Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data
Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electroca...
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| creator | Chan, Xin Hui S Win, Yan Naung Haeusler, Ilsa L Tan, Jireh Y Loganathan, Shanghavie Saralamba, Sompob Chan, Shu Kiat S Ashley, Elizabeth A Barnes, Karen I Baiden, Rita Bassi, Peter U Djimde, Abdoulaye Dorsey, Grant Duparc, Stephan Hanboonkunupakarn, Borimas Ter Kuile, Feiko O Lacerda, Marcus V G Nasa, Amit Nosten, François H Onyeji, Cyprian O Pukrittayakamee, Sasithon Siqueira, André M Tarning, Joel Taylor, Walter R J Valentini, Giovanni van Vugt, Michèle Wesche, David Day, Nicholas P J Huang, Christopher L-H Brugada, Josep Price, Ric N White, Nicholas J |
| description | Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.
We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.
Adjustment for malaria and fever-recovery-related QT lengthening |
| doi_str_mv | 10.1371/journal.pmed.1003040 |
| format | Article |
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We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.
Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1003040</identifier><identifier>PMID: 32134952</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Action Potentials ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antimalarials - adverse effects ; Arrhythmia ; Arrhythmias, Cardiac - chemically induced ; Arrhythmias, Cardiac - diagnostic imaging ; Arrhythmias, Cardiac - parasitology ; Arrhythmias, Cardiac - physiopathology ; Bayesian analysis ; Biology and Life Sciences ; Body temperature ; Body Temperature Regulation ; Cardiotoxicity ; Child ; Child, Preschool ; Clinical trials ; Electrocardiography ; Female ; Fever ; Funding ; Heart Conduction System - drug effects ; Heart Conduction System - parasitology ; Heart Conduction System - physiopathology ; Heart rate ; Heart Rate - drug effects ; Humans ; Infant ; Malaria ; Malaria - diagnosis ; Malaria - drug therapy ; Malaria - parasitology ; Malaria - physiopathology ; Male ; Mathematical models ; Medicine ; Medicine and Health Sciences ; Meta-analysis ; Middle Aged ; Parasitic diseases ; Patients ; Pharmacy ; Physical Sciences ; Predictive Value of Tests ; Regression analysis ; Research and Analysis Methods ; Risk Assessment ; Risk Factors ; Severity of Illness Index ; Software ; Systematic review ; Treatment Outcome ; Ventricle ; Young Adult</subject><ispartof>PLoS medicine, 2020-03, Vol.17 (3), p.e1003040</ispartof><rights>2020 Chan 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 Chan et al 2020 Chan et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-1873e2ee1dee0cb97ab60e06c4d4f6e022783f006f7316977e82e6c634d4c6283</citedby><cites>FETCH-LOGICAL-c526t-1873e2ee1dee0cb97ab60e06c4d4f6e022783f006f7316977e82e6c634d4c6283</cites><orcidid>0000-0003-4566-4030 ; 0000-0002-7620-4822 ; 0000-0002-9649-4847 ; 0000-0001-8729-1442 ; 0000-0003-3663-5617 ; 0000-0003-2309-1171 ; 0000-0001-9553-6112 ; 0000-0002-9078-5029 ; 0000-0003-2000-2874 ; 0000-0003-0740-0317 ; 0000-0002-2890-447X ; 0000-0003-2208-0294 ; 0000-0003-0062-2283 ; 0000-0002-9941-6975 ; 0000-0002-5547-820X ; 0000-0002-7951-0745 ; 0000-0002-1897-1978</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/PMC7058280/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058280/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32134952$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Beeson, James G.</contributor><creatorcontrib>Chan, Xin Hui S</creatorcontrib><creatorcontrib>Win, Yan Naung</creatorcontrib><creatorcontrib>Haeusler, Ilsa L</creatorcontrib><creatorcontrib>Tan, Jireh Y</creatorcontrib><creatorcontrib>Loganathan, Shanghavie</creatorcontrib><creatorcontrib>Saralamba, Sompob</creatorcontrib><creatorcontrib>Chan, Shu Kiat S</creatorcontrib><creatorcontrib>Ashley, Elizabeth A</creatorcontrib><creatorcontrib>Barnes, Karen I</creatorcontrib><creatorcontrib>Baiden, Rita</creatorcontrib><creatorcontrib>Bassi, Peter U</creatorcontrib><creatorcontrib>Djimde, Abdoulaye</creatorcontrib><creatorcontrib>Dorsey, Grant</creatorcontrib><creatorcontrib>Duparc, Stephan</creatorcontrib><creatorcontrib>Hanboonkunupakarn, Borimas</creatorcontrib><creatorcontrib>Ter Kuile, Feiko O</creatorcontrib><creatorcontrib>Lacerda, Marcus V G</creatorcontrib><creatorcontrib>Nasa, Amit</creatorcontrib><creatorcontrib>Nosten, François H</creatorcontrib><creatorcontrib>Onyeji, Cyprian O</creatorcontrib><creatorcontrib>Pukrittayakamee, Sasithon</creatorcontrib><creatorcontrib>Siqueira, André M</creatorcontrib><creatorcontrib>Tarning, Joel</creatorcontrib><creatorcontrib>Taylor, Walter R J</creatorcontrib><creatorcontrib>Valentini, Giovanni</creatorcontrib><creatorcontrib>van Vugt, Michèle</creatorcontrib><creatorcontrib>Wesche, David</creatorcontrib><creatorcontrib>Day, Nicholas P J</creatorcontrib><creatorcontrib>Huang, Christopher L-H</creatorcontrib><creatorcontrib>Brugada, Josep</creatorcontrib><creatorcontrib>Price, Ric N</creatorcontrib><creatorcontrib>White, Nicholas J</creatorcontrib><title>Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.
We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.
Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.</description><subject>Action Potentials</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antimalarials - adverse effects</subject><subject>Arrhythmia</subject><subject>Arrhythmias, Cardiac - chemically induced</subject><subject>Arrhythmias, Cardiac - diagnostic imaging</subject><subject>Arrhythmias, Cardiac - parasitology</subject><subject>Arrhythmias, Cardiac - physiopathology</subject><subject>Bayesian analysis</subject><subject>Biology and Life Sciences</subject><subject>Body temperature</subject><subject>Body Temperature Regulation</subject><subject>Cardiotoxicity</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Clinical trials</subject><subject>Electrocardiography</subject><subject>Female</subject><subject>Fever</subject><subject>Funding</subject><subject>Heart Conduction System - drug effects</subject><subject>Heart Conduction System - parasitology</subject><subject>Heart Conduction System - physiopathology</subject><subject>Heart rate</subject><subject>Heart Rate - drug effects</subject><subject>Humans</subject><subject>Infant</subject><subject>Malaria</subject><subject>Malaria - diagnosis</subject><subject>Malaria - drug therapy</subject><subject>Malaria - parasitology</subject><subject>Malaria - physiopathology</subject><subject>Male</subject><subject>Mathematical models</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Meta-analysis</subject><subject>Middle Aged</subject><subject>Parasitic diseases</subject><subject>Patients</subject><subject>Pharmacy</subject><subject>Physical Sciences</subject><subject>Predictive Value of Tests</subject><subject>Regression analysis</subject><subject>Research and Analysis Methods</subject><subject>Risk Assessment</subject><subject>Risk Factors</subject><subject>Severity of Illness Index</subject><subject>Software</subject><subject>Systematic review</subject><subject>Treatment Outcome</subject><subject>Ventricle</subject><subject>Young 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affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data</title><author>Chan, Xin Hui S ; Win, Yan Naung ; Haeusler, Ilsa L ; Tan, Jireh Y ; Loganathan, Shanghavie ; Saralamba, Sompob ; Chan, Shu Kiat S ; Ashley, Elizabeth A ; Barnes, Karen I ; Baiden, Rita ; Bassi, Peter U ; Djimde, Abdoulaye ; Dorsey, Grant ; Duparc, Stephan ; Hanboonkunupakarn, Borimas ; Ter Kuile, Feiko O ; Lacerda, Marcus V G ; Nasa, Amit ; Nosten, François H ; Onyeji, Cyprian O ; Pukrittayakamee, Sasithon ; Siqueira, André M ; Tarning, Joel ; Taylor, Walter R J ; Valentini, Giovanni ; van Vugt, Michèle ; Wesche, David ; Day, Nicholas P J ; Huang, Christopher L-H ; Brugada, Josep ; Price, Ric N ; White, Nicholas J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-1873e2ee1dee0cb97ab60e06c4d4f6e022783f006f7316977e82e6c634d4c6283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Action Potentials</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antimalarials - adverse effects</topic><topic>Arrhythmia</topic><topic>Arrhythmias, Cardiac - chemically induced</topic><topic>Arrhythmias, Cardiac - diagnostic imaging</topic><topic>Arrhythmias, Cardiac - parasitology</topic><topic>Arrhythmias, Cardiac - physiopathology</topic><topic>Bayesian analysis</topic><topic>Biology and Life Sciences</topic><topic>Body temperature</topic><topic>Body Temperature Regulation</topic><topic>Cardiotoxicity</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Clinical trials</topic><topic>Electrocardiography</topic><topic>Female</topic><topic>Fever</topic><topic>Funding</topic><topic>Heart Conduction System - drug effects</topic><topic>Heart Conduction System - parasitology</topic><topic>Heart Conduction System - physiopathology</topic><topic>Heart rate</topic><topic>Heart Rate - drug effects</topic><topic>Humans</topic><topic>Infant</topic><topic>Malaria</topic><topic>Malaria - diagnosis</topic><topic>Malaria - drug therapy</topic><topic>Malaria - parasitology</topic><topic>Malaria - physiopathology</topic><topic>Male</topic><topic>Mathematical models</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Meta-analysis</topic><topic>Middle Aged</topic><topic>Parasitic diseases</topic><topic>Patients</topic><topic>Pharmacy</topic><topic>Physical Sciences</topic><topic>Predictive Value of Tests</topic><topic>Regression analysis</topic><topic>Research and Analysis Methods</topic><topic>Risk Assessment</topic><topic>Risk Factors</topic><topic>Severity of Illness Index</topic><topic>Software</topic><topic>Systematic review</topic><topic>Treatment Outcome</topic><topic>Ventricle</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chan, Xin Hui S</creatorcontrib><creatorcontrib>Win, Yan Naung</creatorcontrib><creatorcontrib>Haeusler, Ilsa L</creatorcontrib><creatorcontrib>Tan, Jireh Y</creatorcontrib><creatorcontrib>Loganathan, Shanghavie</creatorcontrib><creatorcontrib>Saralamba, Sompob</creatorcontrib><creatorcontrib>Chan, Shu Kiat S</creatorcontrib><creatorcontrib>Ashley, Elizabeth A</creatorcontrib><creatorcontrib>Barnes, Karen I</creatorcontrib><creatorcontrib>Baiden, Rita</creatorcontrib><creatorcontrib>Bassi, Peter U</creatorcontrib><creatorcontrib>Djimde, Abdoulaye</creatorcontrib><creatorcontrib>Dorsey, Grant</creatorcontrib><creatorcontrib>Duparc, Stephan</creatorcontrib><creatorcontrib>Hanboonkunupakarn, Borimas</creatorcontrib><creatorcontrib>Ter Kuile, Feiko O</creatorcontrib><creatorcontrib>Lacerda, Marcus V G</creatorcontrib><creatorcontrib>Nasa, Amit</creatorcontrib><creatorcontrib>Nosten, François H</creatorcontrib><creatorcontrib>Onyeji, Cyprian O</creatorcontrib><creatorcontrib>Pukrittayakamee, Sasithon</creatorcontrib><creatorcontrib>Siqueira, André M</creatorcontrib><creatorcontrib>Tarning, Joel</creatorcontrib><creatorcontrib>Taylor, Walter R J</creatorcontrib><creatorcontrib>Valentini, Giovanni</creatorcontrib><creatorcontrib>van Vugt, Michèle</creatorcontrib><creatorcontrib>Wesche, David</creatorcontrib><creatorcontrib>Day, Nicholas P J</creatorcontrib><creatorcontrib>Huang, Christopher L-H</creatorcontrib><creatorcontrib>Brugada, Josep</creatorcontrib><creatorcontrib>Price, Ric N</creatorcontrib><creatorcontrib>White, Nicholas J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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>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>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>Chan, Xin Hui S</au><au>Win, Yan Naung</au><au>Haeusler, Ilsa L</au><au>Tan, Jireh Y</au><au>Loganathan, Shanghavie</au><au>Saralamba, Sompob</au><au>Chan, Shu Kiat S</au><au>Ashley, Elizabeth A</au><au>Barnes, Karen I</au><au>Baiden, Rita</au><au>Bassi, Peter U</au><au>Djimde, Abdoulaye</au><au>Dorsey, Grant</au><au>Duparc, Stephan</au><au>Hanboonkunupakarn, Borimas</au><au>Ter Kuile, Feiko O</au><au>Lacerda, Marcus V G</au><au>Nasa, Amit</au><au>Nosten, François H</au><au>Onyeji, Cyprian O</au><au>Pukrittayakamee, Sasithon</au><au>Siqueira, André M</au><au>Tarning, Joel</au><au>Taylor, Walter R J</au><au>Valentini, Giovanni</au><au>van Vugt, Michèle</au><au>Wesche, David</au><au>Day, Nicholas P J</au><au>Huang, Christopher L-H</au><au>Brugada, Josep</au><au>Price, Ric N</au><au>White, Nicholas J</au><au>Beeson, James G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2020-03-01</date><risdate>2020</risdate><volume>17</volume><issue>3</issue><spage>e1003040</spage><pages>e1003040-</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.
We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.
Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32134952</pmid><doi>10.1371/journal.pmed.1003040</doi><orcidid>https://orcid.org/0000-0003-4566-4030</orcidid><orcidid>https://orcid.org/0000-0002-7620-4822</orcidid><orcidid>https://orcid.org/0000-0002-9649-4847</orcidid><orcidid>https://orcid.org/0000-0001-8729-1442</orcidid><orcidid>https://orcid.org/0000-0003-3663-5617</orcidid><orcidid>https://orcid.org/0000-0003-2309-1171</orcidid><orcidid>https://orcid.org/0000-0001-9553-6112</orcidid><orcidid>https://orcid.org/0000-0002-9078-5029</orcidid><orcidid>https://orcid.org/0000-0003-2000-2874</orcidid><orcidid>https://orcid.org/0000-0003-0740-0317</orcidid><orcidid>https://orcid.org/0000-0002-2890-447X</orcidid><orcidid>https://orcid.org/0000-0003-2208-0294</orcidid><orcidid>https://orcid.org/0000-0003-0062-2283</orcidid><orcidid>https://orcid.org/0000-0002-9941-6975</orcidid><orcidid>https://orcid.org/0000-0002-5547-820X</orcidid><orcidid>https://orcid.org/0000-0002-7951-0745</orcidid><orcidid>https://orcid.org/0000-0002-1897-1978</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1676 |
| ispartof | PLoS medicine, 2020-03, Vol.17 (3), p.e1003040 |
| issn | 1549-1676 1549-1277 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_2460795199 |
| 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 | Action Potentials Adolescent Adult Aged Aged, 80 and over Antimalarials - adverse effects Arrhythmia Arrhythmias, Cardiac - chemically induced Arrhythmias, Cardiac - diagnostic imaging Arrhythmias, Cardiac - parasitology Arrhythmias, Cardiac - physiopathology Bayesian analysis Biology and Life Sciences Body temperature Body Temperature Regulation Cardiotoxicity Child Child, Preschool Clinical trials Electrocardiography Female Fever Funding Heart Conduction System - drug effects Heart Conduction System - parasitology Heart Conduction System - physiopathology Heart rate Heart Rate - drug effects Humans Infant Malaria Malaria - diagnosis Malaria - drug therapy Malaria - parasitology Malaria - physiopathology Male Mathematical models Medicine Medicine and Health Sciences Meta-analysis Middle Aged Parasitic diseases Patients Pharmacy Physical Sciences Predictive Value of Tests Regression analysis Research and Analysis Methods Risk Assessment Risk Factors Severity of Illness Index Software Systematic review Treatment Outcome Ventricle Young Adult |
| title | Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data |
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