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. 2020 Sep 7;9:99. Originally published 2020 Feb 10. [Version 2] doi: 10.12688/f1000research.21925.2

Comparison of major bleeding in patients with acute coronary syndrome that underwent coronary artery bypass grafting treated with clopidogrel or ticagrelor: a systematic review and meta-analysis

Mohammad Saifur Rohman 1, Yeni Purnamasari 2, Muhammad Ilmawan 2, Bagus Aulia Mahdi 3, Fredo Tamara 4,a, Aditya Indra Mahendra 4, Mazen Mazen 4, Teuku Heriansyah 5,b, Muhammad Yamin 6, Budi Susetio Pikir 7,c, Jonny Karunia Fajar 4,d
PMCID: PMC7885293  PMID: 33732438

Version Changes

Revised. Amendments from Version 1

We have revised our manuscript in some part to increase the consistency of the text and to avoid the unnecessary repetition without changing the meanings or findings. Two columns in Table 1 have also been added: Age and Bleeding assessment.

Abstract

Background: There is controversy among physicians regarding the use of dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients treated with coronary artery bypass grafting (CABG). Moreover, the evidence of previous studies about this topic remained inconclusive. This study aimed to perform a meta-analysis concerning the relation between the risk of major bleeding and the use of different DAPT (clopidogrel or ticagrelor) in ACS patients treated with CABG.

Methods: A meta-analysis was conducted during March to October 2019. Searches were carried out in Pubmed, Embase, Cochrane, and Web of Science. The predictor covariate in our present study was DAPT (clopidogrel or ticagrelor), and the outcome measure was the risk of major bleeding. Sub-group analysis was also performed, where data were classified into pre- and post-CABG. Furthermore, to determine the correlation and effect estimation, data were analyzed using fixed or random effect model.

Results: A total of 13 studies consisting 34,015 patients treated with clopidogrel and 32,661 patients treated with ticagrelor was included in our study. Our pooled calculation revealed that the incidence of major bleeding was not different significantly between clopidogrel and ticagrelor. In pre- and post-CABG sub-groups, our results also found no significant difference in major bleeding incidence between clopidogrel and ticagrelor groups.

Conclusions: Our meta-analysis clarifies that clopidogrel, compared to ticagrelor, or vice versa, is not associated with the risk of major bleeding in ACS patients treated with CABG.

Keywords: major bleeding, coronary artery bypass grafting, clopidogrel, ticagrelor

Introduction

In the last two decades, the management of acute coronary syndrome (ACS) has been well defined and periodically updated. Management has developed drastically over this period 1. Management options are numerous, and they depend on the facilities of the hospital. Of these treatment options, coronary artery bypass grafting (CABG) is considered the most challenging and the final option when other treatment options, including percutaneous coronary intervention (PCI) and thrombolytic therapy, fail to restore blood flow in the infarct-related artery 2. Moreover, the drugs used in ACS patients in all management options are complex, and dual antiplatelet therapy (DAPT) is commonly used. DAPT is globally used to treat patients with ACS. It was first reported in 1996 3, and was first recommended for treating ACS patients in 2007 in American College of Cardiology (ACC)/American Heart Association (AHA) guidelines 4. Since then, DAPT has been widely used in the early management of ACS patients 5, 6.

Recently, when performing DAPT, whether to use clopidogrel or ticagrelor (the choice between acetylsalicylic acid (ASA) + clopidogrel and ASA + ticagrelor) has remained controversial due to the current assumption that one of the two might provide higher risk of major bleeding 7, 8. In the Indonesian National Health Insurance drug catalog, in 2018 clopidogrel was withdrawn and substituted with ticagrelor. However, in the drug price list ( https://e-katalog.lkpp.go.id/; website in Indonesian), ticagrelor is more expensive than clopidogrel. It is unclear whether the assumptions made about the risk of major bleeding caused by clopidogrel or ticagrelor were supported by the evidence or were possibly the result of conspiracy among pharmaceutical industries to increase their products marketing. Ticagrelor may provide a more potent platelet inhibition effect, therefore reducing the risk of a thrombotic event 9. In the context of ACS, the greater effect may be accompanied more complications. Therefore, the benefits of DAPT and the risk of complications (bleeding) should balance. In the case of ACS patients undergoing CABG, to prevent major bleeding, it is recommended that DAPT should be discontinued for at least three and five days before elective CABG for ticagrelor and clopidogrel, respectively 10. Furthermore, in the case of emergency or urgent CABG, DAPT should be discontinued prematurely 11. The discontinuation of DAPT might increase the risk of a thrombotic event 12. However, delay in CABG had also been shown to associate with poor clinical outcome and increased risk of mortality 13. Therefore, identifying the appropriate DAPT, whether ticagrelor or clopidogrel, is crucial to prevent the risk of major bleeding. Although 2016 ACC/AHA guidelines recommended ticagrelor over clopidogrel because ticagrelor is considered to have a more potent anti-platelet effect than clopidogrel 14, the evidence from previous studies regarding the association between the risk of major bleeding and the use of different DAPT using either clopidogrel or ticagrelor in ACS patients treated with CABG were inconclusive. Therefore, those inconclusive data of previous studies required clarification using a meta-analysis approach.

Therefore, the present study aimed to perform a meta-analysis whether the use of different DAPT (clopidogrel or ticagrelor) might affect the risk of major bleeding or not in ACS patients treated with CABG. Our study outcome could clarify the real effect of the use of DAPT (clopidogrel or ticagrelor) to the risk of major bleeding in ACS patients treated with CABG. Moreover, we also expect that our current meta-analysis might correct previous assumptions concerning the use of different DAPT.

Methods

Study design

A Meta-analysis was performed during March to October 2019 to assess the association between the incidence of major bleeding and the use of DAPT either clopidogrel or ticagrelor in ACS patients treated with CABG. In effort to attain our goal, potentially relevant papers were identified and collected from PubMed, Embase, Cochrane, and Web of Science to calculate odd ratio (OR) and 95% confidence interval (95%CI) using either fixed or random effect model. A checklist adapted from Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) and the design of our previous meta-analyses 15– 20 were used to guide the meta-analysis protocols in our present study 21. See Reporting guidelines for a completed PRISMA checklist for this study 22.

Search strategy

We conducted a systematic search in PubMed, Embase, Cochrane, and Web of Science up to 20 September 2019. The search strategy, conformed to medical subjects heading (MeSH), involved the use of combination the following keywords: ["Major Bleeding"] AND ["Coronary Artery Bypass Grafting" OR "CABG"] AND ["Dual Anti Platelet Therapy" OR "DAPT"], and ["Clopidogrel" OR "Ticagrelor"]. In our searching strategy, language restrictions were not applied. We only used the study with the larger sample size and that was more up-to-date if we found the same data among studies. Moreover, we also searched the potential papers from the reference list of relevant or eligible studies. We also employed the "related article" option in PubMed to broaden our searching strategy. The potentially relevant papers were identified by two independent investigators (Y.P., M.I.). Disagreement between two independent investigators was resolved by discussion and/or by consulting to the senior investigator (J.K.F.).

Eligibility criteria and data extraction

The inclusion criteria for this study were (1) retrospective studies, (2) prospective studies, (3) randomized controlled trials (RCTs), (4) evaluating the association between the incidence of major bleeding and DAPT either using clopidogrel or ticagrelor in ACS patients treated with CABG, (5) providing sufficient data for calculation of OR with 95% CI. While, articles were excluded if the following criteria were found: (1) irrelevant topic, (2) review, (3) conference presentation, and (4) having low quality (see Quality assessment). For data extraction, information related to (1) name of the first author, (2) year of publication, (3) country of origin, (4) sample sizes of case and controls, and (5) the incidence of major bleeding were extracted from each study. To prevent human errors, data extraction was performed by two independent authors. If discrepancy occurred, a consensus or discussion was established.

Covariates and sub-group analysis

The predictor covariate in this study was DAPT either using clopidogrel or ticagrelor. While, the main outcome measure was the incidence of major bleeding in patients receiving both clopidogrel and ticagrelor. The major bleeding included in our analysis was restricted to thrombolysis in myocardial infarction 23 and platelet inhibition and outcomes criteria 24. Moreover, to confer a comprehensive analysis, we also performed sub-group analysis. Data were classified into the incidence of major bleeding in ACS patients treated with DAPT (clopidogrel or ticagrelor) before and after CABG.

Quality assessment

To ensure the quality of each study and to avoid the potential bias in each study, the quality of retrieved studies was controlled and collected by two independent investigators (Y.P., M.I.). The quality and risk of bias of each study was assessed using Methodological Index for Non-Randomized Studies (MINORS) score 25. The MINORS score ranged from 0 to 24, and consisted of 12 items. Each item was assessed as 0 if the item was not reported, 1 if the item was inadequate reported, and 2 if the item was adequate reported. Each study was interpreted as having low quality if the score was less than or equal to 12, moderate if the score was less than or equal to 16 and more than 12, and high quality if the score was more than 16 25. If disagreement was found between two independent authors, consensus was achieved through discussion between the two investigators. If the disagreement was not resolved, a consultation to senior researcher (JKF) was conducted.

Statistical analysis

The comparison and effect estimation of major bleeding between DAPT with clopidogrel and ticagrelor were determined using the Z-test. The pooled calculation and effect estimation were described using forest plots. The model of forest plot for describing the comparison and effect estimation was conformed with a Q test. Before analysis using the Z-test, we evaluated heterogeneity and potential publication bias. A Q-test was employed to evaluate heterogeneity. P-value of less than 0.10 was considered to indicate heterogeneity. If we found heterogeneity, a random effect model was used. While, if heterogeneity was not found, a fixed effect model was used. For testing publication bias, an Egger test was used. A P-value of less than 0.05 was considered significantly having publication bias. All analyses in our study were carried out using Review Manager version 5.3 (RevMan Cochrane, London, UK) and Comprehensive Meta-Analysis (CMA, New Jersey, US) version 2.1.

Results

Eligible studies

A flowchart of article searches and study selection is shown in Figure 1. Initially, 37 articles were identified from the literature search. However, eight of them were excluded because they did not have relevance to the topic, leaving a total of 29 articles. The full text of these articles was retrieved and reviewed; it was found that 16 studies did not meet the eligibility criteria because they were reviews (n=5), commentaries (n=4), family-based studies (n=3), included the same study data (n=2), and not providing sufficient data for calculation of OR and 95%CI (n=2). Finally, a total of 13 studies were eligible for our meta-analysis. Baseline characteristics of studies included in our analysis are provided in Table 1.

Figure 1. A Flowchart diagram of the article search and study selection.

Figure 1.

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Table 1. Baseline characteristics of studies included in the meta-analysis.

Author and year Clopidogrel Ticagrelor Setting
(before/after
CABG)		 Case Study design Ethnicity Age
(mean±SD)		 Bleeding
assessment		 MINORS
MB n MB n
Becker et al. 2011 26 476 9186 446 9235 after CABG STEMI &
NSTEMI		 RCT Mixed 65.5±4.9 TIMI 24
Chang et al. 2019 2 7 100 7 100 after CABG NSTEMI Case - control Asian 64.0±10.0 TIMI 16
Dery et al. 2014 27 37 328 6 55 after CABG ACS Case - control Caucasian 65.5±2.2 BARC-CABG
major
bleeding		 18
Dinicolantonio et al.
2013 28 		654 9186 619 9235 before CABG ACS Case - control Mixed 64.5±2.2 TIMI 18
Gajayana et al. 2018 29 44 1721 7 860 before CABG ACS Case - control Caucasian 63.0±2.6 TIMI 17
Hansson et al. 2014 30 213 232 166 173 before CABG ACS Case - control Caucasian 67.0±9.6 TIMI 24
Hansson et al. 2016 31 95 978 90 1266 before CABG ACS Case - control Caucasian 67.5±9.5 BARC-CABG
major
bleeding		 19
Held et al. 2011 32 375 629 362 632 before CABG ACS Case - control Caucasian 64.0±12.0 TIMI 24
Holm et al. 2019 33 474 1293 381 1018 before CABG ACS Cohort Mixed 66.3±9.6 PLATO 24
Kang et al. 2015 34 929 9291 961 9332 after CABG ACS Case - control Asian 61.3±9.0 PLATO 23
Russo et al. 2018 35 19 413 5 95 before CABG ACS Case - control Caucasian 66.7±13.0 BARC-CABG
major
bleeding		 22
Schaefer et al. 2016 36 0 28 2 28 before CABG ACS Case - control Caucasian 73.0±6.4 TIMI 14
Varenhorst et al.
2012 37 		62 629 32 632 before CABG ACS RCT Mixed 66.8±3.2 TIMI 24
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MB, major bleeding; n, sample size; CABG, coronary artery bypass grafting; RCT, randomized controlled trial; MINORS, Methodological Index for Non-Randomized Studies; STEMI, ST-Elevation Myocardial Infarction; NSTEMI, Non-ST-elevation myocardial infarction; ACS, acute coronary syndrome; TIMI, Thrombolysis In Myocardial Infarction; BARC, Bleeding Academic Research Consortium; PLATO, Platelet inhibition and Outcomes.

Data synthesis

A total of 13 studies 2, 26– 37, consisting 34,014 patients treated with clopidogrel and 32,661 patients treated with ticagrelor, were included in our study. Of those, the correlation between the use of DAPT (either clopidogrel or ticagrelor) and the risk of major bleeding was found in only three studies 29, 30, 37. A further ten studies failed to clarify the association 2, 26– 28, 31– 36. Our calculation revealed ( Figure 2A) that the incidence of major bleeding was not significantly different between clopidogrel and ticagrelor (OR = 1.10, 95%CI = 0.98–1.24, p = 0.0990). Moreover, in pre-CABG sub-group, we included nine studies 28– 33, 35– 37 consisting of 15,109 patients treated with clopidogrel and 13,939 patients treated with ticagrelor. Our results found ( Figure 2B) that no significant different of major bleeding incidence was observed between clopidogrel and ticagrelor (OR = 1.19, 95%CI = 0.97–1.45, p = 0.0910). While, in the post-CABG sub-group, a total of four papers 2, 26, 27, 34 consisting of 18,905 patients treated with clopidogrel and 18,722 patients treated with ticagrelor was enrolled for our analysis. Our pooled data ( Figure 2C) confirmed no significant different in major bleeding incidence between clopidogrel and ticagrelor (OR = 1.00, 95%CI = 0.93–1.08, p = 0.9230). The summary of correlation and effect estimation between the risk of major bleeding and the use of different DAPT is provided in Table 2.

Figure 2. Forest plot of major bleeding comparison between clopidogrel and ticagrelor.

Figure 2.

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( A) Overall analysis. ( B) Pre-coronary artery bypass grafting (CABG) sub-group. ( C) Post-CABG sub-group.

Table 2. Summary of the association between the use of different dual antiplatelet therapies and the risk of major bleeding.

Parameters Clopidogrel Ticagrelor Model OR 95%CI pHet pE P-value
MB, n [%] Patients,
n		 MB, n [%] Patients,
n
Overall analysis 3,385 [9.95] 34,014 3084 [9.44] 32,661 Random 1.10 0.98–1.24 0.0050 0.1310 0.0990
Pre-CABG sub-group 1,936 [12.81] 15,109 1664 [11.94] 13,939 Random 1.19 0.97–1.45 0.0020 0.2060 0.0910
Post-CABG sub-group 1,449 [7.66] 18,905 1,420 [7.58] 18,722 Fixed 1.00 0.93–1.08 0.6470 <0.0001 0.9230
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CABG, coronary artery bypass grafting; MB, major bleeding; OR, odds ratio; CI, confidence interval; pHet, p heterogeneity; pE, p Egger.

Heterogeneity and publication bias

Evidence of heterogeneity was assessed using the Q-test. Our analysis found that evidence of heterogeneity (p <0.10) was observed in overall analysis and pre-CABG sub-group. Therefore, random effect model was applied to determine the correlation and effect estimation. While, for post-CABG sub-group, we used fixed effect model to assess the correlation and effect estimation because we did not find the evidence of heterogeneity. Furthermore, potential publication bias was assessed using an Egger test. Our analysis confirmed that potential publication bias was found in post-CABG sub-group (p <0.05). In overall analysis and pre-CABG sub-group, we found no publication bias. The summary of study heterogeneity and potential publication is described in Table 2.

Discussion

Our current findings confirmed that neither clopidogrel nor ticagrelor was associated with risk of major bleeding among ACS patients treated with CABG. To our knowledge, no previous meta-analysis has reported the comparison between clopidogrel and ticagrelor in the context of CABG. Therefore, we were unable to perform a direct comparison. However, in other case settings, meta-analyses have been conducted in the case of PCI and thrombolytic for treating ACS patients. In the case of PCI for treating ACS patients, the reports from previous meta-analyses remained conflicting. A study conducted by Fan et al. 38 found that clopidogrel was associated with increased risk of major bleeding compared to ticagrelor. On the other hand, Guan et al. 39 revealed that ticagrelor was proven to correlate with increased risk of major bleeding compared to clopidogrel. A meta-analysis conducted by Westman et al. 40 involved 15 papers, consisting of 26,093 patients treated with clopidogrel and 7,192 patients treated with ticagrelor. The authors revealed that although ticagrelor was associated with increased risk of minor bleeding compared to clopidogrel, the incidence of major bleeding was not significantly different between ticagrelor and clopidogrel. Moreover, in the case of fibrinolytic, a meta-analysis involving three RCTs showed that neither ticagrelor nor clopidogrel was correlated with the risk of major bleeding 41. Furthermore, in the case of ACS, a meta-analysis involving 10 studies revealed that the risk of bleeding was not significantly different between patients receiving clopidogrel and ticagrelor 42. Therefore, it makes sense that in our current meta-analysis, no association was observed between the use of DAPT either clopidogrel or ticagrelor and the risk of major bleeding.

Our findings in sub-group analysis were consistent with our main findings, we emphasized that the incidence of major bleeding either in pre- and post-CABG was not significantly different between clopidogrel and ticagrelor. To our knowledge, until now the major bleeding effect of clopidogrel and ticagrelor in the setting of before and after CABG has not been well defined. Besides the existence of no previous meta-analysis concerning this subject, reports in other case settings did not assess this effect in the pre- or post-intervention context of. Hence, the possible direct and indirect explanations was difficult to clarify. To date, the major bleeding effect of DAPT therapy before and after CABG remained conflicting. A previous study revealed that discontinuation of DAPT therapy 24–72 hours before emergency CABG was proven to increase the risk of major bleeding 35. Moreover, Deo et al. 43 also reported that increased risk of major bleeding was observed in post CABG patients treated with ASA and clopidogrel. However, a study by Solo et al. 44 might support our findings. They evaluated the incidence of major bleeding between ASA and clopidogrel and ASA and ticagrelor. Although statistical analysis was not directly performed, they confirmed that the risk of major bleeding in post CABG patients among different anti-platelets had no strong evidence. Therefore, due to inconclusive reports regarding the risk of major bleeding and DAPT therapy before and after CABG, further studies are required to clarify our current findings.

The theory underlying the risk of major bleeding due to clopidogrel or ticagrelor is not well defined. However, some theories have been proposed. To stimulate inhibition of platelet aggregation, both clopidogrel and ticagrelor are P2Y12 antagonists. However, associated with the risk of major bleeding, each agent has a different mechanism. Clopidogrel is known to irreversibly induce bleeding by inhibiting P2Y12 receptors, and may cause persistent blockade of the adenosine diphosphate (ADP) binding site. Those inhibitory effects may persist until the platelets are renewed in 7–10 days 45. Therefore, as it has a longer inhibitory effect than ticagrelor, those treated with clopidogrel may be more vulnerable to risk of bleeding than ticagrelor 42. Ticagrelor is a reversible P2Y12 receptor antagonist. It works directly on P2Y12 receptors, and therefore may produce rapid inhibition effects and provide rapid recovery of platelet function 46. It has been already reported that ticagrelor has faster onset and offset than clopidogrel 47. As a result, when each drug is stopped, the effect of ticagrelor may disappear faster than clopidogrel. In animal subjects, a study proposed that clopidogrel was found to have 3.5-fold associated with higher bleeding risk compared to ticagrelor 48. Clopidogrel is metabolized by cytochrome P2C19 enzyme 49, and recent gene-disease interaction studies reported that cytochrome P2C19 CYP2C19*20 C-889T>G (SNP rs11568732) was associated with the risk of bleeding in ACS patients treated with clopidogrel 50– 52. Therefore, theoretically, the risk of major bleeding with clopidogrel should be higher than with ticagrelor. However, the evidence from previous large-scale studies, including our present meta-analysis, are conflicting and have not clarified the association. Hence, because it was not supported by the evidence, in our opinion, the risk of major bleeding due to different DAPT, for this time being, might be considered as a hypothesis. In the near future, we expected that more complex study designs might be applied to elucidate the real association between the risk of major bleeding and the use of different DAPT.

To the best of our knowledge, our present study was the first meta-analysis assessing the association between the risk of major bleeding and the use of different DAPT in ACS patients treated with CABG. Our current meta-analysis might clarify the inconclusive findings of previous studies regarding this topic, and we emphasized that clopidogrel, compared to ticagrelor, or vice versa, was not associated with the risk of major bleeding in ACS patients treated with CABG. In the last decade, the use of DAPT, either clopidogrel or ticagrelor, has brought about a dilemma for physicians due to the assumption that one of them was considered to trigger the risk of major bleeding. This dilemma was worsened owing to drug marketing competition among pharmaceutical industries to recommend ticagrelor over clopidogrel. However, our present study indicates that the dilemma was not supported by evidence, and therefore the dilemma might be considered as "the ocean without the waves". The present meta-analysis emphasizes the safety of DAPT administration, either clopidogrel or ticagrelor, in the context of the risk of major bleeding, and hence we expect that our present meta-analysis might reduce the dilemma regarding the risk of major bleeding due to the use of DAPT either clopidogrel or ticagrelor among physicians. The management of ACS patients using CABG has developed in the last decade, and therefore the use of DAPT in CABG management should conform with the adequate evidence. Furthermore, we hope that our current meta-analysis might be involved in the future revision of CABG management for treating patients with ACS.

In our present study, several crucial limitations were observed. First, some factors that might contribute to the risk of major bleeding, such as coagulation factors, history of stroke, chronic kidney disease, hyperglycemia, and anemia 53, were not included and controlled for. Second, our current findings should be interpreted with caution due to relatively small sample size. Third, more than a half of our included studies were cross-sectional studies, and might provide the methodological bias. Therefore, our results should be interpreted with caution. In the near future, we expected that further meta-analyses by including papers with higher study design might be conducted to obtain better evidence. Fourth, human factors (skills) were not involved in the analysis. Fifth, other drugs that might govern the risk of bleeding were not analyzed.

Conclusion

Our meta-analysis reveals that the use of different DAPT either clopidogrel or ticagrelor is not associated with the risk of major bleeding in ACS patients treated with CABG. Our sub-group analysis also fails to confirm this association both in pre- and post-CABG sub-groups. Our findings may provide the clarification of previous conflicting studies in the context of the risk of major bleeding and the use of different DAPT in ACS patients treated with CABG. We also expect that our findings may contribute to the future recommendation of the use of DAPT among ACS patients treated with CABG.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Figshare: PRISMA checklist for ‘Comparison of major bleeding in patients with acute coronary syndrome that underwent coronary artery bypass grafting treated with clopidogrel or ticagrelor: a systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.11688525.v1 22.

Acknowledgements

We thank MIT-Indonesia Research Alliance (MIRA), Lembaga Pengelola Dana Pendidikan (LPDP), and DSKF publishing campus for supporting our project.

Funding Statement

This project was funded by MIT-Indonesia Research Alliance (MIRA) (No. 23/G/R/V/2019).

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

[version 2; peer review: 2 approved

References

  • 1. Burlacu A, Tinica G, Nedelciuc I, et al. : Strategies to Lower In-Hospital Mortality in STEMI Patients with Primary PCI: Analysing Two Years Data from a High-Volume Interventional Centre. J Interv Cardiol. 2019;2019: 3402081. 10.1155/2019/3402081 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Chang HW, Kim HJ, Yoo JS, et al. : Clopidogrel versus Ticagrelor for Secondary Prevention after Coronary Artery Bypass Grafting. J Clin Med. 2019;8(1):E104. 10.3390/jcm8010104 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Schömig A, Neumann FJ, Kastrati A, et al. : A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334(17):1084–9. 10.1056/NEJM199604253341702 [DOI] [PubMed] [Google Scholar]
  • 4. Anderson JL, Adams CD, Antman EM, et al. : ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007;116(7):e148–304. 10.1161/CIRCULATIONAHA.107.181940 [DOI] [PubMed] [Google Scholar]
  • 5. Amsterdam EA, Wenger NK, Brindis RG, et al. : 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139–e228. 10.1016/j.jacc.2014.09.017 [DOI] [PubMed] [Google Scholar]
  • 6. Roffi M, Patrono C, Collet JP, et al. : 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267–315. 10.1093/eurheartj/ehv320 [DOI] [PubMed] [Google Scholar]
  • 7. Arora S, Shemisa K, Vaduganathan M, et al. : Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;73(19):2454–64. 10.1016/j.jacc.2019.03.470 [DOI] [PubMed] [Google Scholar]
  • 8. Li B, Jin X, Wang L, et al. : Loss of dominance of ticagrelor over clopidogrel in East Asian patients with acute coronary syndrome. Int J Clin Exp Med. 2019;12(5):4528–39. Reference Source [Google Scholar]
  • 9. Jiang Z, Zhang R, Sun M, et al. : Effect of Clopidogrel vs Ticagrelor on Platelet Aggregation and Inflammation Markers After Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction. Can J Cardiol. 2018;34(12):1606–12. 10.1016/j.cjca.2018.08.024 [DOI] [PubMed] [Google Scholar]
  • 10. Valgimigli M, Bueno H, Byrne RA, et al. : 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213–60. 10.1093/eurheartj/ehx419 [DOI] [PubMed] [Google Scholar]
  • 11. Wallentin L, Becker RC, Budaj A, et al. : Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. 10.1056/NEJMoa0904327 [DOI] [PubMed] [Google Scholar]
  • 12. Gimbel ME, Minderhoud SCS, Ten Berg JM: A practical guide on how to handle patients with bleeding events while on oral antithrombotic treatment. Neth Heart J. 2018;26(6):341–51. 10.1007/s12471-018-1117-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Sobolev BG, Levy AR, Kuramoto L, et al. : The risk of death associated with delayed coronary artery bypass surgery. BMC Health Serv Res. 2006;6: 85. 10.1186/1472-6963-6-85 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. 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: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation. 2016;134(10):e123–55. 10.1161/CIR.0000000000000404 [DOI] [PubMed] [Google Scholar]
  • 15. Fajar JK, Andalas M, Harapan H: Comparison of Apgar scores in breech presentations between vaginal and cesarean delivery. Ci Ji Yi Xue Za Zhi. 2017;29(1):24–9. 10.4103/tcmj.tcmj_5_17 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Fajar JK, Harapan H: Socioeconomic and attitudinal variables associated with acceptance and willingness to pay towards dengue vaccine: a systematic review. Arch Clin Infet Dis. 2017;12(3):e13914 10.5812/archcid.13914 [DOI] [Google Scholar]
  • 17. Fajar JK, Heriansyah T, Rohman MS: The predictors of no reflow phenomenon after percutaneous coronary intervention in patients with ST elevation myocardial infarction: A meta-analysis. Indian Heart J. 2018;70(Suppl 3):S406–S18. 10.1016/j.ihj.2018.01.032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Fajar JK, Mahendra AI, Tamara F, et al. : The Association Between Complete Blood Count and the Risk of Coronary Heart Disease. Turkiye Klinikleri J Med Sci. 2019;39(1):56–64. 10.5336/medsci.2018-61970 [DOI] [Google Scholar]
  • 19. Fajar JK, Taufan T, Syarif M, et al. : Hip geometry and femoral neck fractures: A meta-analysis. J Orthop Translat. 2018;13:1–6. 10.1016/j.jot.2017.12.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Prihatiningsih S, Fajar JK, Tamara F, et al. : Risk factors of tuberculosis infection among health care workers: a meta-analysis. Indian J Tuberc. 2020;67(1):121–129. 10.1016/j.ijtb.2019.10.003 [DOI] [PubMed] [Google Scholar]
  • 21. Moher D, Liberati A, Tetzlaff J, et al. : Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. 10.1371/journal.pmed.1000097 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Fajar JK: PRISMA: Comparison of major bleeding in patients with acute coronary syndrome that underwent coronary artery bypass grafting treated with clopidogrel or ticagrelor: a systematic review and meta-analysis. figshare.Dataset.2020. 10.6084/m9.figshare.11688525.v1 [DOI] [PMC free article] [PubMed]
  • 23. Mehran R, Rao SV, Bhatt DL, et al. : Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–47. 10.1161/CIRCULATIONAHA.110.009449 [DOI] [PubMed] [Google Scholar]
  • 24. Husted S, James SK, Bach RG, et al. : The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2014;35(23):1541–50. 10.1093/eurheartj/ehu075 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Slim K, Nini E, Forestier D, et al. : Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712–6. 10.1046/j.1445-2197.2003.02748.x [DOI] [PubMed] [Google Scholar]
  • 26. Becker RC, Bassand JP, Budaj A, et al. : Bleeding complications with the P 2Y 12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011;32(23):2933–44. 10.1093/eurheartj/ehr422 [DOI] [PubMed] [Google Scholar]
  • 27. Dery J, Dagenais F, Mohammadi S, et al. : Risk of bleeding complications in patients treated with ticagrelor undergoing urgent coronary artery bypass grafting surgery: a single center experience. Can J Cardiol. 2014;30(10):S328 10.1016/j.cjca.2014.07.595 [DOI] [Google Scholar]
  • 28. DiNicolantonio JJ, D'Ascenzo F, Tomek A, et al. : Clopidogrel is safer than ticagrelor in regard to bleeds: a closer look at the PLATO trial. Int J Cardiol. 2013;168(3):1739–44. 10.1016/j.ijcard.2013.06.135 [DOI] [PubMed] [Google Scholar]
  • 29. Gajanana D, Weintraub WS, Kolm P, et al. : The impact of in-hospital P2Y12 inhibitor switch in patients with acute coronary syndrome. Cardiovasc Revasc Med. 2018;19(8):912–6. 10.1016/j.carrev.2018.09.007 [DOI] [PubMed] [Google Scholar]
  • 30. Hansson EC, Jidéus L, Aberg B, et al. : Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel: a nationwide study. Eur Heart J. 2016;37(2):189–97. 10.1093/eurheartj/ehv381 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Hansson EC, Rexius H, Dellborg M, et al. : Coronary artery bypass grafting-related bleeding complications in real-life acute coronary syndrome patients treated with clopidogrel or ticagrelor. Eur J Cardiothorac Surg. 2014;46(4):699–705. 10.1093/ejcts/ezt662 [DOI] [PubMed] [Google Scholar]
  • 32. Held C, Asenblad N, Bassand JP, et al. : Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2011;57(6):672–84. 10.1016/j.jacc.2010.10.029 [DOI] [PubMed] [Google Scholar]
  • 33. Holm M, Biancari F, Khodabandeh S, et al. : Bleeding in Patients Treated With Ticagrelor or Clopidogrel Before Coronary Artery Bypass Grafting. Ann Thorac Surg. 2019;107(6):1690–8. 10.1016/j.athoracsur.2019.01.086 [DOI] [PubMed] [Google Scholar]
  • 34. Kang HJ, Clare RM, Gao R, et al. : Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Am Heart J. 2015;169(6):899–905.e1. 10.1016/j.ahj.2015.03.015 [DOI] [PubMed] [Google Scholar]
  • 35. Russo JJ, James TE, Ruel M, et al. : Ischemic and bleeding outcomes after coronary artery bypass grafting among patients initially treated with a P2Y 12 receptor antagonist for acute coronary syndromes: Insights on timing of discontinuation of ticagrelor and clopidogrel prior to surgery. Eur Heart J Acute Cardiovasc Care. 2008;2048872617740832. 10.1177/2048872617740832 [DOI] [PubMed] [Google Scholar]
  • 36. Schaefer A, Sill B, Schoenebeck J, et al. : Preoperative Ticagrelor administration leads to a higher risk of bleeding during and after coronary bypass surgery in a case-matched analysis. Interact Cardiovasc Thorac Surg. 2016;22(2):136–40. 10.1093/icvts/ivv296 [DOI] [PubMed] [Google Scholar]
  • 37. Varenhorst C, Alström U, Scirica BM, et al. : Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol. 2012;60(17):1623–30. 10.1016/j.jacc.2012.07.021 [DOI] [PubMed] [Google Scholar]
  • 38. Fan ZG, Zhang WL, Xu B, et al. : Comparisons between ticagrelor and clopidogrel following percutaneous coronary intervention in patients with acute coronary syndrome: a comprehensive meta-analysis. Drug Des Devel Ther. 2019;13:719–30. 10.2147/DDDT.S196535 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Guan W, Lu H, Yang K: Choosing between ticagrelor and clopidogrel following percutaneous coronary intervention: A systematic review and Meta-Analysis (2007–2017). Medicine (Baltimore). 2018;97(43):e12978. 10.1097/MD.0000000000012978 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Westman PC, Lipinski MJ, Torguson R, et al. : A comparison of cangrelor, prasugrel, ticagrelor, and clopidogrel in patients undergoing percutaneous coronary intervention: A network meta-analysis. Cardiovasc Revasc Med. 2017;18(2):79–85. 10.1016/j.carrev.2016.10.005 [DOI] [PubMed] [Google Scholar]
  • 41. Kheiri B, Osman M, Abdalla A, et al. : Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a systematic review and meta-analysis of randomized clinical trials. J Thromb Thrombolysis. 2018;46(3):299–303. 10.1007/s11239-018-1706-2 [DOI] [PubMed] [Google Scholar]
  • 42. Wang D, Yang XH, Zhang JD, et al. : Compared efficacy of clopidogrel and ticagrelor in treating acute coronary syndrome: a meta-analysis. BMC Cardiovasc Disord. 2018;18(1):217. 10.1186/s12872-018-0948-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Deo SV, Dunlay SM, Shah IK, et al. : Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis. J Card Surg. 2013;28(2):109–16. 10.1111/jocs.12074 [DOI] [PubMed] [Google Scholar]
  • 44. Solo K, Lavi S, Kabali C, et al. : Antithrombotic treatment after coronary artery bypass graft surgery: systematic review and network meta-analysis. BMJ. 2019;367:l5476. 10.1136/bmj.l5476 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Becker RC, Gurbel PA: Platelet P2Y 12 receptor antagonist pharmacokinetics and pharmacodynamics: A foundation for distinguishing mechanisms of bleeding and anticipated risk for platelet-directed therapies. Thromb Haemost. 2010;103(3):535–44. 10.1160/TH09-07-0491 [DOI] [PubMed] [Google Scholar]
  • 46. VAN Giezen JJ, Nilsson L, Berntsson P, et al. : Ticagrelor binds to human P2Y 12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost. 2009;7(9):1556–65. 10.1111/j.1538-7836.2009.03527.x [DOI] [PubMed] [Google Scholar]
  • 47. 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(25):2577–85. 10.1161/CIRCULATIONAHA.109.912550 [DOI] [PubMed] [Google Scholar]
  • 48. van Giezen JJJ, Berntsson P, Zachrisson H, et al. : Comparison of ticagrelor and thienopyridine P2Y(12) binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis. Thromb Res. 2009;124(5):565–71. 10.1016/j.thromres.2009.06.029 [DOI] [PubMed] [Google Scholar]
  • 49. Sangkuhl K, Klein TE, Altman RB: Clopidogrel pathway. Pharmacogenet Genomics. 2010;20(7):463–5. 10.1097/FPC.0b013e3283385420 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Wallentin L, James S, Storey RF, et al. : Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376(9749):1320–8. 10.1016/S0140-6736(10)61274-3 [DOI] [PubMed] [Google Scholar]
  • 51. Novkovic M, Matic D, Kusic-Tisma J, et al. : Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel. Eur J Clin Pharmacol. 2018;74(4):443–51. 10.1007/s00228-017-2401-5 [DOI] [PubMed] [Google Scholar]
  • 52. Mirabbasi SA, Khalighi K, Wu Y, et al. : CYP2C19 genetic variation and individualized clopidogrel prescription in a cardiology clinic. J Community Hosp Intern Med Perspect. 2017;7(3):151–6. 10.1080/20009666.2017.1347475 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, et al.: Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4. 10.1111/j.1538-7836.2005.01204.x [DOI] [PubMed] [Google Scholar]
F1000Res. 2021 Feb 15. doi: 10.5256/f1000research.29314.r77741

Reviewer response for version 2

Mircea Ovanez Balasanian 1

I consider this systematic review interesting because it shows no significant differences in the risk of major bleeding events of different DAPT use, clopidogrel or ticagrelor, in ACS patients treated with CABG, and also in the pre- and post-CABG settings.

The rationale and objectives of this review are clearly stated, and the methodology and analysis can be replicated, with appropriate interpretation. The conclusions are supported by the results obtained in this review.

I think it is a well done work that could serve as a point for further studies in this area.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

Yes

Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Reviewer Expertise:

Cardiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

F1000Res. 2020 Aug 25. doi: 10.5256/f1000research.24175.r69370

Reviewer response for version 1

Sheng-Hu He 1, Bing Xu 1

This systematic review and meta-analysis aimed to compare the risk of major bleeding between clopidogrel and ticagrelor in ACS patients treated with CABG. It is a meaningful clinical topic that needs more support from evidence-based medicine. According to the results of this study, ticagrelor should be used more confidently in ACS patients treated with CABG.

However, there are disadvantages in some issues:

  1. The characteristic summary of the 13 included trials was not shown in the manuscript. It is an important part of a meta-analysis, which should contain the data of age, gender, race, doses of medication, and bleeding risk scores.

  2. Because only 2 of them are RCTs, most of them are case-control trails, the methodological bias of the included studies should be analyzed. There are many methods that can estimate the qualities of the included studies, at least one of them should be used in this study to remind the readers interpreting the results with caution.

  3. Although this study has analyzed the main observation, the risk of major bleeding, and did subgroup analysis for pre-surgery and post-surgery patients, other factors should be considered using subgroup analysis, for example, race, region, dose and time, bleeding risk scores if possible.

  4. The logic of the discussion is not very clear. The structure of this part should be modified, some points should be simplified, and some duplicate expressions should be removed to make readers understand quicker and easier.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

Yes

Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Reviewer Expertise:

Interventional cardiology

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

F1000Res. 2020 Sep 1.
Jonny Fajar 1

1. This systematic review and meta-analysis aimed to compare the risk of major bleeding between clopidogrel and ticagrelor in ACS patients treated with CABG. It is a meaningful clinical topic that needs more support from evidence-based medicine. According to the results of this study, ticagrelor should be used more confidently in ACS patients treated with CABG. However, there are disadvantages in some issues: The characteristic summary of the 13 included trials was not shown in the manuscript. It is an important part of a meta-analysis, which should contain the data of age, gender, race, doses of medication, and bleeding risk scores.

Response: We have provided the additional characteristics in Table 1.

2. Because only 2 of them are RCTs, most of them are case-control trails, the methodological bias of the included studies should be analyzed. There are many methods that can estimate the qualities of the included studies, at least one of them should be used in this study to remind the readers interpreting the results with caution.

Response: The additional information regarding the possibility of methodological bias and to interpret our results with caution has been provided in study limitations.

"Third, more than a half of our included studies were cross-sectional studies, and might provide the methodological bias. Therefore, our results should be interpreted with caution."

3. Although this study has analyzed the main observation, the risk of major bleeding, and did subgroup analysis for pre-surgery and post-surgery patients, other factors should be considered using subgroup analysis, for example, race, region, dose and time, bleeding risk scores if possible.

Response: We have tried to perform sub-group analyses in accordance with ethnicity, region, dose, and bleeding risk score; however, the data were imbalanced, and therefore the calculation was unable to be performed.

4. The logic of the discussion is not very clear. The structure of this part should be modified, some points should be simplified, and some duplicate expressions should be removed to make readers understand quicker and easier.

Response: We have revised our manuscript in some part to increase the consistency of the text and to avoid the unnecessary repetition without changing the meanings or findings.

F1000Res. 2020 Jun 23. doi: 10.5256/f1000research.24175.r61678

Reviewer response for version 1

Jinesh Bahubali Nagavi 1

  • The article is well explained with all the data and results.

  • The conclusion is very short and precise.

  • Search strategy should be elaborated.

  • Objectives should be mentioned clearly in the abstract.

  • The discussion part is explained well in detail.

  • Statistical analysis and its interpretation is appropriate

  • Choice of references is very opt and good.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

Yes

Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Reviewer Expertise:

Drug interaction studies

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

F1000Res. 2020 Sep 1.
Jonny Fajar 1

Thank you for reviewer comments. We have revised our manuscript in some part to increase the consistency of the text without changing the meanings or findings.

1. The article is well explained with all the data and results.

Response: Thank you.

2. The conclusion is very short and precise.

Response: Thank you.

3. Search strategy should be elaborated.

Response: The search strategy has been provided in methods.

"Search strategy

We conducted a systematic search in PubMed, Embase, Cochrane, and Web of Science up to 20 September 2019. The search strategy, conformed to medical subjects heading (MeSH), involved the use of combination the following keywords: ["Major Bleeding"] AND ["Coronary Artery Bypass Grafting" OR "CABG"] AND ["Dual Anti Platelet Therapy" OR "DAPT"], and ["Clopidogrel" OR "Ticagrelor"]. In our searching strategy, language restrictions were not applied. We only used the study with the larger sample size and that was more up-to-date if we found the same data among studies. Moreover, we also searched the potential papers from the reference list of relevant or eligible studies. We also employed the "related article" option in PubMed to broaden our searching strategy. The potentially relevant papers were identified by two independent investigators (Y.P., M.I.). Disagreement between two independent investigators was resolved by discussion and/or by consulting to the senior investigator (J.K.F.)."

4. Objectives should be mentioned clearly in the abstract.

Response: The objective of our study has been outlined in abstract.

"This study aimed to perform a meta-analysis concerning the relation between the risk of major bleeding and the use of different DAPT (clopidogrel or ticagrelor) in ACS patients treated with CABG."

5. The discussion part is explained well in detail.

Response: Thank you.

6. Statistical analysis and its interpretation is appropriate.

Response: Thank you.

7. Choice of references is very opt and good.

Response: Thank you.

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Data Citations

    1. Fajar JK: PRISMA: Comparison of major bleeding in patients with acute coronary syndrome that underwent coronary artery bypass grafting treated with clopidogrel or ticagrelor: a systematic review and meta-analysis. figshare.Dataset.2020. 10.6084/m9.figshare.11688525.v1 [DOI] [PMC free article] [PubMed]

    Data Availability Statement

    Underlying data

    All data underlying the results are available as part of the article and no additional source data are required.

    Reporting guidelines

    Figshare: PRISMA checklist for ‘Comparison of major bleeding in patients with acute coronary syndrome that underwent coronary artery bypass grafting treated with clopidogrel or ticagrelor: a systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.11688525.v1 22.

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