MONITORAGGIO DELLA FUNZIONE PIASTRINICA DURANTE TERAPIA CON TIENOPIRIDINE Rossella Marcucci 30 novembre 2013 CardioLucca 2013
CLOPIDOGREL: A MODEL FOR PERSONALIZED MEDICINE High on-treatment platelet reactivity
ACUTE CORONARY SYNDROME PATIENTS UNDERGOING PCI WITH STENT IMPLANTATION DUAL ANTIPLATELET THERAPY ACUTE PHASE ISCHAEMIC EVENTS BLEEDING
Buonamici P, JACC 2007 n=804 RECLOSE TRIAL 10 micromol ADP LTA
Cardiovascular death and nonfatal myocardial infarction in acute coronary 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 No RPR (PRU <240) n= 683 ACS patients CV death-free Survival 1.00 0.98 0.96 0.94 RPR (PRU 240) VerifyNow P2Y12 log-rank test p=0.02 0.92 0 2 4 6 8 10 12 Time (months) HR=2.55 (95%CI 1.08-6.07), p=0.034 Marcucci R et al, Circulation 2009
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
Prospective observational single center cohort study JAMA 2011;306(11):1215-1223
STUDY FLOW n= 1789 n= 1525 n= 247 14% JAMA 2011;306(11):1215-1223
Kaplan Meier survival curves for primary end point events Estimate risk 27.5% (18.3-36.7) in HRPR group 14.5% (12.1-16.9) in LRPR group 2 YRS FOLLOW-UP JAMA 2011;306(11):1215-1223
CLOPIDOGREL: A MODEL FOR PERSONALIZED MEDICINE - Genetic Factors
C3435T Ile1145Ile ABCB1 Roles in clopidogrel activity of proteins with known genetic polymorphisms A672T Q192R PON1 CYP1A2 (35.8%) CYP2B6 (19.4%) CYP2C19 (44.9%) T744C H1/H2 P2Y12 T196C Leu59Pro ITGB3 CYP2B6 (32.9%) CYP2C9 (6.8%) CYP2C19 (20.6%) CYP3A4 (39.8%) Simon T et al, N Engl J Med 2009 Kazui M et al, Drug Metab Dispos 2009
Distribution of maximal platelet aggregation after different stimuli in the overall study population according to CYP2C19*2 genotypes 1419 ACS patients on dual antiplatelet therapy undergoing percutaneous coronary intervention (PCI) and stent implantation CYP2C19*2 genotypes *1/*1 *1/*2 *2/*2 p (overall) *1/*2+*2/*2 p (vs. *1/*1) Subjects N (%) 974 (68.6%) 405 (28.6%) 40 (2.8%) 445 (31.4%) Aggregation according to stimulus % ADP (2µM) ADP (10µM) AA (0.5 mg/ml) 26 (1-100) 32 (1-94)* 41 (5-84)* <0.0001 33 (1-94) <0.0001 49 (1-100) 54 (2-100) * 62 (26-100)*# <0.0001 56 (2-100) <0.0001 11 (1-100) 12 (1-100) 14 (5-85) 0.060 12 (1-100) 0.043 *p<0.0001 vs *1/*1; p=0.028 vs *1/*2; #p=0.015 vs *1/*2; Giusti B et al, Pharmacogenetics and Genomics 2007; 17(12):1057-1064
Cardiovascular death, MI or ischemic stroke JAMA 2010
Stent Thrombosis JAMA 2010
JAMA, 2011 ELEVATE TIMI 56 Conclusion Among patients with stable cardiovascular 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 300 mg 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 polymorphism 12 month follow-up Marcucci R et al, Platelets 2012
Erythrocyte deformability TRANSIENT Acute phase Platelet turn-over Inflammation Reticulated platelets ADAMTS-13 activity High on-treatment platelet reactivity Compliance Drug interactions CYP2C19 polymorphism DRUG RESISTANCE PERMANENT Diabetes Chronic Systolic function Age, sex PERSISTENT
Multivariate logistic regression analysis on risk of having RPR * IPF vs. AA-RPR 1.77 (1.05-2.99) p=0.03 H-IPF vs. AA-RPR 1.62 (1.05-2.51) p=0.03 IPF vs. ADP-RPR H-IPF vs. ADP-RPR 1.76 (1.07-2.90) 1.74 (1.14-2.64) p=0.02 p=0.01 0 1 2 OR 95%CI *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 4
CYTOCHEMOKINE LEVELS ACCORDING TO PLATELET REACTIVITY by 10 µm ADP in ACS Gori et al., Atherosclerosis 2009 p<0.01 IL-6 p<0.001 IP-10 p<0.05 IL-4 p<0.05 IL-10
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.
Clinical and laboratory characteristics according to platelet reactivity by 10 microm ADP-PA ACS patients (n=386) Elective PCI (n=482) With RPR (n=99) Without RPR (n=287) p With RPR (n=93) Without RPR (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 use of clopidogrel (%) Ejection Fraction 40% (%) Leukocytes (x 10 9 /L) 4.4 7.7 ns 28.9 41.8.02 61.2 41.0.003 38.3 26.0.04 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 Marcucci R et al, Atherosclerosis 2007
CLOPIDOGREL: A MODEL FOR PERSONALIZED MEDICINE - Genetic Factors -Acquired Factors: Drug-drug interactions
ORs for MACE according to PPI use (n=46,037) Hulot et al, JACC 2010
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 PRU 12-24 hrs post-pci 400 300 200 Red dots: patients with CV death, MI, or ST 230 PRU 100 0 N=1105 N= 586 ITT population High Residual Reactivity Not High Residual Reactivity
Collet JP et al., N Engl J Med 201 Pts scheduled to undergo DES implantation EXCLUSION criteria: primary PCI for STEMI planned use of GpIIb/IIIa inhib.
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
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
GIANT STUDY Clopidogrel Genotyping for Antiplatelet Guidance in MI Stenting: Maybe Reduced Ischemic Risk November 06, 2013 TCT 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 clopidogrelcontaining antiplatelet therapy after stenting.
GIANT STUDY Clopidogrel Genotyping for Antiplatelet Guidance in MI Stenting: Maybe Reduced Ischemic Risk November 06, 2013 TCT 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 Of note, the composite end point was about five times higher for the 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-treatment platelet 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: CLOPIDOGREL (generic drug) PLAVIX PRASUGREL 1 year 0.57 E/cp 205E 0.65 E/cp 234E 2.57 E/cp 925E TICAGRELOR 1.80 E/cp 648E
CLOPIDOGREL HYDROGEN SULFATE
n= 21 HEALTHY volunteers Clin Res Cardiol 2009
n=150 pts CHS= Clopidogrel Hydrogensulfate CB= clopidogrel besylate Thromb Res 2011
CLOPIDOGREL BASE (n=741) CLOPIDOGREL HYDROGENSULFATE (n=838) 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 p 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
Oct. Nov. Dec. Jan. Feb. Mar. = Clopidogrel hydrogensulfate = Clopidogrel base 2010 45/166 (27%) 2011 58/144 (40%) P<0.05 2010 43/144 (30%) P<0.05 2011 53/126 (42%) 2010 38/133 (29%) P=0.060 2011 51/135 (38%) 2011 37/124 (30%) P<0.05 2012 50/114 (44%) 2011 31/130 (24%) P<0.05 2012 45/99 (44%) 2011 19/141 (13%) P<0.005 2012 57/123 (45%) ADP (%) 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 TOTAL 213/838 (25.4 %) 314/741 (42.4%) P<0.0001 52.3±19.4 57.9±19.8 0 10 20 30 40 50 (%) Marcucci R et al. JACC 2013
Marcucci R et al. JACC 2013 Italian Generic Clopidogrel Worse Than Brand Name at Suppressing Platelets Acompany press releasereports 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.
The next FUTURE. - Prasugrel / Ticagrelor for ALL patients? - Prasugrel/Ticagrelor: duration of therapy?
CHRONIC PHASE ISCHAEMIC EVENTS BLEEDING
Consensus and Update on the Definition of On-Treatment Platelet Reactivity to ADP Associated with Ischemia and BLEEDING 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.
Sibbing D et al, J Thromb Haemost 2010
Prospective Evaluation of On-Clopidogrel Platelet Reactivity Over Time in PatientsTreated With Percutaneous Coronary Intervention Relationship With Gene Polymorphisms and Clinical Outcome Campo G, JACC 2011
Residual Platelet Reactivity, Bleedings, and Adherence to Treatment in Patients Having Coronary Stent Implantation Treated With Prasugrel Parodi et al., AJC Oct 2011 Multivariate analysis LTA 10 µm ADP < 40% : 96/298 (32%) 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 therapy to 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..