NPC Archive Item: Apixaban vs. enoxaparin as thromboprophylaxis in knee replacement surgery

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22 January 2010

In a non-inferiority design, ADVANCE-1 found that results for oral apixaban were similar to s.c. LMWH enoxaparin 30 mg twice daily (not non-inferior) for a primary composite endpoint comprising both disease and patient orientated outcomes in patients undergoing elective total knee replacement.

Use of apixaban was associated with a lower rate of major and clinically relevant non-major bleeding.  Both drugs were started 10 to 12 hours after surgery and continued for 10 to 14 days.

N.B. This was a North American study and the dosing regimen for LMWH used in study is different from that used in the UK.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Apixaban has been proposed for a NICE appraisal, but no timeline for this has been set currently. The drug has not been submitted for a European licence yet, although a recent press report suggests a submission may be made in 2010 to prevent venous thromboembolism (VTE) in patients who have had orthopaedic surgery.  If apixaban receives a marketing authorisation, local decision making bodies will need to consider its role alongside other options. These include two other fixed-dose oral anticoagulants dabigatran etexilate (Pradaxa®) and rivaroxaban (Xarelto®), both of which have been recommended by NICE as options to low molecular weight heparin (LMWH) for patients undergoing elective total hip replacement (THR) or knee replacement (TKR) surgery.

What is the background to this?
Patients having orthopaedic surgery are at increased risk of VTE and should be offered low molecular weight heparin (LMWH) in addition to mechanical prophylaxis, according to a NICE guideline published in 2007. Fondaparinux, within its licensed indications, may be used as an alternative to LMWH. NICE is developing guidance on prevention of VTE in all patients admitted to hospital which will incorporate and update the previous advice for patients undergoing surgery. The role of the fixed dose oral anticoagulants, dabigatran and rivaroxaban, in orthopaedic surgery is also included. The anticipated publication date for this guidance is early in 2010. The scoping document for this new guidance states that a recent UK survey found that 71% of patients assessed to be at medium or high risk of developing deep vein thrombosis (DVT) did not receive any form of prophylaxis.

LMWHs predominantly target factor Xa indirectly, but to some extent also inhibit thrombin. Apixaban, an orally active anticoagulant, is a specific direct factor Xa inhibitor which works in a similar manner to rivaroxaban.  Dabigatran etexilate (a direct thrombin inhibitor) and rivaroxaban are both licensed for use in patients undergoing elective THR or TKR surgery.

NICE has recommended both dabigatran and rivaroxaban as options to LMWH or fondaparinux for the prevention of VTE in adults having elective THR or TKR surgery. A scoping exercise has been undertaken for a proposed NICE appraisal of apixaban; no timelines are available at present.

Further information about VTE is available on the venous thromboembolism section of NPC. In addition, an e-learning package has been published by the Chief Medical Officer’s Venous Thromboembolism (VTE) Implementation Working Group and eLearning for Healthcare which aims to raise awareness and improve understanding of VTE.

What does this study claim?
Apixaban failed to show non-inferiority to enoxaparin 30mg twice daily in this study. The rate of the primary efficacy outcome (a composite of adjudicated asymptomatic and symptomatic deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause during treatment) was 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk 1.02, 95% confidence interval [CI] 0.78 to 1.32).

The above endpoint contains a mix of disease orientated and patient orientated outcomes. Rates for the patient orientated outcome of symptomatic VTE and related death were 1.2% in the apixaban group and 0.8% for enoxaparin, (relative risk 1.46, 95% CI 0.72 to 2.95).

The primary safety outcome was bleeding during the treatment period or within 2 days after the last dose of study medication. The trial protocol specified that an analysis be done of the composite incidence of major bleeding and clinically relevant non-major bleeding. This was less with apixaban (2.9%) as compared to 4.3% with enoxaparin (P=0.03).

The adverse event profile for the two drugs was similar, but patients treated with apixaban had a higher rate of pulmonary embolism, 1.0% vs. 0.4% for enoxaparin.  A P value was not quoted as part of the primary study analysis, but has been estimated to be P=0.06 according to recent correspondence, which, if true, means that this difference is not statistically significant.  Pulmonary embolism was the adjudicated cause of death in four patients (two in each group).

How does this relate to other studies?
The postoperative regimen of enoxaparin given via s.c. injection 30mg every 12 hours was selected as the comparator because this had been approved by the US Food and Drug Administration. However in the UK, enoxaparin is licensed for orthopaedic patients at 40mg 12 hours before surgery then 40mg every 24 hours for 7 to 10 days. Completed, but not yet published, studies involving apixaban (ADVANCE-2 and ADVANCE-3) used enoxaparin 40mg each day for 12 days (for TKR) and 5 weeks (for THR), respectively. Once these are published, the issue of a possible increase in the risk of pulmonary embolism with apixaban and its role in relation to enoxaparin may be clarified.

A recent review of dabigatran and rivaroxaban has noted the considerable limitations in the published evidence for both drugs. The authors state that they have not been directly compared with each other or with anticoagulants, other than enoxaparin, in elective, major lower limb orthopaedic surgery. Oral dosing without monitoring may seem attractive when patients are not willing or capable to self-inject an alternative. Although the published evidence to date does not seem to suggest a particular safety concern with either drug, the authors concluded, “until more robust clinical efficacy and safety data are available for both drugs, it is advisable to use a more established alternative where possible.”

So what?
The use of a composite primary endpoint, including asymptomatic DVT, is recommended by the European Medicines Agency to assess the efficacy of this class of drugs and to meet licensing requirements. However this approach may mislead if the components are of widely differing importance to patients and the size of the effect differs markedly across components. The clinical significance of measuring a disease orientated outcome such as asymptomatic DVT in clinical trials has also been questioned.

One reason for not being able to prove non-inferiority in this study may be that fewer events occurred than had been predicted.

Other trials of apixaban for the treatment of DVT, prevention of stroke in patients with atrial fibrillation (AF) and acute coronary syndrome have been completed or in progress. Clinical trials of rivaroxaban and dabigatran for similar indications are currently ongoing. Using oral agents for VTE prophylaxis has the potential to increase patient compliance and release nurse time from either administering injections or teaching patients to self-inject.  Unlike warfarin, these drugs do not need laboratory monitoring. Therefore if, in the future, fixed-dose oral anticoagulants receive a marketing authorisation for long-term conditions such as prevention of stroke in patients with AF, this will have financial and service delivery implications for both primary and secondary care. Comparator trial data would assist in making these decisions.

Study details
Lassen M R, Raskob G E, Gallus A et al.  Apixaban or Enoxaparin for Thromboprophylaxis after Knee Replacement. N Engl J Med 2009;361:594-604

Design: Phase III, double-blind, double-dummy clinical trial in which patients undergoing TKR surgery were randomised to apixaban and placebo injection or enoxaparin and placebo tablets. Allocation was concealed. At the end of the treatment period patients underwent mandatory bilateral venography.

Intervention: 2.5mg of apixaban orally twice daily commenced 12 to 24 hours after surgery and continued for 10 to 14 days (n=1,599).

Comparison: 30mg of enoxaparin subcutaneously every 12 hours commenced 12 to 24 hours after surgery and continued for 10 to 14 days (n=1,596).

Outcomes: The primary efficacy outcome was a composite of adjudicated asymptomatic and symptomatic deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause during treatment. The primary safety outcome was bleeding during the treatment period or within 2 days after the last dose of study medication. Major bleeding was defined as acute, clinically overt bleeding accompanied by one or more of the following events: a decrease in the hemoglobin level of 2 g/dl, a transfusion of ³ 2 units of packed red cells, bleeding at a critical site (i.e., intracranial, intraspinal, intraocular, pericardial, or retroperitoneal bleeding), bleeding into the operated joint requiring intervention, intramuscular bleeding with the compartment syndrome, or fatal bleeding.

Results: 908 subjects were not included in the efficacy analysis, due to lack of, or unreadable, venography.  The overall rate of primary events was much lower than anticipated: 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk, 1.02, 95%CI 0.78 to 1.32, P=0.06 for non-inferiority). Major bleeding events occurred in 0.7% of the apixaban group and 1.4% of the enoxaparin patients (P=0.053). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 2.9% of apixaban patients and in 4.3% of the enoxaparin group (P=0.03).

Elevated aminotransferase or bilirubin levels were uncommon in both groups. The criteria for hepatoxicity were not met in any patient receiving apixaban. Arterial thromboembolic events during the combined treatment period of 10 to 14 days after surgery and the 60-day follow-up period occurred in 0.1% apixaban patients vs. 0.4% enoxaparin.

Nine patients died during the treatment and follow-up period (three in the apixaban group and six in the enoxaparin group). Pulmonary embolism was the adjudicated cause of death in two in each group.

Sponsorship: Bristol-Myers Squibb and Pfizer.

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