A Cross-Country Comparison of Rivaroxaban Spontaneous Adverse Event Reports and Concomitant Medicine Use with the Potential to Increase the Risk of Harm

Background: Concerns with the safety profiles of the newer anticoagulants have been raised because of differences in treatment populations between pre-marketing studies (randomized controlled trials) and clinical practice. Little is known about the potential safety issues and the reporting in spontaneous adverse event databases associated with rivaroxaban.

Objectives: To analyse spontaneous adverse event reports associated with the oral anticoagulant rivaroxaban from Australia, Canada and the USA; and to examine concomitant medicine use that may increase the risk of adverse events.

Methods: Spontaneous adverse event report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with rivaroxaban and concomitant medicines from 1 August 2005 to 31 March 2013. Disproportionality analysis (the proportional reporting ratio [PRR] and reporting odds ratio [ROR]) was conducted for quantitative detection of signals, using the US database.

Results: There were 244 spontaneous adverse event reports associated with rivaroxaban from Australia, 536 from Canada and 1,638 from the USA. Reporting of haemorrhage (any type) was common, ranging from 30.7 % for Australia to 37.5 % for Canada. Gastrointestinal haemorrhage was the most commonly reported haemorrhage, accounting for 13.9 % of Australian, 16.4 % of Canadian and 11.1 % of US adverse event reports. Positive signals were confirmed in the US data (haemorrhage [any type] PRR 11.93, χ² 4,414.78 and ROR 13.41, 95 % confidence interval [CI] 12.13–14.81; gastrointestinal haemorrhage PRR 12.52, χ² 2,018.48 and ROR 13.15, 95 % CI 11.36–15.21). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 63.7 % in Australia to 89.2 % in Canada.

Conclusion: A large proportion of adverse event reports for rivaroxaban were associated with use of concomitant medicines, which may have increased the risk of adverse events—in particular, haemorrhage. Increased awareness of a patient’s comorbidity and associated medicine use is needed when rivaroxaban is used in clinical practice.