Trimetazidine and left ventricular ischaemic dysfunction: an overview of clinical evidence
The Division of Cardiology, Ospedale S. Martino e Cliniche, Universitarie Convenzionate, Genoa, Italy
* Correspondence: S.L. Chierchia, Division of Cardiology, Monoblocco 7° Piano, Ospedale S. Martino, Largo R. Benzi 10, Genoa, Italy.
Abstract
The myocardial effects of trimetazidine, the prototypal agent of the new class of 3-ketoacyl coenzyme A thiolase inhibitors, has been assessed in three randomized, double-blind, placebo-controlled studies in patients with ischaemic cardiomyopathy, stable angina or hibernating myocardium treated for periods ranging from 15 days to 6 months.
Twenty patients with severe ischaemic cardiomyopathy (class III and IV of the New York Heart Association [NYHA]) treated with classic combination therapy were randomized to either placebo or trimetazidine 20 mg three times daily. Ejection fraction at rest was assessed by radionucleide angiography and clinical symptoms both at baseline and after 6 months of treatment. All patients treated with trimetazidine improved clinically in that they gained one stage of NYHA classification, whereas only one patient had improvement in the placebo group (
). Ejection fraction increased from 28·7 ± 3·8% to 29·6 ± 3·2% in the trimetazidine group, whereas it decreased from 22·3 ± 2·4% to 18·6 ± 2·0% in the placebo group (
).
Fifteen patients with coronary artery disease confirmed by angiography and a positive response to dobutamine testing were treated with placebo or trimetazidine 20 mg three times daily following a double-blind, cross over design. Stress echocardiography was performed during baseline and after both 2-week treatment periods. Compared with placebo, treatment with trimetazidine significantly reduced the wall motion score index in patients with a positive test (1·63 ± 0·40 versus 1·73 ± 0·46; 
). Furthermore, treatment with trimetazidine increased the dobutamine infusion time (17·5 ± 4·9 min versus 15·2 ± 4·1 min; 
) and the maximum dose of dobutamine administered to reach the ischaemic threshold (27·9 ± 8·0 µg . kg–1 . min–1 versus 22·1 ± 5·8 µg . kg–1 . min–1; 
).
Forty-four patients with post-necrotic left ventricular dysfunction (ejection fraction = 33 ± 5%) and multivessel coronary artery disease were randomized to either placebo or trimetazidine 20 mg three times daily and were treated over 8 weeks in combination with conventional antianginal medications. Patients were assessed using low-dose dobutamine (5–20 mg . kg–1 . min–1) echocardiography and symptom-limited cardiopulmonary exercise test. After trimetazidine, the systolic wall thickening score index (SWTI) improved by 20·8% ( versus control); ejection fraction at peak dobutamine also increased (+14%; ). Out of 14 patients who showed improved SWTI, 11 had a concomitant increase in peak VO2, wheras none of the five patients who had no improvement in contractility showed an increased peak VO2.
In conclusion, treatment with the metabolic agent trimetazidine is able to improve myocardial function in several situations where left ventricular function is impaired. Improvement in cardiac function occurs without haemodynamic change due to a metabolic intra-mitochondrial effect within the myocyte. Trimetazidine was very well tolerated in all three clinical trials.
Key Words: Cardioprotection • ischaemia • metabolism • myocardial dysfunction