Risk-benefit profile of edoxaban and warfarin in patients with atrial fibrillation: a comprehensive systematic review and meta-analysis of randomized trials

Risk-benefit profile of edoxaban and warfarin in patients with atrial fibrillation: a comprehensive systematic review and meta-analysis of randomized trials | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Risk-benefit profile of edoxaban and warfarin in patients with atrial fibrillation: a comprehensive systematic review and meta-analysis of randomized trials View ORCID Profile Muhammad Ahmad Sohail , View ORCID Profile Asna Moghis , View ORCID Profile Muhammad Waleed Imran , View ORCID Profile Misha Khalid , View ORCID Profile Sanwal Sardar Nawaz , View ORCID Profile Muhammad Hamza Akram , Asaad Akbar Khan doi: https://doi.org/10.1101/2025.03.05.25323458 Muhammad Ahmad Sohail 1 Shifa College of Medicine, Shifa Tameer-e-Millat University , Islamabad, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Muhammad Ahmad Sohail For correspondence: ahmadsohail{at}live.co.uk Asna Moghis 2 Allama Iqbal Medical College , Lahore, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Asna Moghis Muhammad Waleed Imran 1 Shifa College of Medicine, Shifa Tameer-e-Millat University , Islamabad, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Muhammad Waleed Imran Misha Khalid 3 Karachi Medical and Dental College , Karachi, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Misha Khalid Sanwal Sardar Nawaz 1 Shifa College of Medicine, Shifa Tameer-e-Millat University , Islamabad, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sanwal Sardar Nawaz Muhammad Hamza Akram 1 Shifa College of Medicine, Shifa Tameer-e-Millat University , Islamabad, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Muhammad Hamza Akram Asaad Akbar Khan 4 Shifa International Hospitals , Islamabad, Pakistan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Introduction Atrial fibrillation is the most prevalent cardiac arrhythmia in the United States and substantially increases the risk of stroke and heart failure in patients with non-valvular atrial fibrillation, those undergoing percutaneous coronary intervention, and transcatheter aortic valve repair. Warfarin, a vitamin K antagonist, has long been the standard anticoagulant therapy but is limited by drug interactions and monitoring requirements, while edoxaban, a factor Xa inhibitor, has shown favorable bleeding outcomes. Methods This meta-analysis included five randomized controlled trials identified through a comprehensive search of PubMed, Medline, Embase, Google Scholar, CENTRAL, and ClinicalTrials.gov from January 2014 to October 2024 (PROSPERO ID: CRD420250648890). Data were pooled using the inverse variance method with hazard ratios and 95% confidence intervals, DerSimonian–Laird random-effects model was applied in Stata version 17. Risk of bias was assessed using the Cochrane RoB v2 tool and certainty of evidence using GRADE assessment tool, with statistical significance set at P < 0.05. Results Edoxaban demonstrated a greater reduction in stroke or systemic embolism overall but was less effective in patients with prior myocardial infarction (HR 0.58, 95% CI 0.32–1.05). Major adverse cardiovascular events marginally favored edoxaban over warfarin (HR 0.90, 95% CI 0.83–0.98, P = 0.01), whereas warfarin performed better in patients with CHA₂DS₂-VASc scores ≥4. No significant difference was observed in all-cause mortality (P = 0.32). For clinically relevant non-major bleeding, warfarin was more favorable in patients aged ≥65 years and those with normal renal function, while edoxaban reduced major bleeding more effectively in patients with <25% heart failure; warfarin showed slight superiority when heart failure prevalence was ≥25%. Conclusion Overall, edoxaban shows robust efficacy across multiple outcomes, while warfarin remains essential in specific high-risk subgroups, warranting further confirmatory studies. Introduction The most common arrhythmia worldwide is Atrial Fibrillation (AF), a major risk factor for common comorbidities such as stroke, dementia, and heart failure.[ 1 ] Unfortunately, its numbers are on the rise, with a predicted increase in cases reaching 12 million in the United States alone by 2030. This trend can be credited to changing lifestyle patterns and the increasing elderly population. [ 2 , 3 ] To treat AF efficiently, it is important to understand its two primary causes. The first, Valvular AF, is mainly associated with mitral stenosis or artificial heart valves. The second, non-valvular type can be attributed to all other forms of valvular heart disease. [ 4 , 5 ] Procedures such as transcatheter aortic valve replacement (TAVR) and percutaneous coronary intervention (PCI) may also cause new onset AF (NOAF), by causing increased ectopic activity within atrial muscles. [ 6 , 7 , 8 ] This cause is particularly concerning as 13% of TAVR patients develop NOAF and have a higher risk of stroke, Myocardial infarction, and mortality as compared to those with pre-existing AF. [ 9 , 10 ] The most pivotal therapy for AF to date has been anticoagulants. A widely known anticoagulant is Warfarin, which works by inhibiting hepatic synthesis of clotting factors (II, VII, IX, and X).[ 11 ] By significantly reducing clot formation and hence the risk of stroke in NVAF patients, Warfarin was considered the gold standard for a long time.[ 12 ] However, along with its benefits come several drawbacks, including its narrow therapeutic range and frequent drug interactions. Moreover, strict INR monitoring became necessary to prevent toxicity and bleeding.[ 13 ] In order to conquer these obstacles, Asinger et al. emphasized substitute therapeutic agents such as direct oral anticoagulants (DOACs) having similar efficacy to warfarin. However, variable safety of different DOACs depending on the type of drug and its dose were reported particularly in the.elderly population. This requires critical consideration in choosing the most appropriate anticoagulation therapy. [ 14 ]One factor Xa inhibitor, edoxaban, a promising DOAC, has demonstrated its efficacy and safety equivalent to warfarin. The key trial ENGAGE AF-TIMI 48 trial demonstrated that both drugs had comparable effects in stroke prevention and systemic embolism (SSE), with edoxaban indicating much reduced percentages of hemorrhage and heart-related death. [ 15 , 16 , 17 ] Our detailed meta-analysis highlights the importance of opting for the suitable anticoagulation among patients with NVAF, including. those that received PCI and TAVR, based on various key indicators to improve patient’s survival and mortality. Our synthesis of evidence based on a variety of studies provides an in-depth analysis and understanding of the efficacy and safety profiles of edoxaban and warfarin. Methods Data Sources and Searches The meta-analysis comprised five studies that were located subsequent to a systematic review of PubMed, the Embase, Google scholar, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL). The search strategy has been entered on PROSPERO (CRD420250648890).The search keywords and Medical Subject Headings (MeSH) were edoxaban, warfarin, atrial fibrillation, efficacy and safety. The search was optimized with the help of Boolean operators (AND, OR). There were no restrictions of language. Also, the screening of the relevant articles and systematic reviews was performed manually in order to further identify the eligible studies. Selection Criteria One criterion was used that incorporated the following 1) We included studies that report specific data on 5 outcomes: Major Adverse Cardiac Events, stroke or systemic embolism (S/SE), all-cause mortality, major bleeding and clinically relevant non-major bleeding. 2) Edoxaban and warfarin clinical trials in the atrial fibrillation patients. 3) Reporting at least one outcome of interest, e.g. stroke and systemic embolism, major bleeding, all-cause mortality, clinically relevant non-major bleeding, major adverse cardiac events or serious adverse effects. Further, we excluded studies that: 1) were Non-comparative, a case report, observational, and/or editorials. 2) Patients who were enrolled and had other indications than atrial fibrillation. 3) Lead to inadequate or redundant data. Two reviewers examined the title and abstract of the identified studies and then evaluated eligibility by full-text. When discrepancies were identified, a discussion or consultation with a third reviewer was done to resolve them. Data Mining and Acuity Evaluation The identified data were collected in a standardized data extraction sheet where the necessary information was provided such as the characteristics of the study (author, year, design, sample size, follow-up duration), patient characteristics, intervention characteristics (dosage, administration), and clinical outcomes. Two independent reviewers extracted the data. The risk of bias on included RCTs was evaluated based on the revised Cochrane Risk of Bias tool (RoB 2.0) [ 18 ], which assesses the following domains randomization, deviations of planned interventions, the absence of outcome data, outcome-measurement, and selective reporting. Each outcome has been evaluated based on the quality of provided evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. [ 19 ] The duplicates of the study were eliminated using EndNote X7 software. Data Synthesis and Analysis StataCorp. (2021) was used to conduct a meta-analysis. Stata: Release 17. StataCorp LLC, Texas, USA. DerSimonian-Laird random-effects model [ 20 ] and the inverse-variance approach was applied to all the studies. The estimates of the effects were in the form of Hazard Ratio (HR) with 95% confidence interval (CI). The I2 statistics, [ 21 ] was used to measure heterogeneity with 25, 50 and 75 percent values representing low, moderate and high heterogeneity respectively. They were divided into subgroups, which were analyzed by key clinical characteristics, such as CHA2DS2-VASc score [score>=4, high risk; score<4=moderate risk], age, renal clearance (CrCl), history of myocardial infarction (MI) and heart failure (HF) where percentage prevalence of the four outcomes were regarded in the subgroups respectively. The test by Egger was also carried out to test the publication bias on a rigorous basis. Results This meta-analysis involved 26,832 participants in five clinical trials in order to compare the effectiveness and safety of edoxaban and warfarin in patients with atrial fibrillation. The chosen articles differed in terms of the characteristics of the populations, duration of treatment, and the definition of outcomes, yet all of them fulfilled the inclusion criteria to make the systematic and comprehensive comparison of the two anticoagulants. Figure 1 shows that a PRISMA flowchart displays the criteria. Major adverse cardiac events (MACE), stroke and systemic embolism (SSE), all-cause mortality (ACM), major bleeding (MB), and clinically relevant non-major bleeding (CRNM) were the key outcomes [under analysis] Table 1 indicates baseline characteristics. View this table: View inline View popup Table 1. Baseline characteristics Figure 1 . PRISMA flowchart Major adverse cardiac events (MACE) The combined analysis showed that edoxaban had a major decrease in the risk of MACE as compared to warfarin (HR 0.90, 95% CI 0.83-0.98, p = 0.01). The heterogeneity was low (I2 = 0.00%). This implies that edoxaban can be a more suitable choice in the prevention of major cardiovascular events. Nonetheless, there was a difference in the benefit of this based on the subgroup analysis depending on patient profile. The same trend was observed in patients with preserved renal functioning (CrCl 80 mL/min) in favour of edoxaban. On the other hand, warfarin, which has been thought to be a more effective deterrence of MACE in patients with a CHA 2 DS VASc score of 4 or above, emerged as a potentially significant participant in the prevention of cardiovascular events in patients with a higher thromboembolic risk. The effect of heart failure status on MACE outcomes was also assessed in which patients with substantial burden of HF were more likely to respond better on warfarin as compared to patients with little or no HF which would respond better with edoxaban. This was shown in Figures 1 - 7 . Download figure Open in new tab Figure 1. Major adverse cardiac events Download figure Open in new tab Figure 2. MACE CrCl Download figure Open in new tab Figure 3. MACE CHA 2 DS 2 VASc Download figure Open in new tab Figure 4. MACE heart failure Download figure Open in new tab Figure 5. MACE previous MI Download figure Open in new tab Figure 6. MACE age Download figure Open in new tab Figure 7. MACE with the type of therapy Stroke and Systemic Embolism (SSE) Stroke and systemic embolism (SSE) outcomes analysis showed that edoxaban had a much greater effect in minimizing the probability of these events than warfarin with high heterogeneity (I2 = 92.2). This advantage was not, however, uniform in all groups of patients. The comparisons between the subgroups based on age and renal clearance provided also resulted in the statistically significant interactions (P < 0.05), indicating that the superiority of edoxaban in lessening the risk of SSE was rather constant across various demographic and clinical characteristics, particularly in younger patients and those with a higher creatinine clearance. Edoxaban reduced the protective effect in patients with a history of a previous MI in the past (HR 0.58, 95% CI 0.32 - 1.05), suggesting that patients with a prior history of MI do not get the same amount of risk reduction in SSE as the general population. [ Figures 8 - 13 ] Download figure Open in new tab Figure 8. Stroke and systemic embolism Download figure Open in new tab Figure 9. SSE age Download figure Open in new tab Figure 10. SSE CrCl Download figure Open in new tab Figure 11. SSE HA 2 DS 2 VASc Download figure Open in new tab Figure 12. SSE heart failure Download figure Open in new tab Figure 13. SSE previous MI All-cause mortality (ACM) In the analysis of all-cause mortality, there were no statistically significant differences between edoxaban and warfarin (HR = 0.65, p > 0.05), which proved that agents did not show a definite survival benefit compared to each other. This observation was similar in the different subgroups, which were stratified by age, renal of heart failure status, and renal functioning. The absence of difference in all-cause mortality indicates that whereas the use of edoxaban might prove beneficial in some cardiovascular and bleeding-related consequences, the same does not always lead to better survival as observed in Figures 14 - 16 . Download figure Open in new tab Figure 14. All-cause mortality Download figure Open in new tab Figure 15. ACM CHA 2 DS 2 VASc Download figure Open in new tab Figure 16. ACM heart failure Major bleeding (MB) Risk of significant bleeding was not any different between edoxaban and warfarin with a hazard ratio of 0.95 (95% CI 0.60-1.50, p = 0.83). This result supports the idea that edoxaban can be the alternative with a lower risk of bleeding. Nevertheless, stratification by the burden of heart failure has shown that the effect of edoxaban was greater in those populations with the prevalence of HF less than 25. Conversely in populations where HF prevalence was >=25 warfarin seemed to confer a minor and consequently non-significant benefit in the risk of major bleeding (HR 0.95, I2 = 93.0). Aged patients above the age of 65 demonstrated this with edoxaban being better than warfarin compared to younger patients where the vice versa was observed. Significant differences were not found within other clinical characteristics CrCl, CHA2DS2VASc and previous MI. This was shown in figures 17 - 22 . Download figure Open in new tab Figure 17. Major bleeding Download figure Open in new tab Figure 18. MB heart failure Download figure Open in new tab Figure 19. MB age Download figure Open in new tab Figure 20. MB CrCl Download figure Open in new tab Figure 21. MB CHA 2 DS 2 VASc Download figure Open in new tab Figure 22. MB previous MI Clinically relevant non-major bleeding (CRNM) Edoxaban and warfarin had a similar risk of clinically relevant non-major bleeding (CRNM) with a hazard ratio of (1.19, 95% CI 0.75 - 1.91, p = 0.46). The warfarin in younger patients (under 65 years) was linked with a greater CRNM risk but not significantly different (HR 2.49, p = 0.90). The heterogeneity was reported to be high. These variations underscore the need to customize the anticoagulant treatment of patients in accordance with the specifics of patients. Additional subgroup analyses based on CHA2DS2-VASc-score and previous MI-status further underscored the complexity of bleeding risk prediction in which warfarin has been found to have better effects in high-risk groups, whereas edoxaban is still a better choice in patients with lower thromboembolic risk profiles. Download figure Open in new tab Figure 23. Clinically relevant non-major bleeding Download figure Open in new tab Figure 24. CRNM age Download figure Open in new tab Figure 25. CRNM CrCl Download figure Open in new tab Figure 26. CRNM CHA 2 DS 2 VASc Download figure Open in new tab Figure 27. CRNM HF Download figure Open in new tab Figure 28. CRNM previous MI Risk of bias and Sensitivity analysis As an evaluation of the risk of bias, Cochrane RoB tool was utilized (Supplementary Figure S1) and GRADE assessment was also conducted to enhance the clinicians in mapping the key decisions based on the evidence of outcomes as presented in Table 2 . To overcome the problem of heterogeneity and the possibility of confounding variables, subgroup analyses were conducted according to the primary clinical variables: age, renal dysfunction, CHAUDSU-VASc score, heart failure, and history of myocardial infarction. The test as performed by Egger was also to study the strength of the results and presented in Supplementary Table S1 reveals that no small-study effects were obtained in studies. View this table: View inline View popup Download powerpoint Table 2. GRADE Assessment Discussion In this systematic review and meta-analysis, we provide a comprehensive evaluation of the efficacy and safety of edoxaban compared to warfarin in patients with NVAF as well as high-risk individuals who have undergone cardiac procedures such as PCI and TAVR. While edoxaban was associated with a reduced risk of major adverse cardiac events (MACE), stroke/systemic embolism (SSE), and major bleeding, warfarin was also a viable treatment choice in certain groups, especially those with a higher CHA 2D s VASc score, previous myocardial infarction (MI), and high heart failure load. These resultshighlight the importance of an individualized approach to anticoagulation treatment to balance thromboembolic protection and bleeding risks to maximize patient outcomes. Patients with AF were at a much greater risk of MACE, SSE, and major bleeding, as they both have prothrombotic factors and cardiovascular factors. MACE, a term commonly used in observational studies and randomised controlled trials to evaluate the safety of cardiovascular events, comprises cardiovascular death, stroke, acute myocardial infarction (AMI), and revascularisation. [ 21 ] Our pooled analysis showed that edoxaban was superior to warfarin in the following areas. These results are consistent with the available literature. Xiangwen Liang et al. proved that edoxaban 30 and 60 mg have a significant impact on cardiovascular disease (CVD), major bleeding, and non-major bleeding events. Moreover, the incidences of stroke, MI, and adverse events (AEs) were not higher with higher doses (120 mg), which is further evidence of the need to optimize the dose in order to balance efficacy and safety. [ 11 ] Influence on Renal Function Renal testing is necessary in the measurement of the anticoagulant effects since kidney failure can be a significant determinant of the drug excretion and therapy. Creatinine clearance (CrCl) is a rapid and inexpensive way of estimating renal function, with ranges of 90-120 mL/min considered normal in healthy young adults. [ 22 ] In our analysis, renal function appeared to play a role in modulating clinical outcomes with edoxaban and warfarin, although findings varied across subgroups. In major bleeding, there was no notable difference between the two anticoagulants at different levels of CrCl. This differs from previous research, which indicated a safety benefit of edoxaban in patients with preserved renal function (CrCl ≥80 mL/min), owing to more efficient clearance of the drug. Although one study used slightly different CrCl categories (>95 and 50–90 mL/min), the overall conclusion that renal function affects pharmacokinetics is still valid. [ 23 ] When considering the outcomes of efficacy, patients with preserved renal function were inclined to respond positively to edoxaban with reference to lowering major adverse cardiovascular events (MACE) and stroke/systemic embolism (SSE). Although the difference in MACE reduction by CrCl subgroup was not statistically significant, the overall trend favored better results with edoxaban in individuals with better renal function. This was better illustrated in the case of SSE, as the relative benefit of edoxaban appeared greater among patients with higher CrCl, indicating increased protective properties against thromboembolic occurrences in this group. To conclude, these results indicate the possibility of renal function as a clinical variable in the process of anticoagulant choice. Moreover, in the literature, dose adjustment in cases of renal dysfunction has also been suggested; one study suggested edoxaban be lowered to 30 mg/day in case of moderate renal impairment (CrCl 30-50 mL/min) to prevent drug accumulation and maximum bleeding risk. [ 24 ] Although our meta-analysis considered different CrCl thresholds and failed to report statistically significant differences in the subgroups, the cumulative evidence was in support of the tailoring of anticoagulation according to the renal function of patients. High CHA□DS□-VASc Scores and Prior Heart Failure In high-risk patients, specifically those with heart failure (HF) or with clinically relevant non-major bleeding (CRNM) because of having previous MI, or with a CHA□DS□-VASc vas score more than four, our study observed an association favoring warfarin over edoxaban. The CHA□DS□-VASc score is a guideline-based instrument that is used to evaluate the risk of thromboembolism and decide whether anticoagulation is required in patients with AF. [ 25 ] An increase in the score signifies the increased risk of thromboembolism, which requires anticoagulation treatment. However, these findings are not fully supported by existing literature. As an example, Natalia S. Rost et al. found that in patients who had a history of an ischemic stroke or transient ischemic attack (IS/TIA), warfarin compared to high-dose edoxaban resulted in higher rates of intracranial hemorrhage per year. [ 26 ] Another analysis also indicated that edoxaban was more likely to prevent thromboembolic events among individuals with a higher CHA□DS□-VASc score [ 27 ] This difference between our findings and these studies may be attributable to differences in the study design, the population of patients, or the fact that the optimal dose has not been optimized in the high-risk populations. More observations should be placed under research to elucidate the same. Previous Exposure to Anticoagulants A key finding in our study was a significant association favoring warfarin in patients previously exposed to vitamin K antagonists (VKA), and edoxaban in VKA-naive patients, defined as those with less than 60 days of continuous exposure to vitamin K antagonists before randomization. [ 28 ] The results of the ENGAGE AF-TIMI 48 trial support this observation and show that low-dose edoxaban was not inferior to warfarin in VKA-naive patients (HR 0.92, 95% CI 0.73–1.15) but inferior to warfarin in VKA-experienced patients (HR 1.31, 95% CI 1.08–1.60; P interaction = 0.019). [ 29 ] The efficacy of low-dose edoxaban and warfarin in stroke prevention is similar among VKA-naïve patients, presumably due to the absence of pre-existing coagulation adaptation. Chronic VKA treatment results in reduced levels of clotting factors II, VII, IX, and X, as warfarin inhibits vitamin K epoxide reductase (VKORC1) [ 30 , 31 ] Dependence on these anticoagulation mechanisms may therefore be increased in patients with long-term VKA exposure. Conversely, VKA-naïve patients lack such adaptations, and direct factor Xa inhibition by edoxaban can be similarly effective in thromboembolic prevention in this population. Influence of Age Age subgroup analysis showed a significant difference in the efficacy and safety profile of edoxaban and warfarin. Edoxaban appeared to be more effective in younger patients (Less than 65 years) as the risk of stroke and systemic embolism (SSE) decreased significantly with the use of this intervention. Though the difference in Clinically Relevant Non-Major bleeding(CRNM) risk was not statistically significant between the two drugs, the trend still showed in favor of edoxaban. Our results challenge earlier studies, such as Gentian Denas et al., which favored warfarin in younger patients.[ 32 ] This difference may be due to changing prescribing trends, better access to DOAC, or populations of patients. Younger people can also possess an improved renal clearance, fewer comorbidities, and improved adherence, which can be beneficial to the clinical efficacy of edoxaban. On the contrary, anticoagulation is also influenced by the physiological changes in elderly population decisions. Frailty, characterized by reduced biological reserves and degraded homeostasis due to increasing age, is an essential element in deciding the anticoagulation in stroke prevention of patients who have atrial fibrillation (AF). [ 33 ] In frail elderly patients, such considerations have lead to warfarin being the preference as the its effects can be easily monitored and reversed compared to DOACs like edoxaban. [ 34 , 35 ] Strengths and limitations This systematic review and meta-analysis encompasses an extensive comparison of the efficacy and safety of edoxaban and warfarin in different scenarios and groups of patients. Five clinical trials were included with a total of 26,832 participants reported in the trials highlights the generalizability and robustness of the findings. Addition of subgroup analyses aided in addressing heterogeneity and provide significant insight about particular groups of patients. Using stringent and detailed tools for defining risk of bias (Cochrane RoB v2 tool and GRADE assessment) were utilized. Additionally, comparison of the effectiveness and safety of edoxaban and warfarin is achieved through the assessment of a number of essential outcomes (SSE, MACE, ACM, CRNM, and MB). This study highlights the practicality of individualized anticoagulation treatment, providing two-fold benefits, which includes assisting clinicians in making educated decisions to maximize patient outcomes and to reduce burden of preventable events. The differences in the study designs, patient populations, and dose optimisations may be the reasons of dissonances and can affect the results comparison. Certain inferences, particularly those related to high-risk populations are not fully supported by the existent literature, and therefore, further studies are warranted in such cohorts. Although strong bias evaluation measures have been used, some inherent biases in the studies used persist, which may affect the overall results. Our study is based on the data of published studies, which might lead to publication bias and prevent the inclusion of unpublished but potentially relevant results. Conclusion Edoxaban was associated with lower rates of major cardiac events, strokes, systemic embolisms, and major bleeding in non-valvular atrial fibrillation patients, especially those with a preserved kidney function and no prior warfarin exposure. However, warfarin maintains its ground for some underserved groups i.e. elderly patients. Personalizing anticoagulation therapy is essential to balance clot prevention with bleeding risks. Further studies are warranted to confirm our findings. Data Availability All data produced in the present work are contained in the manuscript. DECLARATIONS Ethics approval and consent to participate Not applicable Consent for publication Not Applicable Availability of data and materials The datasets supporting the conclusions of this article are included within the article and its additional files. Competing interests The authors declare that they have no competing interests. Funding The authors received no funding for this research. Authors’ contributions MAS, Conceptualization of draft, data extraction, formal analysis and manuscript writing. AM, data extraction, manuscript writing and reviewing. MWI, data screening, analysis and manuscript writing. MK, data screening and data extraction. SS, data analysis and manuscript writing. MHA, reviewing and editing the manuscript. AAK, revision of the manuscript. SUPPLEMENTARY MATERIAL Download figure Open in new tab Figure S1. Cochrane Risk of bias assessment View this table: View inline View popup Download powerpoint Table S1. Egger’s test Acknowledgements Not applicable Footnotes Asnamoghis262{at}gmail.com , waleedimran0022{at}gmail.com , mishakhalidali{at}gmail.com , Sanwal.sardar008{at}gmail.com , hamzaikramjoyia1{at}gmail.com , asaad.akbar{at}gmail.com This version of manuscript has been revised to give the most updated and robust evidence on the efficacy and safety of edoxaban and warfarin in atrial fibrillation patients. It involves improvements in Introduction, results, methods and discussion sections. References 1. ↵ Ko D , Chung MK , Evans PT , Benjamin EJ , Helm RH . Atrial Fibrillation: A Review . JAMA . 2025 Jan 28; 333 ( 4 ): 329 – 42 . OpenUrl PubMed 2. ↵ Wu J , Zhang Y , Liao X , Lei Y . Anticoagulation Therapy for Non-valvular Atrial Fibrillation: A Mini-Review . Front Med . 2020 Jul 21; 7 . 3. ↵ Taduru S , Kamel H , Inohara T , Manning WJ , Piccini JP , Fonarow GC , et al. 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Share Risk-benefit profile of edoxaban and warfarin in patients with atrial fibrillation: a comprehensive systematic review and meta-analysis of randomized trials Muhammad Ahmad Sohail , Asna Moghis , Muhammad Waleed Imran , Misha Khalid , Sanwal Sardar Nawaz , Muhammad Hamza Akram , Asaad Akbar Khan medRxiv 2025.03.05.25323458; doi: https://doi.org/10.1101/2025.03.05.25323458 Share This Article: Copy Citation Tools Risk-benefit profile of edoxaban and warfarin in patients with atrial fibrillation: a comprehensive systematic review and meta-analysis of randomized trials Muhammad Ahmad Sohail , Asna Moghis , Muhammad Waleed Imran , Misha Khalid , Sanwal Sardar Nawaz , Muhammad Hamza Akram , Asaad Akbar Khan medRxiv 2025.03.05.25323458; doi: https://doi.org/10.1101/2025.03.05.25323458 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Cardiovascular Medicine Subject Areas All Articles Addiction Medicine (569) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4442) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1511) Epidemiology (15230) Forensic Medicine (30) Gastroenterology (1126) Genetic and Genomic Medicine (6610) Geriatric Medicine (668) Health Economics (998) Health Informatics (4542) Health Policy (1370) Health Systems and Quality Improvement (1613) Hematology (543) HIV/AIDS (1266) Infectious Diseases (except HIV/AIDS) (15923) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (147) Nephrology (668) Neurology (6607) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1146) Occupational and Environmental Health (957) Oncology (3337) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (664) Pediatrics (1693) Pharmacology and Therapeutics (692) Primary Care Research (712) Psychiatry and Clinical Psychology (5448) Public and Global Health (9238) Radiology and Imaging (2202) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (596) Sexual and Reproductive Health (714) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a01c48dc1ee033e5',t:'MTc3OTc5MzMxNQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();