Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial
IMPORTANCE: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. OBJECTIVE: To assess whether anticoagulant or antiplatelet therapy can safely reduce major advers...
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Veröffentlicht in: | JAMA : the journal of the American Medical Association 2021-11, Vol.326 (17), p.1703-1712 |
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creator | Connors, Jean M Brooks, Maria M Sciurba, Frank C Krishnan, Jerry A Bledsoe, Joseph R Kindzelski, Andrei Baucom, Amanda L Kirwan, Bridget-Anne Eng, Heather Martin, Deborah Zaharris, Elaine Everett, Brendan Castro, Lauren Shapiro, Nancy L Lin, Janet Y Hou, Peter C Pepine, Carl J Handberg, Eileen Haight, Daniel O Wilson, Jason W Majercik, Sarah Fu, Zhuxuan Zhong, Yongqi Venugopal, Vidya Beach, Scott Wisniewski, Steve Ridker, Paul M |
description | IMPORTANCE: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. OBJECTIVE: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. INTERVENTIONS: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. RESULTS: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calcu |
doi_str_mv | 10.1001/jama.2021.17272 |
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OBJECTIVE: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. INTERVENTIONS: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. RESULTS: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, –2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, –1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, –2.7% to 6.8%), 4.5% (95% CI, –0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. CONCLUSIONS AND RELEVANCE: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273</description><identifier>ISSN: 0098-7484</identifier><identifier>EISSN: 1538-3598</identifier><identifier>DOI: 10.1001/jama.2021.17272</identifier><identifier>PMID: 34633405</identifier><language>eng</language><publisher>United States: American Medical Association</publisher><subject>Adult ; Anticoagulants ; Antiplatelet therapy ; Aspirin ; Aspirin - adverse effects ; Aspirin - therapeutic use ; Bleeding ; Cerebral infarction ; Clinical outcomes ; Clinical trials ; Comments ; Coronaviruses ; COVID-19 ; COVID-19 - complications ; COVID-19 Drug Treatment ; Dose-Response Relationship, Drug ; Double-Blind Method ; Double-blind studies ; Early Termination of Clinical Trials ; Factor Xa Inhibitors - administration & dosage ; Factor Xa Inhibitors - adverse effects ; Factor Xa Inhibitors - therapeutic use ; Female ; Glomerular filtration rate ; Hemorrhage - chemically induced ; Hospitalization ; Humans ; Male ; Middle Aged ; Myocardial infarction ; Online First ; Original Investigation ; Patients ; Placebos ; Platelet Aggregation Inhibitors - adverse effects ; Platelet Aggregation Inhibitors - therapeutic use ; Pyrazoles - administration & dosage ; Pyrazoles - adverse effects ; Pyrazoles - therapeutic use ; Pyridones - administration & dosage ; Pyridones - adverse effects ; Pyridones - therapeutic use ; Randomization ; Therapy ; Thromboembolism ; Thrombosis ; Thrombosis - prevention & control</subject><ispartof>JAMA : the journal of the American Medical Association, 2021-11, Vol.326 (17), p.1703-1712</ispartof><rights>Copyright American Medical Association Nov 2, 2021</rights><rights>Copyright 2021 American Medical Association. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a353t-a5ca52e91f593e9fb5e58a790f622ee5cb3f13fbd5d6dcadfbbcc76edea68bc73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jama/articlepdf/10.1001/jama.2021.17272$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2021.17272$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,230,314,776,780,881,3327,27901,27902,76232,76235</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34633405$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Connors, Jean M</creatorcontrib><creatorcontrib>Brooks, Maria M</creatorcontrib><creatorcontrib>Sciurba, Frank C</creatorcontrib><creatorcontrib>Krishnan, Jerry A</creatorcontrib><creatorcontrib>Bledsoe, Joseph R</creatorcontrib><creatorcontrib>Kindzelski, Andrei</creatorcontrib><creatorcontrib>Baucom, Amanda L</creatorcontrib><creatorcontrib>Kirwan, Bridget-Anne</creatorcontrib><creatorcontrib>Eng, Heather</creatorcontrib><creatorcontrib>Martin, Deborah</creatorcontrib><creatorcontrib>Zaharris, Elaine</creatorcontrib><creatorcontrib>Everett, Brendan</creatorcontrib><creatorcontrib>Castro, Lauren</creatorcontrib><creatorcontrib>Shapiro, Nancy L</creatorcontrib><creatorcontrib>Lin, Janet Y</creatorcontrib><creatorcontrib>Hou, Peter C</creatorcontrib><creatorcontrib>Pepine, Carl J</creatorcontrib><creatorcontrib>Handberg, Eileen</creatorcontrib><creatorcontrib>Haight, Daniel O</creatorcontrib><creatorcontrib>Wilson, Jason W</creatorcontrib><creatorcontrib>Majercik, Sarah</creatorcontrib><creatorcontrib>Fu, Zhuxuan</creatorcontrib><creatorcontrib>Zhong, Yongqi</creatorcontrib><creatorcontrib>Venugopal, Vidya</creatorcontrib><creatorcontrib>Beach, Scott</creatorcontrib><creatorcontrib>Wisniewski, Steve</creatorcontrib><creatorcontrib>Ridker, Paul M</creatorcontrib><creatorcontrib>ACTIV-4B Investigators</creatorcontrib><title>Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial</title><title>JAMA : the journal of the American Medical Association</title><addtitle>JAMA</addtitle><description>IMPORTANCE: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. OBJECTIVE: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. INTERVENTIONS: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. RESULTS: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, –2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, –1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, –2.7% to 6.8%), 4.5% (95% CI, –0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. CONCLUSIONS AND RELEVANCE: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273</description><subject>Adult</subject><subject>Anticoagulants</subject><subject>Antiplatelet therapy</subject><subject>Aspirin</subject><subject>Aspirin - adverse effects</subject><subject>Aspirin - therapeutic use</subject><subject>Bleeding</subject><subject>Cerebral infarction</subject><subject>Clinical outcomes</subject><subject>Clinical trials</subject><subject>Comments</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>COVID-19 - complications</subject><subject>COVID-19 Drug Treatment</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Early Termination of Clinical Trials</subject><subject>Factor Xa Inhibitors - administration & dosage</subject><subject>Factor Xa Inhibitors - adverse effects</subject><subject>Factor Xa Inhibitors - therapeutic use</subject><subject>Female</subject><subject>Glomerular filtration rate</subject><subject>Hemorrhage - chemically induced</subject><subject>Hospitalization</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Myocardial infarction</subject><subject>Online First</subject><subject>Original Investigation</subject><subject>Patients</subject><subject>Placebos</subject><subject>Platelet Aggregation Inhibitors - adverse effects</subject><subject>Platelet Aggregation Inhibitors - therapeutic use</subject><subject>Pyrazoles - administration & dosage</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - therapeutic use</subject><subject>Pyridones - administration & dosage</subject><subject>Pyridones - adverse effects</subject><subject>Pyridones - therapeutic use</subject><subject>Randomization</subject><subject>Therapy</subject><subject>Thromboembolism</subject><subject>Thrombosis</subject><subject>Thrombosis - prevention & control</subject><issn>0098-7484</issn><issn>1538-3598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkV9v0zAUxS3ExLrBMxIPyBLP6fwnTmIekEoYW6VJlVgZj9aNY1NXSZw5LlL3Sfi4JHTrwC-2dH_nnGsdhN5SMqeE0IsttDBnhNE5zVnOXqAZFbxIuJDFSzQjRBZJnhbpKTobhi0ZD-X5K3TK04zzlIgZ-n1prdERe4sXXXRxE3xb-eg0Xm9MgH6PfYfLxnVOQ4NXu6h9awbsuundQ3SmiwP-MQqPVLPHtxGqxuDbfdtH38JkV67ull8SKj9OxnhRrpd3SfoZf4Ou9q17MPVzyjo4aF6jEwvNYN483ufo-9fLdXmd3KyuluXiJgEueExAaBDMSGqF5EbaShhRQC6JzRgzRuiKW8ptVYs6qzXUtqq0zjNTG8iKSuf8HH06-Pa7qjW1Hv8ToFF9cC2EvfLg1P-Tzm3UT_9LFYJkTGajwYdHg-Dvd2aIaut3oRt3VkzIEcgJmWIuDpQOfhiCsccEStRUpZqqVFOV6m-Vo-L9v4sd-afuRuDdAZiET1OWF4LRgv8B896mSw</recordid><startdate>20211102</startdate><enddate>20211102</enddate><creator>Connors, Jean M</creator><creator>Brooks, Maria M</creator><creator>Sciurba, Frank C</creator><creator>Krishnan, Jerry A</creator><creator>Bledsoe, Joseph R</creator><creator>Kindzelski, Andrei</creator><creator>Baucom, Amanda L</creator><creator>Kirwan, Bridget-Anne</creator><creator>Eng, Heather</creator><creator>Martin, Deborah</creator><creator>Zaharris, Elaine</creator><creator>Everett, Brendan</creator><creator>Castro, Lauren</creator><creator>Shapiro, Nancy L</creator><creator>Lin, Janet Y</creator><creator>Hou, Peter C</creator><creator>Pepine, Carl J</creator><creator>Handberg, Eileen</creator><creator>Haight, Daniel O</creator><creator>Wilson, Jason W</creator><creator>Majercik, Sarah</creator><creator>Fu, Zhuxuan</creator><creator>Zhong, Yongqi</creator><creator>Venugopal, Vidya</creator><creator>Beach, Scott</creator><creator>Wisniewski, Steve</creator><creator>Ridker, Paul M</creator><general>American Medical Association</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>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TS</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20211102</creationdate><title>Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial</title><author>Connors, Jean M ; Brooks, Maria M ; Sciurba, Frank C ; Krishnan, Jerry A ; Bledsoe, Joseph R ; Kindzelski, Andrei ; Baucom, Amanda L ; Kirwan, Bridget-Anne ; Eng, Heather ; Martin, Deborah ; Zaharris, Elaine ; Everett, Brendan ; Castro, Lauren ; Shapiro, Nancy L ; Lin, Janet Y ; Hou, Peter C ; Pepine, Carl J ; Handberg, Eileen ; Haight, Daniel O ; Wilson, Jason W ; Majercik, Sarah ; Fu, Zhuxuan ; Zhong, Yongqi ; Venugopal, Vidya ; Beach, Scott ; Wisniewski, Steve ; Ridker, Paul M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a353t-a5ca52e91f593e9fb5e58a790f622ee5cb3f13fbd5d6dcadfbbcc76edea68bc73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>Anticoagulants</topic><topic>Antiplatelet therapy</topic><topic>Aspirin</topic><topic>Aspirin - adverse effects</topic><topic>Aspirin - therapeutic use</topic><topic>Bleeding</topic><topic>Cerebral infarction</topic><topic>Clinical outcomes</topic><topic>Clinical trials</topic><topic>Comments</topic><topic>Coronaviruses</topic><topic>COVID-19</topic><topic>COVID-19 - complications</topic><topic>COVID-19 Drug Treatment</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Double-blind studies</topic><topic>Early Termination of Clinical Trials</topic><topic>Factor Xa Inhibitors - administration & dosage</topic><topic>Factor Xa Inhibitors - adverse effects</topic><topic>Factor Xa Inhibitors - therapeutic use</topic><topic>Female</topic><topic>Glomerular filtration rate</topic><topic>Hemorrhage - chemically induced</topic><topic>Hospitalization</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Myocardial infarction</topic><topic>Online First</topic><topic>Original Investigation</topic><topic>Patients</topic><topic>Placebos</topic><topic>Platelet Aggregation Inhibitors - adverse effects</topic><topic>Platelet Aggregation Inhibitors - therapeutic use</topic><topic>Pyrazoles - administration & dosage</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - therapeutic use</topic><topic>Pyridones - administration & dosage</topic><topic>Pyridones - adverse effects</topic><topic>Pyridones - therapeutic use</topic><topic>Randomization</topic><topic>Therapy</topic><topic>Thromboembolism</topic><topic>Thrombosis</topic><topic>Thrombosis - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Connors, Jean M</creatorcontrib><creatorcontrib>Brooks, Maria M</creatorcontrib><creatorcontrib>Sciurba, Frank C</creatorcontrib><creatorcontrib>Krishnan, Jerry A</creatorcontrib><creatorcontrib>Bledsoe, Joseph R</creatorcontrib><creatorcontrib>Kindzelski, Andrei</creatorcontrib><creatorcontrib>Baucom, Amanda L</creatorcontrib><creatorcontrib>Kirwan, Bridget-Anne</creatorcontrib><creatorcontrib>Eng, Heather</creatorcontrib><creatorcontrib>Martin, Deborah</creatorcontrib><creatorcontrib>Zaharris, Elaine</creatorcontrib><creatorcontrib>Everett, Brendan</creatorcontrib><creatorcontrib>Castro, Lauren</creatorcontrib><creatorcontrib>Shapiro, Nancy L</creatorcontrib><creatorcontrib>Lin, Janet Y</creatorcontrib><creatorcontrib>Hou, Peter C</creatorcontrib><creatorcontrib>Pepine, Carl J</creatorcontrib><creatorcontrib>Handberg, Eileen</creatorcontrib><creatorcontrib>Haight, Daniel O</creatorcontrib><creatorcontrib>Wilson, Jason W</creatorcontrib><creatorcontrib>Majercik, Sarah</creatorcontrib><creatorcontrib>Fu, Zhuxuan</creatorcontrib><creatorcontrib>Zhong, Yongqi</creatorcontrib><creatorcontrib>Venugopal, Vidya</creatorcontrib><creatorcontrib>Beach, Scott</creatorcontrib><creatorcontrib>Wisniewski, Steve</creatorcontrib><creatorcontrib>Ridker, Paul M</creatorcontrib><creatorcontrib>ACTIV-4B Investigators</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>JAMA : the journal of the American Medical Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Connors, Jean M</au><au>Brooks, Maria M</au><au>Sciurba, Frank C</au><au>Krishnan, Jerry A</au><au>Bledsoe, Joseph R</au><au>Kindzelski, Andrei</au><au>Baucom, Amanda L</au><au>Kirwan, Bridget-Anne</au><au>Eng, Heather</au><au>Martin, Deborah</au><au>Zaharris, Elaine</au><au>Everett, Brendan</au><au>Castro, Lauren</au><au>Shapiro, Nancy L</au><au>Lin, Janet Y</au><au>Hou, Peter C</au><au>Pepine, Carl J</au><au>Handberg, Eileen</au><au>Haight, Daniel O</au><au>Wilson, Jason W</au><au>Majercik, Sarah</au><au>Fu, Zhuxuan</au><au>Zhong, Yongqi</au><au>Venugopal, Vidya</au><au>Beach, Scott</au><au>Wisniewski, Steve</au><au>Ridker, Paul M</au><aucorp>ACTIV-4B Investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial</atitle><jtitle>JAMA : the journal of the American Medical Association</jtitle><addtitle>JAMA</addtitle><date>2021-11-02</date><risdate>2021</risdate><volume>326</volume><issue>17</issue><spage>1703</spage><epage>1712</epage><pages>1703-1712</pages><issn>0098-7484</issn><eissn>1538-3598</eissn><abstract>IMPORTANCE: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. OBJECTIVE: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. INTERVENTIONS: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. RESULTS: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, –2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, –1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, –2.7% to 6.8%), 4.5% (95% CI, –0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. CONCLUSIONS AND RELEVANCE: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273</abstract><cop>United States</cop><pub>American Medical Association</pub><pmid>34633405</pmid><doi>10.1001/jama.2021.17272</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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identifier | ISSN: 0098-7484 |
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language | eng |
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source | MEDLINE; American Medical Association Journals |
subjects | Adult Anticoagulants Antiplatelet therapy Aspirin Aspirin - adverse effects Aspirin - therapeutic use Bleeding Cerebral infarction Clinical outcomes Clinical trials Comments Coronaviruses COVID-19 COVID-19 - complications COVID-19 Drug Treatment Dose-Response Relationship, Drug Double-Blind Method Double-blind studies Early Termination of Clinical Trials Factor Xa Inhibitors - administration & dosage Factor Xa Inhibitors - adverse effects Factor Xa Inhibitors - therapeutic use Female Glomerular filtration rate Hemorrhage - chemically induced Hospitalization Humans Male Middle Aged Myocardial infarction Online First Original Investigation Patients Placebos Platelet Aggregation Inhibitors - adverse effects Platelet Aggregation Inhibitors - therapeutic use Pyrazoles - administration & dosage Pyrazoles - adverse effects Pyrazoles - therapeutic use Pyridones - administration & dosage Pyridones - adverse effects Pyridones - therapeutic use Randomization Therapy Thromboembolism Thrombosis Thrombosis - prevention & control |
title | Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial |
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