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
Hauptverfasser: 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
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container_end_page 1712
container_issue 17
container_start_page 1703
container_title JAMA : the journal of the American Medical Association
container_volume 326
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 &amp; 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 &amp; dosage ; Pyrazoles - adverse effects ; Pyrazoles - therapeutic use ; Pyridones - administration &amp; dosage ; Pyridones - adverse effects ; Pyridones - therapeutic use ; Randomization ; Therapy ; Thromboembolism ; Thrombosis ; Thrombosis - prevention &amp; 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 &amp; 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 &amp; dosage</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - therapeutic use</subject><subject>Pyridones - administration &amp; 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 &amp; 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 &amp; 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 &amp; dosage</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - therapeutic use</topic><topic>Pyridones - administration &amp; 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 &amp; 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 &amp; 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 &amp; Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing &amp; 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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issn 0098-7484
1538-3598
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8506296
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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