The authors have declared that no competing interests exist.
Conceived and designed the experiments: JS JX XC. Performed the experiments: XL HZ JH. Analyzed the data: JS JX. Contributed reagents/materials/analysis tools: XL HZ JH RF. Wrote the paper: JS XC. Designed the software used in analysis of HWE: JX.
A number of investigators have evaluated the association between the
We performed a systematic search of PubMed, Scopus and the Cochrane library database for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated by the meta-analysis.
It was demonstrated that the ABCB1 C3435T variation was associated with the risk of early major adverse cardiovascular events (MACE) (T vs. C OR, 1.34; 95% CI, 1.10 to 1.62;
The evidence from our meta-analysis indicated that the
Clopidogrel inhibits the adenosine-diphosphate-induced platelet aggregation, reducing the cardiovascular complications in patients with coronary atherosclerotic heart disease (CAD), especially in those undergoing percutaneous coronary intervention (PCI)
The
Antiplatelet response could be investigated through poor clinical outcomes and impaired response to antiplatelet therapy in the laboratory test. Simon
First author | year | ethnicity | population studied | treatment protocal | definition of case | case | control | HWE | ||||
CC | CT | TT | CC | CT | TT | |||||||
Spiewak, M. |
2009 | NA | ACS treated with PCI | LD aspirin 300 mg clopidogrel (300 mg or 600 mg)MD aspirin 75 mg clopidogrel 75 mg qd | collagen/adenosine diphosphate (CADP)-CT<130s | 4 | 16 | 10 | 23 | 34 | 11 | 0.791 |
Kim, I. S. |
2012 | Asian | Patients treated with PCI | cilostazol 100 mg bid, clopidogrel 75 mg and aspirin 200 mg qd | 5 mol/l ADP-induced maximal PR (Aggmax)>46%. | 7 | 4 | 1 | 45 | 58 | 12 | 0.287 |
Jeong, Y. H. |
2010 | Asian | AMI treated with coron ary angiography or PCI | MD clopidogrel 150 mg aspirin 200 mg qd | 5 mol/l ADP-induced maximal PR (PRmax)>50%. | 13 | 14 |
56 |
55 |
15 |
0.791 | |
Jeong, Y.H. |
2011 | Asian | AMI treated with PCI | LD aspirin 300 mg clopidogrel 600 mgMD aspirin 100–200 mg clopidogrel 75 mg | 20 mol/L ADP-induced maximal PR(PRmax)>59% | 64 | 54 | 16 | 60 | 54 | 18 | 0.303 |
LD: loading dose; MD: maintenance dose; HWE: Hardy-Weinberg equilibrium.
the number is consisted of CT and TT.
the number is consisted of case group and control group.
First author | Year | ethnicity | Male gender,No. (%) | Hypertension, No. (%) | Diabetes,No. (%) | Hypercholester-olemia No. (%) | Previous or current smoker, No. (%) | Total | HWE | ||
CC | CT | TT | |||||||||
Mega, J. L. |
2010 | Caucasian(97.6) | 1040(70.7) | 1903(64.9) | 321(21.8) | 1424(48.6) | 560(38.1) | 330 | 727 | 414 | 0.750 |
Simon, T. |
2009 | NA | 1559(70.6) | 1280(58.0) | 698(31.6) | 1088(49.3) | 1206(54.6) | 564 | 1050 | 574 | 0.060 |
Spiewak, M. |
2009 | NA | 69(70.4) | 52 (53.1) | 17(17.3) | 35 (35.7) | 43 (43.9) | 26 | 44 | 18 | 0.938 |
Wallentin, L. |
2010 | Caucasian (98) | 3571 (69.0) | NA | 1189 (23) | NA | 3099(60.2) | 1195 | 2518 | 1386 | 0.434 |
Tiroch, K. A. |
2010 | NA | 694(74.8) | 691(74) | 224(24.1) | 482(52) | 339(36.5) | 203 | 457 | 268 | 0.755 |
Campo, G. |
2011 | NA | 231(77) | 215 (72) | 71(23.7) | 153 (51) | 71(23.7) | 69 | 157 | 74 | 0.416 |
Delaney, J. T. |
2012 | Caucasian | 440(63.5) | 560(80.8) | 241(34.8) | 643(92.8) | 419(60.5) | 173 | 336 | 179 | 0.543 |
Wang, X. D. |
2012 | Asian | 361(67.4) | 305(56.9) | 273(50.9) | 295(55.0) | 186(34.7) | 364 | 161 | 11 | 0.478 |
Jeong, Y. H. |
2011 | Asians | 195 (73.3) | 125 (47.0) | 70 (26.3) | 71 (26.7) | 141 (53.0) | 124 | 108 | 34 | 0.216 |
Jaitner, J. |
2012 | Caucasian | 1180(77.4) | 1362(89.4) | 430(28.2) | 1068(70.1) | 207(13.6) | 444 | 740 | 340 | 0.342 |
NA, not applicable.
First author | Year | Population studied | Treatment protocal | Study period | The poor outcomes |
Mega, J. L. | 2010 | ACS treated with PCI | LD clopidogrel 300 mg | 15 months | stent thrombosis |
MD clopidogrel 75 mg qd | major or minor bleeding | ||||
MACE (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) | |||||
Simon, T. | 2009 | AMI treated withcoronary angiography or PCI | LD clopidogrel 300 mg aspirin(98%) | 12 months | outcome event (Death,nonfatal myocardial infarction or stroke) |
Spiewak, M | 2009 | ACS treated with PCI | LD aspirin 300 mg clopidogrel(300 mg or 600 mg) | 1.7 years | cardiovascular deaths and non-fatal myocardial infarction |
MD aspirin 75 mg clopidogrel75 mg qd | |||||
Wallentin, L. | 2010 | Acute coronarysyndrome. | LD clopidogrel 300–600 mg, | 12 months | Cardiovascular death, myocardial infarction, and stroke, |
MD clopidogrel 75 mg qd aspirin (96%) | Definite stent thrombosis | ||||
Major bleeding | |||||
Tiroch, K. A. | 2010 | AMI treated withcoronary angiography | LD clopidogrel 600 mg | 12 months | MACE(including death, MI, TLR, and stroke) |
MD aspirin 100 mg bid clopidogrel 75 mg qd | Stent thrombosis | ||||
Campo, G. | 2011 | Ischemic heart disease underwent PCI | LD aspirin 300 mg clopidogrel 600 mg | 12 months | Ischemic adverse events(Death, MI, stroke, stent thrombosis) |
MD aspirin 300 mg clopidogrel75 mg qd | minor or major bleedings | ||||
Delaney, J. T. | 2012 | MI or treated with PCI | Clopidogrel not applicable | 12–24 months | Primary endpoint cardiovascular events(all-cause mortality, MI, stroke, revascularization, and stent thrombosis) |
Wang, X. D. | 2012 | Patients treatedwith PCI | LD aspirin 100 mg clopidogrel 300 mg | 1 month | Major or Minor bleeding |
MD aspirin 100 mg clopidogrel75 mg qd | Early definite stent thrombosis | ||||
MACE(included cardiovascular death, stent thrombosis, recurrent acute coronary syndrome) | |||||
Jeong, Y. H. | 2011 | AMI treated withcoronary angiography or PCI | LD aspirin 300 mg clopidogrel 600 mg | 12 months | major or minor bleeding |
MD aspirin 100–200 mg clopidogrel 75 mg qd | MACE (cardiovascular death, nonfatal myocardial infarction, and ischemic stroke) | ||||
Jaitner, J. | 2012 | Patients treatedwith PCI | LD aspirin 500 mg clopidogrel 600 mg | 14 months | stent thrombosis |
MD Aspirin 100 mg bid, clopidogrel 75 mg bid*3d then 75 mg qd |
LD: loading dose; MD: maintenance dose; HWE: Hardy-Weinberg equilibrium.
T | C | TT | CC | TT | CT+CC | TT+CT | CC | |||||||||
first author | event | total | event | total | event | total | event | total | event | total | event | total | event | total | event | total |
Wallentin 2010 |
507 | 5290 | 509 | 4908 | 137 | 1386 | 138 | 1195 | 137 | 1386 | 371 | 3713 | 370 | 3904 | 138 | 1195 |
Simon 2009 |
318 | 2198 | 262 | 2178 | 85 | 574 | 57 | 564 | 85 | 574 | 205 | 1614 | 233 | 1624 | 57 | 564 |
Mega 2010 |
158 | 1555 | 106 | 1387 | 52 | 414 | 26 | 330 | 52 | 414 | 80 | 1057 | 106 | 1141 | 26 | 330 |
Campo 2011 |
28 | 305 | 14 | 226 | 8 | 74 | 1 | 69 | 8 | 74 | 13 | 226 | 20 | 231 | 1 | 69 |
Tiroch 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 22 | 725 | 63 | 203 |
Spiewak 2009 |
12 | 80 | 8 | 96 | 3 | 18 | 1 | 26 | 3 | 18 | 7 | 70 | 9 | 62 | 1 | 26 |
Jeong 2011 |
7 | 176 | 19 | 356 | 1 | 34 | 7 | 124 | 1 | 34 | 12 | 232 | 6 | 142 | 7 | 124 |
first author | T | C | TT | CC | TT | CT+CC | TT+CT | CC | ||||||||
event | Total | event | total | event | total | event | total | event | total | event | total | event | total | event | total | |
Simon 2009 |
160 | 2198 | 128 | 2178 | 41 | 574 | 25 | 564 | 574 | 41 | 1614 | 103 | 1624 | 119 | 564 | 25 |
Mega 2010 |
102 | 1555 | 62 | 1387 | 35 | 414 | 15 | 330 | 414 | 35 | 1057 | 47 | 1141 | 67 | 330 | 15 |
Wang 2012 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 172 | 5 | 364 | 15 |
first author | T | C | TT | CC | TT | CT+CC | TT+CT | CC | |||||||||||
event | total | event | total | event | total | event | total | event | total | event | total | event | total | event | total | ||||
Mega 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | 48 | 414 | 70 | 1057 | NA | NA | NA | NA | |||
Campo 2011 |
18 | 305 | 8 | 295 | 5 | 74 | 0 | 69 | 5 | 74 | 8 | 226 | 13 | 231 | 0 | 69 | |||
Tiroch 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 16 | 725 | 6 | 203 | |||
Wang 2012 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 2 | 172 | 7 | 364 | |||
Delaney 2012 |
33 | 694 | 43 | 682 | 6 | 179 | 11 | 173 | 6 | 179 | 32 | 509 | 27 | 515 | 11 | 173 |
first author | T | C | TT | CC | TT | CT+CC | TT+CT | CC | ||||||||
event | total | event | total | event | total | event | total | event | total | event | total | event | total | event | total | |
Wallentin 2010 |
41 | 5290 | 35 | 4908 | 13 | 1386 | 10 | 1195 | 13 | 1386 | 25 | 3713 | 28 | 3904 | 10 | 1195 |
Mega 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | 2 | 414 | 3 | 1057 | NA | NA | NA | NA |
Campo 2011 |
2 | 305 | 2 | 295 | 1 | 74 | 1 | 69 | 1 | 74 | 1 | 226 | 1 | 231 | 1 | 69 |
Tiroch 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 7 | 725 | 1 | 203 |
Delaney 2012 |
1 | 694 | 1 | 682 | NA | NA | NA | NA | 0 | 179 | 1 | 509 | 1 | 515 | 0 | 173 |
first author | T | C | TT | CC | TT | CT+CC | CT+TT | CC | ||||||||
event | total | event | total | event | total | event | total | event | total | event | total | event | total | event | total | |
Mega 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | 5 | 414 | 8 | 1057 | NA | NA | NA | NA |
Campo 2011 |
8 | 305 | 4 | 295 | 2 | 74 | 0 | 69 | 2 | 74 | 4 | 226 | 6 | 221 | 0 | 69 |
Tiroch 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 47 | 725 | 17 | 203 |
Delaney 2012 |
12 | 694 | 16 | 682 | 4 | 179 | 6 | 173 | 4 | 179 | 10 | 509 | 8 | 515 | 6 | 173 |
first author | T | C | TT | CC | TT | CT+CC | TT+CT | CC | ||||||||
event | total | event | total | event | total | event | total | event | total | event | total | event | total | event | total | |
Wallentin2010 |
56 | 3487 | 62 | 3239 | 14 | 917 | 17 | 793 | 14 | 917 | 45 | 2446 | 42 | 2570 | 17 | 793 |
Mega 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | 5 | 392 | 12 | 1004 | NA | NA | NA | NA |
Campo 2011 |
6 | 305 | 2 | 295 | 2 | 74 | 0 | 69 | 2 | 74 | 2 | 226 | 4 | 231 | 0 | 69 |
Tiroch 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 7 | 725 | 3 | 203 |
Wang 2012 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 1 | 172 | 5 | 364 |
Delaney 2012 |
7 | 694 | 15 | 682 | 1 | 179 | 5 | 173 | 1 | 179 | 10 | 509 | 6 | 515 | 5 | 173 |
Jaitner 2012 |
69 | 1420 | 63 | 1628 | 19 | 340 | 16 | 444 | 19 | 340 | 47 | 1184 | 50 | 1080 | 16 | 444 |
first author | T | C | TT | CC | TT | CT+CC | TT+CT | CC | ||||||||
event | total | event | total | event | total | event | total | event | total | event | total | event | total | event | total | |
Wallentin 2010 |
519 | 5272 | 477 | 4884 | 137 | 2508 | 116 | 1188 | 137 | 1382 | 361 | 3696 | 382 | 3890 | 116 | 1188 |
Mega 2010 |
NA | NA | NA | NA | NA | NA | NA | NA | 15 | 414 | 26 | 1052 | NA | NA | NA | NA |
Campo 2011 |
16 | 305 | 22 | 335 | 4 | 157 | 7 | 69 | 4 | 74 | 15 | 226 | 12 | 231 | 7 | 69 |
Jeong 2011 |
5 | 176 | 11 | 356 | 1 | 108 | 4 | 124 | 1 | 34 | 7 | 232 | 4 | 142 | 4 | 124 |
Wang 2012 |
NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | 10 | 172 | 20 | 364 |
NA, not applicable.
Three electronic databases (PubMed, Scopus and the Cochrane library) were searched (the last search was updated in March 2012 with the following terms combined: antiplatelet, clopidogrel, aspirin, platelet activity,
Comparison: TT+TC vs. CC.
T vs. C | TT vs. CC | TT vs. CC + CT | CT + TT vs.CC | |||||||||
Variables | OR(95%CI) |
|
|
OR(95%CI) |
|
|
OR(95%CI) |
|
|
OR(95%CI) |
|
|
Platelet activity | 1.06 (0.53, 2.13) | 0.02 | 0.86 | 1.36 (0.35, 5.30) | 0.05 | 0.66 | 1.20 (0.69, 2.08) | 0.19 | 0.53 | 1.01 (0.51, 1.97) | 0.07 | 0.99 |
MACE | 1.16 (0.94, 1.45) | 0.01 | 0.17 | 1.39 (0.86, 2.24) | 0.007 | 0.18 | 1.26 (0.98, 1.63) | 0.01 | 0.08 | 1.09 (0.77, 1.54) | 0.008 | 0.62 |
LD 600 mg | 1.13 (0.55, 2.29) | 0.19 | 0.74 | 2.05 (0.13, 31.97) | 0.07 | 0.61 | 1.48 (0.51, 4.29) | 0.27 | 0.47 | 1.06 (0.43, 2.64) | 0.12 | 0.09 |
LD 300 mg | 1.28 (1.10, 1.48) | 0.53 | 0.001 | 1.59 (1.19, 2.13) | 0.79 | 0.002 | 1.42 (0.98, 2.06) | 0.01 | 0.07 | 1.39 (1.08, 1.79) | 0.43 | 0.01 |
others | 1.09 (0.61, 1.93) | 0.16 | 0.78 | 1.24 (0.32, 4.88) | 0.17 | 0.76 | 1.00 (0.81, 1.22) | 0.48 | 0.99 | 1.20 (0.32, 4.56) | 0.15 | 0.79 |
MACE early | 1.34 (1.10, 1.62) | 0.39 | 0.003 | 1.77 (1.19, 2.63) | 0.70 | 0.005 | 1.47 (0.85, 2.56) | 0.06 | 0.17 | 1.48 (1.06, 2.06) | 0.48 | 0.02 |
MI | 0.81 (0.55, 1.18) | 0.53 | 0.27 | 1.78 (0.08, 39.04) | 0.04 | 0.72 | 1.26 (0.54, 2.93) | 0.03 | 0.59 | 0.95 (0.57, 1.58) | 0.38 | 0.84 |
Stroke | 1.08 (0.70, 1.67) | 0.99 | 0.73 | 1.11 (0.50, 2.44) | 0.90 | 0.8 | 1.46 (0.80, 2.66) | 0.94 | 0.22 | 1.03 (0.54, 1.96) | 0.73 | 0.93 |
All-cause mortality | 0.98 (0.52, 1.83) | 0.18 | 0.94 | 0.96 (0.32, 2.88) | 0.23 | 0.94 | 1.39 (0.67, 2.88) | 0.91 | 0.38 | 0.75 (0.46, 1.23) | 0.31 | 0.25 |
Thrombosis | 0.97 (0.61, 1.53) | 0.06 | 0.88 | 1.60 (0.96, 2.68) | 0.14 | 0.07 | 1.06 (0.74, 1.52) | 0.34 | 0.75 | 0.90 (0.63, 1.28) | 0.42 | 0.56 |
Bleeding | 1.00 (0.88, 1.13) | 0.76 | 0.98 | 0.51 (0.40, 0.66) | 0.39 | <0.001 | 1.06 (0.87, 1.28) | 0.72 | 0.58 | 0.98 (0.80, 1.20) | 0.55 | 0.83 |
The studies that met the following criteria were included: (1) published in English, (2) case- control studies on platelet activity and prospective cohort studies on clinical outcomes, (3) the evaluation of the
Comparison: TT+TC vs. CC.
Two reviewers independently extracted the data and reached a consensus on all items. The following information was achieved from each study: the first author’s name, publication date, ethnicity, population studied, characteristic of target population, treatment protocal,definition of cases, poor outcomes, study period and gene information, respectively.
Comparison: TT+TC vs. CC.
The two parts of endpoints (high platelet activity and poor clinical outcomes) were studied. The poor clinical outcomes included major adverse cardiovascular events (MACE) which were composed of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, as well as all-cause mortality, MI, stroke, definite or probable stent thrombosis and major or minor bleeding.
Comparison: TT+TC vs. CC.
The observed genotype frequencies in controls or entire cohorts were tested to compare with the expected genotype frequencies by Hardy-Weinberg equilibrium (HWE). Crude odds ratio (OR) with 95% confidence interval (CI) in each study was used to assess the strength of association between
Comparison: TT+TC vs. CC.
Subgroup analyses were applied to identify the heterogeneity. Sensitivity analyses were conducted by sequential omission of individual studies respectively to detect the potential influence of each study set to the pooled ORs. In addition, publication bias was carried out by the funnel plot, and the symmetry of the plot distribution indicated the absence of publication bias
Comparison: TT+TC vs. CC.
A total of 113 studies on the
Comparison: TT+TC vs. CC.).
When four eligible studies were pooled, the association between platelet high activity and the
Comparison: (1) TT+TC vs. CC;(2) TT vs. CC.
The major adverse cardiovascular events (more than one year) had no significant association with
(A) platelet activity (Begg’s test,
The effect of the
Three studies provided data (MACE happened in about one month), and the heterogeneity was low for all comparisons except for that of TT vs. CC + CT (I2 = 72%;
Myocadial infarction in the five cohort studies included in the primary analysis was 5.10% (200 of the 3923 patients). The summary ORs showed no association between
The ischemic stroke rate in the five cohort studies was 0.69% (54 of the 7858). As described in
A total of 97 deaths (four trials, 3387 total patients) occurred during follow-up. When all eligible studies were pooled, the association between all-cause and the
Seven cohort studies reported stent thrombosis data (1.97%, 173 of the 8775). The cumulative incidence of stent thrombosis was not associated with
The bleeding rate in the five cohort studies was 7.82% (596 of the 7619). The comparison of TT vs. CC was associated with a significant reduction in the outcome of bleeding (TT vs. CC: OR, 0.51; 95% CI, 0.40 to 0.66;
In platelet activity studies, there was significant heterogeneity in three genetic contrasts of the
Furthermore, significant heterogeneity existed in all the four genetic models of the
In addition, the heterogeneity existed in allele comparison with regard to stent thrombosis (
Although we also found the heterogeneity in two genetic model contrasts of Myocadial infarction and one genetic model contrast of early MACE (
Sensitivity analysis was performed in the
Funnel plot as well as Begg’s and Egger’s tests were carried out to access the publication bias of studies. Data showed that there was no evidence of publication bias in comparison of TT+TC vs. CC (
Clopidogrel, as a pro-drug, was known to require metabolic activation before inhibiting platelet aggregation. The
In the present meta-analysis, since we included newer studies
Four studies
Clopidogrel inhibits the platelet activity, and high platelet activity in patients treated with Clopidogrel indicates clopidogrel resistance or poor response to clopidogrel, which will lead to poor clinical outcome in the future. Though we have found some association between
Besides, from the different aspirin doses or triple antiplatelet therapy our studies included, we believe that interaction between gene and drug combination may also exist. Prolonged use of aspirin may reduce the intestinal absorption of clopidogrel by inducing the expression of
Although considerable efforts have been put into the test, there are some limitations inherent in the study. First, the number of studies included are limited, especially for the information on the risk of MACE in patients treated with clopidogrel LD 300 mg and the outcome of bleeding. Thus the conclusion about these should be considered with caution. Second, detailed information such as the ethnicity and other main characteristic are not available in some studies, which further limit our evaluation. Third, gene-gene or gene-environment interaction, different loading or maintenance dose, influence from main clinical characteristics, standardized unbiased platelet activity evaluation and genotyping methods may affect the results. These variables can be planned more effectively by a separate analysis of these elements, to which we did not have access.
In summary, our meta-analysis indicated that the
(DOC)
We are very grateful and thank Dr. Jessica Tod Delaney and Dr. Gianluca Campo providing additional information and data on their studies. We also thank all the participants in this study.