Safety And Efficacy Of Novel Oral Anticoagulant Combined With Single Or Dual Antiplatelet Therapy After Acute Coronary Syndrome: A Systematic Review And Meta-analysis

Background and objectives: Novel oral anticoagulant combined with single or dual antiplatelet therapy,defined as dual antithrombotic therapy or triple antithrombotic therapy,was one of the promising regimens to reduce the incidence of recurrent ischemic events after acute coronary syndrome.However,there are still controversies about the safety and efficacy of this regimen.The purpose of our meta-analysis was to evaluate the safety and efficacy of novel oral anticoagulant combined with single or dual antiplatelet therapy in acute coronary syndrome patients,focusing on clinical efficacy based on diabetes status.Methods: We systematically searched the Pub Med,EMBASE,Cochrane Library,China National Knowledge Infrastructure,Wanfang,and Weipu electronic databases to retrieve randomized controlled trials from inception to September 29,2020.The primary safety outcome was clinically significant bleeding.The efficacy outcome included major adverse cardiovascular and cerebrovascular events,consisted of mortality,stroke,myocardial infarction,stent thrombosis and urgent revascularization.The trial was included if the following inclusion criteria were met:（1）patients aged 18 years older with acute coronary syndrome;（2）the intervention group was novel oral anticoagulant combined with single or dual antiplatelet therapy;（3）the control group consisted of placebo and antiplatelet drugs;（4）safety and/or efficacy outcomes of interest to us were reported;（5）randomized controlled trials;（6）follow-up duration ≥ 6 months.The exclusion criteria were as follows:（1）non-novel oral anticoagulant（such as warfarin,unfractionated heparin,low-molecular-weight heparin）in the intervention group and novel oral anticoagulant which were no longer clinically available;（2）literatures from the same original research;（3）ongoing research;（4）the full-text of the trial was not available.The pool of outcomes was expressed by relative risk（RR）and 95% confidence interval（CI）.The Der Simonian＆ Laird random-effect model and Inverse-Variance fixed-effect model were applied to calculate the pooled effect size.The anticipated sample sizes required to obtain true positive results for each outcome were calculated by the Trial Sequential Analysis.Meanwhile,the risk of bias at trial level and quality of evidence at each outcome level were conducted by the Cochrane Collaboration risk-of-bias-tool 1（Ro B 1）and Grades of Recommendations Assessment,Development and Evaluation（GRADE）approach,respectively.Results: 29,455 patients with acute coronary syndrome were extracted from six randomized controlled trials.Novel oral anticoagulant combined with single or dual antiplatelet therapy can significantly increase the risk of clinically significant bleeding（RR 2.28;95% CI 2.06-2.52）and reduce the incidence of major adverse cardiovascular and cerebrovascular events（RR 0.86;95% CI 0.78-0.94）compared with antiplatelet therapy.Novel oral anticoagulant combined with antiplatelet therapy can increase the risk of major bleeding（RR 2.92;95% CI 1.18-7.21）and reduce the incidence of major adverse cardiovascular and cerebrovascular events without statistical significance（RR 0.94;95% CI 0.81-1.10）in patients with acute coronary syndrome and diabetes.Novel oral anticoagulant combined with antiplatelet therapy can also increase the risk of major bleeding（RR 3.74;95% CI 2.33-6.01）and reduce the incidence of major adverse cardiovascular and cerebrovascular events（RR 0.82;95% CI 0.73-0.93）among acute coronary syndrome patients without diabetes.Conclusions: Novel oral anticoagulant combined with single or dual antiplatelet therapy can increase the risk of clinically significant bleeding and reduce the incidence of major adverse cardiovascular and cerebrovascular events in patients with acute coronary syndrome.This regimen can also increase the risk of major bleeding and reduce the incidence of major adverse cardiovascular and cerebrovascular events among acute coronary syndrome patients without diabetes.However,this regimen can increase the risk of major bleeding with a non-significant reduction of the incidence of ischemic events in patients with acute coronary syndrome and diabetes.（PROSPERO:CRD42020198599）.