Guidance on the use of rivaroxaban in the prophylaxis of venous thromboembolism (VTE) has been published by NICE in Technology Appraisal 170.1 Rivaroxaban, within its marketing authorisation, is recommended as an option for the prevention of VTE in adults having elective total hip replacement surgery or elective total knee replacement surgery.1
Rivaroxaban is a potent, selective active-site directed, oral Factor Xa inhibitor. Factor Xa is located at a critical part of the haemostatic pathway that leads to thrombin formation; selective inhibition of Factor Xa terminates the amplified burst of thrombin generation created during the hypercoagulable state that occurs after total knee and hip replacement. This may result in improved efficacy in the prevention of thrombus formation and a better safety profile than other anticoagulants.
The recommendation for the use of rivaroxaban in the prevention of VTE is supported by phase III clinical trial results from over 12,000 patients studied internationally. In a pooled analysis of data from the entire RECORD (REgulation of Coagulation in ORthopaedic surgery to prevent Deep-vein thrombosis and pulmonary embolism) studies, rivaroxaban proved to be superior to enoxaparin (low molecular weight heparin) at reducing total VTE after total hip and total knee replacement.2 In the RECORD2 study, patients receiving rivaroxaban in extended thromboprophylaxis of 31–39 days were compared to patients receiving enoxaparin in short-term thromboprophylaxis of 10–14 days. There were significant reductions in the incidence of:3
- composite events of any deep-vein thrombosis, non-fatal pulmonary embolism, and all-cause mortality—rivaroxaban (2%) compared with enoxaparin (9.3%); p<0.0001
- major VTE—rivaroxaban (0.6%) compared with enoxaparin (5.1%); p<0.0001
- symptomatic VTE—rivaroxaban (0.2%) compared with enoxaparin (1.2%); p=0.0040.
There was no difference in the incidence of bleeding between the two groups: 6.6% vs 5.5% for rivaroxaban and enoxaparin, respectively.
Post surgery and discharge
As a prophylactic treatment, rivaroxaban should be administered once daily in an oral dose of 10 mg, which should be started 6–10 hours after the end of surgery, as long as haemostasis has been established. Significantly, in up to 75% of total hip replacement and 57% of total knee replacement cases, VTE is diagnosed after hospital discharge (a few days after surgery).4 It is, therefore, important that extended prophylaxis continues after the patient is discharged home for the following amount of time:1
- 5 weeks for patients after major hip surgery
- 2 weeks for patients after major knee surgery.
I would imagine that in most cases the relevant number of tablets would be prescribed by the discharging hospital. It is important for GPs to know why patients are taking rivaroxaban, especially if there are complications such as bleeding or bruising, or if consideration is being given to continuing prophylaxis.
Patients who have prolonged immobility following discharge, may need to continue prophylaxis of VTE until these risks become clinically negligible. In some cases, patients will require long-term antithrombotic therapy with warfarin; and aspirin or clopidogrel may be introduced to reduce the risk of arterial thrombosis. It is likely that primary care would be involved in this decision.
If significant bleeding occurs after discharge, the effects of rivaroxaban can be assessed by any prolongation of the prothrombin time or more precisely by a specific anti-Factor Xa assay in a specialised hospital laboratory. There is no specific antidote to reverse the clinical effects, but after referral back to hospital, control of bleeding should be managed by appropriate blood product replacement therapy with fresh frozen plasma, II, VII, IX, X concentrate, or recombinant Factor VIIa.
Pharmacological properties and interactions
Rivaroxaban does not need to be regularly monitored by a blood test (unlike the prothrombin time used in warfarin therapy). At the time of discharge, the risk of post-operative bleeding, particularly into the newly replaced joint, is very unlikely to occur. Possible drug interactions are relatively limited and are not usually associated with drugs prescribed in the primary care setting.
The plasma concentration of rivaroxaban increases rapidly after oral administration, reaching a maximum in about 2–4 hours. The half life ranges from 7–11 hours after multiple dose administration,5 but can be higher in elderly patients particularly those with impaired renal clearance.
Rivaroxaban has also been used in conjunction with regional spinal anaesthesia with no associated reported risk of the development of epidural haematoma (pers.comm). The administration of rivaroxaban should be avoided in patients who have been given spinal anaesthesia and who have other defects in haemostasis, particularly a low platelet count below 80 x 109/l or a prolonged prothrombin time preoperatively.
Restarting preoperative drug therapy
If patients were receiving antiplatelet drugs (such as aspirin or clopidogrel) preoperatively, these can be restarted upon discharge home. Long-term anticoagulant therapy with warfarin can be re-started at the previous maintenance dose several days before the extended prophylaxis with rivaroxaban is completed.
Analgesia with non-steroidal anti-inflammatory drugs (e.g. diclofenac, naproxen) can be safely prescribed as required providing that excessive skin bruising or other bleeding events have not occurred.
Cost of treatment
An economic model assessing the cost effectiveness of rivaroxaban compared with enoxaparin was submitted by the manufacturer. The prophylaxis part of the model was informed by clinical trial events: first 35 days for total hip replacement and 14 days for total knee replacement post-surgery. The cost of treatment with rivaroxaban was estimated to be £63 for knee replacement surgery and £157.50 for hip replacement surgery, although costs may vary because of negotiated procurement discounts.1 The Appraisal Committee concluded that on balance, rivaroxaban, enoxaparin, and dabigatran had very similar costs and benefits in the prevention of VTE.1
Patients undergoing major orthopaedic surgery are at high risk of developing post-operative VTE. There is strong evidence that extended prophylaxis for up to 5 weeks days following hip replacement surgery and up to 2 weeks after knee replacement surgery is needed to reduce the risk of further thrombotic events. The orthopaedic surgical team should assess individual risk factors for VTE and bleeding, and issue suitable advice for GPs on the optimal duration of VTE prophylaxis after discharge. If this advice is not supplied, GPs should proactively obtain it.
When a GP is looking after a patient taking rivaroxaban following discharge home from hospital they should be aware of the advantages and simple pharmacokinetics of the drug. This is of particular importance when asked to reassess the patient if further problems arise. These could be related to ongoing impaired mobility and the introduction of any other long-term antithrombotic or antiplatelet regime, or problems, such as skin bleeding or bruising.
- Rivaroxaban is recommended by NICE for the prophylaxis of VTE after knee and hip replacement surgery
- Post-operative thrombosis remains a significant cause of mortality and readmission to hospital
- The costs of rivaroxaban are reasonable when compared with the overall tariff price for these procedures
- Treatment with rivoraxaban costs:a
- £63 for knee replacement surgery (tariff cost c. £3714, code HB22C)
- £157.50 for hip replacement surgery (tariff cost c. £5269, code HB12C)
- Example tariff costs for DVT non elective admission are £1941 (code EB11Z) or £1616 for pulmonary embolus (code DZ09C)a
- Commissioners should negotiate urgently with their providers of acute care as to the implementation of this NICE guidance and possibly include quality clauses in contracts to ensure it is implemented
- National Institute for Health and Care Excellence. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement. Technology Appraisal 170. London: NICE, 2009. Available at: www.nice.org.uk/guidance/TA170
- Turpie, A, Lassen, M, Kakkar A et al. Pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery. Br Journal Haematology 2009; 145 (suppl 1): 4.
- Kakkar A, Brenner B, Dahl O et al; RECORD2 Investigators. 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 (9632): 31–39.
- Warwick D, Friedman R, Agnelli G et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events. J Bone Joint Surg Br 2007; 89 (6): 799–807.
- Bayer Schering Pharma. Xarelto summary of product characteristics. May 2009. Available at: emc.medicines.org.uk/document.aspx?documentId=21265G