MONITORAGGIO DELLA FUNZIONE PIASTRINICA DURANTE TERAPIA CON

TIENOPIRIDINE

Rossella Marcucci30 novembre 2013

CardioLucca 2013

CLOPIDOGREL:

A MODEL FOR PERSONALIZED MEDICINE

High on-treatment platelet reactivity

ACUTE CORONARY SYNDROME PATIENTSUNDERGOING PCI WITH STENT IMPLANTATION

ISCHAEMIC

EVENTSBLEEDING

DUAL ANTIPLATELET THERAPY

ACUTE PHASE

Buonamici P, JACC 2007 n=804

10 micromol ADP LTA

RECLOSE TRIAL

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

JAMA 2011;306(11):1215-1223

Prospective observational single center cohort study

JAMA 2011;306(11):1215-1223

STUDY FLOW

n= 1789

n= 1525

n= 24714%

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

CLOPIDOGREL:

A MODEL FOR PERSONALIZED MEDICINE

- Genetic Factors

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;

Cardiovascular death,MI or ischemic stroke

JAMA 2010

Stent Thrombosis

JAMA 2010

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

Hulot et al, JACC 2010

ORs for MACE according to PPI use (n=46,037)

CLOPIDOGREL:

HOW TO OVERCOME HIGH PLATELET REACTIVITY

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

Collet JP et al., N Engl J Med 2012

847/1213 loading dose…and the others?

Collet JP et al., N Engl J Med 2012

Collet JP et al., N Engl J Med 2012

Whole cohort

Non carriers

of CYP2C19*2

Carriers

of CYP2C19*2

Roberts, Lancet 2012

Roberts, Lancet 2012

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

TRANSIENT

Acute phase

High on-treatmentplatelet reactivity

NATURAL HISTORY OF HPR BY ADP IN ACS PATIENTS

AMI FLORENCE STUDY

Atherosclerosis 2013

Atherosclerosis 2013

The next FUTURE….

- Prasugrel / Ticagrelor for ALL patients?

- Prasugrel/Ticagrelor: duration of therapy?

NSTEMI 2011

NSTEMI 2011

2012

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 HYDROGEN SULFATE

n= 21 HEALTHY volunteers

Clin Res Cardiol 2009

CHS= Clopidogrel Hydrogensulfate

CB= clopidogrel besylate

n=150 pts

Thromb Res 2011

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?

ISCHAEMIC

EVENTS BLEEDING

CHRONIC PHASE

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

Sibbing D et al, J Thromb Haemost 2010

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

From clopidogrel – through drug resistance – to NEW antiplatelets

from MONITORING antiplatelet therapyto the identification of

a risk marker ON dual antiplatelets

….Toward a tailored antiplatelet treatment based on symptoms,

clinical and procedural characteristics and platelet function testing…..