Once-daily, oral, direct factor Xa inhibitor rivaroxaban (Xarelto, Bayer) successfully met the primary efficacy endpoint of non-inferiority in the prevention of stroke and non-central nervous system embolism in non-valvular atrial fibrillation, with superior efficacy demonstrated compared to warfarin whilst on active treatment. The principal safety outcome – the composite of major and non-major clinically relevant bleeding events – was similar in both treatment arms.
Results from the double blind, double dummy ROCKET AF (Rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) phase III clinical study, published in the New England Journal of Medicine (NEJM), showed that stroke or non-central nervous systemic embolism occurred in 188 patients in the rivaroxaban group and in 241 patients in the warfarin group (1.7% vs 2.2% per year, hazard ratio in the rivaroxaban group, 0.79; CI 0.66 to 0.96, p<0.001 for non inferiority). Subsequent hierarchical testing confirmed superior efficacy of rivaroxaban versus warfarin whilst on active treatment, with a 21% relative risk reduction per year and an absolute risk reduction of 0.5% per year in stroke and non-central nervous systemic embolism in the pre-specified on-treatment population (1.7% vs 2.2% per year, p=0.01 for superiority).
An additional sensitivity analysis in the intent to treat (ITT) population which followed all patients in the trial until its completion demonstrated non-inferiority (2.1% vs 2.4% per year, (HR 0.88; 95% CI, 0.75 to 1.03; p<0.001 for non-inferiority).
“The trial results showed a comparable treatment effect versus warfarin and better efficacy when patients were on treatment,” said Keith Fox, co-chair of the ROCKET AF executive steering committee and professor of cardiology at the University of Edinburgh, UK. “The benefits of rivaroxaban were consistent across key patient subgroups, irrespective of their INR control, with the efficacy of once-daily rivaroxaban versus warfarin being preserved, even in centres with optimal INR control. These findings are therefore relevant to the UK, where in general, good INR control is achieved.”
On the principal safety measure of major and non-major clinically relevant bleeding events, rivaroxaban was similar compared with warfarin. Rates of major bleeding were also comparable between rivaroxaban and warfarin. Importantly, patients treated with rivaroxaban had fewer intracranial haemorrhages, fewer critical organ bleeds and lower bleeding-related deaths than those on warfarin. Major bleeding from a gastrointestinal site was more common in the rivaroxaban group. Rates of haemoglobin drop and transfusion requirements were increased when compared to patients who received warfarin.
Rivaroxaban is indicated for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Rivaroxaban is not licensed for use in the prevention of stroke and non-central nervous systemic embolism in patients with non-valvular AF.