A Comparison of the Effects of Ticagrelor and Clopidogrel in Patients with Acute ST-Segment Elevation Myocardial Infarction: A systematic review and Meta-analysis

doi:10.21203/rs.3.rs-2512875/v1

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A Comparison of the Effects of Ticagrelor and Clopidogrel in Patients with Acute ST-Segment Elevation Myocardial Infarction: A systematic review and Meta-analysis

https://doi.org/10.21203/rs.3.rs-2512875/v1

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Background

Rupture of unstable coronary atherosclerotic plaque leads to acute ST segment elevation myocardial infarction which is the most critical type of acute coronary syndrome. Dual anti-platelet therapy is one the main treatments and the combination of Aspirin and Clopidogrel is recognized as the standard oral regimen in most cases. Ticagrelor is a new generation of P2Y12 receptor inhibitors, which is a direct P2Y12 receptor antagonist. The goal of this study is to compare the effect of Ticagrelor and Clopidogrel in treatment of STEMI.

Methods

In this study, Pub Med, Scopus, Google Scholar Web of Science, Embase and Cochrane library clinical trials.gov databases were investigated. Inhomogeneity between studies was assessed using the I2 index and the Q statistic. The random effects model was used to combine studies. The Funnel plot and Egger's test were used to assess the publication bias. A probability value of less than 5 percent was considered a significant level.

Results

Eleven studies were included in this meta-analysis. Five thousand two hundred seventy-four patients in the Ticagrelor group and 5,295 patients in the Clopidogrel group were examined. The mean (standard deviation) age of the patients was 58.84 years (2.70) and 59.92 years (3.19) in the Ticagrelor group and the Clopidogrel group, respectively. Based on the results of the meta-analysis, compared to Clopidogrel, Ticagrelor had a protective effect on the outcomes of recurrent myocardial infarction, stroke, Major Adverse Cardiovascular Events (MACE), post-myocardial infarction bleeding according to Bleeding Academic Research Consortium (BARC) criteria, mortality, and reperfusion state regarding thrombolysis in myocardial infarction (TIMI) Flow Grading system. However, this effect was not statistically significant, and the publication bias was not statistically significant either.

Conclusions

According to the present study, although Ticagrelor increased the chance of bleeding according to the BARC score, compared to Clopidogrel, there was more improvement in TIMI score and fewer problems related to stroke, mortality, MI, and MACE in patients who took Ticagrelor.

Acute Coronary syndrome

Ticagrelor

Clopidogrel

Anti-platelet

Acute Coronary Syndrome (ACS) is a clinical syndrome that includes unstable angina, non-ST elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). Among these, acute STEMI is the most critical type of ACS, characterized by poor prognosis, rapid onset, dangerous progression, and high mortality rate. Rupture of unstable coronary atherosclerotic plaque, which causes thrombosis, acute MI, and even necrosis, leads to acute STEMI. Therefore, the opening of the Infarct-Related Artery (IRA), which restores the ischemic myocardium and reperfuse the vessel, leads to the successful treatment of acute STEMI(1). Therapy in STEMI patients can be pursued with two strategies, primary percutaneous coronary intervention (PPCI) and aggressive Pharmacological Interventions (PIs)(2). PIs are defined as the early administration of fibrinolytic therapy followed by Percutaneous Coronary Intervention (PCI) (3). Although according to clinical guidelines, PPCI is the preferred reperfusion method chosen for these patients, fibrinolytic therapy is the first line of treatment in situations where timely treatment of the patient with PPCI is not possible. (1, 4)

Antiplatelet therapy is an essential part of the treatment regimen of patients with coronary artery disease, and the importance of dual antiplatelet therapy in the treatment of STEMI patients has been acknowledged(5–7). The combination of Aspirin and Clopidogrel is recognized as the standard oral antiplatelet regimen in ACS. However, the antiplatelet effect of Clopidogrel requires sequential and time-consuming metabolic steps, a fact that leads to a delay in achieving platelet inhibition. In addition, a very small proportion of patients are genetically resistant to Clopidogrel, and the level of response to this agent can be somewhat unpredictable. These disadvantages of Clopidogrel have led to the development of more potent and faster antiplatelet drugs such as Ticagrelor(8–10). Ticagrelor has been introduced as a new generation of P2Y12 receptor inhibitors, which is a direct P2Y12 receptor antagonist (11, 12). Although the superiority of Ticagrelor's clinical efficacy has been shown in various studies, issues related to its side effects, such as the risk of major bleeding, which increases the mortality rate, require further investigation(4, 13–15). This present study aims at performing a meta-analysis of Randomized Clinical Trial (RCT) studies to compare the effects of Ticagrelor and Clopidogrel in STEMI patients.

This systematic meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (16).

Data Sources

In order to compare the efficacy of Clopidogrel and Ticagrelor in patients with STEMI, a systematic review of published studies was conducted. For this purpose, the databases PubMed, Scopus, Google Scholar Web of Science, and Embase Cochrane library clinical trials.gov were searched using the logical combination of keywords and their MeSH terms, including, Ticagrelor, Clopidogrel, ST-segment elevation myocardial infarction, P2Y12 inhibitors, and antiplatelet therapy. This search was conducted until the end of June 2022.

Selection criteria and data extraction

Randomized Clinical Trial (RCT) studies published in English and compared antiplatelet therapy with Ticagrelor and Clopidogrel in STEMI patients were included in this study. Studies whose full text was not available were excluded. In case of overlapping research data, such as information from the same RCT published in multiple articles, the most complete and up-to-date report was selected for inclusion in the meta-analysis. For further clarification, direct contact with authors was initiated for cases with either vague or incomplete information. In addition, an identical search strategy was adopted in other databases, and the key journals and reference lists of the presented articles were also searched. Finally, searches were combined using Endnote X5.

The following inclusion criteria were considered for the review of articles: 1) Randomized clinical trial studies (RCT), 2) Articles published in English or Farsi, whose full text was available, 3) Studies conducted on human subjects over 18 years of age and 4) Studies comparing antiplatelet treatment with Ticagrelor and Clopidogrel in STEMI patients. The inclusion criteria included the following: 1) studies that examined patients with comorbidity, 2) studies that provided incomplete information about the intended outcomes of the study, and 3) studies that had a design other than RCT and were written in a language other than Farsi or English.

The researchers extracted the information from the articles in Excel form. This information included the bibliographic information of the articles (title, authors, year of publication, country, TRIAL registry number), patient characteristics (sample size, age, sex ratio of each gender), study drug characteristics (dose, follow-up, number of patients in each arm of the study, loading dose and maintenance dose) and information about the outcomes of the study (mortality, stroke, MI, MACE, BARC, and TIMI Flow Grade).

Major Adverse Cardiovascular Events (MACE)

MACE is the sum of outcomes such as re-hospitalization due to heart failure (HF), total death, MI, revascularization including percutaneous interventions and surgical bypass grafts, and stroke. (17)

Bleeding academic research consortium (BARC) score

New advances in the treatment of ACS, including the prescription of dual antiplatelet therapies and anticoagulants simultaneously, as well as revascularization methods such as thrombolytics and invasive trans-arterial revascularization methods, have lowered the risk of mortality and many other adverse effects post-MI. However, they significantly increase the risk of major bleeding. To evaluate the safety of antithrombotic treatments in clinical trials regarding the risk of bleeding, academic research consortium (BARC) criteria were defined in February 2010. The BARC criteria divided the post-MI bleeding into 5 types, from type0: no bleeding to type:5 fetal bleeding. (18)

Thrombolysis in myocardial infarction (TIMI)Flow Grade

Thrombolysis in myocardial infarction (TIMI) criteria is defined by the contrast flow rate assessed visually during coronary angiography before and after treatment, and it’s been proven to have prognostic information in post-MI patients. The criteria were first introduced in 1984 and consists of 3 stages: stage 0: no antegrade flow to stage 3: which shows normal flow distal to the coronary artery lesion. (19)

The Standard Cochrane Collaboration risk of bias tool checklist in Revman 5.3 software was used to evaluate the methodology of the included articles. Also, the GRADE (The Grading of Recommendation Assessment, Development, and Evaluation) tool was used to check the quality of the evidence obtained from the meta-analyzer. All steps of the search, selection of studies, data extraction, and quality assessment were carried out by two independent authors, and if there were any differences, they were resolved by discussion until reaching a consensus or by consulting the third author.

Statistical analysis

The number of occurrences for each outcome was extracted along with the sample size of the articles. I2 index and Q statistic were used to check the lack of homogeneity between studies. An I2 value greater than 50% was considered as the presence of inhomogeneity. Random effects model was used to combine studies, and the Risk Ratio was calculated. Funnel Plot and Egger's tests were used to check the publication bias. A probability value of less than 5 percent was considered a significant level. For data analysis, the meta package available in R software version 4.2.1 was used. The result of quality assessment has been shown in figure 2

Meta-analysis results:

Literature screening results

3416 relevant studies from Pub Med, Scopus, Google Scholar Web of Science, Embase, and Cochrane library clinical trials.gov databases were investigated were preliminarily retrieved using keywords search.1138 studies were replicated studies. by reviewing titles and abstracts, 2006 articles were removed. in the next step, 261 articles were removed through full-text review. finally, 11 articles meet the criteria for inclusion in the present study. Figure 1

Basic characteristics of included studies and Quality assessment results

11 studies(20-31) were included in this systematic review and meta-analysis. 5,274 participants in the ticagrelor group and 5295 participants in the clopidogrel group were examined(4, 6, 13, 24, 27, 32-37). 5 studies(21, 22, 24, 28, 31) were prospective, randomized, open-label, and 1 was(27) prospective, randomised, double-blind. 1 study(20) was prospective, randomized, parallel design. The mean (standard deviation) ages of patients in the ticagrelor group and the clopidogrel group were 58.84 years (2.70) and 59.92 years (3.19), respectively. 873 patients in the ticagrelor group (16.55%) and 882 patients in the clopidogrel group (16.65%) had diabetes. characteristics of the included studies are shown in Table 1. The result of quality assessment has been shown in figure 2

Mortality

In 6 studies deaths had been reported in two groups of patients. The number of patients in the Ticagrelor and Clopidogrel groups was 2,480 and 2,443, respectively. Also, the number of deaths observed in the Ticagrelor and Clopidogrel groups was 78 and 91, respectively. Based on the results of the meta-analysis, the risk ratio of death in the ticagrelor group was 0.86 more than that of the clopidogrel group, which was not statistically significant (RR=0.857, 95% CI = (0.637-1.153), z-value=-1.02, p-value= 0.31). The forest plot related to the combination of results is shown in figure 3.

Stroke

In 5 studies, stroke rates had been reported in two groups of patients. The number of patients in the Ticagrelor and Clopidogrel groups was 2,312 and 2,276, respectively. Also, the prevalence of stroke amongst the Ticagrelor and Clopidogrel groups was 29 and 36, respectively. Based on the results of the meta-analysis, the Risk Ratio for Stroke in the ticagrelor group was 0.83 more than that of the clopidogrel group, which was not statistically significant (RR=0.83, 95% CI = (0.508-1.348), z-value=-0.76, p-value =0.45). The forest plot related to the combination of results is shown in the figure 4.(38)

Recurrent myocardial infarction (MI)

In 6 studies, Recurrent MI was reported in two groups of patients. The number of patients in the Ticagrelor and clopidogrel groups was 2467 and 2470, respectively, and the number of recurrent MI observed in the Ticagrelor and Clopidogrel groups was 49 and 58, respectively. Based on the results of the meta-analysis, the Risk Ratio for MI in the Ticagrelor group was 0.68 more than that of the Clopidogrel group, which was not statistically significant (RR=0.68, 95% CI = (0.333-1.382), z-value=-1.07, p-value =0.28). The forest plot related to the combination of results is shown in figure 5.

MACE: Major Adverse Cardiovascular Events

In 4 studies, MACE was reported in two groups of patients. The number of patients in the ticagrelor and clopidogrel groups was 457 and 488, respectively. Also, the incidence of MACE observed in the Ticagrelor and Clopidogrel groups was 10 and 20, respectively. Based on the results of the meta-analysis, the Risk Ratio for MACE in the ticagrelor group was 0.63 more than that of the clopidogrel group, which was not statistically significant (RR=0.63, 95% CI = (0.226-1.75), z-value=-0.89, p-value =0.37). The forest plot related to the combination of results is shown in the figure 6.

Bleeding academic research consortium (BARC) criteria

In 7 studies, BARC scores were reported in two groups of patients. The number of patients in the Ticagrelor and Clopidogrel groups was 2,635 and 2,637, respectively, and the number of BARC scores equal and more than 3(BARC≥3), defined by overt bleeding causing hemoglobin drop or intracranial hemorrhage, observed in the Ticagrelor and Clopidogrel groups was 48 and 48, respectively. Based on the results of the meta-analysis, the Risk Ratio for BARC≥3 in the Ticagrelor group was 1.02 times more than that of the Clopidogrel group, which was not statistically significant (RR=1.02, 95% CI = (0.651-1.595), z-value=0.08, p-value= 0.93). The forest plot related to the combination of results is shown in the figure 7.

Thrombolysis in myocardial infarction (TIMI)Flow Grade

In 5 studies, TIMI Flow Grade was reported according to angiographic findings in two groups of patients. The number of patients in the Ticagrelor and Clopidogrel groups was 2,067 and 2,032, respectively. An increase in TIMI Flow Grade was reported in the 135 and 130 participants of the Ticagrelor and Clopidogrel groups. Based on the results of the meta-analysis, the Risk Ratio for an increase in the TIMI Flow Grade amongst the ticagrelor group was 1.02 more than that of the clopidogrel group, which was not statistically significant (RR=1.02, 95% CI = (0.86-1.201), z-value=0.19, p- value=0.85). The forest plot related to the combination of results is shown in the figure 8.

Publication Bias

To assess the publication bias and Egger test results, Funnel plots related to each of the results are shown in the figures 9. Egger's test was significant for MI outcomes, while the publication bias was not statistically significant for the rest of the studied outcomes.

GRADE results

GRADE results for evaluating the strength of the obtained evidence are shown in Table 2. Based on the GRADE approach, the pooled RR value for the outcomes of Mortality, MACE, BARC, and TIMI Flow Grade was graded as High in terms of the strength of the evidence. The pooled RR value for the MI outcome was graded as Moderate due to the fact that the publication bias in this outcome was uncertain.

In this systematic review and meta-analysis, 11 eligible studies with RCT design were included, in which the primary treatment strategy for 10,569 STEMI patients before and after either PPCI and fibrinolytic therapy was dual antiplatelet therapy with aspirin associated with Ticagrelor or Clopidogrel. Among the main findings of this study, it can be mentioned that the administration of Ticagrelor was associated with a decrease in the chance of mortality, stroke, and recurrent MI and also decreased MACE compared to receiving Clopidogrel; however, it increased the chance of bleeding calculated by BARC score. The TIMI flow grade increased in patients treated with Ticagrelor compared to Clopidogrel.

Recently, several systematic review and meta-analysis studies have investigated and compared the efficacy and safety of Ticagrelor and Clopidogrel drugs(33, 39, 40). However, many of these studies have only included RCT studies conducted on ACS patients and have ignored the heterogeneity between primary studies. This is because one of the important issues in the management of ACS patients is considering the type of ACS. Moreover, the treatment guidelines for STEMI and non-STEMI are completely different. For example, STEMI patients should undergo PPCI as soon as possible, while the timing of PCI in non-STEMI patients is not precisely known (41). On the other hand, fibrinolytic therapy is prescribed in STEMI patients who cannot perform timely PPCI, while fibrinolytic drugs are not recommended in non-STEMI patients at all(24). For this reason, in this systematic review and meta-analysis, we included only studies that included STEMI patients, and in this way, the results of our research can provide more definitive evidence for the decision of doctors to choose between two anti-platelet drugs: Ticagrelor and Clopidogrel.

One of the most important issues that make the choice between Ticagrelor and Clopidogrel difficult is major bleeding. Since the balance between the benefits that the drug provides to the patient and the risk of causing side effects should be considered while choosing the drug, several studies and meta-analyses have investigated the effect of each of these drugs on the risk of major bleeding amongst ACS patients so far(42). For instance, Fan et al. investigated the effect of these two drugs after PCI in ACS patients, and they found that the risk of major bleeding was higher in the Clopidogrel group(43, 44). However, Guan et al. obtained completely different results and indicated that Ticagrelor was associated with a higher risk in this outcome(45). In the meta-analysis conducted by Westman et al, although Ticagrelor was associated with a higher risk of bleeding, the difference was not significant. These outcomes are evaluated by TIMI and BARC. In the present study, we analyzed both of these features, and our meta-analysis results showed the superiority of Ticagrelor, this superiority was not statistically significant. In the meta-analysis by Kheiri et al., which compared these two drugs in STEMI patients, none of the drugs was superior in creating a lower risk of major bleeding(46).This difference in the results of our research and Kheiri's can be due to the number of studies that were investigated. In our meta-analysis, we analyzed 7 eligible studies, while Kheiri did 3 studies.

Ticagrelor has the potential to reduce the mortality rate, and the present study also showed a reduction in mortality rate as a result of the use of this drug compared to Clopidogrel. However, it must be taken into account that the risk of death in patients also highly depends on the type of ACS and the main treatment strategy(47). Different clinical guidelines suggest the administration of P2Y12 receptor inhibitors along with aspirin for the management of both ACS and post-PCI patients. Also, the superiority of Ticagrelor and Prasugrel over Clopidogrel has been proven in many large RCTs. The European Society of Cardiology especially considers Ticagrelor and Prasugrel as better options than Clopidogrel regarding the rapid onset of action and greater potency.(48)

One of the known complications that may occur after Acute Myocardial Infarction (AMI) is ischemic stroke, which can have devastating consequences. Antiplatelet therapy is the main therapy for ACS, and these drugs are developing over time; new drugs such as Ticagrelor were added to them(49). One of the causes of ischemic stroke is the aggregation of platelets, and antiplatelet treatments interfere with this process; therefore, they have a preventive effect on stroke. Clopidogrel and Aspirin are among the drugs approved by the US Food and Drug Administration for the secondary prevention of ischemic stroke(50). The effectiveness of Ticagrelor for the prevention of ischemic stroke compared to Clopidogrel has been shown in a meta-analysis. In this study which included patients with vascular risk factors, the researchers concluded that Ticagrelor can be effective in reducing ischemic stroke in patients(51). This finding was consistent with the results of the present study. Although the results of our research were not statistically significant, this may be due to the small number of studies (5 studies) that reported this outcome. Also, many of the studies included in the present research excluded patients with a history of stroke.

Standard treatment guidelines recommend Dual Antiplatelet Therapy (DAPT) for ACS patients who should undergo PCI because this therapeutic combination reduces MACE(52). To reduce MACE due to the reocclusion of coronary arteries, most patients are given dual antiplatelet therapy after PCI. Findings in the present study resulted in a decrease in the MACE, although this decrease was not statistically significant. A meta-analysis that included studies with ACS patients did not prove the superiority of Ticagrelor over Clopidogrel in this outcome (53). This is notable that since there is a possibility of bleeding and upper gastrointestinal complications in patients who receive the combination of Clopidogrel and Aspirin, these patients are prescribed drugs such as proton-pump inhibitors such as pantoprazole, which reduces the risk of bleeding by protecting the digestive tract mucosa, simultaneously(54). However, the simultaneous use of two drugs, Clopidogrel and Pantoprazole, causes a disturbance in the mechanism of action of Clopidogrel, as a result of which the risk of MACE increases. Though Ticagrelor does not affect these mechanisms, it appears to reduce the incidence of MACE compared to Clopidogrel.

According to the present study, although the use of Ticagrelor has advantages such as higher TIMI flow as well as lower MACE, MI and stroke mortality compared to Clopidogrel after PCI, it increases the risk of major bleeding. For this reason, the superiority of Ticagrelor in this study compared to Clopidogrel was not established, and needs more studies. which was consistent with the findings of the previous studies.

One of the issues that may lead to publication bias in this research is that we only included studies in English. The second limitation was that the Eager's test was not performed based on the existing guidelines because the number of studies for each outcome was below 10 studies. Also, the use of other drugs, including beta blockers, ACEI/angiotensin-renin blockers, and statins, might have affected the results

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All the data analysed during the current study are included in the published article. The files are also available on request from the corresponding author.

Competing interests

The authors declare no competing interests.

Funding

This research received no external funding.

Authors’ contributions

Mehdi Geravandi: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Resources, Writing - Original Draft, Article Review & Editing; Mohammad Nourabi: Conceptualization, Investigation, Data curation, Writing - Original Draft, Review & Editing; Sepehr Nabavifar: Validation, Data curation, Review & Editing; Sina Dolatshahi: Validation, Data curation, Resources, Writing - Original Draft, Review & Editing; Sara Zand: Conceptualization, Investigation, Data curation, Resources; Zahra Hooshanginezhad: Conceptualization, Methodology, Validation, Investigation, Data curation, Resources, Writing - Original Draft, Review & Editing.

All authors have read and agreed to the published version of the manuscript.

Acknowledgments

Not applicable

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Table 1

The characteristics of the included studies
Autho	Type of study	follow-up	sample size		SPECT after primary PCI
Autho	Type of study	follow-up	ticagrelor	clopidogrel	ticagrelor	clopidogrel
Alexopoulos .et al(2015)	prospective, randomized, parallel design		28	28	180 mg	600 mg
Dehghani .et al(2017)	prospective, randomized, open label phase III	30 days	74	66	180mg	300mg
Gao .et al(2018)	Cohort study	30 days	97	96	loading dose of 180 mg, maintenance dose of 90 mg once, twice a day	loading dose of 600 mg, maintenance dose of 75 mg once, once a day)
Mont Alverne Filho .et al(2016)	prospective, randomized trial	April 2011 and September 2014	46	44
Berwanger .et al(2018)	randomized, open-label	30 days	1913	1886	180mg	300 to 600 mg)
Tang .et al(2016)		six months	200	200	loading dose of (180 mg) prior to PPCI followed by ticagrelor (90 mg twice daily for one year)	loading dose(600 mg) prior to PPCI followed by clopidogrel (75 mg once daily for one year)
Velders .et al(2015)	prospective, randomised, double-blind,	286 days	2463	2486	180 mg loading dose followed by a maintenance dose of 90 mg twice daily	300 mg loading dose followed by 75 mg once daily.
Winter .et al(2014)	open label randomized study		34	36	180	600
Yao .et al(2018)		February 2013 to September 2017	155	194	loading dose: 180 mg; then 90 mg bid; AstraZeneca, AB, Sweden)	loading dose: 600 mg PO then 75 mg qd; Sanofi Winthrop Industrie, France)
Hamilos .et al(2021)	prospective, randomised, open-label	3 month	168	167	180 mg loading dose and a 90 mg bid maintenance dose	300 mg loading dose 75 mg maintenance dose

Table 2

The Grade results to assess the quality of evidence for outcomes
	Certainty assessment							№ of patients		Effect	Certainty
Outcomes	№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Ticagrelor	Clopidogrel	Relative (95% CI)	Certainty
Mortality	6	RCT	not serious	not serious	not serious	not serious	none	78/2480 (3.1%)	91/2443 (3.7%)	RR 0.857 (0.637 to 1.153)	⨁⨁⨁⨁ High
MI	6	RCT	not serious	not serious	not serious	not serious	publication bias strongly suspected	49/2467 (2.0%)	58/2470 (2.3%)	RR 0.680 (0.333 to 1.382)	⨁⨁⨁◯ Moderate
Major Adverse Cardiovascular Events	4	RCT	not serious	not serious	not serious	not serious	none	10/457 (2.2%)	20/488 (4.1%)	RR 0.630 (0.226 to 1.750)	⨁⨁⨁⨁ High
BARC	7	RCT	not serious	not serious	not serious	not serious	none	48/2635 (1.8%)	48/2637 (1.8%)	RR 1.020 (0.651 to 1.595)	⨁⨁⨁⨁ High
TIMI Flow Grade Major	5	RCT	not serious	not serious	not serious	not serious	none	135/2067 (6.5%)	130/2032 (6.4%)	RR 1.020 (0.860 to 1.201)	⨁⨁⨁⨁ High
Stroke	5	RCT	not serious	not serious	not serious	not serious	none	29/2312 (1.3%)	36/2276 (1.6%)	RR 0.830 (0.508 to 1.348)	⨁⨁⨁⨁ High

No competing interests reported.

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A Comparison of the Effects of Ticagrelor and Clopidogrel in Patients with Acute ST-Segment Elevation Myocardial Infarction: A systematic review and Meta-analysis

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