Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib
The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral p...
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| Veröffentlicht in: | The American heart journal 2020-04, Vol.222, p.157-165 |
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| creator | Tardif, Jean-Claude Dubé, Marie-Pierre Pfeffer, Marc A. Waters, David D. Koenig, Wolfgang Maggioni, Aldo P. McMurray, John J.V. Mooser, Vincent White, Harvey D. Heinonen, Therese Black, Donald M. Guertin, Marie-Claude |
| description | The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene. |
| doi_str_mv | 10.1016/j.ahj.2020.01.007 |
| format | Article |
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In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.</description><identifier>ISSN: 0002-8703</identifier><identifier>EISSN: 1097-6744</identifier><identifier>DOI: 10.1016/j.ahj.2020.01.007</identifier><identifier>PMID: 32087417</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acute coronary syndromes ; Adenylate cyclase ; Adenylyl Cyclases - genetics ; Adenylyl Cyclases - metabolism ; Anticholesteremic Agents - administration & dosage ; Atherosclerosis ; Atherosclerosis - epidemiology ; Atherosclerosis - genetics ; Atherosclerosis - prevention & control ; C-reactive protein ; Cerebral infarction ; Cholesterol ; Cholesteryl ester transfer protein ; Diabetes ; Dose-Response Relationship, Drug ; Double-Blind Method ; Efflux ; Female ; Follow-Up Studies ; Gene polymorphism ; Genetic Testing ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Genotype ; Genotype & phenotype ; Global Health ; Heart failure ; Hospitalization ; Humans ; Hypotheses ; Incidence ; Inflammation ; Laboratories ; Male ; Medicine ; Middle Aged ; Mortality ; Myocardial infarction ; Pharmacogenetics - methods ; Pharmacology ; Polymorphism ; Polymorphism, Genetic ; Precision medicine ; Precision Medicine - methods ; Prognosis ; Prospective Studies ; Proteins ; Retrospective Studies ; Sulfhydryl Compounds - administration & dosage</subject><ispartof>The American heart journal, 2020-04, Vol.222, p.157-165</ispartof><rights>2020 The Author(s)</rights><rights>Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><rights>2020. The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-87059c7bcd09a3835cd91abd642859538422dcdfd458dcd56807e9a7d5b32eef3</citedby><cites>FETCH-LOGICAL-c424t-87059c7bcd09a3835cd91abd642859538422dcdfd458dcd56807e9a7d5b32eef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2417031415?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976,64364,64366,64368,72218</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32087417$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tardif, Jean-Claude</creatorcontrib><creatorcontrib>Dubé, Marie-Pierre</creatorcontrib><creatorcontrib>Pfeffer, Marc A.</creatorcontrib><creatorcontrib>Waters, David D.</creatorcontrib><creatorcontrib>Koenig, Wolfgang</creatorcontrib><creatorcontrib>Maggioni, Aldo P.</creatorcontrib><creatorcontrib>McMurray, John J.V.</creatorcontrib><creatorcontrib>Mooser, Vincent</creatorcontrib><creatorcontrib>White, Harvey D.</creatorcontrib><creatorcontrib>Heinonen, Therese</creatorcontrib><creatorcontrib>Black, Donald M.</creatorcontrib><creatorcontrib>Guertin, Marie-Claude</creatorcontrib><creatorcontrib>for the dal-GenE Investigators</creatorcontrib><creatorcontrib>dal-GenE Investigators</creatorcontrib><title>Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib</title><title>The American heart journal</title><addtitle>Am Heart J</addtitle><description>The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.</description><subject>Acute coronary syndromes</subject><subject>Adenylate cyclase</subject><subject>Adenylyl Cyclases - genetics</subject><subject>Adenylyl Cyclases - metabolism</subject><subject>Anticholesteremic Agents - administration & dosage</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - epidemiology</subject><subject>Atherosclerosis - genetics</subject><subject>Atherosclerosis - prevention & control</subject><subject>C-reactive protein</subject><subject>Cerebral infarction</subject><subject>Cholesterol</subject><subject>Cholesteryl ester transfer protein</subject><subject>Diabetes</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>Efflux</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene polymorphism</subject><subject>Genetic Testing</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Global Health</subject><subject>Heart failure</subject><subject>Hospitalization</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Incidence</subject><subject>Inflammation</subject><subject>Laboratories</subject><subject>Male</subject><subject>Medicine</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Myocardial infarction</subject><subject>Pharmacogenetics - methods</subject><subject>Pharmacology</subject><subject>Polymorphism</subject><subject>Polymorphism, Genetic</subject><subject>Precision medicine</subject><subject>Precision Medicine - methods</subject><subject>Prognosis</subject><subject>Prospective Studies</subject><subject>Proteins</subject><subject>Retrospective Studies</subject><subject>Sulfhydryl Compounds - administration & dosage</subject><issn>0002-8703</issn><issn>1097-6744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kUFv1DAUhC0EokvhB3BBlrhwIOHZseNEnKpSClIlDsDZcuyXXUfZeLGdRf33eNnCgQOnp5G-GT3NEPKSQc2Ate-m2uymmgOHGlgNoB6RDYNeVa0S4jHZAACvOgXNBXmW0lRky7v2KbloOHRKMLUh4Wte3T11mPx2oWGkH8xc3eJy85YaetiZuDc2bHHB7C3N0ZuZZhO3RS5bGtGtNvvw22hNdD4cTbLrbCLFIy450Z8-76gzs8UczcEPz8mT0cwJXzzcS_L9482360_V3Zfbz9dXd5UVXOTT07K3arAOetN0jbSuZ2ZwreCd7GXTCc6ddaMTsitXth0o7I1ycmg44thckjfn3EMMP1ZMWe99sjjPZsGwJs2bloNqpWAFff0POoU1LuU7zUtH0DDBZKHYmbIxpBRx1Ifo9ybeawb6tIaedFlDn9bQwHRZo3hePSSvwx7dX8ef-gvw_gxgqeLoMepkPS4WnY9os3bB_yf-F_2cmrI</recordid><startdate>202004</startdate><enddate>202004</enddate><creator>Tardif, Jean-Claude</creator><creator>Dubé, Marie-Pierre</creator><creator>Pfeffer, Marc A.</creator><creator>Waters, David D.</creator><creator>Koenig, Wolfgang</creator><creator>Maggioni, Aldo P.</creator><creator>McMurray, John J.V.</creator><creator>Mooser, Vincent</creator><creator>White, Harvey D.</creator><creator>Heinonen, Therese</creator><creator>Black, Donald M.</creator><creator>Guertin, Marie-Claude</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</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>3V.</scope><scope>7QO</scope><scope>7RV</scope><scope>7TS</scope><scope>7X7</scope><scope>7XB</scope><scope>88C</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M0T</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>202004</creationdate><title>Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib</title><author>Tardif, Jean-Claude ; Dubé, Marie-Pierre ; Pfeffer, Marc A. ; Waters, David D. ; Koenig, Wolfgang ; Maggioni, Aldo P. ; McMurray, John J.V. ; Mooser, Vincent ; White, Harvey D. ; Heinonen, Therese ; Black, Donald M. ; Guertin, Marie-Claude</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-87059c7bcd09a3835cd91abd642859538422dcdfd458dcd56807e9a7d5b32eef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acute coronary syndromes</topic><topic>Adenylate cyclase</topic><topic>Adenylyl Cyclases - genetics</topic><topic>Adenylyl Cyclases - metabolism</topic><topic>Anticholesteremic Agents - administration & dosage</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis - epidemiology</topic><topic>Atherosclerosis - genetics</topic><topic>Atherosclerosis - prevention & control</topic><topic>C-reactive protein</topic><topic>Cerebral infarction</topic><topic>Cholesterol</topic><topic>Cholesteryl ester transfer protein</topic><topic>Diabetes</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>Efflux</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene polymorphism</topic><topic>Genetic Testing</topic><topic>Genome-wide association studies</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Global Health</topic><topic>Heart failure</topic><topic>Hospitalization</topic><topic>Humans</topic><topic>Hypotheses</topic><topic>Incidence</topic><topic>Inflammation</topic><topic>Laboratories</topic><topic>Male</topic><topic>Medicine</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Myocardial infarction</topic><topic>Pharmacogenetics - methods</topic><topic>Pharmacology</topic><topic>Polymorphism</topic><topic>Polymorphism, Genetic</topic><topic>Precision medicine</topic><topic>Precision Medicine - methods</topic><topic>Prognosis</topic><topic>Prospective Studies</topic><topic>Proteins</topic><topic>Retrospective Studies</topic><topic>Sulfhydryl Compounds - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tardif, Jean-Claude</creatorcontrib><creatorcontrib>Dubé, Marie-Pierre</creatorcontrib><creatorcontrib>Pfeffer, Marc A.</creatorcontrib><creatorcontrib>Waters, David D.</creatorcontrib><creatorcontrib>Koenig, Wolfgang</creatorcontrib><creatorcontrib>Maggioni, Aldo P.</creatorcontrib><creatorcontrib>McMurray, John J.V.</creatorcontrib><creatorcontrib>Mooser, Vincent</creatorcontrib><creatorcontrib>White, Harvey D.</creatorcontrib><creatorcontrib>Heinonen, Therese</creatorcontrib><creatorcontrib>Black, Donald M.</creatorcontrib><creatorcontrib>Guertin, Marie-Claude</creatorcontrib><creatorcontrib>for the dal-GenE Investigators</creatorcontrib><creatorcontrib>dal-GenE Investigators</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Physical Education Index</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Healthcare Administration Database (Alumni)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Healthcare Administration Database</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>The American heart journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tardif, Jean-Claude</au><au>Dubé, Marie-Pierre</au><au>Pfeffer, Marc A.</au><au>Waters, David D.</au><au>Koenig, Wolfgang</au><au>Maggioni, Aldo P.</au><au>McMurray, John J.V.</au><au>Mooser, Vincent</au><au>White, Harvey D.</au><au>Heinonen, Therese</au><au>Black, Donald M.</au><au>Guertin, Marie-Claude</au><aucorp>for the dal-GenE Investigators</aucorp><aucorp>dal-GenE Investigators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib</atitle><jtitle>The American heart journal</jtitle><addtitle>Am Heart J</addtitle><date>2020-04</date><risdate>2020</risdate><volume>222</volume><spage>157</spage><epage>165</epage><pages>157-165</pages><issn>0002-8703</issn><eissn>1097-6744</eissn><abstract>The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32087417</pmid><doi>10.1016/j.ahj.2020.01.007</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acute coronary syndromes Adenylate cyclase Adenylyl Cyclases - genetics Adenylyl Cyclases - metabolism Anticholesteremic Agents - administration & dosage Atherosclerosis Atherosclerosis - epidemiology Atherosclerosis - genetics Atherosclerosis - prevention & control C-reactive protein Cerebral infarction Cholesterol Cholesteryl ester transfer protein Diabetes Dose-Response Relationship, Drug Double-Blind Method Efflux Female Follow-Up Studies Gene polymorphism Genetic Testing Genome-wide association studies Genome-Wide Association Study Genomes Genotype Genotype & phenotype Global Health Heart failure Hospitalization Humans Hypotheses Incidence Inflammation Laboratories Male Medicine Middle Aged Mortality Myocardial infarction Pharmacogenetics - methods Pharmacology Polymorphism Polymorphism, Genetic Precision medicine Precision Medicine - methods Prognosis Prospective Studies Proteins Retrospective Studies Sulfhydryl Compounds - administration & dosage |
| title | Study design of Dal-GenE, a pharmacogenetic trial targeting reduction of cardiovascular events with dalcetrapib |
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