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Meta-analysis of Comparison of the Newer P2Y12 Inhibitors (Oral Preparation or Intravenous) to Clopidogrel in Patients With Acute Coronary Syndrome

Zhang, Lu MD; Lu, Jun PhD; Dong, Weihua PhD; Tian, Huiping MD; Feng, Weiyi PhD; You, Haisheng PhD; He, Hairong MD; Ma, Jing MD; Dong, Yalin PhD

Journal of Cardiovascular Pharmacology: March 2017 - Volume 69 - Issue 3 - p 147–155
doi: 10.1097/FJC.0000000000000451
Original Article

Aims: New P2Y12 adenosine diphosphate receptor antagonists have been used in the treatment of acute coronary syndrome (ACS) with different results. This systematic review analyzed and compared the evidence from large, clinical trials regarding the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of cardiovascular events in patients with ACS.

Methods and Results: This analysis compared newer P2Y12 inhibitors with clopidogrel of 13 clinical trials involved a total of 87,985 patients with ACS. The newer P2Y12 inhibitors include cangrelor, prasugrel, and ticagrelor. Newer P2Y12 inhibitors significantly decreased the risk of myocardial infarction and showed a trend toward reduction of cardiovascular death (odds ratio [OR] = 0.86, 95% confidence interval [CI], 0.77–0.96, and I2 = 54%, P < 0.05); (OR = 0.85, 95% CI, 0.77–0.93, and I2 = 42%, P < 0.001). The rates of stroke events and the incidence in patients with ACS did not differ statistically between the clopidogrel group and the group with newer P2Y12 inhibitors (OR = 0.95, 95% CI, 0.79–1.14, and I2 = 0%, P = 0.57). However, newer P2Y12 inhibitors showed a significant increase in thrombosis in MI major or minor bleeding (OR = 1.21, 95% CI, 1.03–1.42, and I2 = 56%, P = 0.02) compared with clopidogrel.

Conclusions: Based on this meta-analysis, newer P2Y12 inhibitors were significantly more effective than clopidogrel in the events of myocardial infarction and cardiovascular death in patients with ACS, although the incidence of thrombosis in MI-defined bleeding was higher compared with clopidogrel.

*Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China; and

Clinical Research Center, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China.

Reprints: Yalin Dong, PhD, Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, 277, West yanta Road, Xi'an 710061, China (e-mail: dongyalin@mail.xjtu.edu.cn).

The authors report no conflicts of interest.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Received November 08, 2016

Accepted November 15, 2016

The important point: Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of newer P2Y12 inhibitors (oral preparation or intravenous) with clopidogrel in patients with ACS.

The reasons are as follows: (1) The ways of administration are different, but the pharmacological mechanism is same basically. (2) The indications for 3 drugs are consistent basically. (3) Both of these drugs are available clinically. (4) There was no significant relationship between the end point and the route of administration.

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INTRODUCTION

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the mainstay of treatment for acute coronary syndrome (ACS), whether these patients undergo a percutaneous coronary intervention (PCI) or are managed medically. In recent years, the incidence of bleeding and the degree of inhibition of platelet aggregation caused by P2Y12 receptor inhibition have been of great concern.1–3 Clopidogrel is usually the antiplatelet drug of choice in patients with ACS; however, its lower bioavailability, slower onset of platelet inhibition, uncertainty of patient response, and drug resistance3 have led to the development of newer P2Y12 inhibitors such as cangrelor, prasugrel, and ticagrelor. Recently, these 3 drugs have been deemed acceptable for use in more and more patients who need antiplatelet therapy. Cangrelor, a nonthienopyridine adenosine triphosphate analog, is classified as an intravenous inhibitor of the adenosine diphosphate (ADP) receptor P2Y12 and could have a role in the treatment of patients who require rapid, predictable, profound, and reversible platelet inhibition,4–6 whereas 2 newer ADP inhibitors, prasugrel and ticagrelor, have been associated with less interpatient variability and more potent antiplatelet-aggregation response.7–11 Several meta-analyses have been conducted to explore the efficacy and safety of cangrelor, prasugrel, and ticagrelor in comparison with those of clopidogrel in patients with ACS.12–14 However, none of the meta-analyses involving the newer P2Y12 inhibitors (oral or intravenous preparations) have comprehensively assessed for a difference in cardiovascular events compared with clopidogrel in patients with ACS. Therefore, in this study, we performed a systematic evaluation and meta-analysis to compare the available evidence from large clinical trials on the efficacy of cangrelor, prasugrel, and ticagrelor relative to clopidogrel in decreasing the incidence of cardiovascular events in patients with ACS.

Based on this meta-analysis, newer P2Y12 inhibitors were significantly more effective than clopidogrel in the events of myocardial infarction (MI) and cardiovascular death in patients with ACS, although the incidence of thrombosis in MI (TIMI)-defined bleeding was higher compared with clopidogrel.

Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of the newer P2Y12 inhibitors with clopidogrel in patients with ACS. This meta-analysis provides evidence for the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of MI and death from cardiovascular causes. However, newer P2Y12 inhibitors were associated with a higher risk of TIMI-defined bleeding compared with clopidogrel group.

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METHODS

This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement15 and the Cochrane Collaboration guidelines.16

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Search Strategy and Study Selection

Systematic searches of the PubMed and Embase databases were conducted using the following keywords and subject terms: acute coronary syndromes, clopidogrel, cangrelor, prasugrel, and ticagrelor. Searches were also conducted for evaluations of clopidogrel. The materials in this analysis were only derived from journal articles, and the publication language was limited to English. All references in the determined research were also inspected as part of the evaluation of supplementary interrelated work. The literature search was last updated on August 20, 2016.

Studies were included if they met the following criteria1: clinical trial comparing clopidogrel versus cangrelor, prasugrel, or ticagrelor2; inclusion of patients with ACS, of whom 83,586 (95%) were treated after angiography and 4399 (5%) were treated without angiography or were undergoing PCI. The exclusion criteria consisted of the following1: ongoing studies,2 duplicate reports,3 unpublished studies (with data unavailable from the principal investigators),3 studies with incomplete follow-up.

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Outcome Measures

The primary efficacy end point was the incidence of major adverse cardiovascular and vascular effects, and was defined as the composite events of MI and stroke. TIMI-defined bleeding was chosen as a primary safety end point.

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Data Collection and Quality Assessment

Two investigators were all alone data evaluated using a standardized data-extraction protocol. Differing conclusions were resolved by discussion with a third investigator. The following data were extracted from each reference: author's name, year of publication, patient's age, sex, type of ACS, previous PCI, dose and method of drugs, number of patients, number of patients with cardiovascular events, follow-up time, and efficacy and safety of treatment. The quality of the included studies was assessed by evaluating the risk of bias in accordance with the Cochrane Collaboration methods.16 Subsequently, the following data were evaluated in detail: sequence generation, incomplete data, and allocation of different group ratios for concealment, double-blindness, selective reporting, and other biases. The scoring system used was not formal. The selection of journal, author, and institution was fair.

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Statistical Methods

Analyses were performed using Review Manager 5.3. Statistics were used to assess agreement between reviewers for study selection. The treatment effect was evaluated using the odds ratio (OR) and 95% confidence interval (CI). All the results of the study were assessed using pooled ORs and 95% CIs by a fixed-effect or a random-effect model. The I2 test was used to assess the heterogeneity of the results, with I2 values greater than 75% indicating that the 2 groups had a high heterogeneity, independence, and no significance of meta-analysis.17–20 I2 values <50% and >50% were analyzed using fixed-effect and random-effect models, respectively. Sensitivity analysis was used to take into account the influence of study quality. The cutoff for statistical significance for each test was set at P < 0.05. If the I2 exceeded 50%, we considered heterogeneity to be substantial. Sensitivity analysis was performed, when possible, by removing one study at a time. Potential publication bias was evaluated using funnel plots.

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RESULTS

Literature Search

A schematic of the study selection process is presented in Figure 1. The database and manual searches yielded 1376 citations, of which 786 were duplicates and thus excluded after either title or abstract evaluation, and 8 were excluded after full-text screening because they did not fulfill the inclusion criteria. Ultimately, 13 studies involving 87,985 patients were included in this systematic review.21–33

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Methodological Quality of Studies Included

The detailed characteristics of the included 13 studies are shown in Tables 1 and 2. The methodological quality of the studies was determined by assessing the risk of biases (Fig. 2). Disagreements concerning data evaluation were resolved by consensus. All studies reported random sequence generation and selective reporting by lottery,21–33 whereas the methods used in the remaining studies to randomly categorize patients were insufficiently described. The random allocation concealment of all the studies was briefly mentioned.21–33 In addition, all the studies, except one, describe the blinding of participants and personnel in detail.32 On the basis of this information, it was easy to discover detection bias in 3 studies21,26,32 in the secondary outcomes of side effects. Nine of the studies reported missing data.21–23,25–30 Owing to the incompleteness of some primary outcome indicators (eg, bleeding), selection bias was found to exist in 2 studies.24,30

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Quantitative Data Synthesis

Primary Efficacy End Point

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MI

The rates of MI events in patients with ACS were identified in 9 of the included studies.21–23,25–27,30,31 As shown in Figure 3, the risk of MI was significantly lower for newer P2Y12 inhibitors than that for clopidogrel (OR = 0.86, 95% CI, 0.77–0.96, I2 = 54%, and P < 0.05). No obvious heterogeneity among studies was observed.

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Stroke

Nine of the research groups investigated the incidence of stroke events in patients with ACS.21,23,25–27,29–32 The rates of stroke events in patients with ACS did not differ statistically between the clopidogrel group and the group of newer P2Y12 inhibitors (OR = 0.95, 95% CI, 0.79–1.14, I2 = 0%, and P = 0.57) (Fig. 4). The heterogeneity among studies was low.

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Death From Cardiovascular Causes/Vascular Causes

The rates of death from cardiovascular causes in patients with ACS were identified in 12 of the 13 studies included in this review.21–32 Newer P2Y12 inhibitors had a significantly decreased incidence of death from cardiovascular causes than the clopidogrel group (OR = 0.85, 95% CI, 0.77–0.93, I2 = 42%, and P < 0.001) (Fig. 5). There was low heterogeneity among the 9 studies.

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Primary Safety End Point

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TIMI-Defined Bleeding (Major and Minor)

The incidences of bleeding events in patients with ACS were identified in 11 articles.21–23,25–27,29–33 Newer P2Y12 inhibitors significantly increased the risk of TIMI-defined bleeding compared with clopidogrel (OR = 1.21, 95% CI, 1.03–1.42, I2 = 56%, and P = 0.02) (Fig. 6). Although high heterogeneity between 2 studies was found (I2 = 60%), no outliers were identified after sensitivity analysis.

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Publication Bias

Symmetry in the funnel plot was observed (Fig. 7).

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DISCUSSION

Findings

Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of newer P2Y12 inhibitors with clopidogrel in patients with ACS. This meta-analysis provides evidence for the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of cardiovascular events in patients with ACS. Thirteen studies were included in this analysis: 3 compared clopidogrel and cangrelor, 6 compared clopidogrel and prasugrel, and 4 compared clopidogrel and ticagrelor. The main findings of this review can be summarized as follows:

1. There were no differences in the primary efficacy end points of stroke between patients with ACS taking clopidogrel and newer P2Y12 inhibitors.

2. The incidences of MI and death from cardiovascular causes significantly decreased in the newer P2Y12 inhibitor group than in the clopidogrel group.

3. However, newer P2Y12 inhibitors were associated with a higher risk of TIMI-defined bleeding compared with the clopidogrel group.

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Heterogeneity

Of the studies evaluated, the average age of patients ranged from 52–77 years, and the course of disease ranged from 2–15 years. The specific intervention strategies used in the newer P2Y12 inhibitors group included cangrelor, prasugrel, or ticagrelor. Moreover, 3 studies administered cangrelor through intravenous (IV) drip, whereas the others involved orally administered prasugrel or ticagrelor. In addition, the disparity in age, treatment duration, the “unclear risk of bias” involved in patient allocation, concealment, and blinding, and the lack of description of details associated with patient characteristics were likely important sources of heterogeneity associated with this meta-analysis. Although the heterogeneity between studies allows us to make only preliminary conclusions, future larger clinical trials should enhance our ability to draw more definite conclusions regarding the use of the newer P2Y12 inhibitors as an adjuvant treatment for ACS. Sensitivity analysis failed to show any outliers, confirming the robustness of our results.

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Clinical Significance of the Findings

Clopidogrel is an orally administered, irreversible P2Y12 receptor inhibitor. Because clopidogrel is a prodrug, it needs to undergo in vivo activation to exert antiplatelet action. Clopidogrel's antiplatelet potency is closely related to the patient's CYP2C19 genotype, in vivo absorption, and drug metabolism. Genotypes with fast or moderate drug metabolism are required to have a good therapeutic effect with oral clopidogrel. For patients with slow metabolism, cardiovascular events such as death or early stent thrombosis may occur even if a preoperative dose of clopidogrel is administered before PCI, and the risk of such events is high.34 Furthermore, because clopidogrel is a prodrug, its onset of action is slow. A meta-analysis of studies with 3960 patients suggested that 25% of patients possess clopidogrel resistance and that their risk of recurrent ischemic events was 3 times greater than in other patients.35 The presence of clopidogrel resistance has driven the development and marketing of a new generation of antiplatelet agents, such as cangrelor, prasugrel, and ticagrelor. Compared with clopidogrel, the greatest advantage of cangrelor, ticagrelor, and prasugrel is that they have more effective antiplatelet action, faster inhibition of platelet aggregation, higher potency, more resistance to genotype variability, and fewer individual differences. Ticagrelor in particular has an advantage in that it acts directly and is reversible. For ACS patients with high thrombotic risk, these 3 drugs are more suitable for antiplatelet therapy after PCI.

Cangrelor was the first intravenous and competitive P2Y12 inhibitor developed, with a reversible mode of action and a very short half-life of 5 minutes. Cangrelor belongs to a new family of drugs: ADP analogs. Its rapid onset of action is possible because it acts directly on the P2Y12 receptor, without the need for in vivo bioactivation.21 It has a high inhibitory effect on ADP-induced platelet aggregation, with immediate onset on intravenous administration and rapid recovery of platelet function 1–2 hours after discontinuation in patients with ACS without persistent ST-segment elevation (NSTE-ACS).21 The 2015 European Society of Cardiology (ESC) guidelines for the management of NSTE-ACS report that selected patients who require noncardiac surgery after recently implanted stents may benefit from bridging therapy with small-molecule GPIIb/IIIa inhibitors (ie, tirofiban or eptifibatide) after discontinuation of the P2Y12 inhibitor; in contrast, cangrelor has so far been tested as a bridging therapy to coronary artery bypass grafting (IIb). Prasugrel, similar to clopidogrel, is also a prodrug, and needs to be converted into its active metabolites in vivo to bind to the platelet P2Y12 receptor and produce an antiplatelet effect.36 The normal dose of prasugrel in healthy volunteers and patients with ACS, including those undergoing PCI, inhibits ADP-induced platelet aggregation faster, stronger, and more consistently than the standard or higher doses of clopidogrel.25 However, in patients with ACS with scheduled PCI, prasugrel treatment was associated with an additional risk of major bleeding that could be fatal.25 Ticagrelor is a new ADP receptor inhibitor that was recently recommended as a substitute for clopidogrel for first-line treatment. Unlike other P2Y12 receptor inhibitors, ticagrelor does not require in vivo activation, and its metabolites are also pharmacologically active, resulting in more rapid platelet inhibition. Ticagrelor also has a reversible mode of action. The 2016 American College of Cardiology/American Health Association (ACC/AHA) Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With ACS suggests: “In patients with ACS (NSTE-ACS or STEMI) treated with DAPT after coronary stent implantation and in patients with NSTE-ACS treated with medical therapy alone (without revascularization), it is reasonable to use ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy (I).37 Compared to clopidogrel, the new generation of P2Y12 receptor inhibitors (ticagrelor or prasugrel) reduces the risk of ischemia and increases the risk of hemorrhagic shock.37

The findings suggest that the newer P2Y12 inhibitors could replace clopidogrel in clinical practice. However, 3 major problems cannot be ignored, with the first being hemorrhagic risk. The risk of bleeding when taking the new generation of antiplatelet drugs still requires assessment. The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with ACS recommendations state that the assessment of bleeding risk should consider the possibility of hemorrhage. Patients with severe bleeding reactions should stop using P2Y12 receptor inhibitors. Second, breathing difficulties are a possible adverse effect; for breathing difficulties that last longer than 30 days, remission may be considered as an alternative to clopidogrel. Lastly, prasugrel and cangrelor are listed in the Health Insurance Directory in China, but ticagrelor is not. The national per capita medical expenditure was 1165 yuan in 2015, no more than 3.2 yuan per day. However, the daily cost of ticagrelor treatment is 25.7 yuan, far more than the per capita health insurance consumption. Therefore, from a cost-effectiveness standpoint, it is better to take clopidogrel.38

In summary, based on our meta-analysis, newer P2Y12 inhibitors are significantly more effective than clopidogrel in preventing MI and cardiovascular death in patients with ACS. However, our meta-analysis suggests that the new generation of P2Y12 inhibitors can also increase the risk of bleeding in patients. Therefore, application of these new inhibitors should only be considered after evaluating the individual's bleeding risk. The use of these drugs can be guided by a hierarchical comparison of the ischemic and hemorrhagic risks of the patients. In the future, data from more design-perfect, large-scale, multi-center randomized controlled trials would greatly aid in the decision-making process of providing safe and convenient anticoagulant therapy for patients with ACS.

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Limitations

This systematic review had one major limitation: all of the information in previously published articles was already screened for refinement, resulting in the exclusion of highly heterogeneous results. The heterogeneity of the clinical outcomes in this article was not significant and did not affect the overall study conclusion. Of course, more large clinical trials are needed to achieve more accurate results.

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CONCLUSIONS

Our meta-analysis represents the first systemic analysis comparing the efficacy and safety of cangrelor, prasugrel, and ticagrelor with clopidogrel in patients with ACS. This meta-analysis provides evidence for the efficacy of cangrelor, prasugrel, and ticagrelor relative to clopidogrel relative in reducing the incidence of MI and death from cardiovascular causes. However, these newer P2Y12 inhibitors were also associated with a higher risk of TIMI-defined bleeding compared with clopidogrel.

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REFERENCES

1. Chen ZM, Jiang LX, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607–1621.
2. Yusuf S, Zhao F, Mehta SR, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.
3. Steinhubl SR, Berger PB, Mann JT III, et al; for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420.
4. Thygesen K, Alpert JS, Jaffe AS, et al; Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction; ESC Committee for Practice Guidelines (CPG). Third universal definition of myocardial infarction. Circulation. 2012;126:2020–2035.
5. Steg PG, Bhatt DL, Hamm CW, et al; for the CHAMPION Investigators. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet. 2013;382:1981–1992.
6. Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res. 2008;121:527–534.
7. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21–30.
8. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120:2577–2585.
9. Montalescot G, Bolognese L, Dudek D, et al; for the ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369:999–1010.
10. Wallentin L, Becker RC, Budaj A, et al; for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
11. Sibbing D, Steinhubl SR, Schulz S, et al. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window. J Am Coll Cardiol. 2010;56:317–318.
12. Bavishi C, Panwar S, Messerli FH, Bangalore S. Meta-analysis of comparison of the newer oral P2Y12 inhibitors (prasugrel or ticagrelor) to clopidogrel in patients with NoneST-elevation acute coronary syndrome. Am J Cardiol. 2015;116:809–817.
13. Pandit A, Aryal MR, Aryal Pandit A, et al. Cangrelor versus clopidogrel in percutaneous coronary intervention: a systematic review and meta-analysis. EuroIntervention. 2013;9:1–11.
14. Bellemain-Appaix A, Brieger D, Beygui F, et al. New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis. J Am Coll Cardiol. 2010;56:1542–1551.
15. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–269.
16. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011. http://http://www.cochrane-handbook.org.htm. Accessed January 10, 2014.
17. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.
18. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol. 2005;28:123–137.
19. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560.
20. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 2007;28:105–114.
21. Bhatt DL, Lincoff AM, Gibson CM, et al; CHAMPION PLATFORM Investigators. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361:2330–2341.
22. Bhatt DL, Stone GW, Mahaffey KW, et al; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303–1313.
23. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009;361:2318–2329.
24. Goldstein P, Grieco N, Ince H, et al. Mortality in primary angioplasty patients starting antiplatelet therapy with prehospital prasugrel or clopidogrel: a 1-year follow-up from the European MULTIPRAC Registry. Vasc Health Risk Manag. 2016;12:143–151.
25. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015.
26. Roe MT, Armstrong PW, Fox KA, et al; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367:1297–1309.
27. Wiviott SD, Antman EM, Winters KJ, et al; JUMBO-TIMI 26 Investigators. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation. 2005;111:3366–3373.
28. Damman P, Varenhorst C, Koul S, et al. Treatment patterns and outcomes in patients undergoing percutaneous coronary intervention treated with prasugrel or clopidogrel (from the Swedish Coronary Angiography and Angioplasty Registry [SCAAR]). Am J Cardiol. 2014;113:64–69.
29. Klingenberg R, Heg D, Räber L, et al. Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland. Heart. 2015;101:854–863.
30. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor Antagonist, Compared with clopidogrel, in patients with non–ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;19:1844–1851.
31. Cannon CP, Harrington RA, James S, et al; for the PLATelet inhibition and patient Outcomes (PLATO) investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375:283–293.
32. Chen I-C, Lee C-H, Fang C-C, et al. Efficacy and safety of ticagrelor versus clopidogrel in acute coronary syndrome in Taiwan: a multicenter retrospective pilot study. J Chin Med Assoc. 2016;79:521–530.
33. Hiasa Y, Teng R, Emanuelsson H. Pharmacodynamics, pharmacokinetics and safety of ticagrelor in Asian patients with stable coronary disease. Cardiovasc Interv Ther. 2014;29:324–333.
34. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003;107:2908–2913.
35. Combescure C, Fontana P, Mallouk N, et al; for the CLOVIS Study Group. Clinical implications of clopidogrel nonresponse in cardiovascular patients: a systematic review and metaanalysis. J Thromb Haemost. 2010;8:923–933.
36. Roffi M, Patrono C, Collet J-P, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal. 2016;37:267–315.
37. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. J Thorac Cardiovasc Surg. 2016;152(5):1243–1275.
38. Deng Qian, LI Donghua, Xiao Li, et al. Study on Status Quo of Disease–Based Score Payment Under the Global Budget Control in Basic Medical Insurance of China. Medicine and Society. 2016;9:11–13.
Keywords:

new P2Y12 inhibitors; clopidogrel; meta-analysis

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