<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01708798</url>
  </required_header>
  <id_info>
    <org_study_id>H12-00185</org_study_id>
    <nct_id>NCT01708798</nct_id>
  </id_info>
  <brief_title>Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer</brief_title>
  <official_title>A Prospective Randomized Placebo-controlled Study of the Effect of Eplerenone on Left Ventricular Diastolic Function in Women Receiving Anthracycline Therapy for Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Cancer Society (CCS)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of British Columbia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Doxorubicin and other anthracyclines are commonly used to treat breast cancer and other types&#xD;
      of cancer. Unfortunately, they can cause heart muscle damage, resulting in scarring, abnormal&#xD;
      contraction and relaxation, and heart failure symptoms. This side effect occurs more&#xD;
      frequently at higher doses, and limits the total dose that can be given to cancer patients.&#xD;
      Eplerenone is an oral medication that prevents or reverses heart damage in other disease&#xD;
      states, and is commonly used to treat heart failure. This study will investigate the use of&#xD;
      eplerenone to protect the heart from these harmful side effects of doxorubicin.&#xD;
&#xD;
      Few therapies have been shown to prevent heart damage in patients receiving anthracyclines.&#xD;
      Small studies have suggested that other heart failure medications (ACE inhibitors,&#xD;
      beta-blockers) may reduce the incidence of cardiac toxicity, but eplerenone and other drugs&#xD;
      in its class (aldosterone antagonists) have not previously been studied. Eplerenone inhibits&#xD;
      enzyme pathways that cause scarring of the heart, and animal studies suggest that&#xD;
      anthracyclines cause damage through these same pathways.&#xD;
&#xD;
      This study aims to investigate whether eplerenone protects the heart from the harmful effects&#xD;
      of doxorubicin chemotherapy. Specifically, it will measure the effect that eplerenone has on&#xD;
      heart muscle relaxation. It will randomly assign women undergoing chemotherapy with&#xD;
      doxorubicin to one of two groups: one group will receive eplerenone, and the other group will&#xD;
      receive placebo (sugar) pills. The subjects will not know which type of pills they are&#xD;
      taking. Heart muscle relaxation will be measured at baseline, after completion of&#xD;
      chemotherapy (8-12 weeks), and after 6 months. There will also be various blood tests&#xD;
      measured in the study subjects, to determine whether there might be certain blood tests that&#xD;
      identify patients at particularly high risk of heart toxicity after doxorubicin therapy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Futility&#xD;
  </why_stopped>
  <start_date>May 2014</start_date>
  <completion_date type="Actual">November 2016</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in average E' (averaged septal E' and lateral E')</measure>
    <time_frame>6 months</time_frame>
    <description>The average early diastolic tissue velocity of the mitral valve annulus measured by tissue Doppler echocardiography (averaged velocities of the mitral annulus measured at the lateral edge and the septal edge)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Development of worsening diastolic function</measure>
    <time_frame>6 months</time_frame>
    <description>Development of worsening diastolic function, defined as a decline by at least one American Society of Echocardiography gradation of diastolic dysfunction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Development of worsening systolic function</measure>
    <time_frame>6 months</time_frame>
    <description>Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in septal E'</measure>
    <time_frame>6 months</time_frame>
    <description>Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lateral E'</measure>
    <time_frame>6 months</time_frame>
    <description>Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in E/E'</measure>
    <time_frame>6 months</time_frame>
    <description>Change in the ratio of early diastolic mitral inflow velocity (E, measured by pulse wave Doppler echocardiography) to the average early diastolic tissue velocity of the mitral annulus (E', measured by tissue Doppler echocardiography)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in E/A</measure>
    <time_frame>6 months</time_frame>
    <description>Change in the ratio of peak early diastolic mitral inflow velocity (E) to peak mitral inflow velocity during atrial systole (A), both measured by pulse wave Doppler echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left atrial volume index</measure>
    <time_frame>6 months</time_frame>
    <description>Change in the left atrial volume index, defined as the left atrial volume measured on the 2D echocardiogram indexed to body surface area</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in left ventricular ejection fraction (LVEF)</measure>
    <time_frame>6 months</time_frame>
    <description>Change in LVEF, measured by echocardiogram using Simpson's method</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biomarkers</measure>
    <time_frame>Baseline, 1 week, 2 weeks, 4 weeks, 6 months</time_frame>
    <description>Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Incidence of hyperkalemia</measure>
    <time_frame>6 months</time_frame>
    <description>Incidence of hyperkalemia defined as serum potassium &gt;5.5 mmol/L</description>
  </other_outcome>
  <other_outcome>
    <measure>Incidence of adverse events leading to discontinuation of study drug</measure>
    <time_frame>6 months</time_frame>
    <description>Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure</description>
  </other_outcome>
  <other_outcome>
    <measure>Signal-averaged ECG (SAECG) changes</measure>
    <time_frame>Baseline, 8-12 weeks, 6 months</time_frame>
    <description>Change in late potentials measured on SAECG</description>
  </other_outcome>
  <other_outcome>
    <measure>Exercise stress test</measure>
    <time_frame>Baseline, 6 months</time_frame>
    <description>Change in QT/RR interval slope, exercise capacity, peak heart rate, heart rate recovery, ventricular arrhythmias during exercise, ventricular arrhythmias during recovery, presence of ischemia</description>
  </other_outcome>
  <other_outcome>
    <measure>Genetic predictors of cardiotoxicity and of response to eplerenone</measure>
    <time_frame>6 months</time_frame>
    <description>Genetic predictors of cardiotoxicity and of response to eplerenone</description>
  </other_outcome>
  <other_outcome>
    <measure>ECG changes</measure>
    <time_frame>Pre- and post-chemotherapy infusions (over 8-12 weeks)</time_frame>
    <description>Change in QT interval, arrhythmias</description>
  </other_outcome>
  <other_outcome>
    <measure>Global longitudinal strain (GLS)</measure>
    <time_frame>6 months</time_frame>
    <description>Change in GLS from baseline to 6 months</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">44</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>One tablet by mouth daily. If serum potassium level is &lt;5.0 mmol/L at four weeks, increase to two tablets by mouth daily.&#xD;
If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: one tablet by mouth every other day. If serum potassium level is &lt;5.0 mmol/L at four weeks, increase to one tablet by mouth daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Eplerenone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eplerenone 25 mg tablet by mouth daily. If serum potassium level is &lt;5.0 mmol/L at four weeks, increase to two 25 mg tablets by mouth daily.&#xD;
If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: eplerenone 25 mg tablet by mouth every other day. If serum potassium level is &lt;5.0 mmol/L at four weeks, increase to 25 mg tablet by mouth daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eplerenone</intervention_name>
    <arm_group_label>Eplerenone</arm_group_label>
    <other_name>Inspra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stage I-III breast cancer&#xD;
&#xD;
          -  Scheduled to undergo treatment with doxorubicin-based chemotherapy regimen&#xD;
&#xD;
          -  Able to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of anthracycline agents other than doxorubicin&#xD;
&#xD;
          -  Baseline LVEF ≤50% by any modality (nuclear, echo, MRI)&#xD;
&#xD;
          -  Atrial fibrillation or flutter&#xD;
&#xD;
          -  Mitral valve disease (More than mild mitral stenosis or regurgitation, previous mitral&#xD;
             valve replacement or repair)&#xD;
&#xD;
          -  Inability to obtain adequate echo images for required analysis&#xD;
&#xD;
          -  Hyperkalemia (K+ &gt;5.0)&#xD;
&#xD;
          -  Glomerular filtration rate (GFR) &lt;30 ml/min/1.73m2&#xD;
&#xD;
          -  Uncontrolled hypertension, defined as having a systolic blood pressure &gt; 180 mmHg&#xD;
             and/or a diastolic blood pressure &gt;110 mmHg&#xD;
&#xD;
          -  Symptomatic hypotension or systolic blood pressure &lt;85 mmHg&#xD;
&#xD;
          -  History of hypersensitivity to eplerenone or spironolactone&#xD;
&#xD;
          -  Significant hepatic disease (e.g., previously documented positive serology for viral&#xD;
             hepatitis) or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)&#xD;
             &gt;3 times the upper limits of normal&#xD;
&#xD;
          -  Concomitant treatment with spironolactone, potassium-sparing diuretics, potassium&#xD;
             supplements, or strong inhibitors of cytochrome P450 3A4 (CYP3A4) (i.e. ketoconazole,&#xD;
             itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir)&#xD;
&#xD;
          -  History of alcohol and/or any other drug abuse&#xD;
&#xD;
          -  Women who are either pregnant, lactating or of childbearing potential and not using an&#xD;
             acceptable method of contraception&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with trial participation or&#xD;
             investigational product administration or may interfere with the interpretation of&#xD;
             trial results and, in the judgment of the investigator, would make the subject&#xD;
             inappropriate for entry into this trial&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sean A Virani, MD, MSc, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of British Columbia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Margot Davis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of British Columbia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>British Columbia Cancer Agency, Vancouver Centre</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 4E6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979 Nov;91(5):710-7. doi: 10.7326/0003-4819-91-5-710.</citation>
    <PMID>496103</PMID>
  </reference>
  <reference>
    <citation>Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelman A, Reddy S, Pendergrass K, Velez-Garcia E, Ewer MS, Bianchine JR, Gams RA. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol. 1997 Apr;15(4):1318-32. doi: 10.1200/JCO.1997.15.4.1318.</citation>
    <PMID>9193323</PMID>
  </reference>
  <reference>
    <citation>Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005 Dec;131(5):561-78. doi: 10.1111/j.1365-2141.2005.05759.x.</citation>
    <PMID>16351632</PMID>
  </reference>
  <reference>
    <citation>Kizaki K, Ito R, Okada M, Yoshioka K, Uchide T, Temma K, Mutoh K, Uechi M, Hara Y. Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice. Pharmacol Res. 2006 Apr;53(4):341-6. doi: 10.1016/j.phrs.2006.01.001. Epub 2006 Feb 7.</citation>
    <PMID>16455267</PMID>
  </reference>
  <reference>
    <citation>Goetzenich A, Hatam N, Zernecke A, Weber C, Czarnotta T, Autschbach R, Christiansen S. Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. J Heart Lung Transplant. 2009 Oct;28(10):1087-93. doi: 10.1016/j.healun.2009.06.025. Erratum In: J Heart Lung Transplant. 2009 Dec;28(12):1348.</citation>
    <PMID>19782292</PMID>
  </reference>
  <reference>
    <citation>Spallarossa P, Altieri P, Garibaldi S, Ghigliotti G, Barisione C, Manca V, Fabbi P, Ballestrero A, Brunelli C, Barsotti A. Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res. 2006 Feb 15;69(3):736-45. doi: 10.1016/j.cardiores.2005.08.009. Epub 2005 Oct 6.</citation>
    <PMID>16213474</PMID>
  </reference>
  <reference>
    <citation>Zhao Y, McLaughlin D, Robinson E, Harvey AP, Hookham MB, Shah AM, McDermott BJ, Grieve DJ. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res. 2010 Nov 15;70(22):9287-97. doi: 10.1158/0008-5472.CAN-10-2664. Epub 2010 Sep 30.</citation>
    <PMID>20884632</PMID>
  </reference>
  <reference>
    <citation>Clark JE, Sarafraz N, Marber MS. Potential of p38-MAPK inhibitors in the treatment of ischaemic heart disease. Pharmacol Ther. 2007 Nov;116(2):192-206. doi: 10.1016/j.pharmthera.2007.06.013. Epub 2007 Jul 24.</citation>
    <PMID>17765316</PMID>
  </reference>
  <reference>
    <citation>Bellahcene M, Jacquet S, Cao XB, Tanno M, Haworth RS, Layland J, Kabir AM, Gaestel M, Davis RJ, Flavell RA, Shah AM, Avkiran M, Marber MS. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. J Am Coll Cardiol. 2006 Aug 1;48(3):545-55. doi: 10.1016/j.jacc.2006.02.072. Epub 2006 Jul 12.</citation>
    <PMID>16875982</PMID>
  </reference>
  <reference>
    <citation>Martos R, Baugh J, Ledwidge M, O'Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007 Feb 20;115(7):888-95. doi: 10.1161/CIRCULATIONAHA.106.638569. Epub 2007 Feb 5.</citation>
    <PMID>17283265</PMID>
  </reference>
  <reference>
    <citation>Klappacher G, Franzen P, Haab D, Mehrabi M, Binder M, Plesch K, Pacher R, Grimm M, Pribill I, Eichler HG, et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol. 1995 May 1;75(14):913-8. doi: 10.1016/s0002-9149(99)80686-9.</citation>
    <PMID>7733000</PMID>
  </reference>
  <reference>
    <citation>Host NB, Jensen LT, Bendixen PM, Jensen SE, Koldkjaer OG, Simonsen EE. The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol. 1995 Nov 1;76(12):869-73. doi: 10.1016/s0002-9149(99)80251-3.</citation>
    <PMID>7484822</PMID>
  </reference>
  <reference>
    <citation>Di Zhang A, Nguyen Dinh Cat A, Soukaseum C, Escoubet B, Cherfa A, Messaoudi S, Delcayre C, Samuel JL, Jaisser F. Cross-talk between mineralocorticoid and angiotensin II signaling for cardiac remodeling. Hypertension. 2008 Dec;52(6):1060-7. doi: 10.1161/HYPERTENSIONAHA.108.117531. Epub 2008 Nov 3.</citation>
    <PMID>18981328</PMID>
  </reference>
  <reference>
    <citation>Hori Y, Yoshioka K, Kanai K, Hoshi F, Itoh N, Higuchi S. Spironolactone decreases isoproterenol-induced ventricular fibrosis and matrix metalloproteinase-2 in rats. Biol Pharm Bull. 2011;34(1):61-5. doi: 10.1248/bpb.34.61.</citation>
    <PMID>21212518</PMID>
  </reference>
  <reference>
    <citation>Rude MK, Duhaney TA, Kuster GM, Judge S, Heo J, Colucci WS, Siwik DA, Sam F. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension. 2005 Sep;46(3):555-61. doi: 10.1161/01.HYP.0000176236.55322.18. Epub 2005 Jul 25.</citation>
    <PMID>16043662</PMID>
  </reference>
  <reference>
    <citation>Zannad F, Dousset B, Alla F. Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension. 2001 Nov;38(5):1227-32. doi: 10.1161/hy1101.099484.</citation>
    <PMID>11711528</PMID>
  </reference>
  <reference>
    <citation>Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102(22):2700-6. doi: 10.1161/01.cir.102.22.2700. Erratum In: Circulation 2001 Jan 23;103(3):476.</citation>
    <PMID>11094035</PMID>
  </reference>
  <reference>
    <citation>Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002 May;13(5):699-709. doi: 10.1093/annonc/mdf132.</citation>
    <PMID>12075737</PMID>
  </reference>
  <reference>
    <citation>Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R, Pouleur H. Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J. 1989 Jul;118(1):92-8. doi: 10.1016/0002-8703(89)90077-x.</citation>
    <PMID>2741800</PMID>
  </reference>
  <reference>
    <citation>Ewer MS, Ali MK, Mackay B, Wallace S, Valdivieso M, Legha SS, Benjamin RS, Haynie TP. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin. J Clin Oncol. 1984 Feb;2(2):112-7. doi: 10.1200/JCO.1984.2.2.112.</citation>
    <PMID>6699662</PMID>
  </reference>
  <reference>
    <citation>Dodos F, Halbsguth T, Erdmann E, Hoppe UC. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol. 2008 May;97(5):318-26. doi: 10.1007/s00392-007-0633-6. Epub 2008 Jan 14.</citation>
    <PMID>18193371</PMID>
  </reference>
  <reference>
    <citation>Di Lisi D, Bonura F, Macaione F, Peritore A, Meschisi M, Cuttitta F, Novo G, D'Alessandro N, Novo S. Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction. Anticancer Drugs. 2011 Jun;22(5):468-72. doi: 10.1097/CAD.0b013e3283443704. Erratum In: Anticancer Drugs. 2011 Sep;22(8):825. D'Alessandro, Natale [added].</citation>
    <PMID>21301318</PMID>
  </reference>
  <reference>
    <citation>Nagy AC, Cserep Z, Tolnay E, Nagykalnai T, Forster T. Early diagnosis of chemotherapy-induced cardiomyopathy: a prospective tissue Doppler imaging study. Pathol Oncol Res. 2008 Mar;14(1):69-77. doi: 10.1007/s12253-008-9013-4. Epub 2008 Mar 15.</citation>
    <PMID>18347931</PMID>
  </reference>
  <reference>
    <citation>Pudil R, Horacek JM, Strasova A, Jebavy L, Vojacek J. Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines. Exp Oncol. 2008 Jun;30(2):160-2.</citation>
    <PMID>18566583</PMID>
  </reference>
  <reference>
    <citation>Tassan-Mangina S, Codorean D, Metivier M, Costa B, Himberlin C, Jouannaud C, Blaise AM, Elaerts J, Nazeyrollas P. Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study. Eur J Echocardiogr. 2006 Mar;7(2):141-6. doi: 10.1016/j.euje.2005.04.009. Epub 2005 Jun 6.</citation>
    <PMID>15941672</PMID>
  </reference>
  <reference>
    <citation>Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol. 2001 Jan;37(1):278-85. doi: 10.1016/s0735-1097(00)01056-1.</citation>
    <PMID>11153752</PMID>
  </reference>
  <reference>
    <citation>Hayashi SY, Rohani M, Lindholm B, Brodin LA, Lind B, Barany P, Alvestrand A, Seeberger A. Left ventricular function in patients with chronic kidney disease evaluated by colour tissue Doppler velocity imaging. Nephrol Dial Transplant. 2006 Jan;21(1):125-32. doi: 10.1093/ndt/gfi075. Epub 2005 Oct 12.</citation>
    <PMID>16221719</PMID>
  </reference>
  <reference>
    <citation>Kasner M, Westermann D, Steendijk P, Gaub R, Wilkenshoff U, Weitmann K, Hoffmann W, Poller W, Schultheiss HP, Pauschinger M, Tschope C. Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation. 2007 Aug 7;116(6):637-47. doi: 10.1161/CIRCULATIONAHA.106.661983. Epub 2007 Jul 23.</citation>
    <PMID>17646587</PMID>
  </reference>
  <reference>
    <citation>Edwards NC, Ferro CJ, Kirkwood H, Chue CD, Young AA, Stewart PM, Steeds RP, Townend JN. Effect of spironolactone on left ventricular systolic and diastolic function in patients with early stage chronic kidney disease. Am J Cardiol. 2010 Nov 15;106(10):1505-11. doi: 10.1016/j.amjcard.2010.07.018.</citation>
    <PMID>21059444</PMID>
  </reference>
  <reference>
    <citation>Vizzardi E, D'Aloia A, Giubbini R, Bordonali T, Bugatti S, Pezzali N, Romeo A, Dei Cas A, Metra M, Dei Cas L. Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure. Am J Cardiol. 2010 Nov 1;106(9):1292-6. doi: 10.1016/j.amjcard.2010.06.052. Epub 2010 Sep 9.</citation>
    <PMID>21029826</PMID>
  </reference>
  <reference>
    <citation>Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004 Aug 3;110(5):558-65. doi: 10.1161/01.CIR.0000138680.89536.A9. Epub 2004 Jul 26.</citation>
    <PMID>15277317</PMID>
  </reference>
  <reference>
    <citation>Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31. Erratum In: N Engl J Med. 2003 May 29;348(22):2271.</citation>
    <PMID>12668699</PMID>
  </reference>
  <reference>
    <citation>Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14.</citation>
    <PMID>21073363</PMID>
  </reference>
  <reference>
    <citation>Pinto JT, Delman BN, Dutta P, Nisselbaum J. Adriamycin-induced increase in serum aldosterone levels: effects in riboflavin-sufficient and riboflavin-deficient rats. Endocrinology. 1990 Sep;127(3):1495-501. doi: 10.1210/endo-127-3-1495.</citation>
    <PMID>2387263</PMID>
  </reference>
  <reference>
    <citation>Cardinale D, Sandri MT. Role of biomarkers in chemotherapy-induced cardiotoxicity. Prog Cardiovasc Dis. 2010 Sep-Oct;53(2):121-9. doi: 10.1016/j.pcad.2010.04.002.</citation>
    <PMID>20728699</PMID>
  </reference>
  <reference>
    <citation>Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensin-converting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet. 1996 Feb 3;347(8997):297-9. doi: 10.1016/s0140-6736(96)90469-9.</citation>
    <PMID>8569365</PMID>
  </reference>
  <reference>
    <citation>Georgakopoulos P, Roussou P, Matsakas E, Karavidas A, Anagnostopoulos N, Marinakis T, Galanopoulos A, Georgiakodis F, Zimeras S, Kyriakidis M, Ahimastos A. Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up. Am J Hematol. 2010 Nov;85(11):894-6. doi: 10.1002/ajh.21840.</citation>
    <PMID>20872550</PMID>
  </reference>
  <reference>
    <citation>Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002 Mar 1;20(5):1215-21. doi: 10.1200/JCO.2002.20.5.1215.</citation>
    <PMID>11870163</PMID>
  </reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>October 15, 2012</study_first_submitted>
  <study_first_submitted_qc>October 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 17, 2012</study_first_posted>
  <last_update_submitted>January 3, 2017</last_update_submitted>
  <last_update_submitted_qc>January 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 5, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diastolic heart failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Eplerenone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01708798
org study id: H12-00185
nct id: NCT01708798
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Doxorubicin and other anthracyclines are commonly used to treat breast cancer and other types
      of cancer. Unfortunately, they can cause heart muscle damage, resulting in scarring, abnormal
      contraction and relaxation, and heart failure symptoms. This side effect occurs more
      frequently at higher doses, and limits the total dose that can be given to cancer patients.
      Eplerenone is an oral medication that prevents or reverses heart damage in other disease
      states, and is commonly used to treat heart failure. This study will investigate the use of
      eplerenone to protect the heart from these harmful side effects of doxorubicin.

      Few therapies have been shown to prevent heart damage in patients receiving anthracyclines.
      Small studies have suggested that other heart failure medications (ACE inhibitors,
      beta-blockers) may reduce the incidence of cardiac toxicity, but eplerenone and other drugs
      in its class (aldosterone antagonists) have not previously been studied. Eplerenone inhibits
      enzyme pathways that cause scarring of the heart, and animal studies suggest that
      anthracyclines cause damage through these same pathways.

      This study aims to investigate whether eplerenone protects the heart from the harmful effects
      of doxorubicin chemotherapy. Specifically, it will measure the effect that eplerenone has on
      heart muscle relaxation. It will randomly assign women undergoing chemotherapy with
      doxorubicin to one of two groups: one group will receive eplerenone, and the other group will
      receive placebo (sugar) pills. The subjects will not know which type of pills they are
      taking. Heart muscle relaxation will be measured at baseline, after completion of
      chemotherapy (8-12 weeks), and after 6 months. There will also be various blood tests
      measured in the study subjects, to determine whether there might be certain blood tests that
      identify patients at particularly high risk of heart toxicity after doxorubicin therapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in average E' (averaged septal E' and lateral E')
time frame: 6 months
description: The average early diastolic tissue velocity of the mitral valve annulus measured by tissue Doppler echocardiography (averaged velocities of the mitral annulus measured at the lateral edge and the septal edge)
measure: Development of worsening diastolic function
time frame: 6 months
description: Development of worsening diastolic function, defined as a decline by at least one American Society of Echocardiography gradation of diastolic dysfunction
measure: Development of worsening systolic function
time frame: 6 months
description: Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%
measure: Change in septal E'
time frame: 6 months
description: Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)
measure: Change in lateral E'
time frame: 6 months
description: Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)
measure: Change in E/E'
time frame: 6 months
description: Change in the ratio of early diastolic mitral inflow velocity (E, measured by pulse wave Doppler echocardiography) to the average early diastolic tissue velocity of the mitral annulus (E', measured by tissue Doppler echocardiography)
measure: Change in E/A
time frame: 6 months
description: Change in the ratio of peak early diastolic mitral inflow velocity (E) to peak mitral inflow velocity during atrial systole (A), both measured by pulse wave Doppler echocardiography
measure: Change in left atrial volume index
time frame: 6 months
description: Change in the left atrial volume index, defined as the left atrial volume measured on the 2D echocardiogram indexed to body surface area
measure: Change in left ventricular ejection fraction (LVEF)
time frame: 6 months
description: Change in LVEF, measured by echocardiogram using Simpson's method
measure: Biomarkers
time frame: Baseline, 1 week, 2 weeks, 4 weeks, 6 months
description: Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity
measure: Incidence of hyperkalemia
time frame: 6 months
description: Incidence of hyperkalemia defined as serum potassium >5.5 mmol/L
measure: Incidence of adverse events leading to discontinuation of study drug
time frame: 6 months
description: Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure
measure: Signal-averaged ECG (SAECG) changes
time frame: Baseline, 8-12 weeks, 6 months
description: Change in late potentials measured on SAECG
measure: Exercise stress test
time frame: Baseline, 6 months
description: Change in QT/RR interval slope, exercise capacity, peak heart rate, heart rate recovery, ventricular arrhythmias during exercise, ventricular arrhythmias during recovery, presence of ischemia
measure: Genetic predictors of cardiotoxicity and of response to eplerenone
time frame: 6 months
description: Genetic predictors of cardiotoxicity and of response to eplerenone
measure: ECG changes
time frame: Pre- and post-chemotherapy infusions (over 8-12 weeks)
description: Change in QT interval, arrhythmias
measure: Global longitudinal strain (GLS)
time frame: 6 months
description: Change in GLS from baseline to 6 months
arm group label: Placebo
arm group type: Placebo Comparator
description: One tablet by mouth daily. If serum potassium level is <5.0 mmol/L at four weeks, increase to two tablets by mouth daily.
If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: one tablet by mouth every other day. If serum potassium level is <5.0 mmol/L at four weeks, increase to one tablet by mouth daily.
arm group label: Eplerenone
arm group type: Experimental
description: Eplerenone 25 mg tablet by mouth daily. If serum potassium level is <5.0 mmol/L at four weeks, increase to two 25 mg tablets by mouth daily.
If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: eplerenone 25 mg tablet by mouth every other day. If serum potassium level is <5.0 mmol/L at four weeks, increase to 25 mg tablet by mouth daily.
intervention type: Drug
intervention name: Eplerenone
arm group label: Eplerenone
other name: Inspra
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sean A Virani, MD, MSc, MPH
role: Principal Investigator
affiliation: University of British Columbia
last name: Margot Davis, MD
role: Principal Investigator
affiliation: University of British Columbia
facility: 
country: Canada
citation: Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, Muggia FM. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979 Nov;91(5):710-7. doi: 10.7326/0003-4819-91-5-710.
PMID: 496103
citation: Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelman A, Reddy S, Pendergrass K, Velez-Garcia E, Ewer MS, Bianchine JR, Gams RA. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol. 1997 Apr;15(4):1318-32. doi: 10.1200/JCO.1997.15.4.1318.
PMID: 9193323
citation: Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005 Dec;131(5):561-78. doi: 10.1111/j.1365-2141.2005.05759.x.
PMID: 16351632
citation: Kizaki K, Ito R, Okada M, Yoshioka K, Uchide T, Temma K, Mutoh K, Uechi M, Hara Y. Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice. Pharmacol Res. 2006 Apr;53(4):341-6. doi: 10.1016/j.phrs.2006.01.001. Epub 2006 Feb 7.
PMID: 16455267
citation: Goetzenich A, Hatam N, Zernecke A, Weber C, Czarnotta T, Autschbach R, Christiansen S. Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. J Heart Lung Transplant. 2009 Oct;28(10):1087-93. doi: 10.1016/j.healun.2009.06.025. Erratum In: J Heart Lung Transplant. 2009 Dec;28(12):1348.
PMID: 19782292
citation: Spallarossa P, Altieri P, Garibaldi S, Ghigliotti G, Barisione C, Manca V, Fabbi P, Ballestrero A, Brunelli C, Barsotti A. Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res. 2006 Feb 15;69(3):736-45. doi: 10.1016/j.cardiores.2005.08.009. Epub 2005 Oct 6.
PMID: 16213474
citation: Zhao Y, McLaughlin D, Robinson E, Harvey AP, Hookham MB, Shah AM, McDermott BJ, Grieve DJ. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res. 2010 Nov 15;70(22):9287-97. doi: 10.1158/0008-5472.CAN-10-2664. Epub 2010 Sep 30.
PMID: 20884632
citation: Clark JE, Sarafraz N, Marber MS. Potential of p38-MAPK inhibitors in the treatment of ischaemic heart disease. Pharmacol Ther. 2007 Nov;116(2):192-206. doi: 10.1016/j.pharmthera.2007.06.013. Epub 2007 Jul 24.
PMID: 17765316
citation: Bellahcene M, Jacquet S, Cao XB, Tanno M, Haworth RS, Layland J, Kabir AM, Gaestel M, Davis RJ, Flavell RA, Shah AM, Avkiran M, Marber MS. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. J Am Coll Cardiol. 2006 Aug 1;48(3):545-55. doi: 10.1016/j.jacc.2006.02.072. Epub 2006 Jul 12.
PMID: 16875982
citation: Martos R, Baugh J, Ledwidge M, O'Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007 Feb 20;115(7):888-95. doi: 10.1161/CIRCULATIONAHA.106.638569. Epub 2007 Feb 5.
PMID: 17283265
citation: Klappacher G, Franzen P, Haab D, Mehrabi M, Binder M, Plesch K, Pacher R, Grimm M, Pribill I, Eichler HG, et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on diagnosis and prognosis. Am J Cardiol. 1995 May 1;75(14):913-8. doi: 10.1016/s0002-9149(99)80686-9.
PMID: 7733000
citation: Host NB, Jensen LT, Bendixen PM, Jensen SE, Koldkjaer OG, Simonsen EE. The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol. 1995 Nov 1;76(12):869-73. doi: 10.1016/s0002-9149(99)80251-3.
PMID: 7484822
citation: Di Zhang A, Nguyen Dinh Cat A, Soukaseum C, Escoubet B, Cherfa A, Messaoudi S, Delcayre C, Samuel JL, Jaisser F. Cross-talk between mineralocorticoid and angiotensin II signaling for cardiac remodeling. Hypertension. 2008 Dec;52(6):1060-7. doi: 10.1161/HYPERTENSIONAHA.108.117531. Epub 2008 Nov 3.
PMID: 18981328
citation: Hori Y, Yoshioka K, Kanai K, Hoshi F, Itoh N, Higuchi S. Spironolactone decreases isoproterenol-induced ventricular fibrosis and matrix metalloproteinase-2 in rats. Biol Pharm Bull. 2011;34(1):61-5. doi: 10.1248/bpb.34.61.
PMID: 21212518
citation: Rude MK, Duhaney TA, Kuster GM, Judge S, Heo J, Colucci WS, Siwik DA, Sam F. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension. 2005 Sep;46(3):555-61. doi: 10.1161/01.HYP.0000176236.55322.18. Epub 2005 Jul 25.
PMID: 16043662
citation: Zannad F, Dousset B, Alla F. Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension. 2001 Nov;38(5):1227-32. doi: 10.1161/hy1101.099484.
PMID: 11711528
citation: Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102(22):2700-6. doi: 10.1161/01.cir.102.22.2700. Erratum In: Circulation 2001 Jan 23;103(3):476.
PMID: 11094035
citation: Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002 May;13(5):699-709. doi: 10.1093/annonc/mdf132.
PMID: 12075737
citation: Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R, Pouleur H. Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J. 1989 Jul;118(1):92-8. doi: 10.1016/0002-8703(89)90077-x.
PMID: 2741800
citation: Ewer MS, Ali MK, Mackay B, Wallace S, Valdivieso M, Legha SS, Benjamin RS, Haynie TP. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin. J Clin Oncol. 1984 Feb;2(2):112-7. doi: 10.1200/JCO.1984.2.2.112.
PMID: 6699662
citation: Dodos F, Halbsguth T, Erdmann E, Hoppe UC. Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol. 2008 May;97(5):318-26. doi: 10.1007/s00392-007-0633-6. Epub 2008 Jan 14.
PMID: 18193371
citation: Di Lisi D, Bonura F, Macaione F, Peritore A, Meschisi M, Cuttitta F, Novo G, D'Alessandro N, Novo S. Chemotherapy-induced cardiotoxicity: role of the tissue Doppler in the early diagnosis of left ventricular dysfunction. Anticancer Drugs. 2011 Jun;22(5):468-72. doi: 10.1097/CAD.0b013e3283443704. Erratum In: Anticancer Drugs. 2011 Sep;22(8):825. D'Alessandro, Natale [added].
PMID: 21301318
citation: Nagy AC, Cserep Z, Tolnay E, Nagykalnai T, Forster T. Early diagnosis of chemotherapy-induced cardiomyopathy: a prospective tissue Doppler imaging study. Pathol Oncol Res. 2008 Mar;14(1):69-77. doi: 10.1007/s12253-008-9013-4. Epub 2008 Mar 15.
PMID: 18347931
citation: Pudil R, Horacek JM, Strasova A, Jebavy L, Vojacek J. Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines. Exp Oncol. 2008 Jun;30(2):160-2.
PMID: 18566583
citation: Tassan-Mangina S, Codorean D, Metivier M, Costa B, Himberlin C, Jouannaud C, Blaise AM, Elaerts J, Nazeyrollas P. Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study. Eur J Echocardiogr. 2006 Mar;7(2):141-6. doi: 10.1016/j.euje.2005.04.009. Epub 2005 Jun 6.
PMID: 15941672
citation: Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol. 2001 Jan;37(1):278-85. doi: 10.1016/s0735-1097(00)01056-1.
PMID: 11153752
citation: Hayashi SY, Rohani M, Lindholm B, Brodin LA, Lind B, Barany P, Alvestrand A, Seeberger A. Left ventricular function in patients with chronic kidney disease evaluated by colour tissue Doppler velocity imaging. Nephrol Dial Transplant. 2006 Jan;21(1):125-32. doi: 10.1093/ndt/gfi075. Epub 2005 Oct 12.
PMID: 16221719
citation: Kasner M, Westermann D, Steendijk P, Gaub R, Wilkenshoff U, Weitmann K, Hoffmann W, Poller W, Schultheiss HP, Pauschinger M, Tschope C. Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation. 2007 Aug 7;116(6):637-47. doi: 10.1161/CIRCULATIONAHA.106.661983. Epub 2007 Jul 23.
PMID: 17646587
citation: Edwards NC, Ferro CJ, Kirkwood H, Chue CD, Young AA, Stewart PM, Steeds RP, Townend JN. Effect of spironolactone on left ventricular systolic and diastolic function in patients with early stage chronic kidney disease. Am J Cardiol. 2010 Nov 15;106(10):1505-11. doi: 10.1016/j.amjcard.2010.07.018.
PMID: 21059444
citation: Vizzardi E, D'Aloia A, Giubbini R, Bordonali T, Bugatti S, Pezzali N, Romeo A, Dei Cas A, Metra M, Dei Cas L. Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure. Am J Cardiol. 2010 Nov 1;106(9):1292-6. doi: 10.1016/j.amjcard.2010.06.052. Epub 2010 Sep 9.
PMID: 21029826
citation: Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004 Aug 3;110(5):558-65. doi: 10.1161/01.CIR.0000138680.89536.A9. Epub 2004 Jul 26.
PMID: 15277317
citation: Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31. Erratum In: N Engl J Med. 2003 May 29;348(22):2271.
PMID: 12668699
citation: Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14.
PMID: 21073363
citation: Pinto JT, Delman BN, Dutta P, Nisselbaum J. Adriamycin-induced increase in serum aldosterone levels: effects in riboflavin-sufficient and riboflavin-deficient rats. Endocrinology. 1990 Sep;127(3):1495-501. doi: 10.1210/endo-127-3-1495.
PMID: 2387263
citation: Cardinale D, Sandri MT. Role of biomarkers in chemotherapy-induced cardiotoxicity. Prog Cardiovasc Dis. 2010 Sep-Oct;53(2):121-9. doi: 10.1016/j.pcad.2010.04.002.
PMID: 20728699
citation: Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensin-converting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet. 1996 Feb 3;347(8997):297-9. doi: 10.1016/s0140-6736(96)90469-9.
PMID: 8569365
citation: Georgakopoulos P, Roussou P, Matsakas E, Karavidas A, Anagnostopoulos N, Marinakis T, Galanopoulos A, Georgiakodis F, Zimeras S, Kyriakidis M, Ahimastos A. Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up. Am J Hematol. 2010 Nov;85(11):894-6. doi: 10.1002/ajh.21840.
PMID: 20872550
citation: Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002 Mar 1;20(5):1215-21. doi: 10.1200/JCO.2002.20.5.1215.
PMID: 11870163
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Eplerenone
sharing ipd: No