Rivaroxaban has an improved benefit to risk ratio, and oral administration makes it economical and convenient to use for prevention of venous thromboembolism, according to experts
Predictable efficacy without the need for monitoring and dosage adjustment combined with a low potential for drug-drug interactions makes rivaroxaban a serious competitor for standard treatment with enoxaparin, according to Reinhold Kreutz (professor of clinical pharmacology and toxicology, Charite Campus Mitte, Berlin). Speaking at a satellite symposium at the European Society of Clinical Pharmacy (ESCP) conference in Dubrovnik in October 2008 he outlined the problems of conventional anticoagulation and the benefits of rivaroxaban.
Rivaroxaban is a specific factor Xa inhibitor and has no action on other components of the clotting cascade. Activated factor X (factor Xa) brings about the conversion of prothrombin (factor II) to thrombin (factor IIa), which, in turn converts fibrinogen to fibrin. These steps represent the final common pathway in the clotting cascade and bring about clot formation.
Vitamin K antagonists (VKAs), such as warfarin, inhibit the activation of thrombin and factors VII, IX and X. Their actions are unselective and unspecific, said Professor Kreutz. Although they are given orally they have a slow onset and offset of action and a very poor dose-response relationship. Their use is further complicated by numerous interactions with food and other drugs, he added. This makes them unpredictable in use and makes routine monitoring of coagulation status mandatory.
Heparins act predominantly through inactivation of thrombin and factor Xa and their actions are short lived. They must be given by subcutaneous injection, which is a major limitation in practice. In addition, blood counts must be done at specified intervals and the dose has to be adjusted in renal insufficiency. Thrombocytopaenia and osteoporosis are important side effects of heparins, said Professor Kreutz. Osteoporosis is a particularly important consideration for women on long-term treatment, he commented.
Rivaroxaban binds directly to the active site of factor Xa. It is well absorbed when given orally – with a bioavailability of 80% – and has a rapid onset of action. There is a good relationship between the dose and the prolongation of prothrombin time. Although rivaroxaban has a low potential for drug-drug interactions, Professor Kreutz pointed out that it is a substrate for CYP3A4 and therefore should not be given together with strong CYP3A4 or Pgp inhibitors such as azole antimycotic agents, as this could increase rivaroxaban plasma levels.
Studies in 758 patients undergoing total hip replacements, taking a 10mg dose showed that plasma levels were all within the 90% confidence interval of the mean. The mean patient weight was 75Kg and the average age was 65 years.
In the USA pulmonary embolism is the root cause for 10% of hospital deaths and the surgeon general has identified this a major issue in healthcare, said Benjamin Brenner (professor of haematology, Rambam Medical Centre, Haifa, Israel). Conventional anticoagulants can all decrease the incidence of deep vein thromboses after knee replacement, hip replacement and hip fracture surgery, but they all have limitations, he continued. Moreoever, prophylactic treatment is usually not continued for a long enough period. For example, in the USA only 75% of patients who receive low-molecular-weight heparin (LMWH) in hospital continue treatment after discharge. A recent multinational study found that despite clear guidelines from the American College of Chest Physicians (ACC P) 50% of patients were not prescribed the recommended treatment.
The RECORD trials (REgulation of Coagulation on major Orthopaedic surgery Reducing the risk of DVT and PE) comprise a series of four trials designed to examine the effectiveness of once-daily oral rivaroxaban 10 mg compared with enoxaparin, the “gold standard” prophylaxis for postsurgical venous thromboembolism (VTE) (see Table 1).
The primary efficacy endpoint for all studies was total VTE (a composite of any DVT, nonfatal pulmonary embolism (PE) and all-cause mortality). The primary safety endpoint was major bleeding.
RECORD 1 was designed to compare the effects of extended prophylaxis over a period of five weeks with rivaroxaban and enoxaparin. RECORD 2 was designed to compare extended prophylaxis with rivaroxaban and short-term (two weeks) enoxaparin. Both trials involved patients undergoing total hip replacement.
The results showed that rivaroxaban significantly reduced the frequency of total VTEs with relative risk reductions (RR) of 70% and 79% in RECORD 1 and 2 respectively (Absolute risk reductions were 2.6% and 9.2%).
RECORD trials 3 and 4 involved patients undergoing total knee replacement surgery. Prophylactic treatment was given for a period of two weeks. RECORD 3 used an enoxaparin dose of 40 mg daily whereas RECORD 4 used the USA regimen, 30 mg twice daily.
RECORD 3 and 4 showed RRs of 70% and 31% respectively.
None of the trials has shown any increased bleeding in the rivaroxaban-treated groups. “Better efficacy was not associated with more bleeding – a very good result,” said Professor Brenner. He also noted that there were no differences in the frequency of abnormal liver function tests. This is of interest because ximelagatran, an oral thrombin inhibitor, was withdrawn because of liver toxicity. He concluded that rivaroxaban offers an improved benefit to risk ratio compared with currently available anticoagulants.
Rivaroxaban is associated with economic benefits because of the reduced frequency of clinical events and the avoidance of long-term complications. In addition, oral administration provides important cost-offsets, said Bengt Jonnson (Stockholm School of Economics, Sweden).
The RECORD trials covered relevant situations and realistic timescales, said Professor Jonnson. Trials 1, 2 and 3 have been used for economic analyses because these all use European dosage regimens.
Oral administration saves about 10 minutes per day of nursing time. The time required to train patients to self-administer enoxaparin at home – about 30 minutes per patient – is also saved. An additional saving is possible because at present, according to British estimates, 8% of patients receiving LMWH at home to complete their prophylactic treatment require a visiting nurse to administer the injection, he noted. On top of this, some patients can be admitted on the day of surgery rather than one day in advance, because of the rivaroxaban dosing regimen, thus saving one bed-day.
Economic analyses, using costs of £4.50 per day for rivaroxaban and £4.20 per day for enoxaparin, suggest that rivaroxaban is cost-saving in the short term because of savings in nurse time for administration and in the long term because of the reduction in clinical events and long-term complications. Commenting on RECOR D 1, Professor Jonnson noted that rivaroxaban treatment was associated with a saving of £68 per patient and a gain of 0.0041 QALYs per patient. There is not a big difference because enoxaparin is an effective treatment; however, in practice it is difficult to achieve 35 days of prophylactic treatment with enoxaparin, he explained.
Rivaroxaban (Xarelto®) received European approval in October 2008 for prophylaxis of VTE in patients undergoing elective hip and knee surgery.
Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358(26): 2765-75.
Kakkar AK, Brenner B, Dahl OE, 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(9632):31-39.
Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358(26):2776-2786.
RECORD 4 Study: Regulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE: a controlled, double-blind, randomized study of BAY 59-7939 in the prevention of VTE in subjects undergoing elective total knee replacement. Available at http://clinicaltrials.gov/ct2/show/ NCT00362232.
NOTE: Xarelto is currently undergoing appraisal by the National Institute for Health and Clinical Excellence (NICE) in the UK, which is expected to publish its recommendations in June 2009.