NPC Archive Item: Apixaban after hip replacement surgery has some benefit compared to enoxaparin on a mixture of disease- and patient-orientated outcomes

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On The Horizon Rapid Review NPC Logo

20 April 2011

In ADVANCE-3 (n=5,407), oral apixaban 2.5mg twice daily was associated with lower rates of a composite endpoint of both disease and patient-oriented outcomes than subcutaneous enoxaparin 40mg daily in patients having elective hip replacement. However, neither the rates of the pure patient-oriented outcome of symptomatic venous thromboembolism (VTE) nor VTE-related death differed significantly between apixaban and enoxaparin.  Bleeding events were similar in both groups.

Level of evidence:
Level1 (good quality patient-oriented evidence) according to the SORT criteria.

Apixaban has been referred to NICE for assessment for the prevention of venous thromboembolism in people undergoing elective knee and hip replacement surgery; guidance is expected in April 2012.

The drug has recently received from the European Medicines Agency a Positive Opinion for prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery. If it is marketed before the NICE guidance becomes available, local decision making bodies will need to consider its role alongside currently available options. These include low molecular weight heparin (LMWH), fondaparinux, dabigatran (Pradaxa®) and rivaroxaban (Xarelto®).  Dabigatran and rivaroxaban are 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 hip replacement are at increased risk of VTE. According to NICE guidance they should be assessed and offered a combination of mechanical and pharmacological methods of VTE prophylaxis. The choice includes: dabigatran started 1 to 4 hours after surgery; fondaparinux started 6 hours after surgical closure (provided haemostasis has been established); 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 28 to 35 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 intra-operative bleeding.  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.

NPC eLearning materials on VTE are available. 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 efficacy outcome was a composite of adjudicated asymptomatic or symptomatic deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE) or death from any cause during the intended treatment period (32 to 38 days or within 2 days after the last dose, whichever was longer). As is usual with these types of studies, 28% of apixaban and 29% of enoxaparin patients could not be assessed for the primary outcome (for example because of uninterpretable venograms). For all randomised patients who had a primary efficacy outcome that could be measured, the primary end point was seen in 27 of 1,949 apixaban patients (1.4%) and 74 of 1,917 enoxaparin patients (3.9%). This gives a relative risk of 0.36 (95% confidence interval [CI] 0.22 to 0.54), P<0.001 for non-inferiority, P<0.001 for superiority. Forty patients would need to be treated for 34 days to prevent one composite end point.

The secondary efficacy outcome, major VTE defined as the composite of adjudicated symptomatic or asymptomatic proximal DVT, non-fatal PE and VTE related-death, was seen in 0.5% of apixaban and 1.1% of enoxaparin patients (relative risk 0.40 [95%CI 0.15 to 0.80], P<0.001 for non-inferiority, P=0.01 for superiority). No statistically significant difference was seen between the groups in the risk of symptomatic VTE and VTE-related death, a patient-oriented outcome. This was observed in 0.1% of apixaban patients and 0.4% of enoxaparin patients, P=0.11.

Safety was assessed by recording bleeding events during the treatment period or until two days after the last dose. Adjudicated major bleeding during the treatment period was seen in 0.8% of apixaban and 0.7% of enoxaparin patients (P=0.54).

How does this relate to other studies?
Apixaban has also been compared to enoxaparin in elective total knee replacement surgery trials. In ADVANCE-1, apixaban 2.5mg orally twice daily was compared to the US dose of enoxaparin, 30mg twice a day. Both drugs were started 12-24 after surgery and continued for 10 to 14 days. We discussed this study in a previous Rapid Review. In ADVANCE-2 3,057 patients 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. Further information can be found in our Rapid Review of the trial.

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. This is because in order to power a trial to show differences in symptomatic VTE events would require including many more patients.  Therefore this composite has been used by all recent major trials in this therapy area. However, the reliability of  using a disease-oriented outcome such as asymptomatic DVT in clinical trials has been questioned.

Whilst apixaban appears to be associated with lower rates of VTE without an increased risk of bleeding, an editorial linked to the trial, notes that it can be challenging to translate the findings of clinical trials into actual clinical practice. This can be due to patients selected for the majority of trials generally being younger and having fewer concurrent illnesses than patients in practice. Patients included in ADVANCE-3 had a mean age of 61 years and 88% had normal renal function. In clinical practice many patients are older and some will have, for example, renal impairment.  It should be noted that in the trial subcutaneous medication was initiated 12 hours before surgery, as per the licence of enoxaparin in the UK, which is different to the recommendation in NICE guidance which is to start a LMWH postoperatively.

Study details

Lassen MR, Gallus A, Raskob GE et al for the ADVANCE-3 Investigators. Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement. N Engl J Med 2010; 363:2487-98

Design: Randomised, double-blind, double-dummy, non-inferiority trial with concealed allocation.

Patients: Patients scheduled to have elective total hip replacement or revision were included. Patients with active bleeding were amongst those excluded. The mean age of patients was 61 years.

Intervention and comparison: Patients were randomised to apixaban 2.5mg orally twice a day plus placebo injection daily (n=2,708) or subcutaneous enoxaparin 40mg daily plus placebo tablets twice daily (n=2,699). Subcutaneous medication was initiated 12 hours before surgery. The first dose of oral medication was given 12 to 24 hours after wound closure, with a mean time of 19 hours after would closure. Both regimens were continued for a mean of 34 days after surgery. Mandatory, bilateral venography was undertaken at the end of treatment. Patients had follow-up assessments at 65 and 95 days post-surgery.

Outcomes and results: In addition to the data provided above, adjudicated major or clinically relevant non-major bleeding events during the treatment period were seen in 4.8% of apixaban and 5.0% of enoxaparin patients (P=0.72). Three apixaban patients and one enoxaparin patient died during treatment. Pulmonary embolism was the cause of death in one patient, who died on day 9 of apixaban treatment. The adjudicated cause of death in all the other patients was not related to venous thromboembolism or bleeding.  There were no cases of fatal bleeding.

Increases in hepatic aminotransferases more than three times the upper limit of normal (ULN) were reported in 1.3% of apixaban and 1.5% of enoxaparin patients during treatment. Bilirubin levels more than twice the ULN were seen in 0.9% and 0.5% of the groups, respectively.

Sponsorship: This study was sponsored by Bristol-Myers Squibb and Pfizer

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