Transient or extended reversal of apixaban anticoagulation by andexanet alfa is equally effective in a porcine polytrauma model
Andexanet alfa (andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated andexanet for reversing apixaban anticoagulation in a porcine polytrauma model. Oral apixaban (20 mg q.d., n=2...
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| Veröffentlicht in: | British journal of anaesthesia : BJA 2019-08, Vol.123 (2), p.186-195 |
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| creator | Grottke, Oliver Braunschweig, Till Rossaint, Rolf Akman, Necib Leeds, Janet M. Conley, Pamela B. Honickel, Markus |
| description | Andexanet alfa (andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated andexanet for reversing apixaban anticoagulation in a porcine polytrauma model.
Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss.
Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P |
| doi_str_mv | 10.1016/j.bja.2019.04.059 |
| format | Article |
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Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss.
Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P<0.01]. Controls exhibited total blood loss of 3403 (766) ml, with 100% mortality. Andexanet bolus or bolus plus infusion significantly reduced blood loss to 1264 (205) and 1202 (95) ml, respectively), and increased survival to 100%. Haemodynamic parameters and markers of shock recovered to pre-trauma levels in andexanet-treated animals.
Andexanet effectively reversed apixaban anticoagulation and reduced blood loss induced by severe trauma. Andexanet bolus alone had a similar impact on survival and blood loss as bolus plus infusion. Therefore, a 2 h andexanet infusion after the bolus may not be necessary to restore normal haemostatic mechanisms.</description><identifier>ISSN: 0007-0912</identifier><identifier>EISSN: 1471-6771</identifier><identifier>DOI: 10.1016/j.bja.2019.04.059</identifier><identifier>PMID: 31202564</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>andexanet alfa ; Animals ; anticoagulants ; Anticoagulants - pharmacology ; antidotes ; apixaban ; Blood Coagulation - drug effects ; coagulation ; Critical Care ; Disease Models, Animal ; Factor Xa - pharmacology ; Factor Xa Inhibitors - pharmacology ; haemorrhage ; Male ; Multiple Trauma ; Pyrazoles - pharmacology ; Pyridones - pharmacology ; Recombinant Proteins - pharmacology ; Swine ; trauma</subject><ispartof>British journal of anaesthesia : BJA, 2019-08, Vol.123 (2), p.186-195</ispartof><rights>2019 British Journal of Anaesthesia</rights><rights>Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.</rights><rights>2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. 2019 British Journal of Anaesthesia</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-7a4c967c0270c3233c45cbc3087d02ed149ef412486b97cd398370b11e9c7a83</citedby><cites>FETCH-LOGICAL-c517t-7a4c967c0270c3233c45cbc3087d02ed149ef412486b97cd398370b11e9c7a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31202564$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grottke, Oliver</creatorcontrib><creatorcontrib>Braunschweig, Till</creatorcontrib><creatorcontrib>Rossaint, Rolf</creatorcontrib><creatorcontrib>Akman, Necib</creatorcontrib><creatorcontrib>Leeds, Janet M.</creatorcontrib><creatorcontrib>Conley, Pamela B.</creatorcontrib><creatorcontrib>Honickel, Markus</creatorcontrib><title>Transient or extended reversal of apixaban anticoagulation by andexanet alfa is equally effective in a porcine polytrauma model</title><title>British journal of anaesthesia : BJA</title><addtitle>Br J Anaesth</addtitle><description>Andexanet alfa (andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated andexanet for reversing apixaban anticoagulation in a porcine polytrauma model.
Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss.
Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P<0.01]. Controls exhibited total blood loss of 3403 (766) ml, with 100% mortality. Andexanet bolus or bolus plus infusion significantly reduced blood loss to 1264 (205) and 1202 (95) ml, respectively), and increased survival to 100%. Haemodynamic parameters and markers of shock recovered to pre-trauma levels in andexanet-treated animals.
Andexanet effectively reversed apixaban anticoagulation and reduced blood loss induced by severe trauma. Andexanet bolus alone had a similar impact on survival and blood loss as bolus plus infusion. Therefore, a 2 h andexanet infusion after the bolus may not be necessary to restore normal haemostatic mechanisms.</description><subject>andexanet alfa</subject><subject>Animals</subject><subject>anticoagulants</subject><subject>Anticoagulants - pharmacology</subject><subject>antidotes</subject><subject>apixaban</subject><subject>Blood Coagulation - drug effects</subject><subject>coagulation</subject><subject>Critical Care</subject><subject>Disease Models, Animal</subject><subject>Factor Xa - pharmacology</subject><subject>Factor Xa Inhibitors - pharmacology</subject><subject>haemorrhage</subject><subject>Male</subject><subject>Multiple Trauma</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridones - pharmacology</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Swine</subject><subject>trauma</subject><issn>0007-0912</issn><issn>1471-6771</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EotvCA3BBPnJJsB0nXgsJCVVQkCpx2bs1sSfFKyfe2slq99ZH4Vl4MrzaUsGF00ie___HMx8hbzirOePd-23db6EWjOuayZq1-hlZcal41SnFn5MVY0xVTHNxQS5z3jLGldDtS3LRcMFE28kVedgkmLLHaaYxUTzMODl0NOEeU4ZA40Bh5w_Qw0Rhmr2NcLcEmH2caH8sTw4PMOH86yeEAajPFO8XCOFIcRjQzn6P1Bcr3cVk_YSlhuOcYBmBjtFheEVeDBAyvn6sV2Tz5fPm-mt1-_3m2_Wn28q2XM2VAml1pywTitlGNI2Vre1tw9bKMYGOS42D5EKuu14r6xq9bhTrOUdtFaybK_LxHLtb-hGdLQsnCGaX_AjpaCJ4829n8j_MXdybrlOdEKeAd48BKd4vmGcz-mwxhLJ9XLIRQgrernXbFCk_S22KOSccnsZwZk7gzNYUcOYEzjBpCrjiefv3_54cf0gVwYezAMuR9h6TybZgs-h8Knc2Lvr_xP8GadKtEw</recordid><startdate>20190801</startdate><enddate>20190801</enddate><creator>Grottke, Oliver</creator><creator>Braunschweig, Till</creator><creator>Rossaint, Rolf</creator><creator>Akman, Necib</creator><creator>Leeds, Janet M.</creator><creator>Conley, Pamela B.</creator><creator>Honickel, Markus</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190801</creationdate><title>Transient or extended reversal of apixaban anticoagulation by andexanet alfa is equally effective in a porcine polytrauma model</title><author>Grottke, Oliver ; Braunschweig, Till ; Rossaint, Rolf ; Akman, Necib ; Leeds, Janet M. ; Conley, Pamela B. ; Honickel, Markus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c517t-7a4c967c0270c3233c45cbc3087d02ed149ef412486b97cd398370b11e9c7a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>andexanet alfa</topic><topic>Animals</topic><topic>anticoagulants</topic><topic>Anticoagulants - pharmacology</topic><topic>antidotes</topic><topic>apixaban</topic><topic>Blood Coagulation - drug effects</topic><topic>coagulation</topic><topic>Critical Care</topic><topic>Disease Models, Animal</topic><topic>Factor Xa - pharmacology</topic><topic>Factor Xa Inhibitors - pharmacology</topic><topic>haemorrhage</topic><topic>Male</topic><topic>Multiple Trauma</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridones - pharmacology</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Swine</topic><topic>trauma</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grottke, Oliver</creatorcontrib><creatorcontrib>Braunschweig, Till</creatorcontrib><creatorcontrib>Rossaint, Rolf</creatorcontrib><creatorcontrib>Akman, Necib</creatorcontrib><creatorcontrib>Leeds, Janet M.</creatorcontrib><creatorcontrib>Conley, Pamela B.</creatorcontrib><creatorcontrib>Honickel, Markus</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of anaesthesia : BJA</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grottke, Oliver</au><au>Braunschweig, Till</au><au>Rossaint, Rolf</au><au>Akman, Necib</au><au>Leeds, Janet M.</au><au>Conley, Pamela B.</au><au>Honickel, Markus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transient or extended reversal of apixaban anticoagulation by andexanet alfa is equally effective in a porcine polytrauma model</atitle><jtitle>British journal of anaesthesia : BJA</jtitle><addtitle>Br J Anaesth</addtitle><date>2019-08-01</date><risdate>2019</risdate><volume>123</volume><issue>2</issue><spage>186</spage><epage>195</epage><pages>186-195</pages><issn>0007-0912</issn><eissn>1471-6771</eissn><abstract>Andexanet alfa (andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated andexanet for reversing apixaban anticoagulation in a porcine polytrauma model.
Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss.
Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P<0.01]. Controls exhibited total blood loss of 3403 (766) ml, with 100% mortality. Andexanet bolus or bolus plus infusion significantly reduced blood loss to 1264 (205) and 1202 (95) ml, respectively), and increased survival to 100%. Haemodynamic parameters and markers of shock recovered to pre-trauma levels in andexanet-treated animals.
Andexanet effectively reversed apixaban anticoagulation and reduced blood loss induced by severe trauma. Andexanet bolus alone had a similar impact on survival and blood loss as bolus plus infusion. Therefore, a 2 h andexanet infusion after the bolus may not be necessary to restore normal haemostatic mechanisms.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31202564</pmid><doi>10.1016/j.bja.2019.04.059</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | andexanet alfa Animals anticoagulants Anticoagulants - pharmacology antidotes apixaban Blood Coagulation - drug effects coagulation Critical Care Disease Models, Animal Factor Xa - pharmacology Factor Xa Inhibitors - pharmacology haemorrhage Male Multiple Trauma Pyrazoles - pharmacology Pyridones - pharmacology Recombinant Proteins - pharmacology Swine trauma |
| title | Transient or extended reversal of apixaban anticoagulation by andexanet alfa is equally effective in a porcine polytrauma model |
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