They noted that ischemia management leaves much to be desired. Cabral said management of ischemic heart disease remains largely dependent on hemodynamic agents that "we have been using for the past 35 years" with limitations. They cited findings by Pepine et al. showing that 64 percent of patients with chronic stable angina were taking at least two cardiovascular drugs yet nine out of 10 of them continued to have effort angina. Lao said the same study showed that 70 percent of the patients had more than one associated illness, "[indicating that] we may need to not just treat ischemic heart disease but deal with comorbid conditions."

    Cabral and Lao traced the high failure rate to the plateau effect of hemodynamic agents. They said all these drugs work by reducing myocardial oxygen demand, altering hemodynamic gradients by direct coronary vasodilation, and redistributing blood flow to the subendocardium. They have no effect at the cellular level, and combining them offers no added benefit.

Metabolic Switch

    The two said another way to treat ischemia is to increase cardiac efficiency to help the heart to make the most of the available substrates to produce the needed energy and restore supply-demand balance. The way to do this is to switch the energy substrate preference in the heart from fatty acid to glucose oxidation.

    During moderate ischemia, both fatty acid and glucose oxidation are impaired because of lower oxygen supply. Glycolysis accelerates, but glucose is not oxidized. "There is a derangement in the function, an uncoupling or decoupling of the glycolytic system so that pyruvate does not go straight to acetyl-coenzyme-A formation," explained Lao. Cabral noted that to compensate for this, glycolysis increases, fueled by endogenous glycogen stores. As a result, lactate and hydrogen accumulate in the myocardium, leading to acidosis and further reducing cardiac efficiency.

    Lao said this sequence of events at the cellular level "is what we have to try to arrest."

    Trimetazidine addresses this metabolic impairment by inhibiting 3-ketoacyl CoA thiolase (3-KAT), thereby reducing fatty acid oxidation. In the process, the heart uses only glucose as source of energy. Since glucose is used up, energy is produced with less oxygen consumption. In the process also, "the cell is protected because of the manipulation of the metabolic modulators of ischemia," said Lao.

    "The inhibition of fatty acid oxidation and stimulation of glucose oxidation improves cardiac efficiency," added Cabral.

    The two doctors said there is growing evidence of trimetazidine efficacy in angina, congestive heart failure, and severe forms of ischemia. They cited a metaanalysis by Mario Marzilli and Werner W. Klein (Coronary Artery Disease 2003;14: 171-179) in which the drug was shown to have performed better in reducing weekly anginal attacks (by 39 percent), increasing exercise tolerance, and reducing ST segment depression.

    Trimetazidine's new formulation (Vastarel MR) is a 35mg tablet with a hydrophilic matrix that allows for controlled release of the drug for twice-daily dosing and better compliance. Cabral said Vastarel MR best matches the natural circadian rhythm for myocardial ischemia. It also "confers better protection from myocardial ischemia over 24 hours because of its higher concentration at trough than the old formulation," she said. On the other hand, its maximum plasma concentration is slightly lower, making it safer.

    Cabral and Lao noted that a four-month study showed that Vastarel MR achieved sustained anginal efficacy at trough with greater change in time to 1-mm ST-segment depression and longer time to onset of angina. It also decreased the number of anginal attacks over time (50 percent better than placebo) and showed excellent tolerability profile. Elenore Uy