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Role of Genotyping and Point of Care Role of Genotyping and Point-of-Care Testing in Clopidogrel, Prasugrel, Testing in Clopidogrel, Prasugrel, and Ticagrelor
Ron Waksman, MD Ron Waksman, MD Professor of Medicine (Cardiology), Georgetown UniversityAssociate Director, Division of Cardiology, Washington Hospital Center
UNDERSTANDING ANTIPLATELET UNDERSTANDING ANTIPLATELET RESPONSE VARIABILITYRESPONSE VARIABILITYRESPONSE VARIABILITYRESPONSE VARIABILITY
Pharmacogenomics, Metabolism, and Platelet Reactivityg y
Antiplatelet Drug Resistance / Response Variability: An Emerging Clinical ProblemAn Emerging Clinical Problem
Individual Response Variability to Dual Antiplatelet Individual Response Variability to Dual Antiplatelet Therapy in theTherapy in the Steady State PhaseSteady State Phase of Treatmentof TreatmentTherapy in the Therapy in the Steady State PhaseSteady State Phase of Treatmentof Treatment
2020
1515
ents
ents Bleeding riskBleeding risk Ischemic riskIschemic risk
1010
er o
f Pat
ieer
of P
atie gg
55Num
beN
umbe
97 597 592.592.5
87 587 582.582.5
77 577 572.572.5
67 567 562.562.5
57 557 552.552.5
47 547 542.542.5
37 537 532.532.5
27 527 522.522.5
17 517 512.512.5
7 57 52.52.5
00
% Platelet Aggregation (LTA% Platelet Aggregation (LTA--ADP 20ADP 20µµmol/L)mol/L)97.597.587.587.577.577.567.567.557.557.547.547.537.537.527.527.517.517.57.57.5
Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.
Baseline Platelet Reactivity* Determines Clinical Baseline Platelet Reactivity* Determines Clinical Outcomes** Following Coronary StentingOutcomes** Following Coronary Stenting
1 01.0
0.9 Low Reactivity Group
0.8
y p
0.7
0 6
High Reactivity Group
0.6
0.5P=0.01
P=0.006 P=0.043
0 100 200 300 Time (Days)
* Fibrinogen binding in response to 0.2 µM ADP** Composite MI, UR, RevascularizationKabbani SS et al. Am J Cardiol. 2003;91:876-878.
Non-responsiveness to Clopidogrel Is a Predictor of p p gStent Thrombosis in Patients Receiving a DES
I 804 ti t d i • In 804 patients undergoing stenting, stent thrombosis was found to be more prevalent in 96
98
100
mbo
sis
98±1
found to be more prevalent in patients with post-treatment platelet aggregation ≥70% in 90
92
94
babl
e st
ent t
hrom 91±3
Responders
Nonresponders
platelet aggregation ≥70% in response to 10 µM ADP
• The incidence of stent 82
84
86
88
Def
inite
or p
rob
Log rank P <0.001
The incidence of stent thrombosis was 8.6% in nonresponders and 2.3% in
80
82
0 30 60 90 120 150 180Time (days) nonresponders and 2.3% in
responders (P <0.001).
Buonamici P et al. J Am Coll Cardiol. 2006;49:2312-2317.
Interindividual Variability in Platelet Reactivity to Clopidogrel in Patients Undergoing Coronary Stenting
2 HoursResistance = 31%
20ResistanceResistance = 63%Resistance
24
24 HoursClopidogrel in Patients Undergoing Coronary Stenting
10
20Resistance
tients
(%)
12
≤ -30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
>60
Pa
≤ -30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
>60
5 DaysResistance = 15%
28Resistance = 31%Resistance
22
30 Days
Resistance14
atien
ts (%
)
11
≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60
Pa
≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60
Gurbel PA et al. Circulation. 2003;107:2908-2913.
∆ Aggregation (%)
30(-30,-20]
( 20, 10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
60
∆ Aggregation (%)
( ] ( ] ( ] ( ] ( ] ( ] ( ]
Platelet Function TestsPlatelet Function Tests•• Platelet Aggregation Platelet Aggregation
Light transmittance aggregometry (LTA)Light transmittance aggregometry (LTA) gold standardgold standardImpedance platelet aggregationImpedance platelet aggregation
•• Flow CytometryFlow CytometryGPIIb/IIIa receptor activationGPIIb/IIIa receptor activationPP--selectin expressionselectin expressionMonocyteMonocyte--platelet aggregatesplatelet aggregatesMonocyteMonocyte--platelet aggregatesplatelet aggregatesVasodilatorVasodilator--associated stimulated phosphoprotein (VASP)associated stimulated phosphoprotein (VASP)
•• PointPoint--ofof--carecareUltegra rapid platelet function analyzer (VerifyNow)Ultegra rapid platelet function analyzer (VerifyNow)Thromboelastagraph (TEG)Thromboelastagraph (TEG)PFAPFA--100100PlateletworksPlateletworksCone and plate(let) analyzer (IMPACT)Cone and plate(let) analyzer (IMPACT)Cone and plate(let) analyzer (IMPACT)Cone and plate(let) analyzer (IMPACT)
•• Genetic testingGenetic testing
How does the VerifyNow Assay Work?• Whole blood, closed-tube sampling with no pipetting required• Assay results in less than 5 minutes (assay time)• Good correlation with LTA and VASP
Mixing
LightSource
MixingChamber
Aspirin Assay – AAP2Y12 assay – ADP + PGE1GpIIbIIIa assay – iso-TRAP
Agonists:
+Agonist
Platelets in whole blood maximally activated by
agonist in mixing chamber
Fibrinogen-coated beads Agglutinated beads aggregate in clusters
GRAVITAS Trial DesignGRAVITAS Trial DesignggGauging Responsiveness with a VerifyNow Assay Gauging Responsiveness with a VerifyNow Assay –– Impact on Impact on Thrombosis and Safety Thrombosis and Safety
• This trial is designed to evaluate whether tailored clopidogrel therapy, using a point-of-care platelet function assay, reduces major adverse cardiovascular events after DES implantation
Stable angina/ischemia or non-ST-elevation acute coronary syndrome undergoing PCI with DES
High Residual Platelet Reactivity on Clopidogrel Therapy 12 to 24 hours Post PCI
Not High Residual Platelet Reactivity on Clopidogrel Therapy 12 to 24 hours Post PCI py
Standard DosingClopidogrel 75 mg once
High DoseClopidogrel 450 mg loading dose followed by
p g py
• The primary end point is the time to first occurrence of cardiovascular death, nonfatal di l i f ti d fi it / b bl t t th b i
p g gdaily x 6 months
p g g g y150 mg once daily x 6 months
myocardial infarction, or definite/probable stent thrombosis.
Price MJ et al. Am Heart J. 2009;157:818-824.
Power Analysis: Sample Size Estimate
• Assumptions:
• An event rate of 5% in patients on standard-dose clopidogrel at 6-months
• 50% risk reduction with high-dose clopidogrelp g
2200 patients needed to provide 80% p ppower at a two-sided 0.05 significance levellevel
GRAVITAS Patient Flow
5429 patients screened with VerifyNow P2Y12 12 24 hours post PCI12-24 hours post-PCI
2214 (41%) with high residual platelet reactivity
3215 (59%) without high residual platelet reactivityp y
(PRU ≥ 230)p y
(PRU < 230)
ClopidogrelHi h D
ClopidogrelSt d d DHigh Dose
N=1109Standard Dose
N=1105
Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test.
Bleeding Events: Safety Population
Severe or life threatening: Fatal bleeding intracranial hemorrhage or bleeding that causes hemodynamic compromise requiring
P by log rank test; observed event rates listed. HD, high-dose; SD, standard dose
Severe or life-threatening: Fatal bleeding, intracranial hemorrhage, or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical interventionModerate: Bleeding that leads to transfusion but does not meet criteria for severe bleeding
GRAVITAS Patient Flow: Secondary Analysis
5429 patients screened with VerifyNow P2Y12 12 24 hours post PCI12-24 hours post-PCI
2214 (41%) with high residual platelet reactivity
3215 (59%) without high residual platelet reactivityp y
(PRU ≥ 230)p y
(PRU < 230)
Random selection
ClopidogrelHi h D
ClopidogrelSt d d D
ClopidogrelStandard Dose
Random selection
High DoseN=1109
Standard DoseN=1105
Standard DoseN=586
Non-Randomized Comparison
Baseline Characteristics: Non-Randomized Comparison
CharacteristicSD –
High RPRN 1105
SD – Not High RPR
N 586 pN=1105 N=586 p
Residual platelet reactivity, median (IQR)
283 PRU (255 - 321)
151 PRU (105 - 191) <0.001
Age, years 64 ± 11 62± 10 <.0001
Male sex 65% 80% <0.001Di b t M llit 47% 29% <0 001Diabetes Mellitus 47% 29% <0.001Body mass index (median) 31 29 <0.001Cr Cl< 60 ml/min 42% 27% <0.001Proton pump inhibitor 30% 20% <0.001Indication for PCI 0.41
Stable angina or ischemia 60% 56%Stable angina or ischemia 60% 56%UA, no ST depression 24% 28%NSTE-ACS
UA, ST-dep, biomarker (-) 5% 5%Cardiac biomarker (+) 10% 11%
Secondary Comparison: High vs. Not High Reactivity
Observed event rates are listed. P value by log-rank test.
CV Events and Post-PCI PRU In Pts With High and Not High Reactivity Treated With Standard-Dose Clopidogrel
500
400Red dots: patients with CV death, MI, or ST
300PRU 12 - 24 hrs
200post-PCI 230 PRU
100
0
High Residual Not High
N=1105 N= 586
High ResidualReactivity
Not HighResidual Reactivity
ITT population
GRAVITAS: Possible Explanations
• Underpowered: patients low-risk, low event rates.Gi HR f 1 01 ft 2200 ti t lik l th t• Given HR of 1.01 after 2200 patients, unlikely that a larger trial would show a clinically meaningful benefit
• Pharmacodynamic effect of the intervention was too weak?• Stronger intervention, goal-directed therapy with serial
t it t dmeasurements merit study• Platelet reactivity is a non-modifiable risk factor?
• To be further examined in TARGET-PCI, ARCTIC, TRIGGER-PCI
• VerifyNow results not predictive of risk?• However, at least 7 studies involving more than 3,000
patients demonstrate a correlation with MACE
GRAVITAS does not support a pptreatment strategy of high-dose clopidogrel in low risk patients withclopidogrel in low-risk patients with high reactivity identified by a single g y y gplatelet function test after PCI.
UNDERSTANDING PLATELET GENOMICSUNDERSTANDING PLATELET GENOMICS
Pharmacogenomics, Metabolism, and Platelet Reactivityg y
Mechanism of Action of Prasugrelg
Bhatt DL. N Engl J Med. 2009;361:940-942.
Ticagrelor: Ticagrelor: PharmacologyPharmacologygg
A P2Y i t t i t • A P2Y12 purinoceptor antagonist • Does not require cytochrome P450
metabolic activation to exert its inhibitory yeffects on platelet aggregation
• No active metaboliteR id t f ti• Rapid onset of action
• Reversibly binds to the P2Y12 receptor– Potential advantage if needing to g g
discontinue therapy due to surgery• Compared with clopidogrel, produces a
greater and more consistent inhibition of greater and more consistent inhibition of ADP-induced platelet aggregation
Adapted from: Owen RT et al. AZD6140. Drugs of the Future. 2007;32:845-853.
Effects of CYP2C19*2 and *17 Combined
N=445 patients; 24 hours post 600-mg clopidogrel loading doseSl
Normal
Slow
Fast Normal
PRI=platelet reactivity index; VASP=vasodilator-stimulated phosphoprotein.Frére C, et al. J Thromb Haemost. 2009;7(8):1409-1411.
Frequency 3% 3.5%
CYP2C19 and CVD, MI, or Stroke
N=1477 ACS/PCI Subjects Treated with Clopidgrel in TRITON-TIMI 38
12.112
13
14
CarriersCYP2C19 Reduced-Function Allele Carriers Hazard Ratio 3.09(95% CI 1.19-8.00)
(%)
4
8.0
or S
trok
e (%
)
7
8
9
10
11
Non-carriers
P=0.015
2.6
Sten
tThr
ombo
sis
(
2
3
CarriersCYP2C19 Reduced-Function Allele Carriers
Hazard Ratio 1.53(95% CI 1 07 2 19)
CV
Dea
th, M
I, o
3
4
5
6
7
0.8
finite
or P
roba
ble
S
1
2
Non-carriers
(95% CI 1.07-2.19)P=0.014
Days After Randomization
0
1
2
0 30 90 180 270 360 450
Def
00 30 90 180 270 360 450
Days After Randomization
1064 1009 999 980 870 755 542
Number at Risk:
Non-Carrier
395 364 360 348 306 270 181Carrier
1014 1004 1001 989 885 765 547375 368 366 359 316 279 186
Number at Risk:Non-CarrierCarrier
* Carriers ~30% of the population
Mega JL, Close S, Wiviott SD et al. N Eng J Med. 2009; 360:354-62.
CYP2C19*2 and Outcomes
al (%
)en
t-Fre
eas
c) S
urvi
vul
ativ
e Ev
erg
ent R
eva
Cum
uea
th, M
I, U
r(D
e
Collet JP et al. Lancet 2009;373:309-317.
Stent Thrombosis:(HR 6.02, 95% CI 1.81-20.04, P=0.0009)
CYP2C19*2 and Outcomes
1.98 (1.10-3.58)
0.69 (0.51-0.93)
1.00
P=0.003
Simon T et al. N Eng J Med. 2009; 360:363-375.
CYP2C19 and Treatment with ClopidogrelPredominantly for PCI
CVD, MI, or Stroke
1 2 CYP2C19 RFA N C i
Hazard Ratio (95% CI) P Value
1 57 (1 13 2 16) 0 006
N=9,68591.5% PCI
y
1 or 2 CYP2C19 RFA vs Non-Carriers 1.57 (1.13-2.16) 0.006
1 CYP2C19 RFA vs Non-Carriers 1.55 (1.11-2.17) 0.011 CYP2C19 RFA vs Non Carriers 1.55 (1.11 2.17) 0.01
2 CYP2C19 RFA vs Non-Carriers 1.76 (1.24-2.50) 0.002
Stent Thrombosis
1 or 2 CYP2C19 RFA vs Non-carriers 2.81 (1.81-4.37) <0.0001
N=5,894
1 CYP2C19 RFA vs Non-Carriers 2.67 (1.69-4.22) <0.001
2 CYP2C19 RFA vs Non-Carriers 3.97 (1.75-9.02) 0.001
Risk Higher withCYP2C19 Variant
Risk Lower withCYP2C19 Variant
21.0 105
RFA=reduced-function allele
Mega JL, Simon T, Collet JP et al.JAMA 2010;304(16):1821-30 .
CURE Genetics Substudy
No association seen between CYP2C19and outcomes inand outcomes in clopidogrel arm.
BUT patients treatedBUT, patients treated conservatively (only ~15% rate of PCI).
Pare et al. NEJM 2010; 363(18):1704-14.
Magnitude of PGx Interaction Will Depend R l ti B fit f Cl id lon Relative Benefit of Clopidogrel
Conservatively managed Invasively managedy g
Placebo0 12
0.14
y g
Aspirin Monotherapy
Stro
ke 0.10
0.12
85% Risk
20% Risk
Clopidogrel
eath
, MI,
S
0.06
0.08 85% Risk Reduction
20% Risk Reduction
CV
De
0.02
0.04 Dual Antiplatelet Therapy
Months of follow-up0 3 6 9 12
0.0
CURE. NEJM 2001;345:494-502 STARS. NEJM 1998; 339: 1665.
CYP2C19 and Treatment with ClopidogrelCVD, MI, or Stroke:Carriers of 1 or 2 CYP2C19 Variants vs Non-Carriers
Meta-Analysis (91.5% PCI)
Est. Hazard Ratio (95% CI)
1.57 (1.13-2.16)Meta Analysis (91.5% PCI) 1.57 (1.13 2.16)
PLATO (66% l d PCI)PLATO (66% planned PCI)
Meta-Analysis + PLATO 1.43 (1.11-1.84)
CURE (15.5% PCI)
CHARISMA (stable CAD or risk factors)
M t A l i PLATOMeta-Analysis + PLATO + CURE + CHARISMA 1.32 (1.07-1.63)
Risk Higher withCYP2C19 Variant
Risk Lower withCYP2C19 Variant
1.51.0 3.00.5Mega JL, Simon T, Collet JP et al.JAMA 2010;304(16):1821-30 .
Alternative Treatments: Pharmacodynamics
500100100 PrasugrelClopidogrel
4008080
300235
6060
%)
%)
200
235PRU
PRU
4040IPA
(%IP
A (%
10000
2020
Clopidogrel Responder
Cl id l Ti l0--2020
00Clopidogrel Non-responder
*Responder = ≥25% IPA at 4 and 24 h
Storey RF, et al. JACC 2010; 122(11):1056-67.
Clopidogrel Ticagrelor
Peak
Brandt JT et al., Am Heart J 2007;153:e9-e16.
TRITON-TIMI 38 Genetic Substudy1477 Pts w/ ACS and Planned PCI
Clopidogrel1466 Pts w/ ACS and Planned PCI
Prasugrel
12.1
11
12
13
14
CarriersCYP2C19 Reduced-Function
Allele Carriers
%)
11
12
13
14
Non-carriers of a CYP2C19reduced function allele%
)
8.0
I, or
Str
oke
(%)
7
8
9
10
Non-carriersNon-carriers
or S
trok
e (% 9.8
8.57
8
9
10
I, or
Str
oke
(%) Non-carriers
Carriers
reduced function allele
Carriersor S
trok
e (%
Hazard Ratio 1.53(95% CI 1 07 2 19)
CV
Dea
th, M
I
3
4
5
6
HR 1.53(95% CI 1 07 2 19)V D
eath
, MI,
Hazard Ratio 0.89(95% CI 0 60 1 31)
3
4
5
6
CV
Dea
th, M
V D
eath
, MI,
(95% CI 1.07-2.19)P=0.014
Days After Randomization
0
1
2
0 30 90 180 270 360 450
(95% CI 1.07-2.19)P=0.014
CV (95% CI 0.60-1.31)
P=0.27
0
1
2
0 30 90 180 270 360 450Days After Randomization
CV
1064 1009 999 980 870 755 542
Number at Risk:y
Non-Carrier
395 364 360 348 306 270 181Carrier1048 991 982 951 849 750 541407 383 376 364 320 276 188
Number at Risk:ays te a do at o
Non-CarrierCarrier
P=0.046 for interaction between benefit of prasugrel vs. clopidogrel and CYP2C19 genotypeP 0.046 for interaction between benefit of prasugrel vs. clopidogrel and CYP2C19 genotype
Mega JL, Close SL, Wiviott SD et al. Circulation 2009; 119:2553-2560.
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm#ds
STENT THROMBOSIS (n=4905)Odds Ratio, fixed model
Bilateral CI, 95% for trials, 95% for MA
2C19*2 2C19*12C19*2 better 2C19*2 orse 2C19*2 2C19*1
10/375 8/1014
2C19*2 better 2C19*2 worse
Mega et al. (0.26)
8/73 4/186
g ( )
Collet et al. (0.15)
13/247 11/525
10/680 7/1805
Giusti et al. (0.34)
Sibbing et al (0 24) 10/680 7/1805
41/1375 30/3530Total
Sibbing et al. (0.24)
events / sizeOdd R ti
OR 3.45 95% CI: 2.14‐5.57, p<0.001, phet=0.78
/Odds Ratio
J Am Coll Cardiol 2010; 56(2):134-143
Collaborative Meta‐analysis: CYP2C19 and S Th b i i P i Cl id lStent Thrombosis in Patients on Clopidogrel
C i
Risk Ratio(95% CI) P value
Carriers vsNoncarriers
2.81 (1.81‐4.37) < .0001
Heterozygotes vs Wild Type
2.67 (1.69‐4.22) < .0001
Homozygotes vs Wild Type
3.97 (1.75‐9.02) < .001
0.5 1.0 15.0
N = 5772 Risk Higher WithCYP2C19 V i t
Risk Lower WithCYP2C19 Variant5 CYP2C19 VariantCYP2C19 Variant
Mega JL. American Heart Association; November 2009; Orlando, Florida.
Pharmacogenomics of Antiplatelet TherapiesgCarriers vs Non-carriers of a Reduced-function CYP2C19 Allele
More Ischemic Less Ischemic
CLINICAL OUTCOMES
Prasugrel 0.89 P=0.27Events Events
Clopidogrel 1.53 P=0.01
0.046
Clopidogrel 1.53 P 0.01
3.5 3.0 2.5 2.0 1.5 1.0 0.5
Odds Ratio
Modified from: Mega JL et al. Circulation. 2009;119:2553-2560.* Data adapted from: Mega JL et al. N Engl J Med. 2009;360:354-362.
EventEvent--free Survival Over 1 Year of Followfree Survival Over 1 Year of Follow--upupIn Patients Treated with Clopidogrel Following PCI*In Patients Treated with Clopidogrel Following PCI*
No. of CYP2C19*2 allelesNo. of CYP2C19*2 alleles CYP2C19*2 variant accounts for 12% CYP2C19*2 variant accounts for 12% 0011
clopidogrel response variation of platelet clopidogrel response variation of platelet aggregation to ADP.aggregation to ADP.
ng E
vent
ng E
vent
3030
4040
5050 All patientsAll patients Patients taking Patients taking clopidogrel at time clopidogrel at time
of eventof event
Patients not taking Patients not taking clopidogrel at time clopidogrel at time
of eventof event
% E
xper
ienci
% E
xper
ienci 3030
1010
2020
%%
9090 18018000
DaysDays
270270 360360 9090 180180 270270 360360 9090 180180 270270 36036000
DaysDays DaysDays
00
yy yy yy
0 0 158 154 150 144 143 66 64 62 58 57 92 90 88 87 861 1 67 61 56 53 50 27 23 18 17 16 40 38 38 36 33
No. at riskNo. at riskNo. of CYP2C19*2 allelesNo. of CYP2C19*2 alleles
Shuldiner A et al. JAMA. 2009;302:849-858.
* CYP2C19*2 variant accounts for 12% of clopidogrel response variation of platelet aggregation to ADP
TRITON-TIMI 38ABCB1 and CYP2C19 Polymorphisms DiminishTRITON-TIMI 38ABCB1 and CYP2C19 Polymorphisms DiminishABCB1 and CYP2C19 Polymorphisms DiminishClopidogrel Antiplatelet EffectABCB1 and CYP2C19 Polymorphisms DiminishClopidogrel Antiplatelet Effect
Both polymorphisms =highest risk 14
12MI, 12·6
13·6
12
10
8r dea
th,
e (%
)11·5
8
6
4vasc
ular
or s
trok
e
6·3
4
2
0
Car
diov o
— CYP2C19 reduced-function carrier and ABCB1 3435 TT— CYP2C19 reduced-function non-carrier and ABCB1 3435 TT— CYP2C19 reduced-function carrier and ABCB1 3435 CC/CT— CYP2C19 reduced-function non-carrier and ABCB1 3435 CC/CT
No polymorphisms = lowest risk
00 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Days from randomisationp=0·0018 across genotype.
Mega JL, et al. Lancet. 2010;376:1312-1319.CC = ABCB1 normal function; C→T = ABCB1 reduced function; Post-hoc analysis.
p g yp
Genetic and Platelet Function Testing
GENOME TRANSCRIPTOME PHENOTYPEPROTEOME
ENVIRONMENT
GENOME TRANSCRIPTOME PHENOTYPE
post-translationmodificationtranscription translation
PROTEOME
p
~2×104
genes
~105
proteins~106
modifiedproteins
>105
~107 SNPs
10transcripts
PLATELET FUNCTION TESTING
Proximal to phenotypeCaptures environmental & genetic
variability
GENETIC TESTING
FixedLifelong impact y
More difficult to assessVaries with time
gEasy to assess
Distanced from phenotype
Clopidogrel ReloadingAmong Genetic Carriers
Bonello et al JACC 2010
Tailoring Antiplatelet Therapy Based on Tailoring Antiplatelet Therapy Based on Platelet Function Testing and Genotyping
• Paul Gurbel, August 2010"The bottom line is we have no prospective studies at this time that alteration of therapy based on genotype or phenotype really affects patient outcomes”
• Whit P JACC 2010 (B ll /G b l t l)• White Paper, JACC 2010 (Bonello/Gurbel et al)“However, until the results of large scale trials of personalized antiplatelet therapy are available the routine use of platelet function measurements in the therapy are available, the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended”
• 2010 ACCF/ACG/AHA Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines"The role of either pharmacogenomic testing or platelet function testing in The role of either pharmacogenomic testing or platelet-function testing in managing therapy with thienopyridines and PPIs has not yet been established"
Conclusions• The CYP2C19 reduced function genotypes
are associated with worse outcomes in the setting of treatment with clopidogrel. Novel antiplatelets appear to be less so.
• ABCB1 and PON-1 may offer similar risk stratification.
• Genetics and platelet function appear to offer complementary information.
• Routine use of genetic and platelet function g ptesting for alteration of therapy is not ready for prime time
Recommended