Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.
Eliquis (Bristol Myers Squibb)
2.5 mg film-coated tablets
Approved indication: prevention of postoperative venous thrombosis
Australian Medicines Handbook section 7.1.4
Patients undergoing knee and hip surgery have a high incidence of venous thromboembolism postoperatively. Thromboprophylaxis reduces this risk and current recommendations include heparins (enoxaparin, dalteparin) and the factor Xa inhibitor, fondaparinux. Oral anticoagulants – dabigatran and rivaroxaban – are also available for this indication.
Apixaban is a reversible, direct inhibitor of clotting factor Xa with a similar action to rivaroxaban (Aust Prescr 2009;32:22-7 ). By blocking factor Xa, it decreases levels of thrombin.
The efficacy of oral apixaban has been compared to subcutaneous enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-1 and -2.1,2and hip replacement (ADVANCE-3).3 Apixaban was started 12–24 hours after surgery and continued for 10–14 days in the knee trials and for 35 days in the hip trial. The primary outcome was the same in all of the trials and was a composite of deep vein thrombosis (symptomatic or asymptomatic), non-fatal pulmonary embolism, or death from any cause during treatment. Deep vein thrombosis was assessed using bilateral venography.
In ADVANCE-1, apixaban 2.5 mg (twice daily) failed to meet non-inferiority criteria compared to enoxaparin 30 mg (every 12 hours), despite the primary outcome occurring at similar rates (9% vs 8.8%). The enoxaparin dose used in this trial was different from the standard dose used in Australia – enoxaparin 40 mg once daily.4Although the number of deep vein thromboses was similar between groups, pulmonary emboli were more common with apixaban (16/1599 vs 7/1596).1
In ADVANCE-2, apixaban 2.5 mg (twice daily) was non-inferior to enoxaparin 40 mg once daily. The primary outcome occurred in 15% of patients receiving apixaban versus 24% of those receiving enoxaparin (p=2Again, pulmonary emboli were more common with apixaban (4/1528 vs 0/1529).2
Similarly in the hip replacement trial (ADVANCE-3, 5407 patients) the twice-daily dose of apixaban was non-inferior to once-daily enoxaparin 40 mg for preventing the primary outcome (1.4% vs 3.9% p=3
Apixaban was associated with statistically similar rates of major bleeding events compared with enoxaparin in ADVANCE-1 (0.7% vs 1.4%, p=0.053)1, ADVANCE-2 (0.6% vs 0.9%, p=0.30)2 and ADVANCE-3 (0.8% vs 0.7%, p=0.54).3 In the ADVANCE-2 and -3 trials, enoxaparin was started 12 hours before the operation. However in contemporary Australian practice, postoperative prophylaxis is often recommended.45
Other adverse events associated with apixaban included nausea (14.1%), constipation (9.4%), vomiting (6.9%), anaemia (2.6%) and bruising (1.5%). Rates were similar to those reported with enoxaparin.
Caution is urged when giving apixaban to patients with an increased risk of bleeding, such as people with ulcerative gastrointestinal disease, bacterial endocarditis, thrombocytopenia, history of haemorrhagic stroke, uncontrolled high blood pressure and recent brain, spinal or eye surgery. Patients taking apixaban should be monitored for signs of bleeding. An unexplained fall in haemoglobin or blood pressure should be investigated. Apixaban is contraindicated with active bleeding and should be stopped if bleeding occurs. Indwelling epidural or intrathecal catheters should be removed at least five hours before the first dose of apixaban because of the risk of developing a spinal haematoma.
Care should be taken when apixaban is given with other drugs that affect haemostasis, such as non-steroidal anti-inflammatory drugs and aspirin. Concomitant use of platelet aggregation inhibitors and other antithrombotic drugs is not recommended. A trial in acute coronary syndrome, comparing apixaban 5 mg twice daily versus placebo in patients receiving antiplatelet therapy, was stopped early because of an increase in major bleeding events with apixaban.6
Drug interactions with apixaban are likely as it is mainly metabolised by cytochrome P450 3A4, and is a substrate of P-glycoprotein. Strong inhibitors (e.g. azole antifungals) are contraindicated, and inducers (e.g. rifampicin) should be used with caution.
Apixaban is rapidly absorbed after administration and can be taken with or without food. It has a half-life of 12 hours and is eliminated predominantly in the faeces, but also in urine.
No dose adjustment is required in mild to moderate renal impairment. However, caution is urged in patients with severe renal impairment (creatinine clearance 15–29 mL/minute) and apixaban is contraindicated in patients with creatinine clearance less than 15 mL/minute, or in those undergoing dialysis. Apixaban should be used cautiously in hepatic impairment and is contraindicated if it is severe or associated with coagulopathy and clinically relevant bleeding risk.
Apixaban is not recommended for patients having hip fracture surgery. As with similar drugs like dabigatran and rivaroxaban, apixaban is being studied in atrial fibrillation.7
Apixaban is effective for preventing venous thrombosis after hip and knee replacement surgery. Although it failed to meet non-inferiority criteria compared to twice-daily enoxaparin 30 mg, it was non-inferior to once-daily enoxaparin 40 mg. The risk of major bleeding with apixaban was statistically similar to once-daily enoxaparin 40 mg. However, it is questionable whether the pre-operative enoxaparin dosing was a valid comparator for Australian practice. There is no antidote for apixaban.
The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009;361:594-604.
- Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375:807-15.
- Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-98.
- Venous thromboembolism [revised June 2008]. In: eTG complete [internet]. Melbourne: Therapeutic Guidelines Limited; June 2008.
- National Health and Medical Research Council. Clinical practice guideline for the prevention of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to Australian hospitals. Melbourne: National Health and Medical Research Council; 2009.
- Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708.
- Granger GB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011 (online 28 Aug).