The ATPCI trial: a new international phase 3 study assessing the clinical impact of adding a metabolic agent to post-PCI angina treatment



Interview with R. Ferrari, Italy

Roberto FERRARI, MD Department of Cardiology and LTTA Centre University Hospital of Ferrara ITALY

Can you tell us what ATPCI stands for?

ATPCI is the short name of an international, multicenter, randomized, doubleblind, placebo-controlled study in patients treated with trimetazidine for 2 to 4 years. The full title of the trial is “efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by percutaneous Coronary Interventions.” The sponsor of the study is the Institut de Recherches Internationales Servier (I.R.I.S.) and it is registered with the World Health Organization (WHO) under the universal trial number (UTN) UIIII-1145-1743.

The acronym ATPCI is particularly appropriate for the study as it targets patients with ischemic heart disease who have received a percutaneous coronary intervention (PCI) and pharmacological treatment by trimetazidine—the active drug under testing, a piperazine derivative with anti-ischemic properties that are different from any other anti-ischemic drugs—a drug that increases the adenosine triphosphate (ATP) levels. The standard approach to treat coronary artery disease (CAD) is based on increasing oxygen supply to the myocardium and/or reducing oxygen consumption by means of hemodynamic effects, acting via the heart rate in the case of ivabradine, or via heart rate and myocardial contractility in the case of b-blockers and verapamil or diltiazem, and via the peripheral arterial coronary and/or venous resistance in the case of dihydropyridine calcium-channel blockers and nitrates. An alternative approach is to improve the efficiency and the energy of the heart for a given supply of oxygen, which is reduced during ischemia. In other words, such an approach aims to increase the level of ATP. This metabolic approach is interesting considering that trimetazidine does not have hemodynamic effects, but acts as a modulator of cardiac metabolism.

Under physiological conditions, the energy demand of the heart is met by the metabolism of two main substrates—glucose and free fatty acids (FFAs). Glucose metabolism occurs by means of glycolysis and oxidation. Whereas the oxidative pathway converts pyruvate into acetyl-coenzyme A (CoA), which is incorporated in the Krebs cycle and produces 36 molecules of ATP, the conversion of glucose to pyruvate during glycolysis produces only two molecules of ATP, but this ATP is important as oxygen is not required in the process.1 The FFAs are the main sources of ATP, corresponding to about 70% of the myocardial production, but the oxidation of FFAs requires about 10% more oxygen than that of glucose to produce an equivalent amount of energy.1 During ischemia and/or angina, all oxidative processes are depressed, leading to acetyl-coA accumulation in the mitochondria with ablock of FFA b-oxidation and of the activity of pyruvate dehydrogenase, the enzyme that allows the entry of pyruvate into the mitochondria. Pyruvate is then converted into lactic acid, which is released from the myocytes into the extracellular space, thus reducing the pH and causing pain by irritation of the myocardial nerve fibers. Thus, in ischemia, glycolysis, contrary to oxidation, continues in an anaerobic fashion, having as final product lactate instead of pyruvate, and becomes the only and most important source of anaerobic ATP.1 Trimetazidine further inhibits FFA b-oxidation and, indirectly, stimulates the activity of pyruvate dehydrogenase, thus directing pyruvate into the mitochondria, avoiding lactic acid formation, and allowing anaerobic glycolysis to continue. This has two important consequences—reduction in intra- and extracellular acidosis, thus preventing pain, and improvement in anaerobic ATP production through glycolysis, ensuring maintenance of cellular homeostasis and viability.2 As ancillary properties resulting from the maintenance of ATP, trimetazidine has also been shown to reduce oxygen free radical production and oxidative stress and to inhibit the opening of mitochondrial calcium pores with the consequent release of cytochrome C, thus reducing apoptosis and attenuating inflammation. 2

The acronym ATPCI is well-suited to this study, which aims to test whether treatment with trimetazidine to maintain ATP levels after PCI is useful to reduce symptoms and improve outcomes in patients with ischemic heart diseases.

What is the rationale of the study and what is the main objective of ATPCI?

ATPCI aims to assess the long-term efficacy and safety of trimetazidine versus placebo, when given in addition to other evidence-based cardiovascular therapies in patients having had a recent PCI. The rationale for ATPCI is based on three considerations.

The first is that, despite the wide use of PCI for patients with chronic or acute angina, it is not clear whether this intervention results in an improvement in outcomes when compared with medical therapy. In addition, several studies have shown that, after PCI, not all patients are angina free or stop the antianginal treatment.3

The second consideration relies on the unique anti-ischemic and antianginal effects of trimetazidine, which could be ideal after PCI. The antianginal effect of trimetazidine in stable angina pectoris is well-known and documented by 25 studies, including more than 4000 patients, in which trimetazidine was compared with placebo or active comparator. Efficacy has always been assessed on ergometric criteria and symptoms.

In addition, a first Cochrane meta-analysis conducted in 2005, involving a total of 1378 patients, reported a statistically significant and clinically relevant efficacy of trimetazidine in the treatment of angina, either alone or in combination with conventional antianginal treatments.4 In 2012, a second Cochrane meta-analysis, including 2283 patients and two additional ergometric criteria—total exercise duration and time to onset of angina—confirmed the conclusion of the first meta-analysis (unpublished data). A third network meta-analysis was then conducted in 2011, including studies with positive results as well as studies with inconclusive results, as required by European guidelines. The conclusion was that trimetazidine is as efficacious as other antianginal agents despite the different mechanism of action.5

The third consideration is related to the increasing evidence of microvascular dysfunction as a cause of angina. Trimetazidine, by improving energy metabolism, could be particularly useful in this setting, where classic agents, which mainly act on the epicardial coronary artery, are less likely to be active.

A previous proof-of-concept study showed a benefit of trimetazidine over placebo in reducing the incidence of recurrent angina in CAD patients after drug-eluting stent implantation. 6 Another study showed a reduction in major adverse cardiovascular events after 1-year follow-up in patients who received trimetazidine for at least 1 month after PCI.7 A recent meta-analysis evaluates the effects of trimetazidine on patients undergoing PCI in a total of 778 patients.8 The additional use of trimetazidine, before intervention, reduced angina attacks and electrocardiographic changes during PCI and cardiac troponin level. It also improved the left ventricular ejection fraction.8

What is the study design and who are the target patients?

ATPCI is a phase 3, international, multicenter, doubleblind, placebo-controlled study randomized in two parallel and balanced arms—on top of post-PCI recommended treatment for CAD, patients receive either trimetazidine 35 mg twice daily or placebo—for both secondary prevention and regular antianginal therapies, as per current guidelines. Randomization at inclusion is stratified according to country and nature of PCI procedure, whether elective or urgent after an acute presentation but without STEMI. A total of 5800 patients from 27 countries will be included within 30 days of PCI and followed-up during a 2- to 4-year treatment period with a maximum of 10 visits. ATPCI includes patients (women or men ≥21 years old and <85 years old of any ethnic origin) presenting with a single or multivessel CAD and having undergone PCI for at least one stenosis to either a native coronary artery or a coronary graft where the PCI fell into any of the following categories: (i) indicated because of angina pectoris occurring either in the context of stable angina (elective PCI) or in the context of an acute presentation, such as unstable angina/non–ST-segment elevation myocardial infarction (NSTEMI), but excluding ST-segment elevation myocardial infarction (STEMI); (ii) achieved by stent implantation or by other acceptable interventional (nonsurgical) means; (iii) successful as planned by the operator and with no further revascularization (either percutaneous or surgical) planned; or (iv) uncomplicated, such that the patient’s discharge was not delayed because of a cardiac or cerebrovascular problem.

A measurement of left ventricular ejection fraction (LVEF) needs to be performed within 3 months before inclusion for patients having undergone elective PCI and between PCI and inclusion for patients having undergone index PCI performed in the context of an acute syndrome. Patients can be selected after PCI regardless of whether they are asymptomatic or symptomatic with regard to angina, and regardless of their Canadian Cardiovascular Society (CCS) class.

What is the primary end point of the study?

The primary efficacy end point of ATPCI is the time to first occurrence of an event in the composite of: (i) cardiac death; (ii) hospitalization for a cardiac event; (iii) recurrent or persistent angina leading to adding, switching, or increasing the dose of one of the evidence-based antianginal therapies; and (iv) recurrent or persistent angina, leading to performance of a coronary angiography, all of which will be reviewed by an independent adjudication committee. The primary safety end point is the incidence of serious emergency adverse events (in all visits) with trimetazidine as compared with placebo.

The secondary end points are the time to first occurrence of each of the separate four components of the primary end point, with the addition of evidence of ischemia (documented by stress imaging and leading to adding, switching, or increasing the dose of one of the evidence-based antianginal therapies). Other efficacy end points include the following: CCS class of angina symptoms, number of angina episodes per week, number of doses of short-acting nitrates taken per week, number of antianginal drugs taken by the patient, Seattle Angina Questionnaire scores (in countries where a validated translation is available), EQ-5D-3L Questionnaire scores, and level of cardiac troponin (before each repeat PCI and between 6 and 24 hours after).

What might we expect from the study?

ATPCI will improve our knowledge of CAD and its treatment by PCI. It will also identify the role of metabolic therapy in this setting of patients. It is the first study to test the value of increasing the energy status of the ischemic myocyte with trimetazidine in terms of hard end points such as cardiac death and hospitalization. This is particularly relevant considering that a recent study with ranolazine, another piperazine derivative, in a similar patient setting failed to show a benefit.9

Acknowledgments. This work was supported by a grant from Fondazione Anna Maria Sechi per il Cuore (FASC), Italy.

References

1. Ferrari R, Williams AJ. The role of mitochondria in myocardial damage occurring on post-ischaemic reperfusion. J Appl Cardiol. 1986;1:501-519. 
2. Cargnoni A, Pasini E, Ceconi C, Curello S, Ferrari R. Insight into cytoprotection with metabolic agents. Eur Heart J. 1999;1(suppl O):O40-O48. 
3. Babu GG, Walker J M, Yellon DM, Hausenloy DJ. Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for cardioprotection. Eur Heart J. 2011;32:23-32. 
4. Ciapponi A, Pizzarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst Rev. 2005;(4):CD003614. 
5. 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. 
6. Xiaohan X, Zhang W, Zhou Y, et al. Effect of trimetazidine on recurrent angina pectoris and left ventricular structure in elderly multivessel coronary heart disease patients with diabetes mellitus after drug-eluting stent implantation: a singlecentre, prospective, randomized, double-blind study at 2-year follow-up. Clin Drug Investig. 2014;34:251-258. 
7. Chen J, Zhou S, Jin J, et al. Chronic treatment with trimetazidine after discharge reduces the incidence of restenosis in patients who received coronary stent implantation: a 1-year prospective follow-up study. Int J Cardiol. 2014;174:634- 639. 
8. Zhang Y, Xiao-juan M, Da-zhuo S. Effect of trimetazidine in patients undergoing percutaneous coronary intervention: a meta-analysis. PLoS One. 2015;10(9): e0137775. 
9. Weisz G, Généreux P, Iñiguez A; RIVER-PCI investigators. Ranolazine in patients with incomplete revascularization after percutaneous coronary intervention (RIVER-PCI): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10014):136-145.