Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA‐HF trial
ABSTRACT Aims In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA‐HF), high‐dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low‐dose spironolactone (25 mg daily) in patients already receiving spi...
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| Veröffentlicht in: | European journal of heart failure 2020-08, Vol.22 (8), p.1451-1461 |
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| creator | Denus, Simon Leclair, Grégoire Dubé, Marie‐Pierre St‐Jean, Isabelle Zada, Yassamin Feroz Oussaïd, Essaïd Jutras, Martin Givertz, Michael M. Mentz, Robert J. Tang, W.H. Wilson Ferreira, João Pedro Rouleau, Jean Butler, Javed Kalogeropoulos, Andreas P. |
| description | ABSTRACT
Aims
In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA‐HF), high‐dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low‐dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long‐acting active metabolites of spironolactone [canrenone and 7α‐thiomethylspironolactone (7α‐TMS)] in the high‐dose group could have contributed to these neutral results.
Methods and results
In patients randomized to high‐dose spironolactone not previously treated with spironolactone (high‐dose‐naïve, n = 112), concentrations of canrenone and 7α‐TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P |
| doi_str_mv | 10.1002/ejhf.1802 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7958586</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2385709834</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4152-892134d520a4724cc370032731f8e567fd1e5d345376797b240de2384c9526ba3</originalsourceid><addsrcrecordid>eNp1kc1uEzEQx1cIRD_gwAsgH-GwrT9jLwekqEoIVQUHytlyvLNdV1472A5Vb32EPiNPgkPaCg6cZqT56Tcz-jfNG4JPCMb0FK7H4YQoTJ81h0TJrsWK8-e1Z0q1neL0oDnK-RpjIiv-sjlglDKJCT1s_LeNSzFEb2yJAdAExayjdwWQjcFCKMkUF0NGLqAebJw2ELIp0KMRTCpoMM5vE3yo8-yuxpLRkOKEyghofrlafJn_urtfLVFJzvhXzYvB-AyvH-px8325uDxbtRdfP30-m1-0lhNBW9VRwngvKDZcUm5tvRUzKhkZFIiZHHoComdcMDmTnVxTjnugTHHbCTpbG3bcfNx7N9v1BP3-C683yU0m3eponP53Etyor-JPLTuhhJpVwbsHQYo_tpCLnly24L0JELdZ12VC4k4xXtH3e9SmmHOC4WkNwXqXjt6lo3fpVPbt33c9kY9xVOB0D9w4D7f_N-nF-Wr5R_kbJ1Kbnw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2385709834</pqid></control><display><type>article</type><title>Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA‐HF trial</title><source>MEDLINE</source><source>Wiley Online Library Free Content</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Denus, Simon ; Leclair, Grégoire ; Dubé, Marie‐Pierre ; St‐Jean, Isabelle ; Zada, Yassamin Feroz ; Oussaïd, Essaïd ; Jutras, Martin ; Givertz, Michael M. ; Mentz, Robert J. ; Tang, W.H. Wilson ; Ferreira, João Pedro ; Rouleau, Jean ; Butler, Javed ; Kalogeropoulos, Andreas P.</creator><creatorcontrib>Denus, Simon ; Leclair, Grégoire ; Dubé, Marie‐Pierre ; St‐Jean, Isabelle ; Zada, Yassamin Feroz ; Oussaïd, Essaïd ; Jutras, Martin ; Givertz, Michael M. ; Mentz, Robert J. ; Tang, W.H. Wilson ; Ferreira, João Pedro ; Rouleau, Jean ; Butler, Javed ; Kalogeropoulos, Andreas P.</creatorcontrib><description>ABSTRACT
Aims
In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA‐HF), high‐dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low‐dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long‐acting active metabolites of spironolactone [canrenone and 7α‐thiomethylspironolactone (7α‐TMS)] in the high‐dose group could have contributed to these neutral results.
Methods and results
In patients randomized to high‐dose spironolactone not previously treated with spironolactone (high‐dose‐naïve, n = 112), concentrations of canrenone and 7α‐TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady‐state concentrations had not been reached by 48 h. In patients previously on low‐dose, high‐dose spironolactone (high‐dose‐previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high‐dose groups had higher concentrations of both metabolites than the low‐dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high‐dose‐previous vs. high‐dose‐naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady‐state has not been reached in high‐dose‐naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints.
Conclusions
Lower‐than‐anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high‐dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA‐HF trial.</description><identifier>ISSN: 1388-9842</identifier><identifier>EISSN: 1879-0844</identifier><identifier>DOI: 10.1002/ejhf.1802</identifier><identifier>PMID: 32237012</identifier><language>eng</language><publisher>Oxford, UK: John Wiley & Sons, Ltd</publisher><subject>Aged ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Canrenone ; Drug concentrations ; Female ; Heart failure ; Heart Failure - drug therapy ; Humans ; Male ; Middle Aged ; Mineralocorticoid Receptor Antagonists ; Spironolactone ; Stroke Volume ; Ventricular Function, Left</subject><ispartof>European journal of heart failure, 2020-08, Vol.22 (8), p.1451-1461</ispartof><rights>2020 European Society of Cardiology</rights><rights>2020 European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4152-892134d520a4724cc370032731f8e567fd1e5d345376797b240de2384c9526ba3</citedby><cites>FETCH-LOGICAL-c4152-892134d520a4724cc370032731f8e567fd1e5d345376797b240de2384c9526ba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fejhf.1802$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fejhf.1802$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32237012$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Denus, Simon</creatorcontrib><creatorcontrib>Leclair, Grégoire</creatorcontrib><creatorcontrib>Dubé, Marie‐Pierre</creatorcontrib><creatorcontrib>St‐Jean, Isabelle</creatorcontrib><creatorcontrib>Zada, Yassamin Feroz</creatorcontrib><creatorcontrib>Oussaïd, Essaïd</creatorcontrib><creatorcontrib>Jutras, Martin</creatorcontrib><creatorcontrib>Givertz, Michael M.</creatorcontrib><creatorcontrib>Mentz, Robert J.</creatorcontrib><creatorcontrib>Tang, W.H. Wilson</creatorcontrib><creatorcontrib>Ferreira, João Pedro</creatorcontrib><creatorcontrib>Rouleau, Jean</creatorcontrib><creatorcontrib>Butler, Javed</creatorcontrib><creatorcontrib>Kalogeropoulos, Andreas P.</creatorcontrib><title>Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA‐HF trial</title><title>European journal of heart failure</title><addtitle>Eur J Heart Fail</addtitle><description>ABSTRACT
Aims
In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA‐HF), high‐dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low‐dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long‐acting active metabolites of spironolactone [canrenone and 7α‐thiomethylspironolactone (7α‐TMS)] in the high‐dose group could have contributed to these neutral results.
Methods and results
In patients randomized to high‐dose spironolactone not previously treated with spironolactone (high‐dose‐naïve, n = 112), concentrations of canrenone and 7α‐TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady‐state concentrations had not been reached by 48 h. In patients previously on low‐dose, high‐dose spironolactone (high‐dose‐previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high‐dose groups had higher concentrations of both metabolites than the low‐dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high‐dose‐previous vs. high‐dose‐naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady‐state has not been reached in high‐dose‐naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints.
Conclusions
Lower‐than‐anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high‐dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA‐HF trial.</description><subject>Aged</subject><subject>Angiotensin Receptor Antagonists</subject><subject>Angiotensin-Converting Enzyme Inhibitors</subject><subject>Canrenone</subject><subject>Drug concentrations</subject><subject>Female</subject><subject>Heart failure</subject><subject>Heart Failure - drug therapy</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mineralocorticoid Receptor Antagonists</subject><subject>Spironolactone</subject><subject>Stroke Volume</subject><subject>Ventricular Function, Left</subject><issn>1388-9842</issn><issn>1879-0844</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1uEzEQx1cIRD_gwAsgH-GwrT9jLwekqEoIVQUHytlyvLNdV1472A5Vb32EPiNPgkPaCg6cZqT56Tcz-jfNG4JPCMb0FK7H4YQoTJ81h0TJrsWK8-e1Z0q1neL0oDnK-RpjIiv-sjlglDKJCT1s_LeNSzFEb2yJAdAExayjdwWQjcFCKMkUF0NGLqAebJw2ELIp0KMRTCpoMM5vE3yo8-yuxpLRkOKEyghofrlafJn_urtfLVFJzvhXzYvB-AyvH-px8325uDxbtRdfP30-m1-0lhNBW9VRwngvKDZcUm5tvRUzKhkZFIiZHHoComdcMDmTnVxTjnugTHHbCTpbG3bcfNx7N9v1BP3-C683yU0m3eponP53Etyor-JPLTuhhJpVwbsHQYo_tpCLnly24L0JELdZ12VC4k4xXtH3e9SmmHOC4WkNwXqXjt6lo3fpVPbt33c9kY9xVOB0D9w4D7f_N-nF-Wr5R_kbJ1Kbnw</recordid><startdate>202008</startdate><enddate>202008</enddate><creator>Denus, Simon</creator><creator>Leclair, Grégoire</creator><creator>Dubé, Marie‐Pierre</creator><creator>St‐Jean, Isabelle</creator><creator>Zada, Yassamin Feroz</creator><creator>Oussaïd, Essaïd</creator><creator>Jutras, Martin</creator><creator>Givertz, Michael M.</creator><creator>Mentz, Robert J.</creator><creator>Tang, W.H. Wilson</creator><creator>Ferreira, João Pedro</creator><creator>Rouleau, Jean</creator><creator>Butler, Javed</creator><creator>Kalogeropoulos, Andreas P.</creator><general>John Wiley & Sons, Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>202008</creationdate><title>Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA‐HF trial</title><author>Denus, Simon ; Leclair, Grégoire ; Dubé, Marie‐Pierre ; St‐Jean, Isabelle ; Zada, Yassamin Feroz ; Oussaïd, Essaïd ; Jutras, Martin ; Givertz, Michael M. ; Mentz, Robert J. ; Tang, W.H. Wilson ; Ferreira, João Pedro ; Rouleau, Jean ; Butler, Javed ; Kalogeropoulos, Andreas P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4152-892134d520a4724cc370032731f8e567fd1e5d345376797b240de2384c9526ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Angiotensin Receptor Antagonists</topic><topic>Angiotensin-Converting Enzyme Inhibitors</topic><topic>Canrenone</topic><topic>Drug concentrations</topic><topic>Female</topic><topic>Heart failure</topic><topic>Heart Failure - drug therapy</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mineralocorticoid Receptor Antagonists</topic><topic>Spironolactone</topic><topic>Stroke Volume</topic><topic>Ventricular Function, Left</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Denus, Simon</creatorcontrib><creatorcontrib>Leclair, Grégoire</creatorcontrib><creatorcontrib>Dubé, Marie‐Pierre</creatorcontrib><creatorcontrib>St‐Jean, Isabelle</creatorcontrib><creatorcontrib>Zada, Yassamin Feroz</creatorcontrib><creatorcontrib>Oussaïd, Essaïd</creatorcontrib><creatorcontrib>Jutras, Martin</creatorcontrib><creatorcontrib>Givertz, Michael M.</creatorcontrib><creatorcontrib>Mentz, Robert J.</creatorcontrib><creatorcontrib>Tang, W.H. Wilson</creatorcontrib><creatorcontrib>Ferreira, João Pedro</creatorcontrib><creatorcontrib>Rouleau, Jean</creatorcontrib><creatorcontrib>Butler, Javed</creatorcontrib><creatorcontrib>Kalogeropoulos, Andreas P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of heart failure</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Denus, Simon</au><au>Leclair, Grégoire</au><au>Dubé, Marie‐Pierre</au><au>St‐Jean, Isabelle</au><au>Zada, Yassamin Feroz</au><au>Oussaïd, Essaïd</au><au>Jutras, Martin</au><au>Givertz, Michael M.</au><au>Mentz, Robert J.</au><au>Tang, W.H. Wilson</au><au>Ferreira, João Pedro</au><au>Rouleau, Jean</au><au>Butler, Javed</au><au>Kalogeropoulos, Andreas P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA‐HF trial</atitle><jtitle>European journal of heart failure</jtitle><addtitle>Eur J Heart Fail</addtitle><date>2020-08</date><risdate>2020</risdate><volume>22</volume><issue>8</issue><spage>1451</spage><epage>1461</epage><pages>1451-1461</pages><issn>1388-9842</issn><eissn>1879-0844</eissn><abstract>ABSTRACT
Aims
In Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA‐HF), high‐dose spironolactone (100 mg daily) did not improve efficacy endpoints over usual care [placebo or continued low‐dose spironolactone (25 mg daily) in patients already receiving spironolactone] in the treatment of acute heart failure (HF). We hypothesized that low concentrations of the long‐acting active metabolites of spironolactone [canrenone and 7α‐thiomethylspironolactone (7α‐TMS)] in the high‐dose group could have contributed to these neutral results.
Methods and results
In patients randomized to high‐dose spironolactone not previously treated with spironolactone (high‐dose‐naïve, n = 112), concentrations of canrenone and 7α‐TMS increased at 48 and 96 h compared to baseline, and between 48 and 96 h (all P < 0.005), indicating that steady‐state concentrations had not been reached by 48 h. In patients previously on low‐dose, high‐dose spironolactone (high‐dose‐previous, n = 37), concentrations of canrenone increased at 48 and 96 h compared to baseline (both P < 0.0005), with a marginal increase between 48 and 96 h (P = 0.0507). At 48 h, both high‐dose groups had higher concentrations of both metabolites than the low‐dose spironolactone group (P < 0.0001). Moreover, concentrations of both metabolites were higher in high‐dose‐previous vs. high‐dose‐naïve patients (P < 0.01), indicating that previous spironolactone use was significant, and that steady‐state has not been reached in high‐dose‐naïve patients at 48 h. We found limited and inconsistent evidence of correlation between metabolite concentrations and endpoints.
Conclusions
Lower‐than‐anticipated concentrations of spironolactone active metabolites were observed for at least 48 h in the high‐dose spironolactone group and may have contributed to the absence of pharmacological effects of spironolactone in the ATHENA‐HF trial.</abstract><cop>Oxford, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>32237012</pmid><doi>10.1002/ejhf.1802</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of heart failure, 2020-08, Vol.22 (8), p.1451-1461 |
| issn | 1388-9842 1879-0844 |
| language | eng |
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| source | MEDLINE; Wiley Online Library Free Content; Access via Wiley Online Library; EZB-FREE-00999 freely available EZB journals |
| subjects | Aged Angiotensin Receptor Antagonists Angiotensin-Converting Enzyme Inhibitors Canrenone Drug concentrations Female Heart failure Heart Failure - drug therapy Humans Male Middle Aged Mineralocorticoid Receptor Antagonists Spironolactone Stroke Volume Ventricular Function, Left |
| title | Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA‐HF trial |
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