Table 1.
Characteristics of included studies of effect of variants of the cytochrome P450 (CYP) 2C19 genotype on clinical efficacy of clopidogrel
| Study | Design | Diagnosis at entry | Demographics (mean (SD) unless stated otherwise) | Cardiovascular risk factors | Clopidogrel loading dose, treatment duration; aspirin comedication | No (%) of events | No (%) of participants with ≥1 allele; MAF | |
|---|---|---|---|---|---|---|---|---|
| Loss of function CYP2C19 (at least *2) | Gain of function CYP2C19*17 | |||||||
| Trenk,63 2008, Germany, single centre | Cohort, retrospective, 12 months | Stable and unstable angina (ACS 27.4%, PCI 100%, DES 36.5%) | n=797, 78.0% men, age 66.4 (9.1) years, BMI 27.7 (3.9) | Smoking 10.9%, hypertension 82.3%, dyslipidaemia NR, diabetes 24.8% | 600 mg, median 1 (range 1-6) months (1 month for BMS, 6 months for DES); 100% aspirin | MACE (death, MI), 24 (3.0%) | 245 (30.7%), (*2); 16.4% | ND |
| Malek,64 2008, Poland, single centre | Cohort, prospective, 12 months | ACS (STEMI 81.9%, PCI 100%, DES NR) | n=105, 70.5% men, age 60.0 years, BMI 27.6 | Smoking 44.8%, hypertension 50.5%, dyslipidaemia 34.3%, diabetes 17.1% | 300 or 600 mg, NR; 100% aspirin | MACE (CV death, MI), 6 (5.7%) | 21 (20.0%) (*2); 10.5% | ND |
| Mega,34 2009; US, Europe, Oceania, Africa; multicentre | Substudy of RCT, retrospective, 15 months | ACS (STEMI 29.2%, PCI 95%, DES 47%†) | n=1459, 70.5% men, age 60.1 (11.1) years, median BMI 28† | Smoking 38.1%, hypertension 65.8%, dyslipidaemia 49.1%, diabetes 21.8% | 300 mg, ≤15 months (median 14.5 months)†; 99% aspirin† | MACE (CV death, MI, stroke) 129 (8.8%); ST (definite and probable) 17 (1.2%) | 395 (27.1%) (*2,*3,*4,*5,*8); 14.8% | ND |
| Simon,65 2009, France, multicentre | Cohort, retrospective, 12 months | Acute MI (STEMI 53.2%, PCI 69.5%, DES NR) | n=2208, 70.6% men, age 66.2 years, BMI 27.2 | Smoking 54.6%†, hypertension 58.0%, dyslipidaemia 49.3%, diabetes 31.6% | <300-900 (mean 300) mg, NR; 98.4% aspirin | MACE (death, MI, stroke) 294 (13.3%) | 635 (28.8%) (*2,*3,*4,*5), MAF: 15.7% | 774 (35.8%), MAF: 20.2% |
| Collet,66 2009, France, multicentre | Cohort, retrospective, mean: 34.6 (maximum 96) months | MI (STEMI 78.8%, PCI 73.0%, DES 32.0%) | n=259, 92.3% men, age 40.1 (5.1), BMI 25.7 (3.8) | Smoking 56.0%, hypertension 20.1%, dyslipidaemia 54.0%, diabetes 10.4% | NR, median 13.0 (IQR 3.4-36.0) months; 97.3% aspirin | MACE (CV death, MI), 19 (7.3%);ST (definite), 12 (5.4%) | 73 (28.2%) (*2,*3,*4,*5,*6); 15.8% | ND |
| Sibbing,67 2009, Germany, single centre | Substudy of RCTs, retrospective, 1 month | Stable and unstable angina and NSTEMI (ACS 34%, PCI 100%, DES 25.1%) | n=2485, 78.3% men, age 66.5 (10.2) years, BMI 27.2 (3.9) | Smoking 16.2%, hypertension 62.9%, dyslipidaemia 48.5%, diabetes 35.5% | 600 mg, ≥1 month; >95% aspirin | MACE (death, MI) 173 (7.0%); ST (definite) 17 (0.7%) | 680 (27.4%) (*2); 14.6% | ND |
| Giusti,68 2009, Italy, single centre | Cohort, retrospective, 6 months | Stable angina and ACS (ACS 65.7% PCI 100%, DES 100%) | n=772, 74.6% men, age 69 (11) years‡, BMI NR | Smoking 34.4%, hypertension 65.4%, dyslipidaemia 59.7%, diabetes 22.2% | 600 mg, ≥6 months; 100% aspirin | MACE (CV death), 18 (2.3%); ST (definite) 11 (1.4%) | 247 (32.0%) (*2); 17.7% | ND |
| Sibbing,69 2010, Germany, single centre | Cohort, retrospective, 1 month | Stable angina and ACS (ACS 33.1%§, PCI 100%, DES 98.0%§) | n=1524, 77.4% men, age 67.4 years, BMI 27.5 | Smoking 13.6%, 91. hypertension 3%, dyslipidaemia 70.1%, diabetes 28.2% | 600 mg, NR; 99.1% aspirin§ | MACE (MI) 50 (3.3%); ST (definite and probable) 14 (0.9%) | ND | 622 (40.8%), MAF: 22.9% |
| Tiroch,70 2010, Germany, single centre | Cohort, prospective, 12 months | Acute MI (STEMI NR, PCI 97.5%, DES >90%) | n=928, 74.8% men, age 64.8 years, BMI 27.0 | Smoking 36.5%, hypertension 74.5%, dyslipidaemia 51.9%, diabetes 24.1% | 600 mg, ≥6 months; 97.4% aspirin | MACE (death, MI, stroke) 82 (8.8%); ST (definite and probable) 10 (1.1%) | 248 (26.7%) (*2); 14.4% | 363 (39.1%), MAF: 22.5% |
| Wallentin,18 2010; America, Europe, Oceania, Asia; multicentre | Substudy of RCT, retrospective, 12 months | ACS (STEMI 38%¶, PCI 60.8%¶, DES 18.9%¶) | n=4904, 69.4% men, age 62.5 (11.0) years, median BMI 27¶ | Smoking 35.5%, hypertension 65.1%¶, dyslipidaemia 46.7%¶, diabetes 23.1% | 300-600 mg, median 9.2 (IQR 6-12) months; 96.1% aspirin | MACE (CV death, MI, stroke) 481 (9.8%); ST (definite) 56 (1.7%) | 1388 (28.3%) (*2,*3,*4,*5,*6,*7,*8); 15.4% | NR (no association with efficacy outcome reported) |
| Pare,19 2010; America, Europe, Oceania; multicentre | Substudy of RCT (CURE), retrospective, 12 months | Unstable angina and NSTEMI (STEMI 0%, PCI 15.5%, DES 0%) | n=2530, 58.8% men, age 63.8 (11.0) years, BMI 27.7 (4.2) | Smoking 23.1%, hypertension 59.9%**, dyslipidaemia NR, diabetes 20.7% | 300 mg, mean 9 (range 3-12) months; >94% aspirin | MACE (CV death, MI, stroke) 230 (9.1%) | 650 (25.7%) (*2,*3); 14.1% | 999 (39.1%); NA |
| Harmsze,71 2010, Netherlands, multicentre | Case-control, retrospective, 12 months | Stable angina and ACS (ACS 40.1%, PCI 100%, DES 42.6%) | n=596, 79.0% men, age 62.7 (10.3) years, BMI 27.3 | Smoking 15.1%, hypertension 48.7%, dyslipidaemia 51.0%, diabetes 16.8% | NR, ≥ 12 months; 100% aspirin | ST (definite) 176 (29.5%)†† | 193 (32.4%) (*2); 18.3% | ND |
| Sawada,72 2010, Japan, single centre | Cohort, prospective, mean 8.1 (range 0.23 to 18.2) months | Stable angina and ACS (ACS 9.0%, PCI 100%, DES 100%) | n=100, 85.0% men, age 69.6 years, BMI 23.7 | Smoking 41.0%, hypertension 81.0%, dyslipidaemia 69.0%, diabetes 42.0% | 300 mg, ≥follow-up period; 100% aspirin | MACE (death, MI) 4 (4.0%) | 42 (42.0%) (*2); NA | ND |
| Bouman,20 2010a; Germany, Netherlands; multicentre | Case-cohort, prospective, 18 months | Stable angina and ACS (ACS 50.9%, PCI 100%, DES 40.2%) | n=7719, 79.5% men, age 61.2 (8.5) years, BMI 27.0 (3.2) | Smoking 34.8%, hypertension 55.4%, dyslipidaemia 51.8%, diabetes 25.9% | 300-600 mg, median 12 (range 6-12) months; 91.2% aspirin | ST (definite) 41 (0.5%) | 2394 (31.0%)‡‡ (*2,*3,*4,*5); 16.9% | ND |
| Bouman,20 2010b; Germany, Netherlands; multicentre | Cohort, prospective, 12 months | ACS (STEMI 38.6% PCI 100%, DES 30.9%) | n=1982, 71.3% men, age 62.1 (10.2) years, BMI 27.1 (4.2) | Smoking 35.8%, hypertension 62.7%, dyslipidaemia 55.4%, diabetes 24.3% | 600 mg, ≥12 months; 100% aspirin | MACE (CV death, MI, stroke) 216 (10.9%); ST (definite) 44 (2.2%) | 678 (34.2%) (*2,*3,*4,*5,*6,*7,*8); 18.8% | 747 (37.7%); 20.9% |
ACS=acute coronary syndrome; BMI=body mass index; CV death=cardiovascular death; DES=drug eluting stent; IQR=interquartile range; MACE=major adverse cardiovascular event; MAF=minor allele frequency; MI=myocardial infarction; ND=not determined; NR=not reported; NA=not available from reported data; NSTEMI=non-ST segment elevation myocardial infarction; PCI=percutaneous coronary intervention; RCT=randomised controlled trial; SD=standard deviation; ST=stent thrombosis; STEMI=ST segment elevation myocardial infarction; BMS=bare metal stent.
†In 6795 patients assigned to clopidogrel treatment.79
‡In 804 patients.80
§In 1608 patients.81
¶In 9291 patients assigned to clopidogrel treatment.82
**In 6259 patients assigned to clopidogrel treatment.83
††Because of case-control design percentage does not reflect proportion of events in population.
‡‡Genotype distribution extrapolated to total cohort.