Rivaroxaban vs. Enoxaparin for Preventing Venous Thromboembolism and Wound Complications after Knee Surgery: A Meta-Analysis

By Shasha He¹, Xiangbao Yin², Yingqi Xu³, Zhiwei Zhong³

Affiliations

1. Department of Endocrinology and Metabolism, the First Affiliated Hospital of Nanchang University, Nanchang, China
2. Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, China
3. Department of Vascular Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, China

doi: 10.29271/jcpsp.2025.10.1318

ABSTRACT
A systematic review was conducted to compare rivaroxaban with enoxaparin in the prevention of venous thromboembolism (VTE) and wound complications after total knee arthroplasty. Comprehensive searches of electronic databases were conducted, encompassing Medline/PubMed, Embase, and the International Clinical Trials Registry Platform (ICTRP), covering all the available literature up to January 2022. Adhering to the Cochrane methodology for systematic reviews, two independent researchers meticulously screened the retrieved studies, extracted pertinent data, and assessed the quality of the evidence. The review included six studies with 6,627 patients, sourced from Medline/PubMed, Embase, and clinical trial registries. Meta-analysis showed that rivaroxaban significantly reduced symptomatic VTE and deep vein thrombosis (DVT), with relative risks (RR) of 0.55 (p = 0.009) and 0.44 (p = 0.007), respectively. However, there was no significant difference in symptomatic pulmonary embolism (PE), wound complications, major bleeding, or mortality (all p >0.05). Rivaroxaban demonstrated superior efficacy for VTE and DVT prevention without increasing major risks.

Key Words: Enoxaparin, Meta-analysis, Rivaroxaban, Wound complications.

INTRODUCTION

Venous thromboembolism (VTE), which includes both deep vein thrombosis (DVT) and pulmonary embolism (PE), ranks as one of the predominant postoperative complications following total knee arthroplasty.¹ Without timely medical intervention, there is a high risk of developing post-thrombotic syndrome. This condition is characterised by severe symptoms such as swelling, ulceration, and gangrene, which can tragically lead to death or necessitate amputation. Such outcomes place a considerable strain on the families of patients and exert a profound socioeconomic impact. Data indicate that, in scenarios lacking preventive measures against thrombosis, the prevalence of DVT can escalate to 40% to 60%, and the occurrence of life-threatening PE is noted to be around 1%.^2,3 Anticoagulant therapy has long been established as the cornerstone for the prevention of VTE. Within this therapeutic category, rivaroxaban stands out as an innovative oral anticoagulant that eliminates the need for regular monitoring of coagulation functions, thereby streamlining the management process for patients who can administer it orally.^4-6

 Rivaroxaban's clinical efficacy and convenience have positioned it as a pivotal option in treatment protocols worldwide, especially following significant orthopaedic surgeries. In managing these conditions, the use of low molecular weight heparin and factor Xa inhibitors is widespread. Additionally, warfarin is often prescribed for patients who are in need of gastrointestinal care. Despite its widespread use, warfarin is known for its narrow therapeutic window, requiring careful dosage adjustments to avoid potential complications. The need for routine monitoring in the context of many anticoagulants stems from their significant interactions with other medications, which can complicate patient management. Rivaroxaban, distinguished as an oral direct factor Xa inhibitor, has been validated in clinical trials for its effectiveness in both the prevention and management of VTE.⁷ Comparative studies have established that rivaroxaban, when measured against enoxaparin, does not substantially increase the risk associated with severe bleeding episodes.⁸ This study aimed to conduct a comprehensive evaluation of the effectiveness of rivaroxaban in comparison to enoxaparin, specifically focusing on its ability to prevent VTE and reduce postoperative wound  complications  following  total  knee arthroplasty.

METHODOLOGY

The study was conducted in strict adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.⁹ A total of six studies were included in the study.

The retrieval of data for qualified studies was conducted using Medline/PubMed, Embase, and the International Clinical Trials Registry Platform (ICTRP) as primary sources. This comprehensive search was conducted up to January 2022, using specific search terms. Keywords such as Enoxaparin or Enoxaparine, and Rivaroxaban or BAY 597939, were combined with the term knee to accurately filter the studies. The methodology was designed to be inclusive, with no limitations on the scope of search to ensure a broad capture of the relevant literature.

The inclusion criteria for this study focused on individuals aged 18 years or older who underwent total knee arthroplasty for various reasons, provided they showed no signs of VTE, as confirmed by preoperative colour Doppler imaging. Exclusion criteria included patients with a previous history of thrombosis, those unable to tolerate enoxaparin or rivaroxaban due to severe adverse events (such as major bleeding), and individuals with active bleeding or a high risk for bleeding. The latter was defined as having prothrombin activity below 60% and a platelet count under 100×10⁹/L. Additionally, studies were excluded if they contained incomplete data, were previously published, or were retrospective in nature.

The study focused on several primary clinical outcomes, including the occurrence of symptomatic VTE, comprising both DVT and PE, as well as complications associated with wound healing. Major safety outcomes were defined as all-cause mortality and the occurrence of major bleeding events.

Following the established inclusion and exclusion criteria, two independent evaluators meticulously reviewed the pertinent literature, extracted the data and assessed the methodological soundness of the investigations. A standardised data extraction form used to ensure consistency, including comprehensive details such as publication year, participant counts in both experimental and control groups, types of interventions, outcome measures, and duration of follow-up periods. The methodological quality of the randomised controlled trials (RCTs) was evaluated using the Cochrane risk of bias tool version 5.0.2.¹⁰ For prospective studies, quality assessments were performed with the Newcastle-Ottawa Scale (NOS), adhering to the guidelines recommended by the Cochrane Collaboration.¹¹ The integrity and rigour of the included studies were independently evaluated by the first and last researchers of this study. In instances of disagreement, the evaluators engaged in thorough discussions to address and resolve the discrepancies. If a resolution could not be reached through discussion alone, the views of an impartial third party were sought to facilitate consensus, thereby ensuring the credibility and  reliability  of  the  study  evaluations.

The meta-analysis was conducted using the RevMan 5.2 software, focusing primarily on evaluating the relative risk (RR) and its associated 95% confidence interval (CI) to ascertain the aggregate effects across different studies. To rigorously assess heterogeneity among the results from the included studies, a χ² test was applied, with a significance level set at p <0.01, and the extent of heterogeneity was further quantified using the I² statistic. In instances where the data exhibited negligible or minor statistical heterogeneity, characterised by a p-value of 0.01 or higher and an I² value of 50% or less, the analysis was conducted using a fixed-effect model (p ≥1, when I² ≤50%). This model was chosen to synthesise the results, providing a consolidated view where the underlying assumption is that all included studies estimate a common underlying effect size. Conversely, when substantial heterogeneity was observed (indicated by p <0.01 and I² greater than 0%), an initial investigation was conducted to identify potential sources of variability. This involved a detailed analysis of contributing factors, relying on professional expertise and domain-specific knowledge. If the heterogeneity was deemed minimal or unrelated to professional or methodological issues, a random-effects model was applied in this meta-analysis. This approach adjusted for variability among the included studies by assuming that they may have measured effects under varying conditions, and therefore, may not have estimated the same effect size.

RESULTS

The electronic database provided an initial tally of 622 records potentially relevant to the study objectives. From this collection, 182 entries were redundant and were therefore excluded from further analysis. Upon a thorough examination of the titles and abstracts, 415 articles did not meet the established inclusion criteria and were therefore excluded. From the remaining pool, 25 articles warranted deeper examination based on their alignment with the research focus. Specifically, six RCTs were meticulously selected for detailed analysis.^12-17 These trials investigated the comparative effectiveness of rivaroxaban and enoxaparin in preventing thrombosis and addressing wound complications, in accordance with the predefined criteria. Most of the articles were having a low risk of bias, indicating a relatively high level of data reliability. Particularly, reporting bias was found to be at 100% low risk.

A comprehensive meta-analysis incorporated findings from six distinct studies, with a total of 6,339 combined participants, to compare the effectiveness of rivaroxaban with enoxaparin in the prevention of symptomatic VTE. Of these, 3,282 individuals received rivaroxaban, while 3,057 individuals were treated with enoxaparin. A rigorous statistical analysis of the results revealed no evidence of heterogeneity, as indicated by a p-value of 0.92 and an I² statistic of 0%, supporting the consistency across the findings. Given these conditions, the fixed-effect model was appropriately used to conduct this meta-analysis. The analysis conclusively established that rivaroxaban significantly outperformed enoxaparin in preventing the occurrences of symptomatic VTE. In this analysis, the calculated RR for rivaroxaban use was 0.55, with a 95% CI that extended from 0.35 to 0.86, reinforcing the robustness of the findings. Furthermore, the statistical analysis yielded a p-value of 0.009, underscoring the significance of the results, as comprehensively depicted in Figure 1. Additionally, a funnel plot analysis confirmed the absence of any significant publication bias, further reinforcing the reliability of these findings.

Figure 1: Rivaroxaban versus enoxaparin: Symptomatic VTE after total knee arthroplasty.
  Figure 2: Rivaroxaban versus enoxaparin: Symptomatic DVT after total knee arthroplasty.
  Figure 3: Rivaroxaban versus enoxaparin: Symptomatic PE after total knee arthroplasty.
  Figure 4: Rivaroxaban versus enoxaparin: Wound complications after total knee arthroplasty. Figure 5: Rivaroxaban versus enoxaparin: Major bleeding events after total knee arthroplasty.
  Figure 6: Rivaroxaban versus enoxaparin: All-cause mortality after total knee arthroplasty.

In an analysis encompassing six studies with a total of 5,229 participants, the prophylactic impact of rivaroxaban versus enoxaparin in preventing symptomatic DVT was assessed. From this patient cohort, 2,721 participants were administered rivaroxaban, while 2,508 received enoxaparin. The statistical evaluation of these studies showed a lack of heterogeneity among the collected data, as indicated by a p-value of 0.85 and an I² of 0%. Using a fixed-effect model for the meta-analysis, significant differences were identified in the efficacy of rivaroxaban compared to enoxaparin in preventing symptomatic DVT. The value of RR was 0.44, with a 95% CI that ranged from 0.25 to 0.80. The results were statistically significant, with a p-value of 0.007, as shown in Figure 2. Furthermore, the analysis of the funnel plot revealed no significant publication bias.

The effects of rivaroxaban and enoxaparin on symptomatic PE were assessed in six studies, comprising a total of 6,339 patients. Of these, 3,282 patients were in the rivaroxaban group, and 3,057 patients were in the enoxaparin group. There was no significant statistical heterogeneity among the included studies (p >0.48, I² = 0%). A fixed-effect model was applied in the meta-analysis, which found no significant difference between the two treatments in preventing symptomatic PE, (RR = 0.48; 95% CI: [0.19, 1.24]; p = 0.13; Figure 3). Furthermore, the funnel plot revealed no significant publication bias.

A detailed meta-analysis assessed data from six distinct studies, encompassing a total of 6,221 participants, to compare the impact of rivaroxaban versus enoxaparin on wound complications. The participant allocation across these studies was evenly distributed, assigning 3,108 patients to the rivaroxaban group, while 3,113 to the enoxaparin group. A detailed statistical examination of the aggregated results showed minimal heterogeneity, with a p-value of 0.35 and an I² of 10%, indicating a consistent pattern across the contributing studies. Due to the minimal variability observed in the outcomes across the studies, a fixed-effect model was employed in the meta-analysis. The results demonstrated that the efficacy of rivaroxaban in reducing wound complications was statistically comparable to that of enoxaparin, with both treatments showing similar outcomes in terms of healing and complication rates. The calculated RR was 1.11, with a 95% CI ranging from 0.79 to 1.57 and a p-value of 0.54, suggesting that neither treatment offered a superior advantage. These findings are visually summarised in Figure 4. Additionally, the funnel plot analysis confirmed no significant publication bias, reinforcing the validity of the results.

A detailed meta-analysis was conducted, pooling results from six comprehensive studies that collectively included 6,221 patients, to assess the preventive impact of rivaroxaban and enoxaparin on major bleeding events. Of which, 3,108 patients received rivaroxaban; 3,103 patients received enoxaparin, ensuring a balanced comparison between the two treatment groups. The statistical analysis demonstrated a very low heterogeneity, with a p-value greater than 0.59 and an I² value of 0%, highlighting the consistency of the treatment effects across all the included studies. Given the uniformity of the data, a fixed-effect model was used for the meta-analysis. Employing a rigorous statistical methodology, it was found that rivaroxaban’s effectiveness in preventing significant bleeding episodes did not differ significantly from that of enoxaparin. The calculated RR was 1.59, with a 95% CI that ranged from 0.77 to 3.27 and no statistically significant difference, as reflected by a p-value of 0.21. Detailed visual representation of these outcomes is shown in Figure 5. Furthermore, to ensure the absence of publication bias, a detailed funnel plot analysis was conducted. The results confirmed that there were no discernible biases, thereby substantiating the integrity and robustness of the meta-analysis results.

An in-depth meta-analysis synthesised the results from six studies, which collectively involved 6,103 participants, to evaluate the comparative effects of rivaroxaban and enoxaparin on mortality outcomes. This patient cohort was evenly distributed, with 3,046 participants treated with rivaroxaban and 3,057 with enoxaparin. The analysis of the results indicated moderate statistical heterogeneity, with a p-value of 0.09 and an I² statistic of 66%, suggesting some variability in the effects observed across different studies. Given these parameters, the fixed-effect model was deemed appropriate for the meta-analysis. The comprehensive analysis indicated that the reduction in mortality rates, when comparing rivaroxaban to enoxaparin, did not achieve statistical significance. This observation was supported by an RR value of 0.52, with a 95% CI that ranged from 0.20 to 1.34. Moreover, the analysis produced a p-value of 0.17, further substantiating the lack of a significant disparity between the two treatments in terms of their mortality reduction capabilities. These results are clearly illustrated in Figure 6. Additionally, the analysis of the funnel plot for potential publication bias did not show any significant distortions.

DISCUSSION

Following total knee arthroplasty, patients exhibit an elevated risk of VTE during both the postoperative phase and after discharge, with the financial cost of treating VTE being considerably high. A minority of these cases may progress to PE, which is a major cause of perioperative mortality in orthopaedic patients.¹⁸ Rivaroxaban, a highly selective and targeted oral direct factor Xa inhibitor, has demonstrated VTE prevention efficacy comparable to that of enoxaparin, as evidenced in two extensive, multicentre RCTs.^19,20 Atkins has advocated for the use of rivaroxaban as a prophylactic measure against VTE.²¹ In a comprehensive meta-analysis, the effectiveness of rivaroxaban versus enoxaparin in preventing VTE, DVT, and PE, following knee arthroplasty, was rigorously assessed, along with their impact on wound complications, major bleeding episodes, and mortality rates. The analysis incorporated data from 6,627 participants pooled from six RCTs. Of these participants, 3,514 were treated with rivaroxaban, while 3,113 received enoxaparin. The study's results indicated that the rates of wound complications were similar between the treatment groups [RR = 1.11, p = 0.54]. Nonetheless, the data indicated that rivaroxaban had a considerably stronger effect in lowering the occurrence of symptomatic VTE, evidenced by an RR of 0.55 and a statistically significant p-value of 0.009. This implies that rivaroxaban may offer superior anticoagulant benefits compared to enoxaparin. In the rivaroxaban group, the reduction in the risk for symptomatic DVT was significantly greater, as indicated by an RR of 0.44 and a statistically significant p-value of 0.007. Conversely, the effectiveness of the two drugs in preventing symptomatic PE did not differ significantly [RR = 0.48, p = 0.13], indicating a similar level of efficacy in this aspect. Additionally, the occurrence of major bleeding events was comparable between the two groups [RR = 1.59, p = 0.21], and no significant difference was observed in the mortality rates among the study participants [RR = 0.52, p = 0.17].

Wound infections are classified into superficial and deep types, with deep infections representing particularly grave complications. These severe infections frequently occur after joint formation, necessitating multiple, intensive debridement procedures and the administration of high doses of antibiotics. Such medical interventions, although necessary, impose considerable physiological and economic burden on the patients.²² Extensive research has meticulously documented the impact of these complications on the duration of hospital stays.²³ According to Jameson's findings, patients grappling with severe wound complications necessitated hospital stays averaging 14.2 days, substantially longer than the 6.6 days required for patients without such complications. This pronounced difference was statistically verified with a significance level of p <0.001, highlighting the profound impact of deep wound infections on healthcare outcomes. Evaluating the safety profile of rivaroxaban, an anticoagulant renowned for its efficacy, involves examining its potential to increase bleeding risk, impair wound healing, and induce joint infections. Comparative studies between rivaroxaban and enoxaparin reveal minimal differences in the incidence of these complications, likely because both agents interrupt endogenous and exogenous coagulation pathways. Additionally, both drugs reduce thrombin production and mitigate thrombosis through the inhibition of factor Xa. Rivaroxaban is notable for its lack of influence on thrombin (factor II activator) and platelet functionality, supporting its favourable safety profile. Unlike heparin which requires antithrombin III for its anticoagulative effects, rivaroxaban directly and competitively inhibits both free and bound forms of factor Xa, as well as the activity of the prothrombinase complex. The inhibitory effect results in a dose-responsive prolongation of activated partial thromboplastin time and prothrombin time. This creates a unique therapeutic profile that contrasts with heparin, which does not influence factor Xa activity within the proenzyme complex.²⁴ Rivaroxaban stands out in anticoagulation therapy as an oral agent that directly targets coagulation factor Xa, eliminating the discomfort commonly associated with subcutaneous injections.⁵ However, its higher cost may pose a barrier to its widespread adoption. In contrast, enoxaparin sodium, with its lower cost, is more accessible, particularly in economically disadvantaged regions, making it a favourable option where budget constraints are a significant concern. Despite its affordability, the need for subcutaneous administration of enoxaparin could complicate its use, as improper injection techniques may cause complications such as subcutaneous haematomas, potentially reducing patient compliance. Both rivaroxaban and enoxaparin have demonstrated efficacy in preventing deep venous thrombosis following knee arthroplasty, yet they carry inherent risks of bleeding, as noted in clinical trials.²⁵ The unique characteristics of these profiles highlight the critical need for a thorough evaluation of the advantages and disadvantages of antithrombotic treatments. It is imperative to select such treatments with careful consideration of individual patient factors and the specific clinical context.

Despite implementing a comprehensive search strategy, with cross-checking of the literature screening and data extraction during the preparation of this systematic review, several limitations remained. There was insufficient RCT data on the use of rivaroxaban for preventing wound complications in orthopaedic major surgeries. Some of the included RCTs did not use blinding and specify the allocation concealment methods, which might have affected the credibility of the results. The number of relevant studies was limited, with a sample size of 6,627 patients. Some of the included studies did not provide comprehensive experimental data on wound complications, making it difficult to analyse the specific complication rates for each group. Therefore, more research is needed to provide a more thorough insight into the use of rivaroxaban and enoxaparin in major orthopaedic surgery.

CONCLUSION

The analysis demonstrated statistical benefits of rivaroxaban over enoxaparin, particularly noting a significant reduction in the rates of symptomatic VTE and DVT associated with rivaroxaban use. Conversely, no significant benefits were observed in the rivaroxaban cohort regarding symptomatic PE, wound complications, major bleeding events, or all-cause mortality when compared to the enoxaparin group. The meta-analysis incorporated only RCTs; however, the limited number of studies included suggests a need for further investigation. Consequently, it is imperative to conduct additional large-scale, multicentre RCTs to gather robust evidence.

FUNDING:
This work was funded by the Natural Science Youth Foundation of Jiangxi Province (20232BAB216010), Youth Fund of Education Department of Jiangxi Province (GJJ210251), National Natural Incubation Programme of the Second Affiliated Hospital of Nanchang University (2022YNFY1201), and Applied Research and Cultivation Programme of Jiangxi Provincial Health Committee (20181BBG78060).

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
SH, XY, YX, ZZ: Conceived and designed the meta-analysis, concluded the search for the article, performed data analysis, drafted the manuscript, supervised the study, revised the manuscript, and approved the manuscript’s results and conclusions.
SH, XY, YX: Contributed equally to this work.
All authors approved the final version of the manuscript to be published.

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