Platelet inhibition and clinical outcomes of low dose ticagrelor in patients with coronary artery disease: a meta-analysis of randomized controlled trials

95%CI 5.45 − 25.44, P = 0.002) and risk of dyspnea (RR 0.81, 95%CI 0.75 − 0.88, P (cid:0) 0.00001), but similar rates of HTPR (RR 1.63, 95%CI 0.40 − 6.70, P = 0.50) and minor or minimal bleeding (RR 1.36, 95%CI 0.78 − 2.38, P = 0.28). coronary syndromes and random*. and standard dose clopidogrel, low dose ticagrelor had similar risks of MACE and major bleeding, but the incidence of minor or minimal bleeding was signicantly lower than standard dose ticagrelor. (3) The rate of dyspnea of low dose ticagrelor was signicantly lower than standard dose ticagrelor, but signicantly higher than standard dose clopidogrel.


Introduction
Coronary artery disease (CAD) is a pathological process characterized by atherosclerotic plaque accumulation in the epicardial arteries, whether obstructive or non-obstructive. The disease can have long, stable periods but can also become unstable at any time, typically due to an acute atherothrombotic event caused by plaque rupture or erosion. The dynamic nature of the CAD process results in various clinical presentations, which can be conveniently categorized as either acute coronary syndromes (ACS) or chronic coronary syndromes (CCS) [1] .
Ticagrelor is a reversible non-thienopyridine oral P2Y 12 inhibitor that provides faster, more potent and consistent platelet inhibition than clopidogrel [2] . The PLATO trial demonstrated in patients who have an ACS, treatment with ticagrelor 90 mg twice daily as compared with clopidogrel 75 mg once daily signi cantly reduced the rate of ischemic complications without an increase in the rate of overall major bleeding [3] . In the PEGASUS-TIMI 54 study of post-MI patients with additional high-risk features and low bleeding risks, the bene t-to-risk pro le appears to be numerically more favorable for ticagrelor 60 mg twice daily [4] . In this, the current guidelines recommend ticagrelor 90 mg twice daily in ACS patients for 12 months and 60 mg twice daily in MI patients with high ischaemic-risk who have tolerated dual antiplatelet therapy (DAPT) without a bleeding complication for longer than 12 months [5][6][7] .
However, antithrombotic therapy for patients with CAD is a long-term management. The optimal antiplatelet therapy aims to prevent thrombosis while avoiding hemorrhage. To account for this, different strategies have been proposed, such as de-escalation strategy [8] and platelet function [9] or genotype-guided strategy [10] . Recently, several studies have displayed low dose ticagrelor could provide better safety and tolerability than standard usage of ticagrelor while achieving greater and more consistent platelet inhibition than standard usage of clopidogrel [11][12][13] . Therefore, we conducted a meta-analysis to assess the platelet inhibition and clinical outcomes of low dose ticagrelor in patients with CAD.

Literature Search
This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We systematically searched Medline, EMBASE and Cochrane Databases for all relevant articles comparing low dose ticagrelor with standard dose clopidogrel or standard dose ticagrelor in patients with CAD through March, 2021. Literature was searched with the following keywords: ticagrelor, AZD6140, AZD 6140, AZD-6140, 30, 45, 60, quarter, half, low, reduced, once, coronary disease, coronary artery disease, coronary heart disease, acute coronary syndrome, myocardial infarction, unstable angina, chronic coronary syndromes and random*. A comprehensive search of reference lists of all review articles and original studies retrieved by this method was performed to identify additional studies.

Selection criteria
The inclusion criteria were the following: (1) trials designed as RCT; (2) trials based on patients with CAD; (3) trials compared low dose ticagrelor with standard dose clopidogrel or standard dose ticagrelor; (4) trials reported outcomes included platelet inhibition, ischemic events or bleeding events.

Data Abstraction
Two investigators (Cheng Xie and Xiaoliang Ding) independently assessed studies for possible inclusion by reading titles and/or abstracts, then viewed the full-texts of the remaining publications to pick up the ultimately available studies. Data extraction was done by one reviewer (Cheng Xie), and subsequently cross-checked by the other reviewer (Xiaoliang Ding). Any divergences were discussed or determined by a third investigator (Qiong Qin). Following information was abstracted: the rst author and publication year, country, sample size, baseline features of patients, intervention features, follow-up time, platelet inhibition and clinical outcomes and their de nitions.

Bias Risk and Study Quality Assessment
The methodological quality of eligible studies was assessed by the Cochrane collaboration's tool for assessing risk of bias including the following criteria: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other issues. The bias risk of each study was scored as low, unclear, or high in each section.

Statistical Analysis
Dichotomous data were expressed risk ratio (RR) with 95% con dence interval (CI). Continuous data were expressed as mean difference (MD). Heterogeneity of effect size across the studies was tested using Q statistics at the P < 0.10 level of signi cance. We also calculated the I 2 statistic with a quantitative measure of inconsistency across the studies. The data were pooled by random-effects model in case signi cant heterogeneity (Cochran test with P < 0.10 or I 2 > 50%) was found. Otherwise, the xed-effects model was used. Sensitivity analyses with xed-effect models were performed to assess consistency among effect estimates that were obtained with random-and xed-effects models. Meta-analysis was performed with the software of Cochrane Review Manager 5.1.2 (Cochrane Library Software, Oxford, UK).

Sensitivity analyses
There was no difference in the results between the xed-effect model and the random-effect model for the platelet inhibition and clinical outcomes.

Discussion
Antiplatelet agents are the cornerstone of secondary prevention in patients with CAD. Ticagrelor has the most predictable and consistently high level of P2Y12 inhibition during maintenance therapy, and also has more rapid onset, as well as more rapid and predictable offset of action compared with clopidogrel [25,26] . How to reduce thrombotic complications while minimizing the occurrence of bleeding and other adverse events is the hotspot of current antiplatelet therapy. In this meta-analysis, we assessed the platelet inhibition and clinical outcomes of low dose ticagrelor in patients with CAD. The main ndings of this meta-analysis were as follows: (1) Although the PRU of low dose ticagrelor was signi cantly higher than standard dose ticagrelor, the rate of HTPR was similar, and both of them were signi cantly lower than standard dose clopidogrel. (2) Compared with standard dose ticagrelor and standard dose clopidogrel, low dose ticagrelor had similar risks of MACE and major bleeding, but the incidence of minor or minimal bleeding was signi cantly lower than standard dose ticagrelor. (3) The rate of dyspnea of low dose ticagrelor was signi cantly lower than standard dose ticagrelor, but signi cantly higher than standard dose clopidogrel.
Plaque rupture and thrombosis are the major concerns in patients with CAD, and excessive platelet activation and aggregation are central to the pathogenesis of CAD. Although correlations between various platelet function assays were not robust, the most widely used assays such as VerifyNow P2Y12 assay have overcome many of the technical and methodological limitations of previous assays [27,28] . In the past decades, compelling evidence from numerous observational studies has emerged demonstrating a strong association between HTPR and ischemic events [29,30] .
Bleeding, as the most common side effects of ticagrelor, has been well evaluated in previous studies. Although both the PLATO trial [3] and PEGASUS-TIMI 54 trial [4] demonstrated ticagrelor achieved greater reduction of MACE, at the expense of more non-fatal bleeding and dyspnoea. The recent completion of RCTs comparing ticagrelor with clopidogrel, speci cally dedicated to the evaluation of those Page 5/12 particular patient populations, such as elderly [31] or Asian patients [32] , found clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of MACE. Combined with the results of our meta-analysis, low dose ticagrelor may provide an additional antiplatelet strategy to balance the risk of ischemia and bleeding.
Dyspnea was another important side effect of ticagrelor. The PLATO trial showed that dyspnea was more common in the ticagrelor group than in the clopidogrel group (13.8% vs. 7.8%, P 0.001) and more patients discontinued treatment (0.9% vs. 0.1%, P 0.001). Zhang et al.
did a meta-analysis including 21 RCTs showed ticagrelor was associated with an increased risk of dyspnea compared with clopidogrel (RR 2.15, 95%CI 1.59-2.92, P 0.01) and was consistent in subgroups with different follow-up durations [33] . On the other hand, the DISPERSE [34] and DISPERSE-2 [35] trial reported that the increased rate of dyspnea was dose-dependent. These results were consistent with our meta-analysis.
We acknowledge our meta-analysis had several limitations. First, various low doses of ticagrelor were included. Second, because of limited data, patients with ACS and CCS were pooled together. Third, given the limited number of studies included in the analysis, our ndings should be con rmed with future research.

Conclusions
Low dose ticagrelor may provide an additional choice for secondary prevention in CAD patients. However, the speci c dose of ticagrelor should be selected according to the patients' clinical characteristics.

Declarations
Authors contribution CX and YZ contributed to the conception or design of the work. CX, XD and QQ contributed to the acquisition, analysis, or interpretation of data for the work. CX and XD drafted the manuscript. JL and YZ critically revised the manuscript. All gave nal approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Funding
No external funding was used for this research.

Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Compliance with Ethical Standards
Con ict of Interest      Forest plot of dyspnea

Supplementary Files
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