Rivaroxaban (Xarelto®) and reports of lack of efficacy in orthopaedic surgery indication

Rivaroxaban (Xarelto^®, Bayer (South East Asia) Pte Ltd) has been registered in Singapore since November 2008 for the prevention of venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) or total knee replacement surgery (TKR). In March 2012, the registered indication for Xarelto^® was extended to include prevention of stroke and systemic embolism in subjects with non-valvular atrial fibrillation, as well as for treatment of deep vein thrombosis (DVT) and the prevention of recurrent DVT and pulmonary embolism (PE).

Recently, a review of the ADR reports received by the Netherlands Pharmacovigilance Centre, Lareb, raised a possible signal of lack of efficacy with Xarelto^® for the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery.¹ The reports from HSA's ADR database have not shown a similar trend for inefficacy and the safety signal observed in the Netherlands could be due to stimulated reporting,i.e. reporters are more likely to report possible adverse events of new drugs as compared to older drugs. Nonetheless, HSA would like to update healthcare professionals with this information and encourage continued safety monitoring of this anticoagulant.

Information from Netherlands Pharmacovigilance Centre, Lareb

As of March 2012, Lareb had received 48 ADR reports related to the use of rivaroxaban. Of these, 31 were reported as serious and the most frequently reported serious ADRs were bleeding events. There were also eight reports of PE associated with the use of rivaroxaban, which indicated a possible lack of efficacy in certain patients. Of these eight reports, four were confirmed with Computed Tomography (CT) scan. In comparison, the number of PE reports associated with rivaroxaban was disproportionately higher than that for low molecular weight heparin (LMWH) products, which were much more commonly used than rivaroxaban. There were nine PE reports for nadroparin, four for dalteparin, and none for both enoxaparin and tinzaparin. Hence, Lareb has assessed that attention to lack of drug effect manifested through the occurrence of PE is warranted when using rivaroxaban following hip or knee replacement surgery.

Findings reported in literature

Neuman et al performed a systematic review and meta-analysis to evaluate the benefits and harm of oral direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, YM150, TAK442, betrixaban and LY517717) versus LMWH in patients undergoing THR or TKR.² In this study, no significant difference in non-fatal PE was found between factor Xa inhibitors and LMWH.

Local situation

Since 2008, HSA has received 20 ADR reports associated with the use of rivaroxaban. Among these cases, there were two cases that were related to drug inefficacy. These included one case of intracardiac thrombus (concomitant disease of left ventricular systolic dysfunction and dilated cardiomyopathy) where the indication was not reported and one case of stroke reported with the use of rivaroxaban for prevention of stroke and non-central system systemic embolism. The other ADRs were mainly due to haemorrhage, a known adverse effect associated with rivaroxaban.

HSA's advisory

HSA continues to monitor for reports of PE associated with rivaroxaban although there is no report of PE locally. Healthcare professionals are advised to monitor their patients for possible lack of efficacy. Healthcare professionals are also encouraged to report any adverse reactions suspected to be related to the use of rivaroxaban to the Vigilance Branch of HSA.

References

1. Netherlands Pharmacovigilance Centre Lareb Quarterly Newsletter, 4^thquarter of 2012 NR8

2. Ann Intern Med 2012; 156: 710-9