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S. Husted and J.J .J . van Giezen CV Therap 27- 259 adenosine.pdf
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S. Husted and J.J .J . van Giezen CV Therap 27- 259 adenosine.pdf
Cardiovascular Therapeutics 27 (2009) 259–274
Abciximab is an ant ibodyAbciximab is an ant ibodySmall peptides
Type Monoclonal antibodyfragment
Small Molecular(KGD
sequence)
Small Molecular(RGD
sequence)Platelet bound
half lifeHours Seconds Seconds
Plasma half live Minutes 2.5 hours 1.8 hours
Drug to receptor ratio
1.5-2.0 250-2500 >260
½ of dose in bolus
75% <2-5% <2-5%
Renal adjust NONE YES YES
2b/3a receptor2b/3a receptor
FibrinogenFibrinogen
Platelet
IV platelet inhibition
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Only Abciximab is an antibody (do not repeat 2 weeks)Only Abciximab is an antibody (do not repeat 2 weeks)
Small peptides
Type Monoclonal antibody fragment
Small Molecular(KGD sequence)
Small Molecular(RGD sequence)
IIb/IIIa xxx xxx xxx
avb3 xxx x
Mac-1 x
Thrombingeneration
xx x x
ACT ++30 seconds +20 seconds 0
Reversible withoutplatelets
24 hrs 4 hrs 4 hrs
Reversible with platelets
YES no no
2b/3a receptor2b/3a receptor
FibrinogenFibrinogen
Platelet
Clinical trials
Highlight summary
Irreversible binding to P2Y12 receptor…clopidogrel & prasugrel
Ticagrelor reversible binding to P2Y12, given bid in preclinical trials, and releases adenosine in animal studies
IV 2b/3a inhibitors: 7E3 is antibody and should not be given for 2 weeks after treatment, but is the only platelet reversible compound
Highlight summary
Irreversible binding to P2Y12 receptor…clopidogrel & prasugrel
Ticagrelor reversible binding to P2Y12, given bid in preclinical trials, and releases adenosine in animal studies
IV 2b/3a inhibitors: 7E3 is antibody and should not be given for 2 weeks after treatment, but is the only platelet reversible compound
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Irreversible P2Y12 receptor antagonistProdrug metabolized by CYP450 enzymesCYP2C19 reducedreduced--functionfunction allele (CYP2C19*2) associated with 32% reduction in exposure to active metabolite of clopidogrel
Mega JL, et al. N Engl J Med. 2009;360(4):354-362.
Long term (>1 month)•N=359•Coronary stenting/stroke
41.9 ±20.8%* 52.9 ±8.1%*
Serebruany VL, et al. Am Heart J. 2007;153(3):371-377.Serebruany VL, et al. J Am Coll Cardiol. 2005;45(2):246-251.
*Mean ±SD
0 10–20 30–40 50–60 70–80 >90
5 M ADP Platelet Aggregation (%)
60
120
180
0
Inhibition of Platelet Aggregation (%)
35–40 41–45 45–50 51–55 56–60 61–65 66–70
40
0
20
60
80
100
No.
of
Pati
ents
No.
of
Pati
ents
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Pharmacogenomics of Antiplatelet Intervention Study (PAPI)7 days clopidogrelN=429 healthy Amish Platelet aggregometryGenome wide association study
JAMA. 2009;302(8):849-858
Carriers of the CYP2C19*2 genotype have higher cardiovascular Carriers of the CYP2C19*2 genotype have higher cardiovascular event rates compared with event rates compared with noncarriersnoncarriers
(20.9% vs 10.0%; hazard ratio [HR], 2.42; 95% CI, 1.18-4.99; P=.02)
CYP2C19 reducedreduced--functionfunction allele (CYP2C19*2) associated with 32% reduction in exposure to active metabolite of clopidogrel JAMA. 2009;302(8):849-858
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White population: 24% have at least 1 alleleMexican population: 18%African American population: 33%Asian population: 51%
FDA…The CYP2C19*2 and *3 alleles have no functional metabolism of Plavix.
GI absorption is limited by the P-glycoprotein efflux-transporter encoded by the adenosine triphosphate-binding cassette containing gene ABCB1, also known as the multidrug resistant (MDR1) gene
AMI populationPrimary EP (death, nonfatal MI, or stroke at 1 year)
Prospective, observational, single center, cohort studyN=1069All receive clopidogrel for PCI5 Tests
VerifyNOW P2y12Plateletworks assaysIMPACT-RPFA-100PFA P2YPrimary endpoint: all cause death, MI, thrombosis, stroke
JAMA. 2010;303(8):754-762
Platelet blockedHigh Reactivity0
5
10
15
6 5.7 6.1
11.7 13.3 12.6
% of Patients - Primary EP
All p<0.001
VerifyNow and Plateletworks good in post stent patients preds events JAMA 303- 754 Werkum.pdf
Amish studyPatients with the CYP2C19*2 variant (reduced function) were more likely (20.9% vs 10.0%) to have a CV ischemic event or death during 1 year of follow-up
Other studies support the clinical importance of risk allele CYP2C19*2Loss of function genotype varies in different ethic groupsCombination of both ABCB1 polymorphism with CYP2C19*2 increases risk for CV event 5X
Clopidogrel-CYP2C19*2 reduced function allele (drug not metabolized to active form). 150 mg qd increase cost to level higher than prasugrel
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Prasugrel..TRITON-TIMI 38 trial-FDA approvedTicagrelor..PLATO trial pending FDA approval
Contra-indication /caution by FDA-History of transient ischemic attack or stroke
75 years of age<60 kg
Prasugrel
Double-blind, randomized phase III
Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-2015.
13,608 patientsACS (STEMI/NSTE ACS) and planned PCI
Treatment duration: 6–15 mo
Aspirin75–162 mg
•1° composite endpoint: CV death/nonfatal MI/nonfatal stroke•2° endpoints at 30 and 90 days: composite of CV death/nonfatal MI/nonfatal
stroke, composite of CV death/nonfatal MI/urgent target vessel revascularization (uTVR)
150-mg dose of dabigatran was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage N Engl J Med 2009;361:1139-51
Risk factors and inflammation increases prothrombotic cardiovascular risk
Oral P2Y12 inhibitors have very different actions, but all work if platelets are inhibitedIV 2b/3a inhibitors: 7E3 is reversible with platelets
Atrial fibrillation patients: dabigatran (first direct oral thrombin inhibitor) was associated with lower rates of stroke and systemic embolism but with a similar rate of major hemorrhage to warfarin