Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty

Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty

Thrombosis Research 130 (2012) 147–151 Contents lists available at SciVerse ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/loc...

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Thrombosis Research 130 (2012) 147–151

Contents lists available at SciVerse ScienceDirect

Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Regular Article

Concomitant use of medication with antiplatelet effects in patients receiving either rivaroxaban or enoxaparin after total hip or knee arthroplasty☆ Bengt I. Eriksson a,⁎, Nadia Rosencher b, Richard J. Friedman c, Martin Homering d, Ola E. Dahl e a

Department of Orthopaedics, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden Department of Anesthesiology and Intensive Care, Cochin Hospital (AP-HP), Paris 5 University, Paris, France Department of Orthopaedic Surgery, Roper Hospital and Charleston Orthopedic Associates, Charleston, SC, USA d Bayer HealthCare, Berlin, Germany e Department of Orthopaedics, Elverum Central Hospital, Elverum, Norway b c

a r t i c l e

i n f o

Article history: Received 14 October 2011 Received in revised form 30 November 2011 Accepted 4 December 2011 Available online 5 January 2012 Keywords: Drug interactions Non-steroidal anti-inflammatory agents Platelet function inhibitors Rivaroxaban Total hip arthroplasty Total knee arthroplasty

a b s t r a c t Introduction: The RECORD programme compared oral rivaroxaban with enoxaparin for prevention of venous thromboembolism after elective total hip or knee replacement. This analysis compared the safety of concomitant use of specified medications with rivaroxaban and enoxaparin by evaluating postoperative bleeding rates from the pooled RECORD1–4 data. Materials and methods: The co-medications were non-steroidal anti-inflammatory drugs and platelet function inhibitors, including acetylsalicylic acid (no dose restriction). The endpoints evaluated were the composite of major and non-major clinically relevant bleeding and any bleeding occurring after first oral study drug intake. The time relative to surgery was stratified into three time periods: day 1–3, day 4–7 and after day 7. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel–Haenszel methods and compared between rivaroxaban and enoxaparin groups. Results: Co-medication use with rivaroxaban or enoxaparin resulted in non-significant increases in bleeding events. Respective rate ratios were not significantly different between rivaroxaban and enoxaparin for all bleeding endpoints with concomitant use of non-steroidal anti-inflammatory drugs (any bleeding, 1.22 vs 1.22; major and non-major clinically relevant bleeding, 1.28 vs 0.90) and with concomitant use of platelet function inhibitors/acetylsalicylic acid (any bleeding, 1.32 vs 1.40; major and non-major clinically relevant bleeding, 1.11 vs 1.13). Conclusions: This explorative analysis indicates that there is no significant increase in bleeding risk for rivaroxaban compared with enoxaparin when co-administered with non-steroidal anti-inflammatory drugs or acetylsalicylic acid, although, because of low usage, the experience with platelet function inhibitors (except acetylsalicylic acid) was limited. © 2012 Elsevier Ltd. All rights reserved.

Introduction

Abbreviations: ASA, acetylsalicylic acid; ATC, Anatomical Therapeutic Chemical Classification; bid, twice daily; CI, confidence interval; CrCl, creatinine clearance; NMCR, non-major clinically relevant; NSAIDs, non-steroidal anti-inflammatory drugs; od, once daily; PFIs, platelet function inhibitors; TKA, total knee arthroplasty; THA, total hip arthroplasty; VTE, venous thromboembolism. ☆ Presented at: American Society of Hematology (ASH) 50th Annual Meeting and Exposition, San Francisco, CA, USA, December 6–9, 2008; European Association of Hospital Pharmacists (EAHP) 14th Congress, Barcelona, Spain, 25–27 March, 2009; 10th European Federation of National Associations of Orthopaedics and Traumatology (EFORT) Congress, Vienna, Austria, June 3–6, 2009; International Society on Thrombosis and Haemostasis (ISTH) XXII Congress, Boston, MA, USA, July 11–16, 2009; and American Academy of Orthopaedic Surgeons (AAOS) 2010 Annual Meeting, New Orleans, LA, USA, March 9–13, 2010. ⁎ Corresponding author at: Department of Orthopaedics, Sahlgrenska University Hospital/ Mölndal, SE-43180 Mölndal, Sweden. Tel.: +46 313 434 408; fax: +46 313 434 092. E-mail address: [email protected] (B.I. Eriksson). 0049-3848/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.12.005

Patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) are at significantly increased risk of developing venous thromboembolism (VTE), and the routine use of anticoagulant prophylaxis is recommended in these patients. Current evidencebased guidelines, including those from the American College of Chest Physicians, recommend the use of a low molecular weight heparin (e.g. enoxaparin), fondaparinux (Arixtra; GlaxoSmithKline: Research Triangle Park, NC, USA) or vitamin K antagonists (e.g. warfarin) to prevent postoperative VTE after THA or TKA [1]. To address some of the well-known limitations of these established agents, several new oral anticoagulants have been developed [2], including the direct Factor Xa inhibitor rivaroxaban (Xarelto; Bayer Pharma AG: Berlin, Germany). Rivaroxaban has been approved in more than 110 countries worldwide for the prevention of VTE in adult patients after elective hip or knee replacement surgery. In the phase III RECORD (REgulation of Coagulation

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in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism) programme, which enrolled more than 12,500 patients in four studies, rivaroxaban demonstrated superior efficacy to enoxaparin for the prevention of VTE in this setting, without a significant increase in major bleeding [3–6]. In most phase III clinical trials of the use of anticoagulants after THA or TKA, the primary safety endpoints investigated are major bleeding events. In addition to these events, there are several other safety issues that may be relevant to everyday clinical practice. Among these concerns are potential interactions with other drugs; these interactions are a considerable burden associated with the use of vitamin K antagonists. Interactions with drugs that affect haemostasis are of particular interest because of the potential effect on bleeding risk; these include non-steroidal anti-inflammatory drugs (NSAIDs), platelet function inhibitors (PFIs) and other anticoagulants. It is estimated that approximately 30 million people worldwide take NSAIDs and/or acetylsalicylic acid (ASA) on a daily basis [7]. In the US alone, more than 111 million prescriptions for NSAIDs are made each year [8], with many more people taking these as over-the-counter drugs, and approximately one-third of individuals aged 65 or over are reported to take NSAIDs on a daily basis [8]. These drugs are used for their analgesic, anti-inflammatory and antipyretic properties, and ASA is also prescribed for the prevention and treatment of cardiovascular disease and the prevention of stroke in at-risk patients. Moreover, perioperative myocardial infarction is a significant cause of morbidity and mortality after THA or TKA [9]; therefore, ASA is often given with thromboprophylaxis and interruption of ASA therapy is not recommended in patients undergoing orthopaedic surgery. NSAIDs are frequently used as pain relief in patients with osteoarthritis or rheumatoid arthritis [10,11], or osteophytes around a hip prosthesis, and are recommended for analgesia after THA or TKA [12,13]. Patients undergoing THA or TKA are also recommended to receive anticoagulants for postoperative VTE prevention according to guidelines [1]. Sole use of either class of drug is associated with certain risks: NSAID use can lead to gastrointestinal ulcers and bleeding [14,15], and, by their nature, anticoagulants can increase the risk of bleeding. With the emergence of new oral anticoagulants, safety data on the potential risks of concomitant use of NSAIDs with these agents will be required, particularly on the risk of bleeding in the postoperative setting. Potential interactions between rivaroxaban and NSAIDs and ASA have been investigated in healthy young subjects [16,17]. In the RECORD programme, the concomitant use of rivaroxaban and NSAIDs, including ASA and other PFIs, was permitted in accordance with the study protocol. The objective of this analysis was to investigate the safety of concomitant use of rivaroxaban and these medications compared with enoxaparin by evaluating the incidence of postoperative bleeding events in patients undergoing THA or TKA in the RECORD programme.

(RECORD3 and RECORD4) received rivaroxaban or enoxaparin for 10–14 days [3–6]. Specified co-medications The co-medications investigated in this prespecified analysis were NSAIDs and PFIs or ASA. PFIs and ASA were grouped together as one of the prespecified classes of co­medications and, therefore, outcomes were not recorded for PFIs and ASA separately. The co-medications documented in the case report forms were coded according to the World Health Organization Drug Dictionary, version 2005/Q3, in which NSAIDs were coded as anti-inflammatory and antirheumatic products, non-steroids (Anatomical Therapeutic Chemical Classification [ATC] code M01A), and PFIs or ASA were coded as PFIs excluding heparin (ATC code B01AC) and/or multiple-ingredient drugs containing ASA. There was no limitation on the choice of a specific drug or dose of NSAIDs and PFIs or ASA in the study protocols. These analyses and the definition of co­medications were prespecified in the RECORD1–4 pooled statistical analysis plan prior to unblinding of any of the RECORD studies. Analysis of bleeding endpoints Potential drug–drug interactions were investigated by analysis of prespecified adjudicated bleeding endpoints in all patients who underwent surgery and received study medication. The endpoints evaluated were the composite of major and non-major clinically relevant bleeding, and any bleeding occurring after first postoperative oral study drug intake (rivaroxaban or matching placebo tablet). No other safety endpoints were analysed in this investigation. These events were analysed in the at-risk period, which was from the day of surgery (defined as day 1) until 2 days after the last intake of study drug or until event onset, whichever came first. This included the placebo phase of the RECORD2 study. The use of co-medications was considered a timedependent covariate because patients could stop and restart the comedications of interest in the evaluated risk period. The time relative to surgery was stratified into three time periods: day 1–3, day 4–7 and after day 7. This was based on the consideration that the risk of a first bleeding event decreases over time after surgery and the prevalence of co-medication use may vary over time. However, the bleeding risk was assumed to be constant within each time period to allow the application of patient–time-based approaches. Relative bleeding rates were calculated for each time period, as well as for the entire at­risk period, and expressed as rates per 100 patient-weeks. The time at-risk with co-medication use was prespecified as a patient's time under co-medication use plus the 2 days following the cessation of the co-medication, if it was stopped. Relative bleeding rate ratios for co-medication use versus non-use were derived using stratified Mantel–Haenszel methods and compared between rivaroxaban and enoxaparin/placebo groups.

Materials and methods

Results

Study design

Patients concomitantly receiving either NSAIDs, or PFIs or ASA were similarly distributed between the rivaroxaban and enoxaparin/placebo groups (Table 1). The characteristics of these patients (gender, age, weight) were similar between the rivaroxaban and enoxaparin/placebo groups (Table 1). Over 70% of patients in both groups concomitantly used NSAIDs (at least once) in the time period of interest. PFIs or ASA were taken at least once by 9% of patients in both groups (Table 1), although less than 1% of patients in each group took the potent PFIs clopidogrel or ticlopidine. The proportion of patient–time with NSAID co-medication use decreased over time and was similar in both groups (days 1–3: 62% vs 62%; days 4–7: 51% vs 52%; after day 7: 29% vs 28%, for rivaroxaban and enoxaparin/placebo, respectively). The proportion of patient–time

This analysis was part of a prespecified analysis of pooled data from the four phase III studies of the RECORD programme. In a doubledummy design, patients were randomised to receive either oral rivaroxaban 10 mg once daily (od) starting 6–8 hours after surgery or subcutaneous enoxaparin 40 mg od starting 12 hours before surgery (RECORD1–3) [3–5] or enoxaparin 30 mg twice daily (bid) starting 12–24 hours after wound closure or after adequate haemostasis was achieved (RECORD4) [6]. Patients undergoing THA received oral rivaroxaban for 31–39 days or subcutaneous enoxaparin for 31–39 days (RECORD1) or enoxaparin for 10–14 days with placebo tablets for 31–39 days (RECORD2); patients undergoing TKA

B.I. Eriksson et al. / Thrombosis Research 130 (2012) 147–151 Table 1 Patient demographics.

NSAIDs Number of patients with co­medication use,* n (%) Male (%) Age, mean (years) Weight, mean (kg) CrCl, mean (ml/min) PFIs or ASA Number of patients with co-medication use,* n (%) Male (%) Age, mean (years) Weight, mean (kg) CrCl, mean (ml/min)

Rivaroxaban

Enoxaparin/placebo

N = 6093

N = 6107

4396 (72)

4432 (73)

39 64 79 91

41 64 79 91

563 (9)

526 (9)

47 68 82 86

47 68 83 86

*Co-medication use refers to use in the at-risk period, which starts on day 1 (day of surgery) and ends up to 2 days after the last intake of study medication. ASA, acetylsalicylic acid; CrCl, creatinine clearance; NSAIDs, non-steroidal anti-inflammatory drugs; PFIs, platelet function inhibitors.

with PFIs or ASA co-medication use was relatively constant over the time intervals and was similar in both rivaroxaban-treated and enoxaparin/placebo-treated groups (3–5%). The most common NSAIDs and PFIs taken by both groups of patients are given in the online supplementary material. Most medication use in the PFI or ASA class was attributed to the use of ASA, with few patients taking clopidogrel while on study medication.

Effect of concomitant use of non-steroidal anti-inflammatory drugs Any bleeding events The relative rate ratios for any bleeding events with NSAID comedication use versus non-use remained relatively constant over the three time intervals (Table 2). The ratios were similar between the rivaroxaban and enoxaparin/placebo study groups as indicated by overlapping 95% confidence intervals (CIs) of the rate ratios. Over the total at-risk period, the relative rate ratios for any bleeding events (stratified by time windows) were 1.22 in both groups (rivaroxaban 95% CI 0.99–1.50; enoxaparin 95% CI 0.98–1.51; Table 3, Fig. 1). Table 2 Relative bleeding rates for use versus non-use of co-medications with rivaroxaban and enoxaparin over three time windows in the at-risk period⁎. Bleeding endpoint

Rate (per 100 patient-weeks) ratio for use versus non-use (95% CI) Day 1–3

Day 4–7

NSAIDs Any bleeding Rivaroxaban 10 mg od 1.43 (1.03–1.98) 1.09 Enoxaparin 1.41 (0.98–2.04) 1.24 Major and non-major clinically relevant bleeding Rivaroxaban 10 mg od 1.29 (0.77–2.15) 1.03 Enoxaparin 1.00 (0.58–1.73) 0.83 PFIs or ASA Any bleeding Rivaroxaban 10 mg od 1.49 (0.75–2.93) 1.62 Enoxaparin 1.94 (0.94–4.02) 0.55 Major and non-major clinically relevant bleeding Rivaroxaban 10 mg od 0.91 (0.23–3.65) 1.47 Enoxaparin 1.34 (0.33–5.42) 0.50

After day 7

(0.76–1.54) (0.90–1.71)

1.07 (0.70–1.65) 0.89 (0.54–1.47)

(0.59–1.81) (0.49–1.42)

1.55 (0.92–2.60) 0.84 (0.34–2.13)

(0.81–3.26) (0.18–1.70)

0.83 (0.31–2.25) 2.26 (1.04–4.88)

(0.46–4.68) (0.07–3.55)

1.02 (0.32–3.25) 2.19 (0.52–9.28)

⁎At-risk period was from the day of surgery (day 1) until 2 days after the last intake of study drug or until event onset, whichever was first. ASA, acetylsalicylic acid; CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs; PFIs, platelet function inhibitors; od, once daily.

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Major and non-major clinically relevant bleeding events The relative rate ratios for the composite of major and non-major clinically relevant bleeding events with NSAID co-medication use versus non-use were also relatively constant and were similar between rivaroxaban and enoxaparin groups over the three time intervals (Table 2). Over the total at-risk period, the relative rate ratios for the composite of major and non-major clinically relevant bleeding events (stratified by time windows) were 1.28 in the rivaroxaban group (95% CI 0.94–1.73) and 0.90 in the enoxaparin group (95% CI 0.63–1.28; Table 3, Fig. 1). Effect of concomitant use of platelet function inhibitors or acetylsalicylic acid Any bleeding events The relative rate ratios for any bleeding events with PFI or ASA comedication use versus non-use remained relatively constant and were similar between rivaroxaban and enoxaparin groups over the three time intervals (Table 2). Over the total at-risk period, the relative rate ratios for any bleeding events (stratified by time windows) were 1.32 in the rivaroxaban group (95% CI 0.85–2.05) and 1.40 in the enoxaparin/placebo group (95% CI 0.87–2.25; Table 3, Fig. 1). Major and non-major clinically relevant bleeding events The relative rate ratios for the composite of major and nonmajor clinically relevant bleeding with PFI or ASA co-medication use versus non-use remained relatively constant and were similar between rivaroxaban and enoxaparin groups over the three time intervals (Table 2). Relative rate ratios for the composite of major and non-major clinically relevant bleeding (stratified by time windows) were 1.11 in the rivaroxaban group (95% CI 0.55–2.55) and 1.13 in the enoxaparin/placebo group (95% CI 0.47–2.75) over the total period (Table 3, Fig. 1). Table 3 Relative bleeding rates for use versus non-use of co-medications with rivaroxaban and enoxaparin over the total at-risk period. Bleeding endpoint

NSAIDs Any bleeding events with NSAID use, % (n/n) Rate per 100 patient-weeks With co-medication Without co-medication Rate ratio* for use versus non-use (95% CI) Major and non-major clinically relevant bleeding events with NSAID use, % (n/n) Rate per 100 patient-weeks With co-medication Without co-medication Rate ratio* for use versus non-use (95% CI) PFIs or ASA Any bleeding events with PFI or ASA use, % (n/n) Rate per 100 patient-weeks With co-medication Without co-medication Rate ratio* for use versus non-use (95% CI) Major and non-major clinically relevant bleeding events with PFI or ASA use, % (n/n) Rate per 100 patient-weeks With co-medication Without co-medication Rate ratio* for use versus non-use (95% CI)

Rivaroxaban regimens

Enoxaparin regimens

(N = 6093)

(N = 6107)

4.7 (208/4396) 2.67 1.26 1.22 2.1

4.4 (194/4432)

(2.32–3.06) 2.51 (2.17–2.88) (1.08–1.47) 1.17 (0.99–1.36) (0.99–1.50) 1.22 (0.98–1.51) (92/4396) 1.4 (64/4432)

1.15 (0.93–1.41) 0.81 (0.62–1.03) 0.57 (0.45–0.71) 0.47 (0.36–0.59) 1.28 (0.94–1.73) 0.90 (0.63–1.28) 3.6 (20/563) 2.04 1.76 1.32 1.4

3.2 (17/526)

(1.25–3.15) 2.06 (1.20–3.29) (1.58–1.95) 1.63 (1.46–1.81) (0.85–2.05) 1.40 (0.87–2.25) (8/563) 1.0 (5/526)

0.78 (0.34–1.54) 0.59 (0.19–1.38) 0.78 (0.67–0.91) 0.59 (0.49–0.70) 1.11 (0.55–2.55) 1.13 (0.47–2.75)

*Stratified by time windows day 1–3, day 4–7 and after day 7. Bleeding events determined from the day of surgery to last day of study medication intake plus 2 days. ASA, acetylsalicylic acid; CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs; PFIs, platelet function inhibitors.

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NSAIDs Any bleeding

Rivaroxaban Enoxaparin

Major and NMCR bleeding

Rivaroxaban Enoxaparin

PFIs or ASA Any bleeding

Rivaroxaban Enoxaparin

Major and NMCR bleeding

Rivaroxaban Enoxaparin

0.1

1

10

Rate ratio and 95% CI Fig. 1. Relative bleeding rates for use versus non-use of co-medications with rivaroxaban and enoxaparin in the RECORD1–4 pool over the total at-risk period (logarithmic scale). ASA, acetylsalicylic acid; CI, confidence interval; NMCR, non-major clinically relevant; NSAIDs, non-steroidal anti-inflammatory drugs; PFIs, platelet function inhibitors.

Discussion In this explorative subgroup analysis of the pooled RECORD1–4 data, there was no significant difference in relative rate ratios with NSAID co-medication use versus non-use between the rivaroxaban and enoxaparin/placebo groups for the postoperative bleeding outcomes analysed. For patients receiving PFIs or ASA, there was no significant difference in relative rate ratios between groups with use versus nonuse for the same outcomes. Concomitant use of rivaroxaban 10 mg od or enoxaparin and NSAIDs, PFIs or ASA was frequently associated with an increase in the risk of postoperative bleeding; an expected finding based on results from other studies of combined anticoagulant and antiplatelet therapy for cardiovascular disease [18]. Importantly, the risk of bleeding was not significantly different for patients receiving rivaroxaban compared with patients receiving enoxaparin, the standard of care for thromboprophylaxis after THA or TKA. The randomised, double-dummy design of the RECORD studies adds validity to this prespecified analysis. The high proportion of patients (>70% in both groups) using concomitant NSAIDs and the adjudication of all bleeding endpoints by an external independent committee are further strengths of the analysis. In addition, because there were no restrictions on the choice of a specific drug or dose of NSAIDs and PFIs or ASA, the use and dosage is likely to reflect real-world co-medication use. Limitations of this analysis include the relatively low proportion of patients (9% in both groups) concomitantly using PFIs and ASA. Furthermore, most medication use in the class of PFIs or ASA relates to low-dose ASA, with very few patients taking clopidogrel while on study medication. Data on the use of the more potent agents may be particularly informative for surgeons. Time-based approaches were used to account for varying comedication use and changes in the risk of bleeding over time; however, these approaches make certain assumptions, which may not be applicable for all patients or situations. In addition, because the analyses include bleeding events starting after first postoperative intake of oral study drug, the potential effect of the co-medications of interest on bleeding events during surgery or prior to surgery is not considered here.

These results, in a representative THA and TKA patient population (mean age 64 years), are consistent with earlier investigations of rivaroxaban in healthy, young subjects. In the first of these studies, the effect of ASA on the safety and pharmacological profile of rivaroxaban was examined in a two-way crossover study (mean subject age 35 years) [17]. Compared with rivaroxaban alone, there was no difference in the incidence of adverse events when ASA was given in combination with rivaroxaban. The combination of the two agents had no additional effect on clotting parameters or on the inhibitory effect of ASA on platelet aggregation. Compared with ASA alone, rivaroxaban co-administered with ASA resulted in a statistically significant increase in bleeding time. However, this increase was small and was not considered clinically relevant, owing to the lack of effect on platelet aggregation [17]. In an interaction study with the NSAID naproxen (mean subject age 33 years), no differences in the incidence of adverse events between the groups was observed, and slight increases in the effect of rivaroxaban on clotting tests and time to maximum effect were not considered clinically relevant [16]. Rivaroxaban did not affect the action of naproxen on platelet aggregation, nor was an additive effect observed. Bleeding time was prolonged in subjects receiving rivaroxaban and naproxen and the extent of prolongation varied between subjects [16]. Whether this was indicative of an increased postoperative bleeding risk could not be interpreted from this study, but a post hoc analysis in pooled populations of two phase II THA or TKA studies [19,20], demonstrated no increased risk of bleeding when rivaroxaban (up to 10 mg bid) was administered with NSAIDs [16]. Combined bleeding rates for patients receiving rivaroxaban 2.5, 5 and 10 mg bid without NSAIDs were 1.1%, 3.9% and 5.2%, respectively, and for those receiving the same doses of rivaroxaban with NSAIDs the rates were 2.9%, 4.8% and 4.3%, respectively [16]. In addition to rivaroxaban, several other oral anticoagulants have been developed, including the direct thrombin inhibitor dabigatran etexilate (Pradaxa; Boehringer Ingelheim International GmbH: Ingelheim am Rhein, Germany) and the direct Factor Xa inhibitor apixaban (Eliquis; Bristol-Myers Squibb: New York, USA and Pfizer: New York, USA). Dabigatran etexilate has been approved in the European Union for the prevention of VTE in patients undergoing elective THA or TKA. Interaction analyses from studies comparing dabigatran etexilate with enoxaparin in patients undergoing THA or TKA showed that concomitant use of dabigatran etexilate and NSAIDs or ASA was associated with a similar risk of major bleeding to dabigatran etexilate alone (1.5% vs 1.4%, respectively, for dabigatran etexilate 220 mg od: odds ratio 1.05, 95% CI 0.55–2.01) [21]. The bleeding risk with enoxaparin plus NSAIDs was also similar to that with enoxaparin alone (1.6% vs 1.2%, respectively: odds ratio 1.32, 95% CI 0.67–2.57) [21]. There are limited clinical data available regarding interactions with apixaban, although a rabbit arterial thrombosis model has been used to investigate the safety of apixaban in combination with PFIs. Apixaban in combination with ASA or ASA plus clopidogrel demonstrated enhanced antithrombotic efficacy without excessive increases in bleeding time, although bleeding time is not a very good predictor of bleeding risk in a clinical setting [22]. Further studies will be required to provide safety data and recommendations for the use of apixaban with ASA and other NSAIDs in venous thrombosis models and in the clinical setting. Safety data for new oral anticoagulants with potentially coadministered drugs will become increasingly valuable as these agents become approved for, and implemented into, clinical practice. After THA and TKA, concomitant medications that can be used without increasing the risk of postoperative bleeding will be particularly advantageous in a generally elderly patient population that is likely to be receiving other medications. This analysis of pooled data from the RECORD1–4 studies has demonstrated that, although the risk of bleeding with anticoagulants can be increased with concomitant use of NSAIDs, there is no significant difference in postoperative bleeding risk for rivaroxaban compared with enoxaparin when co-administered

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with NSAIDs, PFIs or ASA after THA or TKA. However, experience with PFIs in this study is limited because, with the exception of ASA, they were used infrequently. Supplementary materials related to this article can be found online at doi:10.1016/j.thromres.2011.12.005. Conflict of interest statement B.I. Eriksson is a consultant for Boehringer Ingelheim, Bayer HealthCare, Astellas, Takeda, BMS and Pfizer. N. Rosencher has been a member of a steering committee and advisory boards for (and, as such, her institution had received money from) Bayer HealthCare Pharmaceuticals, BMS, Pfizer, GSK, Sanofi-Aventis and Boehringer Ingelheim. R.J. Friedman has received research or institutional support from Boehringer Ingelheim and Astellas US and has been a paid consultant for Astellas US, Boehringer Ingelheim, Johnson & Johnson, and DJO Surgical. M. Homering is an employee of Bayer HealthCare Pharmaceuticals. O.E. Dahl has been a consultant for Bayer HealthCare Pharmaceuticals and received honoraria for attending advisory boards. Acknowledgments This study was supported by Bayer HealthCare Pharmaceuticals and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The study sponsors were involved in the design of the study and the collection and analysis of the data. The authors would like to acknowledge Sarah Atkinson who provided editorial support with funding from Bayer HealthCare Pharmaceuticals and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. References [1] Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:381S–453S. [2] Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008;133:234S–56S. [3] 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;358:2765–75. [4] Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31–9. [5] Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776–86.

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