Trimetazidine: targeting the cardiac cell in stable angina



by M. Gliebova, France

Mariia GLIEBOVA, MD Servier International Global Medical Strategy and Information Department Cardiovascular Suresnes, France


Angina is now recognized as a multifaceted disease where coronary artery obstructions are only one among many contributing factors. Because of its central involvement in a number of ischemic processes, the cardiac cell is recognized as a major player in cardiac ischemia. At the cell level, myocardial ischemia is characterized by altered myocardial energy metabolism, which results in an ionic imbalance, misuse of and deficit in energy, and ultimately functional defects. During ischemia, trimetazidine acts directly at the cell level by decreasing fatty acid oxidation and increasing glucose oxidation, which helps restore normal energy metabolism. This leads to an overall improvement in the general function of the cell and, at the organ level, provides anti-ischemic activity. By directly targeting the cardiac cell, trimetazidine’s mechanism of action complements those of hemodynamically active antianginal therapies, thus maximizing clinical efficacy when used in a combination strategy. Trimetazidine has been shown to provide additional reduction in symptoms and increase exercise capacity in angina patients whose symptoms are inadequately controlled by b-blockers and/or calcium channel blockers. The beneficial effect of trimetazidine has been demonstrated in various angina patients, including those with a history of myocardial infarction, previous percutaneous coronary intervention, diabetes, or left ventricular dysfunction. In addition to its proven antianginal effect, trimetazidine may also provide extra benefits in terms of cardioprotection and prognosis in many cardiovascular patients.

Stable angina pectoris, a clinical manifestation of myocardial ischemia, is a chronic disease associated with poor prognosis and impaired quality of life. Patients with severe angina are at greater risk for cardiovascular events, including myocardial infarction or death, and the rate of hospitalizations is particularly high in this population.

One therapeutic option for relieving angina symptoms is the use of invasive procedures, such as myocardial revascularization. However, this type of approach has unclear effects on survival,1 and its use is restricted to angina patients with obstructive coronary artery stenosis. Thus, medical therapy—by reducing the symptoms of angina, increasing exercise tolerance, and improving quality of life—remains a cornerstone in the management of angina patients.2 antianginal drugs exert their effects by reducing cardiac workload, ie, reducing myocardial oxygen consumption and/or increasing oxygen supply to the heart. This is the mode of action of standard antianginal treatments, such as b-blockers or calcium channel blockers. another approach consists in optimizing oxygen use by directly increasing energy production at the cardiac level, such as with the anti-anginal agent trimetazidine. In view of their complementary mechanisms of action, antianginal drugs are often used in combination for additive or synergic effects. Here we review the pharmacological rationale and clinical efficacy of trimetazidine in patients with stable angina pectoris, in light of recent experimental and clinical findings.

Angina: a single clinical entity with multiple etiologie

Angina pectoris is generally recognized as the clinical expression of underlying coronary artery disease (CaD). In patients with CaD, myocardial ischemia results from flow-limiting obstructions in the epicardial coronary arteries, as documented by coronary angiography. However, a significant proportion of patients with typical angina symptoms do not present obstructive lesions in their angiograms. In a recent report, 83.5% of angina patients with no previously documented CaD had no evidence of obstructive CaD.3 These patients often present with occult coronary abnormalities, which explain their angina symptoms. These vascular defects often occur concomitantly, supporting the notion that multiple causative mechanisms in angina—including endothelial dysfunction, microvascular impairment, and myocardial bridging—are common.4 Beyond coronary mechanisms, additional nonvascular mechanisms can contribute to myocardial ischemia (Table I). These are particularly relevant in a significant minority of angina patients for whom there is no coronary explanation for their symptoms.4 Because of its central involvement in a number of ischemic processes, including inflammation and impaired myocardial energy metabolism, the cardiac cell is recognized as a major nonvascular player in ischemic heart disease (Table I).5,6 Progression in angina is a complex and multifactorial process, with both vascular and nonvascular contributing mechanisms. Coronary obstruction represents only one piece of the puzzle.

Targeting the cardiac cell for increased clinical efficacy

The recognition of myocardial ischemia as a multifactorial process implies that antianginal management should not solely focus on large coronary vessels, but also on the microvessels and cardiac cell. One option would be to adjust treatment for each patient according to the underlying causes of angina. However, this would prove difficult to diagnose in practice. a more convenient approach would consist in a global therapeutic strategy that encompasses all causes of ischemia.

Table I. Multiple causes of stable ischemic heart disease. These different mechanisms of ischemia are not mutually exclusive and often occur concomitantly during angina. Modified from reference 6: Pepine and Douglas. J Am Coll Cardiol. 2012;60(11): 957-959.

In the euro Heart Survey, over half of stable angina patients (59%) were prescribed two or more antianginal drugs.7 Combining different anti-ischemic drugs, each with its own distinct mechanism of action, may improve clinical efficacy by additive or even synergistic effects. Moreover, a combination strategy allows more treatment flexibility, by permitting drug selection according to a patient’s comorbidities and/or cardiac function.

The heart requires a large amount of energy to support its continuous contractile activity, making energy metabolism a fundamental process in the cardiac cell. Under normal conditions, the main source of energy in the cardiac cell comes from the oxidative metabolism of fatty acids in the mitochondria, which provides 70% of total adenosine triphosphate (aTP). However, the mitochondrial oxidation of glucose remains a more efficient metabolic process, as it requires 12% less oxygen than fatty acids for an equivalent aTP production. During ischemia, where oxygen supply is limited, oxidative metabolism is dramatically reduced, and glycolysis (ie, conversion of glucose to pyruvate) becomes a preponderant source of energy (Figure 1).8 This alteration in myocardial metabolism is accompanied by an uncoupling of glycolysis and glucose oxidation, an increase in intracellular lactate and protons, and an ionic imbalance, with serious consequences at the cellular level. These maladaptive metabolic changes cause a depletion in the cellular energy store, as evidenced by a decrease in aTP production and other high-energy phosphate levels. In order to maintain ionic homeostasis, aTP-dependent ion transporters are activated to eject protons and sodium out of the cardiac cell. This consumption of aTP for noncontractile purposes further impairs cardiac function, in a context where energy levels are already dramatically reduced. This vicious cycle has been summarized by Pepine et al in the following terms: “ischemia begets more ischemia”.9

Trimetazidine acts directly at the cell level by inhibiting longchain 3-ketoacyl coenzyme a thiolase, a mitochondrial enzyme involved in fatty acid oxidation. Inhibition of this enzyme leads to a decrease in fatty acid oxidation and, as a consequence, stimulates glucose oxidation and inhibits glycolysis (Figure 1).10 This beneficial effect of trimetazidine on energy metabolism pathways is accompanied by a restoration of intracellular energy levels.

Figure 1. The alteration in fatty acid oxidation during cardiac ischemia is accompanied by an increase in glycolysis and a decrease in glucose oxidation, with deleterious consequences for cardiac homeostasis and efficiency (black arrows). The inhibition of fatty acid oxidation with trimetazidine restores the coupling of glycolysis to glucose oxidation, which in turn increases production of ATP and restores cell function (red arrows). Modified after reference 8: Fillmore et al. Br J Pharmacol. 2014; 171:2080-2090. © 2014, The British Pharmacological Society.

This has been demonstrated in animal studies11-13 and confirmed in a clinical setting,14 where treatment with trimetazidine for 3 months was shown to increase myocardial levels of high energy phosphates in heart failure patients by 33%. This overall improvement in aTP production with trimetazidine protects the cell against acidosis and ionic imbalance during ischemia.12,15,16 notably, trimetazidine has been shown to prevent calcium overload,17 the production of free radicals,18 and apoptosis19 in the cardiac cell during reperfusion. By preventing all these deleterious effects, trimetazidine maintains the contractile function of the cardiac cell and reduces anginal symptoms.12,20 To summarize, trimetazidine exerts its anti-ischemic effects directly at the cardiac cell level, by optimizing aTP use and opposing deleterious changes that occur during ischemia.

Clinical efficacy of trimetazidine in stable angina

The anti-ischemic and antianginal efficacy of trimetazidine has been demonstrated in a range of randomized clinical trials involving nearly 4000 patients with chronic stable angina worldwide. 20 This clinical efficacy is associated with a good safety profile. The positive benefit-risk balance of trimetazidine in stable angina was recently reaffirmed in an assessment of the european Medicines agency in 2012 and recognized in the latest european Society of Cardiology guidelines for the treatment of stable CaD in 2013,22 and for the treatment of heart failure in 2016.23

Efficacy of trimetazidine in comparison with β-blockers
The antianginal efficacy of trimetazidine (60 mg daily) was compared with that of propranolol (120 mg daily) in a randomized, double-blind, multicenter study in 149 patients with stable angina and documented CaD.24 results indicated that the antianginal efficacy of trimetazidine was similar to that of the b-blocker.

The improvement in clinical parameters was comparable in both groups of patients after 3 months of treatment (mean propranolol-trimetazidine difference in number of weekly angina attacks, –2.0 [P=0.117]; and in weekly use of short-acting nitrates, –1.1 [P=0.426]). a similar anti-ischemic effect for trimetazidine and propranolol was observed during exercise testing.

Figure 2. Mean number of weekly angina attacks in patients whose symptoms were inadequately controlled with propranolol before (D0) and after (D60) add-on treatment with isosorbide dinitrate (beige bar) or trimetazidine (red bar).

This study shows that trimetazidine possesses the clinical efficacy of a first-line antianginal agent. The comparable efficacy of trimetazidine and b-blocker was acknowledged in the 2013 european Society of Cardiology guidelines on the management of stable CaD.22

Efficacy of trimetazidine in comparison with calcium channel blockers
The antianginal efficacy of trimetazidine (60 mg daily) was compared with that of nifedipine (40 mg daily) in a randomized, double-blind study with a cross-over design in 39 patients with stable angina and documented CaD.25 each treatment lasted for 6 weeks, separated by a 1-week washout period. Both treatments reduced the frequency of angina attacks to a similar degree. The comparable anti-ischemic activity of the two drugs was also shown by a similar improvement in exercise test parameters (ie, increase in total workload of 24% and 30% for trimetazidine and nifedipine, respectively; in duration of exercise of 13% and 17%; and in time to 1-mm ST-segment depression of 17% and 19% [with no significant difference between treatments]).

In a separate study using a parallel-arm design, trimetazidine and the nondihydropyridine calcium channel blocker diltiazem decreased the number of weekly angina attacks and nitrate consumption to the same extent. Moreover, both drugs had a similar effect profile with regards to exercise test parameters. 26 These clinical data suggest that trimetazidine could be an effective alternative to calcium channel blockers in the treatment of stable angina patients.

Efficacy of trimetazidine as a combination therapy with β-blockers
The antianginal efficacy of trimetazidine as an add-on therapy to b-blockers was evaluated in a series of randomized clinical studies.27-29 In the TrIMPOL-II (TrIMetazidine in POLand- II) study, a total of 426 stable angina patients with documented CaD were randomized to trimetazidine (60 mg daily) or placebo, in addition to receiving a background treatment of metoprolol (100 mg daily).30 exercise testing, evaluated at baseline and after 3 months of treatment, revealed a significant improvement in the trimetazidine-treated group compared with the placebo group (increase in total exercise duration of 16% and 10% for trimetazidine and placebo, respectively; in total workload of 14% and 7%; in time to onset of angina of 24% and 13%; and in time to 1-mm ST-segment depression of 29% and 22% [P<0.01 for all]). Clinical symptoms (number of angina attacks, use of nitrate, and intensity of anginal pain) were also significantly reduced with trimetazidine plus metoprolol compared with placebo plus metoprolol.

In a separate randomized, double-blind study, the antianginal efficacy of trimetazidine in combination with propranolol was evaluated versus isosorbide dinitrate plus propranolol.31 Stable angina patients (n=53) for whom symptoms were not adequately controlled by propranolol (120 mg daily) received add-on therapy with trimetazidine (60 mg daily) or isosorbide dinitrate (30 mg daily) for 2 months. Patients who received trimetazidine had a greater reduction in the weekly number of angina attacks (Figure 2) and in consumption of short-acting nitrates compared with the reference group. Moreover, exercise test results only improved in the group where trimetazidine was used (increase in exercise duration of 14% versus 2% for trimetazidine versus isosorbide dinitrate, respectively; and in time to 1-mm ST-segment depression of 15% versus 3%). Overall, trimetazidine appeared to have better antianginal efficacy compared with the long-acting nitrate isosorbide dinitrate.

The use of trimetazidine in combination with a b-blocker provides better clinical efficacy than b-blocker alone or another combination strategy. This may be related to an additive, or possibly synergetic, effect of the two drugs, each of which works via a distinct mechanism of action. The use of trimetazidine, which acts directly at the cardiac level, appears a rational choice for optimizing the treatment of patients inadequately controlled by b-blockers.

Antianginal effectiveness of trimetazidine in different clinical situations

In everyday practice
The antianginal effectiveness of trimetazidine in clinical practice was evaluated in a large prospective cohort of 1213 outpatients with stable angina inadequately controlled by standard therapy consisting of b-blocker alone or a combination of b-blocker plus long-acting nitrate or calcium channel blocker.32 all patients received trimetazidine (35 mg modified-release formulation, twice daily) on top of their standard treatment for 2 months. In all patients, trimetazidine significantly reduced the number of weekly angina attacks, regardless of the background therapy (Figure 3). Moreover, in this study maximal antianginal efficacy was achieved with a dual combination of trimetazidine and b-blocker only. These data suggest that combination therapy with b-blocker and trimetazidine should be considered for the optimal management of stable angina patients in real-life situations.

Figure 3. Mean number of weekly angina attacks in outpatients whose symptoms were inadequately controlled by standard therapy (b-blocker alone, b-blocker + long-acting nitrate, or b-blocker + calcium channel blocker) before (gray bars) and after (red bars) add-on treatment with trimetazidine for 2 months. Data are presented in patients who had ≥7 angina attacks per week at inclusion. Modified after reference 32: Nesukay. Ukr J Cardiol. 2014;2:43-47. © 2014, Ukrcardio.

In angina patients with diabetes
Angina patients often present with associated comorbidities that make their therapeutic management particularly challenging. Patients with concomitant diabetes mellitus and CaD are considered to be at especially high cardiovascular risk.22 In fact, type 2 diabetes patients without previous myocardial infarction have a similar risk of myocardial infarction to that of nondiabetic patients with previous myocardial infarction.33 In diabetic patients, cardiac energy metabolism is significantly altered, and these alterations are further amplified in the presence of underlying ischemic heart disease. Trimetazidine appears an attractive tool for the management of angina patients with diabetes. This hypothesis is supported by findings from the DIeTrIC trial (estudio prospectivo en pacientes DIabéticos de la efectividad y tolerabilidad de la TrImetazidina en asociación al tratamiento previo de su enfermedad Coronaria), a prospective, observational study that investigated the antianginal effect of trimetazidine in 580 outpatients with type 2 diabetes and CaD.34 The addition of trimetazidine (60 mg/day) to conventional background therapy for 6 months decreased the number of angina episodes in clinical practice (from 2.8/week at baseline to 0.9/week after treatment [P<0.001]). Short-acting nitrate consumption was also reduced (from 2.5/week at baseline to 0.7/week after treatment [P<0.001]). Interestingly, in a separate study in the same population (diabetic patients with CaD), the addition of trimetazidine on top of standard treatment was able to reduce not only symptomatic episodes of myocardial ischemia, but also silent ischemia, a feature commonly observed in diabetic patients and associated with a worse prognosis.35

Trimetazidine has also been demonstrated to have benefits in challenging clinical situations, such as in elderly diabetic patients with multivessel coronary heart disease undergoing percutaneous coronary intervention (PCI).36 In this population (n=700), treatment with trimetazidine (60 mg daily) for two years on top of conventional treatment significantly reduced the incidence of angina, recurrent angina, and silent ischemia compared with placebo. Moreover, these beneficial effects of trimetazidine were associated with a stabilization of cardiac function and structure.

Overall, these data suggest that the efficacy of trimetazidine in angina patients with diabetes goes beyond the relief of angina symptoms by providing additional benefits in terms of cardioprotection.

In angina patients with left ventricular dysfunction
A number of reports tend to indicate that trimetazidine could improve the cardiac function of patients with ischemic heart disease. In CaD patients with left ventricular dysfunction, 2 years’ treatment with trimetazidine (60 mg daily) on top of background therapy improved both myocardial perfusion and contractile function versus placebo, with single photon emission computerized tomography imaging.37 Trimetazidine was shown to increase left ventricular ejection fraction, reduce left ventricular volumes, and improve the quality of life of CaD patients with left ventricular dysfunction in various clinical settings, including in the elderly38 and diabetic39 patients.

Interestingly, the beneficial effects of trimetazidine on cardiac function observed in CaD may extend to heart failure, whether of ischemic origin or not. a recent meta-analysis of 17 randomized clinical trials in heart failure that included 955 patients treated with trimetazidine or placebo suggests so.40 Treatment with trimetazidine was associated with a significant improvement in left ventricular ejection fraction in patients with ischemic heart failure (weighted mean difference with placebo, +7.37%; 95% CI, 6.05 to 8.70; P<0.01) or nonischemic heart failure (weighted mean difference, +8.72%; 95% CI, 5.51 to 11.92; P<0.01). This was accompanied by a reduction in the risks of all-cause mortality (relative risk [rr], 0.29; 95% CI, 0.17 to 0.49; P<0.00001) and of cardiovascular events and hospitalization (rr, 0.42; 95% CI, 0.30 to 0.58; P<0.00001). These findings are further supported by a retrospective analysis of a cohort of 669 patients with heart failure, in which the use of trimetazidine was associated with improved survival from all-cause death and cardiovascular death.41 The addition of trimetazidine to conventional medical therapy is likely to improve cardiac function and prognosis in patients with left ventricular dysfunction and heart failure. Importantly, trimetazidine has a neutral effect at the hemodynamic level and can thus be safely used in these types of patient. additonally, trimetazidine has been recognized as an effective anti-anginal treatment that is safe to use in heart failure and has been granted with class IIb of recommendation and level a of evidence in the latest eSC guidelines for heart failure treatment.23

In angina patients with a history of myocardial infarction
Trimetazidine may also provide benefits in terms of outcomes in patients after myocardial infarction. The MeTrO study (Management of angina: a reTrospective cOhort) included 353 patients with stable angina treated with at least one antianginal drug (nitrates, b-blockers, calcium channels blockers, trimetazidine, or nicorandil) who had previously been hospitalized for myocardial infarction.42 Of all the antianginal strategies, only the one that included trimetazidine was associated with a significant reduction in all-cause mortality over 6 months following hospital discharge for myocardial infarction (odds ratio [Or], 0.36; 95% CI, 0.15 to 0.86; P=0.022). Similarly, a retrospective analysis of a Korean registry that included 13 733 patients hospitalized for myocardial infarction showed that treatment with trimetazidine during the inhospital period was independently associated with a significant reduction in all-cause mortality (hazard ratio [Hr], 0.41; 95% CI, 0.18 to 0. 97; P=0.042) and major adverse cardiac events (Hr, 0.24; 95% CI, 0.10 to 0.56; P=0.001) over 12 months.43 These data suggest that trimetazidine, in addition to its clinical antianginal efficacy, may offer long-term cardioprotection by improving survival in patients after acute myocardial infarction.

In angina patients with percutaneous coronary intervention
Although it is a minimally invasive procedure, PCI leads to myocardial injury in about one third of patients. a rise in troponin level immediately following PCI, a marker for myocardial injury, is correlated with a worse prognosis in these patients.44 The effect of trimetazidine has been investigated in this specific setting in a randomized study involving 266 angina patients undergoing elective PCI.45 Patients were randomized to trimetazidine (60 mg administered as a single dose 30 minutes before intervention) or no treatment. Treatment with trimetazidine prior to PCI limited periprocedural myocardial injury, as shown by the significant reduction in cardiac troponin Ic level up to 24 hours post-PCI in these patients compared with patients who received no treatment. Thus, the direct effect of trimetazidine on the cardiac cell may provide cardioprotection immediately after PCI.

Figure 4. Incidences of stent restenosis and major adverse cardiac and cerebrovascular events (MACCEs)—including all-cause mortality, nonfatal myocardial infarction, revascularization, stroke, and cerebral bleeding—in the control (gray bars; n=323) and trimetazidine (red bars; n=312) groups 12 months after percutaneous coronary intervention.

A recent report investigated the effect of trimetazidine on the incidence of stent restenosis and major adverse cardiac and cerebrovascular events (MaCCes) inpatients undergoingPCI.46 a total of 786 patients were randomized after implantation of a drug-eluting stent to trimetazidine (60 mg daily) on top of standard treatment for at least 30 days or standard treatment only, ie, no additional therapy. at 1-year follow-up, patients in the trimetazidine group had a significantly lower incidence of stent restenosis and MaCCes compared with those in the control group who received standard treatment only (Figure 4). Interestingly, in a rat model of diabetes, trimetazidine decreased the proliferation of vascular smooth muscle cells and promoted re-endothelialization after injury of the carotid artery.47 Both mechanisms could have contributed to the lower rate of stent restenosis observed with trimetazidine after PCI.

Overall, these findings suggest that beyond its antianginal effect, trimetazidine may improve prognosis in patients undergoing revascularization procedures. This hypothesis is currently being tested in the aTPCI (The efficacy and safety of Trimetazidine in Patients with angina pectoris having been treated by percutaneous Coronary Intervention) study, a large morbidity-mortality trial in angina patients with a post-PCI follow- up of 2 to 4 years.

Conclusion

Trimetazidine is an antianginal treatment with well-established efficacy, whether as monotherapy or part of combination therapy (for patients inadequately controlled by hemodynamically active therapy alone). Based on its mechanism of action that directly targets the cardiac cell, trimetazidine provides robust antianginal efficacy, reduces the burden of myocardial ischemia, and improves exercise capacity in a variety of angina patients, including those with a history of myocardial infarction, previous PCI, diabetes, or left ventricular dysfunction. Moreover, data from clinical trials suggest that trimetazidine may also offer long-term cardioprotection in a broad range of cardiovascular patients.

Acknowledgments: The author would like to thank Julie Salzmann, PhD, for providing medical writing assistance.

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