TRimetazidine as an Agent to affeCt clopidogrEl Response: The TRACER Study

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Abstract

Introduction

This prospective study aimed to determine whether trimetazidine (TMZ) alters the pharmacodynamic (PD) effects of clopidogrel.

Methods

Patients with stable coronary artery disease (SCAD) ( n = 24) who were actively treated with dual antiplatelet therapy (DAPT) of aspirin 81 mg daily and clopidogrel 75 mg daily were recruited. Platelet function was measured with the VerifyNow P2Y12 assay (Accriva Diagnostics, San Diego, CA, USA) and assessed before the initiation of and after 14 days of treatment with TMZ. Results were compared using a paired t test.

Results

Almost 80% of the study population were of South Asian descent and had diabetes mellitus (DM). P2Y12 reaction units (PRUs) were higher in patients on TMZ (204 ± 56 compared with 174 ± 71 before TMZ, p = 0.005). The average increase in PRU score was 29 (95% confidence interval 8.8–49.7). Before TMZ, the proportion of patients with high on-treatment platelet reactivity (PRU > 208 units) was 25%, which increased to 42% for patients on TMZ.

Conclusion

Higher platelet reactivity was seen in patients on TMZ, suggesting that TMZ attenuated the PD effects of clopidogrel in this study of a predominantly South Asian diabetic subpopulation. Alternative therapies should be considered and further research is warranted.

Trial Registration

ClinicalTrials.gov number, NCT03603249.

Related collections

Most cited references 34

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Rivaroxaban in patients with a recent acute coronary syndrome.

Jessica Mega, Eugene Braunwald, Stephen Wiviott … (2012)

Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

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The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.

David Lopaschuk, P Kantor, Kevin Kozak … (2000)

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation.