Rivaroxaban is a new oral anticoagulant, direct factor Xa inhibitor, approved for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors.
Atrial fibrillation (AF), the most common chronic cardiac arrhythmia, is associated with increased rates of mortality, stroke and other thrombo-embolic events, congestive heart failure and hospitalisations, degraded quality of life and reduced exercise capacity, and left ventricular dysfunction. Management of AF patients is aimed at reducing symptoms and at preventing severe complications associated with AF. Prevention of thrombo-embolic complications is based on antithrombotic therapy with oral anticoagulants or antiplatelet agents. The decision to start antithrombotic therapy, as well as the choice of the most appropriate pharmacological alternative should be the result of an individual assessment of the thrombo-embolic and haemorrhagic risks of each patient.
For patients with non-valvular AF and an indication for anticoagulant therapy, the following recommendations should be considered:
- Initiate treatment with a vitamin K antagonist (VKA), except for cases of hypersensitivity or contraindication, history of intracranial haemorrhage and ischaemic stroke at high risk for intracranial haemorrhage, or inability or important difficulty of appropriate INR monitoring.
- Maintain VKA treatment in patients with adequate INR control, history of gastrointestinal haemorrhage or in the presence of digestive disorders which may increase the risk of gastrointestinal bleeding and severe renal impairment.
- Start or switch to new oral anticoagulant (OAC) therapy in patients with poor INR control not due to lack of adherence, history of intracranial haemorrhage (regardless the degree of INR control), patients with ischaemic stroke at high risk for intracranial haemorrhage, allergy or known hypersensitivity to coumarins, serious adverse events associated with VKA therapy, specific contraindications to VKA, or the presence of a significant drug interaction which is difficult to control despite dosage adjustment based on INR (not previously described for new OACs).
There are currently four drugs available with indications for the prevention of stroke and systemic embolism in patients with non-valvular AF: two VKAs (acenocoumarol and warfarin), a direct thrombin inhibitor (dabigatran) and the direct factor Xa inhibitor, rivaroxaban, evaluated in this report.
A randomised clinical trial evaluated the efficacy and safety of rivaroxaban versus warfarin. There are no comparative studies available versus acenocoumarol or dabigatran.
Rivaroxaban was shown to be non-inferior to warfarin for the primary efficacy end point, which was a composite of stroke and systemic embolism, but was not shown superior. Mortality from any cause, stroke and myocardial infarction were evaluated as secondary end points and no statistically significant differences were observed between rivaroxaban and warfarin.
Significant differences were neither detected between rivaroxaban and warfarin for the primary safety end point which was a composite of major and non-major clinically relevant bleeding events (14.9% and 14.5% per year, respectively). Among secondary end points, rates of major bleeding were similar for rivaroxaban and warfarin (3.6% vs. 3.4%, respectively) and rates of intracranial haemorrhage were significantly lower for rivaroxaban than for warfarin (ARR= -0.4%; 95% CI, -0.7% to -0.1%; NNTB ~470 in a year). However, gastrointestinal major bleeding was more common with rivaroxaban than with warfarin (AR Difference = 1.1%; 95% CI: 0.6% to 1.7%; NNTD ~166 in a year).
Rates of bleeding events were higher with rivaroxaban than with warfarin in centres with best INR control, with statistically significant differences. The EMA has pointed out some reasonable doubts with regards to the communication of adverse events in this trial.
Indirect comparisons to date show no substantial differences between rivaroxaban and the new OACs, which is consistent with a similar consideration of use.
Like dabigatran, rivaroxaban does not require monitoring and periodic dosage adjustment, and it is less likely to interact with food and other drugs. However, there is no antidote in case of excessive anticoagulation. And, similarly to other chronic therapies, the lack of monitoring could reduce adherence besides hindering the identification of non-compliant patients.
The cost of rivaroxaban is higher to that of warfarin and of acenocoumarol, and it is similar to dabigatran. The economic impact of the replacement of VKAs for rivaroxaban could reach €44.4 millions in Andalucia.
Taking into account the available evidence, it may be concluded that rivaroxaban may offer an added value in specific situations and may be used as an alternative to VKAs in the same cases as the new OACs, considering each case on an individual basis.