Rivaroxaban Does Not Increase Hemorrhage after Thrombolysis in Experimental Ischemic Stroke

Abstract

The management of acute ischemic stroke during anticoagulation with a novel oral anticoagulant (NOAC) is challenging because intravenous thrombolysis is contraindicated because of a putative increased risk of intracerebral hemorrhagic complications. We examined the risk of secondary postischemic hemorrhage after thrombolysis in rodents pretreated with rivaroxaban or warfarin. Mice were pretreated with either rivaroxaban (30 mg/kg), warfarin (target international normalized ratio 2 to 3) or vehicle. After 2 or 3 hours, middle cerebral artery occlusion (MCAO), mice received 9 mg/kg recombinant tissue plasminogen activator. Twenty-four hours after MCAO, secondary hemorrhage was quantified using a macroscopic hemorrhage score and hemoglobin spectrophotometry. Blood-brain barrier (BBB) permeability was measured by Evans Blue spectrofluorometry. To increase the validity of our findings, experiments were also performed using a thromboembolic model in anticoagulated rats. Infarct size did not differ among groups. Pretreatment with warfarin led to significantly more secondary hemorrhage compared with rivaroxaban and nonanticoagulated controls after 2-and 3-hour ischemia in mice as well as in rats. Blood-brain barrier permeability was significantly higher in the warfarin group compared with rivaroxaban and control. Thus, rivaroxaban in contrast to warfarin does not increase secondary hemorrhage after thrombolysis in experimental cerebral ischemia. Less effects of rivaroxaban on postischemic BBB permeability may account for this difference.

Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association

“…In experimental studies, pretreatment with dabigatran or rivaroxaban did not increase the rate of thrombolysis-associated ICH. 72,73 Data on the safety and efficacy of intravenous thrombolysis in AIS patients receiving NOACs are limited to approximately 2 dozen case reports and a retrospective multicenter cohort study. Among the case reports, ICH and poor outcome were rarely reported when recombinant tissue-type plasminogen activator was administered minutes to 24 hours after the last anticoagulant dose.…”

Recanalization Therapies in Acute Ischemic Stroke Patients

“…8,9 The knowledge about IVT in NOAC patients is limited and based on case reports. [14][15][16][17][18]20,21,24 Data from animal models showed no excessive risk of ICH after IVT in rodents with a prior treatment with rivaroxaban, 43,44 dabigatran, 45,46 and apixaban 44 in comparison with VKA. Currently, the use of IVT for acute ischemic stroke in patients with a recent (<48 hours) intake of a NOAC is regarded off-label.…”

Intravenous thrombolysis for acute ischaemic stroke in patients on direct oral anticoagulants

“…In another experimental study led by the same group, reversion of VKA effects by prothrombin complex concentrates eliminated the excess risk of bleeding after rtPA use [20]. Similar experiments conducted with apixaban showed that the risk of haemorrhagic transformation was lower with DOACs than with VKAs after thrombolysis [21,22].…”