198/1,314

% P

atien

ts on

Clop

idogr

el or

Ticl

opidi

ne

The safety and effectiveness of the TAXUS® Express® Stent have not been established in patients for longer than 12 months. Clopidogrel was prescribed for a period of 6 months post procedure per TAXUS Clinical series protocol.

Long-Term-Thienopyridine Intake in TAXUS Clinical Trial ProgramAn Earlier time-point (2002) than ARRIVE (2004-5) where 12 month Plavix® use = 70%

Being on Plavix® at 6 months (which also predicts Plavix to 12 months) Confers the best benefit for DESThe Duke Landmark analysis

Clopidogrel Use and Long Term Clinical Outcomes After Drug-Eluting Stent Implantation

JAMA, Published online December 5, 2006Dr. David F. Kong, , FDA Panel Meeting December 2006. Eisenstein et al, JAMA 2007;297:159

6-Month Landmark Analysis Adjusted Cumulative Mortality Rates

DES-CDES-C

BMS-CBMS-C

DES+CDES+C

BMS+CBMS+C

00

22

44

66

88

Perc

ent C

umul

ativ

e In

cide

nce

Rat

e Pe

rcen

t Cum

ulat

ive

Inci

denc

e R

ate

1212 1818 242466

0.500.50-0.7 (-2.9, 1.4)-0.7 (-2.9, 1.4)BMS+C – BMS-CBMS+C – BMS-C0.550.550.8 (-1.8, 3.5)0.8 (-1.8, 3.5)DES-C – BMS-CDES-C – BMS-C

0.0110.011-2.5 (-4.4, -0.6)-2.5 (-4.4, -0.6)DES+C – BMS-CDES+C – BMS-C0.180.18-1.7 (-4.2, 0.8)-1.7 (-4.2, 0.8)DES+C – BMS+CDES+C – BMS+C

0.0310.031-3.3 (-6.3, -0.3)-3.3 (-6.3, -0.3)DES+C – DES-CDES+C – DES-Cpp% (95% CI)% (95% CI)

5.35.3

3.73.7

4.54.5

2.02.0

MonthsMonthsEisenstein et al. JAMA 2006Eisenstein et al. JAMA 2006

6-Month Landmark AnalysisAdjusted Cumulative Mortality Rates

DES-CDES-C

DES+CDES+C

00

22

44

66

88

Perc

ent C

umul

ativ

e In

cide

nce

Rat

e Pe

rcen

t Cum

ulat

ive

Inci

denc

e R

ate

1212 1818 242466MonthsMonths

0.0310.031-3.3 (-6.3, -0.3)-3.3 (-6.3, -0.3)DES+C – DES-CDES+C – DES-Cpp% (95% CI)% (95% CI)

5.35.3

2.02.0

Eisenstein et al. JAMA 2006Eisenstein et al. JAMA 2006

Safety of Long-Term Clopidogrel3 Placebo Controlled Trials

IH

IH

SAT LT

LTSAT

0 0.5 1 1.5 2 2.5 3

Cypher

Taxus

%

Overall ST rate, 2.0%

Overall ST rate, 3.2%

p=0.127

Cumulative Stent Cumulative Stent Thrombosis Thrombosis –– 24 Months24 Months

Overall stent thrombosis for both stents at 2 year 2.8%

Definite Probable ST Definite Probable ST Washington Hospital CenterWashington Hospital Center

DPST: slope between 30 days and 2 years = 0.84%/year between 30 days and 1 year = 1.44%/year between 1 year and 2 years = 0.6%/year

Clopidogrel ComplianceClopidogrel Compliance

Clopidogrel Compliance among Patients with Definite Stent Thrombosis

Plavix

No Plavix73.8%

26.2%

Clopidogrel compliance defined as that at the time of stent thrombosis.

0

10

20

30

40

50

60

70

80

90

Subacute ST Late ST

Plav

ix c

ompl

ianc

e %

Overall Population N=61

Independent Predictors of Definite Stent Thrombosis at 1, 6 and 12 months

Hazards ratio Confidence interval

P

1 month

Diabetes 2.0 1.1-3.9 0.03

Acute myocardial infarction 3.0 1.6-5.8 <0.01

Clopidogrel cessation 3.5 1.5-8.3 <0.01

6 months

Acute myocardial infarction 2.4 1.3-4.5 <0.01

Type C lesion 2.1 1.2-3.8 0.02

Number of stents implanted 1.4 1.0-1.8 0.04

Clopidogrel cessation 2.0 1.0-4.2 0.05

12 months

Acute myocardial infarction 2.2 1.2-3.9 <0.01

Lack of IVUS 1.8 1.0-3.1 <0.01

Number of stents implanted 1.5 1.2-2.0 <0.01

335

375

442

343

335

375

442

343

Late Thrombosis with DES after Discontinuation Late Thrombosis with DES after Discontinuation of of AntiplateletAntiplatelet TherapyTherapy

McFadden, Stablile, Lancet 2004; 364: 1519-21

63 yrPCI with TAXUS of LADAspirin DC’ed prior to bladder polyp resection5 days after surgery, pt had AMI

Late thrombosis

73 yrAborted out of hospital arrestPCI of PLAD with TAXUSAspirin DC’ed prior to resection of colon CA7 days after surgery, pt had acute MI

Late thrombosis

42 yrVFPCI of LAD (vision), PCI LCX (Cypher)Pt stopped taking aspirin 1 yr later2 wks later, pt presented with LWMI

Late thrombosis

62 yr PCI LAD (Cypher), PCI LCX (Vision)Pt stopped taking ASA/Plavix 11 months laterBefore colonscopy and polypectomy4 days later, pt had AWMI

Late thrombosis

Why Is There Stent Thrombosis on Clopidogrel: Response Variability

• Poor patient/system compliance• Intestinal absorption: variable absorption/drug interaction

• Hepatic metabolism: genetic polymorphisms in CYP enzymes; drug-drug interaction

• P2Y12 receptor: Genetic polymorphisms P2Y12 receptor; alternate pathways of platelet activation; Increased release of circulating ADP; higher baseline platelet reactivity

• GP IIb/IIIa receptor expression: genetic polymorphism

O’Donoghue and Wiviott Circulation 2006;114:e600

• Should we monitored routinely for antiplatelet responsiveness ???

What We Need to Know to Optimize Clopidogrel Therapy

• Proper clopidogrel dosing:Load 300, 600, 900Maintenance 75; 150; ??

• More about testing for platelet reactivity

WhoWhenHowHow often

• Is there a clopidogrel rebound effect and how can it be avoided?

• What do we do about the need for surgery?

• Is it all about the duration of therapy

Gurbel and Tantry. J Intervent Cardiol 2006;19:439

Variability in Clopidogrel ResponseVariability in Clopidogrel Response

0

20

40

60

80

100

120

-20 0 20 40 60 80 100

Num

ber o

f Pat

ient

sN

umbe

r of P

atie

nts

Change in ADPChange in ADP--Induced Induced Platelet AggregationPlatelet Aggregation

75 mg chronic dosing75 mg chronic dosing

Serebruany. Serebruany. J Am Coll Cardiol.J Am Coll Cardiol. 2005;45:246.2005;45:246.

N=544N=544

Hochholzer W et al., Circulation 2005..

0 2 4 6 8 100

20

40

60

80

100

Time from loading dose to cath (h)

Maximal aggregation 5 µmol/L ADP (%)following 600 mg loading dose

N=1001N=1001

1. Barragan et al. ↑ P2Y12 reactivity ratio (VASP-P levels) Stent Thrombosis(Catheter Cardiovasc Interv. 2003;59::295)

2. Ajzenberg et al. ↑ Shear- Induced platelet aggregation Stent Thrombosis(J Am Coll Cardiol. 2005;45:1753)

3. Gurbel et al. ↑ P2Y12 reactivity ratio (CREST Study) ↑ ADP- induced aggregation Stent Thrombosis

(J Am Coll Cardiol. 2005;46:1827) ↑ Stimulated GPIIb/IIIa expression

4. Matzesky et al. ↑ ADP-Induced platelet aggregation Recurrent Cardiac (Circulation.2005;109:3171) Events (4th quartile)

5. Gurbel et al. ↑ Periprocedural platelet aggregation Myonecrosis and(CLEAR PLATELETS and CLEAR PLATELETS Ib) Inflammation Marker (Circulation. 2005;111:1153, J Am Coll Cardiol;2006 (in press) Release

7. Bliden et al. ↑ Platelet aggregation (pre-PCI) 1 yr Post -PCI Events(J Am Coll Cardiol. 2006; (in press) on chronic clopidogrel

8. Cuisset et al. ↑ Platelet aggregation 30-day Post-PCI events(J Thromb Haemost. 2006;3:542-9)

9. Lev et al. Clopidogrel/Aspirin resistant patients Post-PCI Myonecrosis (J Am Coll Cardiol. 2006;47:27)

10. Cuisset e al. ↑ Platelet aggregation 30-day Post-PCI events (J Am Coll Cardiol. 2006;48:1339-45) 600mg- less events

11. Hochholzer et al. ↑ Platelet aggregation (Upper quartile) 30 day MACE(J Am Coll Cardiol 2006:48:1742-50)

Study Results Clinical Relevance

Studies Linking Ex-Vivo Platelet Function to Clinical Events

Response to ASA and Clopidogrel:Association with CK-MB Release after PCI

Response to ASA and Clopidogrel:Association with CK-MB Release after PCI

38.9

18.4

32.4

17.4

44.4

15.8

0

10

20

30

40

50

ASAResistant

ASASensitive

ClopidogrelResistant

ClopidogrelSensitive

DualResistant

DualSensitive

% p

atie

nts

with

CK

-MB

ele

vatio

n 38.9

18.4

32.4

17.4

44.4

15.8

0

10

20

30

40

50

ASAResistant

ASASensitive

ClopidogrelResistant

ClopidogrelSensitive

DualResistant

DualSensitive

% p

atie

nts

with

CK

-MB

ele

vatio

n

P=0.04 P=0.06 P=0.05

150 pts undergoing elective PCI, treated with Bivailrudin

Lev: JACC: 2006

0

20

40

60

80

100

AA Collagen ADP 5 ADP 200

20

40

60

80

100

AA Collagen ADP 5 ADP 20

Aspirin 53 μmol/L

Ranitidine 1.5 mM

Combination

Aspirin 26.5 μmol/L

Ranitidine 0.75 mMCombination

0.02

0.01

0.01

0.005

0.02

0.002 0.005% ofbaseline

% ofbaseline

Interference with the Antiplatelet Effect of Aspirin by Ranitidine

Lev: AJC: 2007: 99:124

Increasing Dose decreases Platelet AggregationIncreasing Dose decreases Platelet Aggregation

Clopidogrel Dose150 mg/day 75 mg/day

0

20

40

60

80

100

120

AD

P(5

µm

ol/L

)-In

duce

d A

ggre

gatio

n (%

)

●

●●●●●●●●●●●●●●●●●●●●●●●●●●●●

●

●●●●●●●●●

●●●●●●●●●●●●●●●●●●

●●

● P<0.001

Beckerath N et al., ESC 2006

Aggregometry (30 days)

% Platelet aggregation (LTA-ADP 20µM)97.5

92.587.5

82.577.5

72.567.5

62.557.5

52.547.5

42.537.5

32.527.5

22.517.5

12.57.5

2.5

20

15

10

5

0

Num

ber o

f pat

ient

s

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

Individual response variability to dual antiplatelet therapyOPTIMUS-2OPTIMUS-2

Ischemic Risk(including stent thrombosis)

78%

14%8%p=0.04

Influence of Diabetes Mellitus on Clopidogrel-induced Antiplatelet Effects

Angiolillo DJ et al. Diabetes 2005; 54:2430-5

Non responders (Platelet inhibition <10%)

Low responders (Platelet inhibition 10-29%)

Responders (Platelet inhibition >30%)

56%6%

38%

DM No-DM

Acute phase of treatment Long-term phase of treatment

24 hrs post 300 mg LD

Angiolillo DJ et al. J Am Coll Cardiol 2006; 48: 298-304

OPTIMUS-2

0

20

40

60

80

Pla

tele

t agg

rega

tion

(%)

p=0.002p<0.0001

ADP 20µM ADP 6µMDM No-DM DM No-DM

Clopidogrel and Proton Pump Inhibitors: Competition at CYP 2C19?

Clopidogrel and Proton Pump Inhibitors: Competition at CYP 2C19?

61.4

49.5

0

20

40

60

80

100

VASP

-P (%

)

P=0.007P=0.007

PPI

(N=24)No PPI

(N=81) Gilard, J Thromb Hem. 2006: 4: 2508

Future Directions (I): Clopidogrel Resistance

Future Directions (I): Clopidogrel Resistance

New Drugs– Prasugrel– AZD 6140– Cangrelor– PRT 128

Greater and More Consistent IPA with AZD6140 than Clopidogrel:

Final Extent

Greater and More Consistent IPA with AZD6140 than Clopidogrel:

Final ExtentClopidogrel

Time, hours

20

40

60

80

100Day 1 Day 14

Mea

n %

inhi

bitio

n

AZD6140 100 mg bid

Time, hours

Mea

n %

inhi

bitio

n

20

40

60

80

100

2 4 8 12 2 4 8 12 24

Day 1 Day 14

2 4 8 12 2 4 8 12 24

S. Husted et al. ESC 2005

Healthy VolunteerHealthy VolunteerCrossover StudyCrossover Study

--2020

00

2020

4040

6060

8080

100100IP

A a

t 24

hour

s (%

)IP

A a

t 24

hour

s (%

)

Response to Response to Prasugrel 60 mgPrasugrel 60 mg

Response to Response to Clopidogrel 300 mgClopidogrel 300 mg

Clopidogrel ResponderClopidogrel Responder

Clopidogrel NonClopidogrel Non--responderresponder

Inte

rpat

ient

Inte

rpat

ient

Varia

bilit

yVa

riabi

lity

InterpatientInterpatientVariabilityVariability

From Brandt JT AHJ 153: 66e9,2007

N=66

Wiviott SD et al, Circulation 2007

PRIMARY EP Acute Phase: IPA 20 uM ADP

Prasugrel 60 mg

P<0.0001 for eachIP

A (%

; 20 µM

AD

P)

Hours

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4(142)

NNT= 77

1.1 (68)

Days

Endp

oint

(%)

Any Stent at Index PCIAny Stent at Index PCIN= 12,844N= 12,844

Clopidogrel Responsiveness at the Time of PCI and Stent ThrombosClopidogrel Responsiveness at the Time of PCI and Stent Thrombosis After is After Cypher w/i 30 Days: Cypher w/i 30 Days: N=280N=280

Price MJ et al, TCT 2006Price MJ et al, TCT 2006

<10% inhibition

25th

percentile

Reactivity Post-Clopidogrel Treatment (PRUs)

Inhib

itio

n b

y C

lopid

ogre

l (%

)75th percentile

Association with Stent ThrombosisClop NR: p=0.046High post-Rx reactivity: p=0.06Clop NR + high post-Rx reactivity: p=0.02

SCRIPPS CLINIC

AT RISK PATIENT: overweight (> 100 kg), MI, DM, CHFClopidogrel Non-Responder/High Absolute Reactivity

(% inhibition < 10-15%, PRU > 240)

Potential Approach to PlateletPotential Approach to PlateletFunction Screening Function Screening Post-PCIPost-PCI

Increase clopidogrel to 75 mg twice daily (± re-load)

Recheck platelet function in 1 Ğ 2 weeks

Final Comments and Recommendations

• SCAI AHA ACC Guidelines are 12 months of dual antiplatelet therapy if patients do not experience side effects or bleeding complications

• Dual antiplatelet therapy beyond 6 months is recommended but not proven to be prohibitive of late stent thrombosis

• Do not Stop Aspirin and consider higher dose with cessation of Plavix

• DES should be contraindicated for patients with poor compliance or allergic to Plavix or Aspirin.

• New antiplatelet therapy (prasugrel or cangolor ) may be more effective to prevent late thrombosis