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.
Xarelto (Bayer Schering)
10 mg film-coated tablets
Approved indication: prevention of postoperative venous thrombosis
Australian Medicines Handbook section 7.1.3
The search for alternatives to heparin and warfarin has looked at different sections of the coagulation cascade. One approach is to inhibit activated factor X (Xa) which is responsible for the conversion of prothrombin to thrombin. Fondaparinux is an indirect inhibitor of factor Xa, but has to be given by injection. Rivaroxaban offers an oral alternative and has a more direct action.
Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs three hours after a dose. The effect lasts 8-12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible. Rivaroxaban is eliminated in the urine and by metabolism. It is contraindicated in patients with significant renal or hepatic disease. As the hepatic metabolism involves cytochrome P450 3A4 there is a potential for interactions with drugs such as rifampicin and the azole antifungals. There are also theoretical interactions with inhibitors of the P-glycoprotein transporter, such as verapamil and diltiazem.
Anticoagulation after orthopaedic surgery on the lower limb can reduce the incidence of deep vein thrombosis. A dose-ranging study of rivaroxaban was therefore carried out in 873 patients having total hip replacements. These patients were randomised to one of five doses of rivaroxaban or a daily injection of enoxaparin. After 5-9 days of treatment the patients had venography. Deep vein thrombosis was less frequent in the patients taking rivaroxaban. There was no significant relationship between dose and efficacy, but the risk of major bleeding increased with dose.1 A dose of 10 mg rivaroxaban was then selected for the Phase III trials called the RECORD studies.
RECORD1 randomised 2275 patients to daily injections of 40 mg enoxaparin and 2266 to take rivaroxaban after total hip replacement. Efficacy was assessed by venography after 35 days of prophylaxis. The primary outcome measure was a composite of death, pulmonary embolism and deep vein thrombosis. This outcome occurred in 3.7% of the enoxaparin group and 1.1% of the rivaroxaban group. There were four deaths in each group so the difference between the groups was accounted for by a significantly lower incidence of deep vein thrombosis with rivaroxaban.2
RECORD2 also studied patients having a total hip replacement and had the same primary efficacy outcome as RECORD1. A total of 2509 patients were randomised to daily injections of 40 mg enoxaparin for 10-14 days or rivaroxaban for 31-39 days. The enoxaparin group took placebo tablets and the rivaroxaban group had injections of placebo. After 32-40 days the patients had venography. The primary outcome occurred in 9.3% of the enoxaparin group and 2% of the rivaroxaban group. There were significantly fewer thromboses with rivaroxaban.3
RECORD3 had a similar primary efficacy outcome to the other trials, but enrolled patients having total knee replacements. A group of 1277 was randomised to receive 40 mg enoxaparin daily while a group of 1254 took rivaroxaban for 10-14 days. Venography after treatment found deep vein thrombosis in 18.2% of the enoxaparin group and 9.6% of the rivaroxaban group. The primary outcome occurred in 18.9% of the enoxaparin group and 9.6% of the rivaroxaban group.4
RECORD4 also studied patients who had knee replacement surgery, but compared rivaroxaban with an American regimen of enoxaparin (30 mg twice daily). The 3148 patients were treated for 10-14 days and had venography after 40 days. The primary outcome occurred in 10.1% of the enoxaparin group and 6.9% of the rivaroxaban group.
Although rivaroxaban prevents more thromboses than enoxaparin, the frequency of bleeding is slightly higher. In RECORD1 major bleeding occurred in 0.3% of the rivaroxaban group and 0.1% of the enoxaparin group.2 In RECORD3 the corresponding figures were 0.6% and 0.5%.4 Less serious, but clinically relevant, bleeding is also more frequent with rivaroxaban. The incidence of other adverse effects is similar for rivaroxaban and enoxaparin. Special precautions are needed if the patient has had spinal or epidural anaesthesia. Although rivaroxaban can increase the concentrations of liver enzymes it has not yet shown the toxicity which was associated with ximelagatran, another oral anticoagulant. More safety data will emerge from longer-term study of the drug in conditions such as atrial fibrillation. When used for short-term prevention of thrombosis, routine monitoring of the anticoagulant effect is not required.
If overdose occurs there is no specific antidote to rivaroxaban.
The currently available data suggest that rivaroxaban will be as effective as low molecular weight heparin for prophylaxis after surgery to the lower limb. Patients will probably prefer a daily tablet to a daily injection.
The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al; ODIXa-HIP Study Investigators. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006;114:2374-81.
- Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75.
- Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, 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;372:31-9.
- Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-86.