Trimetazidine in ATPCI Trial: Reading beyond the results

The recent results of ATPCI trial were presented at ESC Congress 2020 and simultaneously published in the Lancet that point out that routine use of oral trimetazidine in well-treated mild CAD patients following a successful PCI without complications in addition to guideline-recommended medical therapy does not have a preventative benefit (1). The results which focus on the use this three-decade-old (2) established drug, need to be analyzed in a larger perspective to see and understand the potential role of this drug in cardiac patients.

Role of Trimetazidine

Percutaneous coronary intervention (PCI) is used to alleviate symptoms in stable angina patients who do not respond to medical therapy (3). Also, it improves prognosis in patients with acute coronary syndrome. (4) Despite successful revascularization with antianginal therapy and PCI, angina may continue to persist or reoccur (5)

Trimetazidine is a metabolic modulator which improves the cardiac energy metabolism by favouring glucose over free fatty acid use, in the ischemic myocytes without any hemodynamic changes. It does not have any effect on plaque progression, plaque disruption, and consequently future CV events. Thus, trimetazidine does not help in the prevention of ischemia but prevents some of its consequences. Its metabolic effects are most evident when ischemia is at its peak, for example during physical exertion.(7)

The ESC 2019 guidelines recommend that trimetazidine should be considered as a second-line treatment to reduce angina frequency and improve exercise tolerance in subjects who cannot tolerate, have contraindications to, or whose symptoms are not adequately controlled by beta-blockers, CCBs, and long-acting nitrates (class IIa recommendation) (8)

Trimetazidine exerts its mechanism of action in two ways. Firstly, it improves the activity of pyruvate dehydrogenase -- the enzyme that allows pyruvate entry into the mitochondria from cytosol for subsequent oxidation in Kreb's cycle.(1) Secondly, it inhibits the beta-oxidation of the free fatty acids. This shifts substrate use from free fatty acids to carbohydrates allowing the formation of anaerobic ATP. Through the removal of pyruvate from the cytosol, trimetazidine attenuates the production of lactic acid, thus reducing the acidosis that contributes to angina occurrence.(6)

The efficacy and safety of trimetazidine in the treatment of patients with coronary heart disease and stable angina has been demonstrated in a number of randomized, controlled clinical trials. (9, 10, 11,12)

With the strong role of trimetazidine in angina, Prof Roberto Ferrari, University of Ferrara, Ospedale di Cona, Ferrara, Italy, and colleagues decided to test the efficacy and safety of trimetazidine in patients with angina pectoris having been treated by percutaneous coronary intervention (ATPCI) study was designed to assess the long-term preventive benefits and safety of trimetazidine added to standard evidence-based medical treatment in patients who had a recent successful PCI.

The ATPCI Trial- What happened?

The study was performed as a randomized, double-blind, placebo-controlled, event-driven trial at 365 centres in 27 countries across Europe, South America, Asia, and North Africa. It included patients aged 21-80 years who had undergone a successful PCI in the form of either elective PCI for stable angina or urgent PCI for unstable angina or non-ST segment elevation myocardial infarction less than 30 days before randomization. 6007 patients were enrolled and randomly assigned to receive either oral trimetazidine 35 mg modified-release twice daily (n=2998) or matching placebo (n=3009). Patients were followed for up to five years.

The primary efficacy endpoint was a composite of many factors including cardiac death; hospital admission for a cardiac event; recurrence or persistence of angina requiring an addition, switch, or increase of the dose of at least one antianginal drug; or recurrence or persistence of angina requiring a coronary angiography. Safety was assessed in all patients who had at least one dose of study drug.

Key findings of the study were observed as follows:

The researchers noted that the ATPCI study shows that the prophylactic use of trimetazidine added to guideline-recommended medical therapy did not improve the prognostic outcome of patients after a successful elective or urgent PCI and at the same time no safety issues were identified.

What to make of the results?

The authors did point out to the many limitations the majority of which lay in the selection criteria of the patients. Probably, the decision to enrol patients after a successful PCI procedure without complications had the unintended consequence of the enrolled cohort being healthier than in comparable studies having lower cardiovascular risk. The presence of angina immediately after PCI before enrolment was not recorded.

It was noted that the ATPCI study enrolled a well-treated and relatively young population with mostly single-vessel coronary artery disease following a successful PCI without complications and preserved LVF. The event rate in the ATPCI study was significantly lower than expected and lower than comparable studies, requiring an extension of the follow-up period to a total of five years demonstrating the relative health of the population under study.

"Any potential benefit of trimetazidine might have been attenuated because most patients were routinely treated with β blockers, long-acting nitrates, or calcium blockers, considering that 83% of 2998 patients were hypertensive," the investigators further added.

Besides this, the ATPCI study was conducted outside of the approved indication for trimetazidine, because of which angina after the index PCI was not a prerequisite for inclusion of the patients. Also, no anti-anginal drug till date has shown prognostic benefits in Post-PCI patients.

Further studies are indeed warranted to study the efficacy of this drug in probably a more vulnerable and focussed population such as Post PCI CAD patients who continue to have chest pain or symptomatic angina, those with LV dysfunction and ischemic heart disease, or multivessel disease not willing to undergo CABG/intervention or in those patients with inducible ischemia but no angina due to large perfusion defect as well as in those patients suffering from ACS with severely stenosed vessels where revascularization is not feasible.

References

1. 1. Roberto Ferrari, Ian Ford, Kim Fox, Mario Marzilli, Michal Tendera, Petr Widimský, Jean-Pascal Challeton, Nicolas Danchin,A randomized, double-blind, placebo-controlled trial to assess the efficAcy and safety of Trimetazidine in patients with angina pectoris having been treated by percutaneous coronary intervention (ATPCI study): https://doi.org/10.1016/j.ahj.2018.12.015.
2. 2.Tsioufis K, Andrikopoulos G, Manolis A. Trimetazidine and Cardioprotection: Facts and Perspectives. Angiology. 2015;66(3):204-210. doi:10.1177/0003319714530040
3. 3.Goff SL, Mazor KM, Ting HH, Kleppel R, Rothberg MB. How Cardiologists Present the Benefits of Percutaneous Coronary Interventions to Patients With Stable Angina: A Qualitative Analysis. JAMA Intern Med. 2014;174(10):1614–1621. doi:10.1001/jamainternmed.2014.3328
4. 4.Gunn J, Taggart DPRevascularisation for acute coronary syndromes: PCI or CABG?Heart 2003;89:967-970.
5. 5.Izzo P, Macchi A, De Gennaro L, Gaglione A, Di Biase M, Brunetti ND. Recurrent angina after coronary angioplasty: mechanisms, diagnostic and therapeutic options. European Heart Journal: Acute Cardiovascular Care. 2012;1(2):158-169. doi:10.1177/2048872612449111
6. 6.Brodbin P, O'Connor CA. Trimetazidine in the treatment of angina pectoris. Br J Clin Pract 1968;22:395 –396
7. 7.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: 580–88.
8. 8.Dézsi, Csaba A. MD, PhD Trimetazidine in Practice, American Journal of Therapeutics: May/June 2016 - Volume 23 - Issue 3 - p e871-e879 doi: 10.1097/MJT.0000000000000180
9. 9.Knuuti J Wijns W Saraste A et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020; 41: 407-477
10. 10.Marzilli, Mario; Klein, Werner W. Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials, Coronary Artery Disease: April 2003 - Volume 14 - Issue 2 - p 171-179
11. 11.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
12. 12.Zhao, Y., Peng, L., Luo, Y. et al. Trimetazidine improves exercise tolerance in patients with ischemic heart disease. Herz 41, 514–522 (2016). https://doi.org/10.1007/s00059-015-4392-2
13. 13.Ferrari, Roberto & Pavasini, Rita & Camici, Paolo & Crea, Filippo & Danchin, Nicolas & Pinto, Fausto & Manolis, Athanasios & Marzilli, Mario & Rosano, Giuseppe & López-Sendón, José & Fox, Kim. (2018). Anti-anginal drugs-beliefs and evidence: systematic review covering 50 years of medical treatment. European heart journal. 40. 10.1093/eurheartj/ehy504.