Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis
Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which...
Gespeichert in:
| Veröffentlicht in: | PLoS medicine 2020-12, Vol.17 (12), p.e1003501 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | 12 |
| container_start_page | e1003501 |
| container_title | PLoS medicine |
| container_volume | 17 |
| creator | Kim, Min Seo An, Min Ho Kim, Won Jun Hwang, Tae-Ho |
| description | Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.
We carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), |
| doi_str_mv | 10.1371/journal.pmed.1003501 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_2490317583</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A651487834</galeid><doaj_id>oai_doaj_org_article_6db44eafea334641836c2bdca5ddba69</doaj_id><sourcerecordid>A651487834</sourcerecordid><originalsourceid>FETCH-LOGICAL-c830t-6e0c8303ed3fa8b4d3b7a23b1041b87b89e447a2d2ea9296a390f81cf70c392f3</originalsourceid><addsrcrecordid>eNqVk1tv0zAUxyMEYmPwDRBYQkLwkGLHbhLvAWkqt0oTk7js1TpxTlqPJC6229EPwXfGWbupRX0A5SHW8e_8z80nSZ4yOmK8YG-u7NL10I4WHdYjRikfU3YvOWZjIVOWF_n9nfNR8sj7K0ozSSV9mBxxzouSj4vj5PfEdgtwEMwKCTaN0aDXBPqaeGgwrIltyGIOrgNtWzuL1y0xfUC3wj4Y23vSWEfCHElwCKGL1sFlcnE5fZcyeUrOiF_7gF2MoInDlcHrG_kew7V1P0iHAVKIhay98Y-TBw20Hp9s_yfJ9w_vv00-pecXH6eTs_NUl5yGNEc6HDjWvIGyEjWvCsh4xahgVVlUpUQhoqXOEGQmc-CSNiXTTUE1l1nDT5LnG91Fa73adtKrTEjKWTEueSSmG6K2cKUWznTg1sqCUTcG62YKXCypRZXXlRAYuwWci1ywkuc6q2oN47quIJdR6-022rKKw9KxRw7aPdH9m97M1cyuVFFIQXkRBV5tBZz9uUQfVGe8xraFHu1yyLsQQpa5GPJ-8Rd6uLotNYNYgOkbG-PqQVSd5WMmyvg6RKTSA9QMe4xJ2h4bE817_OgAH78aO6MPOrzec4hMwF9hBkvv1fTrl_9gP_87e3G5z77cYecIbZh72y5vHvc-KDagdtZ7h83dABlVw0bedloNG6m2Gxndnu0O_87pdgX5H9UBMXc</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2490317583</pqid></control><display><type>article</type><title>Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Public Library of Science (PLoS) Journals Open Access</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Kim, Min Seo ; An, Min Ho ; Kim, Won Jun ; Hwang, Tae-Ho</creator><contributor>Kretzschmar, Mirjam E. E.</contributor><creatorcontrib>Kim, Min Seo ; An, Min Ho ; Kim, Won Jun ; Hwang, Tae-Ho ; Kretzschmar, Mirjam E. E.</creatorcontrib><description>Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.
We carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), itolizumab (OR 0.10, 95% CI 0.01 to 0.92, p = 0.042), sofosbuvir plus daclatasvir (OR 0.26, 95% CI 0.07 to 0.88, p = 0.030), anakinra (OR 0.30, 95% CI 0.11 to 0.82, p = 0.019), tocilizumab (OR 0.43, 95% CI 0.30 to 0.60, p < 0.001), and convalescent plasma (OR 0.48, 95% CI 0.24 to 0.96, p = 0.038) were associated with reduced mortality rate in non-ICU setting, while high-dose intravenous immunoglobulin (IVIG) (OR 0.13, 95% CI 0.03 to 0.49, p = 0.003), ivermectin (OR 0.15, 95% CI 0.04 to 0.57, p = 0.005), and tocilizumab (OR 0.62, 95% CI 0.42 to 0.90, p = 0.012) were associated with reduced mortality rate in critically ill patients. Convalescent plasma was the only treatment option that was associated with improved viral clearance rate at 2 weeks compared to standard care (OR 11.39, 95% CI 3.91 to 33.18, p < 0.001). The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal cardiac complications in cardiac-impaired populations (OR 2.23, 95% CI 1.24 to 4.00, p = 0.007). No drug was significantly associated with increased noncardiac serious adverse events compared to standard care. The quality of evidence of collective outcomes were estimated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The major limitation of the present study is the overall low level of evidence that reduces the certainty of recommendations. Besides, the risk of bias (RoB) measured by RoB2 and ROBINS-I framework for individual studies was generally low to moderate. The outcomes deducted from observational studies could not infer causality and can only imply associations. The study protocol is publicly available on PROSPERO (CRD42020186527).
In this NMA, we found that anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and IVIG), convalescent plasma, and remdesivir were associated with improved outcomes of hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin, especially in the vulnerable population. Only 29% of current evidence on pharmacological management of COVID-19 is supported by moderate or high certainty and can be translated to practice and policy; the remaining 71% are of low or very low certainty and warrant further studies to establish firm conclusions.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1003501</identifier><identifier>PMID: 33378357</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine Monophosphate - adverse effects ; Adenosine Monophosphate - analogs & derivatives ; Adenosine Monophosphate - therapeutic use ; Adverse events ; Alanine - adverse effects ; Alanine - analogs & derivatives ; Alanine - therapeutic use ; Anti-Inflammatory Agents - adverse effects ; Anti-Inflammatory Agents - therapeutic use ; Azithromycin - adverse effects ; Azithromycin - therapeutic use ; Bias ; Biology and Life Sciences ; Clinical trials ; Comparative analysis ; Coronaviruses ; COVID-19 ; COVID-19 - mortality ; COVID-19 - therapy ; COVID-19 Drug Treatment ; COVID-19 Serotherapy ; Critical Illness ; Drug discovery ; Heart rate ; Hospitalization ; Humans ; Hydroxychloroquine - adverse effects ; Hydroxychloroquine - therapeutic use ; Immunization, Passive ; Intensive care ; Maximum likelihood method ; Mechanical ventilation ; Medicine and Health Sciences ; Meta-analysis ; Mortality ; Network Meta-Analysis ; Observational studies ; Observational Studies as Topic ; Patients ; Physical Sciences ; Randomized Controlled Trials as Topic ; Research and Analysis Methods ; Safety and security measures ; Treatment outcome ; Ventilation ; Ventilators</subject><ispartof>PLoS medicine, 2020-12, Vol.17 (12), p.e1003501</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Kim et al 2020 Kim et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c830t-6e0c8303ed3fa8b4d3b7a23b1041b87b89e447a2d2ea9296a390f81cf70c392f3</citedby><cites>FETCH-LOGICAL-c830t-6e0c8303ed3fa8b4d3b7a23b1041b87b89e447a2d2ea9296a390f81cf70c392f3</cites><orcidid>0000-0003-2115-7835 ; 0000-0003-2773-9756</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794037/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794037/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33378357$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kretzschmar, Mirjam E. E.</contributor><creatorcontrib>Kim, Min Seo</creatorcontrib><creatorcontrib>An, Min Ho</creatorcontrib><creatorcontrib>Kim, Won Jun</creatorcontrib><creatorcontrib>Hwang, Tae-Ho</creatorcontrib><title>Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.
We carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), itolizumab (OR 0.10, 95% CI 0.01 to 0.92, p = 0.042), sofosbuvir plus daclatasvir (OR 0.26, 95% CI 0.07 to 0.88, p = 0.030), anakinra (OR 0.30, 95% CI 0.11 to 0.82, p = 0.019), tocilizumab (OR 0.43, 95% CI 0.30 to 0.60, p < 0.001), and convalescent plasma (OR 0.48, 95% CI 0.24 to 0.96, p = 0.038) were associated with reduced mortality rate in non-ICU setting, while high-dose intravenous immunoglobulin (IVIG) (OR 0.13, 95% CI 0.03 to 0.49, p = 0.003), ivermectin (OR 0.15, 95% CI 0.04 to 0.57, p = 0.005), and tocilizumab (OR 0.62, 95% CI 0.42 to 0.90, p = 0.012) were associated with reduced mortality rate in critically ill patients. Convalescent plasma was the only treatment option that was associated with improved viral clearance rate at 2 weeks compared to standard care (OR 11.39, 95% CI 3.91 to 33.18, p < 0.001). The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal cardiac complications in cardiac-impaired populations (OR 2.23, 95% CI 1.24 to 4.00, p = 0.007). No drug was significantly associated with increased noncardiac serious adverse events compared to standard care. The quality of evidence of collective outcomes were estimated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The major limitation of the present study is the overall low level of evidence that reduces the certainty of recommendations. Besides, the risk of bias (RoB) measured by RoB2 and ROBINS-I framework for individual studies was generally low to moderate. The outcomes deducted from observational studies could not infer causality and can only imply associations. The study protocol is publicly available on PROSPERO (CRD42020186527).
In this NMA, we found that anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and IVIG), convalescent plasma, and remdesivir were associated with improved outcomes of hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin, especially in the vulnerable population. Only 29% of current evidence on pharmacological management of COVID-19 is supported by moderate or high certainty and can be translated to practice and policy; the remaining 71% are of low or very low certainty and warrant further studies to establish firm conclusions.</description><subject>Adenosine Monophosphate - adverse effects</subject><subject>Adenosine Monophosphate - analogs & derivatives</subject><subject>Adenosine Monophosphate - therapeutic use</subject><subject>Adverse events</subject><subject>Alanine - adverse effects</subject><subject>Alanine - analogs & derivatives</subject><subject>Alanine - therapeutic use</subject><subject>Anti-Inflammatory Agents - adverse effects</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Azithromycin - adverse effects</subject><subject>Azithromycin - therapeutic use</subject><subject>Bias</subject><subject>Biology and Life Sciences</subject><subject>Clinical trials</subject><subject>Comparative analysis</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>COVID-19 - mortality</subject><subject>COVID-19 - therapy</subject><subject>COVID-19 Drug Treatment</subject><subject>COVID-19 Serotherapy</subject><subject>Critical Illness</subject><subject>Drug discovery</subject><subject>Heart rate</subject><subject>Hospitalization</subject><subject>Humans</subject><subject>Hydroxychloroquine - adverse effects</subject><subject>Hydroxychloroquine - therapeutic use</subject><subject>Immunization, Passive</subject><subject>Intensive care</subject><subject>Maximum likelihood method</subject><subject>Mechanical ventilation</subject><subject>Medicine and Health Sciences</subject><subject>Meta-analysis</subject><subject>Mortality</subject><subject>Network Meta-Analysis</subject><subject>Observational studies</subject><subject>Observational Studies as Topic</subject><subject>Patients</subject><subject>Physical Sciences</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Research and Analysis Methods</subject><subject>Safety and security measures</subject><subject>Treatment outcome</subject><subject>Ventilation</subject><subject>Ventilators</subject><issn>1549-1676</issn><issn>1549-1277</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqVk1tv0zAUxyMEYmPwDRBYQkLwkGLHbhLvAWkqt0oTk7js1TpxTlqPJC6229EPwXfGWbupRX0A5SHW8e_8z80nSZ4yOmK8YG-u7NL10I4WHdYjRikfU3YvOWZjIVOWF_n9nfNR8sj7K0ozSSV9mBxxzouSj4vj5PfEdgtwEMwKCTaN0aDXBPqaeGgwrIltyGIOrgNtWzuL1y0xfUC3wj4Y23vSWEfCHElwCKGL1sFlcnE5fZcyeUrOiF_7gF2MoInDlcHrG_kew7V1P0iHAVKIhay98Y-TBw20Hp9s_yfJ9w_vv00-pecXH6eTs_NUl5yGNEc6HDjWvIGyEjWvCsh4xahgVVlUpUQhoqXOEGQmc-CSNiXTTUE1l1nDT5LnG91Fa73adtKrTEjKWTEueSSmG6K2cKUWznTg1sqCUTcG62YKXCypRZXXlRAYuwWci1ywkuc6q2oN47quIJdR6-022rKKw9KxRw7aPdH9m97M1cyuVFFIQXkRBV5tBZz9uUQfVGe8xraFHu1yyLsQQpa5GPJ-8Rd6uLotNYNYgOkbG-PqQVSd5WMmyvg6RKTSA9QMe4xJ2h4bE817_OgAH78aO6MPOrzec4hMwF9hBkvv1fTrl_9gP_87e3G5z77cYecIbZh72y5vHvc-KDagdtZ7h83dABlVw0bedloNG6m2Gxndnu0O_87pdgX5H9UBMXc</recordid><startdate>20201230</startdate><enddate>20201230</enddate><creator>Kim, Min Seo</creator><creator>An, Min Ho</creator><creator>Kim, Won Jun</creator><creator>Hwang, Tae-Ho</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>COVID</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZK</scope><orcidid>https://orcid.org/0000-0003-2115-7835</orcidid><orcidid>https://orcid.org/0000-0003-2773-9756</orcidid></search><sort><creationdate>20201230</creationdate><title>Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis</title><author>Kim, Min Seo ; An, Min Ho ; Kim, Won Jun ; Hwang, Tae-Ho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c830t-6e0c8303ed3fa8b4d3b7a23b1041b87b89e447a2d2ea9296a390f81cf70c392f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenosine Monophosphate - adverse effects</topic><topic>Adenosine Monophosphate - analogs & derivatives</topic><topic>Adenosine Monophosphate - therapeutic use</topic><topic>Adverse events</topic><topic>Alanine - adverse effects</topic><topic>Alanine - analogs & derivatives</topic><topic>Alanine - therapeutic use</topic><topic>Anti-Inflammatory Agents - adverse effects</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Azithromycin - adverse effects</topic><topic>Azithromycin - therapeutic use</topic><topic>Bias</topic><topic>Biology and Life Sciences</topic><topic>Clinical trials</topic><topic>Comparative analysis</topic><topic>Coronaviruses</topic><topic>COVID-19</topic><topic>COVID-19 - mortality</topic><topic>COVID-19 - therapy</topic><topic>COVID-19 Drug Treatment</topic><topic>COVID-19 Serotherapy</topic><topic>Critical Illness</topic><topic>Drug discovery</topic><topic>Heart rate</topic><topic>Hospitalization</topic><topic>Humans</topic><topic>Hydroxychloroquine - adverse effects</topic><topic>Hydroxychloroquine - therapeutic use</topic><topic>Immunization, Passive</topic><topic>Intensive care</topic><topic>Maximum likelihood method</topic><topic>Mechanical ventilation</topic><topic>Medicine and Health Sciences</topic><topic>Meta-analysis</topic><topic>Mortality</topic><topic>Network Meta-Analysis</topic><topic>Observational studies</topic><topic>Observational Studies as Topic</topic><topic>Patients</topic><topic>Physical Sciences</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Research and Analysis Methods</topic><topic>Safety and security measures</topic><topic>Treatment outcome</topic><topic>Ventilation</topic><topic>Ventilators</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Min Seo</creatorcontrib><creatorcontrib>An, Min Ho</creatorcontrib><creatorcontrib>Kim, Won Jun</creatorcontrib><creatorcontrib>Hwang, Tae-Ho</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Coronavirus Research Database</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Medicine</collection><jtitle>PLoS medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Min Seo</au><au>An, Min Ho</au><au>Kim, Won Jun</au><au>Hwang, Tae-Ho</au><au>Kretzschmar, Mirjam E. E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2020-12-30</date><risdate>2020</risdate><volume>17</volume><issue>12</issue><spage>e1003501</spage><pages>e1003501-</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective.
We carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), itolizumab (OR 0.10, 95% CI 0.01 to 0.92, p = 0.042), sofosbuvir plus daclatasvir (OR 0.26, 95% CI 0.07 to 0.88, p = 0.030), anakinra (OR 0.30, 95% CI 0.11 to 0.82, p = 0.019), tocilizumab (OR 0.43, 95% CI 0.30 to 0.60, p < 0.001), and convalescent plasma (OR 0.48, 95% CI 0.24 to 0.96, p = 0.038) were associated with reduced mortality rate in non-ICU setting, while high-dose intravenous immunoglobulin (IVIG) (OR 0.13, 95% CI 0.03 to 0.49, p = 0.003), ivermectin (OR 0.15, 95% CI 0.04 to 0.57, p = 0.005), and tocilizumab (OR 0.62, 95% CI 0.42 to 0.90, p = 0.012) were associated with reduced mortality rate in critically ill patients. Convalescent plasma was the only treatment option that was associated with improved viral clearance rate at 2 weeks compared to standard care (OR 11.39, 95% CI 3.91 to 33.18, p < 0.001). The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal cardiac complications in cardiac-impaired populations (OR 2.23, 95% CI 1.24 to 4.00, p = 0.007). No drug was significantly associated with increased noncardiac serious adverse events compared to standard care. The quality of evidence of collective outcomes were estimated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The major limitation of the present study is the overall low level of evidence that reduces the certainty of recommendations. Besides, the risk of bias (RoB) measured by RoB2 and ROBINS-I framework for individual studies was generally low to moderate. The outcomes deducted from observational studies could not infer causality and can only imply associations. The study protocol is publicly available on PROSPERO (CRD42020186527).
In this NMA, we found that anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and IVIG), convalescent plasma, and remdesivir were associated with improved outcomes of hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin, especially in the vulnerable population. Only 29% of current evidence on pharmacological management of COVID-19 is supported by moderate or high certainty and can be translated to practice and policy; the remaining 71% are of low or very low certainty and warrant further studies to establish firm conclusions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33378357</pmid><doi>10.1371/journal.pmed.1003501</doi><orcidid>https://orcid.org/0000-0003-2115-7835</orcidid><orcidid>https://orcid.org/0000-0003-2773-9756</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1676 |
| ispartof | PLoS medicine, 2020-12, Vol.17 (12), p.e1003501 |
| issn | 1549-1676 1549-1277 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_2490317583 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adenosine Monophosphate - adverse effects Adenosine Monophosphate - analogs & derivatives Adenosine Monophosphate - therapeutic use Adverse events Alanine - adverse effects Alanine - analogs & derivatives Alanine - therapeutic use Anti-Inflammatory Agents - adverse effects Anti-Inflammatory Agents - therapeutic use Azithromycin - adverse effects Azithromycin - therapeutic use Bias Biology and Life Sciences Clinical trials Comparative analysis Coronaviruses COVID-19 COVID-19 - mortality COVID-19 - therapy COVID-19 Drug Treatment COVID-19 Serotherapy Critical Illness Drug discovery Heart rate Hospitalization Humans Hydroxychloroquine - adverse effects Hydroxychloroquine - therapeutic use Immunization, Passive Intensive care Maximum likelihood method Mechanical ventilation Medicine and Health Sciences Meta-analysis Mortality Network Meta-Analysis Observational studies Observational Studies as Topic Patients Physical Sciences Randomized Controlled Trials as Topic Research and Analysis Methods Safety and security measures Treatment outcome Ventilation Ventilators |
| title | Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T18%3A52%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Comparative%20efficacy%20and%20safety%20of%20pharmacological%20interventions%20for%20the%20treatment%20of%20COVID-19:%20A%20systematic%20review%20and%20network%20meta-analysis&rft.jtitle=PLoS%20medicine&rft.au=Kim,%20Min%20Seo&rft.date=2020-12-30&rft.volume=17&rft.issue=12&rft.spage=e1003501&rft.pages=e1003501-&rft.issn=1549-1676&rft.eissn=1549-1676&rft_id=info:doi/10.1371/journal.pmed.1003501&rft_dat=%3Cgale_plos_%3EA651487834%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2490317583&rft_id=info:pmid/33378357&rft_galeid=A651487834&rft_doaj_id=oai_doaj_org_article_6db44eafea334641836c2bdca5ddba69&rfr_iscdi=true |