Clopidogrel 150 vs. 75 mg day−1 in patients undergoing percutaneous coronary intervention: a meta‐analysis
2011; Elsevier BV; Volume: 9; Issue: 4 Linguagem: Inglês
10.1111/j.1538-7836.2011.04216.x
ISSN1538-7933
AutoresPanpan Hao, M. X. Zhang, R. J. Li, Jun-Mo Yang, J. L. Wang, Y. G. Chen, Y. ZHANG,
Tópico(s)Lipoproteins and Cardiovascular Health
ResumoJournal of Thrombosis and HaemostasisVolume 9, Issue 4 p. 627-637 ORIGINAL ARTICLEFree Access Clopidogrel 150 vs. 75 mg day−1 in patients undergoing percutaneous coronary intervention: a meta-analysis P. P. HAO, P. P. HAO These authors contributed to this work equally.Search for more papers by this authorM. X. ZHANG, M. X. ZHANG These authors contributed to this work equally.Search for more papers by this authorR. J. LI, R. J. LI Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorJ. M. YANG, J. M. YANG Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorJ. L. WANG, J. L. WANG Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorY. G. CHEN, Y. G. CHEN Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorY. ZHANG, Y. ZHANG Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this author P. P. HAO, P. P. HAO These authors contributed to this work equally.Search for more papers by this authorM. X. ZHANG, M. X. ZHANG These authors contributed to this work equally.Search for more papers by this authorR. J. LI, R. J. LI Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorJ. M. YANG, J. M. YANG Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorJ. L. WANG, J. L. WANG Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorY. G. CHEN, Y. G. CHEN Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this authorY. ZHANG, Y. ZHANG Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, ChinaSearch for more papers by this author First published: 21 January 2011 https://doi.org/10.1111/j.1538-7836.2011.04216.xCitations: 6 Yu Guo Chen or Yun Zhang, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan 250012, China.Tel.: +86 531 82169307; fax: +86 531 82169524.E-mail: chen919085@yeah.net (Yu Guo Chen) or zhangyun@sdu.edu.cn (Yun Zhang) AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Summary. Background: Whether an increase in the daily oral maintenance dose of clopidogrel may improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) is still debated. Objectives: This meta-analysis aimed to estimate the relative effect of a 150- vs. 75-mg daily maintenance dosage of clopidogrel on clinical and laboratory end-points in patients undergoing PCI. Methods: We searched electronic and printed sources (up to 14 December 2010) for both randomized control trials and observational studies satisfying the predefined inclusion criteria. Results: We retrieved 12 reports of studies including a total of 23 814 patients. Clopidogrel, 150 mg day−1, was associated with significant reductions in major adverse cardiac and/or cerebrovascular events (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.48–0.94), myocardial infarction (OR, 0.72; 95% CI, 0.60–0.86), target vessel revascularization (OR, 0.27; 95% CI, 0.12–0.62) and stent thrombosis (OR, 0.64; 95% CI, 0.53–0.77) and decreased adenosine diphosphate-induced maximal platelet aggregation. However, as compared with 75 mg day−1, the 150-mg daily maintenance dosage significantly increased the risk of minor bleeding (OR, 1.21; 95% CI, 1.08–1.36). Conclusion: As compared with the currently recommended 75-mg day−1 maintenance dosage of clopidogrel, the 150-mg day−1 dosage can reduce major adverse cardiac and/or cerebrovascular events but may increase the risk of minor bleeding. Introduction Platelet activation and aggregation play an important role in ischemic complications occurring during or after percutaneous coronary intervention (PCI) [1]. Clopidogrel in association with aspirin is currently the reference antiplatelet strategy to improve clinical outcomes in patients with coronary artery disease undergoing PCI [2]. Clopidogrel is a thienopyridine compound that, after hepatic metabolization, inhibits adenosine diphosphate (ADP)-induced platelet aggregation by specific and irreversible blockade of the platelet P2Y12 receptor [3, 4]. It dose-dependently inhibits platelet aggregation and prolongs bleeding time [1, 5]. The benefits of clopidogrel pretreatment in patients undergoing PCI emphasize the value of early administration. The clopidogrel maintenance dosage of 75 mg daily was initially chosen because its biological effects were similar to those of ticlopidine, 250 mg twice daily [6]. A higher maintenance dose of clopidogrel was not selected for safety reasons, mostly risk of increased bleeding [1, 5]. However, a wide intra- and inter-individual variability of clopidogrel responsiveness has been reported [6-8], and inadequate dosing has been postulated as a pivotal factor accounting for suboptimal clopidogrel-induced antiplatelet effects [9]. Previous data have shown a loading dose of clopidogrel higher than 75 mg attenuating the response variability and improving clinical outcomes [6, 10-12]. Despite the short-term improvement in platelet response with high loading-dose regimens of clopidogrel, patients may continue to have elevated platelet reactivity in the maintenance phase of antiplatelet therapy. This observation has raised the hypothesis that an increased maintenance dose of clopidogrel may further enhance platelet inhibition and reduce the risk of major adverse cardiac and/or cerebrovascular events (MACE/MACCE). Without a large meta-analysis, the question of whether a higher maintenance dose regimen of clopidogrel should be selected after PCI has not been well addressed. Thus, we conducted a meta-analysis of results of studies comparing the efficacy and safety of clopidogrel, 150 vs. 75 mg day−1, in patients undergoing PCI. Methods Data sources, search strategy, and selection criteria We followed the PRISMA statement for conducting meta-analyses of intervention studies (http://www.prisma-statement.org). Relevant studies were identified by searching the following data sources (as of 14 December 2010): MEDLINE (Ovid), EMBASE, J-STAGE, the Cochrane Library (Cochrane Central Register of Controlled Trials), Global Health, International Pharmaceutical Abstracts, ISI Web of Science, the China National Knowledge Internet, and the grey literature (SIGLE) databases. In addition, we searched for pertinent abstracts and expert presentations from the scientific meetings of the American College of Cardiology (http://www.cardiosource.org/acc), the European Society of Cardiology (http://www.escardio.org), the Transcatheter Cardiovascular Therapeutics (http://www.tctmd.com), and the American Heart Association (http://www.americaheart.org). We also considered published review articles, editorials and internet-based sources of information (http://www.clinicaltrials.gov, http://www.clinicaltrialresults.org, http://www.europcr.com, and http://www.theheart.org) to assess potential information on studies of interest. We had no restriction on language or whether the results had been published. Literatures were searched in MEDLINE with the terms 'clopidogrel' (All Fields) AND ('percutaneous coronary intervention' [All Fields] OR 'PCI' [All Fields] OR 'stents' [MeSH Terms]), with no restriction on subheadings. Similar but adapted search terms were used for the other literature databases or search engines. The reference lists of all retrieved literatures were checked for other potentially relevant citations, and studies not included in the above electronic sources were searched manually. To increase sample size, widen population coverage and increase statistical power, we included results for both randomized control trials (RCTs) and observational studies. The authors of the identified papers and relevant specialists were contacted for additional information. Studies were included if they (i) compared clopidogrel 150 vs. 75 mg day−1 in patients undergoing PCI; (ii) were RCTs or observational studies with at least a 1-month follow-up for each group; and (iii) contained sufficient information for ADP-induced platelet aggregation or MACE/MACCE counts for estimating the pooled weighted mean difference (WMD) or the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI). Studies were excluded if the baseline responsiveness to the two regimens of clopidogrel differed or if two articles reported results of the same study (the article with more complete and recent data was included). Data extraction The following information was extracted from published reports by use of a standardized protocol and reporting form: first author's last name, year of publication, study design, country of origin, number of enrolled patients, subject characteristics at baseline (age, sex, body mass index, smoking status, history of diabetes, hypertension, dyslipidemia and myocardial infarction, left ventricular ejection fraction, family history of cardiovascular disease, and clinical pattern of coronary artery disease), stent type, concomitant medication, dosage and duration of clopidogrel administration, follow-up duration, and end-points. Absolute numbers were recalculated when percentages were reported. Assessment of study quality The methodological quality of eligible studies was assessed with criteria adapted from guidelines for the evaluation of articles on prognosis [13]. The criteria were: enrollment of unselected patients undergoing PCI; a clearly defined inception cohort (i.e. patients enrolled at the time of the initial diagnosis or at a uniform time after diagnosis); more than 90% of patients completed planned follow-up; and blinded outcome assessment. The literature search, data extraction and quality assessment were undertaken independently and blindly by two authors (P.P.H. and M.X.Z.) using a standardized approach. Any disagreements were resolved by a third reviewer (R.J.L.). Statistical analysis RevMan 5.0.24 software, developed by the Cochrane Collaboration (http://www.cc-ims.net/revman, accessed on 16 June 2010), was used for the meta-analysis. The between-study heterogeneity was tested by the chi-square-based Cochran's Q statistic and the inconsistency index (I2). Statistically significant heterogeneity was considered present with a chi-square P < 0.10 and I2 > 50%. Results showing no significant heterogeneity were analyzed by the fixed-effects model and those with significant heterogeneity were analyzed by the random-effects model. Pooled ORs or WMDs were reported with 95% CIs, and a two-tailed P < 0.05 was considered statistically significant for all analyses. In addition, sensitivity or subgroup analyses were conducted to seek more narrowly drawn subsets of reports of studies by removing an individual study each time or studies with similar features to assess individual effects. Finally, we assessed publication bias using a funnel plot and the fail-safe number (Nfs). Any calculated Nfs value smaller than the number of retrieved reports of studies indicated publication bias. We calculated the Nfs0.05 as Nfs0.05 = (ΣZ/1.64)2 − k, where k is the number of reports of studies included in the meta-analysis. Results Figure 1 summarizes the selection of reports of eligible clinical trials. We identified 2026 potentially eligible literature citations, of which 19 were reviewed as full articles and three as presentation slides. Only 12 reports of studies with suitable data were eligible for inclusion: 11 full articles [14-24] and one meeting presentation [25], all in English. A total of 23 814 subjects were enrolled in the studies, of which 19 995 were from nine RCTs [14-21, 25] and 3819 from three observational studies [22-24]. The interobserver agreement for the study selection was excellent (κ = 0.93). Figure 1Open in figure viewerPowerPoint Flowchart of literature selection process. RCT, randomized controlled trial. The detailed characteristics of the studies from the 12 reports are given in Table 1. Results of the GRAVITAS trial [25] were presented at the American Heart Association's Scientific Sessions 2010 in Chicago, and all the other reports were full articles published in English from 2007 to 2010. The sample sizes ranged from 40 to 17 263 participants. The mean ages of the study participants ranged from 56.73 to 64.91 years and the mean follow-up from 30 to 180 days. Three studies [14, 22, 25] enrolled only clopidogrel-resistant patients, and one study [14] included only patients with type 2 diabetes mellitus and coronary artery disease. Table 1. Chief characteristics of the studies included in the meta-analysis Study Beckerath et al. [15] OPTIMUS [14] Abuzahra et al. [16] Angiolillo et al. [20] VASP-02 [17] Nguyen et al. [18] CURRENT-OASIS 7 [19] DOUBLE [21] GRAVITAS [25] Han et al. [23] Lemesle et al. [24] Tavassoli et al. [22] Year of publication 2007 2007 2008 2008 2008 2009 2010 2010 2010 2009 2009 2010 Study design RCT RCT RCT RCT RCT RCT RCT RCT RCT Observational studies Observational studies Observational studies Country of origin Unspecified number of centers; Germany Single-center; USA Single-center; USA Multicenter; USA and Spain Multicenter; France Single-center; Italy Multicenter; Canada, France, Argentina, United Kingdom, NC, Germany, and Czech Republic Single-center; Canada Multicenter; USA and Canada Single-center; China Single-center; France Single-center; France Patients, n 60 40 119 40 153 60 17 263 48 2214 813 2954 52 Mean age, years 64.16 61.5 56.73 63 64.91 60.68 61.2 63 64 64.35 63.48 NA Men, n (%) 55 (91.67) 26 (65) 77 (64.71) 27 (67.5) 126 (82.35) 51 (85) 13 029 (75.47) 43 (89.58) 1439 (65) 599 (73.68) 2299 (77.8) 44 (84.62) Body-mass index, kg m−2 27.94 32.95 31.36 18 (45)* NA 28.19 NA 27 NA NA 27.54 25 (48.08)† Active smokers, n (%) 5 (8.33) 7 (17.5) 71 (59.66) 12 (30) 24 (15.69) 12 (20) 6394 (37.04) 32 (66.67) NA 318 (39.11) 989 (33.5) 14 (26.92) Past medical history, n (%) Diabetes mellitus 17 (28.33) 40 (100) 74 (62.18) 13 (32.5) 37 (24.18) 9 (15) 3844 (22.27) 8 (16.67) 1007 (45.48) 249 (30.63) 857 (29) 18 (34.62) Hypertension 29 (48.33) 37 (92.5) 113 (94.96) 28 (70) 97 (63.4) 37 (61.67) 10 197 (59.07) 23 (47.92) NA 408 (50.18) 1625 (55) 23 (44.23) Dyslipidemia 30 (50) 37 (92.5) 106 (89.08) 24 (60) 100 (65.36) 52 (86.67) 6953 (40.28) 21 (43.75) NA 410 (50.43) 1619 (54.8) 24 (46.15) MI NA 15 (37.5) NA 9 (22.5) 17 (11.11) 15 (25) 2933 (16.99) NA 653 (29.49) NA 653 (22.1) NA LVEF (%) NA NA 25 (21.01)‡ NA NA 56 NA 49.6 NA 55.91 50.56 NA Family history of CV disease NA NA 54 (45.38) NA NA 38 (63.33) NA 10 (20.83) NA 318 (39.11) 841 (28.5) 8 (15.38) Clinical pattern of CAD Stable angina T2DM and CAD Stable angina or ACS Stable or unstable angina Stable angina Stable angina or ACS ACS STEMI Stable angina or ACS ACS Stable angina or ACS Stable angina or ACS ≥ 1 DES implantation, n (%) NA NA NA NA 93 (60.78) NA 6866/16 323 (42.06) 0 (0) NA 813 (100) 1026 (34.7) 24 (46.15) Study Beckerath et al. [15] OPTIMUS [14] Abuzahra et al. [16] Angiolillo et al. [20] VASP-02 [17] Nguyen et al. [18] CURRENT-OASIS 7 [19] DOUBLE [21] GRAVITAS [25] Han et al. [23] Lemesle et al. [24] Tavassoli et al. [22] Concomitant medication Aspirin 60 (100) 40 (100) 119 (100) 40 (100) 153 (100) 59 (98.33) 17 263 (100) 48 (100) NA 813 (100) 2954 (100) 52 (100) Beta blockers 56 (93.33) 33 (82.5) NA 28 (70) 107 (69.93) 43 (71.67) NA 46 (95.83) NA 388 (47.72) NA 36 (69.23) ACE inhibitors or ARB 53 (88.33) 27 (67.5) NA 24 (60) 85 (55.56) 31 (51.67) NA 43 (89.58) NA 181 (22.26) NA 28 (53.85) Statins 59 (98.33) 37 (92.5) NA 40 (100) 120 (78.43) 49 (81.67) NA 31 (64.58) NA 413 (50.8) NA 46 (88.46) Proton pump inhibitors NA NA NA NA 41 (26.80) 11 (18.33) NA 22 (45.83) 664 (30) NA NA 40 (76.92) GP IIb/IIIa inhibitors 0 (0) 0 (0) 0 (0) 0 (0) 6 (3.92) 0 (0) 7010 (40.61) 48 (100) 0 (0) 0 (0) 1119 (37.9) 5 (9.62) Onset of enrolling patients Within 12 h after PCI > 30 days after PCI Before PCI Next morning after PCI Before PCI 1 week prior to PCI Before PCI 24 h after PCI 12–24 h post-PCI Before PCI Before PCI After PCI Loading dose of clopidogrel, mg 150 mg day−1 600 NA 600 600 300–600 300 600 300 NA 600 600 300 75 mg day−1 600 NA 300 600 300–600 300 300 300 NA 600 300 300 Duration of clopidogrel 150 mg day−1, days 30 30 30 30 30 7 7 30 180 30 15 NA Mean follow-up, days 30 60 30 60 30 30 30 30 180 30 60 159 Available end-points MACE: CV death, MI, or TVR; TIMI bleeding; maximal 5-μm ADP-induced platelet aggregation Bleeding; maximal 5-μm and 20-μm ADP-induced platelet aggregation MACE: CV death, MI, or TVR; TIMI bleeding Bleeding; maximal 5-μm and 20-μm ADP-induced platelet aggregation MACCE: CV death, stroke, MI, TVR, or improvement of medical treatment; bleeding TIMI bleeding MACCE: CV death, MI, or stroke; stent thrombosis; TIMI bleeding Stent thrombosis; bleeding; maximal 20-μm ADP-induced platelet aggregation MACE: CV death or MI; stent thrombosis; bleeding MACE: CV death, MI, or TVR; stent thrombosis; TIMI bleeding MACE: CV death or MI; stent thrombosis; bleeding MACE: CV death, MI, or TVR; stent thrombosis; bleeding ACE, angiotensin-converting enzyme; ACS, acute coronary syndrome; ADP, adenosine diphosphate; ARB, angiotensin II receptor blockers; CAD, coronary artery disease; CV, cardiovascular; DES, drug-eluting stents; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiac events; MI, myocardial infarction; NA, not applicable; RCT, randomized controlled trial; STEMI, ST-segment elevation myocardial infarction; TIMI bleeding, bleeding defined by thrombolysis in myocardial infarction criteria; T2DM, Type 2 diabetes mellitus; TVR, target vessel revascularization. Values are numbers and percentages or mean. *Obesity (BMI > 30 kg m−2), n (%); †Excess weight (BMI > 27 kg m−2), n (%); ‡Congestive heart failure, n (%). The methodological quality of the included studies was in general good, with nine [14-19, 22-24] of 12 reports describing three or more of the four quality criteria (Table 2). Reports for all studies clearly defined the inception cohort, and loss to follow-up was reported as > 10% in only three reports [20, 21, 25], although in seven reports it was unclear whether patient enrollment was selective [14-16, 19-21, 25], and for only nine studies was outcome assessment blinded [14-21, 25]. Table 2. Methodological quality of eligible studies Study Consecutive patients Clearly defined inception cohort > 90% completed planned follow-up (%) Blinded outcome assessment RCTs Beckerath et al. [15] Unclear Yes Yes (100) Yes OPTIMUS [14] Unclear Yes Yes (100) Yes Abuzahra et al. [16] Unclear Yes Yes (100) Yes Angiolillo et al. [20] Unclear Yes No (64.52) Yes VASP-02 [17] Yes Yes Yes (98.69) Yes Nguyen et al. [18] Yes Yes Yes (100) Yes CURRENT-OASIS 7 [19] Unclear Yes Yes (99.8) Yes DOUBLE [21] Unclear Yes No (88.89) Yes GRAVITAS [25] Unclear Yes No (85.09) Yes Observational studies Han et al. [23] Yes Yes Yes (100) No Lemesle et al. [24] Yes Yes Yes (97.9) No Tavassoli et al. [22] Yes Yes Yes (100) No Values are percentages. RCT, randomized controlled trial. Clinical end-points We could compare data for eight clinical end-points (Table 3). Cardiovascular events were reviewed for eight trials [15-17, 19, 22-25]. As compared with 75 mg day−1 of clopidogrel, 150 mg day−1 significantly reduced the incidence of MACE/MACCE (3.89% vs. 5.07%), with an OR of 0.67 (95% CI, 0.48–0.94; P = 0.02) (Fig. 2). Table 3. Meta-analysis of risk of clinical events Events References Events/total OR (95% CI) P value I 2, % Heterogeneity P value RCTs Observational studies 150 mg day−1 75 mg day−1 MACE/MACCE 15–17,19,25 22–24 437/11 228 629/12 398 0.67 (0.48–0.94) 0.02 55 0.03 CV death 15–17,19 22–24 205/10 119 274/11 293 0.93 (0.77–1.12) 0.42 0 0.95 MI 15,16,19 22–24 206/10 061 323/11 200 0.72 (0.60–0.86) 0.0003 0 0.60 TVR 15,16 22,23 9/531 31/513 0.27 (0.12–0.62) 0.002 0 0.93 Stent thrombosis 19,21,25 22–24 172/11 074 312/12 239 0.64 (0.53–0.77) < 0.00001 45 0.10 Bleeding complications 14–21,25 22–24 788/11 321 774/12 493 1.21 (1.09–1.34) 0.0003 0 0.91 Major bleeding 14–21,25 22–24 132/11 321 143/12 493 1.17 (0.92–1.49) 0.21 8 0.36 Minor bleeding 14–21,25 22–24 656/11 321 631/12 493 1.21 (1.08–1.36) 0.0009 0 0.87 CI, confidence interval; CV, cardiovascular; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiac events; MI, myocardial infarction; OR, odds ratio; RCT, randomized controlled trial; TVR, target vessel revascularization. Figure 2Open in figure viewerPowerPoint Meta-analysis of results of five RCTs and three observational studies estimating the relative impact of 150- vs. 75-mg daily maintenance dose of clopidogrel on major adverse cardiac and/or cerebrovascular events after PCI. CI, confidence interval; M-H, Mantel-Haenszel; RCT, randomized controlled trial. Although clopidogrel at 150 mg day−1 did not differ from 75 mg day−1 in reducing cardiovascular death (2.03% vs. 2.43%; OR, 0.93; 95% CI, 0.77–1.12; P = 0.42), it significantly reduced myocardial infarction (2.05% vs. 2.88%; OR, 0.72; 95% CI, 0.60–0.86; P = 0.0003), target vessel revascularization (1.69% vs. 6.04%; OR, 0.27; 95% CI, 0.12–0.62; P = 0.002), and stent thrombosis (1.55% vs. 2.55%; OR, 0.64; 95% CI, 0.53–0.77; P < 0.00001; Fig. 3). However, 150 mg day−1 produced a higher incidence of bleeding complications than 75 mg day−1 (6.96% vs. 6.20%; OR, 1.21; 95% CI, 1.09–1.34; P = 0.0003; Fig. 4), especially minor bleeding (5.79% vs. 5.05%; OR, 1.21; 95% CI, 1.08–1.36; P = 0.0009), but not major bleeding (1.17% vs. 1.14%; OR, 1.17; 95% CI, 0.92–1.49; P = 0.21). Figure 3Open in figure viewerPowerPoint Meta-analysis of results of three RCTs and three observational studies estimating the relative impact of 150- vs. 75-mg daily maintenance dose of clopidogrel on stent thrombosis after PCI. CI, confidence interval; M-H, Mantel-Haenszel; RCT, randomized controlled trial. Figure 4Open in figure viewerPowerPoint Meta-analysis of results of nine RCTs and three observational studies estimating the relative impact of 150- vs. 75-mg daily maintenance dose of clopidogrel on bleeding complications after PCI. CI, confidence interval; M-H, Mantel-Haenszel; RCT, randomized controlled trial. Maximal ADP-induced platelet aggregation profiles Three trials [14, 20, 21] assessed 20-μm ADP-induced maximal platelet aggregation (Fig. 5A), and three [14, 15, 20] assessed 5-μm ADP-induced maximal platelet aggregation (Fig. 5B). Both 20- and 5-μm ADP-induced maximal platelet aggregation were significantly lower with 150 than 75 mg day−1 clopidogrel therapy for 30 days (WMD −10.60, 95% CI −14.20 to −6.99, P < 0.00001; WMD −13.13, 95% CI −17.48 to −8.78, P < 0.00001, respectively). Figure 5Open in figure viewerPowerPoint Meta-analysis of results of four RCTs estimating the relative impact of 150- vs. 75-mg daily maintenance dose of clopidogrel on ADP-induced maximal platelet aggregation after PCI. Data for only three RCTs were available to assess the maximal platelet aggregation induced by two different concentrations of ADP, respectively. CI, confidence interval; IV, inverse variance; SD, standard deviation. (A) 20-μm ADP-induced maximal platelet aggregation. (B) 5-μm ADP-induced maximal platelet aggregation. Sensitivity/subgroup analyses In the sensitivity analyses, removal of the largest study [19] produced no substantial alterations in pooled ORs (data not shown). Heterogeneity was not addressed well through sensitivity analyses; therefore, we performed subgroup analyses in terms of the end-point of MACE/MACCE (Table 4). The between-study heterogeneity was explained in part by the variability in study design, loading dose of clopidogrel, treatment duration with clopidogrel 150 mg day−1, follow-up duration, and concomitant use of statins, proton pump inhibitors (PPIs) or GP IIb–IIIa inhibitors. Co-administration of statins reduced but that of PPIs or GP IIb-IIIa inhibitors enhanced the relative impact on the risk of MACE/MACCE after PCI with clopidogrel at 150 vs. 75 mg day−1. In addition, the risk of bleeding complications with the two regimens was similar without GP IIb-IIIa inhibitors (8.64% vs. 7.48%; OR, 1.17; 95% CI, 0.91–1.51; P = 0.22) but was significantly higher with 150 than 75 mg day−1 with GP IIb-IIIa inhibitors prescribed at the discretion of the physician (6.67% vs. 6.00%; OR, 1.22; 95% CI, 1.09–1.37; P = 0.0007). Table 4. Subgroup analyses with regard to the risk of MACE/MACCE Category Studies, n References Patients, n OR (95% CI) P value I 2, % Heterogeneity P value Adjustment for study design RCTs 5 15–17,19,25 19 807 0.85 (0.73–0.98) 0.02 0 0.54 Observational studies 3 22–24 3819 0.34 (0.10–1.18) 0.09 80 0.006 Adjustment for loading dose, mg 300 vs. 300 1 22 52 0.08 (0.02–0.31) 0.0003 NA NA 600 vs. 600 2 15,23 873 0.50 (0.17–1.47) 0.21 0 0.64 600 vs. 300 3 16,19,24 20 336 0.82 (0.72–0.93) 0.003 31 0.24 Adjustment for treatment duration of clopidogrel 150 mg day−1, days 7 or 15 2 19,24 20 217 0.83 (0.72–0.95) 0.006 0 0.47 30 4 15–17,23 1143 0.43 (0.21–0.90) 0.02 0 0.94 Adjustment for mean follow-up duration, days 30 or 60 6 15–17,19,23,24 21 360 1.21 (1.08–1.36) 0.001 0 0.61 159 or 180 2 22,25 2266 1.20 (0.92–1.56) 0.18 0 0.83 Adjustment for concomitant use of statins, % < 80 2 22,23 865 0.19 (0.03–1.08) 0.06 72 0.06 ≥ 80 2 15,17 211 0.72 (0.09–5.76) 0.75 0 0.79 Adjustment for concomitant use of PPIs, % < 50 2 17,25 2365 1.01 (0.59–1.75) 0.96 0 0.68 ≥ 50 1 22 52 0.08 (0.02–0.31) 0.0003 NA NA Adjustment for concomitant use of GP IIb/IIIa inhibitors Prohibition 4 15,16,23,25 3206 0.75 (0.49–1.17) 0.21 23 0.27 At the discretion of the physician 4 17,19,22,24 20 420 0.63 (0.39–1.03) 0.06 74 0.009 CI, confidence interval; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiac events; NA, not applicable; OR, odds ratio; PPIs, proton pump inhibitors; RCT, randomized controlled trial. Publication bias Figure 6 shows the funnel plot of the publication bias of the 12 trials in terms of total bleeding events. The funnel plot showed no publication bias for all studies included in the meta-analysis. We calculated the Nfs0.05 for each comparison and found the Nfs0.05 values for MACE/MACCE, myocardial infarction, target vessel revascularization, stent thrombosis, bleeding and ADP-induced maximal platelet aggregation to be greater than the number of studies included in the meta-analysis. However, the Nfs0.05 value for cardiovascular death was smaller than the number of retrieved studies, which was possibly consistent with small-study-related bias. Figure 6Open in figure viewerPowerPoint Funnel plot of publication bias in terms of bleeding events. Discussion In contrast to the numerous data on different clopidogrel loading doses in patients undergoing PCI, few data exist on different clopidogrel maintenance doses, so our meta-analysis contributes to knowledge of the efficacy and safety of the maintenance dosage of clopidogrel at 150 vs. 75 mg day−1 in patients undergoing PCI. The 150-mg day−1 dosage reduced MACE/MACCE, myocardial infarction, target vessel revascularization and stent thrombosis after PCI but increased minor bleeding, which may be attributed to the dose-dependent inhibition of ADP-induced platelet aggregation. Previous studies have demonstrated great inter-individual
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