MONITORAGGIO DELLA FUNZIONE PIASTRINICA DURANTE … · MONITORAGGIO DELLA FUNZIONE PIASTRINICA...
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MONITORAGGIO DELLA FUNZIONE PIASTRINICA DURANTE TERAPIA CON
TIENOPIRIDINE
Rossella Marcucci30 novembre 2013
CardioLucca 2013
ACUTE CORONARY SYNDROME PATIENTSUNDERGOING PCI WITH STENT IMPLANTATION
ISCHAEMIC
EVENTSBLEEDING
DUAL ANTIPLATELET THERAPY
ACUTE PHASE
1.00
0.98
0.96
0.94
0.92
0 2 4 6 8 10 12
Time (months)
CV death-free Survival
RPR (PRU ≥240)
No RPR (PRU <240)
log-rank test p=0.02
Cardiovascular death and nonfatal myocardial infarction in acutecoronary syndrome patients receiving coronary stenting are
predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12 month follow-up
Marcucci R et al, Circulation 2009
n= 683 ACS patients
VerifyNow P2Y12
HR=2.55 (95%CI 1.08-6.07), p=0.034
Iperattività piastrinica “misurata” con i comuni test di
aggregazione piastrinica e prognosi: metanalisi
Impact of Platelet Reactivity on Clinical Outcomes After Percutaneous
Coronary Intervention Somjot S. Brar et Al. JACC 2011
Kaplan Meier survival curves for primary end point events
JAMA 2011;306(11):1215-1223
Estimate risk
27.5% (18.3-36.7) in HRPR group
14.5% (12.1-16.9) in LRPR group
2 YRS FOLLOW-UP
CYP1A2 (35.8%)CYP2B6 (19.4%)CYP2C19 (44.9%)
CYP2B6 (32.9%) CYP2C9 (6.8%)CYP2C19 (20.6%)CYP3A4 (39.8%)
Kazui M et al, Drug Metab Dispos 2009
Simon T et al, N Engl J Med 2009
Roles in clopidogrel activity of proteins with known genetic
polymorphisms
C3435TIle1145IleABCB1
A672TQ192RPON1
T196CLeu59Pro
ITGB3
T744CH1/H2P2Y12
CYP2C19*2 genotypes
*1/*1 *1/*2 *2/*2 p (overall)
*1/*2+*2/*2p (vs. *1/*1)
SubjectsN (%)
974 (68.6%)
405 (28.6%)
40(2.8%)
445(31.4%)
Aggregation accordingto stimulus
%
ADP(2µM)
26 (1-100) 32 (1-94)* 41 (5-84)*§ <0.0001 33 (1-94) <0.0001
ADP(10µM) 49 (1-100) 54 (2-100) * 62 (26-100)*# <0.0001 56 (2-100) <0.0001
AA(0.5
mg/mL)11 (1-100) 12 (1-100) 14 (5-85) 0.060 12 (1-100) 0.043
Distribution of maximal platelet aggregation after different stimuli in
the overall study population according to CYP2C19*2 genotypes
Giusti B et al, Pharmacogenetics and Genomics 2007; 17(12):1057-1064
1419 ACS patients on dual antiplatelet therapy undergoing percutaneous
coronary intervention (PCI) and stent implantation
*p<0.0001 vs *1/*1; §p=0.028 vs *1/*2; #p=0.015 vs *1/*2;
JAMA , 2011
ELEVATE TIMI 56
Conclusion Among patients with stablecardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers;in contrast, for CYP2C19*2 homozygotes, doses as high as 300mg daily did not result in comparable degrees of platelet inhibition.
CLOPIDOGREL:
A MODEL FOR PERSONALIZED MEDICINE
- Genetic Factors
-Acquired Factors:
clinical characteristics
HIGH ON TREATMENT PLATELET REACTIVITY BY ADP AND INCREASED RISK OF MACE IN GOOD CLOPIDOGREL METABOLIZERS: BEYOND PHARMACOGENETIC APPROACH
n= 892 patients NON carriers of CYP2C19*2 polymorphism12 month follow-up
Marcucci R et al, Platelets 2012
High on-treatmentplatelet reactivity
TRANSIENT
Chronic
Systolic function
Age,sex
Diabetes
PERSISTENT
Acute phase
Reticulated platelets
Platelet turn-over
Erythrocytedeformability ADAMTS-13
activity
Inflammation
ComplianceDrug interactions
CYP2C19polymorphism
DRUG RESISTANCEPERMANENT
4OR 95%CI
Multivariate logistic regression analysis on risk of Multivariate logistic regression analysis on risk of
having RPR *having RPR *
10 2
IPF vs. AA-RPR
H-IPF vs. AA-RPR
IPF vs. ADP-RPR
H-IPF vs. ADP-RPR
1.77 (1.05-2.99)
1.62 (1.05 -2.51)
1.76 (1.07-2.90)
1.74 (1.14-2.64)
p=0.03
p=0.03
p=0.02
p=0.01
*Adjusted for age, gender, family history of CAD, smoking habit, hypertension, diabetes, dyslipidemia, hematocrit,
STEMI/NSTEMI, use of GpIIb/IIIa inhibitors and platelet count
3
Cesari et al, Thromb Haemost 2008
CYTOCHEMOKINE LEVELS ACCORDING TO PLATELET REACTIVITY by 10 µM ADP in ACS
p<0.01 p<0.001IL-6 IP-10
p<0.05p<0.05
IL-10IL-4
Gori et al., Atherosclerosis 2009
High on-thienopyridine platelet reactivity in elderly coronary patients: the
SENIOR-PLATELET study
Silvain L, EHJ 2011
Rate of high platelet reactivity
(PRU . 235) (Figure 2A) and
mean inhibition (%) (Figure 2B)
in patients treated with an MD
of 75 mg of clopidogrel
according to decades of age
identified with the VN-P2Y12
assay. Mean inhibition
corresponds to the ratio PRU
iso-TRAP/PRU ADP-PGE .
Asterisks indicate P , 0.05 with
Kruskall – Wallis test for
multiple comparison.
ACS patients(n=386)
Elective PCI(n=482)
WithRPR (n=99)
WithoutRPR (n=287)
p WithRPR (n=93)
WithoutRPR (n=389)
P
Age 68.3(65.7-70.8) 68.3(66.9-69.8) ns 68.4(66.2-70.6) 67.7(66.6-68.8) ns
Sex (M/F) 69/30 206/81 ns 70/23 294/95 ns
Smoking habit (%) 45.6 48.1 ns 40.5 47.3 ns
Hypertension (%) 63.6 64.7 ns 64.5 70.2 ns
Diabetes (%) 44.3 20.6 .0001 34.2 16.6 .001
Dyslipidemia (%) 25.0 28.5 ns 13.4 22.4 .04
PAD (%) 13.9 7.8 ns 24.6 27.6 ns
AF(%) 15.2 14.8 ns 14.4 15.8 ns
Previous useof clopidogrel (%)
4.4 7.7 ns 28.9 41.8 .02
Ejection Fraction ≤40% (%)
61.2 41.0 .003 38.3 26.0 .04
Leukocytes (x 109/L)
12882(12023-13804)
10000(9550-10471)
.0001 8318(7762-8709)
7244(7079-7413)
.0001
ESR (mm/h)
45.7(39.8-52.5)
29.5(26.9-31.6)
.0001 23.9(20.9-28.2)
18.2(17.0-19.5)
.0001
Clinical and laboratory characteristics according to platelet reactivity by 10 microM ADP-PA
Marcucci R et al, Atherosclerosis 2007
CLOPIDOGREL:
A MODEL FOR PERSONALIZED MEDICINE
- Genetic Factors
-Acquired Factors:
Drug-drug interactions
Iperattività piastrinica e “tailored antiplatelets therapy”
I GRANDI TRIAL
Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention.
Matthew J. Price et Al. JAMA, March 16, 2011
CV Events and Post-PCI PRU In Patients With High and Not High Reactivity Treated With Clopidogrel 75-mg Daily
500
400
300
200
100
0
PRU 12 - 24 hrs post-PCI
High ResidualReactivity
Not HighResidual Reactivity
N=1105 N= 586
ITT population
Red dots: patients with CV death, MI, or ST
230 PRU
Pts scheduled to undergo DES implantation
EXCLUSION criteria:primary PCI for STEMIplanned use of GpIIb/IIIa inhib.
Collet JP et al., N Engl J Med 2012
Collet JP et al., N Engl J Med 2012 Death, MI, stroke/TIA,Urgent revascularization, Stent thrombosis
Point of care genetic testing after PCI can
be done effectively at the bedside and
treatment of identified CYP2C19*2
carriers with prasugrel can reduce high
on-treatment platelet reactivity
Roberts, Lancet 2012
GIANT STUDYClopidogrel Genotyping for Antiplatelet Guidance in MI Stenting: Maybe Reduced Ischemic RiskNovember 06, 2013TCT
In the prospective GIANT trial with 1445 patients, it was discretionary whether clinicians raised the clopidogrel dosage or switched thienopyridine agents based on the assay results, which they had in hand within 48 hours after stenting.
Such changes were made in 86% of the 316 who tested positive for the LOF genotype, a group known to be at increased ischemic risk on standard clopidogrel-containing antiplatelet therapy after stenting.
Among those 272 patients with assay-guided antiplatelet changes, the one-year composite risk of death, MI, or stent thrombosis closely matched that of patients lacking the high-risk genotype
GIANT STUDYClopidogrel Genotyping for Antiplatelet Guidance in MI Stenting: Maybe Reduced Ischemic RiskNovember 06, 2013TCT
Of note, the composite end point was about five times higher forthe remaining 14% of LOF-genotype patients whose antiplatelet therapy wasn't changed based the assay
End point
Normal
n=1118
LOF, treatment is adjusted,
n=272
LOF, treatment is not adjusted,
n=55
Primary 3.04 3.3* 15.6
The next FUTURE….
- Prasugrel / Ticagrelor for ALL patients?
- Prasugrel/Ticagrelor: duration of therapy?
What about costs?
In Italy:
1 year
CLOPIDOGREL (generic drug) 0.57 E/cp 205E
PLAVIX 0.65 E/cp 234E
PRASUGREL 2.57 E/cp 925E
TICAGRELOR 1.80 E/cp 648E
CLOPIDOGREL
BASE
(n=741)
CLOPIDOGREL
HYDROGENSULFATE
(n=838)
p
Age (yrs) 72±12 71±12 0.108
Sex (M/F) 521/220 590/248 0.999
Hypertension, n (%) 510 (68.8) 570 (68) 0.745
Diabetes, n (%) 163 (21.9) 192 (22.9) 0.673
Smoking, n (%) 373 (50.3) 415 (495) 0.762
Dyslipidemia, n (%) 290 (39.1) 330 (39.3) 0.959
STEMI/NSTEMI 363/378 402/436 0.724
HPR by ADP n (%) 314 (42.2) 213 (25.4) <0.0001
10 µM/L ADP-PA 58%±20% 52%±19% <0.001
1 mM arachidonic acid-PA 18%±7% 17%±9% 0.715
2 µg/ml collagen-PA 36.7%±15.2% 33.5%±16.6% <0.001
Marcucci R et al. JACC 2013
2010
2011Oct.
45/166 (27 %)
58/144 (40 %)
0 10 20 30 40 50
(%)
ADP (%)
2010
2011Nov.
43/144 (30 %)
53/126 (42 %)
2010
2011Dec.
38/133 (29 %)
51/135 (38 %)
2011
2012Jan.
37/124 (30 %)
50/114 (44 %)
2011
2012Feb.
31/130 (24 %)
45/99 (44%)
2011
2012Mar.
19/141 (13%)
57/123 (45%)
TOTAL
213/838 (25.4 %)
314/741 (42.4%)
56.7±19.5
57.2±17.9
58.2±18.3
60.8±19.6
54.5±19.4
61.6±19.2
54.2±19.6
56.9±20.5
51.1±19.4
56.5±19.1
46.3±18.2
57.7±20.8
52.3±19.4
57.9±19.8
= Clopidogrel hydrogensulfate = Clopidogrel base
P<0.05
P<0.05
P=0.060
P<0.05
P<0.05
P<0.005
P<0.0001
Marcucci R et al. JACC 2013
A company press release reports that Dr. Reddy’s launched bioequivalent
generic clopidogrel tablets, 75 mg and 300 mg, in the United States on May 18,
2012.
The US version appears to be clopidogrel bisulphate, and not the base form.
In June 2009, the EMEA gave the go-ahead to 6 generic versions of
clopidogrel bisulfate and the drug is now available in several European
countries.
On June 2, 2010, the EMEA approved the generic version clopidogrel base,
stating that 75-mg tablets possess adequate quality and benefit/risk ratio
and are comparable to the reference clopidogrel product.
Italian Generic Clopidogrel Worse Than Brand
Name at Suppressing Platelets
Marcucci R et al. JACC 2013
The next FUTURE….
- Prasugrel / Ticagrelor for ALL patients?
- Prasugrel/Ticagrelor: duration of therapy?
Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, Ten Berg J, Kirtane A, Siller-Matula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, Trenk D, Sibbing D, Gurbel PA.
J Am Coll Cardiol. 2013 Sep 26. doi:pii: S0735-1097(13)05380-1.
Consensus and Update on the Definition of On-Treatment Platelet Reactivity to ADP Associated with Ischemia and
BLEEDING
Campo G, JACC 2011
Prospective Evaluation of On-Clopidogrel Platelet Reactivity Over Time in
PatientsTreated With Percutaneous Coronary Intervention Relationship With Gene
Polymorphisms and Clinical Outcome
Residual Platelet Reactivity, Bleedings, and Adherence toTreatment in Patients Having Coronary Stent Implantation
Treated With PrasugrelParodi et al., AJC Oct 2011
LTA 10 µm ADP < 40% : 96/298 (32%)Multivariate analysis
OR FOR BLEEDING EVENTS Female gender: OR= 2.2 (1.08-4.45),
p=0.029
Low RPR: OR= 0.91 (0.88-0.95), p=0.001