Heart and Metabolism

Number 29, 2006
Bypass surgery for coronary artery disease: a vanishing treatment?
Protective effects of trimetazidine before and after coronary artery bypass surgery

Álvaro D.B. Bordalo
Serviço de Cirurgia Cardiotorácica, Hospital de Santa Maria, Lisboa, Portugal
Correspondence: Dr A.D.B. Bordalo, Cirurgia Cardiotorácica, Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.
E-mail: alvarodbb@hotmail.com

Abstract

Trimetazidine, a 3-ketoacyl coenzyme A thiolase inhibitor, is a well known metabolically active antianginal and anti-ischemic drug with cardioprotective effects in patients with diabetes, depressed left ventricular function, or both. In this review, emphasis is given to the beneficial effects of preoperative treatment with trimetazidine in patients undergoing coronary artery bypass surgery under cardiopulmonary bypass. In view of these cardioprotective effects, treatment with trimetazidine should be extended to the long-term postoperative period, especially in patients with incomplete revascularization or recurrent angina.

Keywords: Coronary artery bypass surgery, trimetazidine, myocardial ischemia, cardioprotection

Trimetazidine is a safe and well tolerated antianginal and anti-ischemic drug that has been widely used in Europe over the past 20 years [1–7]. It has a metabolic mechanism of action, which ensures optimization of myocardial energy metabolism through partial inhibition of fatty acid oxidation in cardiac myocytes, resulting in a shift of energy production from fatty acid β-oxidation to glucose oxidation [8,9]. At the biochemical level, trimetazidine acts by inhibiting 3-ketoacyl coenzyme A thiolase, the last enzyme in the mitochondrial chain of fatty acid oxidation [10]. To date, no deleterious pathophysiological or pharmacological interactions of trimetazidine with other drugs used in ischemic heart disease have been reported.
A series of recent studies yielded consistent evidence suggesting a cardioprotective action of trimetazidine in patients with ischemic cardiomyopathy [11,12] and in patients with diabetic coronary artery disease with depressed left ventricular function [13,14]. This cardioprotective effect consists of a significant progressive [12] and long-term [12–14] enhancement of left ventricular function and myocardial viability [11].
There has been increasing interest in the use of trimetazidine in diabetic patients, even those without overt ischemic heart disease, in view of its novel mechanism of action and its relevance in targeting the changes in myocardial energy metabolism that are observed in diabetes. The cardiac myocyte of the diabetic patient shows a shift in energy metabolism from glucose oxidation to fatty acid oxidation [15], which to a certain extent resembles the situation observed during the reperfusion phase after an episode of myocardial ischemia [16]. The energy metabolism profile in the diabetic heart reflects a state of permanent reperfusion after mild ischemia. This may help to explain the higher coronary morbidity and mortality in diabetic patients with coronary disease, as well as the higher prevalence of heart failure in diabetic individuals. By restoring the abnormal myocardial energy metabolism, trimetazidine may play a very important role in the long-term treatment of diabetic patients, even in the absence of clinically overt ischemic heart disease.
Coronary artery bypass surgery has a very important role in the long-term therapeutic strategy for ischemic heart disease. Its purpose is to improve quality of life and reduce long-term coronary risk. Diabetic patients in whom coronary artery bypass surgery is indicated frequently have increased perioperative risks, even though their systolic left ventricular function may be preserved. In coronary patients with left ventricular dysfunction undergoing coronary artery surgery, preoperative enhancement of systolic function, minimization of perioperative ischemic risk and postoperative cardiac dysfunction, and accelerated functional recovery of hibernating myocardium are important issues. Trimetazidine has an important contribution to make in this setting.
The findings of several small-scale, double-blind, placebo-controlled studies, carried out in patients undergoing coronary artery bypass surgery under cardiopulmonary bypass, suggest a cardioprotective effect of trimetazidine. Fabiani et al [17] showed that preoperative use of trimetazidine (together with addition of the drug to the cardioplegic solutions) resulted in a reduction in surgical ischemia-reperfusion lesions. Tünerir et al [18] (Figure 1) found that preoperative use of trimetazidine was followed by a significantly smaller release of troponin T after surgery, with a reduction in surgical ischemia-reperfusion lesions. Another small-scale overt, placebo-controlled, parallel-group study [19] performed in patients with diabetes or left ventricular dysfunction, or both, who underwent coronary surgery under cardiopulmonary bypass, showed that patients treated with trimetazidine before operation displayed a clear trend toward reduction in perioperative ischemic events and requirement for inotropic drug treatment, and a significant reduction in early postoperative complications (triple composite endpoint: prevalence 11% compared with 56% in the control group; P < 0.005).

Figure 1. In patients undergoing coronary artery bypass grafting, the troponin T concentration (concn) was significantly (P < 0.001) lower in the group pretreated with trimetazidine (Vastarel; ) than in the placebo group (). (Modified from Tünerir et al. [18], with permission.)

Achieving complete revascularization during coronary artery bypass surgery is rarely possible. In most patients, several lesions remain out of reach of the surgical procedure. Consequently, and despite the fact that many patients become clinically asymptomatic, the territories of the arteries that were not operated upon should be protected by pharmacological therapy. Postoperative treatment should therefore include anti-ischemic drugs in combination with lifestyle interventions to address the risk of coronary events and slow down the progression of atheromatous disease. Here again, trimetazidine has a pivotal role, even in asymptomatic patients (in whom warning signs that would normally prompt the use of sublingual glyceryl trinitrate are lacking during ischemic episodes), and particularly so in diabetic individuals and patients with persistent depression of left ventricular function.
Recurrence of angina after surgical revascularization is now an emerging problem, mainly in diabetic patients. The causes of this phenomenon are several: progression of the atheromatous disease in the native arterial beds [20]; atheroma-like degeneration in the bypass conduits [20]; nonoptimal secondary preventive therapy after surgery; persistent lack of compliance with the medical treatment. In this setting, the technical difficulties and the greater risks attached to reintervention (percutaneous interventions or repeat surgery), especially in diabetic or elderly patients [20,21], confer a central role on medical treatment. Identification of “forgotten” risk factors, optimization of antihypertensive therapy, and prevention of new coronary events, by means of antianginal and anti-ischemic drug therapy, are crucial. Use of trimetazidine and other measures addressing small-vessel and microcirculatory dysfunction may result in important clinical improvement as far as angina is concerned. A review of the first TRIMetazidine in POLand (TRIMPOL) I trial data and a subanalysis of the TRIMPOL II trial in patients who underwent revascularization [21] (Figure 2) confirmed the positive clinical impact of trimetazidine in these patients. For the reasons mentioned above, the addition of trimetazidine to the medical treatment regimen will be of greatest benefit to diabetic patients and patients with depressed left ventricular function.

Figure 2. Effective relief of symptoms with trimetazidine (Vastarel) in patients with recurrent angina at baseline (W0) and after 12 weeks (W12). *P < 0.01. (Modified from Szwed [21], with permission.)

Conclusion
There is increasing evidence that the action of trimetazidine on myocardial energy metabolism is responsible both for the antianginal effect of the drug and for the cardioprotection that is evident in patients with coronary disease who have diabetes or depressed left ventricular function, or both. Trimetazidine elicits progressive and sustained improvement in ventricular function. During coronary artery bypass surgery under cardiopulmonary bypass, trimetazidine contributes to reducing surgical ischemia-reperfusion damage, with a consequent reduction in perioperative ischemic events and need for inotropic drug treatment. In patients undergoing coronary artery bypass surgery, because of the antianginal, anti-ischemic, and cardioprotective effects of trimetazidine, its use may be extended to the long-term postoperative period, mainly in individuals with incomplete revascularization and patients with recurrent angina. In diabetic patients, even those without overt ischemic heart disease, trimetazidine may have a pivotal cardioprotective role.

REFERENCES

Although great care has been taken in compiling the information given in this website,
the publisher or the sponsor is not responsible for the continued currency of the information,
for any errors or omissions, or for any consequence arising therefrom.
© 2010 Les Laboratoires Servier

Number 29, 2006Bypass surgery for coronary artery disease: a vanishing treatment? Protective effects of trimetazidine before and after coronary artery bypass surgery

Number 29, 2006Bypass surgery for coronary artery disease: a vanishing treatment?

Number 29, 2006
Bypass surgery for coronary artery disease: a vanishing treatment?
Protective effects of trimetazidine before and after coronary artery bypass surgery

Number 29, 2006
Bypass surgery for coronary artery disease: a vanishing treatment?