The versatile drug Trimetazidine: Applications in angina and beyond

A plethora of clinical studies have assessed the efficacy of TMZ both as a mono-therapeutic agent and as part of a combination regimen in the treatment of angina. Several clinical trials have demonstrated trimetazidine to be efficacious in patients with stable effort-induced angina, with an overall effect like that of other non-heart rate-lowering agents. For example, in TRIMPOL-II (TRIMetazidine in POLand), a randomized double-blind placebo-controlled trial of 426 patients with stable angina treated with metoprolol, the addition of trimetazidine significantly improved performance on exercise testing and reduced the frequency of weekly angina attacks and nitrate consumption compared to placebo.(6 )Similar antianginal benefits were reported for trimetazidine in the TACT(7) (Trimetazidine in Angina Combination Therapy),VASCO-angina(8), and CHOICE-2(9) studies.

In another multicentre study (double-blind parallel group), involving 149 patients with stable angina, Trimetazidine, compared with propranolol, produced similar anti-anginal efficacy in terms of anginal attacks rate per week, exercise duration, and time to 1 mm ST-segment depression.(10)

The results from monotherapy and combination therapy trials is supported by meta-analyses. In the largest meta-analysis, conducted by Danchin et al. evaluating 218 trials with a total 19,028 patients, TMZ significantly improved exercise tolerance, weekly angina episodes, and use of short-acting nitrates when compared with placebo.

There exists an intriguing body of mechanistic and early clinical data to support novel use of TMZ in heart failure, peripheral vascular disease, ischaemia-reperfusion injury, and even contrast nephropathy.(12)

In patients with chronic heart failure, trimetazidine has been shown in two meta-analyses to result in significant improvements in left ventricular dimensions, ejection fraction, and New York Heart Association (NYHA) functional capacity, as well as reducing the frequency of hospital admissions.(13) Interestingly, the beneficial actions of trimetazidine in heart failure have not only been observed in patients with an ischaemic aetiology, but also non-ischaemic causes, including idiopathic dilated cardiomyopathy, diabetic cardiomyopathy, and anthracycline-induced cardiotoxicity.

Trimetazidine has also been shown to reduce infarct size, limit myocardial neutrophil accumulation, and prevent intracoronary platelet aggregation. There is also clinical evidence to suggest that trimetazidine might protect against reperfusion arrhythmias in patients undergoing thrombolysis for acute myocardial infarction,(14) and reduce myocardial injury in patients with stable angina undergoing percutaneous coronary intervention,(15) or coronary artery bypass grafting surgery.(16)

In the METRO (ManagEment of angina: a retrospective cOhort) study, a retrospective analysis of 353 consecutive patients discharged from an intensive care unit after surviving a myocardial infarction, there was a significant reduction in 6-month all-cause mortality in patients with antecedent stable angina who were treated with trimetazidine in addition to other antianginal drugs prior to their event. (17)

Taking all the above together, trimetazidine appears to be an appealing cardiovascular therapeutic agent that could be safely used in different conditions and in patients with multiple comorbidities given its lack of hemodynamic effects and little drug-to-drug interactions.

Although the results of the recent ATPCI (efficAcy and safety of Trimetazidine in patients with angina pectoris treated by Percutaneous Coronary Intervention) study (19) showed no significant difference in the incidence of primary endpoint events between trimetazidine and the placebo group in angina patients who recently underwent PCI, but this study had several limitations in study design, patient selection, and drug effectiveness which limit unequivocal interpretation its findings. These limitations have been highlighted by Dr Tiny Nair and Dr Shashank Joshi in an article published in JAPI titled "Do we need to change the Patient Indications for Trimetazidine after ATPCI?" (20) The authors elaborate on shortcomings of this trial like only few patients in the ATPCI trial had symptomatic angina. Also, patients with diabetes and diffuse disease were not included in the ATPCI trial, symptomatic angina relief in incomplete /partial revascularization is one of the major benefits of trimetazidine but this was not the target population in the ATPCI trial.

In fact, the authors have suggested that the clinical utility of trimetazidine in patient populations is diametrically opposite to those included in ATPCI trial. Based on an abundant database from previous studies, clinicians can find TMZ useful in patients with:

a) Type 2 diabetes, diffuse vessel disease,

b) Reduced LVEF (Left ventricular ejection fraction),

c) Post-PCI CAD (coronary artery disease) who continue to have chest pain or symptomatic angina,

d) Those with multi-vessel disease unwilling to undergo CABG/intervention, inducible ischemia with large perfusion defect, and

e) In those with ACS (acute coronary syndrome) due to bad vessel anatomy where revascularization is not feasible.

1. Jason M Tarkin, Juan Carlos Kaski, Trimetazidine: is there a role beyond angina?, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 4, Issue 2, April 2018, Pages 67–68, https://doi.org/10.1093/ehjcvp/pvx029

2. Dyck JR, Lopaschuk GD. Malonyl CoA control of fatty acid oxidation in the ischemic heart. J Mol Cell Cardiol 2002;34:1099–1109.

3. 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. Circ Res 2000;86:580–588.

4. Ruiz-Meana M, Garcia-Dorado D, Julia M, Gonzalez MA, Inserte J, Soler-Soler J. Pre-treatment with trimetazidine increases sarcolemmal mechanical resistance in reoxygenated myocytes. Cardiovasc Res 1996;32:587–592.

5. Ruixing Y. The role of trimetazidine in inhibiting cardiomyocyte apoptosis. Arch Med Sci 2007;3:517–524.

6. Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, Skibińska E, Szymczak K, Swiatek J, Winter M. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J 2001;22:2267–2274

7. Chazov EI, Lepakchin VK, Zharova EA, Fitilev SB, Levin AM, Rumiantzeva EG, Fitileva TB. Trimetazidine in Angina Combination Therapy--the TACT study: trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am J Ther 2005;12:35–42.

8. Vitale C, Spoletini I, Malorni W, Perrone-Filardi P, Volterrani M, Rosano GMC. Efficacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina--the VASCO-angina study. Int J Cardiol 2013;168:1078–1081.

9. Glezer M, CHOICE-2 study investigators. Real-world evidence for the antianginal efficacy of trimetazidine from the Russian observational CHOICE-2 Study. Adv Ther 2017;34:915–924.

10. Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin Pharmacol 1994;37:279–288.

11. Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology 2011;120:59–72.

12. Cian P. McCarthy, Kieran V. Mullins, David M. Kerins, The role of trimetazidine in cardiovascular disease: beyond an anti-anginal agent, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 2, Issue 4, October 2016, Pages 266–272, https://doi.org/10.1093/ehjcvp/pvv051

13. Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011;97:278–286.

14. Di Pasquale P, Verso Lo P, Bucca V, Cannizzaro S, Scalzo S, Maringhini G, Rizzo R, Paterna S. Effects of trimetazidine administration before thrombolysis in patients with anterior myocardial infarction: short-term and long-term results. Cardiovasc Drugs Ther 1999;13:423–428.

15. Bonello L, Sbragia P, Amabile N, Com O, Pierre SV, Levy S, Paganelli F. Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention. Heart 2007;93:703–707.

16. Zhang N, Lei J, Liu Q, Huang W, Xiao H, Lei H. The effectiveness of preoperative trimetazidine on myocardial preservation in coronary artery bypass graft patients: a systematic review and meta-analysis. Cardiology 2015;131:86–96

17. Iyengar SS, Rosano GMC. Effect of antianginal drugs in stable angina on predicted mortality risk after surviving a myocardial infarction: a preliminary study (METRO). Am J Cardiovasc Drugs 2009;9:293–297.

18. European Medicines Agency—Science Medicines Health. European Medicines Agency recommends restricting use of trimetazidine-containing medicines. Press release. European Medicines Agency 2012;EMA/CHMP/417861/2012.

19. Ferrari R, Ford I, Fox K, Challeton JP, Correges A, Tendera M, Widimský P, Danchin N; ATPCI investigators. Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial. Lancet. 2020 Sep 19;396(10254):830-838. doi: 10.1016/S0140-6736(20)31790-6.

20. https://www.japi.org/x2848464/do-we-need-to-change-the-patient-indications-for-trimetazidine-after-atpci