Trimetazidine (Vastarel MR)
Heart Metab. 2009;42:25–28.د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2011
Despite treatment with conventional drugs, a high proportion of patients remain symptomatic. Both experimental and clinical studies in patients with heart failure have demonstrated that agents that inhibit fatty acid oxidation, with a consequent stimulation of glucose oxidation, may increase contractile function and have cytoprotective effect on cardiomyocytes in the failing heart.
Trimetazidine (Vastarel MR) is the first cytoprotective agent to exert an anti-ischemic effect.
Its lack of effects on hemodynamic parameters gives this drug a potential advantage. This article aims to review the current data on effects of Vastarel MR in patients with chronic coronary artery disease and left ventricular dysfunction.
Myocardial ischemia most commonly develops as an imbalance between coronary artery blood flow and increased demands for myocardial power and oxygen consumption.
As a result of myocardial ischemia, there is a reduction in aerobic formation of ATP,
and consequently anaerobic glycolysis, lactate formation,and a decrease in cell pH may develop.
The increase in myocardial oxygen demand is compensated by an increased blood flow and coronary oxygen supply in normal individuals.
In most patients with chronic CAD, angina is caused by increased myocardial oxygen demands of exercise or emotional stress that cannot be met by an increase in coronary blood flow.
Three classes of drugs traditionally have been used for treatment of chronic coronary artery disease
(CAD): b-blockers, calcium channel blockers, and
nitrates.
Despite optimal treatment with these agents,
more than 50% of patients with CAD optimally treated for exercise-induced angina have clinical manifestations of disease.
On the basis of the pathogenetic mechanism
described above, the treatment of stable angina has been directed primarily towards increasing myocardial blood flow and decreasing oxygen demand in the myocardium. In myocardial ischemia, fatty acid oxidation and glucose oxidation are decreased,whereas anaerobic glycolysis becomes a more prominent source of ATP .High levels of fatty acid oxidation are associated with a decrease in glucose oxidation; thus the inhibition of fatty acid oxidation may have abeneficial metabolic action because, in the ischemic heart, fatty acids are a less efficient source of myocardial energy than glucose with respect to oxygen consumption .
Many experimental and clinical data have shown that shifting the energy substrate preference from fatty acid metabolism to glucose oxidation may be a metabolically economic way of producing ATP with decreased consumption of oxygen .
Trimetazidine (Vastarel MR) is the first agent to be developed that selectively and partially inhibits long-chain 3-ketoacyl coenzyme A thiolase (3-KAT), an enzyme involved in fatty acid b-oxidation.
There are several mechanisms of action by which trimetazidine promotes the preservation of the membrane structure and cellular composition of cardiomyocytes: limitation of intracellular acidosis, prevention of the excessive production of free radicals and calcium overload, and correction of disturbances in transmembrane ion exchange.
A meta-analysis of 12 double-blind, randomized,
controlled clinical trials of trimetazidine in the treatment of stable angina showed that trimetazidine caused significant reductions in the number of angina attacks and improved the time to 1mm ST-segment depression and the total work at peak exercise.Metaanalysis confirmed that trimetazidine is effective as an antianginal agent when used alone or in combination with traditional hemodynamic agents, without compromising hemodynamics and without side effects.
The antiischemic effects of trimetazidine, by decreasing fatty acid oxidation and preserving ATP production at
the cellular level and thereby reducing intracellular
acidosis, influence these overlapping pathogenetic
processes in ischemic heart failure. Prevention of intracellular acidosis and calcium overload can be important ‘‘cardioprotective’’effects in both ischemia and heart failure .The beneficial effect of trimetazidine on energy metabolism may contribute to an improvement in myocardial systolic function in patients with left ventricular dysfunction caused by CAD.
Hemodynamically ‘‘neutral’’ drugs
Brottier et al first showed that treatment with trimetazidine for 6 months increased radionuclide ejection fraction by 9.3% in patients with ischemic cardiomyopathy. The effects of trimetazidine in patients with left ventricular dysfunction and diabetes were assessed in randomized studies by Fragasso et aland Rosano et al .In both studies, 6months of treatment with trimetazidine resulted in a significant increase in left ventricular ejection fraction (LVEF) and a decrease in end-diastolic volumes. Vitale and colleagues showed similar effects of trimetazidine on ventricular function and volumes in elderly.
Conclusions
Analysis of clinical trials suggests that metabolic intervention in the management of patients with CAD and left ventricular dysfunction represents a promising therapeutic approach. Its anti-ischemic properties and absence of hemodynamic effects make the modified-release formulation of trimetazidine, Vastarel MR, a good treatment option in patients with left ventricular dysfunction.The modified-release formulation of daily dose of 70 mg trimetazidine may be more effective than the immediate-release formulation with respect to relief of angina.
This modified-release formulation has no any adverse effects in patients with ischemic cardiomyopathy and may afford better patient compliance with treatment, because of its reduced frequency of administration compared with the conventional formulation.
Improvements in left ventricular contractility and functional class demonstrated in clinical trials with Vastarel MR are further indications that addition of this agent to conventional treatment may have beneficial effects for patients with ischemic left ventricular dysfunction. Recent studies demonstrating beneficial effects on mortality derived from long-term administration of trimetazidine in patients with ischemic left ventricular dysfunction suggest the necessity for a large multicenter trial to prove this influence.
