Safe and effective anticoagulation is often beset with problems for patient management. Will the new oral anticoagulant agents provide the solution?
UCLH NHS Foundation Trust
Honorary Senior Research Fellow
University College London
Venous thromboembolism (VTE) involves the formation of a clot or thrombus within a blood vessel, which occludes the flow of blood through the circulatory system. Most thrombi occur in the deep veins of the legs but dislodged thrombi may travel to the lungs and cause a pulmonary embolus. Higher risk of thrombus formation is normally associated with inactivity or high-risk surgical procedures; the risk is further increased in patients undergoing orthopaedic procedures or lengthy operations.
England sees 25,000 deaths a year due to VTE, while the USA sees 200,000 a year.,
The current mainstay treatment in prevention of VTE involves anticoagulant therapy. This usually involves initial rapid anticoagulation using parenteral products such as unfractionated heparin, low-molecular-weight heparins (LMWHs) or fondaparinux followed by extended therapy using oral vitamin K antagonists such as warfarin.
Whilst LMWHs and fondaparinux have superseded heparin due to their better bioavailability and longer half-life, the ongoing need for subcutaneous injections is still problematic for some patients.
Despite utilisation of the oral route, warfarin use is associated with significant problems. These include slow onset of action, variation in therapeutic dosing, genetic polymorphism, diet and drug interactions and the need for close monitoring.
These issues and concerns have led to a search for newer anticoagulants with more targeted actions within the coagulation cascade. These include indirect inhibitors of factor Xa (idraparinux), direct inhibitors of factor Xa (rivaroxaban and apixaban) and direct inhibitors of thrombin (dabigatran).
Rivaroxaban is a member of the new generation of anticoagulation agents. It is a selective potent inhibitor of both free factor Xa and factor Xa within the prothombinase complex4 and binds in a reversible and competitive manner. Current areas of interest for rivaroxaban include the prevention of VTE in medically ill patients and those undergoing major orthopaedic surgery, prevention of major acute cardiovascular events after acute coronary syndromes and the treatment and secondary prevention of VTE in acute thromboembolic disease. Further interest lies in the prevention of stroke and non-CNS systemic embolism in atrial fibrillation.
Rivaroxaban is well absorbed from the gastrointenstinal tract when taken orally with a bioavailability greater than 80%. Absorption is not affected by food, peak plasma levels are normally attained within three hours and the half-life is approximately nine hours. Rivaroxaban has a dual excretion pathway with approximately 66% being excreted via the kidneys and the rest in faeces. With this excretion pathway, care is needed when administering the drug to patients with renal dysfunction.
The drug is metabolised extensively in the liver by CYP3A4 and CYP2J2 enzymes as well as CYP-independent mechanisms. Caution is needed when treating patients receiving concomitant treatment with potent inhibitors of CYP3A4, (ie, ketoconazole and ritonavir) as well as inducers of CYP3A4 (ie, phenytoin and carbamazepine).
Key clinical trials
A number of trials have attempted to identify the efficacy of rivaroxaban compared to unfractionated heparin, LMWHs and vitamin K antagonists, as well as determining the optimal dose.
Rivaroxaban was directly compared with enoxaparin for thromboprophylaxis after total hip replacement.5 A total of 873 patients were randomised to receive either enoxaparin 40â€‰mg (one dose the evening prior to surgery and another at least six hours postsurgery) or rivaroxaban at doses of 5, 10, 20, 30 or 40â€‰mg (six to eight hours postsurgery). Treatment was continued for five to nine days. Using a primary endpoint of a composite score between any deep-vein thrombosis, objectively confirmed PE and all-cause mortality, the risk of major postoperative bleeding increased as the dose of rivaroxaban was increased, with only the figure for the 10â€‰mg group being less than that for enoxaparin (0.7% vs 1.9%). However, all rivaroxaban regimes demonstrated an improved primary endpoint outcome when compared with enoxaparin.
The ODIXa-DVT6 and the EINSTEIN-DVT7 trials are a pair of phase II trials evaluating the safety and efficacy of rivaroxaban in treating DVT.
ODIXa-DVT is a randomised trial involving 613 patients with symptomatic proximal DVT comparing rivaroxaban 10, 20 and 30â€‰mg twice daily, rivaroxaban 40â€‰mg daily and enoxaparin 1mg/kg twice daily followed by vitamin K antagonist treatment for 12 weeks. The primary endpoint was an improvement in the thrombotic burden without recurrent symptomatic VTE or VTE-related death. The primary efficacy endpoint was met in 44â€”59% cases in the rivaroxaban groups and in 46% of the enoxaparin/vitamin K antagonist group. There was an increase in the incidence of bleeding as the dose of rivaroxaban increased (5â€”11.6%) compared with 6.3% in the enoxaparin/vitamin K antagonist group. Symptomatic VTE or death was observed in 2.1% of patients in the rivaroxaban group vs 0.9% for the enoxaparin group.
The EINSTEIN-DVT trial was of a similar design to the ODIXa-DVT trial but compared rivaroxaban 20, 30 or 40â€‰mg daily to unfractionated heparins or LMWHs with a vitamin K antagonist. The 543 patients enrolled had a symptomatic DVT without a symptomatic pulmonary embolism. The primary endpoint for this trial was a deterioration in the thrombotic burden or symptomatic recurrent VTE. This trial demonstrated a superior efficacy of rivaroxaban (5.4â€”6.6%) compared with other treatments (9.9%) against the recognised endpoint. With lower doses of rivaroxaban used in this trial compared to the ODIXa-DVT trial, the incidences of clinically relevant bleeding were less when compared with the heparin group (2.9â€”7.5% vs 8.8%).
These trials further demonstrated that there is a plateau of efficacy for rivaroxaban at daily doses between 20â€‰mg and 60â€‰mg per day. Furthermore, there was a significant dose relationship for bleeding on a twice-daily regime as compared to a once-daily dosing. Using data from these trials, a 20â€‰mg once-daily dose has been selected for evaluation in phase III trials currently being undertaken in the treatment of VTE and the prevention of stroke in atrial fibrillation.
However, unexpected hepatotoxicity from trials involving ximelagatran has focused awareness on the possibility of hepatic toxicity with the newer oral anticoagulants. To date, this has yet to be seen in phase II trials involving rivaroxaban, but the long-term scrutiny of trial data is warranted.
Despite ongoing trials in a number of different clinical areas, current results suggest that rivaroxaban will provide a suitable alternative to warfarin for oral anticoagulation and possibly as an alternative to LMWHs. Whilst the most efficacious dose has yet to be elucidated, the opportunity afforded with an oral anticoagulant with a fixed therapeutic dosage and minimal monitoring is important especially with the risks involved for patients whose treatment is not closely monitored. However, the costs related to the development and implementation into the healthcare setting, compared with that of warfarin, will be a significant factor in determining its uptake.
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