Each DOAC has been compared to Warfarin in large randomised clinical trials and all have shown either non-inferiority or in some cases slight superiority to Warfarin. It is difficult to compare the drugs head-to-head because the trials all had slightly different design however recently there has been some uncertainty about the Rivaroxaban ROCKET-AF trial. Rivaroxaban has become one of the most popular DOACs because of its once daily dose regimen and is very well-tolerated. To date it has been my DOAC of choice.
The ROCKET-AF trial was criticised after publication for potentially being biased in favour of Rivaroxaban. This was because the time in the therapeutic range for the Warfarin patients was just 55%. In other words, the INR of patients on Warfarin was between 2 and 3 just over half the time. The optimum time in the therapeutic range for a patient on warfarin should be >70%.
More recently the trial has come under fire because the INR monitoring was performed using a point-of-care device that has been subsequently recalled by the FDA. The device produced inaccurately low INR results in some patients. This had the potential to produce falsely low INR readings. This meant that the dose of Warfarin prescribed would have been increased thus exposing patients to potentially higher bleeding tendency.
The faulty INR machine used in the trial led to potential overdosing of warfarin which could have led to higher bleeding in the warfarin group. However, in the trial the annual risk of major bleeding was 3.6% with Rivaroxaban versus 3.4% with Warfarin. If the patients on Warfarin had a higher bleeding tendency because nearly 40% were being over-treated this could have increased the major bleeding rate in the Warfarin group and difference in major bleeding caused by Rivaroxaban
The trial authors have now responded to this by publishing a Research letter in the New England Journal of Medicine. They reporting that 37% of patients treated with Warfarin had a condition that could have been affected by the faulty INR device. They performed an analysis of these patients and reported that the main results of the trial were unaffected.
Sceptics have responded in an article in the British Medical Journal calling for release of the patient-level data as they don’t trust the investigators analysis. So far the company have not indicated that they will release the data.
Should we continue to prescribe Rivaroxaban for new patients and should patients currently on the drug be confident to continue taking it?
In the post-marketing Xantus study with Rivaroxaban the annual rate of major bleeding was 2.1%, stroke 0.7%, and death 1.9% which were either equivalent to or less than those reported in ROCKET-AF. So in real life clinical practice the drug appears to perform in a manner similar to that achieved in the ROCKET-AF trial. Although that is not surprising since it was the Warfarin comparator group where the problem lies and therefore interpreting difference between Warfarin and Rivaroxaban.
Up to this point the main reasons to choose Rivaroxaban are the simple once-daily dosing and good tolerability. Recently Edoxaban has been launched in the UK and this is also once daily. In the clinical trial of Edoxaban versus Warfarin time in the therapeutic range was 68.4%, which is good and a different point of care INR monitoring machine was used. The average CHADS2 score in the trial was 2.8 and Edoxaban was non-inferior to Warfarin for stroke prevention with a trend towards a lower annualised risk of major bleeding of 2.75% versus 3.43% with Warfarin. Certainly Edoxaban looks an attractive candidate to become my DOAC of choice going forward.