Efficacy of trimetazidine – an inhibitor of free fatty acids oxidation in the treatment of patients with stable angina pectoris and heart failure

Aim      To evaluate efficacy of modified-release trimetazidine (TMZ) included into the standard therapy for patients with stable angina and chronic heart failure (CHF) as a part of a subgroup analysis in the PERSPECTIVE study.

Material and methods  The study included 806 patients: group 1 (n=691), patients receiving a standard therapy and modified-release TMZ (TMZ group); and group 2 (n=115), patients receiving a standard therapy (control group). Total duration of the study was 12 months.

Results In the TMZ group, the weekly number of angina attacks decreased by 41.9% (p<0.0001) in 2 months and by 69.6 % (from baseline, р<0.0001) in 12 months, and the frequency of nitroglycerine dosing decreased by 40.8 % (р<0.0001) and 67.7 % (р<0.0001), respectively. In the control group, the respective values did not change. In the TMZ group compared to the control group, the QT interval was shorter (7.9 %; р<0.05), the left ventricular (LV) end-systolic dimension was reduced (13.4 %; р<0.01), interventricular septal thickness and LV posterior wall thickness were decreased (9.5 %; р<0.01 and 12.2 %; р<0.01, respectively), and the ejection fraction was increased (11.4; р<0.05). Following the TMZ treatment, the leukocyte count in peripheral blood was decreased (5.3 %; р<0.01) and the serum concentration of high-sensitivity C-reactive protein was decreased (30.7 %; р<0.01) vs. increases of these indexes in the control group (17.9 %; р<0.05 and 17.8 %; р<0.05, respectively). The proportion of patients hospitalized for exacerbation of CHF or angina for 12 months was 8.6 % in the TMZ group and 15.7 % in the control group (p=0,001).

Conclusion      In patients with stable angina and CHF, inclusion of modified-release TMZ into the standard therapy decreases the number of angina attacks, reduces the activity of inflammatory factors, and improves the course of disease.

1. Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nature Reviews. Cardiology. 2016;13(6):368–78. DOI: 10.1038/nrcardio.2016.25

2. Maddox TM, Januzzi JL, Allen LA, Breathett K, Butler J, Davis LL et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction A Report of the American College of Cardiology Solution Set Oversight Committee. Journal of the American College of Cardiology. 2021;77(6):772–810. DOI: 10.1016/j.jacc.2020.11.022

3. Murphy SP, Ibrahim NE, Januzzi JL. Heart Failure With Reduced Ejection Fraction: A Review. JAMA. 2020;324(5):488. DOI: 10.1001/jama.2020.10262

4. Hariharan N, Sussman MA. Cardiac aging – Getting to the stem of the problem. Journal of Molecular and Cellular Cardiology. 2015;83:32–6. DOI: 10.1016/j.yjmcc.2015.04.008

5. Lazzeroni D, Rimoldi O, Camici PG. From Left Ventricular Hypertrophy to Dysfunction and Failure. Circulation Journal. 2016;80(3):555–64. DOI: 10.1253/circj.CJ-16-0062

6. Doehner W, Frenneaux M, Anker SD. Metabolic Impairment in Heart Failure: the myocardial and systemic perspective. Journal of the American College of Cardiology. 2014;64(13):1388–400. DOI: 10.1016/j.jacc.2014.04.083

7. Fukushima A, Milner K, Gupta A, Lopaschuk G. Myocardial Energy Substrate Metabolism in Heart Failure : from Pathways to Therapeutic Targets. Current Pharmaceutical Design. 2015;21(25):3654–64. DOI: 10.2174/1381612821666150710150445

8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS et al. 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):2129–200. DOI: 10.1093/eurheartj/ehw128

9. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, FunckBrentano C et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal. 2020;41(3):407–77. DOI: 10.1093/eurheartj/ehz425

10. Tereshchenko S.N., Galyavich A.S., Uskach T.M., Ageev F.T., Arutyunov G.P., Begrambekova Yu.L. et al. 2020 Clinical practice guidelines for Chronic heart failure. Russian Journal of Cardiology. 2020;25(11):311–74. DOI: 10.15829/1560-4071-2020-4083

11. Barbarash O.L., Karpov Yu.A., Kashtalap V.V., Boshchenko A.A., Ruda M.Ya., Akchurin R.S. et al. 2020 Clinical practice guidelines for Stable coronary artery disease. Russian Journal of Cardiology. 2020;25(11):201–50. DOI: 10.15829/1560-4071-2020-4076

12. McCarthy CP, Mullins KV, Kerins DM. The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent. European Heart Journal - Cardiovascular Pharmacotherapy. 2016;2(4):266–72. DOI: 10.1093/ehjcvp/pvv051

13. Shu H, Peng Y, Hang W, Zhou N, Wang DW. Trimetazidine in Heart Failure. Frontiers in Pharmacology. 2021;11:569132. DOI: 10.3389/fphar.2020.569132

14. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The Antianginal Drug Trimetazidine Shifts Cardiac Energy Metabolism From Fatty Acid Oxidation to Glucose Oxidation by Inhibiting Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase. Circulation Research. 2000;86(5):580–8. DOI: 10.1161/01.RES.86.5.580

15. Zhong Y, Zhong P, He S, Zhang Y, Tang L, Ling Y et al. Trimetazidine Protects Cardiomyocytes Against Hypoxia/Reoxygenation Injury by Promoting AMP-activated Protein Kinase–dependent Autophagic Flux. Journal of Cardiovascular Pharmacology. 2017;69(6):389–97. DOI: 10.1097/FJC.0000000000000487

16. Bubnova M.G., Aronov D.M., Oganov R.G., Rudomanov O.G. New potential of Trimetazidine MB for coronary heart disease treatment in the real-world clinical practice: results of the Russian multi-centre randomised study PERSPECTIVE (Part II). Cardiovascular Therapy and Prevention. 2011;10(6):70–80. DOI: 10.15829/1728-8800-2011-6-70-80

17. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation. 1977;55(4):613–8. DOI: 10.1161/01.CIR.55.4.613

18. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. European Heart Journal. 2018;39(33):3021–104. DOI: 10.1093/eurheartj/ehy339

19. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy: Fatty acid oxidation in heart disease. British Journal of Pharmacology. 2014;171(8):2080–90. DOI: 10.1111/bph.12475

20. Adamo L, Nassif ME, Novak E, LaRue SJ, Mann DL. Prevalence of lactic acidaemia in patients with advanced heart failure and depressed cardiac output: Lactic acidaemia in advanced heart failure. European Journal of Heart Failure. 2017;19(8):1027–33. DOI: 10.1002/ejhf.628

21. Grodin JL, Tang WHW. I will take my heart failure ‘lactate‐free’ please. European Journal of Heart Failure. 2018;20(6):1019–20. DOI: 10.1002/ejhf.1190

22. Biegus J, Zymliński R, Sokolski M, Gajewski P, Banasiak W, Ponikowski P. Clinical, respiratory, haemodynamic, and metabolic determinants of lactate in heart failure. Kardiologia Polska. 2019;77(1):47–52. DOI: 10.5603/KP.a2018.0240

23. Zymliński R, Biegus J, Sokolski M, Siwołowski P, Nawrocka‐Millward S, Todd J et al. Increased blood lactate is prevalent and identifies poor prognosis in patients with acute heart failure without overt peripheral hypoperfusion. European Journal of Heart Failure. 2018;20(6):1011–8. DOI: 10.1002/ejhf.1156

24. Malyala S, Zhang Y, Strubbe JO, Bazil JN. Calcium phosphate precipitation inhibits mitochondrial energy metabolism. PLOS Computational Biology. 2019;15(1):e1006719. DOI: 10.1371/journal.pcbi.1006719

25. Mohsin AA, Thompson J, Hu Y, Hollander J, Lesnefsky EJ, Chen Q. Endoplasmic reticulum stress-induced complex I defect: Central role of calcium overload. Archives of Biochemistry and Biophysics. 2020;683:108299. DOI: 10.1016/j.abb.2020.108299

26. Lommi J, Kupari M, Yki-Järvinen H. Free Fatty Acid Kinetics and Oxidation in Congestive Heart Failure. The American Journal of Cardiology. 1998;81(1):45–50. DOI: 10.1016/S0002-9149(97)00804-7

27. Rosano GM, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy, Vitale C, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy. Metabolic Modulation of Cardiac Metabolism in Heart Failure. Cardiac Failure Review. 2018;4(2):99–103. DOI: 10.15420/cfr.2018.18.2

28. Swietach P, Youm J-B, Saegusa N, Leem C-H, Spitzer KW, VaughanJones RD. Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling. Proceedings of the National Academy of Sciences. 2013;110(22):E2064–73. DOI: 10.1073/pnas.1222433110

29. Fragasso G. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. European Heart Journal. 2005;27(8):942–8. DOI: 10.1093/eurheartj/ehi816

30. Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect. European Heart Journal. 2007;28(9):1102–8. DOI: 10.1093/eurheartj/ehm071

31. Wu S, Chang G, Gao L, Jiang D, Wang L, Li G et al. Trimetazidine protects against myocardial ischemia/reperfusion injury by inhibiting excessive autophagy. Journal of Molecular Medicine. 2018;96(8):791–806. DOI: 10.1007/s00109-018-1664-3

32. Zheng W. The cystathionine γ-lyase/hydrogen sulfide pathway mediates the trimetazidine-induced protection of H9c2 cells against hypoxia/reoxygenation-induced apoptosis and oxidative stress. The Anatolian Journal of Cardiology. 2019;22(3):102–11. DOI: 10.14744/AnatolJCardiol.2019.83648

33. Argaud L, Gomez L, Gateau-Roesch O, Couture-Lepetit E, Loufouat J, Robert D et al. Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia–reperfusion injury. Journal of Molecular and Cellular Cardiology. 2005;39(6):893–9. DOI: 10.1016/j.yjmcc.2005.09.012

34. Saotome M, Katoh H, Satoh H, Hayashi H, Hajnoczky G. ‘Mitochondrial remodeling’ in coronary heart disease. Research Reports in Clinical Cardiology. 2014;5:111–22. DOI: 10.2147/RRCC.S43364

35. Ma N, Bai J, Zhang W, Luo H, Zhang X, Liu D et al. Trimetazidine protects against cardiac ischemia/reperfusion injury via effects on cardiac miRNA-21 expression, Akt and the Bcl-2/Bax pathway. Molecular Medicine Reports. 2016;14(5):4216–22. DOI: 10.3892/mmr.2016.5773

36. Liu F, Yin L, Zhang L, Liu W, Liu J, Wang Y et al. Trimetazidine improves right ventricular function by increasing miR-21 expression. International Journal of Molecular Medicine. 2012;30(4):849–55. DOI: 10.3892/ijmm.2012.1078

37. Yang Q, Yang K, Li A-Y. Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing microRNA-21 expression. International Journal of Clinical and Experimental Pathology. 2015;8(4):3735–41. PMID: 26097555

38. Dong Y, Chen H, Gao J, Liu Y, Li J, Wang J. Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease. Journal of Molecular and Cellular Cardiology. 2019;136:27–41. DOI: 10.1016/j.yjmcc.2019.09.001

39. Mialet-Perez J, Vindis C. Autophagy in health and disease: focus on the cardiovascular system. Essays in Biochemistry. 2017;61(6):721–32. DOI: 10.1042/EBC20170022

40. Zhang L, Ding W, Wang Z, Tang M, Wang F, Li Y et al. Erratum to: Early administration of trimetazidine attenuates diabetic cardiomyopathy in rats by alleviating fibrosis, reducing apoptosis and enhancing autophagy. Journal of Translational Medicine. 2016;14(1):309. DOI: 10.1186/s12967-016-1068-5

41. Fragasso G, Salerno A, Lattuada G, Cuko A, Calori G, Scollo A et al. Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. Heart. 2011;97(18):1495–500. DOI: 10.1136/hrt.2011.226332

42. Grajek S, Michalak M. The effect of trimetazidine added to pharmacological treatment on all-cause mortality in patients with systolic heart failure. Cardiology. 2015;131(1):22–9. DOI: 10.1159/000375288

43. Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011;97(4):278–86. DOI: 10.1136/hrt.2010.208751

44. Gunes Y, Tuncer M, Guntekin U, Akdag S, Gumrukcuoglu HA. The Effects of Trimetazidine on P-Wave Duration and Dispersion in Heart Failure Patients. Pacing and Clinical Electrophysiology. 2009;32(2):239–44. DOI: 10.1111/j.1540-8159.2008.02208.x

45. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M et al. A Randomized Clinical Trial of Trimetazidine, a Partial Free Fatty Acid Oxidation Inhibitor, in Patients With Heart Failure. Journal of the American College of Cardiology. 2006;48(5):992–8. DOI: 10.1016/j.jacc.2006.03.060

46. Zhang L, Lu Y, Jiang H, Zhang L, Sun A, Zou Y et al. Additional Use of Trimetazidine in Patients With Chronic Heart Failure. Journal of the American College of Cardiology. 2012;59(10):913–22. DOI: 10.1016/j.jacc.2011.11.027

47. González A, Schelbert EB, Díez J, Butler J. Myocardial Interstitial Fibrosis in Heart Failure. Journal of the American College of Cardiology. 2018;71(15):1696–706. DOI: 10.1016/j.jacc.2018.02.021

48. Disertori M, Masè M, Ravelli F. Myocardial fibrosis predicts ventricular tachyarrhythmias. Trends in Cardiovascular Medicine. 2017;27(5):363–72. DOI: 10.1016/j.tcm.2017.01.011

49. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cellular and Molecular Life Sciences. 2014;71(4):549–74. DOI: 10.1007/s00018-013-1349-6

50. Zhang J, He X, Bai X, Sun Y, Jiang P, Wang X et al. Protective effect of trimetazidine in radiation-induced cardiac fibrosis in mice. Journal of Radiation Research. 2020;61(5):657–65. DOI: 10.1093/jrr/rraa043

51. Liu X, Gai Y, Liu F, Gao W, Zhang Y, Xu M et al. Trimetazidine inhibits pressure overload-induced cardiac fibrosis through NADPH oxidase–ROS–CTGF pathway. Cardiovascular Research. 2010;88(1):150–8. DOI: 10.1093/cvr/cvq181

52. Zhao Y, Li S, Quan E, Zhang H, Wu Y, Luo Y et al. Trimetazidine inhibits cardiac fibrosis by reducing reactive oxygen species and downregulating connective tissue growth factor in streptozotocin-induced diabetic rats. Experimental and Therapeutic Medicine. 2019;18(2):1477–85. DOI: 10.3892/etm.2019.7705

53. Aronov D.M., Tartakovsky L.B., Novikova N.K., Pisareva N.A., Smolensky V.S., Zhidko N.I. Significance of Trimetazidine for out of Hospital Physical Rehabilitation after Myocardial Infarction. Kardiologiia. 2002;42(11):14–20.

54. Cera M, Salerno A, Fragasso G, Montanaro C, Gardini C, Marinosci G et al. Beneficial Electrophysiological Effects of Trimetazidine in Patients With Postischemic Chronic Heart Failure. Journal of Cardiovascular Pharmacology and Therapeutics. 2010;15(1):24–30. DOI: 10.1177/1074248409356431

55. Gunes Y, Guntekin U, Tuncer M, Sahin M. The effects of trimetazidine on heart rate variability in patients with heart failure. Arquivos Brasileiros de Cardiologia. 2009;93(2):154–8. DOI: 10.1590/S0066-782X2009000800014

56. Zemljic G, Bunc M, Vrtovec B. Trimetazidine Shortens QTc Interval in Patients With Ischemic Heart Failure. Journal of Cardiovascular Pharmacology and Therapeutics. 2010;15(1):31–6. DOI: 10.1177/1074248409354601

57. Glezer M.G., Vasilyev S.V. Anti-anginal and anti-ischemic effectiveness of trimetazidine MB in patients with unstable angina. Cardiovascular Therapy and Prevention. 2009;8(1):42–6.

58. Sisakian H, Torgomyan A, Barkhudaryan A. The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy. Acta Cardiologica. 2007;62(5):493–9. DOI: 10.2143/AC.62.5.2023413

59. El-Kady T, El-Sabban K, Gabaly M, Sabry A, Abdel-Hady S. Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy: a 24-month study. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions. 2005;5(4):271–8. DOI: 10.2165/00129784-200505040-00006

60. Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database of Systematic Reviews. 2005;19(4):CD003614. DOI: 10.1002/14651858.CD003614.pub2

61. Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart. 2005;91(2):161–5. DOI: 10.1136/hrt.2003.031310

62. Di Napoli P, Di Giovanni P, Gaeta MA, D’Apolito G, Barsotti A. Beneficial effects of trimetazidine treatment on exercise tolerance and B-type natriuretic peptide and troponin T plasma levels in patients with stable ischemic cardiomyopathy. American Heart Journal. 2007;154(3):602.e1-602.e5. DOI: 10.1016/j.ahj.2007.06.033

63. Song M, Chen F, Li Y, Zhang L, Wang F, Qin R et al. Trimetazidine restores the positive adaptation to exercise training by mitigating statininduced skeletal muscle injury. Journal of Cachexia, Sarcopenia and Muscle. 2018;9(1):106–18. DOI: 10.1002/jcsm.12250

64. Yang J, Zhang L, Liu C, Zhang J, Yu S, Yu J et al. Trimetazidine attenuates high-altitude fatigue and cardiorespiratory fitness impairment: A randomized double-blinded placebo-controlled clinical trial. Biomedicine & Pharmacotherapy. 2019;116:109003. DOI: 10.1016/j.biopha.2019.109003

65. Amini N, Sarkaki A, Dianat M, Mard SA, Ahangarpour A, Badavi M. Protective effects of naringin and trimetazidine on remote effect of acute renal injury on oxidative stress and myocardial injury through Nrf-2 regulation. Pharmacological Reports. 2019;71(6):1059–66. DOI: 10.1016/j.pharep.2019.06.007

66. Zhou X, Li C, Xu W, Chen J. Trimetazidine Protects against SmokingInduced Left Ventricular Remodeling via Attenuating Oxidative Stress, Apoptosis, and Inflammation. PLoS ONE. 2012;7(7):e40424. DOI: 10.1371/journal.pone.0040424

67. Shao L, Ma A, Figtree G, Zhang P. Combination Therapy With Coenzyme Q10 and Trimetazidine in Patients With Acute Viral Myocarditis. Journal of Cardiovascular Pharmacology. 2016;68(2):150–4. DOI: 10.1097/FJC.0000000000000396

68. Williams FM, Tanda K, Kus M, Williams TJ. Trimetazidine Inhibits Neutrophil Accumulation After Myocardial Ischaemia and Reperfusion in Rabbits. Journal of Cardiovascular Pharmacology. 1993;22(6):828–33. DOI: 10.1097/00005344-199312000-00008

69. Zhou X, Chen J. Is treatment with trimetazidine beneficial in patients with chronic heart failure? PloS One. 2014;9(5):e94660. DOI: 10.1371/journal.pone.0094660

70. Belardinelli R, Cianci G, Gigli M, Mazzanti M, Lacalaprice F. Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy. Journal of Cardiovascular Pharmacology. 2008;51(6):611–5. DOI: 10.1097/FJC.0b013e31817bdd66

71. Di Napoli P, Di Giovanni P, Gaeta MA, Taccardi AA, Barsotti A. Trimetazidine and Reduction in Mortality and Hospitalization in Patients With Ischemic Dilated Cardiomyopathy: A Post Hoc Analysis of the Villa Pini D’Abruzzo Trimetazidine Trial: Journal of Cardiovascular Pharmacology. 2007;50(5):585–9. DOI: 10.1097/FJC.0b013e31814fa9cb

72. Meiszterics Z, Kónyi A, Hild G, Sárszegi Z, Gaszner B. Effectiveness and safety of anti-ischemic trimetazidine in patients with stable angina pectoris and Type 2 diabetes. Journal of Comparative Effectiveness Research. 2017;6(8):649–57. DOI: 10.2217/cer-2017-0011

73. Chrusciel P, Rysz J, Banach M. Defining the Role of Trimetazidine in the Treatment of Cardiovascular Disorders: Some Insights on Its Role in Heart Failure and Peripheral Artery Disease. Drugs. 2014;74(9):971–80. DOI: 10.1007/s40265-014-0233-5

74. Ferrari R, Ford I, Fox K, Challeton JP, Correges A, Tendera M et al. Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial. The Lancet. 2020;396(10254):830–8. DOI: 10.1016/S0140-6736(20)31790-6