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Published on 10 July 2009

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Simplified thromboprophylaxis with an oral factor Xa inhibitor

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A satellite symposium held at the recent EAHP Congress revealed that rivaroxaban reduces the risk of thromboembolism after hip and knee surgery without increases in the risk of major bleeding

Christine Clark
BSc MSc PhD FRPharmS
FFCP(Hon)

Editor
HPE

When factor X is activated it amplifies thrombin activity several-fold, and therefore it is no coincidence that it should be
the target for drug action, Alexander Turpie (professor of medicine, McMaster University, Canada) told the audience.

The treatment of venous thromboembolism (VTE) had been revolutionised by the introduction of heparin. However, oral anticoagulants (vitamin K antagonists) have remained the same for 60 years, and many people who need them do not get them – partly because of a perception that they are difficult to manage.

In recent years there have been numerous advances resulting from improved understanding of the coagulation process. Factor Xa and 11a (thrombin) have been the main targets of drug action, because factor X is a key coagulation factor at the point where the extrinsic and intrinsic coagulation pathways meet.

The EMEA approved Xarelto (rivaroxaban) in October 2008 for prophylaxis of VTE in patients undergoing elective hip and knee surgery. It has been extensively tested in orthopaedic surgery, and there is ongoing research on its role in the management of atrial fibrillation and acute coronary syndrome.

The ideal anticoagulant would have a fixed, oral, once-daily dose and provide predictable anticoagulation. In addition it would have a wide therapeutic window, not require monitoring and have a low risk of food and drug interactions, suggested Reinhold Kreutz (professor of clinical pharmacology and toxicology, Charite Campus Mitte, Berlin).

The anticoagulants that are currently in development all have single targets, unlike the vitamin K antagonists. Factor Xa and thrombin are common to both the extrinsic and intrinsic clotting cascades. Both fondaparinux and idraparinux are effective inhibitors of factor Xa, but these products work indirectly through the action of antithrombin. Rivaroxaban binds directly with free and fibrin-bound factor X and inhibits its action, thereby preventing thrombin formation.

Rivaroxaban is rapidly absorbed after oral dosing with a bioavailability of 80-100%. Maximum plasma concentrations are achieved 2-4 hours after dosing, and the mean plasma half-life is nine hours. There is a close linear correlation between rivaroxaban plasma levels and prothrombin time. The drug is 92-95% protein bound, there are no circulating major metabolites and approximately one-third of the dose is excreted unchanged via the kidneys. Rivaroxaban pharmacokinetics are not affected by gastric pH or by the presence of food.

In studies, rivaroxaban did not affect platelet aggregation induced by aspirin or naproxen. Co-administration with naproxen caused a slight increase in bleeding time in healthy volunteers, but this effect has not been seen in phase II studies where the two drugs were used concomitantly.

Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein (P-gp) and when rivaroxaban is given with a drug that inhibits both systems clinically relevant effects are seen, said Professor Kreutz. For example, plasma concentrations of rivaroxaban are raised considerably if it is given together with ketoconazole or ritonavir, both of which are strong inhibitors of CYP3A4 and P-gp. For this reason, rivaroxaban is not recommended in patients receiving systemic treatment with azole antimycotics or HIV-protease inhibitors. Fluconazole is expected to have less effect on rivaroxaban and can be co-administered with caution.

Strong CYP3A4 inducers also affect rivaroxaban plasma levels: for example, rifampicin (a strong CYP3A4 inducer) can cause a 50% decrease in the area under the concentration-time curve. Other strong CYP3A4 inducers such as phenytoin, carbamazepine, and St John’s Wort could have similar effects.

Administering rivaroxaban together with other drugs that are metabolised by CYP3A4 or transported by Pglycoprotein (P-gp) is not associated with any clinically significant interactions. Examples here would be midazolam, which is metabolised by CYP3A4, digoxin, which is transported by P-gp, and atorvastatin, which is both metabolised by CYP3A4 and transported by P-gp.

Studies have shown that age and gender have little effect on the pharmacokinetics or pharmacodynamics of rivaroxaban. Plasma levels are raised in patients of less than 50 kg body weight – although this may not be clinically relevant. Severe renal and hepatic impairment do affect clearance of rivaroxaban, so it is not recommended for patients with creatinine clearances of less than 15 ml/minand is contraindicated in patients with severe liver disease associated with coagulopathy and increased risk of bleeding.

Rivaroxaban in a dose of 10 mg once daily is suitable for a wide range of adult patients, including the elderly, those with unusually high or low body weights and those with mild or moderate renal impairment, concluded Professor Kreutz.

Pooled data from the RECORD trials have shown that treatment with rivaroxaban resulted in a 56% relative risk reduction for symptomatic venous thromboembolism (VTE) and all-cause mortality compared with enoxaparin, according to Sylvia Haas (professor of medicine, Technical University of Munich).

The RECORD trials comprise a suite of studies designed to compare the effects of rivaroxaban and enoxaparin in orthopaedic surgery. A single dose of rivaroxaban was selected for the entire programme – 10 mg starting 6-8 hours after surgery, explained Professor Haas.

Enoxaparin was the comparator drug throughout and was started the evening before surgery (RECORD 1, 2 and 3) to reflect European practice and 12-24 hours after surgery (in RECORD 4) to reflect US practice.

The primary efficacy endpoint for all studies was total VTE – a composite of any deep-vein thrombosis (DVT), nonfatal pulmonary embolism (PE) and all-cause mortality — at two weeks. The primary safety endpoint was major bleeding.

RECORD trials 1 and 2 involved patients undergoing total hip replacement (THR). RECORD 1 was designed to compare the effects of extended prophylaxis over a period of five weeks with rivaroxaban and enoxaparin. Treatment in the comparator (enoxaparin) arm of RECORD 2 continued for two weeks only and was designed to satisfy authorities in countries where longer prophylactic treatment is not the norm, explained Professor Haas.

The results showed that rivaroxaban significantly reduced the frequency of total VTEs with relative risk reductions (RRs) of 70% and 79% in RECORD 1 and 2 respectively. In both trials there was an 88% RR for major DVT. In neither trial was there any significant increase in major bleeding.

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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. The results showed that rivaroxaban significantly reduced the frequency of total VTEs, with RRs of 49% and 31% in RECORD 3 and 4 respectively. Once again, there was no significant increase in major bleeding in either trial.

Data for RECORD trials 1, 2 and 3 were pooled to increase the statistical precision of the results. This had been planned from the outset because the number of events was expected to be low in individual studies, said Professor Haas.

More than 9,000 participants were included in the efficacy and safety analyses. The average age of participants was 64 years (range 18-93 years), and the average weight was 78 kg (range 33-159 kg). The proportions of people who reached the primary efficacy endpoint were 0.4% in the rivaroxaban group and 0.8% in the enoxaparin group. The calculated RR was 56%. This value rose to 62% when the total treatment duration was taken into account. Pooled data confirmed that there were no differences in major bleeding.

Professor Haas explained that as part of the analysis other safety endpoints, such as excessive wound haematoma, surgical site bleeding and wound infections, had been explored. Again, no differences had been found. The incidence of cardiovascular events had also been analysed, and there had been no increase in the rivaroxaban group. This contrasted with findings with ximelagatran, she said.

Professor Haas concluded that the data showed clinically relevant differences in favour of rivaroxaban without increases in the risk of major bleeding.

Ben van Hout (professor of medical technology assessment at the Julius Center for Health Sciences and Primary Care, Utrecht University) described how an economic evaluation of rivaroxaban compared with enoxaparin in THR (RECORD 1) and THK (RECORD 3) had been carried out in the Netherlands. A decision tree was constructed to capture all possible events during both the prophylactic phase and for five years afterwards. The reason for the five-year time horizon was to take account of two important factors: first, untreated, symptomatic VTE could progress to symptomatic VTE during the 90-day post-prophylaxis period; and secondly, long-term complications where VTE may recur or present as post-thrombotic syndrome can occur up to five years after surgery. Post-thrombotic syndrome can have a considerable impact on quality of life, noted Professor van Hout. Transition probabilities were calculated from the published trials and used to populate the model so that the frequency of events, such as development of a VTE, could be calculated for each treatment. Utility values for the various health states and costs of treatment were combined to calculate incremental cost-effectiveness ratios for rivaroxaban.

The results showed that the increased cost of rivaroxaban is partly offset by the reduced administration costs and the avoided costs of treating VTE events. In addition, there are small reductions in the costs of treating long-term complications over a five-year period. Rivaroxaban treatment was associated with small gain in quality-adjusted life-years (QALYs) after both elective THR and TKR. Rivaroxaban decreased costs per patient in TKR and slightly increased costs per patient in THR. However, the overall analysis showed that it was costeffective compared with enoxaparin for prevention of VTE in both situations. It may be more cost-effective to discontinue prophylaxis in THR before 35 days, added Professor van Hout.

Resources
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):31-9.

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):2776-86.

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.

Turpie A, Lassen M, Kakkar A, Eriksson B, Misselwitz F, Bandel TJ, Homering M, Westermeier T, Gent M. A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous
thromboembolism after orthopaedic surgery: effect on
symptomatic venous thromboembolism, death, and bleeding. Blood (ASH Annual Meeting Abstracts) 2008;112:36



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