First experience of using valsartan/sacubitril in women with heart failure and breast cancer receiving anthracycline-based adjuvant chemotherapy

Objective. Comparison of the cardioprotective efficacy of valsartan/sacubitril and candesartan in women with heart failure (HF) and an initially reduced left ventricular ejection fraction receiving breast cancer chemotherapy.

Material and methods. A prospective study included 112 women aged 53 to 65 years with systolic heart failure, who received surgical treatment for breast cancer followed by adjuvant polychemotherapy according to the FAC scheme (fluorouracil + doxorubicin + cyclophosphamide) - 6 cycles with intervals between 21 days of administration. After randomization, HF therapy with nebivolol, eplerenone, and valsartan/sacubitril (n = 55) or candesartan (n = 57) was performed. A general clinical laboratory study, electrocardiography, daily Holter monitoring of an electrocardiogram, echocardiography, a 6-minute walk test, quality of life assessment were performed initially and repeatedly after 1, 3, and 6 chemotherapy courses.

Results. Both groups showed a tendency to troponin I level increase and a significant decrease in the concentration of N-terminal prohormone of brain natriuretic peptide. Only the valsartan/sacubitril group showed a statistically significant increase in the 6-minute walk distance, suppression of ventricular cardiac arrhythmias, improved indicators of systolic function of the left ventricle and quality of life when the Minnesota questionnaire was used.

Conclusion. The first randomized trial of valsartan/sacubitril showed superiority compared to candesartan in the treatment of heart failure in women with breast cancer, who received adjuvant chemotherapy, which included anthracycline antibiotic, doxorubicin.

1. Zamorano J.L., Lancellotti P., Rodriguez Muñoz D., Aboyans V., Asteggiano R., Galderisi M. Habib G, Lenihan D.J., Lip G.Y., Lyon A.R., Lopez Fernandez T., Mohty D., Piepoli M.F., Tamargo J., Torbicki A., Suter T.M., Zamorano J.L., Aboyans V., Achenbach S., Agewall S., Badimon L., BarónEsquivias G., Baumgartner H., Bax J.J., Bueno H., Carerj S., Dean V., Erol Ç., Fitzsimons D., Gaemperli O., Kirchhof P., Kolh P., Lancellotti P., Lip G.Y., Nihoyannopoulos P., Piepoli M.F., Ponikowski P., Roffi M., Torbicki A., Vaz Carneiro A., Windecker S.; Authors/Task Force Members; ESC Committee for Practice Guidelines (CPG); Document Reviewers. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). European Journal of Heart Failure. 2017;19(1):9-42. doi: 10.1002/ejhf.654.

2. Moslehi J., Fujiwara K., Guzik T. Cardiooncology: a novel platform for basic and translational cardiovascular investigation driven by clinical need. Cardiovascular Research. 2019;115(5):819-823. doi: 10.1093/cvr/cvz048.

3. Mehta L.S., Watson K.E., Barac A., Beckie T.M., Bittner V., Cruz-Flores S. Dent S, Kondapalli L., Ky B., Okwuosa T., Piña I.L., Volgman A.S. Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association. Circulation. 2018;137(8):e30-e66. doi: 10.1161/CIR.0000000000000556.

4. Cappetta D., Rossi F., Piegari E., Quaini F., Berrino L., Urbanek K., De Angelis A. Doxorubicin targets multiple players: A new view of an old problem. Pharmacological Research. 2018;127:4-14. doi: 10.1016/j.phrs.2017.03.016.

5. Curigliano G., Cardinale D., Dent S., Criscitiello C., Aseyev O., Lenihan D., Cipolla C.M. Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management. CA - A Cancer Journal for Clinicians. 2016;66(4):309-325. doi: 10.3322/caac.21341.

6. Henriksen P.A. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart (British Cardiac Society). 2018;104(12):971-977. doi: 10.1136/ heartjnl-2017-312103.

7. Savarese G., Lund L.H. Global Public Health Burden of Heart Failure. Cardiac failure review. 2017;3(1):7-11. doi: 10.15420/cfr.2016:25:2.

8. Ameri P., Canepa M., Anker M.S., Belenkov Y., Bergler-Klein J., Cohen-Solal A., Farmakis D., López-Fernández T., Lainscak M., Pudil R., Ruschitska F., Seferovic P., Filippatos G., Coats A., Suter T., Von Haehling S., Ciardiello F., de Boer R.A., Lyon A.R., Tocchetti C.G. Cancer diagnosis in patients with heart failure: epidemiology, clinical implications and gaps in knowledge. European Journal of Heart Failure. 2018;20(5):879-887. doi: 10.1002/ejhf.1165.

9. Ponikowski P., Voors A.A., Anker S.D., Bueno H., Cleland J.G.F., Coats A.J.S., Falk V., GonzálezJuanatey J.R., Harjola V.P., Jankowska E.A., Jessup M., Linde C., Nihoyannopoulos P., Parissis J.T., Pieske B., Riley J.P., Rosano G.M.C., Ruilope L.M., Ruschitzka F., Rutten F.H., van der Meer P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European heart journal. 2016;37(27):2129- 2200. doi: 10.1093/eurheartj/ehw128.

10. Yancy C.W., Jessup M., Bozkurt B., Butler J., Casey D.E. Jr., Colvin M.M., Drazner M.H., Filippatos G.S., Fonarow G.C., Givertz M.M., Hollenberg S.M., Lindenfeld J., Masoudi F.A., McBride P.E., Peterson P.N., Stevenson L.W., Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of the American College of Cardiology. 2017;70(6):776-803. doi: 10.1016/j. jacc.2017.04.025.

11. Gulati G., Heck S.L., Ree A.H., Hoffmann P., SchulzMenger J., Fagerland M.W., Gravdehaug B., von Knobelsdorff-Brenkenhoff F., Bratland Å., Storås T.H., Hagve T.A., Røsjø H., Steine K., Geisler J., Omland T. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. European heart journal. 2016;37(21):1671- 1680. doi: 10.1093/eurheartj/ehw022.

12. McMurray J.J., Packer M., Desai A.S., Gong J., Lefkowitz M.P., Rizkala A.R., Rouleau J.L., Shi V.C., Solomon S.D., Swedberg K., Zile M.R. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England journal of medicine. 2014;371(11):993-1004. doi: 10.1056/NEJMoa1409077.

13. Lang R.M., Badano L.P., Mor-Avi V., Afilalo J., Armstrong A., Ernande L. Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. European heart journal cardiovascular Imaging. 2015;16(3):233-270. doi: 10.1093/ehjci/jev014.

14. Nagueh S.F., Smiseth O.A., Appleton C.P., Byrd B.F. 3rd, Dokainish H., Edvardsen T. Flachskampf F.A., Gillebert T.C., Klein A.K., Lancellotti P., Marino P., K. Oh J.K., Popescu B.A., Waggoner A.D. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. European heart journal cardiovascular Imaging. 2016;17(12):1321- 1360. doi: 10.1093/ehjci/jew082.

15. Henriksen P.A. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart (British Cardiac Society). 2018;104(12):971-977. doi: 10.1136/ heartjnl-2017-312103.

16. Stack J.P., Moslehi J., Sayed N., Wu J.C. Cancer therapy-induced cardiomyopathy: can human induced pluripotent stem cell modelling help prevent it? European heart journal. 2019;40(22):1764-1770. doi: 10.1093/eurheartj/ ehx811.

17. Armenian S.H., Lacchetti C., Barac A., Carver J., Constine L.S., Denduluri N., Dent S., Douglas P.S., Durand J.B., Ewer M., Fabian C., Hudson M., Jessup M., Jones L.W., Ky B., Mayer E.L., Moslehi J., Oeffinger K., Ray K., Ruddy K., Lenihan D. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. Journal of clinical oncology. 2017;35(8):893-911. doi: 10.1200/JCO.2016.70.5400.

18. Nadruz W.Jr., West E., Sengeløv M., Grove G.L., Santos M., Groarke J.D., Forman D.E., Claggett B., Skali H., Nohria A., Shah A.M. Cardiovascular phenotype and prognosis of patients with heart failure induced by cancer therapy. Heart (British Cardiac Society). 2019;105(1):34-41. doi: 10.1136/heartjnl-2018-313234.

19. Chandra A., Lewis E.F., Claggett B.L., Desai A.S., Packer M., Zile M.R., Swedberg K., Rouleau J.L., Shi V.C., Lefkowitz M.P., Katova T., McMurray J.J.V., Solomon S.D.. Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial. Journal of the American Medical Association cardiology. 2018;3(6):498-505. doi: 10.1001/jamacardio.2018.0398.

20. Granger C.B., McMurray J.J., Yusuf S., Held P., Michelson E.L., Olofsson B., Östergren J., Pfeffer M.A., Swedberg K. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386):772-776. DOI: 10.1016/S0140- 6736(03)14284-5.

21. Мареев В.Ю., Фомин И.В., Агеев Ф.Т., Беграмбекова Ю.Л., Васюк Ю.А., Гарганеева А.А., Г. Е. Гендлин, М. Г. Глезер, С. В. Готье, Т. В. Довженко, Ж. Д. Кобалава, Н. А. Козиолова, А. В. Коротеев, Ю. В. Мареев, А. Г. Овчинников, Н. Б. Перепеч, Е. И. Тарловская, А. И. Чесникова, А. О. Шевченко, Г. П. Арутюнов, Ю. Н. Беленков, А. С. Галявич, С. Р. Гиляревский, О. М. Драпкина, Д. В. Дупляков, Ю. М. Лопатин, М. Ю. Ситникова, В. В. Скибицкий, Е. В. Шляхто. Клинические рекомендации ОССН – РКО – РНМОТ. Сердечная недостаточность: хроническая (ХСН) и острая декомпенсированная (ОДСН). Диагностика, профилактика и лечение. Кардиология. 2018;58(S6):8-158. doi: 10.18087/cardio.2475. Mareev V.Yu., Fomin I.V., Ageev F.T., Begrambekova Yu.L., Vasyuk Yu.A., Garganeeva A.A. Gendlin G.E., Glezer M.G., Gautier S.V., Dovzhenko T.V., Kobalava Z.D., Koziolova N.A., Koroteev A.V., Mareev Y.V., Ovchinnikov A.G., Perepech N.B., Tarlovskaya E.I., Chesnikova A.I., Shevchenko A.O., Arutyunov G.P., Belenkov Y.N., Galyavich A.S., Gilyarevsky S.R., Drapkina O.M., Duplyakov D.V., Lopatin Y.M., Sitnikova M.Y., Skibitsky V.V., Shlyakhto E.V. Russian Heart Failure Society, Russian Society of Cardiology. Russian Scientific Medical Society of Internal Medicine Guidelines for Heart failure: chronic (CHF) and acute decompensated (ADHF). Diagnosis, prevention and treatment. Kardiologiia. 2018;58(S6):8-158. (In Russ.) doi: 10.18087/cardio.2475.

22. Sheppard C.E., Anwar M. The use of sacubitril/ valsartan in anthracycline-induced cardiomyopathy: A mini case series. Journal of oncology pharmacy practice. 2019;25(5):1231-1234. doi: 10.1177/1078155218783238.

23. Cardinale D., Sandri M.T., Martinoni A., Tricca A., Civelli M., Lamantia G., Cinieri S., Martinelli G., Cipolla C.M., Fiorentini C. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. Journal of the American College of Cardiology. 2000;36(2):517- 522. doi: 10.1016/s0735-1097(00)00748-8.

24. Nikitovic D., Juranek I., Wilks M.F., Tzardi M., Tsatsakis A., Tzanakakis G.N. Anthracyclinedependent cardiotoxicity and extracellular matrix remodeling. Chest. 2014;146(4):1123- 1130. doi: 10.1378/chest.14-0460.

25. Docherty K.F., McMurray J.J.V. Angiotensin receptor-neprilysin inhibitors: A new paradigm in heart failure with reduced ejection fraction. International journal of cardiology. 2019;281:179- 185. doi: 10.1016/j.ijcard.2018.05.124.

26. Sawaya H., Sebag I.A., Plana J.C., Januzzi J.L., Ky B., Cohen V., Gosavi S., Carver J.R., Wiegers S.E., Martin R.P., Picard M.H., Gerszten R.E., Halpern E.F., Passeri J., Kuter I., Scherrer-Crosbie M. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. The American journal of cardiology. 2011;107(9):1375-1380. doi: 10.1016/j.amjcard.2011.01.006.

27. Feola M., Garrone O., Occelli M., Francini A, Biggi A., Visconti G., Albrile F., Bobbio M., Merlano M. Cardiotoxicity after anthracycline chemotherapy in breast carcinoma: effects on left ventricular ejection fraction, troponin I and brain natriuretic peptide. International journal of cardiology. 2011;148(2):194- 198. doi: 10.1016/j.ijcard.2009.09.564.

28. van Boxtel W., Bulten B.F., MavinkurveGroothuis A.M., Bellersen L., Mandigers C.M., Joosten L.A., Kapusta L., de Geus-Oei L.F., van Laarhoven H.W. New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide. Biomarkers. 2015;20(2):143-148. doi: 10.3109/1354750X.2015.1040839.

29. Caram M.E.V., Guo C., Leja M., Smerage J., Henry N.L., Giacherio D., Rubenfire M., Schott A., Davis M., Hayes D.F., Van Poznak C., Cooney K.A., Hertz D.L., Banerjee M., Griggs J.J. Doxorubicin-induced cardiac dysfunction in unselected patients with a history of early-stage breast cancer. Breast cancer research and treatment. 2015;152(1):163- 172. doi: 10.1007/s10549-015-3454-8.

30. De Iuliis F., Salerno G., Taglieri L., De Biase L., Lanza R., Cardelli P., Scarpa S. Serum biomarkers evaluation to predict chemotherapyinduced cardiotoxicity in breast cancer patients. Tumour biology. 2016;37(3):3379-3387. doi: 10.1007/s13277-015-4183-7.

31. Wang Y., Zhou R., Lu C., Chen Q., Xu T., Li D. Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis. Journal of the American Heart Association. 2019;8(13):e012272. doi: 10.1161/JAHA.119.012272.

32. Sawaya H., Sebag I.A., Plana J.C., Januzzi J.L., Ky B., Tan T.C. Cohen V., Banchs J., Carver J.R., Wiegers S.E., Martin R.P., Picard M.H., Gerszten R.E., Halpern E.F., Passeri J., Kuter I., ScherrerCrosbie M. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5(5):596-603. doi: 10.1161/CIRCIMAGING.112.973321.

33. Mazur M., Wang F., Hodge D.O., Siontis B.L., Beinborn D.S., Villarraga H.R., Lerman A., Friedman P.A., Herrmann J. Burden of Cardiac Arrhythmias in Patients With AnthracyclineRelated Cardiomyopathy. JACC. Clinical electrophysiology. 2017;3(2):139-150. doi: 10.1016/j. jacep.2016.08.009.

34. de Diego C., González-Torres L., Núñez J.M., Centurión Inda R., Martin-Langerwerf D.A., Sangio A.D., Chochowski P., Casasnovas P., Blazquéz J.C., Almendral J. Effects of angiotensinneprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart rhythm. 2018;15(3):395-402. doi: 10.1016/j.hrthm.2017.11.012.

35. Cardinale D., Ciceri F., Latini R., Franzosi M.G., Sandri M.T., Civelli M., Cucchi G., Menatti E., Mangiavacchi M., Cavina R., Barbieri E., Gori S., Colombo A., Curigliano G., Salvatici M., Rizzo A., Ghisoni F., Bianchi A., Falci C., Aquilina M., Rocca A., Monopoli A., Milandri C., Rossetti G., Bregni M., Sicuro M., Malossi A., Nassiacos D., Verusio C., Giordano M., Staszewsky L., Barlera S., Nicolis E.B., Magnoli M., Masson S., Cipolla C.M. Anthracycline-induced cardiotoxicity: A multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial. European journal of cancer. 2018;94:126-137. doi: 10.1016/j.ejca.2018.02.005.

36. Kaya M.G., Ozkan M., Gunebakmaz O., Akkaya H., Kaya E.G., Akpek M. Kalay N., Dikilitas M., Yarlioglues M., Karaca H., Berk V., Ardic I., Ergin A., Lam Y.Y. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. International journal of cardiology. 2013;167(5):2306-2310. doi: 10.1016/j.ijcard.2012.06.023

37. El-Shitany N.A., Tolba O.A., El-Shanshory M.R., El-Hawary E.E. Protective effect of carvedilol on adriamycin-induced left ventricular dysfunction in children with acute lymphoblastic leukemia. Journal of cardiac failure. 2012;18(8):607-613. doi: 10.1016/j.cardfail.2012.06.416.

38. Bosch X., Rovira M., Sitges M., Domènech A., OrtizPérez J.T., de Caralt T.M. Morales-Ruiz M., Perea R.J., Monzó M., Esteve J. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). Journal of the American College of Cardiology. 2013;61(23):2355-2362. doi: 10.1016/j.jacc.2013.02.072.

39. Avila M.S., Ayub-Ferreira S.M., de Barros Wanderley MR Jr, das Dores Cruz F., Gonçalves Brandão S.M., Rigaud V.O.C., Higuchi-Dos-Santos M.H., Hajjar L.A., Kalil Filho R., Hoff P.M., Sahade M., Ferrari M.S.M., de Paula Costa R.L., Mano M.S., Bittencourt Viana Cruz C.B., Abduch M.C., Lofrano Alves M.S., Guimaraes G.V., Issa V.S., Bittencourt M.S., Bocchi E.A. Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial. Journal of the American College of Cardiology. 2018;71(20):2281-2290. doi: 10.1016/j.jacc.2018.02.049.

40. Akpek M., Ozdogru I., Sahin O., Inanc M., Dogan A., Yazici C., Berk V., Karaca H., Kalay N., Oguzhan A., Ergin A. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. European journal of heart failure. 2015;17(1):81-89. doi: 10.1002/ejhf.196.

41. Vardeny O., Claggett B., Kachadourian J., Pearson S.M., Desai A.S., Packer M., Rouleau J., Zile M.R., Swedberg K., Lefkowitz M., Shi V., McMurray J.J.V., Solomon S.D. Incidence, Predictors, and Outcomes Associated With Hypotensive Episodes Among Heart Failure Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). Circulation. Heart failure. 2018;11(4):e004745. doi: 10.1161/CIRCHEARTFAILURE.117.004745.

42. Vijayakumar S., Butler J., Bakris G.L. Barriers to guideline mandated renin-angiotensin inhibitor use: focus on hyperkalaemia. European heart journal supplements. 2019;21(Suppl A):A20-A27. doi: 10.1093/eurheartj/suy030.

43. Senni M., McMurray J.J.V., Wachter R., McIntyre H.F., Anand I.S., Duino V. Sarkar A., Shi V., Charney A. Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. European journal of heart failure. 2018;20(3):491-500. doi: 10.1002/ejhf.1054.