title: 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.
authors.affiliation: Department of Neurology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Ploen
authors.affiliation: Department of Neurology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Neurology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Acute Care Research, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heitmeier
authors.affiliation: Department of Internal Medicine I, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zorn
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Jenetzky
authors.affiliation: Department of Neurology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000069552:Rivaroxaban; D020521:Stroke / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015912:Thrombolytic Therapy; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban