Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death
Aims Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. Methods and results...
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| Veröffentlicht in: | European heart journal 2005-03, Vol.26 (6), p.590-597 |
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| creator | De Bruin, M.L. Pettersson, M. Meyboom, R.H.B. Hoes, A.W. Leufkens, H.G.M. |
| description | Aims Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n=5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89–1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines. |
| doi_str_mv | 10.1093/eurheartj/ehi092 |
| format | Article |
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We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n=5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89–1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.</description><identifier>ISSN: 0195-668X</identifier><identifier>EISSN: 1522-9645</identifier><identifier>DOI: 10.1093/eurheartj/ehi092</identifier><identifier>PMID: 15637086</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Adverse Drug Reaction Reporting Systems ; Aged ; Anti-Arrhythmia Agents - therapeutic use ; Arrhythmia ; Arrhythmias, Cardiac - chemically induced ; Biological and medical sciences ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Databases, Factual ; Death, Sudden - etiology ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; Female ; Gender Identity ; Heart ; Heart Ventricles ; Humans ; Long QT Syndrome - chemically induced ; Male ; Medical sciences ; Middle Aged ; Odds Ratio ; Potassium Channel Blockers - adverse effects ; Potassium Channel Blockers - blood ; Potassium Channel Blockers - therapeutic use ; Potassium channels ; Potassium Channels, Voltage-Gated - antagonists & inhibitors ; Pre-clinical drug evaluation ; Risk ; Sudden death ; Torsades de pointes ; World Health Organization</subject><ispartof>European heart journal, 2005-03, Vol.26 (6), p.590-597</ispartof><rights>2005 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Mar 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-58376332500b586cdac3220b8b7fd244c6a0771a9a8b1f200480c91f1f3ee6913</citedby><cites>FETCH-LOGICAL-c500t-58376332500b586cdac3220b8b7fd244c6a0771a9a8b1f200480c91f1f3ee6913</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16606908$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15637086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De Bruin, M.L.</creatorcontrib><creatorcontrib>Pettersson, M.</creatorcontrib><creatorcontrib>Meyboom, R.H.B.</creatorcontrib><creatorcontrib>Hoes, A.W.</creatorcontrib><creatorcontrib>Leufkens, H.G.M.</creatorcontrib><title>Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death</title><title>European heart journal</title><addtitle>Eur Heart J</addtitle><description>Aims Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n=5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89–1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.</description><subject>Adverse Drug Reaction Reporting Systems</subject><subject>Aged</subject><subject>Anti-Arrhythmia Agents - therapeutic use</subject><subject>Arrhythmia</subject><subject>Arrhythmias, Cardiac - chemically induced</subject><subject>Biological and medical sciences</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Databases, Factual</subject><subject>Death, Sudden - etiology</subject><subject>ERG1 Potassium Channel</subject><subject>Ether-A-Go-Go Potassium Channels</subject><subject>Female</subject><subject>Gender Identity</subject><subject>Heart</subject><subject>Heart Ventricles</subject><subject>Humans</subject><subject>Long QT Syndrome - chemically induced</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Odds Ratio</subject><subject>Potassium Channel Blockers - adverse effects</subject><subject>Potassium Channel Blockers - blood</subject><subject>Potassium Channel Blockers - therapeutic use</subject><subject>Potassium channels</subject><subject>Potassium Channels, Voltage-Gated - antagonists & inhibitors</subject><subject>Pre-clinical drug evaluation</subject><subject>Risk</subject><subject>Sudden death</subject><subject>Torsades de pointes</subject><subject>World Health Organization</subject><issn>0195-668X</issn><issn>1522-9645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEFLAzEQhYMotlbvnmQRPK5Okk02OUqprVBQREG8hGySdVPtVpOs2H_vaks9DY_53hvmIXSK4RKDpFeuC43TIS2uXONBkj00xIyQXPKC7aMhYMlyzsXzAB3FuAAAwTE_RAPMOC17MUTz6zb5fDZ5mGbaJP_l0zrTrc1S47Lg41u2qjMbutfct7YzzmY6hGadmqXX8Q-MnbWuzazTqTlGB7V-j-5kO0fo6WbyOJ7l87vp7fh6nhsGkHImaMkpJb2omODGakMJgUpUZW1JURiuoSyxllpUuCYAhQAjcY1r6hyXmI7Q-Sb3I6w-OxeTWqy60PYnFcGs6J8sfiHYQCasYgyuVh_BL3VYKwzqtz21a09t2ustZ9vcrlo6-2_Y1tUDF1tAR6Pf66Bb4-M_xzlwCaLn8g3nY3Lfu70Ob4qXtGRq9vyigNCHezEGJekPlYuIiQ</recordid><startdate>20050301</startdate><enddate>20050301</enddate><creator>De Bruin, M.L.</creator><creator>Pettersson, M.</creator><creator>Meyboom, R.H.B.</creator><creator>Hoes, A.W.</creator><creator>Leufkens, H.G.M.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><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>7QP</scope><scope>K9.</scope></search><sort><creationdate>20050301</creationdate><title>Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death</title><author>De Bruin, M.L. ; Pettersson, M. ; Meyboom, R.H.B. ; Hoes, A.W. ; Leufkens, H.G.M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-58376332500b586cdac3220b8b7fd244c6a0771a9a8b1f200480c91f1f3ee6913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adverse Drug Reaction Reporting Systems</topic><topic>Aged</topic><topic>Anti-Arrhythmia Agents - therapeutic use</topic><topic>Arrhythmia</topic><topic>Arrhythmias, Cardiac - chemically induced</topic><topic>Biological and medical sciences</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Databases, Factual</topic><topic>Death, Sudden - etiology</topic><topic>ERG1 Potassium Channel</topic><topic>Ether-A-Go-Go Potassium Channels</topic><topic>Female</topic><topic>Gender Identity</topic><topic>Heart</topic><topic>Heart Ventricles</topic><topic>Humans</topic><topic>Long QT Syndrome - chemically induced</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Odds Ratio</topic><topic>Potassium Channel Blockers - adverse effects</topic><topic>Potassium Channel Blockers - blood</topic><topic>Potassium Channel Blockers - therapeutic use</topic><topic>Potassium channels</topic><topic>Potassium Channels, Voltage-Gated - antagonists & inhibitors</topic><topic>Pre-clinical drug evaluation</topic><topic>Risk</topic><topic>Sudden death</topic><topic>Torsades de pointes</topic><topic>World Health Organization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Bruin, M.L.</creatorcontrib><creatorcontrib>Pettersson, M.</creatorcontrib><creatorcontrib>Meyboom, R.H.B.</creatorcontrib><creatorcontrib>Hoes, A.W.</creatorcontrib><creatorcontrib>Leufkens, H.G.M.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>European heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Bruin, M.L.</au><au>Pettersson, M.</au><au>Meyboom, R.H.B.</au><au>Hoes, A.W.</au><au>Leufkens, H.G.M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death</atitle><jtitle>European heart journal</jtitle><addtitle>Eur Heart J</addtitle><date>2005-03-01</date><risdate>2005</risdate><volume>26</volume><issue>6</issue><spage>590</spage><epage>597</epage><pages>590-597</pages><issn>0195-668X</issn><eissn>1522-9645</eissn><abstract>Aims Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n=5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89–1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>15637086</pmid><doi>10.1093/eurheartj/ehi092</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adverse Drug Reaction Reporting Systems Aged Anti-Arrhythmia Agents - therapeutic use Arrhythmia Arrhythmias, Cardiac - chemically induced Biological and medical sciences Cardiac dysrhythmias Cardiology. Vascular system Databases, Factual Death, Sudden - etiology ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Female Gender Identity Heart Heart Ventricles Humans Long QT Syndrome - chemically induced Male Medical sciences Middle Aged Odds Ratio Potassium Channel Blockers - adverse effects Potassium Channel Blockers - blood Potassium Channel Blockers - therapeutic use Potassium channels Potassium Channels, Voltage-Gated - antagonists & inhibitors Pre-clinical drug evaluation Risk Sudden death Torsades de pointes World Health Organization |
| title | Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death |
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