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Abstract

Venous thromboembolism (VTE) continues to be a significant source of morbidity after total knee replacement (TKA) and total hip replacement (THA). In many locations, warfarin and low molecular weight heparin (LMWH) have gradually been supplanted as first-line pharmacological thromboprophylaxis by direct oral anticoagulants (DOACs), especially the factor Xa inhibitors rivaroxaban and apixaban. Despite having a similar mode of action, the two medicines' dosage frequency, bioavailability, and clinical trial evidence basis are different. In order to examine the effectiveness, safety, and practical concerns of rivaroxaban and apixaban following THA and TKA, this review synthesizes data from the RECORD (rivaroxaban) and ADVANCE (apixaban) trial programs, as well as subsequent meta-analyses, network meta-analyses, and extensive real-world database investigations. According to available data, apixaban is linked to a better bleeding profile, although rivaroxaban may provide a little efficacy advantage in lowering composite VTE outcomes. As a result, choosing an agent should be based on personal risk assessment rather than a standard guideline.

Keywords

Venous thromboembolism; deep vein thrombosis; pulmonary embolism; rivaroxaban; apixaban; direct oral anticoagulant; total hip arthroplasty; total knee arthroplasty; thromboprophylaxis

Introduction

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    1. Rise of direct oral anticoagulants in orthopaedics thromboprophylaxis

VTE, which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a known side effect of major lower-limb arthroplasty. In the past, 15–30% of patients receiving THA and TKA have been documented to have symptomatic DVT in the absence of prophylaxis; TKA carries a higher overall risk of DVT, whereas THA carries a higher risk of symptomatic and fatal events. Subcutaneous LMWH, the conventional mainstay of prophylaxis, is effective but has limitations due to parenteral delivery, inconsistent compliance, and the requirement for injections provided by the patient or caregiver following discharge. The development of oral factor Xa inhibitors, primarily rivaroxaban and apixaban, which provide fixed oral dose without regular coagulation monitoring, was spurred by this constraint.1,2,3

    1. Rationale for a direct comparison

Although apixaban and rivaroxaban are both direct, reversible inhibitors of activated factor X, their development and validation were carried out through distinct phase III trial programs (RECORD and ADVANCE, respectively) utilizing various enoxaparin comparator regimens and dosage schedules. Comparative reasoning depends on indirect comparisons, network meta-analyses, and big observational registries because no major, sufficiently powered, direct head-to-head randomized controlled trial (RCT) has evaluated the two medicines precisely in the arthroplasty population. The evidence is compiled in this review to aid in the selection of agents in clinical practice.4,5,6

    1. Objectives and scope

The objectives of this review are to: (i) provide an overview of rivaroxaban and apixaban's pharmacological profiles; (ii) compare safety and efficacy results from pivotal trials, meta-analyses, and real-world data; (iii) address dosage, timing, and special population considerations; and (iv) offer a useful framework for customized medication selection following THA and TKA.7,8,9

    1. 2. PHARMACOLOGICAL PROFILE
    2. 2.1 Mechanism of action

Apixaban and rivaroxaban are both direct, competitive, small-molecule inhibitors of factor Xa. They differ mechanistically from heparins and LMWH by reducing thrombin production by inhibiting the prothrombinase complex without the need for antithrombin as a cofactor.10,11,12

 

 

 

 

2.2 Pharmacokinetics

Apixaban has a lower absolute bioavailability (approximately 50%), a similar time to peak concentration (3–4 hours), and a longer elimination half-life (approximately 8–15 hours), which underpins its twice-daily dosing schedule. In contrast, rivaroxaban has a high oral bioavailability (approaching 80–100% with the 10 mg dose taken with or without food) and reaches peak plasma concentration within 2–4 hours.13,14,15

 

 

 

 

2.3 Elimination

Renal excretion (about one-third of the active substance) and hepatic metabolism/biliary excretion are the two ways that rivaroxaban is removed. Apixaban has a theoretical advantage in patients with mild-to-moderate renal impairment because it is primarily eliminated through hepatic and intestinal pathways, with renal clearance accounting for about 25% of total clearance. However, both agents require caution or dose avoidance in significant renal dysfunction.16,17,18

2.4 Approved dosing regimens for THA/TKA prophylaxis

Rivaroxaban is usually started 6–10 hours after surgery and continued for about 35 days following THA and 12–14 days after TKA. The normal dosage is 10 mg orally once daily. Similar duration recommendations (about 32–38 days after THA and 10–14 days after TKA in the pivotal studies) apply to apixaban, which is dosed at 2.5 mg orally twice daily and started 12–24 hours postoperatively.19,20,21

 

 

 

 

3. MECHANISM-BASED COMPARISON

3.1 Onset and offset of anticoagulant effect

Although apixaban's longer half-life results in more stable trough levels between doses, some authors contend that this may translate into a more consistent anticoagulant effect throughout the dosing interval, at the potential expense of a longer washout period prior to invasive procedures. Both medications achieve near-peak anticoagulant effect within a few hours of ingestion.22,23,24

3.2 Once-daily versus twice-daily dosing

Rivaroxaban's once-daily schedule is often mentioned as beneficial for drug adherence, especially when patients self-administer prophylaxis for several weeks following hospital release. Although comparative adherence data specific to the arthroplasty population are scarce and primarily extrapolated from atrial fibrillation cohorts, apixaban's twice-daily regimen may present a somewhat higher adherence burden.24,26,27

3.3 Renal impairment considerations

While rivaroxaban is often avoided when creatinine clearance falls below about 15 mL/min and used cautiously between 15 and 29 mL/min, apixaban is preferred by numerous authors in patients with borderline renal function because it depends less on renal elimination.28,29,30

 

 

 

 

4. EFFICACY OUTCOMES

4.1 Deep vein thrombosis prevention

Rivaroxaban 10 mg once daily outperformed enoxaparin in all four trials of the RECORD program when it came to lowering the composite endpoint of DVT, non-fatal PE, or mortality. The composite primary efficacy outcome in RECORD1 (THA) met pre-specified non-inferiority and subsequently demonstrated superiority, occurring in 0.8% of rivaroxaban-treated patients compared with 3.4% of enoxaparin-treated patients in the per-protocol group. Even the higher US enoxaparin dosage regimen of 30 mg every 12 hours was not as effective as rivaroxaban in RECORD4 (TKA).

Results were more varied in the ADVANCE program. Although apixaban reduced clinically significant bleeding, ADVANCE-1 (TKA), which compared apixaban 2.5 mg twice daily with enoxaparin 30 mg twice daily, did not satisfy the predetermined non-inferiority margin for the primary efficacy outcome. With a comparable rate of significant bleeding, ADVANCE-2 (TKA) demonstrated that apixaban was superior to the European enoxaparin regimen of 40 mg once daily. With the composite primary objective occurring in 1.4% of apixaban patients compared to 3.9% of enoxaparin patients, ADVANCE-3 (THA) clearly showed that apixaban was superior to enoxaparin 40 mg once daily.31,32,33,34,35

 

 

 

 

4.2 Symptomatic pulmonary embolism and mortality

All-cause mortality and symptomatic PE were rare events in both trial programs, which limited statistical power for these specific endpoints; both medicines showed rates that were either lower than or equal to enoxaparin without a signal of extra death.36,37,38

4.3 Indirect and network meta-analyses

Because rivaroxaban and apixaban were each compared against enoxaparin rather than against one another, most comparative conclusions derive from indirect and network meta-analyses. A widely cited meta-analysis comparing rivaroxaban, apixaban, and enoxaparin found bleeding events in 3.41% of rivaroxaban-treated patients and 4.09% of apixaban-treated patients, with rivaroxaban showing a numerically better efficacy signal but apixaban showing no significant efficacy difference from enoxaparin. A subsequent systematic review and network meta-analysis of new oral anticoagulants concluded that rivaroxaban ranked highest for VTE, DVT, and major VTE prevention (by surface under the cumulative ranking curve, SUCRA), while apixaban was associated with a reduced risk of bleeding relative to comparators, leading the authors to recommend rivaroxaban for patients at lower bleeding risk and apixaban for patients at higher bleeding risk.39,40,41

4.4 Real-world and observational comparisons

In comparison to published LMWH benchmarks, a prospective cohort study of 2,431 patients receiving rivaroxaban, dabigatran, or apixaban following THA or TKA revealed similar symptomatic VTE rates across all three DOACs. However, rivaroxaban appeared to be more effective than apixaban and dabigatran, and there was no statistically significant difference in major bleeding between the three agents. While rivaroxaban offers excellent prophylaxis, it may carry a slightly greater bleeding signal than aspirin or enoxaparin in unselected populations, according to large administrative-database analyses of primary THA and TKA. This emphasizes the significance of patient selection.42,43,44

5. SAFETY AND BLEEDING RISK

5.1 Major bleeding

When comparing rivaroxaban to enoxaparin, pooled data from the RECORD trials indicated a slightly higher risk of major or clinically significant non-major bleeding, especially in patients under 65, those with low body weight, and those with renal impairment. On the other hand, when compared to enoxaparin, ADVANCE-1 specifically demonstrated less clinically significant bleeding, and pooled ADVANCE data did not show a significant increase in severe bleeding with apixaban.45,46,47

5.2 Clinically relevant non-major bleeding

Both agents are associated with rates of clinically relevant non-major bleeding broadly comparable to LMWH; however, cross-trial comparisons should be interpreted cautiously given differing bleeding definitions and enoxaparin comparator regimens between the RECORD and ADVANCE programs.48,49,50

5.3 Wound complications

Potent factor Xa inhibitors are known to cause prolonged wound drainage, hematoma formation, and surgical site bleeding. Although absolute event numbers were modest, the prospective cohort comparison of rivaroxaban, dabigatran, and apixaban revealed no statistically significant difference in wound-healing complications or return to theater among the three DOACs.51,52,53

5.4 Bleeding and periprosthetic joint infection

Postoperative hematoma is a recognized risk factor for subsequent periprosthetic joint infection because it provides a nidus for bacterial seeding. While direct causal data specific to rivaroxaban versus apixaban are limited, this mechanistic link underscores why bleeding-risk minimization is not merely a hematologic concern but also an infection-prevention consideration in arthroplasty.54,55,56

6. DRUG INTERACTIONS AND CONTRAINDICATIONS

6.1 Concomitant antiplatelet and NSAID use

Concurrent use of aspirin, other antiplatelet agents, or NSAIDs increases bleeding risk with either DOAC and should prompt careful risk-benefit assessment, particularly in patients on long-term antiplatelet therapy for cardiovascular disease.57,58,59

6.2 CYP3A4 and P-glycoprotein interactions

Apixaban and rivaroxaban are both P-glycoprotein and CYP3A4 substrates. powerful inducers (like rifampin and some anticonvulsants) can decrease efficacy, whereas powerful dual inhibitors (like some azole antifungals and protease inhibitors) can raise plasma concentrations and bleeding risk. Although clinically significant interactions can happen with either drug, apixaban's multiple elimination pathways may render it less vulnerable to severe interaction effects than rivaroxaban.60,61,62

6.3 Contraindications

Both agents are contraindicated in active clinically significant bleeding, severe hepatic impairment with coagulopathy, and pregnancy. Dose adjustment or avoidance is recommended in severe renal impairment, and neither is currently recommended in patients with mechanical heart valves.63,64,65

7. REVERSAL AND PERIOPERATIVE MANAGEMENT

7.1 Reversal agents

Andexanet alfa, a recombinant modified factor Xa decoy protein, is approved for the reversal of life-threatening or uncontrolled bleeding associated with either rivaroxaban or apixaban, offering a shared reversal strategy for both agents.66

7.2 Timing of postoperative initiation

Initiating rivaroxaban or apixaban on postoperative day one instead of the day of surgery is linked to fewer early postoperative bleeding complications without a corresponding increase in thromboembolic events, according to large database analyses of DOAC timing following THA. This supports a delayed-initiation strategy for both agents when clinically appropriate.67

7.3 Preoperative discontinuation and bridging

Although renal function must be taken into consideration in both cases, apixaban's longer half-life typically requires a longer preoperative cessation window than rivaroxaban for revision surgery or unscheduled reoperation in patients already taking chronic DOAC therapy.68

8. SPECIAL POPULATIONS

8.1 Elderly patients

Elderly patients have higher baseline bleeding risk and reduced renal clearance; sub-group analyses from both trial programs suggest bleeding risk with rivaroxaban rises more steeply with age and renal decline than with apixaban, favoring apixaban in frail elderly patients.69

8.2 Obese patients

Data specific to obese arthroplasty patients remain limited for both agents; fixed dosing without weight-based adjustment is standard, though efficacy at extremes of body weight warrants further study.70

8.3 Renal impairment

As above, apixaban's lower dependence on renal clearance provides a theoretical safety margin in mild-to-moderate chronic kidney disease, though both agents require caution or avoidance in severe impairment.71

8.4 Revision arthroplasty

A retrospective cohort study found that giving apixaban on the day following revision THA (rather than the day of surgery) decreased transfusion risk without increasing thromboembolic complications, indicating that timing may be more important than agent choice in this population. Revision surgery carries a higher baseline VTE and bleeding risk due to longer operative times and greater soft-tissue disruption.72

9. COST-EFFECTIVENESS AND ACCESSIBILITY

Oral factor Xa inhibitors are generally found to be cost-effective or cost-saving once avoided nursing time for injection administration, decreased VTE-related readmissions, and improved adherence are taken into account. Pharmacoeconomic analyses of DOACs against enoxaparin have been carried out in several European health systems. While rivaroxaban and apixaban have similar per-tablet prices in some countries, the twice-daily apixaban regimen may slightly raise prescription costs compared to once-daily rivaroxaban. Direct cost comparisons between rivaroxaban and apixaban rely greatly on local drug pricing and formulary status. Any thorough cost-effectiveness model should include account for the downstream costs of bleeding issues and periprosthetic joint infection, giving preference to medicines with lower bleeding signals in high-risk patients.73

10. GUIDELINE RECOMMENDATIONS

Both rivaroxaban and apixaban are listed as acceptable pharmacological options for VTE prophylaxis after THA and TKA by major guideline bodies, such as the American Academy of Orthopaedic Surgeons (AAOS), the American Society of Hematology/American College of Chest Physicians (ACCP), and the UK National Institute for Health and Care Excellence (NICE). These bodies typically do not strongly favor one DOAC over the other. However, real-world audits show inconsistent adherence to guidelines in clinical practice, highlighting a discrepancy between published recommendations and bedside implementation that is at least as important as the selection of specific medicines. Notably, a number of recent assessments contend that revised, risk-stratified recommendations are required since current guidelines are becoming out of date in light of more recent comparative and registry data.74

11. PATIENT-REPORTED OUTCOMES AND ADHERENCE

Rivaroxaban may have a theoretical benefit in real-world compliance because once-daily regimens are consistently linked to higher self-reported adherence than twice-daily regimens across various therapeutic domains, despite the paucity of head-to-head adherence evidence in the arthroplasty population. Regardless of the particular agent, patient satisfaction with oral prophylaxis is typically higher than injectable LMWH, which reflects the DOAC medication class's wider appeal over injectable alternatives.75

12. COMPARATIVE SUMMARY TABLE

 

Parameter

Rivaroxaban

Apixaban

Comment

Target

Factor Xa (direct)

Factor Xa (direct)

Same class

Dosing (THA/TKA)

10 mg once daily

2.5 mg twice daily

Different frequency

Bioavailability

~80–100%

~50%

Rivaroxaban higher

Half-life

5–9 h (11–13 h elderly)

8–15 h

Comparable

Renal clearance

~33% renal

~27% renal

Both partly renal

Time to peak effect

2–4 h

3–4 h

Similar

Landmark trials

RECORD 1–4

ADVANCE 1–3

Both phase III programs

Comparator

Enoxaparin 40 mg OD / 30 mg BID

Enoxaparin 40 mg OD / 30 mg BID

Trial-dependent

Efficacy vs enoxaparin

Superior in RECORD 1–4

Superior in ADVANCE-2/3; non-inferior in ADVANCE-1

Rivaroxaban more consistently superior

Major bleeding

Slightly increased vs enoxaparin in pooled data

Not increased; possibly reduced

Apixaban favors safety

Reversal agent

Andexanet alfa

Andexanet alfa

Same reversal option
 

13. GAPS IN CURRENT EVIDENCE AND FUTURE DIRECTIONS

• The lack of a sizable, well powered, direct head-to-head randomized controlled trial that explicitly compares apixaban with rivaroxaban in the THA/TKA group.

• Indirect comparison is complicated by differences in enoxaparin comparator dose between the RECORD and ADVANCE projects (once-daily European vs. twice-daily North American regimens).

• Limited long-term follow-up information for bleeding, VTE recurrence, and periprosthetic infection outcomes after 90 days.

• Limited information in the revision-arthroplasty, obese, and elderly-frail categories.

• Prospective adherence and patient-reported outcome studies tailored to the arthroplasty population are required.

• The potential for customized dosing regimens based on pharmacogenomics and biomarkers (such as D-dimer-directed).76

CONCLUSION

Rivaroxaban and apixaban are both effective, guideline-endorsed oral factor Xa inhibitors for VTE prophylaxis after total hip and knee arthroplasty. Evidence from the RECORD and ADVANCE trial programs, subsequent network meta-analyses, and large observational registries suggests that rivaroxaban may offer a modest efficacy advantage in reducing composite VTE outcomes, while apixaban demonstrates a more favorable bleeding profile, particularly in elderly or renally impaired patients. In the absence of a definitive head-to-head randomized trial, agent selection should be individualized, balancing thrombotic risk, bleeding risk, renal function, and patient adherence preferences, within the framework of institutional and national guideline recommendations.

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  50. Cohen AT, Wagner MB, Mohamed MS. Risk factors for bleeding in major joint arthroplasty patients using rivaroxaban or enoxaparin: a subanalysis from four trials. Clin Appl Thromb Hemost. 2012;18(4):344-9.
  51. Highcock AJ, As-Sultany M, Finley R, Donnachie NJ. A prospective cohort comparative study of rivaroxaban, dabigatran, and apixaban oral thromboprophylaxis in 2431 hip and knee arthroplasty patients: primary efficacy outcomes and safety profile. J Arthroplasty. 2020;35(11):3160-6.
  52. Lassen MR, Gent M, Kakkar AK, Eriksson BI, Homering M, Berkowitz SD, et al. The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme. J Bone Joint Surg Br. 2012;94(11):1573-8.
  53. Garfinkel JH, Gladnick BP, Roland N, Boettner F, Rodriguez JA. Increased incidence of bleeding and wound complications with factor-Xa inhibitors after total joint arthroplasty. J Arthroplasty. 2018;33(2):533-6.
  54. Pai FY, Chang WL, Tsai SW, Chen CF, Wu PK, Chen WM. Pharmacological thromboprophylaxis as a risk factor for early periprosthetic joint infection following primary total joint arthroplasty. Sci Rep. 2022;12:10464.
  55. Galat DD, McGovern SC, Larson DR, Harrington JR, Hanssen AD, Clarke HD. Surgical treatment of early wound complications following primary total knee arthroplasty. J Bone Joint Surg Am. 2009;91(1):48-54.
  56. Anil U, Kirschner N, Teo GM, Lygrisse KA, Sicat CS, Schwarzkopf R, et al. Aspirin thromboprophylaxis following primary total knee arthroplasty is associated with a lower rate of early prosthetic joint infection compared with other agents. J Arthroplasty. 2023;38(6 Suppl):S345-9.
  57. Davidson BL, Verheijen S, Lensing AWA, Gebel M, Brighton TA, Lyons RM, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-53.
  58. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;23(10):1612-76.
  59. Kumar S, Danik SB, Altman RK, Barrett CD, Lip GYH, Chatterjee S, et al. Non-vitamin K antagonist oral anticoagulants and antiplatelet therapy for stroke prevention in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Cardiol. 2016;39(9):555-63.
  60. Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76(3):455-66.
  61. Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol. 2015;79(5):838-46.
  62. Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338(1):372-80.
  63. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-14.
  64. Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89-98.
  65. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;23(10):1612-76.
  66. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors (ANNEXA-4). N Engl J Med. 2019;380(14):1326-35.
  67. Culler MW, Lim MA, Telang SS, Palmer RC, Iyer A, Chung BC, et al. Delayed administration of apixaban and rivaroxaban is associated with reduced rates of postoperative bleeding without increasing thromboembolic risk following elective total hip arthroplasty. J Arthroplasty. 2026;41(4):e123-e130.
  68. Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-78.

Roupe M, Rosengren A, Pivodic A, Bertilsson R, Philipson J, Svennerholm K, et al. Bleeding risk on rivaroxaban versus apixaban in older patients with venous thromboembolism: a nationwide observational register-based study. Eur J Intern Med. 2025;142:106438.

  1. Piran S, Traquair H, Chan N, Bhagirath V, Schulman S. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study. Res Pract Thromb Haemost. 2018;2(4):684-8.
  2. Mandt SR, Thadathil N, Klem C, Russ C, McNamee PL, Stigge K, et al. Apixaban use in patients with kidney impairment: a review of pharmacokinetic, interventional, and observational study data. Am J Cardiovasc Drugs. 2024;24(5):603-24.
  3. Culler MW, Lim MA, Telang SS, Palmer RC, Iyer A, Chung BC, et al. Delayed administration of apixaban and rivaroxaban is associated with reduced rates of postoperative bleeding without increasing thromboembolic risk following elective total hip arthroplasty. J Arthroplasty. 2026;41(4):e123-e130.
  4. Gómez-Outes A, Avendaño-Solá C, Terleira-Fernández AI, Vargas-Castrillón E. Pharmacoeconomic evaluation of dabigatran, rivaroxaban and apixaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement in Spain. Pharmacoeconomics. 2014;32(9):919-36.
  5. Anderson DR, Morgano GP, Bennett C, Dentali F, Francis CW, Garcia DA, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-944.
  6. Laliberté F, Nelson WW, Lefebvre P, Schein JR, Rondeau-Leclaire J, Duh MS. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Adv Ther. 2012;29(8):675-90.
  7. Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124(2):196-203.

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  20. Piple AS, Wang JC, Kang HP, Mills ES, Mayfield CK, Lieberman JR, et al. Safety and efficacy of rivaroxaban in primary total hip and knee arthroplasty. J Arthroplasty. 2023;38(11):2270-6.
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  24. Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-78.
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  30. Mandt SR, Thadathil N, Klem C, Russ C, McNamee PL, Stigge K, et al. Apixaban use in patients with kidney impairment: a review of pharmacokinetic, interventional, and observational study data. Am J Cardiovasc Drugs. 2024;24(5):603-24.
  31. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-75.
  32. Turpie AGG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-80.
  33. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
  34. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375(9717):807-15.
  35. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-98.
  36. Turpie AGG, Lassen MR, Eriksson BI, Gent M, Berkowitz SD, Homering M, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty: pooled analysis of four studies. Thromb Haemost. 2011;105(3):444-53.
  37. Cohen AT, Wagner MB, Mohamed MS. Risk factors for bleeding in major joint arthroplasty patients using rivaroxaban or enoxaparin: a subanalysis from four trials. Clin Appl Thromb Hemost. 2012;18(4):344-9.
  38. Raskob GE, Gallus AS, Pineo GF, Chen D, Ramirez LM, Wright RT, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br. 2012;94(2):257-64.
  39. Yu Z, Shan P, Yang X, Lou XJ. Comparison of efficiency and safety of rivaroxaban, apixaban and enoxaparin for thromboprophylaxis after arthroplastic surgery: a meta-analysis. Biosci Rep. 2018;38(6):BSR20180423.
  40. Yi Y, Gong S, Gong T, Zhou L, Hu C, Xu W. New oral anticoagulants for venous thromboembolism prophylaxis in total hip and knee arthroplasty: a systematic review and network meta-analysis. Front Pharmacol. 2022;12:775126.
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  42. Highcock AJ, As-Sultany M, Finley R, Donnachie NJ. A prospective cohort comparative study of rivaroxaban, dabigatran, and apixaban oral thromboprophylaxis in 2431 hip and knee arthroplasty patients: primary efficacy outcomes and safety profile. J Arthroplasty. 2020;35(11):3160-6.
  43. Piple AS, Wang JC, Kang HP, Mills ES, Mayfield CK, Lieberman JR, et al. Safety and efficacy of rivaroxaban in primary total hip and knee arthroplasty. J Arthroplasty. 2023;38(11):2270-6.
  44. Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ. 2012;344:e3675.
  45. Cohen AT, Wagner MB, Mohamed MS. Risk factors for bleeding in major joint arthroplasty patients using rivaroxaban or enoxaparin: a subanalysis from four trials. Clin Appl Thromb Hemost. 2012;18(4):344-9.
  46. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
  47. Raskob GE, Gallus AS, Pineo GF, Chen D, Ramirez LM, Wright RT, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br. 2012;94(2):257-64.
  48. Neumann I, Rada G, Claro JC, Carrasco-Labra A, Thorlund K, Akl EA, et al. Oral direct Factor Xa inhibitors versus low-molecular-weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis. Ann Intern Med. 2012;156(10):710-9.
  49. Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. BMJ. 2012;344:e3675.
  50. Cohen AT, Wagner MB, Mohamed MS. Risk factors for bleeding in major joint arthroplasty patients using rivaroxaban or enoxaparin: a subanalysis from four trials. Clin Appl Thromb Hemost. 2012;18(4):344-9.
  51. Highcock AJ, As-Sultany M, Finley R, Donnachie NJ. A prospective cohort comparative study of rivaroxaban, dabigatran, and apixaban oral thromboprophylaxis in 2431 hip and knee arthroplasty patients: primary efficacy outcomes and safety profile. J Arthroplasty. 2020;35(11):3160-6.
  52. Lassen MR, Gent M, Kakkar AK, Eriksson BI, Homering M, Berkowitz SD, et al. The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme. J Bone Joint Surg Br. 2012;94(11):1573-8.
  53. Garfinkel JH, Gladnick BP, Roland N, Boettner F, Rodriguez JA. Increased incidence of bleeding and wound complications with factor-Xa inhibitors after total joint arthroplasty. J Arthroplasty. 2018;33(2):533-6.
  54. Pai FY, Chang WL, Tsai SW, Chen CF, Wu PK, Chen WM. Pharmacological thromboprophylaxis as a risk factor for early periprosthetic joint infection following primary total joint arthroplasty. Sci Rep. 2022;12:10464.
  55. Galat DD, McGovern SC, Larson DR, Harrington JR, Hanssen AD, Clarke HD. Surgical treatment of early wound complications following primary total knee arthroplasty. J Bone Joint Surg Am. 2009;91(1):48-54.
  56. Anil U, Kirschner N, Teo GM, Lygrisse KA, Sicat CS, Schwarzkopf R, et al. Aspirin thromboprophylaxis following primary total knee arthroplasty is associated with a lower rate of early prosthetic joint infection compared with other agents. J Arthroplasty. 2023;38(6 Suppl):S345-9.
  57. Davidson BL, Verheijen S, Lensing AWA, Gebel M, Brighton TA, Lyons RM, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-53.
  58. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;23(10):1612-76.
  59. Kumar S, Danik SB, Altman RK, Barrett CD, Lip GYH, Chatterjee S, et al. Non-vitamin K antagonist oral anticoagulants and antiplatelet therapy for stroke prevention in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Cardiol. 2016;39(9):555-63.
  60. Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76(3):455-66.
  61. Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol. 2015;79(5):838-46.
  62. Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338(1):372-80.
  63. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-14.
  64. Kubitza D, Roth A, Becka M, Alatrach A, Halabi A, Hinrichsen H, et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2013;76(1):89-98.
  65. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;23(10):1612-76.
  66. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors (ANNEXA-4). N Engl J Med. 2019;380(14):1326-35.
  67. Culler MW, Lim MA, Telang SS, Palmer RC, Iyer A, Chung BC, et al. Delayed administration of apixaban and rivaroxaban is associated with reduced rates of postoperative bleeding without increasing thromboembolic risk following elective total hip arthroplasty. J Arthroplasty. 2026;41(4):e123-e130.
  68. Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-78.

Roupe M, Rosengren A, Pivodic A, Bertilsson R, Philipson J, Svennerholm K, et al. Bleeding risk on rivaroxaban versus apixaban in older patients with venous thromboembolism: a nationwide observational register-based study. Eur J Intern Med. 2025;142:106438.

  1. Piran S, Traquair H, Chan N, Bhagirath V, Schulman S. Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study. Res Pract Thromb Haemost. 2018;2(4):684-8.
  2. Mandt SR, Thadathil N, Klem C, Russ C, McNamee PL, Stigge K, et al. Apixaban use in patients with kidney impairment: a review of pharmacokinetic, interventional, and observational study data. Am J Cardiovasc Drugs. 2024;24(5):603-24.
  3. Culler MW, Lim MA, Telang SS, Palmer RC, Iyer A, Chung BC, et al. Delayed administration of apixaban and rivaroxaban is associated with reduced rates of postoperative bleeding without increasing thromboembolic risk following elective total hip arthroplasty. J Arthroplasty. 2026;41(4):e123-e130.
  4. Gómez-Outes A, Avendaño-Solá C, Terleira-Fernández AI, Vargas-Castrillón E. Pharmacoeconomic evaluation of dabigatran, rivaroxaban and apixaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement in Spain. Pharmacoeconomics. 2014;32(9):919-36.
  5. Anderson DR, Morgano GP, Bennett C, Dentali F, Francis CW, Garcia DA, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-944.
  6. Laliberté F, Nelson WW, Lefebvre P, Schein JR, Rondeau-Leclaire J, Duh MS. Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients. Adv Ther. 2012;29(8):675-90.
  7. Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124(2):196-203.

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Dr. S. Sathyamoorthi
Corresponding author

Ortho, DNB (ortho), FIJS, FASM., Consultant Orthopaedics Surgeon, Trauma, Arthroplasty (Joint Replacement) & Arthroscopy, Vivekanandha Medical Care Hospital

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A. Prathap
Co-author

Swamy Vivekanandha College of Pharmacy

Photo
R. Preethi
Co-author

Swamy Vivekanandha College of Pharmacy

Photo
B. Rashmi Avanticaa
Co-author

Swamy Vivekanandha College of Pharmacy

Photo
C. Rifa Sidhik Fathima
Co-author

Swamy Vivekanandha College of Pharmacy

Dr. S. Sathyamoorthi, A. Prathap, R. Preethi, B. Rashmi Avanticaa, C. Rifa Sidhik Fathima, Rivaroxaban Vs. Apixaban After Hip and Knee Arthroplasty: A Head-To-Head Pharmacological Comparison, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 9, 2863-2877, https://doi.org/10.5281/zenodo.22914905

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