Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin‐converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)
Identifieur interne : 001645 ( Istex/Corpus ); précédent : 001644; suivant : 001646Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin‐converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)
Auteurs : John J. V. Mcmurray ; Milton Packer ; Akshay S. Desai ; Jim Gong ; Martin P. Lefkowitz ; Adel R. Rizkala ; Jean Rouleau ; Victor C. Shi ; Scott D. Solomon ; Karl Swedberg ; Michael R. ZileSource :
- European Journal of Heart Failure [ 1388-9842 ] ; 2013-09.
Abstract
Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter‐regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.
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DOI: 10.1093/eurjhf/hft052
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Mcmurray</name><affiliation><mods:affiliation>BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK</mods:affiliation></affiliation></author><author><name sortKey="Packer, Milton" sort="Packer, Milton" uniqKey="Packer M" first="Milton" last="Packer">Milton Packer</name><affiliation><mods:affiliation>University of Texas Southwestern Medical Center, TX, Dallas, USA</mods:affiliation></affiliation></author><author><name sortKey="Desai, Akshay S" sort="Desai, Akshay S" uniqKey="Desai A" first="Akshay S." last="Desai">Akshay S. 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V." last="Mcmurray">John J. V. Mcmurray</name><affiliation><mods:affiliation>BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK</mods:affiliation></affiliation></author><author><name sortKey="Packer, Milton" sort="Packer, Milton" uniqKey="Packer M" first="Milton" last="Packer">Milton Packer</name><affiliation><mods:affiliation>University of Texas Southwestern Medical Center, TX, Dallas, USA</mods:affiliation></affiliation></author><author><name sortKey="Desai, Akshay S" sort="Desai, Akshay S" uniqKey="Desai A" first="Akshay S." last="Desai">Akshay S. 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Zile</name><affiliation><mods:affiliation>The Medical University of South Carolina and RHJ Department of Veterans Administration Medical center, SC, Charleston, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Heart Failure</title><title level="j" type="abbrev">European Journal of Heart Failure</title><idno type="ISSN">1388-9842</idno><idno type="eISSN">1879-0844</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2013-09">2013-09</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1062">1062</biblScope><biblScope unit="page" to="1073">1073</biblScope></imprint><idno type="ISSN">1388-9842</idno></series><idno type="istex">E4BCF3A412832D79167B147CF84A85AE73D01D6F</idno><idno type="DOI">10.1093/eurjhf/hft052</idno><idno type="ArticleID">EJHFHFT052</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1388-9842</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter‐regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>John J. V. McMurray</name><affiliations><json:string>BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK</json:string></affiliations></json:item><json:item><name>Milton Packer</name><affiliations><json:string>University of Texas Southwestern Medical Center, TX, Dallas, USA</json:string></affiliations></json:item><json:item><name>Akshay S. Desai</name><affiliations><json:string>Cardiovascular Medicine, Brigham and Women's Hospital, MA, USA</json:string></affiliations></json:item><json:item><name>Jim Gong</name><affiliations><json:string>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</json:string></affiliations></json:item><json:item><name>Martin P. Lefkowitz</name><affiliations><json:string>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</json:string></affiliations></json:item><json:item><name>Adel R. Rizkala</name><affiliations><json:string>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</json:string></affiliations></json:item><json:item><name>Jean Rouleau</name><affiliations><json:string>Institut de Cardiologie, Université de Montréal, Montréal, Canada</json:string></affiliations></json:item><json:item><name>Victor C. Shi</name><affiliations><json:string>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</json:string></affiliations></json:item><json:item><name>Scott D. Solomon</name><affiliations><json:string>Cardiovascular Medicine, Brigham and Women's Hospital, MA, USA</json:string></affiliations></json:item><json:item><name>Karl Swedberg</name><affiliations><json:string>Cardiovascular Medicine Department, University of Gothenburg, Gothenburg, Sweden</json:string></affiliations></json:item><json:item><name>Michael R. 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V.</forename><surname>McMurray</surname></persName><note type="correspondence"><p>Correspondence: Corresponding author. Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK. Tel: +44 141 330 3479, Fax: +44 141 330 6955, Email:</p></note><affiliation>BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK</affiliation></author><author xml:id="author-2"><persName><forename type="first">Milton</forename><surname>Packer</surname></persName><affiliation>University of Texas Southwestern Medical Center, TX, Dallas, USA</affiliation></author><author xml:id="author-3"><persName><forename type="first">Akshay S.</forename><surname>Desai</surname></persName><affiliation>Cardiovascular Medicine, Brigham and Women's Hospital, MA, USA</affiliation></author><author xml:id="author-4"><persName><forename type="first">Jim</forename><surname>Gong</surname></persName><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation></author><author xml:id="author-5"><persName><forename type="first">Martin P.</forename><surname>Lefkowitz</surname></persName><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation></author><author xml:id="author-6"><persName><forename type="first">Adel R.</forename><surname>Rizkala</surname></persName><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation></author><author xml:id="author-7"><persName><forename type="first">Jean</forename><surname>Rouleau</surname></persName><affiliation>Institut de Cardiologie, Université de Montréal, Montréal, Canada</affiliation></author><author xml:id="author-8"><persName><forename type="first">Victor C.</forename><surname>Shi</surname></persName><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation></author><author xml:id="author-9"><persName><forename type="first">Scott D.</forename><surname>Solomon</surname></persName><affiliation>Cardiovascular Medicine, Brigham and Women's Hospital, MA, USA</affiliation></author><author xml:id="author-10"><persName><forename type="first">Karl</forename><surname>Swedberg</surname></persName><affiliation>Cardiovascular Medicine Department, University of Gothenburg, Gothenburg, Sweden</affiliation></author><author xml:id="author-11"><persName><forename type="first">Michael R.</forename><surname>Zile</surname></persName><affiliation>The Medical University of South Carolina and RHJ Department of Veterans Administration Medical center, SC, Charleston, USA</affiliation></author></analytic><monogr><title level="j">European Journal of Heart Failure</title><title level="j" type="abbrev">European Journal of Heart Failure</title><idno type="pISSN">1388-9842</idno><idno type="eISSN">1879-0844</idno><idno type="DOI">10.1002/(ISSN)1879-0844</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><date type="published" when="2013-09"></date><biblScope unit="volume">15</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1062">1062</biblScope><biblScope unit="page" to="1073">1073</biblScope></imprint></monogr><idno type="istex">E4BCF3A412832D79167B147CF84A85AE73D01D6F</idno><idno type="DOI">10.1093/eurjhf/hft052</idno><idno type="ArticleID">EJHFHFT052</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2013-11-26</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter‐regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.</p></abstract><abstract><p>Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT‐proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM‐HF). Patients entered a single‐blind enalapril run‐in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run‐in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.</p></abstract><abstract><p>PARADIGM‐HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM‐HF may change our approach to neurohormonal modulation in HF.</p></abstract><abstract><p>NCT01035255</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Chronic heart failure</term></item><item><term>Renin–angiotensin</term></item><item><term>ACE inhibitor</term></item><item><term>Angiotensin receptor blocker</term></item><item><term>Natriuretic peptides</term></item><item><term>Neprilysin</term></item><item><term>Neutral endopeptidase</term></item><item><term>Angiotensin receptor neprilysin inhibitor</term></item><item><term>LCZ696</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Study Design</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2013-01-24">Received</change><change when="2013-02-08">Registration</change><change when="2013-11-26">Created</change><change when="2013-09">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/E4BCF3A412832D79167B147CF84A85AE73D01D6F/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en" xml:id="EJHFHFT052"><header><publicationMeta level="product"><doi origin="wiley">10.1002/(ISSN)1879-0844</doi><issn type="print">1388-9842</issn><issn type="electronic">1879-0844</issn><idGroup><id type="product" value="EJHF"></id></idGroup><countGroup><count type="figureTotal" number="1"></count><count type="tableTotal" number="5"></count><count type="referenceTotal" number="46"></count></countGroup><titleGroup><title type="main" sort="EUROPEAN JOURNAL OF HEART FAILURE">European Journal of Heart Failure</title><title type="short">European Journal of Heart Failure</title></titleGroup><attributeValueGroup><attributeValue element="legalStatement" attribute="type" value="creativeCommonsBy-nc"></attributeValue></attributeValueGroup></publicationMeta><publicationMeta level="part" position="90"><doi origin="wiley">10.1002/ejhf.2013.15.issue-9</doi><copyright ownership="publisher">© 2013 European Society of Cardiology</copyright><numberingGroup><numbering type="journalVolume" number="15">15</numbering><numbering type="journalIssue">9</numbering></numberingGroup><coverDate startDate="2013-09">September 2013</coverDate></publicationMeta><publicationMeta level="unit" position="150" type="article" status="forIssue" accessType="open"><doi origin="wiley">10.1093/eurjhf/hft052</doi><idGroup><id type="unit" value="EJHFHFT052"></id></idGroup><countGroup><count type="pageTotal" number="12"></count></countGroup><titleGroup><title type="articleCategory">Study Design</title><title type="tocHeading1">Study Design</title></titleGroup><copyright ownership="thirdParty">Published on behalf of the European Society of Cardiology. All rights reserved. © 2013 the Authors</copyright><legalStatement type="creativeCommonsBy-nc"><p>This is an open access article under the terms of the <url href="http://creativecommons.org/licenses/by-nc/3.0/">Creative Commons Attribution‐NonCommercial</url> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</p></legalStatement><eventGroup><event type="manuscriptReceived" date="2013-01-24"></event><event type="manuscriptAccepted" date="2013-02-08"></event><event type="xmlCreated" agent="Aptara" date="2013-11-26"></event><event type="publishedOnlineFinalForm" date="2014-01-27"></event><event type="firstOnline" date="2014-01-27"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.6.4 mode:FullText" date="2015-10-01"></event></eventGroup><numberingGroup><numbering type="pageFirst">1062</numbering><numbering type="pageLast">1073</numbering></numberingGroup><correspondenceTo>Corresponding author. Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK. Tel: +44 141 330 3479, Fax: +44 141 330 6955, Email: <email>john.mcmurray@glasgow.ac.uk</email></correspondenceTo><objectNameGroup><objectName elementName="appendix">Appendix 1.</objectName></objectNameGroup><linkGroup><link type="toTypesetVersion" href="file://EJHF.EJHFHFT052.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin‐converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)</title></titleGroup><creators><creator xml:id="ejhfhft052-cr-0001" creatorRole="author" affiliationRef="#ejhfhft052-aff-0001" corresponding="yes"><personName><familyName>McMurray</familyName><givenNames>John J. V.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0002" creatorRole="author" affiliationRef="#ejhfhft052-aff-0002" corresponding="no"><personName><familyName>Packer</familyName><givenNames>Milton</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0003" creatorRole="author" affiliationRef="#ejhfhft052-aff-0003" corresponding="no"><personName><familyName>Desai</familyName><givenNames>Akshay S.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0004" creatorRole="author" affiliationRef="#ejhfhft052-aff-0004" corresponding="no"><personName><familyName>Gong</familyName><givenNames>Jim</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0005" creatorRole="author" affiliationRef="#ejhfhft052-aff-0004" corresponding="no"><personName><familyName>Lefkowitz</familyName><givenNames>Martin P.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0006" creatorRole="author" affiliationRef="#ejhfhft052-aff-0004" corresponding="no"><personName><familyName>Rizkala</familyName><givenNames>Adel R.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0007" creatorRole="author" affiliationRef="#ejhfhft052-aff-0005" corresponding="no"><personName><familyName>Rouleau</familyName><givenNames>Jean</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0008" creatorRole="author" affiliationRef="#ejhfhft052-aff-0004" corresponding="no"><personName><familyName>Shi</familyName><givenNames>Victor C.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0009" creatorRole="author" affiliationRef="#ejhfhft052-aff-0003" corresponding="no"><personName><familyName>Solomon</familyName><givenNames>Scott D.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0010" creatorRole="author" affiliationRef="#ejhfhft052-aff-0006" corresponding="no"><personName><familyName>Swedberg</familyName><givenNames>Karl</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0011" creatorRole="author" affiliationRef="#ejhfhft052-aff-0007" corresponding="no"><personName><familyName>Zile</familyName><givenNames>Michael R.</givenNames></personName></creator><creator xml:id="ejhfhft052-cr-0012" creatorRole="author" noteRef="#ejhfhft052-note-0001" corresponding="no"><groupName>on behalf of the PARADIGM‐HF Committees and Investigators</groupName></creator></creators><affiliationGroup><affiliation xml:id="ejhfhft052-aff-0001" type="organization" countryCode="GB"><orgDiv>BHF Cardiovascular Research Centre</orgDiv><orgName>University of Glasgow</orgName><address><city>Glasgow</city><country>UK</country></address></affiliation><affiliation xml:id="ejhfhft052-aff-0002" type="organization" countryCode="US"><orgName>University of Texas Southwestern Medical Center</orgName><address><city>Dallas</city><countryPart>TX</countryPart><country>USA</country></address></affiliation><affiliation xml:id="ejhfhft052-aff-0003" type="organization" countryCode="US"><orgName>Brigham and Women's Hospital</orgName><orgDiv>Cardiovascular Medicine</orgDiv><address><city>MA</city><country>USA</country></address></affiliation><affiliation xml:id="ejhfhft052-aff-0004" type="organization" countryCode="US"><orgName>Novartis Pharmaceutical Corporation</orgName><address><city>East Hanover</city><countryPart>NJ</countryPart><country>USA</country></address></affiliation><affiliation xml:id="ejhfhft052-aff-0005" type="organization" countryCode="CA"><orgName>Université de Montréal</orgName><orgDiv>Institut de Cardiologie</orgDiv><address><city>Montréal</city><country>Canada</country></address></affiliation><affiliation xml:id="ejhfhft052-aff-0006" type="organization" countryCode="SE"><orgName>University of Gothenburg</orgName><orgDiv>Cardiovascular Medicine Department</orgDiv><address><city>Gothenburg</city><country>Sweden</country></address></affiliation><affiliation xml:id="ejhfhft052-aff-0007" type="organization" countryCode="US"><orgName>The Medical University of South Carolina and RHJ Department of Veterans Administration Medical center</orgName><address><city>Charleston</city><countryPart>SC</countryPart><country>USA</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="ejhfhft052-kwd-0001">Chronic heart failure</keyword><keyword xml:id="ejhfhft052-kwd-0002">Renin–angiotensin</keyword><keyword xml:id="ejhfhft052-kwd-0003">ACE inhibitor</keyword><keyword xml:id="ejhfhft052-kwd-0004">Angiotensin receptor blocker</keyword><keyword xml:id="ejhfhft052-kwd-0005">Natriuretic peptides</keyword><keyword xml:id="ejhfhft052-kwd-0006">Neprilysin</keyword><keyword xml:id="ejhfhft052-kwd-0007">Neutral endopeptidase</keyword><keyword xml:id="ejhfhft052-kwd-0008">Angiotensin receptor neprilysin inhibitor</keyword><keyword xml:id="ejhfhft052-kwd-0009">LCZ696</keyword></keywordGroup><abstractGroup><abstract type="main"><section xml:id="ejhfhft052-sec-0001"><title type="main">Aims</title><p>Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter‐regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.</p></section><section xml:id="ejhfhft052-sec-0002"><title type="main">Methods</title><p>Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT‐proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM‐HF). Patients entered a single‐blind enalapril run‐in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run‐in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.</p></section><section xml:id="ejhfhft052-sec-0003"><title type="main">Perspectives</title><p>PARADIGM‐HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM‐HF may change our approach to neurohormonal modulation in HF.</p></section><section xml:id="ejhfhft052-sec-0004"><title type="main">Trial registration</title><p>NCT01035255</p></section></abstract></abstractGroup></contentMeta><noteGroup xml:id="ejhfhft052-ntgp-0001"><note xml:id="ejhfhft052-note-0001"><label>†</label>See Appendix 1 for a complete list of the PARADIGM‐HF Committees and Investigators.</note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin‐converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin‐converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)</title></titleInfo><name type="personal"><namePart type="given">John J. V.</namePart><namePart type="family">McMurray</namePart><affiliation>BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK</affiliation><description>Correspondence: Corresponding author. Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK. Tel: +44 141 330 3479, Fax: +44 141 330 6955, Email: </description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Milton</namePart><namePart type="family">Packer</namePart><affiliation>University of Texas Southwestern Medical Center, TX, Dallas, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Akshay S.</namePart><namePart type="family">Desai</namePart><affiliation>Cardiovascular Medicine, Brigham and Women's Hospital, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jim</namePart><namePart type="family">Gong</namePart><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martin P.</namePart><namePart type="family">Lefkowitz</namePart><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adel R.</namePart><namePart type="family">Rizkala</namePart><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean</namePart><namePart type="family">Rouleau</namePart><affiliation>Institut de Cardiologie, Université de Montréal, Montréal, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Victor C.</namePart><namePart type="family">Shi</namePart><affiliation>Novartis Pharmaceutical Corporation, NJ, East Hanover, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Scott D.</namePart><namePart type="family">Solomon</namePart><affiliation>Cardiovascular Medicine, Brigham and Women's Hospital, MA, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Karl</namePart><namePart type="family">Swedberg</namePart><affiliation>Cardiovascular Medicine Department, University of Gothenburg, Gothenburg, Sweden</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael R.</namePart><namePart type="family">Zile</namePart><affiliation>The Medical University of South Carolina and RHJ Department of Veterans Administration Medical center, SC, Charleston, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="corporate"><namePart>on behalf of the PARADIGM‐HF Committees and Investigators</namePart></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2013-09</dateIssued><dateCreated encoding="w3cdtf">2013-11-26</dateCreated><dateCaptured encoding="w3cdtf">2013-01-24</dateCaptured><dateValid encoding="w3cdtf">2013-02-08</dateValid><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter‐regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.</abstract><abstract>Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT‐proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM‐HF). Patients entered a single‐blind enalapril run‐in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run‐in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.</abstract><abstract>PARADIGM‐HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM‐HF may change our approach to neurohormonal modulation in HF.</abstract><abstract>NCT01035255</abstract><subject><genre>keywords</genre><topic>Chronic heart failure</topic><topic>Renin–angiotensin</topic><topic>ACE inhibitor</topic><topic>Angiotensin receptor blocker</topic><topic>Natriuretic peptides</topic><topic>Neprilysin</topic><topic>Neutral endopeptidase</topic><topic>Angiotensin receptor neprilysin inhibitor</topic><topic>LCZ696</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Heart Failure</title></titleInfo><titleInfo type="abbreviated"><title>European Journal of Heart Failure</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Study Design</topic></subject><identifier type="ISSN">1388-9842</identifier><identifier type="eISSN">1879-0844</identifier><identifier type="DOI">10.1002/(ISSN)1879-0844</identifier><identifier type="PublisherID">EJHF</identifier><part><date>2013</date><detail type="volume"><caption>vol.</caption><number>15</number></detail><detail type="issue"><caption>no.</caption><number>9</number></detail><extent unit="pages"><start>1062</start><end>1073</end><total>12</total></extent></part></relatedItem><identifier type="istex">E4BCF3A412832D79167B147CF84A85AE73D01D6F</identifier><identifier type="DOI">10.1093/eurjhf/hft052</identifier><identifier type="ArticleID">EJHFHFT052</identifier><accessCondition type="use and reproduction" contentType="creativeCommonsBy-nc">This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><enrichments><json:item><type>multicat</type><uri>https://api.istex.fr/document/E4BCF3A412832D79167B147CF84A85AE73D01D6F/enrichments/multicat</uri></json:item></enrichments><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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