NOACs combined with antiplatelet in the treatment of acute coronary syndrome and atrial fibrillation undergoing PCI or complicating ACS

NOACs combined with antiplatelet in the treatment of acute coronary syndrome and atrial fibrillation undergoing PCI or complicating ACS | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 3 March 2025 V1 Latest version Share on NOACs combined with antiplatelet in the treatment of acute coronary syndrome and atrial fibrillation undergoing PCI or complicating ACS Authors : Lexie Bai [email protected] , Shu-Yun Lin , De Long Liu , BingBing Zhang , LiLi Liu , and Guo-Jun Zhao Authors Info & Affiliations https://doi.org/10.22541/au.174102513.34720937/v1 331 views 113 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract A dual-pathway approach combining anticoagulation and antiplatelet (APT) therapy is challenging for the trade-off of benefits and bleeding risks. By selectively inhibiting the coagulation cascade-factor Xa or thrombin, novel oral anticoagulants (NOACs) combined with APT may be more conducive to achieve this balance. The study aimed to evaluate comprehensively the role of NOACs combined with APT in acute coronary syndrome (ACS) and AF undergoing PCI or complicating ACS. To identify relevant RCTs, a systematic literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. We summarized the results using the Mantel–Haenszel (M-H) random-effect models. The risk ratio (RR) value and 95% confidence intervals (CI) calculated were applied to dichotomous outcomes. Seventeen trials randomizing 49345 participants reported our predefined outcomes. For ACS patients, compared with control groups, NOACs combined with APT significantly reduced MACEs, ST, ischemic stroke and all-cause death, accompanied by increased TIMI major bleeding, trial-defined primary bleeding and ISTH major bleeding . For patients with AF undergoing PCI or complicating ACS, NOACs plus APT markedly decrease the risk of bleeding compared with the control groups, including TIMI major bleeding, trial-defined primary bleeding, ISTH major bleeding and ISTH CRNM bleeding. However, there were no obvious differences in all efficacy outcomes. These findings support the application of NOACs combined with APT in patients with ACS and AF undergoing PCI or complicating ACS; however, appropriate regimens should be designed to obtain the maximal benefit and balance the bleeding risk in clinical practice. Novel oral anticoagulants combined with antiplatelet in the treatment of acute coronary syndrome and atrial fibrillation undergoing PCI or complicating ACS: a systematic review and meta-analysis Le-Xie Bai 1 , Shu-Yun Lin 1 , De-Long Liu 2 , Bing-Bing Zhang 2 , Li-Li Liu 1 , Guo-Jun Zhao 1* 1 Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China. 2 Dali University, Dali, China. * Corresponding author: Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong, China. e-mail: [email protected] . ABSTRACT Objectives: A dual-pathway approach combining anticoagulation and antiplatelet (APT) therapy is challenging for the trade-off of benefits and bleeding risks. By selectively inhibiting the coagulation cascade-factor Xa or thrombin , novel oral anticoagulants (NOACs) combined with APT may be more conducive to achieve this balance. The study aimed to evaluate comprehensively the role of NOACs combined with APT in acute coronary syndrome (ACS) and AF undergoing PCI or complicating ACS. Methods: To identify relevant RCTs, a systematic literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. We summarized the results using the Mantel–Haenszel (M-H) random-effect models. The risk ratio (RR) value and 95% confidence intervals (CI) calculated were applied to dichotomous outcomes. Results: Seventeen trials randomizing 49345 participants reported our predefined outcomes. For ACS patients, compared with control groups, NOACs combined with APT significantly reduced MACEs (RR=0.87, 95% CI [0.81,0.94], P=0.0003), ST (RR=0.73, 95% CI [0.58,0.92], P=0.008), ischemic stroke (RR=0.67, 95% CI [0.48,0.93], P=0.02) and all-cause death (RR=0.82, 95% CI [0.70,0.97], P=0.02) , accompanied by increased TIMI major bleeding (RR=2.67, 95% CI [1.67,4.25], P<0.0001), trial-defined primary bleeding (RR=2.01, 95% CI [1.39,2.90], P=0.0002) and ISTH major bleeding (RR=2.01, 95% CI [1.55,2.62], P<0.00001). For patients with AF undergoing PCI or complicating ACS, NOACs plus APT markedly decrease the risk of bleeding compared with the control groups, including TIMI major bleeding (RR=0.62, 95% CI [0.48,0.80], P=0.0002), trial-defined primary bleeding (RR=0.69, 95% CI [0.61,0.80], P<0.00001), ISTH major bleeding (RR=0.69, 95% CI [0.53,0.89], P=0.005) and ISTH CRNM bleeding (RR=0.75, 95% CI [0.66, 0.84], P<0.00001). However, there were no obvious differences in all efficacy outcomes. Conclusions: These findings support the application of NOACs combined with APT in patients with ACS and AF undergoing PCI or complicating ACS; however, appropriate regimens should be designed to obtain the maximal benefit and balance the bleeding risk in clinical practice. Keywords: NOACs, APT, ACS, AF, PCI, Randomized controlled trials, Systematic review, Meta-analysis Key points Compared with APT with/without additional anticoagulant treatment, NOACs combined with APT reduced ischemic events in ACS patients. 2、Compared with vitamin K antagonist combined with APT therapy, NOACs plus APT reduced bleeding risks in patients with AF undergoing PCI or complicating ACS. 3、 Low- dose DOACs combined with APT or NOACs plus single APT therapy are associated with fewer bleeding risks i n patients with ACS and AF undergoing PCI or complicating ACS. 4、Low-dose DOACs plus APT therapy was associated with reduced all-cause death in ACS patients. A survival benefit was not observed in the high-dose DOAC plus APT group due to the increased risk of bleeding offsets the benefits of MACEs driven by MI and ST. INTRODUCTION Acute coronary syndrome (ACS) and atrial fibrillation (AF) are the two leading cardiovascular disorders (CVD) that cause substantial morbidity and mortality. Globally, over 7 million individuals and 43 million individuals are affected by ACS and AF annually, respectively [1,2] . ACS is an ischemic heart syndrome, characterized by an abrupt decrease in blood delivery to the heart muscle. Most ACS are caused by sudden luminal thrombosis by reason of atherosclerotic plaque rupture or erosion [3] , these conditions can be fatal, and for survivors, can severely affect their quality of life [4] . AF is the most prevalent cardiac arrhythmia, severe comorbidity such as heart failure, ischemic stroke, and sudden cardiac arrest are linked to AF, which raises morbidity and mortality [5] . Despite evidence-based therapy, including revascularization and dual antiplatelet (DAPT), patients remain at a high risk of recurrent ischemic events during the year after ACS [6] . Given that this risk may be related to the overproduction of thrombin by persistent activation of the coagulation mechanism at the acute stage of ACS, previous studies have evaluated the effects of OACs after ACS [7] . Improved outcomes have been reported for patients with ACS patients who were treated with the anticoagulant warfarin in addition to aspirin [8] . AF is both a risk factor and a result of ACS, with around one-f ifth of all AF patients undergoing percutaneous coronary intervention (PCI) [9] . Anticoagulant medications are necessary for AF patients to prevent the risk of stroke and systemic embolism; however, it has not been demonstrated to prevent stent thrombosis (ST) and is typically not recommended for secondary prevention after ACS [10] . DAPT has been proven more effective in reducing recurrent ischemic events and ST [11] . Therefore, a dual-pathway approach combining anticoagulation and APT therapy has advantages over single-component treatment for patients. However, with the recognition of the prognostic relevance of major bleeding from such a regimen, the widespread use of this regimen has been limited [12,13] . Especially when adding old oral anticoagulants (OACs) vitamin K antagonists to DAPT therapy, there is a substantial risk of major bleeding in patients with AF undergoing PCI or complicating ACS [14] . This has turned the focus of this approach to balance the efficacy and bleeding risks. Novel oral anticoagulants (NOACs) are a novel strategy that prevents thrombosis by selectively inhibiting two key targets in the joint pathway of the coagulation cascade-factor Xa or thrombin [15] , including rivaroxaban, apixaban, edoxaban, dabigatran, etc. According to randomized controlled trials (RCTs), the risks of bleeding with low-dose rivaroxaban combined with P2Y12 inhibitor is similar to aspirin plus P2Y12 inhibitor in ACS patients [16] . For patients with AF undergoing PCI or complicating ACS, NOACs plus APT with potentially lower bleeding events compared to warfarin without compromise efficacy [17,18] . In addition, NOACs have many potential advantages, such as easier use due to no need for regular monitoring, more predictable pharmacokinetics, and fewer drug-drug and drug-food interactions. Hence NOACs combined with APT may be an attractive regimen considering the bleeding risks and efficacy in patients with ACS and AF undergoing PCI or complicating ACS. In the past, to obtain the maximal benefit and balance the risk of bleeding, several studies have assessed varying combinations of APT and NOACs regimens to find a preferred method for treating ACS and AF undergoing PCI or complicating ACS. However, these studies yielded controversial results . What’s more, there have been many new reports on the therapies in recent years, especially on individuals with ACS and AF undergoing PCI or complicating ACS, thus it is necessary to reassess the current evidence regarding the effect of NOACs combined with APT for ACS and AF undergoing PCI or complicating ACS. The study aimed to evaluate synthetically the efficacy and safety of NOACs combined with APT in ACS and AF undergoing PCI or complicating ACS. 2. METHODS The study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [19] . 2.1. Data sources and search strategy Two reviewers systematically and independently searched the databases PubMed, Embase, Cochrane Library, and Web of Science from the inception to November 2024. Furthermore, the references of all relevant systematic reviews and clinical trials were manually searched to find more eligible research. Only published articles in the English language were considered for inclusion. The search subject terms included “oral anticoagulants”, “antiplatelet”, “acute coronary syndrome”, “atrial fibrillation”, “percutaneous coronary intervention” and “Randomized Controlled Trial (RCT)”. The detailed search strategy was offered in Supplementary Material. 2.2. Selection and eligibility criteria The search results were imported into NoteExpress software. Duplicate records were removed before screening. Two independent reviewers separately screened the remaining records. The original selection was according to the title and abstract, and the eligible records were further evaluated comprehensively based on the full text. All disagreements were solved by consensus or adjudicated by a third reviewer if disagreement persisted. Finally, reasons for exclusion were recorded for studies that were excluded. Studies were given eligible for inclusion if fulfill the following criteria: (a) RCT; (b)patients: ACS, AF undergoing PCI or complicating ACS; (c) intervention arm: NOACs combined with aspirin and/or P2Y12 inhibitors; (d) control arm: antiplatelet agents with/without additional anticoagulant treatment, antiplatelet agent and a vitamin K antagonist; (e) efficacy and safety outcomes. Otherwise, records were excluded if (i)they were conference abstracts, case reports, editorial letters, comments, or protocol; (ii)treatment duration < 6 months; (iii) animals or healthy human subjects; (iv)review or meta-analysis; (v)duplicates: For studies with overlapping patients, we included studies with more relevant information, unless they provide different data for this meta-analysis. 2.3. Data extraction Two reviewers used a predesigned extraction sheet independently extracted the following information: first author, publication year, blinding, duration of follow-up, gender, age, intervention drugs, control drugs, number of participants recruited, concurrent illness (hypertension, diabetes, heart failure), prior medical history (MI, stroke, PCI) and the efficacy and safety outcomes. The primary efficacy outcome was MACEs, a composite of either all-cause or cardiovascular death (CV-death), myocardial infarction (MI), stroke, ST, revascularization, unstable angina (UA) or severe recurrent ischaemia (SRI). Secondary efficacy outcomes included MI, ST, ischemic stroke, CV-death, and all-cause death. The primary safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding and the secondary safety outcomes were trial-defined primary bleeding, International Society on Thrombosis and Haemostasis (ISTH) Major bleeding, and ISTH clinically relevant nonmajor (CRNM) bleeding. All disagreements in extracted data were solved by consensus or adjudicated by a third reviewer if disagreement persisted. 2.4. Risk of bias assessment The Cochrane Collaboration’s tool was utilized to evaluate the risk of bias of all included RCTs by two independent reviewers [20] . The risk assessment of every field was classified as low, unclear, or high risk of bias. Overall bias risk was marked as low only when the risks in all domains were low. All disagreements were solved by consensus or adjudicated by a third reviewer if disagreement persisted. 2.5. Data synthesis and statistical analysis Statistical analysis was performed with Review Manager 5.4 and StataMP 17.0 software. Data were summarized using the Mantel–Haenszel (M-H) random-effect models, and the risk ratio (RR) value and 95% confidence intervals (CI) calculated were applied to dichotomous outcomes. It was considered statistically significant when the p-value<0.05. Statistical heterogeneity was assessed using I 2 statistics, and heterogeneity was classified into three degrees of low (25%), medium (50%), and high (75%). Besides, the numbers needed to treat (NNT) and numbers needed to harm (NNH) were provided. Typically, smaller NNT indicates greater efficacy while larger NNH value represents greater tolerability. Subgroup analyses were conducted based on the dose and type of NOACs, and therapy regimens (NOACs combined with single or dual antiplatelet therapy). Publication bias was tested by funnel plots, Egger’s test, and Begg’s test. 2.6. Trial sequential analysis Cumulative meta-analysis updating with new RCTs may result in false positive results because of the increased probability of random error from sparse data [21] . Trial sequential analysis (TSA) provides the possibility to determine the credibility of our meta-analyses results. TSA which combines the required information size (RIS) with the trial sequential monitoring boundaries (TSMB) was performed using TSA software (version 0.9.5.10 beta) [22] . TSA was performed based on the average incidence rate from all included studies, with an assumed type-I error of 5% and a power of 80%. If the Z-curve reached the TSMB or entered the futility area, it indicated that the anticipated intervention effect showed firm evidence; otherwise, evidence was insufficient. 2.7. Quality of evidence assessment The quality of the evidence for outcomes was assessed based on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) [23] . The quality of evidence was classified as very low, low, moderate, or high according to five domains, which included bias risk, inconsistency, indirectness, imprecision, and publication bias. The GRADE summary was generated through the GRADEpro GDT software. 3. RESULTS 3.1. Search results A total of 1768 potential records were identified in an initial literature search. After removing duplicates, 1698 records were retained. At the level of title and abstract, 1626 records were removed due to they did not meet the inclusion criteria. The remaining 72 records were further evaluated in the full text. Finally, 17 records were included in the study after removing duplicate records and non-RCT. The detailed selection process is shown in Figure 1. Figure 1. Flow diagram of study selection. 3.2. Study characteristics The baseline characteristics of the included studies were listed in Table 1. A total of 49345 participants were involved in 17 studies. All the studies were RCTs published between 2003 and 2023. These studies were launched in China (n=3), Japan (n=1), or international (n=13). All the studies included both male and female participants. Eleven studies analyzed ACS patients, with a total of 38170 participants and an average follow-up of 7.4 months. Six studies tested AF undergoing PCI or complicating ACS, with a total of 11175 participants and an average follow-up of 14 months. The clinical characteristics of the included patients and the efficacy and safety outcomes of included studies were shown in Table S1 and Table S2. Table 1. Baseline characteristics of the included studies. ACS Zhou et al, 2023 [24] Zhang et al, 2022 [25] Ohman et al, 2017[ 16] Ogawa et al, 2013 [26] Mega et al, 2012 [27] Alexander et al, 2011 [28] Oldgren et al, 2011 [29] Steg et al, 2011 [30] Alexander et al, 2009 [31] Mega et al, 2009 [32] Wallentin et al, 2003 [33] AF undergoing PCI or complicating ACS Bai et al, 2022 [17] Liu et al, 2021 [18] Vranckx et al, 2019 [34] Lopes et al, 2019 [35] Cannon et al, 2017 [36] Gibson et al, 2016 [37] multinational China multinational multinational multinational multinational multinational multinational multinational multinational multinational China China Japan multinational multinational multinational Open-label Open-label Double-blind Double-blind Double-blind Double-blind Double-blind Double-blind Double-blind Double-blind Double-blind ND ND Open-label Open-label Open-label Open-label 6 6 12 6 13 8 6 6 6 6 6 12 12 12 6 12 30 rivaroxaban 2.5mg BID, aspirin 100mg QD and clopidogrel 75mg QD rivaroxaban 5mg BID, aspirin 100mg QD and clopidogrel 75mg QD 1 mg/kg enoxaparin BID, aspirin 100mg QD and clopidogrel 75mg QD rivaroxaban 2.5 mg BID, aspirin 100mg QD and P2Y12 inhibitor aspirin 100mg QD and P2Y12 inhibitor rivaroxaban 2.5mg BID and P2Y12 inhibitor aspirin 100mg QD and P2Y12 inhibitor apixaban 2.5mg BID and aspirin with or without P2Y12 inhibitor apixaban 5.0mg BID and aspirin with or without P2Y12 inhibitor placebo and aspirin with or without P2Y12 inhibitor rivaroxaban, 2.5mg BID, aspirin and clopidogrel or ticlopidine rivaroxaban,5mg BID, aspirin and clopidogrel or ticlopidine placebo, aspirin and clopidogrel or ticlopidine apixaban 5mg BID, aspirin and P2Y12 inhibitor placebo, aspirin and P2Y12 inhibitor dabigatran 50mg BID, aspirin and clopidogrel dabigatran 75mg BID, aspirin and clopidogrel dabigatran 110mg BID, aspirin and clopidogrel dabigatran 150mg BID, aspirin and clopidogrel placebo, aspirin and clopidogrel darexaban (5mg BID,10mg QD,15mg BID,30mg QD, 30mg BID and 60mg QD) or placebo plus dual APT apixaban 2.5mg BID, aspirin and clopidogrel apixaban 5mg BID, aspirin and clopidogrel placebo, aspirin and clopidogrel rivaroxaban（5, 10, and 20 mg QD/BID）and aspirin alone rivaroxaban (5, 10, 15, and 20 mg QD/BID), aspirin and a thienopyridine placebo and aspirin alone placebo, aspirin and a thienopyridine ximelagatran 24mg BID and aspirin 160mg QD ximelagatran 36mg BID and aspirin 160mg QD ximelagatran 48mg BID and aspirin 160mg QD ximelagatran 60m g BID and aspirin 160mg QD placebo and aspirin 160 mg QD rivaroxaban 15mg QD and clopidogrel 75mg QD warfarin, clopidogrel 75mg QD and aspirin 100mg QD rivaroxaban 15mg QD and ticagrelor 90mg BID aspirin 100mg QD, clopidogrel 75mg QD, and a dose adjusted vitamin K antagonist warfarin edoxaban 60mg QD and P2Y12 inhibitor vitamin K antagonist (VKA), P2Y12 inhibitor and aspirin 100mg QD apixaban 2.5 mg BID and P2Y12 inhibitor apixaban 2.5 mg BID, aspirin and P2Y12 inhibitor vitamin K Antagonis and P2Y12 inhibitor vitamin K Antagonis, aspirin and P2Y12 inhibitor dabigatran 110mg BID and clopidogrel or ticagrelor warfarin, aspirin and P2Y12 inhibitor dabigatran 150mg BID and P2Y12 inhibitor rivaroxaban 15mg QD and P2Y12 inhibitor rivaroxaban 2.5mg BID and DAPT dose-adjusted vitamin K antagonist and DAPT 683 683 680 139 140 1519 1518 49 50 52 5174 5176 5176 3705 3687 369 368 406 347 371 1258 317 318 611 508 1823 253 907 307 303 311 324 638 49 51 54 52 751 755 1153 1153 1154 1154 981 981 763 709 709 706 n: number of participants; ND: no data; 3.3. Risk of bias assessment All studies were assessed as low risk of detection bias, attrition bias, reporting bias, and other bias. Two [24,25] studies reporting ACS patients and three [34,36,37] studies reporting AF patients who underwent PCI or complicating ACS were classified as having high-performance bias. Details of the risk of bias evaluation are shown in Figure 2. Figure 2. RCTs quality assessment. (A)Risk of bias summary. (B)risk of bias. 3.4. Meta- analysis of outcomes 3.4.1. Combination of DOACs with APT in patients with ACS For patients with ACS, compared with control groups (only APT therapy or enoxaparin combined with APT therapy), the combination of DOACs with APT therapy significantly reduced MACEs (RR=0.87, 95% CI [0.81,0.94], P=0.0003; NNT=76), ST (RR=0.73, 95% CI [0.58,0.92], P=0.008; NNT=288), ischemic stroke (RR=0.67, 95% CI [0.48,0.93], P=0.02; NNT=402) and all-cause death (RR=0.82, 95% CI [0.70,0.97], P=0.02; NNT=333); nevertheless, there were no obvious differences in MI (RR=0.90, 95% CI [0.79,1.02], P=0.11; NNT=156) and CV-death (RR=0.87, 95% CI [0.75,1.01], P=0.07; NNT=284). Besides, the additional treatment of DOACs to APT markedly increased the rate of TIMI major bleeding (RR=2.67, 95% CI [1.67,4.25], P<0.0001; NNH=124), trial-defined primary bleeding (RR=2.01, 95% CI [1.39,2.90], P=0.0002, NNH=43) and ISTH major bleeding (RR=2.01, 95% CI [1.55,2.62], P<0.00001; NNH=120). Notably, the regimen decreased the risk of ISTH CRNM bleeding (RR=0.85, 95% CI [0.39, 1.85], 0.68; NNT=484) despite there was no significant difference compared with control groups. Among all the outcomes, the NNT of MACEs was the smallest, while the NNH of TIMI major bleeding was the largest. T hese results suggested that the benefits of the additional treatment of DOACs to APT for MACEs were great, and the tolerability of TIMI major bleeding was greater Figure 3 . Figure 3. Efficacy and safety outcomes of NOACs combined with APT in patients with ACS. RR: risk ratio; CI: confidence interval; MACEs: major adverse cardiovascular events; TIMI: Thrombolysis in Myocardial Infarction; ISTH: International Society on Thrombosis and Haemostasis; CRNM: clinically relevant nonmajor; NNT: numbers needed to treat; NNH: numbers needed to harm. 3.4.2. Combination of DOACs with APT in patients with AF undergoing PCI or complicating ACS For patients with AF undergoing PCI or complicating ACS, there were no significant difference in MACEs (RR=1.01, 95% CI [0.89,1.14], P=0.91; NNH=207), MI (RR=1.03, 95% CI [0.84,1.28], P=0.77; NNH=849), ST (RR=1.21, 95% CI [0.84,1.75], P=0.31; NNH=605), Ischemic stroke (RR=0.90, 95% CI [0.45,1.77], P=0.75; NNT=414), CV-death (RR=1.06, 95% CI [0.83,1.36], P=0.63; NNH=505) and all-cause death (RR=1.07, 95% CI [0.87,1.31], P=0.51; NNH=250) between the NOACs plus APT and the control groups ( vitamin K antagonist combined with APT therapy). But NOACs plus APT substantially decrease the risk of bleeding, included TIMI major bleeding (RR=0.62, 95% CI [0.48,0.80], P=0.0002; NNT=102), trial-defined primary bleeding (RR=0.69, 95% CI [0.61,0.80], P<0.00001, NNT=19), ISTH major bleeding (RR=0.69, 95% CI [0.53,0.89], P=0.005; NNT=56) and ISTH CRNM bleeding (RR=0.75, 95% CI [0.66, 0.84], P<0.00001; NNT=36). Among all the safety outcomes, the NNT of trial-defined primary bleeding was the smallest, which suggested that the DOACs combined with APT for a reduction of trial-defined primary bleeding was considerable ( Figure 4 ). Figure 4. Efficacy and safety outcomes of NOACs combined with APT in patients with AF undergoing PCI or complicating ACS. RR: risk ratio; CI: confidence interval; MACEs: major adverse cardiovascular events; TIMI: Thrombolysis in Myocardial Infarction; ISTH: International Society on Thrombosis and Haemostasis; CRNM: clinically relevant nonmajor; NNT: numbers needed to treat; NNH: numbers needed to harm. 3.5. Subgroup analysis 3.5.1. Do se of NOACs For patients with ACS, only high-dose NOACs combined with APT significantly reduced MI ( RR=0.85, 95% CI [0.74,0.98], P=0.02 ) and ST (RR=0.72, 95% CI [0.53,0.97], P=0.03) . It should be noted that the high-dose NOACs plus APT therapy did not significantly reduce all-cause death, only low-dose NOACs was associated with reduced all-cause death (RR=0.75, 95% CI [0.60,0.93], P=0.01) . Moreover, low-dose NOACs combined with APT did not significantly increase the risks of TIMI major bleeding (RR=1.6, 95% CI [0.77,3.32], P=0.21) and ISTH major bleeding (RR=1.49, 95% CI [0.96,2.31], P=0.08) ( Figure 5 ) . For patients with AF undergoing PCI or complicating ACS, there were no significant difference between low-dose NOACs combined with APT groups and high-dose NOACs combined with APT groups for all efficacy outcomes. Notably, high-dose NOACs combined with APT were not associated with reduced risks of trial-defined primary bleeding (RR=0.73, 95% CI [0.37,1.42], P=0.35) and ISTH major bleeding (RR=0.76, 95% CI [0.50,1.16], P=0.2) ( Figure 6 ) compared with control groups. In that case, the results should be accounted for with prudence. Figure 5. Subgroup analysis of outcomes for lower-dose or higher-dose NOACs combined with APT in patients with ACS：(A) efficacy outcomes; (B) safety outcomes. RR: risk ratio; CI: confidence interval; MACEs: major adverse cardiovascular events; TIMI: Thrombolysis in Myocardial Infarction; ISTH: International Society on Thrombosis and Haemostasis; CRNM: clinically relevant nonmajor; NNT: numbers needed to treat; NNH: numbers needed to harm. Figure 6. Subgroup analysis of outcomes for lower-dose or higher-dose NOACs combined with APT in patients with AF undergoing PCI or complicating ACS: (A) efficacy outcomes; (B) safety outcomes. RR: risk ratio; CI: confidence interval; MACEs: major adverse cardiovascular events; TIMI: Thrombolysis in Myocardial Infarction; ISTH: International Society on Thrombosis and Haemostasis; CRNM: clinically relevant nonmajor; NNT: numbers needed to treat; NNH: numbers needed to harm. 3.5.2. Therapy regimens For patients with ACS, only NOACs plus dual APT were associated with reduced MACEs ( RR=0.89, 95% CI [0.81,0.99], P=0.02 ), ST (RR=0.69, 95% CI [0.54,0.89], P=0.004) and all-cause death (RR=0.80, 95% CI [0.66,0.95], P=0.01). Notably, NOACs combined with a single APT significantly reduced ischemic stroke (RR=0.49, 95% CI [0.27,0.90], P=0.02). However, NOACs combined with dual APT did not reduce ischemic stroke (RR=0.73, 95% CI [0.47,1.11], P=0.14). Besides, NOACs plus single APT did not significantly increase the risks of TIMI major bleeding (RR=1.25, 95% CI [0.49,3.16], P=0.64) and trial-defined primary bleeding (RR=1.57, 95% CI [0.99,2.49], P=0.05) ( Figure S1 ). For patients with AF undergoing PCI or complicating ACS, there was no significant difference between NOACs plus single APT groups and NOACs plus dual APT groups for all efficacy outcomes. It should be noted that NOACs plus dual APT did not significantly reduce the risks of TIMI major bleeding (RR=0.76, 95% CI [0.49,1.19], P=0.23) and ISTH major bleeding (RR=0.76, 95% CI [0.53,1.10], P=0.14) compared with control groups ( Figure S2 ). 3.5.3. Type of NOACs For patients with ACS, only direct factor Xa inhibitors plus APT significantly reduced MACEs (RR=0.88, 95% CI [0.81,0.95], P=0.002). However, direct factor Xa inhibitors combined with APT did not significantly reduce ischemic stroke (RR=0.79, 95% CI [0.59,1.06], P=0.11). The overall showed that the addition of NOACs to APT significantly decreased all-cause death. However, there were no significant differences in the subgroup of direct factor Xa inhibitors (RR=0.84, 95% CI [0.70,1.00], P=0.05) or direct thrombin inhibitors (RR=0.76, 95% CI [0.46,1.25], P=0.28) combined with APT compared with the control group for all-cause death. Moreover, compared with the control group, the subgroup of direct factor Xa inhibitors (RR=1.78, 95% CI [0.89,3.56], P=0.1) or direct thrombin inhibitors (RR=1.74, 95% CI [0.22,14.12], P=0.6) combined with APT were both not associated with significant increase of TIMI major bleeding. Direct thrombin inhibitors plus APT also did not significantly increase the risk of ISTH major bleeding (RR=1.97, 95% CI [0.92,4.23], P=0.08) ( Figure S3 ). The further subgroup analysis of specific drugs showed rivaroxaban combined with APT were associated with significant decrease of MACEs (RR=0.84, 95% CI [0.75,0.94], P=0.002), CV-death (RR=0.81, 95% CI [0.67,0.99], P=0.04) and all-cause death (RR=0.81, 95% CI [0.67,0.98], P=0.03). In addition, rivaroxaban plus APT did not significantly increase bleeding risks. Apixaban combined with APT did not show benefit in all efficacy outcomes, while the use of this regimen was related to the increase of TIMI major bleeding, trial-defined primary bleeding, and ISTH major bleeding ( Table S3 ). 3.6. Sensitivity analysis and meta-regressions analysis Similar results were observed with a fixed-effect model for all efficacy and safety outcomes in both patients with ACS (Table S4) and patients with AF undergoing PCI or complicating ACS ( Table S5 ). Darexaban and ximelagatran were not marketed. Except for changes in ischemic stroke (RR=0.73, 95% CI [0.52,1.03], P=0.07), the overall efficacy and safety outcomes remained unchanged after excluding data on these two compounds for patients with ACS ( Table S6 ). The meta-regressions analysis showed that there were no significant associations between baseline variables such as age, sex ratio and outcomes (Table S7). 3.7. Publication bias In patients with ACS, funnel plots did not find appar ent asymmetry on the MACEs, MI; CV-death, all-cause death, TIMI major bleeding, trial-defined primary bleeding, and ISTH major bleeding, while the distribution of scatter points in the funnel plots of ischemic stroke was asymmetric indicating publication bias might be present ( Figure S4 ). Furthermore, Egger’s test indicated a potential publication bias in ischemic stroke (Egger’s, P=0.045) ( Table S8 ). In patients with AF undergoing PCI or complicating ACS, asymmetry about the MACEs, MI, TIMI major bleeding, and trial-defined primary bleeding events was not found by visually assessing of the funnel plots (Figure S5). Further, Begg’s test and Egger’s test also did not find any publication bias (Table S9). 3.8 Trial sequential analysis In ACS patients, the TSA showed that the cumulative Z curves for MACEs crossed both the conventional boundaries and TSMB ( monitoring boundary for benefit), and the number of participants reached the RIS, indicating that it was a true positive result for the anticipated intervention effect of NOACs combined with APT. T he cumulative Z curve for TIMI major bleeding exceeded the RIS but entered the futility area without crossing the conventional boundaries or the TSMB, revealing that the current evidence failed to support a significant difference between NOACs combined with APT and the control group in TIMI major bleeding ( Figure S6 ). In patients with AF undergoing PCI or complicating ACS, the cumulative Z curves for MACEs neither crossed the TSMB nor crossed the futility boundary, and the number of participants did not reach the RIS, hinting that a lack of evidence for the effect of NOACs combined with APT in MACEs. For the safety endpoint, the cumulative Z curves for TIMI major bleeding crossed both the conventional boundaries and TSMB (monitoring boundary for benefit), and the number of participants reached the RIS, suggesting that it was a true positive result (Figure S7). 3.9 Quali ty of evidence assessment According to the GRADE assessment, the quality of the present evidence for outcomes was low to high. In patients with ACS, GRADE evidence for MACEs, ST, TIMI major bleeding, and ISTH major bleeding were high, while these outcomes for MI, CV-death, all-cause death, and ISTH CRNM bleeding were categorized as moderate-quality evidence in consequence of serious imprecision. The outcome for trial-defined primary bleeding was rated as moderate-quality evidence since serious inconsistency and ischemic stroke was evaluated to be low due to serious imprecision and serious risk of bias ( Table S10 ) . In patients with AF undergoing PCI or complicating ACS, the quality of evidence for outcomes of bleeding in all categories was high whereas all efficacy outcomes were evaluated as moderate-quality evidence due to serious imprecision ( Table S11 ) . 4. DISCUSSION The present study systematically reviewed the current available RCTs, providing comprehensive and updated data on the effect of NOACs combined with APT in patients with ACS and AF undergoing PCI or complicating ACS. Seventeen RCTs with 55192 participants were contained in this analysis. According to the available evidence, NOACs combined with APT offer a promising result in terms of efficacy for ACS patients but a substantial increase in bleeding. The MACEs were a composite efficacy outcome, and it has been chosen as the primary efficacy outcome in this study. We found that NOACs combined with APT administration reduced MACEs. Importantly, the result was validated by TSA and was rated a high quality by GRADE in the present study. Additionally, our study revealed that the combination of NOACs and APT can decrease ST, ischemic stroke, and all-cause death. By contrast, for patients with AF undergoing PCI or complicating ACS, NOACs combined with APT more superior than vitamin K antagonists combined with APT in preventing bleeding events. The result was similar to Agasthi et al.’s study [38] . More significantly, we added two recent studies [17,18] , and the result was rated high quality by GRADE and with firm evidence from TSA. We attempted to determine whether the dose of NOACs would affect significant differences in outcomes by performing a subgroup analysis. Interestingly, for ACS patients, low-dose NOACs combined with APT were associated with reduced all-cause death, a survival benefit was not observed in high-dose NOACs plus APT. Moreover, low-dose NOACs plus APT result in fewer bleeding events than high-dose NOACs plus APT in ACS patients. However, only high-dose NOACs plus APT offer significant benefits in reducing MI and ST. This may explain why the benefits observed on MACEs by combining high-dose NOACs with APT were not translated into a benefit on all-cause death. In fact, high-dose NOACs plus APT excessively inhibit coagulation pathways, which markedly increases bleeding risks. These bleeding events outweigh the benefit of MACEs driven by MI and ST. Additionally, studies indicated that bleeding was significantly associated with noncardiovascular death, while ST was not significantly associated with either cardiovascular or all-cause death [39] . Similarly, low-dose NOACs plus APT had fewer bleeding risks than high-dose NOACs plus APT in patients with AF undergoing PCI or complicating ACS. As such, customizing the optimal individualized dosage of NOACs is important to achieve this benefit-risk balance when considering NOACs combined with APT, the bleeding events may even be the primary consideration. In the present study, we suggested combining low-dose NOACs with APTs use in ACS patients considering reduced all-cause death and fewer bleeding events than high-dose NOACs plus APT. Likewise, such a regimen was proposed for use in patients with AF undergoing PCI or complicating ACS due to high-dose NOACs plus APT may compromise the bleeding risk reduction benefit typically observed with NOACs (vs. vitamin K antagonists) when combined with APT. The differences in therapy regimens may also affect the results. Our subgroup analysis suggested that NOACs plus single APT caused fewer bleeding events than NOACs plus dual APT in both patients with ACS and patients with AF undergoing PCI or complicating ACS. What’s more, NOACs combined with single APT rather than dual APT reduced ischemic stroke. In the present study, four studies [17,18,34,36] analyzed the role of NOACs combined with single APT in patients with AF undergoing PCI or complicating ACS, and two studies [35,37] simultaneously analyzed NOACs plus a single APT or dual APT. However, studies reviewed ACS patients were almost treated with triple antithrombotic therapy, consisting of NOACs with aspirin and P2Y12 inhibitor, only three studies [16,32,33] investigated the regimen combining NOACs with single APT. This may explain why NOACs combined with APT led to an increase in bleeding events for ACS patients in the overall analysis, while there was a lower bleeding rate in patients with AF undergoing PCI or complicating ACS. Moreover, all studies analyzed patients with AF undergoing PCI or complicating ACS used vitamin K antagonists as controls. Nevertheless, studies that investigated ACS patients regarded placebo as controls except a study [24] employing enoxaparin as controls. Parenteral enoxaparin is a preferred anticoagulant in addition to DAPT for use in the acute stage of ACS and before selective reperfusion therapy to reduce the risk of ischemic events [40,41] . Zhou et al. found that both rivaroxaban 2.5 mg and 5.0mg in addition to DAPT were noninferior to enoxaparin combined with DAPT in bleeding rates, and rivaroxaban 5 mg plus DAPT lowered the MACEs compared with enoxaparin [24] . In addition, NOACs have the advantage of being an oral medication with a fixed dose for all patients. These results are encouraging for rivaroxaban may be a rational alternative scheme to enoxaparin which improves medication adherence without increasing the bleeding risk, prudent interpretation of the results is warranted. Nevertheless, the power was low due to the small sample size and short study period. Besides, patients were assigned in an open-label fashion. Further research is needed on a larger scale and with higher quality. But overall, it was still strongly suggested that combining DOACs with a single APT used in patients with ACS and patients with AF undergoing PCI or complicating ACS, as this regimen may be more conducive to reducing bleeding risks in patients. The dual pathway antithrombotic therapy combining NOACs and P2Y12 inhibitors without aspirin may be favorable to reduce the risks of bleeding for ACS patients with high bleeding risks without compromising the therapeutic efficacy. Results from Dewilde et al showed the use of clopidogrel without aspirin has not caused an increase in thrombotic events and showed a lower risk of bleeding events in patients taking OACs and undergoing PCI [42] . The most recent AF guideline from the 2023/American College of Cardiology (ACC)/American Heart Association (AHA)/American College of Chest Physicians (ACCP)/Heart rhythm Society (HRS) Guideline for the Diagnosis and Management of AF recommended “For most AF patients taking oral APT and undergoing PCI, early discontinuation of aspirin and continuation of DAPT therapy with OACs and a P2Y12 inhibitor is preferred over triple therapy (OACs, P2Y12 inhibitor, and aspirin) to reduce the risk of clinically relevant bleeding” [43] . Meanwhile, both the European Society of Cardiology and ACC/AHA guidelines provide class II recommendations for short-term of DAPT followed by P2Y12 inhibitor monotherapy in ACS patients with high bleeding risk [44,45] . The omission of oral anticoagulants could cause an increased risk of recurrent ischemia. Therefore, combining NOACs and P2Y12 inhibitors may be useful for ACS patients with high bleeding risks and will not lead to a higher risk of recurrent ischemia. In the current study, six studies have confirmed the benefit of combining NOACs and P2Y12 inhibitors in reducing bleeding for patients with AF undergoing PCI or complicating ACS. However, only a study [16] analyzed the regimen using low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor, which showed a similar risk of bleeding as with aspirin and a P2Y12 inhibitor. These findings suggest that the efficacy and safety of this novel dual pathway antithrombotic regimen without aspirin is warranted to further explore in ACS patients. We recognize the limitation of pooling all NOACs as one treatment; hence, we compared the efficacy and safety outcomes among different DOACs in patients with ACS. The results showed only direct factor Xa inhibitors plus APT significantly reduced MACEs while direct thrombin inhibitors did not detect at a statistically significant level. The possible explanation for this result was the small sample size in direct thrombin inhibitors. The further subgroup analysis of specific NOAC drugs showed rivaroxaban plus APT were related to significant decreases of MACEs, CV-death, and all-cause death. However, apixaban plus APT did not show a significant benefit in MACEs compared with control group . Additionally, compared to rivaroxaban, it has a higher risk of bleeding. Nevertheless, the available data on other specific NOACs is insufficient to compare them and determine the optimal NOAC drugs. This study has several strengths. Unprecedentedly, we compared the benefit-risk difference between patients with ACS and AF undergoing PCI or complicating ACS. This was a comprehensive and up-to-date overview of NOACs combined with APT in the two populations, providing new insights into the clinical use of NOACs combined with APT in the treatment of CVD . We separately analyzed the MACE components as well as evaluated bleeding events with different definitions in this meta-analysis. The heterogeneity was low and no obvious publication bias. More importantly, we performed sensitivity analysis to detect the robustness of the results and applied TSA to estimate and confirm the effects of NOACs plus APT in patients. Eventually, the quality of the evidence for most outcomes were classified as moderate to high for most outcomes. Last but not least, we also considered the impact of different drugs, doses, and therapy regimens on outcomes. However, we acknowledge that our meta-analysis has several shortcomings that must also be considered. First and foremost, we did not conduct prospective registration for this review on websites, which may cause bias of result. Besides, our meta-analysis used converged study-level statistics rather than individual patient data. Second, the RCTs included in this study had varying observation periods (ranging from 6 weeks to 30 weeks), which may affect the accuracy of the results. Unfortunately, we were unable to conduct subgroup analysis based on different follow-up times due to insufficient data. Moreover, there are several potential confounding factors, such as concurrent illness (hypertension, diabetes, heart failure) and prior medical history (MI, stroke, PCI). Third, because of the difference in the definitions of outcomes among research, the reliability of assessing the outcomes were diminished. Lastly, although we compared the efficacy and safety among different drugs and therapy regimens, available data for the therapy regimens were limited for a thorough assessment. Therefore, continuous collection of patient data using different regimens from large high-quality standardized research is crucial for finding regimens fit enough to be individualized and to benefit from such treatment . Additionally, darexaban and ximelagatran are not marketed; thus, data on these two compounds are medically irrelevant. More positively, the overall efficacy and safety results remained unchanged except ischemic stroke after disregarding the two compounds. Despite our present study has several limitations, our conclusions were strongly supported because we adopted rigorous analytic procedures with a series of sensitivity analysis, subgroup analysis, and TSA to confirm the results. 5. CONCLUSIONS This meta-analysis revealed that NOACs combined with APT could decrease MACEs, ST, ischemic stroke and all-cause death in ACS patients; albeit, it was also related to an increased risk of bleeding. For patients with AF undergoing PCI or complicating ACS , the benefits of NOACs plus APT therapy for reducing bleeding events were considerable . Notwithstanding, it was underpowered to obtain a conclusion on MACEs. More importantly, low-dose DOACs combined with APT and NOACs plus single APT therapy may be beneficial for reducing the risks of bleeding. Moreover, a survival benefit was found in low-dose NOACs plus APT rather than high-dose plus APT group for ACS patients. Therefore, the regimen should be applicated based on the trade-off of efficacy and bleeding risks in clinical practice. SUPPORTING INFORMATION The Supplementary data associated with this article can be found online at Supplementary Material. FUND ING This study was supported by the National Natural Science Foundation of China (81870337) and the Natural Science Foundation of Guangdong Province (2024A1515012850). CONFLICT OF INTEREST The authors declared no competing interests for this work. 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Keywords cardiac pharmacology clinical pharmacology safety pharmacology Authors Affiliations Lexie Bai [email protected] Qingyuan People's Hospital View all articles by this author Shu-Yun Lin Qingyuan People's Hospital View all articles by this author De Long Liu Dali University View all articles by this author BingBing Zhang Dali University View all articles by this author LiLi Liu Qingyuan People's Hospital View all articles by this author Guo-Jun Zhao Qingyuan People's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 331 views 113 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Lexie Bai, Shu-Yun Lin, De Long Liu, et al. NOACs combined with antiplatelet in the treatment of acute coronary syndrome and atrial fibrillation undergoing PCI or complicating ACS. Authorea . 03 March 2025. 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