3 June 2010
In ADVANCE-2 3,057 patients undergoing elective total knee replacement were randomised to oral apixaban 2.5mg twice a day, started 12 to 24 hours after surgery, or 40mg enoxaparin daily, started 12 hours before surgery. Apixaban appeared to be more effective than enoxaparin for the primary composite end point comprising both disease and patient-orientated outcomes. However, the rate for the pure patient-orientated outcome of symptomatic VTE or VTE-related death was the same in each group.
No differences in the rates of major or clinically relevant non-major bleeding were observed between the groups.
Further data are required to determine whether apixaban is equivalent to or better or worse or than available alternatives for this indication.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Apixaban was referred to NICE in January 2010 but no timeline for a technology appraisal (TA) has yet been set. The drug has not been submitted for a European licence yet, although a recent press report suggests that a submission may be made in 2010 for prevention of venous thromboembolism (VTE) in patients who have had orthopaedic surgery. If apixaban receives a marketing authorisation and the planned NICE TA is not available, local decision making bodies will need to consider its role alongside currently available options. These include LMWH, fondaparinux, dabigatran▼ (Pradaxa®) and rivaroxaban▼ (Xarelto®), fixed-dose oral anticoagulants which are recommended by NICE as options for patients undergoing elective total hip or knee replacement surgery.
What is the background to this?
Patients having elective knee replacement are at increased risk of VTE. They should be assessed and offered a combination of mechanical and pharmacological methods of VTE prophylaxis according to NICE guidance published in January 2010. The choice includes: dabigatran started 1 to 4 hours after surgery; fondaparinux started 6 hours after surgical closure (provided haemostasis has been established); low molecular weight heparin (LMWH) started 6 to 12 hours after surgery; rivaroxaban started 6 to 10 hours after surgery; or unfractionated heparin (for patients with renal failure) started 6 to 12 hours after surgery. These should be continued for 10 to 14 days, according to the summary of product characteristics for the individual agent being used. The NICE recommendation to start a LMWH postoperatively, an off-label use, is due to concerns about the risk of bleeding into the joint. These patients will be protected preoperatively by mechanical means.
Oral apixaban is a specific direct factor Xa inhibitor which works in a similar way to rivaroxaban. LMWHs predominantly target factor Xa indirectly, but to some extent also inhibit thrombin. Dabigatran works by directly inhibiting thrombin.
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?
The primary endpoint was a composite of adjudicated asymptomatic or symptomatic deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality during the intended treatment period (12 days) or within two days of the last dose, whichever was longer.
As is common in these types of studies, 36% of apixaban and 35% of enoxaparin patients could not be assessed for the primary outcome (for example, because of uninterpretable venography). For all randomised patients with an assessable efficacy outcome the primary end point was seen in 147 of 976 apixaban patients (15.06%) and 243 of 997 enoxaparin patients (24.37%). This gives a relative risk (RR) of 0.62 (95% confidence interval [CI] 0.51 to 0.74), P<0.0001 and an absolute risk reduction (ARR) of 9.27% (95%CI 5.79 to 12.74).
The main secondary outcome measure (major venous thromboembolism) was the composite of adjudicated symptomatic or asymptomatic proximal deep vein thrombosis, non-fatal pulmonary embolism, and venous thromboembolism-related death during intended treatment period. Apixaban was superior to enoxaparin (RR 0·50, 95% CI 0·26–0·97, one sided p=0·0186 for superiority; absolute risk reduction1·04%, 0·05–2·03).
However, rates of symptomatic venous thromboembolism and venous thromboembolism-related death did not differ between study groups (RR 1·00, 0·35–2·85; absolute risk reduction 0·00%, –0·48 to 0·48). There were only 7/1528 (0.46%) events in the apixaban group and a similar number i.e. 7/1529 (0.46%) in the enoxaparin group. The study was not powered for this outcome and it seems likely that there were too few patient-orientated outcomes to demonstrate a difference if one truly exists.
The adverse event profiles for the two medicines were not statistically significant. The main safety outcome was bleeding during treatment. There was no difference in the rates of all bleeding events in the two groups: 6.9% vs. 8.4%, giving an ARR of 1.39% (95%CI –0.51 to 3.29), P=0.1412. Adjudicated major or clinically relevant non-major bleeding events were seen in 3.5% of apixaban patients and 4.8% of enoxaparin patients, ARR 1.24 (95% CI –0.18 to 2.66, P=0.0881).
How does this relate to other studies?
In ADVANCE-1, the subject of a previous blog, apixaban was compared to the US dose of enoxaparin, 30mg twice a day. That study failed to show that apixaban was no worse than enoxaparin. The primary efficacy outcome (a composite of adjudicated asymptomatic and symptomatic DVT, non-fatal PE, or death from any cause during treatment) was seen in 9.0% of apixaban patients and 8.8% of enoxaparin patients (RR 1.02, 95%CI 0.78 to 1.32, P=0.06 for non-inferiority). Apixaban was associated with less major and clinically relevant non-major bleeding: 2.9% vs. 4.7% (P=0.03).
A further phase III trial, ADVANCE-3, has been completed, but not yet published. This assessed apixaban or enoxaparin 40mg each day for five weeks in total hip replacement surgery.
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.
Further data are required to determine whether apixaban is equivalent or better or worse than available alternatives for this indication. 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.
Further study details
Lassen MR, Raskob GE, Gallus A et al for the ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375:807-15
Design: Randomised, double-blind, double-dummy, non-inferiority trial. Allocation was concealed.
Patients: Patients undergoing elective unilateral or same-day bilateral total knee replacement, including revision, were randomised. Patients at high risk of bleeding were excluded. Patients were mainly women, with a mean age of 66 years.
Intervention and comparison: Patients were randomised to oral apixaban 2.5mg twice daily, starting 12 to 24 hours after surgery (n=1,528) or subcutaneous enoxaparin 40mg daily started 12 hours before the operation (n=1,529) and continued for 10 to 14 days (mean of 12.1 days in each group). At the end of the treatment period patients underwent bilateral venography.
Outcomes and results:
In addition to the data provided above, four patients died during treatment and follow-up. Three of these were in the apixaban group, two of whom had PE. The other had a possible infection and abnormal liver function tests, to which contribution by this drug cannot be excluded.
Serious adverse events were also not different between the groups. Due to the withdrawal of the anticoagulant ximelagatran because of liver damage, liver function tests were performed in ADVANCE-2. Liver transaminase concentrations were raised more than three times the upper limit of normal (ULN) in 0.9% of apixaban patients and 0.7% of enoxaparin patients. Bilirubin concentrations more than twice the ULN were reported in 0.5% of apixaban patients compared to 0.3% of enoxaparin patients.
Sponsorship: Bristol-Myers Squibb, Pfizer
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