Table 1.

Studies assessing genetic polymorphism and response to clopidogrel.

Reference	Subjects	Clopidogrel dose	Observed LoF polymorphic alleles	Outcomes
Barker et al. [95]	41 subjects with CAD who had received 75 mg MD for >7 days or <7 days following ≥300 mg LD	LD: ≥300 mg MD: 150 mg	CYP2C19∗2, ∗3, ∗4	Although no statistically significant relation between LoF alleles and high on-treatment platelet reactivity was found, authors observed a tendency toward diminished reduction of this factor in patients with two copies of the LoF allele
Bonello et al. [96]	411 patients with non-ST elevation ACS undergoing PCI	LD: 600 mg, tailored according to the VASP index	CYP2C19∗2	The VASP index significantly higher in carriers of at least one ∗2 allele
Bauer et al. [97]	1024 CLP pretreated patients with CAD undergoing elective coronary stenting	LD: 300 or 600 mg	CYP2C19∗2	Patients with the CYP2C19∗2 allele showed higher on-treatment platelet reactivity
Brandt et al. [59]	89 healthy subjects of predominantly Caucasian origin	LD: 300 mg	CYP2C19∗2 CYP2C9∗2, ∗3 CYP3A4∗1B CYP3A5∗2, ∗3 CYP1A2∗1D, ∗1F, ∗1L CYP2B6∗15A	Significant influence of CYP2C19∗2 and CYP2C9 LoF alleles was observed on poor CLP response (measured as IPA) as well as lower AUC and C max⁡ of the active metabolite. No association was found between other observed genetic variants and decreased response to CLP
Collet et al. [98]	110 patients from the CLOVIS-2 study	LD: 300 or 900 mg MD: 75 mg	CYP2C19∗2, ∗4	Lowest reduction in platelet aggregation and reduced pharmacokinetic response was associated with the presence of CYP2C19∗2 variant
Collet et al. [99]	259 patient aged <45 years who survived MI of mainly White European or North African origin	MD: ≥75 mg	CYP2C19∗2,∗3, ∗4	CYP2C19∗2 had a strong impact on cardiovascular outcomes expressed as cardiovascular death, MI, or urgent revascularization (adjusted hazard ratio 5.38)
Fontana et al. [100]	94 healthy subjects of Caucasian origin	LD: 300 mg MD: 75 mg	CYP2C19∗2 CYP3A4 (IVS10 + 12A)	Subjects with CYP2C19∗2 had lower reduction in platelet aggregation than wt (P = 0.001), whereas no association between pharmacodynamic effect and CYP3A4 (IVS10 + 12A) was observed
Frére et al. [48]	603 patients with non-ST elevation ACS	LD: 600 mg	CYP2C19∗2 CYP3A4∗1B	CYP2C19∗2 allele carriers had higher platelet reactivity to ADP and were more likely to be “nonresponders” (P = 0.03). CYP3A4∗1B did not influence either platelet reactivity or platelet response to CLP
Geisler et al. [101]	237 patients of Caucasian origin after implantation of stents owing to symptomatic CAD	LD: 600 mg MD: 75 mg	CYP2C19∗2, ∗3 CYP3A4∗1B CYP3A5∗3	Patients with at least one CYP2C19∗2 had an increased risk of developing high RPA (P < 0.0001). No significant association between CYP3A4∗1B and CYP3A5∗3 on RPA
Giusti et al. [102]	1472 patients with acute coronary syndrome	LD: 600 mg MD: 75 mg	CYP2C19∗2 CYP3A4 IVS10 + 12G > A	Only CYP2C19∗2 was associated with higher platelet reactivity after stimulation with ADP and arachidonic acid
Giusti et al. [103]	772 patients enrolled in the RECLOSE trial with acute coronary syndromes	LD: 600 mg MD: 75 mg	CYP2C19∗2	CYP2C19∗2 was an independent factor of stent thrombosis and a composite end point for stent thrombosis and cardiac mortality
Gladding et al. [104]	60 patients undergoing elective PCI enrolled in the PRINC study	LD: 600 or split 1200 mg MD: 75 or 150 mg	CYP2C19∗2, ∗4 CYP2C9∗2, ∗3 CYP3A5∗3	CYP2C19∗2 and ∗4 carriers had attenuated response to CLP. No other observed CYP450 polymorphism had a significant impact on platelet inhibition
Harmsze et al. [105]	428 patients undergoing coronary stent implantation either on chronic CLP maintenance therapy or receiving a LD of CLP	LD: 300 mg MD: 75 mg	CYP2C19∗2 CYP2C9∗2, ∗3 CYP3A4∗1B	Both CYP2C19∗2 and CYP2C9∗3 were associated with attenuated response to CLP and higher platelet reactivity. The modulating effect of CYP2C9∗3 was present only in patients receiving a 300 mg LD of CLP (10-fold increase of risk of poor response). Impact of CYP3A4∗1B genetic variant on response was not observed
Hochholzer et al. [106]	760 patients from EXCELSIOR study	LD: 600 mg MD: 75 mg	CYP2C19∗2	CYP2C19∗2 can be described as a predictor for high on-treatment RPA (P < 0.001)
Hulot et al. [107]	28 healthy subjects	MD: 75 mg	CYP2C19∗2, ∗3, ∗4, ∗5, ∗6 CYP3A5∗3 CYP2B6∗5 CYP1A2∗1F	Response to CLP (expressed as ADP-induced platelet aggregation) was strongly influenced by CYP2C19 genotype while other studied polymorphisms had no significant impact
Jinnai et al. [108]	30 patients of Japanese origin scheduled for PCI	LD: 300 mg MD: 75 mg	CYP2C19∗2, ∗3 CYP3A4 (IVS10 + 12G > A)	The IPA values of intermediate and poor metabolizers were significantly lower than that of extensive metabolizers (P = 0.04 and P = 0.02, resp.). No differences were found for the CYP3A4 allele
Kim et al. [109]	62 patients of CLP arm of ACCELAMI2C19 study of East Asian origin	LD: 600 mg MD: 150 mg	CYP2C19∗2, ∗3	Presence of LoF allele significantly affected platelet reactivity in a 30-day followup after 20 μmol/L ADP-induced LTA but not in 5 μmol/L ADP-induced LTA
Lee et al. [110]	387 patients after PCI of Korean origin undergoing DAT or TAT antiplatelet therapy	LD: 300 mg MD: 75 mg	CYP1A1∗2 CYP1A2 1545T > C CYP2C19∗2, ∗3 CYP3A4 (IVS7 + 268A > G), (IVS10 + 12G > A) CYP3A5∗3 CYP2J2 A > T (rs2046934)	Only CYP2C19∗3 allele was significantly more prevalent in the CLP-resistant group in both dual and triple antiplatelet therapy (P = 0.01)
Maeda et al. [111]	97 Japanese patients with CAD in CLP branch of the study	Data not shown	CYP2C19∗2, ∗3	Platelet aggregation significantly higher in poor and intermediate metabolizers
Mega et al. [63]	162 healthy subjects and 1477 patients with ACS from TRITON-TIMI 38 trial with planned PCI	LD: 300 mg MD: 75 mg	CYP2C19∗2A, ∗3, ∗4, ∗5A, ∗6, ∗8, ∗9, ∗10 CYP2C9∗2A, ∗3A, ∗6, ∗9, ∗11A, ∗12 CYP2B6∗6, ∗9, ∗13 CYP3A5∗2A, ∗3A, ∗3F, ∗6 CYP1A2∗1C, ∗1D, ∗1E	Carriers of the reduced-function allele of CYP2C19 and CYP2B6 tended to have lower exposure to the active metabolite of CLP. Difference was also observed in the pharmacodynamic effect expressed as reduction of maximal platelet aggregation. Moreover, CYP2C19 LoF alleles carriers had higher risk for MI, stroke, or death from cardiovascular causes. No association between other CYP450 genotypes and clinical outcomes was found
Oh et al. [112]	2146 patients of East Asian origin treated with PCI	LD: 300 or 600 mg MD: 75 mg	CYP2C19∗2	Carriers of CYP2C19∗2 had a higher on-treatment platelet reactivity (P < 0.001). Although presence of LoF allele had no significant impact on revascularization, MI, cardiac death, or MACE separately, composite hard outcome was higher in the carrier group (P = 0.009)
Park et al. [113]	114 patients of Korean origin diagnosed with ACS	MD: 75 or 150 mg	CYP2C19∗2, ∗3	Lower plasma concentrations of CLP in CYP2C19 LoF carriers compared to wt genotype (P = 0.0574)
Park et al. [114]	236 patients receiving DAT and 238 patients receiving TAT of East Asian origin	LD: 300–600 mg MD: 75 mg	CYP2C19∗2, ∗3	Carriers of LoF allele in DAT group had lower platelet inhibition as compared to the noncarriers but not in the TAT group
Pettersen et al. [115]	219 patients from the ASCET substudy with stable CAD	MD: 75 mg	CYP2C19∗2	Higher prevalence of CLP resistance was observed in CYP2C19∗2 carriers
Simon et al. [116]	2208 patient from the FAST-MI study	LD: 300 mg (mean) MD: 75 mg (mean)	CYP2C19∗2, ∗3, ∗4, ∗5 CYP3A5∗3	LoF alleles of CYP2C19 were associated with increased risk of death, MI, or stroke
Shuldiner et al. [117]	429 healthy Amish persons and 227 patients undergoing PCI	Amish: LD: 300 mg; MD: 75 mg for 6 days Patients: LD: 300 or 600 mg MD: 75 mg	Genome-wide study including SNP with allele frequency greater than 1%, including CYP2C19 ∗2, ∗3, ∗5	Higher platelet aggregation in CYP2C19∗2 carriers after therapy with clopidogrel (both Amish and patient groups) and higher cardiovascular event rate after 1-year followup in the patient group
Umemura et al. [118]	47 healthy subjects of Japanese origin	LD: 300 mg	CYP2C19∗2, ∗3	Intermediate and poor metabolizers had lower response to CLP and lower values of AUC and C max⁡ of CLP active metabolite than extensive metabolizers
Wallentin et al. [51]	5148 patients in the CLP arm of the PLATO trial	LD: 300–600 mg MD: 75 mg	CYP2C19∗2, ∗3, ∗4, ∗5, ∗6, ∗8	Higher rates of cardiovascular events at 30 days in carriers of LoF allele
Angiolillo et al. [119]	82 patients of Caucasian origin with stable CAD and 45 CLP-naive patients	LD: 300 mg MD: 75 mg	CYP3A4∗1B, IVS7 + 258A > G, IVS7 + 894C > T, IVS10 + 12G > A	IVS10 + 12G > A had an influence on platelet activation; however, it did not have effect on the platelet aggregation profile
Suh et al. [120]	32 healthy volunteers and 348 patients after coronary angioplasty with stent implantation of Korean origin	LD: 300 mg MD: 75 mg	CYP3A5∗3	In the healthy group, CYP3A5∗3 did not alter significantly platelet inhibition. In the patients group, atherothrombotic events occurred more frequently in carriers of CYP3A5∗3
Smith et al. [121]	Total 94 patients listed for elective PCI	LD: 300 or 600 mg MD: 75 mg	CYP3A5∗3	Studied variation did not significantly influence CLP antiplatelet response

ACS: acute coronary syndrome; ADP: adenosine diphosphate; AUC: area under the curve concentration versus time; CAD: coronary artery disease; CLP: clopidogrel; DAT: dual antiplatelet therapy; GoF: gene alleles coding an enzyme with gain of function; IPA: inhibition of platelet aggregation; LD: loading dose; LoF: gene alleles coding an enzyme with loss of function; LTA: light transmittance aggregometry; MD: maintenance dose; MI: myocardial infarction; PCI: percutaneous coronary intervention; RPA: residual platelet aggregation; SNP: single nucleotide polymorphism; TAT: triple antiplatelet therapy; VASP: vasodilator-stimulated phosphoprotein (from [42]).