Number 20, 2003
Hibernation preconditioning

Introducing Vastarel MR, the twice-daily 3-KAT inhibitor with sustained antianginal efficacy at trough

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Ioana Holban
Centre Hospitalier Frederic Joliot, Paris, France
Correspondence: Dr Ioana Holban, Centre Hospitalier Frederic Joliot, 4 Place General Leclerc, 1400 Orsay, France. Tel: +33 1 69867700

A new twice-daily formulation
New modified-release trimetazidine (Vastarel MR) is a twice-daily formulation of the first 3-KAT inhibitor, a metabolic anti-ischemic drug, free of hemodynamic effects. Unlike conventional antianginal agents, modified-release trimetazidine acts through a different mechanism of action based on optimization of cardiac metabolism, secondary to inhibition of the mitochondrial 3-KAT enzyme [1]. This results in a shift towards glucose oxidation and better use of the energy supply, thus reducing ischemia-induced metabolic damage. Clinical data show that modified-release trimetazidine can reduce ischemia-reperfusion–induced ionic imbalance, thus providing a cytoprotective effect by raising tolerance to reperfusion injury. In comparison with immediate-release trimetazidine 20 mg, modified-release trimetazidine offers an optimized pharmacokinetic profile (Table I).

Table I. Comparative pharmacokinetic features of modified-release trimetazidine and the immediate-release formulation.

The new modified-release formulation was designed to provide twice-daily dosing to maintain antianginal efficacy beyond the trough (12 hours after last drug intake) through increased minimal plasma concentrations, while being bioequivalent to the immediate-release formulation [2, 3]. To meet these criteria, the modified-release trimetazidine 35-mg tablet has an innovative hydrophilic matrix with polymers which swell in contact with gastrointestinal fluids, producing gels which create a barrier. This slows down the diffusion of the drug [4].

An optimized pharmacokinetic profile leading to round-the-clock cardio- protection
A bioequivalence study was performed to compare the pharmacokinetic profile of the modified-release formulation with that of the immediate-release formulation [2]. This open-label, randomized, two-period crossover study was conducted in 12 healthy volunteers. After 4 days’ oral administration of immediate-release trimetazidine 20 mg tid or modified-release trimetazidine 35 mg bid, with a washout interval of at least 3 days between the two treatment periods, pharmacokinetic analysis showed that the modified-release formulation is strictly bioequivalent to the immediate-release formulation. Furthermore, modified-release trimetazidine offers increased minimum plasma concentrations (+31%) (Figure 1), which is of particular interest in the early morning hours when patients are more prone to cardiovascular events, reduced plasma level fluctuations, and a prolonged plateau of concentrations.

Figure 1. Comparative pharmacokinetic profile of modified-release trimetazidine bid and trimetazidine immediate release tid.

The improved features of the new formulation ensure that the patient receives true round-the-clock cardioprotection.

Sustained antianginal efficacy at trough
The third major innovation of modified-release trimetazidine is its sustained antianginal efficacy demonstrated at trough. A multi-center, double-blind, randomized, placebo-controlled study, performed in France by Professor Sellier’s team, aimed to assess the anti-ischemic and antianginal efficacy at trough and the safety of modified-release trimetazidine 35 mg bid in 223 patients with stable angina and a positive exercise test despite a background of b-blocker therapy (50 mg atenolol od) given for ethical reasons [3]. In terms of efficacy (assessed by exercise test and clinical evaluation at trough, 12 hours after last drug intake), there was a significant difference in ST-segment depression in favor of modified-release trimetazidine versus placebo. Patients receiving modified-release trimetazidine experienced a 50% reduction in the number of angina attacks per week (Figure 2).

Figure 2. Patients treated with modified-release trimetazidine experience 50% fewer angina attacks per week.

In terms of safety and acceptability, there was no difference between the two groups (incidence of adverse events, vital signs, and laboratory parameters were equivalent).
Modified-release trimetazidine can be used alone or in combination with other cardiovascular drugs. In monotherapy, trimetazidine was shown to have the same antianginal and anti-ischemic effects as a b-blocker or a calcium channel blocker [5, 6]. In combination therapy, due to its metabolic mechanism of action, free of hemodynamic impact, trimetazidine can provide additive efficacy when used on top of a hemodynamic agent [7, 8]. A recent double-blind, randomized, placebo-controlled trial, TRIMPOL II, confirmed these findings in patients resistant to monotherapy with metoprolol [9]. The superiority of the combination of a b-blocker plus trimetazidine over the combination of a b-blocker plus a long-acting nitrate was also confirmed in a clinical study where no significant benefit was shown by the combination of two hemodynamic antianginal agents [10].

Clinical evidence in at-risk patients
At-risk coronary patients such as diabetics, the elderly, or patients with left ventricular dysfunction can also benefit from treatment with modified-release trimetazidine due to its specific metabolic mechanism of action. The efficacy and tolerance of trimetazidine were studied in 50 diabetic patients with stable angina who had been receiving treatment with conventional hemodynamic agents [11]. The results showed the same benefits in diabetic patients (in whom metabolic myocardial disturbances are also present) as in nondiabetic coronary patients. Furthermore, trimetazidine preserved glycemic control.
In elderly coronary patients, modified-release trimetazidine also represents an interesting new approach. Its metabolic action preserves this fragile population from any hemodynamic unwanted effects. The clinical safety of modified-release trimetazidine was assessed in a multicenter, double-blind, placebo-controlled study in unselected elderly patients [12]. The results demonstrate good long-term safety of the drug.
As a cardioprotective agent, modified-release trimetazidine has beneficial effects on left ventricular function, as demonstrated in several clinical studies. Short- and long-term administration of trimetazidine improved left ventricular function in diabetic and nondiabetic patients with severe ischemic cardiomyopathy [13, 14]. In three clinical trials trimetazidine was also shown to protect the heart from reperfusion damage during and after myocardial infarction and coronary angioplasty [15–18].
Modified-release trimetazidine can benefit a wide range of coronary patients due to its excellent acceptability. In a pivotal study the acceptability of the new formulation was evaluated over a 6-month period and tolerance of the drug was found to be comparable to that of placebo [3].
The new formulation of modified-release trimetazidine is easy to use in daily practice. Its twice-daily regimen presents an opportunity to improve patients’ compliance. With its optimized pharmacokinetic profile, modified-release trimetazidine is the first twice-daily 3-KAT inhibitor available for clinical use worldwide, providing coronary patients with round-the-clock metabolic cardioprotection, sustained antianginal efficacy at trough, and greater ease of use.

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