Determinants to optimize response to clopidogrel in acute coronary syndrome

Figures & data

Figure 1 Mechanisms of clopidogrel response variability.

Figure 2 Mechanism of action of clopidogrel.

Abbreviations: ABCB1, ATP-binding cassette, sub-family B; MDR/TAP, member 1 gene coding for the P-glycoprotein involved in the clopidogrel intestinal absorption; CYP1A2 is cytochrome P450, family 1, subfamily A, polypeptide 2; CYP2B6, cytochrome P450, family 2, subfamily B, polypeptide 6; CYP2C19, cytochrome P450, family 2, subfamily C, polypeptide 19; CYP2C9, cytochrome P450, family 2, subfamily C, polypeptide 9; CYP3A4, cytochrome P450, family 3, subfamily A, polypeptide 4; P2Y12, purinergic receptor P2Y, G-protein coupled, 12.

Table 1 Association of CYP2C19*2 loss-of-function polymorphism with response variability to clopidogrel treatment in healthy subjects

Study	N subjects	Treatment	Functional evaluation	CYP2C19*2 carriers %	Association
Hulot et al^Citation35	28 Caucasian males	75 mg/day for 7 days	10 μM ADP-induced PA	28.6	Yes
Fontana et al^Citation96	94 Caucasians	300 mg the first day then 75 mg day^−1 for 7 days	20 μM ADP-induced PA	27.7	Yes
Brandt et al^Citation36	74 Caucasians (57 male/17 female)	300 mg	20 μM ADP-induced PA Active metabolite by LC + MS	25.8	Yes
Kim et al^Citation97	24 Koreans	300 mg the first day then 75 mg day^−1 for 7 days	5 μM ADP-induced PA PCC by LC + MS	66.6 (selected)	Yes
Umemura et al^Citation98	47 Japanese	300 mg	20 μM ADP-induced PA VASP ph Active metabolite by LC + MS	61.7	Yes
Mega et al^Citation40	162 (130 male/32 female)	300–600 mg ± 75 mg/day for 7 days	20 μM ADP-induced PA Active metabolite by LC + MS	34.0	Yes

Abbreviations: N, number; PA, platelet aggregation; LC + MS, liquid chromatography with tandem mass spectrometry; PCC, plasma concentrations of clopidogrel; VASPph, vasodilator-stimulated phosphoprotein phosphorylation.

Table 2 Association of CYP2C19*2 loss-of-function polymorphism with response variability to clopidogrel treatment in high risk vascular patients

Study	N subjects	Treatment	Functional evaluation	CYP2C19*2 carriers %	Association
Giusti et al^Citation37	1419 PCI + stent	600 mg LD + 75 mg/day maintaining	10 μM ADP-induced PA	31.4	Yes
Frere et al^Citation100	603 NSTE	600 mg LD	10 μM ADP-induced PA VASP ph ADP-induced P-selectin	27.6	Yes
Trenk et al^Citation38	797 PCI + stent	600 mg LD + 75 mg/day maintaining	5 μM and 20 μM ADP-induced PA ADP-induced P-selectin, activated GPIIa/IIIb, CD63, CD40L, CD41 (GPIIb)	30.7	Yes
Geisler et al^Citation101	237 PCI	600 mg LD + 75 mg/day maintaining	20 μM ADP-induced PA	26.0	Yes
Gladding et al^Citation102	60 PCI	600/1200 mg LD + 75/150 mg/day	VerifyNow^® P2Y12		Yes
Jinnai et al^Citation103	30 PCI Japanese	300 mg LD + 75 mg/day maintaining	5 μM ADP-induced PA	56.0	Yes

Abbreviations: N, number; PCI, percutaneous coronary intervention; LD, loading dose; PA, platelet aggregation; NSTE, non-ST elevation; VASPph, vasodilator-stimulated phosphoprotein phosphorylation state of whole blood-we performed a dual color flow cytometric assay; GPIIa/IIIb, glycoprotein IIa/IIIb (PAC-1); GPIIb, glycoprotein IIb.

Table 3 Association of CYP2C19*2 loss-of-function polymorphism with occurrence of major adverse cardiovascular events (MACE)

Study	N subjects	Treatment	Outcome (follow-up)	CYP2C19 alleles	Association
Trenk et al^Citation38	797 PCI + stent	600 mg LD + 75 mg/day maintaining	Death + MI (1 year)	*2	No
Simon et al^Citation39	2208 AMI (1535 PCI)	300 mg mean LD + 75 mg/day maintaining	Death + nonfatal stroke + MI (1 year)	Any two of *2, *3,*4, *5	Yes (HR = 1.98) Yes (HR = 3.58)
Mega et al^Citation40	1477 ACS	300 mg LD + 75 mg/day maintaining	Cardiovascular death + MI + stroke (15 months)	*2	Yes (HR = 1.53)
			ST (15 months)		Yes (HR = 3.09)
Collet et al^Citation41	259 MI (<45 years)	600 mg LD + 75 mg/day maintaining	Death + MI + coronary revascularization (6 months)	*2	Yes (HR = 3.69)
			ST (6 months)		Yes (HR = 6.02)
Giusti et al^Citation42	772 PCI + DES	600 mg LD + 75 mg/day maintaining	Cardiovascular death + ST (6 months)	*2	Yes (OR = 2.70)
			ST (6 months)		Yes (OR = 3.43)
Sibbing et al^Citation43	2485 PCI + stent	600 mg LD + 75 mg/day maintaining	ST (30 days)	*2	Yes (HR = 3.81)

Abbreviations: N, number; LD, loading dose; PCI, percutaneous coronary intervention; MI, myocardial infarction; AMI, acute myocardial infarction; ACS, acute coronary syndrome; ST, intra stent thrombosis; DES, drug-eluting stent; HR, hazard ratio; OR, odds ratio.

Figure 3 Proposed form to collect patient information for the algorithm estimating individual risk and best personalized therapeutic strategy.

Abbreviations: MI, myocardial infarction; LVEF, left ventricular ejection fraction; PPI, proton pump inhibitor; ADP-PA, platelet aggregation induced by ADP; AA-PA, platelet aggregation induced by arachidonic acid; collagen-PA, platelet aggregation induced by collagen.

HulotJSBuraAVillardECytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjectsBlood20061082244224716772608

 PubMed Web of Science ®Google Scholar

FontanaPHulotJSDe MoerloosePGaussemPInfluence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjectsJ Thromb Haemost200752153215517697139

 PubMed Web of Science ®Google Scholar

BrandtJTCloseSLIturriaSJCommon polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrelJ Thromb Haemost200752429243617900275

 PubMed Web of Science ®Google Scholar

KimKAParkPWHongSJParkJYThe effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistanceClin Pharmacol Ther20088423624218323861

 PubMed Web of Science ®Google Scholar

UmemuraKFurutaTKondoKThe common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjectsJ Thromb Haemost200861439144118532997

 PubMed Web of Science ®Google Scholar

MegaJLCloseSLWiviottSDCytochrome p-450 polymorphisms and response to clopidogrelN Engl J Med200936035436219106084

 PubMed Web of Science ®Google Scholar

GiustiBGoriAMMarcucciRCytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high risk vascular patientsPharmacogenet Genomics2007171057106418004210

 PubMed Web of Science ®Google Scholar

FrereCCuissetTMorangePEEffect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndromeAm J Cardiol20081011088109318394438

 PubMed Web of Science ®Google Scholar

TrenkDHochholzerWFrommMFCytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stentsJ Am Coll Cardiol2008511925193418482659

 PubMed Web of Science ®Google Scholar

GeislerTSchaeffelerEDipponJCYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantationPharmacogenomics200891251125918781853

 PubMed Web of Science ®Google Scholar

GladdingPWebsterMZengIThe pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trialJACC Cardiovasc Interv2008162062719463375

 PubMed Web of Science ®Google Scholar

JinnaiTHoriuchiHMakiyamaTImpact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in JapanCirc J2009731498150319531897

 PubMed Web of Science ®Google Scholar

SimonTVerstuyftCMary-KrauseMGenetic determinants of response to clopidogrel and cardiovascular eventsN Engl J Med200936036337519106083

 PubMed Web of Science ®Google Scholar

ColletJPHulotJSPenaACytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort studyLancet200937330931719108880

 PubMed Web of Science ®Google Scholar

GiustiBGoriAMMarcucciRRelation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosisAm J Cardiol200910380681119268736

 PubMed Web of Science ®Google Scholar

SibbingDStegherrJLatzWCytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary interventionEur Heart J20093091692219193675

 PubMed Web of Science ®Google Scholar