Search methods and selection criteria

Two reviewers (CJ and HD) independently performed electronic searches for CYP2C19 polymorphism and clopidogrel in PubMed/Medline, EMBASE and the Cochrane Library, with the following search strategy “(clopidogrel) and (P450 2C19 OR CYP2C19) and (coronary heart disease or coronary artery disease)”, from their inception through to February 2013. The language was restricted to English or Chinese. The selection criteria for eligible studies were as follows: study type (prospective cohort studies or post-hoc analyses of randomized controlled trials); participants (coronary artery disease patients treated with clopidogrel); definite clinical endpoints (fatal or non-fatal myocardial infarction [MI], cardiovascular death, all-cause death, definite or probable stent thrombosis [ST], target lesion revascularization [TLR], target vessel revascularization [TVR], urgent revascularization, ischaemic stroke and bleeding); genotyping (loss-of-function genotypes [CYP2C19*2–*8], especially CYP2C19*2, should be detected in the studies); comparison (comparison of the outcomes between mutant gene carriers and non-carriers). Meeting abstracts, case reports, editorials and reviews were excluded.

Data extraction and quality assessment

Data extraction was completed by two investigators (LM and LC), independently. Study type, country, population characteristics, number of patients, mean age, clopidogrel dose, combination of aspirin, genotyping method, genotype distribution, length of follow-up, study endpoints, number of each event, adjustment for confounding factors and conclusions were collected. Any occurrence of events, such as fatal or non-fatal MI, cardiovascular or all-cause death, definite or probable ST, TVR, TLR, urgent revascularization, ischaemic stroke or bleeding, was considered to be an adverse clinical outcome in our meta-analysis. Disagreements were resolved by discussion between the two investigators.

The Newcastle-Ottawa quality assessment scale was used to assess the quality of the included studies . This scale consists of three categories: selection (representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure and demonstration that the outcome of interest was not present at the start of the study); comparability (comparability of cohorts on the basis of the design or analysis); and outcome (assessment of outcome, follow-up long enough for outcomes to occur, adequacy of follow-up of the cohorts). The highest score that a study can be awarded is nine.

Statistical analysis

In this article, the P value was set at 0.10 for heterogeneity tests and at 0.05 for others. All the P values were two-tailed. Cochran’s Q test and I ² were used to investigate heterogeneity; the funnel plot analysis was used to evaluate publication bias. I ² values > 25%, > 50% and > 75% were considered as evidence of low, moderate and severe statistical heterogeneity, respectively. If I ² was > 50% or P was < 0.10, a random-effect model was chosen. Accordingly, we ran a fixed-effect model if I ² was < 50% or P was > 0.10. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association between cytochrome CYP2C19 polymorphism and clinical prognosis. All statistical tests were performed with Review Manager 5.1 for Windows, available from the Cochrane Collaboration.

Study selection

A total of 421 relevant publications were evaluated initially. Finally, 21 studies met the inclusion criteria . The study selection flow diagram is shown in Fig. 1 . In total, 23,035 patients were included in this meta-analysis. Among these patients, 7670 were carriers of the CYP2C19 variant allele (mostly CYP2C19*2); the other 15,365 patients were non-carriers. Eight studies were from Asia and thirteen were from Europe or the USA. The loading dose of clopidogrel was 300 mg or 600 mg in 18 studies and all the participants were given a maintenance dose of 75 mg/day. The TaqMan (Applied Biosystems, Foster City, CA, USA) polymerase chain reaction (PCR) was chosen as the genotyping method in 61.9% of the studies. The length of follow-up ranged from 1 month to 4 years. Study characteristics are reported in Table 1 .

Flow diagram of the systematic review process.

Table 1

Main characteristics of all the studies included in the meta-analysis.

Study	Year	Country	Study population	Age (years)	C arriers/non-carriers ( n / n )	Clopidogrel dose (LD→MD)	Follow-up (months)	Endpoints	Genotyping method	Genetic variant	NOS
Nishio et al.	2012	Japan	PCI	69.8	100/60	300 mg → 75 mg/day	21.5	Death, ST, MI, TLR	TaqMan PCR	*2, *3	9
Peng et al.	2013	China	CAD	64.9	271/235	300 mg → 75 mg/day	12	Non-fatal MI, death, stroke, revascularization	TaqMan PCR	*2	9
Trenk et al.	2008	Germany	Elective PCI	66.3	245/552	600 mg → 75 mg/day	12	RPA, death, non-fatal MI	TaqMan PCR	*2	9
Harmsze et al.	2010	Netherlands	PCI	62.7	193/403	NA	12	ST	PCR	*2, *3	8
Tang et al.	2012	China	PCI	58.9	384/286	300 mg → 75 mg/day	12	Cardiovascular death, MI, TVR, ST	LDR	*2, *3, *17	9
Bouman et al.	2011	Germany	CAD + PCI	61.2	37/75	600 mg → 75 mg/day	18	ST	TaqMan PCR	*2	9
Sawada et al.	2011	Japan	PCI	69.6	42/58	300 mg → 75 mg/day	18.2	ST, death, MI, TVR	TaqMan PCR	*2	7
Pare et al.	2010	Canada	NSTE-ACS	63.8	650/1880	300 mg → 75 mg/day	12	Death, non-fatal MI, stroke	TaqMan PCR	*2, *3	9
Yamamoto et al.	2010	Japan	Stable CHD	68.6	62/36	300 mg → 75 mg/day	12	Death, non-fatal MI, ischaemic stroke	PCR	*2, *3	8
Giusti et al.	2009	Italy	ACS + PCI	NA	247/525	600 mg → 75 mg/day	6	ST	PCR	*2	9
Collet et al.	2009	France	MI	40.1	73/186	NA → 75 mg/day	> 48	Death, non-fatal MI, urgent revascularization	TaqMan PCR	*2	9
Shuldiner et al.	2009	America	Elective PCI	65.1	67/158	600 or 300 mg → 75 mg/day	12	MI, stroke, ST, death	SNPlex a	*2	9
Wallentin et al.	2010	America, Europe	ACS	62.5	1388/3516	600 or 300 mg → 75 mg/day	12	Cardiovascular death, MI, stroke	TaqMan PCR	*2∼*8, *17	8
Tiroch et al.	2010	Germany	Acute MI	64.8	248/680	600 mg → 75 mg/day	12	TLR, death, MI	TaqMan PCR	*2, *17	9
Mega et al.	2009	America, Europe	ACS + PCI	60.1	395/1064	300 mg → 75 mg/day	15	Cardiovascular death, MI, stroke	PCR	*2	9
Sibbing et al.	2009	Germany	CAD + PCI	66.5	680/1805	600 mg → 75 mg/day	1	ST	TaqMan PCR	*2	8
Simon et al.	2009	France	Acute MI	66.2	617/1561	300–900 mg → 75 mg/day	12	Death, non-fatal MI, stroke	SNPlex a	*2∼*5, *17	8
Malek et al.	2008	Poland	ACS + PCI	60.0	21/84	300 or 600 mg → 75 mg/day	12	Death, MI	TaqMan PCR	*2	8
Tang et al.	2011	China	CHD + PCI	58.0	137/130	300 mg → 75 mg/day	12	Death, angina recurrence, MI, urgent revascularization, ST	MALDI- TOF MS	*2	9
Luo et al.	2011	China	CHD + PCI	70.8	802/936	300 mg → 75 mg/day	6	ST, death, MI, ischaemic stroke, bleeding	TaqMan PCR	*2	9
Oh et al.	2011	Korea	PCI	60.8	1011/1135	300 or 600 mg → 75 mg/day	12	Death, non-fatal MI, ST, TVR, TLR	TaqMan PCR	*2	9

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