Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer

Summary

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.

Timeline

Start

2014-05

Primary completion

2016-11

Completion

2016-11

Publications

• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.

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