Elsevier

Thrombosis Research

Volume 130, Issue 2, August 2012, Pages 147-151
Thrombosis Research

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

https://doi.org/10.1016/j.thromres.2011.12.005Get rights and content

Abstract

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.

Introduction

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 evidence-based 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 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], [4], [5], [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.

Section snippets

Study design

This analysis was part of a prespecified analysis of pooled data from the four phase III studies of the RECORD programme. In a double-dummy 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], [4], [5] or enoxaparin 30 mg twice daily (bid) starting 12–24 hours after wound closure or after adequate haemostasis was achieved (RECORD4) [6]. Patients

Results

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

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 non-use for the same outcomes. Concomitant use of rivaroxaban 10 mg od or enoxaparin and NSAIDs,

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

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 (22)

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    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.

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