How Long Should We Prescribe Plavix??? Resistance and ... · Being on Plavix® at 6 months (which...
Transcript of How Long Should We Prescribe Plavix??? Resistance and ... · Being on Plavix® at 6 months (which...
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