Effect of Remote Ischaemic Conditioning in Oncology Patients Undergoing Chemotherapy: Rationale and Design of the ERIC-ONC Study--A Single-Center, Blinded, Randomized Controlled Trial

Robin Chung, Angshuman Maulik, Ashraf Hamarneh, Daniel Hochhauser, Derek J Hausenloy, J Malcolm Walker, Derek M Yellon, Robin Chung, Angshuman Maulik, Ashraf Hamarneh, Daniel Hochhauser, Derek J Hausenloy, J Malcolm Walker, Derek M Yellon

Abstract

Cancer survival continues to improve, and thus cardiovascular consequences of chemotherapy are increasingly important determinants of long-term morbidity and mortality. Conventional strategies to protect the heart from chemotherapy have important hemodynamic or myelosuppressive side effects. Remote ischemic conditioning (RIC) using intermittent limb ischemia-reperfusion reduces myocardial injury in the setting of percutaneous coronary intervention. Anthracycline cardiotoxicity and ischemia-reperfusion injury share common biochemical pathways in cardiomyocytes. The potential for RIC as a novel treatment to reduce subclinical myocyte injury in chemotherapy has never been explored and will be investigated in the Effect of Remote Ischaemic Conditioning in Oncology (ERIC-ONC) trial (clinicaltrials.gov NCT 02471885). The ERIC-ONC trial is a single-center, blinded, randomized, sham-controlled study. We aim to recruit 128 adult oncology patients undergoing anthracycline-based chemotherapy treatment, randomized in a 1:1 ratio into 2 groups: (1) sham procedure or (2) RIC, comprising 4, 5-minute cycles of upper arm blood pressure cuff inflations and deflations, immediately before each cycle of chemotherapy. The primary outcome measure, defining cardiac injury, will be high-sensitivity troponin-T over 6 cycles of chemotherapy and 12 months follow-up. Secondary outcome measures will include clinical, electrical, structural, and biochemical endpoints comprising major adverse cardiovascular clinical events, incidence of cardiac arrhythmia over 14 days at cycle 5/6, echocardiographic ventricular function, N-terminal pro-brain natriuretic peptide levels at 3 months follow-up, and changes in mitochondrial DNA, micro-RNA, and proteomics after chemotherapy. The ERIC-ONC trial will determine the efficacy of RIC as a novel, noninvasive, nonpharmacological, low-cost cardioprotectant in cancer patients undergoing anthracycline-based chemotherapy.

Trial registration: ClinicalTrials.gov NCT02471885.

© 2016 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

Figures

Figure 1
Figure 1
Reperfusion injury and doxorubicin cardiotoxicity pathways. Pathological activation of RoS formation, calcium overload, and altered mitochondrial respiration in reperfusion injury are also found in anthracycline cardiotoxicity. (Reproduced under license from Yellon and Hausenloy86 and the Massachusetts Medical Society/New England Journal of Medicine.). Abbreviations: ICAM‐1, intercellular cell adhesion molecule‐1; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; PTP, permeability transition pore.
Figure 2
Figure 2
Study flowchart diagram. Abbreviations: BP, blood pressure; DCM, dilated cardiomyopathy; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; FBC, full blood count; HCM, hypertrophic cardiomyopathy; hsTnT, high‐sensitivity troponin‐T; LN, lymph node; NT pro‐BNP, N‐terminal pro‐brain natriuretic peptide; RIC, remote ischemic conditioning; U + E, urea and electrolytes.

References

    1. Cancer Research UK . Survive cancer for 10 or more years, 2010–11, England and Wales. . Accessed April 2014.
    1. Siegel R, Desantis C, Virgo K. Cancer treatment and survivorship statistics. Cancer J Clin. 2012;62:220–241.
    1. Maddams J, Utley M, Møller H. Projections of cancer prevalence in the United Kingdom, 2010–2040. Br J Cancer. 2012;107:1195–1202.
    1. Kero AE, Järvelä LS, Arola M, et al. Cardiovascular morbidity in long‐term survivors of early‐onset cancer: a population‐based study. Int J Cancer. 2014;134:664–673.
    1. Ning Y, Shen Q, Herrick K. Cause of death in cancer survivors [abstract]. Cancer Res. 2012;72:LB‐339.
    1. Tewey KM, Rowe TC, Yang L, et al. Adriamycin‐induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226:466–468.
    1. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res. 1983;43:460–472.
    1. Link G, Tirosh R, Pinson A. Role of iron in the potentiation of anthracyclinecardiotoxicity: identification of heart cell mitochrondria as a major site of iron‐anthracycline interaction. J Lab Clin Med. 1996;127:272–278.
    1. Lyu YL, Kerrigan JE, Lin C, et al. Topoisomerase II‐beta mediated DNA double‐strand breaks: implications in doxorubicin cardiotoxicity prevention by dexrazoxane. Cancer Res. 2007;67:8839–8846.
    1. Zhang S, Lui X, Bawa‐Khalfe T, et al. Identification of the molecular basis of doxorubicin‐induced cardiotoxicity. Nature Med. 2012;18:1639–1642.
    1. Ali SR, Hippenmeyer S, Saadat LV, et al. Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc Natl Acad Sci U S A. 2014;111:8850–8855.
    1. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010;7:564–575.
    1. Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428:664–668.
    1. Vejpongsa P, Yeh ETH. Prevention of anthracycline‐induced cardiotoxicity. J Am Coll Cardiol. 2014;64:938–945.
    1. Dodd DA. Doxorubicin cardiomyopathy is associated with a decrease in calcium release channel of the sarcoplasmic reticulum in a chronic rabbit model. J Clin Invest. 1993;91:1697–1705.
    1. Lim CC. Anthracyclines induce calpain‐dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem. 2004;279:8290–8299.
    1. Montaigne D, Marechal X, Preau S, et al. Doxorubicin induces mitochondrial permeability transition and contractile dysfunction in the human myocardium. Mitochondrion. 2011;11:22–26.
    1. Von Hoff DD, Layard MW, Basa P. Risk factors for doxorubicin‐induced congestive heart failure. Ann Intern Med. 1979;91:710–717.
    1. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long‐term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077–1084.
    1. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869–2879.
    1. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131:1981–1988.
    1. Lotrionte M, Biondi‐Zoccai G, Abbate A, et al. Review and meta‐analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013;112:1980–1984.
    1. Valdievieso M, Burgess MA, Ewer MS. Increased therapeutic index of weekly doxorubicin in the therapy of non‐small cell lung cancer: a prospective, randomized study. J Clin Oncol. 1984;2:207–214.
    1. Legha SS, Benjamin RS, Mackay B. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med. 1982;96:133–139.
    1. Waterhouse DN, Tardi PG, Mayer LD. A comparison of liposomal formulations of doxorubicin with drug administered in free form changing toxicity profiles. Drug Saf. 2001;24:903–920.
    1. U.S. Food and Drug Administration . FDA statement on dexrazoxane. . Published July, 20, 2011. Accessed October 24, 2014.
    1. Ammar el SM, Said SA, Suddek GM, et al. Amelioration of doxorubicin‐induced cardiotoxicity by deferiprone in rats. Can J Physiol Pharmacol. 2011;89:269–276.
    1. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin‐treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351:145–153.
    1. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin‐treated children with high‐risk acute lymphoblastic leukaemia: long‐term follow‐up of a prospective, randomised, multicentre trial. Lancet Oncol. 2010;11:950–961.
    1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136.
    1. Fröhlich GM, Meier P, White SK, et al. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J. 2013;34:1714–1722.
    1. Lipshultz SE, Karnik R, Sambatakos P, et al. Anthracycline‐related cardiotoxicity in childhood cancer survivors. Curr Opin Cardiol. 2014;29:103–112.
    1. Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7:108–113.
    1. Jirkovsky E, Popelová O, Kriváková‐Stanková P, et al. Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on nuclear factor erythroid 2‐related factor 2 and mitochondrial biogenesis pathways. J Pharmacol Exp Ther. 2012;343:468–478.
    1. Gharanei M, Hussain A, Janneh O, et al. Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore. Toxicol Appl Pharmacol. 2013;268:149–156.
    1. Sandhu H, Maddock H. Molecular basis of cancer‐therapy‐induced cardiotoxicity: introducing microRNA biomarkers for early assessment of subclinical myocardial injury. Clin Sci (Lond). 2014;126:377–400.
    1. Sterba M, Popelová O, Vávrová A, et al. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal. 2013;18:899–929.
    1. Cancer Research UK . Cancer statistics for the UK. Cancer mortality 2012. . Accessed October 27, 2014.
    1. Kubo T, Kitaoka H, Yamanaka S, et al. Significance of high‐sensitivity cardiac troponin T in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2013;62:1252–1259.
    1. Palladini G, Barassi A, Klersy C, et al. The combination of high‐sensitivity cardiac troponin T (hs‐cTnT) at presentation and changes in N‐terminal natriuretic peptide type B (NT‐proBNP) after chemotherapy best predicts survival in AL amyloidosis. Blood. 2010;116:3426–3430.
    1. Feustel A, Hahn A, Schneider C, et al. Continuous cardiac troponin I release in Fabry disease. PLoS One. 2014;9:e91757.
    1. Zografos TA, Katritsis GD, Tsiafoutis I, et al. Effect of one‐cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention. Am J Cardiol. 2014;113:2013–2017.
    1. Hershman DL, McBride RB, Eisenberger A, et al. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B‐cell non‐Hodgkin's lymphoma. J Clin Oncol. 2008;26:3159–3165.
    1. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata‐driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381.
    1. Candilio L, Malik A, Ariti C, et al. Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial. Heart. 2015;101:185–192.
    1. Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370:575–579.
    1. Hoole SP, Heck PM, Sharples L, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study: a prospective, randomized control trial. Circulation. 2009;119:820–827.
    1. Thielmann M, Kottenberg E, Kleinbongard P, et al. Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single‐centre randomised, double‐blind, controlled trial. Lancet. 2013;382:597–604.
    1. Katsurada K, Ichida M, Sakuragi M, et al. High‐sensitivity troponin T as a marker to predict cardiotoxicity in breast cancer patients with adjuvant trastuzumab therapy. Springerplus. 2014;3:620.
    1. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2014;15:1063–1093.
    1. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126:2020–2035.
    1. Grinstein J, Bonaca MP, Jarolim P, et al. Prognostic implications of low level cardiac troponin elevation using high‐sensitivity cardiac troponin T. Clin Cardiol. 2015;38:230–235.
    1. Ahmed AN, Blonde K, Hackam D, et al. Prognostic significance of elevated troponin in non‐cardiac hospitalized patients: a systematic review and meta‐analysis. Ann Med. 2014;46:653–663.
    1. Grodin JL, Neale S, Wu Y, et al. Prognostic comparison of different sensitivity cardiac troponin assays in stable heart failure. Am J Med. 2015;128:276–282.
    1. Hochholzer W, Valina CM, Stratz C, et al. High‐sensitivity cardiac troponin for risk prediction in patients with and without coronary heart disease. Int J Cardiol. 2014;176:444–449.
    1. Kuster N, Monnier K, Baptista G, et al. Estimation of age‐ and comorbidities‐adjusted percentiles of high‐sensitivity cardiac troponin T levels in the elderly. Clin Chem Lab Med. 2015;53:691–698.
    1. Qian G, Wu C, Zhang Y, et al. Prognostic value of high‐sensitivity cardiac troponin T in patients with endomyocardial‐biopsy proven cardiac amyloidosis. J Geriatr Cardiol. 2014;11:136–140.
    1. Yiu KH, Lau KK, Zhao CT, et al. Predictive value of high‐sensitivity troponin‐I for future adverse cardiovascular outcome in stable patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2014;13:63.
    1. Auner HW, Tinchon C, Linkesch W, et al. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Haematol. 2003;82:218–222.
    1. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high‐dose chemotherapy. Circulation. 2004;109:2749–2754.
    1. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful marker for early detection of anthracycline cardiotoxicity. Ann Oncol. 2005;16:798–804.
    1. Thavendiranathan P, Grant AD, Negishi T, et al. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol. 2013;61:77–84.
    1. Ewer MS, Ali MK, Mackay B. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving adriamycin. J Clin Oncol. 1984;2:112–117.
    1. Cardinale D, Sandri MT, Martinoni A, et al. Myocardial injury revealed by plasma troponin I in breast cancer with high‐dose chemotherapy. Ann Oncol. 2002;13:710–715.
    1. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline‐induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55:213–220.
    1. Hidalgo JD, Krone R, Rich MW, et al. Supraventricular tachyarrhythmias after hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Bone Marrow Transplant. 2004;34:615–619.
    1. Hu YF, Liu CJ, Chang PM, et al. Incident thromboembolism and heart failure associated with new‐onset atrial fibrillation in cancer patients. Int J Cardiol. 2013;165:355–357.
    1. Kilickap S, Barista I, Akgul E, et al. Early and late arrhythmogenic effects of doxorubicin. South Med J. 2007;100:262–265.
    1. Okuma K, Furuta I, Ota K. Acute cardiotoxicity of anthracyclines‐‐analysis by using Holter ECG [in Japanese]. Gan To Kagaku Ryoho. 1984;11:902–911.
    1. Cove‐Smith L, Woodhouse N, Hargreaves A, et al. An integrated characterization of serological, pathological, and functional events in doxorubicin‐induced cardiotoxicity. Toxicol Sci. 2014;140:3–15.
    1. Montaigne D, Marechal X, Lefebvre P, et al. Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof‐of‐concept study in patients with metabolic syndrome in whom post‐operative atrial fibrillation develops. J Am Coll Cardiol. 2013;62:1466–1473.
    1. Dresdale AR, Barr LH, Bono RO. Prospective randomized study of the role of N‐acetylcysteine in reversing doxorubicin‐induced cardiomyopathy. Am J Clin Oncol. 1982;5:657–663.
    1. Hasinoff BB, Patel D, Wu X. The oral iron chelator ICL 670A (deferasirox) does not protect myocytes against doxorubicin. Free Radic Biol Med. 2003;35:1469–1479.
    1. van Dalen EC, Raphaël MF, Caron HN, et al. Treatment including anthracyclines versus treatment not including anthracyclines for childhood Cancer. Cochrane Database Syst Rev. 2014;9:CD006647.
    1. Funabiki K, Onishi K, Dohi K, et al. Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure. Am J Physiol Heart Circ Physiol. 2004;287:H2487–H2492.
    1. Seicean S, Seicean A, Plana JC, et al. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol. 2012;60:2384–2390.
    1. Kaya MG, Ozkan M, Gunebakmaz O, et al. Protective effects of nebivolol against anthracycline‐induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013;167:2306–2310.
    1. Seicean S, Seicean A, Alan N, et al. Cardioprotective effect of Beta‐adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow‐up study of heart failure. Circ Heart Fail. 2013;6:420–426.
    1. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high‐dose chemotherapy‐induced cardiotoxicity in high‐risk patients by angiotensin‐converting enzyme inhibition. Circulation. 2006;114:2474–2481.
    1. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta‐analysis. Eur J Cancer. 2013;49:2900–2909.
    1. Hellmann K. Dexrazoxane‐associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without evidence. J Clin Oncol. 2007;25:4689–4690.
    1. Lipshultz SE, Lipsitz SR, Orav EJ. Dexrazoxane‐associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without compelling evidence. J Clin Oncol. 2007;25:3179–3180.
    1. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane‐associated risk of acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007;25:493–500.
    1. Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol. 2011;8:619–629.
    1. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993;342:276–277.
    1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–1135.
    1. Davies WR, Brown AJ, Watson W, et al. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long‐term follow‐up. Circ Cardiovasc Interv. 2013;6:246–251.
    1. Rentoukas I, Giannopoulos G, Kaoukis A, et al. Cardioprotective role of remote ischemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc Interv. 2010;3:49–55.
    1. Botker HE, Kharbanda R, Schmidt MR, et al. Remote ischemic conditioning before hospital admission, as a complement to angioplasty and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375:727–734.
    1. White SK, Frohlich GM, Sado DM, et al. Remote Ischemic conditioning reduces myocardial infarct size and edema in patients with ST‐segment elevation myocardial infarction. JACC Cardiovasc Interv. 2014;14:01073–01075.
    1. Bautin AE, Galagudza MM, Datsenko SV, et al. Effects of remote ischemic preconditioning on perioperative period in elective aortic valve replacement [in Russian]. Anesteziol Reanimatol. 2014;(3):11–17.
    1. Zarbock A, Schmidt C, Van Aken H, et al. Effect of remote ischemic preconditioning on kidney injury among high‐risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015;313:2133–2141.
    1. Sloth AD, Schmidt MR, Munk K, et al. CONDI Investigators. Improved long‐term clinical outcomes in patients with ST‐elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014;35:168–175.
    1. Hausenloy DJ, Candilio L, Laing C, et al. Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi‐centre randomized double‐blinded controlled clinical trial. Clin Res Cardiol. 2012;101:339–348.
    1. Maxwell YL. ERICCA: remote ischemic preconditioning fails to improve long‐term outcomes after CABG. TCTMD website. . Published March 16, 2015. Accessed March 16, 2015.
    1. Martin‐Gill C, Wayne M, Guyette FX, et al. Feasibility of remote ischemic peri‐conditioning during air medical transport of STEMI patients [published online August 13, 2015]. Prehosp Emerg Care. doi:10.3109/10903127.2015.1056894
    1. Li C, Xu M, Wu Y, et al. Limb remote ischemic preconditioning attenuates lung injury after pulmonary resection under propofol‐remifentanil anesthesia: a randomized controlled study. Anesthesiology. 2014;121:249–259.
    1. Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high‐dose chemotherapy. J Am Coll Cardiol. 2000;36:517–522.
    1. Sandri MT, Cardinale D, Zorzino L, et al. Minor increases in plasma troponin I predict decreased left ventricular ejection fraction after high‐dose chemotherapy. Clin Chem. 2003;49:248–252.
    1. Haney S, Cresti N, Verrill M, et al. Cardiac troponin release following standard dose anthracycline‐based adjuvant chemotherapy [abstract]. Eur Heart J. 2013;34(suppl 1):1074.

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