Accumulating data on rivaroxaban for venous thromboembolism in clinical practice

https://doi.org/10.1160/TH17-08-0573 Thromb Haemost 2017; 117: ■■■ Editorial Focus on ▶Coleman et al. Thromb Haemost 2017; 117: ■■■ Clinical practice data on effectiveness and safety of new drugs are useful for supporting the results from randomised clinical trials. The latter are limited in size and certain patient subsets are typically underrepresented, including the elderly, those with multiple co-morbidities or with a history of poor compliance. For the non-vitamin K antagonist oral anticoagulants (NOACs), following the chronology of regulatory approvals, the first clinical practice data on long-term treatment to be published were on dabigatran for stroke prevention in atrial fibrillation. For the indication acute venous thromboembolism (VTE), rivaroxaban was the first NOAC to reach the market. Several studies on rivaroxaban in clinical practice for the management of VTE have already been published or are being performed, as recently reviewed (1). These consist of retrospective cohort studies, registries and health care databases. In general, these studies confirmed the results of the phase III clinical trials on rivaroxaban for the treatment of deep vein thrombosis (2) or pulmonary embolism (3). After various adjustments using Cox proportional hazard model or propensity score hazard model, there was similar effectiveness and safety with rivaroxaban as with low-molecular-weight-heparin overlapping with a vitamin K antagonist (1). In this issue of Thrombosis and Haemostasis, Coleman et al. have analysed health care database information covering approximately half of the population of the United States (4). They were able to include almost 46,000 patients treated with rivaroxaban or (the majority) with warfarin. This is the largest cohort in clinical practice analysed so far for the VTE treatment indication. The recently published Danish national study included 12,000 patients (5). Coleman et al. found, as opposed to the other clinical practice studies, that even after adjustments the risk of recurrent VTE and of major bleeding was significantly reduced among those prescribed rivaroxaban. The authors made extraordinary efforts to reduce the risk of bias by using inverse probability of treatment weighting based on the propensity score for 52 different variables. In subsequent analyses of the population according to age, sex, obesity, presence of pulmonary embolism, or cancer there was consistently a reduction of the risks for the rivaroxaban-treated group, with the exception for patients with cancer (active or history of), where there was equipoise. Are the favourable results in this study identified due to the much larger sample size than in previous clinical practice studies? The reduction of recurrent VTE by 19% here can be compared with the (after adjustments) non-significant 45% or 9% reduction or 11% increase in the other studies (1). The reduction of major bleeding by 21% here can similarly be compared with the previously published non-significant decrease of 23%, 17%, or 0% (1). It is thus possible that the power of large numbers helped to demonstrate the statistically significant benefits. However, it must still be kept in mind that despite all the adjustments performed, the populations prescribed rivaroxaban or warfarin were different, with older age and more comorbidities in the warfarin group. Therefore, one cannot exclude the presence of other confounders that were not adjusted for. Another, even larger administrative healthcare database study by Canadian Network for Observational Drug Effect Studies (NCT02833987) is expected to be published soon, and it will be interesting to see if it confirms the positive results.