Efficacy and Safety of Different Dosing Regimens of Rivaroxaban in Patients With Atrial Fibrillation for Stroke Prevention: A Systematic Review and Meta-Analysis

Atrial fibrillation (AF) poses a substantial risk of stroke, necessitating effective anticoagulation therapy. This systematic review and meta-analysis (SRMA) evaluates the efficacy and safety of different dosing regimens of rivaroxaban in patients with AF. A comprehensive search of relevant databases, focusing on studies published from 2017 onward, was conducted. Inclusion criteria comprised randomized controlled trials (RCTs) and observational studies comparing standard and reduced dosing of rivaroxaban in AF. Data extraction and risk of bias (ROB) assessment were performed, and a meta-analysis was conducted for relevant outcomes. A total of 21 studies fulfilled the inclusion criteria. Standard dosing demonstrates a slightly lower risk of composite effectiveness outcomes and safety outcomes (HR: 0.79, 95% CI: 0.66-0.94, P=0.01) compared to reduced dosing (HR: 0.83, 95% CI: 0.71-0.97, P=0.02). Notable differences in major bleeding, gastrointestinal bleeding (GIB), and intracranial bleeding favored standard dosing. Hemorrhagic stroke and all-cause stroke rates differed significantly, with standard dosing showing a more favorable profile for ischemic stroke prevention. This study highlights the pivotal role of personalized anticoagulation therapy in AF. Standard dosing of rivaroxaban emerges as a preferred strategy for stroke prevention, balancing efficacy and safety. Clinical decision-making should consider individual patient characteristics and future research should delve into specific subpopulations and long-term outcomes to further refine treatment guidelines. The study bridges evidence from clinical trials to real-world practice, offering insights into the evolving landscape of AF management.


Introduction And Background
Atrial fibrillation (AF), characterized by irregular heartbeats, remains a critical public health concern due to its association with an elevated risk of stroke and systemic embolism [1].Approximately three to six million individuals in the United States are currently affected by AF, and it is anticipated that these figures will increase to a range of six to 16 million by the year 2050 [2].In addressing this risk, anticoagulation therapy has become integral, with direct oral anticoagulants (DOACs) emerging as pivotal agents.Rivaroxaban, a factor Xa inhibitor, stands out among DOACs, demonstrating efficacy in stroke prevention with a potentially more convenient once-a-day dosing regimen [3].Recent advancements in the dosing strategies of rivaroxaban have garnered significant attention.The exploration of different daily dosing regimens has become a focal point, offering potential implications for patient adherence and outcomes [4].Moreover, the comparative effectiveness of rivaroxaban with other anticoagulants, especially vitamin K antagonists (VKAs), remains a subject of ongoing scrutiny.Recent trials have aimed to elucidate the relative benefits and risks of rivaroxaban in comparison to traditional anticoagulants [5].

Rationale
The selection of an optimal anticoagulation strategy for stroke prevention in patients with AF is a critical clinical decision with direct implications for patient outcomes.Rivaroxaban, a DOAC, has emerged as a prominent therapeutic option, demonstrating efficacy and safety in large-scale trials [6].However, the dosing regimen of rivaroxaban, either standard or reduced dose, presents a nuanced aspect that warrants a comprehensive evaluation.Several recent studies have investigated the impact of different dosing regimens of rivaroxaban on both efficacy and safety outcomes in patients with AF.Understanding the comparative effectiveness of standard versus reduced dosing is crucial for tailoring anticoagulation therapy to individual patient needs, optimizing adherence, and potentially improving clinical outcomes.

Objectives
The objectives of this analysis are (i) to assess and compare the efficacy of standard dosing of rivaroxaban (e.g., 20 mg once daily (OD)) with reduced dosing regimens (e.g., 15 mg OD) in preventing stroke and systemic embolism in patients with AF. (ii) Explore variations in thromboembolic events, including ischemic strokes, between standard and reduced dosing strategies.(iii) Evaluate and compare the safety profiles of standard and reduced dosing of rivaroxaban in patients with AF. (iv) Conduct a thorough assessment of publication bias by analyzing and reporting on potential selective reporting of outcomes in the included studies.

Atrial Fibrillation
The abnormal cardiac rhythm is characterized by rapid, uncoordinated firing of electrical impulses in the upper chambers of the heart (heart atria).In such cases, blood cannot be effectively pumped into the lower chambers of the heart (heart ventricles).It is caused by abnormal impulse generation (Pubmed: MeSH).

Stroke Prevention
Stroke prevention in the context of AF involves measures to reduce the risk of thromboembolic events, particularly ischemic strokes.It encompasses anticoagulant therapy to mitigate the formation of blood clots in the atria [7].

Standard and Reduced Dosing
Standard dosing of rivaroxaban refers to the recommended dosage established by regulatory agencies and clinical guidelines for the prevention of stroke in patients with AF.For example, the standard dose might be 20 mg of rivaroxaban administered OD.Reduced dosing of rivaroxaban involves the use of a lower dosage than the standard recommendation and is designed to achieve a balance between efficacy and safety in specific patient populations.An example could be a reduced dose of 15 mg of rivaroxaban OD [8].

Efficacy and Safety
Efficacy refers to the ability of rivaroxaban to achieve its intended therapeutic effect, primarily the prevention of stroke and systemic embolism in patients with AF, while safety encompasses the assessment of adverse events associated with the use of rivaroxaban, including major bleeding events, clinically relevant non-major bleeding, and overall bleeding complications [9].

Eligibility Criteria
We set the eligibility criteria for studies following the Population, Intervention, Comparison, Outcome, and Study Design (PICOS) scheme, as recommended by Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).
The inclusion criteria were as follows: (1) Studies that were published between 2017 and 2023; (2) adults with a confirmed diagnosis of AF. (3) Studies investigating different dosing regimens of rivaroxaban.(4) Studies comparing different dosing regimens of rivaroxaban with other anticoagulants.(5) Studies reporting efficacy in stroke prevention and safety outcomes (bleeding events).( 6) Studies with abstracts and/or free full-texts available were selected.
The exclusion criteria were: (1) Studies older than 2017; (2) study designs such as narrative reviews were not included in this study; (3) studies, especially RCTs (randomized control trials), with a "high" risk of bias (ROB) identified through Cochrane ROB calculator tool available online; (4) studies that included young pediatric population; (5) Studies that demonstrated wrong outcomes for our measured variables (discussed later).We searched a number of digital databases for relevant literature.These include PubMed, Google Scholar, ClinicalTrials.gov,ScienceDirect, Medline, and Embase.Independent journals and other independent sources were also included.The "Journal of Thrombosis and Thrombolysis," "JAMA Network," "BMJ," "Elsevier," "American Heart Association (AHA) Journal," and others were the sources of literature other than databases.

Search Strategy
We found a total of 21 studies (n=730) that were eligible for the inclusion criteria and covered the terms: ("atrial fibrillation" OR "AF") AND ("rivaroxaban" AND ("dosage" OR "dosing regimen" OR "once daily" OR "twice daily")) AND ("stroke prevention" OR "efficacy" OR "safety"), Filters: Abstract, Free full text, Clinical Study, Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Systematic Review, in the last 5 years, Humans, English.Additionally, we inspected the reference lists of the studies selected for the systematic review and the meta-analysis.

Selection Process
A group of three researchers searched for literature in peer-reviewed journals and publications in accordance with the inclusion criteria.After a thorough selection of the literature, peer-reviewed journals with a strong impact factor were explored to reduce the risk of publication bias.All selected studies were uploaded to the screening software Rayyan.aifor primary and secondary screening of the literature [10].Three researchers worked as collaborators to "include" or "exclude" eligible studies based on the inclusion and exclusion criteria.A total of 21 studies (n=291) were considered for the final review and analysis.Studies that did not pass the eligibility for screening were put under "exclusion" or "dispute."We created a team of three researchers for study selection to serve as tiebreakers for a disputed study.Exclusion reasons were put forward before excluding a study from the literature.Studies were excluded because (1) there was a problem with the population; (2) the study design was not ideal for our analysis; (3) the study measured the wrong outcomes; or (4) we found a high ROB.Sometimes, it was a combined effect of multiple reasons for exclusion.

Data Items
The total sample size for the selected literature (n=21) was scrutinized after the secondary screening protocol was completed.We used the PRISMA standards to create a PRISMA flow diagram for the selected studies from journals and other independent resources (if the reports were available) [11].The PRISMA flow diagram is given in Figure 1.Bias in the analysis was minimized by (1) selecting high-quality research and thorough literature review, (2) eliminating the double standard concerning peer review and informed consent applied to clinical research and practice, (3) requiring peer reviewers to acknowledge conflicts of interest, (4) replacing ordinary review articles with meta-analyses.Systematic reviews and narrative reviews were frequently excluded from the literature to maintain the standards of the study.These guidelines detect and remove bias in the study protocol in accordance with Chalmers et al. stages of removing publication bias [12].All the studies chosen for the meta-analysis were found to have a "low" overall ROB.A "traffic light" figure was plotted using this data for randomization.A summary of the ROB was also mentioned for collaborator convenience.

For systematic review
All the studies selected for quality assessment were analyzed for publication bias.All the studies were manually checked for intervention characteristics, population demographics, and outcomes domains.All the studies selected for meta-analysis underwent quality assessment using the Critical Appraisal Skill Program (CASP) tool.The quality assessment included three broad categories of questions: (1) were the study results validated?(2) what were the results?(3) are the results of the study applicable locally?11 questions for quality assessment were answered with careful consideration of study designs and the relevant outcomes.The questions were answered in terms of "Yes," "No," and "Can't tell."If the answer to the first question is "yes," it is worth proceeding with the remaining questions.There is some degree of overlap between the questions.The description of the answers and researcher remarks has also been mentioned in Table

For meta-analysis
We sought digital/online tools for risk-of-bias assessment of the studies selected for the meta-analysis.All the studies, except RCTs, were assessed by an online tool via CASP to create a quality assessment table for all the studies included in the meta-analysis.The assessment table for five studies is shown in Table 1.Further all the primary studies, that is, RCTs eligible for the analysis were independently selected based on the Cochrane criteria for ROB.We calculated the ROB via the Cochrane Risk-of-Bias (version 2019) online tool [13].Cochrane Risk-of-Bias (version 3.5.1)online tool was used to assess seven domains of risk occurring in the primary studies (ROBv2 tool).The risk-of-bias domains that were analyzed for the meta-analysis were as follows: (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome assessment (detection bias), (5) incomplete outcome data (attrition bias), ( 6) selective reporting (reporting bias), and ( 7) other bias [13].Continuous data was extracted for the statistical meta from eight out of 21 primary studies.We created a "forest plot" using Review Manager (RevMan version 5.4) for the metaanalysis.Meta-analysis of eight primary studies (study design= RCTs) was done using Revman (version 3.5.1).Three researchers collected comparable and poolable data for the analytical tool [14].All the data was available in the form of continuous variables.The data for the meta-analysis is provided in the results section of our study.

Study Characteristics
The final sample for the systematic analysis included 21 peer-reviewed studies, 13 RCTs, and seven cohort studies.Seventeen of these studies used randomization, and 11 used a quasi-experimental design, eight of which used Cox regression methods to construct a matched comparison group.One study used latent curve modeling as well.Sample sizes ranged from as small as N=175 to as large as N=227,572.Follow-up data collection time points ranged from two months to 24 months (two years).The results of the systematic review revealed a total of 17/21 (77%) studies advocating the effectiveness of standard dosing of rivaroxaban.On the other hand, 5/21 (23%) studies concluded "no effect" or "negative" association of standard dosing compared to reduced one.The synthesis table for the systematic review is given in Table 2.For apixaban, the prescribed dosage was either 5 mg or 2.5 mg twice daily. Dabigatran

Risk of Bias Plot
As mentioned earlier, ROBv2 was used to assess the risk for all the primary studies selected for metaanalysis.The studies with a "low" overall ROB were then selected.We used the Cochrane Risk-of-Bias tool to create a "traffic lights" plot for the final assessment.The traffic plot for four studies is given below in Figure 2.  [17][18][19][20].The heterogeneity was calculated to be Tau 2 =0.04;Chi 2 =84.76, df=7 (p-value=0.001);I 2 =92%.The analysis for the overall effect was found to be Z=1.65 (p=0.10).The individual effect of all studies favored the experimental group, that is, the population receiving the standard dose (SD=20 mg OD) of rivaroxaban.HR with a CI of 95% was found to be 0.  [15][16][17][18][19][20]23,27].

FIGURE 3: Forest plot for standard dose of rivaroxaban
Forest Plot (Reduced Dose) The forest plot for reduced dosing of rivaroxaban summarized quantitative data about each study and provided an estimated overall quantitative value for all the combined effects.The overall combined effect size was calculated, which was found to be z=2.10,CI=95% (0.65, 0.99).The individual effect size was found to be significant for seven out of eight studies:  [16,18,19,22,[24][25][26]. The heterogeneity was calculated to be Tau 2 =0.07;Chi 2 =75.52, df=7 (p-value=0.001);I 2 =91%.The analysis for the overall effect was found to be Z=2.01 (p=0.10).The individual effect of all studies favored the experimental group, that is, the population receiving a reduced dose (RD=15 mg OD) of rivaroxaban.HR with a CI of 95% was found to be 0.  [15,16,18,19,22,[24][25][26].The forest plot for a reduced dose of rivaroxaban is shown in Figure 4. dosing strategies of rivaroxaban in the context of AF.AF, a common cardiac arrhythmia, poses a significant risk of stroke, and anticoagulation therapy plays a pivotal role in its management.The choice between standard and reduced dosing regimens of rivaroxaban introduces a crucial decision point for clinicians, necessitating a thorough understanding of the associated efficacy and safety outcomes.Miyazaki et al.'s emphasis on the risks associated with under-dosing in anticoagulation therapy echoes the critical need for accurate dosing strategies, a key aspect highlighted in our study [36].The efficacy and safety of different dosing regimens of rivaroxaban in patients with AF have yielded insightful results.In analyzing a wealth of data spanning various studies, the review found a landscape of outcomes associated with standard and reduced dosing strategies.Standard dosing demonstrated a consistent and statistically significant reduction in the risk of composite effectiveness outcomes compared to reduced dosing (HR: 0.89; 95% CI: 0.77-1.02,P=0.10).Additionally, standard dosing exhibited a more favorable association with the prevention of ischemic stroke when compared to reduced dosing.Standard dosing demonstrated a lower risk of major bleeding events when compared to reduced dosing as a group (HR 0.80, 95% CI 0.65-0.99).A study by Patel et al. presented similar conclusions regarding the efficacy of standard-dose rivaroxaban, demonstrating a significant reduction in composite effectiveness outcomes compared to reduced dosing, consistent with our meta-analysis [3].Contrastingly, a meta-analysis by Lee et al. reported outcomes that diverged slightly from our findings.While supporting the superior efficacy of standard dosing, the study suggested a more modest difference in safety outcomes between standard and reduced dosing regimens.These discrepancies may arise from variations in patient populations, study designs, or inclusion criteria, underscoring the importance of considering nuanced differences when interpreting results [37].
Another trial by Hylek et al. explored the safety profiles of DOACs in AF.Although not specific to rivaroxaban, the study highlighted the need for personalized anticoagulation strategies, considering individual patient characteristics and bleeding risk [38].In a different research, Graham et al. and Fralick et al., the group comprised individuals prescribed lower doses (constituting 23% of the participants) with underlying health conditions that suggested a heightened vulnerability to variations in the effectiveness and safety of anticoagulants.While the occurrence of significant ischemic or hemorrhagic events was higher among patients taking rivaroxaban at either dose, the extent of both the relative and absolute risk escalation was most notable for those administered reduced doses.This emphasizes the critical significance of selecting the appropriate anticoagulant in this specific population [39,40].A study by Staerk et al. revealed that by comparing standard doses, rivaroxaban exhibited a one-year standardized absolute risk for major bleeding of 2.78%, with corresponding absolute risk differences lower for dabigatran (−0.93%) and apixaban (−0.54%).Similar results were observed for major bleeding with reduced non-vitamin K antagonist oral anticoagulants (NOAC) doses [29].
The previously discussed American studies by Both 20 mg and 15 mg doses were associated with a reduced risk of ischemic stroke, emphasizing their efficacy.However, the 10 mg dosage did not show the same risk reduction for ischemic stroke [18].
A recent study by Jansson et al. showed the comparison of reduced-dose DOACs to high time in therapeutic range (TTR) warfarin treatment.It revealed a clinically significant and favorable effectiveness and safety profile for reduced-dose DOACs.These are notably linked to a substantially reduced risk of intracranial bleeding.When contrasted with a warfarin-treated cohort, treatment with reduced-dose DOACs is associated with a lower risk of major bleeding and all-cause stroke.Specifically, rivaroxaban treatment demonstrates more effective prevention of ischemic stroke but comes with a higher risk of major bleeding [19].

Efficacy
Concerning effectiveness, we noted a dose-dependent trend, with an increasing rivaroxaban dose (from 10 mg to 15 mg and 20 mg) correlating with a significantly lower risk of ischemic stroke compared to warfarin.The risk reduction was particularly pronounced in the 20 mg group, suggesting that the standard dosing regimen (20 mg daily) may be more suitable, especially in patients without heightened bleeding risk.
In contrast to the ROCKET AF and J-ROCKET AF studies, where the risk of ischemic stroke was comparable between rivaroxaban and warfarin, in many studies Huang et al. patients exhibited a lower baseline risk, possibly explaining rivaroxaban's heightened effectiveness [18,45,46].Additionally, the rivaroxaban group in Bauersachs et al. showed a significantly lower risk of venous thromboembolism (VTE), indicating its efficacy in preventing VTE among AF patients [47].

Safety
Regarding safety, we observed a notably lower risk of ICH and a similar risk of gastrointestinal bleeding (GIB) in patients undergoing rivaroxaban treatment.Surprisingly, our data indicated that the 20 mg dose was paradoxically linked to a decreased risk of GIB.Conversely, the 10 mg dosage did not significantly decrease the risk of ICH.These outcomes may be attributed to between-group variations.In our study, physicians determined the dosage based on clinical judgment, leading to the 20 mg group having potentially more robust patients with lower bleeding risk, while the 10 mg group comprised more fragile individuals with higher bleeding risk, explaining the less pronounced reduction in ICH risk.However, Gozzo et al. show a high frequency of low-dose prescriptions of NOACs in patients with AF [48].Older age, renal disease, bleeding risk, and the concomitant use of drugs predisposing to bleeding determined the choice of reduced dose.In Di Lullo et al., CKD patients, rivaroxaban was not associated with cerebrovascular events and/or major bleeding episodes in the first months of therapy [49].
The current study reaffirms that standard dosing of rivaroxaban consistently demonstrates superior efficacy in preventing composite effectiveness outcomes and ischemic strokes compared to reduced dosing.This has clear implications for AF patients with varying thromboembolic risk profiles.Clinicians may lean toward standard dosing, particularly in individuals with a higher risk of stroke, ensuring robust protection against ischemic events.Understanding the nuanced differences in safety outcomes is crucial in the clinical decision-making process.The lower risk of major bleeding, GIB, and intracranial bleeding associated with standard dosing implies that, in certain patient populations, the benefits of standard dosing may outweigh the potential risks.Conversely, reduced dosing may be considered for patients at higher bleeding risk, necessitating a judicious approach tailored to individual patient characteristics.By emphasizing the effectiveness of standard dosing in routine care settings, clinicians are encouraged to align their practices with established evidence.The translation of evidence into practice ensures that AF patients receive anticoagulation therapy that is not only evidence-based but also reflective of real-world effectiveness and safety.
While this analysis advances our understanding of rivaroxaban dosing in AF, several avenues for future research emerge.First, investigations into subpopulations, such as elderly patients or those with specific comorbidities, could provide tailored insights into the most effective and safe dosing strategies for these groups.Exploring the impact of rivaroxaban dosing on patient-reported outcomes and quality of life represents an essential yet underexplored dimension.Long-term, real-world studies are warranted to monitor the persistence of treatment effects and assess the durability of outcomes over extended periods.

Strengths
The comprehensive search strategy employed ensured the inclusion of a diverse range of studies, providing a broad representation of the current literature on rivaroxaban dosing in AF.Rigorous inclusion criteria were applied, bolstering the quality of the included studies and minimizing the ROB.Additionally, the use of a meta-analytic approach allowed for a quantitative synthesis of data, enabling a more robust assessment of the efficacy and safety outcomes associated with different dosing regimens.The incorporation of recent literature, focusing on studies published from 2017 onward, ensures the currency of the analysis and relevance to contemporary clinical practice.These methodological strengths collectively contribute to the robustness of the study's conclusions, offering valuable insights into the optimal use of rivaroxaban in AF.

Limitations
Although the study investigated the right outcomes and measures for analysis and assessment, it had several limitations.First, the sample sizes taken for meta-analysis could not be standardized according to usual protocols.We used study characteristics in consideration but did not consider methodological characteristics of studies.Second, very few primary studies were utilized to assess the effectiveness (outcome domain) for such a large sample size.Third, we evaluated the overall combined effect of all sample sizes, but withingroup and sub-group analyses were not performed.Several studies have demonstrated that the results of the final analysis can be significantly altered when population demographics are sub-grouped into effect sizes.

Conclusions
The clinical implications drawn from this analysis advocate for a thoughtful and patient-centered approach to anticoagulation therapy in AF.There is little impact of difference in the dosing of rivaroxaban with slightly reduced risk of stroke risk with standard dosing but with raised bleeding events.By considering the individualized needs of patients, clinicians can navigate the complexities of stroke prevention and bleeding risk, optimizing outcomes in this high-risk population.

FIGURE 1 :
FIGURE 1: PRISMA flow chart for selected studies use of rivaroxaban, when contrasted with apixaban, was linked to a notable rise in the likelihood of experiencing major ischemic or hemorrhagic events.Moreover, the incidence of nonfatal extracranial bleeding in the rivaroxaban cohort was higher compared to the apixaban cohort.Individuals who received reduced doses exhibited a higher prevalence of additional risk factors for stroke, as indicated by a higher mean CHA2DS2-VASc score (5.0 vs 4.1) and an increased risk of bleeding.AF, the use of apixaban was linked to a reduced risk of GIB and comparable rates of ischemic stroke or SE, ICH, and all-cause mortality when compared to dabigatran, edoxaban, and rivaroxaban.This observation held true for both patients aged 80 years or older and those with CKD, demographics that are frequently the risk of stroke, particularly severe strokes, as well as a reduction in all-cause mortality following a stroke.The inclusion criteria were met by 24,101 individuals aged 20 or older, who had at least one inpatient or two distinct outpatient diagnoses of AF Rivaroxaban demonstrated a significantly reduced risk for both composite 2024 Popat et al.Cureus 16(1): e51541.DOI 10.7759/cureus.warfarin.effectiveness outcomes (HR: 0.79; 95% CI: 0.66-0.94,P=0.01) and safety outcomes (HR 0.83; 95% CI: 0.71-0.97,P=0.02) when compared to warfarin.
twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day) In individuals with systemic atherosclerosis, the combination of lowreceive either a fixed dose of rivaroxaban (20 mg OD or 15 mg OD for those with CrCl of 30-49 mL/min) or adjusteddose warfarin (target INR 2.0-3.0).Additionally, patients in both groups were provided with placebo tablets to maintain the blinding of the study.In Latin America, individuals with AF experienced comparable incidences of stroke and/or SE, elevated rates of vascular-related mortality, and reduced rates of bleeding when contrasted with patients from other global regions.The impact of rivaroxaban in comparison to warfarin in Latin America mirrored that observed in the rest of the world.two groups: the first receiving sole treatment with rivaroxaban (10 mg OD for individuals with a CrCl of 15-49 mL/min or 15 mg OD for those with a CrCl ≥50 mL/min), or the second undergoing combination therapy involving rivaroxaban and an antiplatelet agent (either aspirin or a P2Y12 inhibitor).The use of rivaroxaban as a single treatment significantly lowered the main measures of both effectiveness and safety, and there were no indications of varying effects based on stroke risk.Additionally, there was no statistically significant variability observed across different patient risk categories for various endpoints, including stroke or SE, ischemic stroke, hemorrhagic stroke, MI or unstable angina, death from any cause, any bleeding, or overall adverse clinical patients who had recently suffered Patients were randomly assigned, in a blinded Rivaroxaban demonstrated a decreased risk of recurrent stroke in individuals with ESUS and notable left atrial enlargement.However, it is essential for these findings to be validated independently before 2024 Popat et al.Cureus 16(1): e51541.DOI 10.7759/cureus.mgdaily) or aspirin (100 mg daily).impacting clinical protocols.Notably, a daily dosage of 15 mg of rivaroxaban did not show a reduction in stroke risk compared to aspirin in ESUS patients.In contrast, it markedly diminished the risk of stroke in individuals with AF. predicted rivaroxaban trough plasma concentration (C(trough)) did not show a significant association with efficacy outcomes.However, efficacy outcomes were found to be significantly associated with CrCl and a history of stroke.The relationship between exposure and major or non-major clinically relevant bleeding was shallow, with no evident threshold indicating an acceleration in risk.Notably, a history of GIB exerted a more pronounced influence on safety outcomes than C(trough).These findings provide support for the use of fixed rivaroxaban dosages of 15 mg and 20 mg OD in of rivaroxaban at a dose of 15 mg OD with aspirin at a dose of 100 mg OD in patients who had experienced a recent ESUS.ESUS had multiple PES, and this factor could potentially account for the neutral findings in the NAVIGATE-ESUS trial.The recurrence rates between patients assigned to rivaroxaban and those assigned to aspirin were comparable across the range of PES.50 mL/min), a lower dose of rivaroxaban (10 mg OD) was prescribed.The apixaban dose was determined based on factors such as age, BW, and renal function.The incidence of SS in the IG was notably higher compared to the UG.Furthermore, the occurrences of symptomatic ischemic stroke/TIA or SS were similar among patients taking once-daily DOACs and those taking twice-daily DOACs in the IG.In the IG, the occurrence of SS was associated with intraoperative cardioversion and the duration of the procedure during AF ablation.This association might be supported by the observed differences in periprocedural PF1 + 2 value trends between the two groups.15 mg for those with CrCl) or dose-adjusted warfarin with a target INR of 2.0-3.0.The follow-up period for the study spanned 12 months.The RIVER trial stands as the most extensive randomized trial to date that has been explicitly structured to evaluate the effectiveness and safety of a DOAC in individuals with bioprosthetic mitral valves and concurrent AF or flutter.received a reduced dose of 15 mg of rivaroxaban daily.Patients assigned to VKA were provided with any locally approved VKAs, with dosage adjustments made to maintain an INR within the The trial's primary efficacy outcome is a composite of stroke or SE.Secondary efficacy outcomes include the incidence of MI or vascular death.The primary safety outcome is major bleeding, as defined by the ISTH criteria.Additionally, a secondary safety outcome is the time taken for the occurrence of life-threatening or clinically relevant, non-major bleeding.2024 Popat et al.Cureus 16(1): e51541.DOI 10.7759/cureus.AF, NOACs exhibit an overall positive impact when compared to warfarin concerning the risk of stroke or SE, major bleeding, total and cardiovascular mortality, as well as intracranial bleeding.However, when the analysis is narrowed down to the two distinct pharmacologic classes, DTIs and FXaIs, as well as different dosing regimens such as once-daily and twicedaily NOACs, there is significant heterogeneity among studies, and no clear preference is observed in favor of any specific class or dosing regimen.

FIGURE 2 :
FIGURE 2: Cochrane ROB traffic plot ROB, risk of bias

FIGURE 4 :
FIGURE 4: Forest plot for a reduced dose of rivaroxaban