What is the role of trimetazidine in managing stable angina?

Trimetazidine in the Management of Stable Angina

Trimetazidine is a second-line metabolic modulator that significantly improves exercise tolerance, reduces weekly angina episodes, and decreases short-acting nitrate consumption in patients with stable angina, without affecting hemodynamic parameters, making it particularly valuable for patients who cannot tolerate first-line agents or remain symptomatic despite optimal therapy. 1

Mechanism of Action

• Trimetazidine is a piperazine derivative that increases cellular tolerance to ischemia by inhibiting mitochondrial 3-ketoacyl-CoA thiolase, shifting cardiac metabolism from fatty acid to glucose utilization 1
• Unlike traditional antianginal medications (beta-blockers, calcium channel blockers, nitrates), trimetazidine does not affect oxygen demand but improves metabolic efficiency of ischemic myocytes 1
• This metabolic modulation leads to less proton and lactic acid production from ischemic myocardium and more anaerobic ATP production 1
• Treatment with trimetazidine for 3 months has been shown to increase myocardial high-energy phosphate levels by 33% in heart failure patients 1

Clinical Efficacy

• Meta-analyses demonstrate that trimetazidine significantly reduces weekly angina attacks compared to placebo (mean difference -1.44,95% CI -2.10 to -0.79; P < 0.0001) 2
• Trimetazidine decreases weekly nitroglycerin consumption (95% CI -1.47 to -2.20, -0.73; P < 0.0001) and improves exercise time to 1 mm ST-segment depression (P=0.0002) 2
• Real-world observational studies show rapid improvement (within 2 weeks) in angina symptoms that is maintained over 6 months regardless of angina duration 3
• In patients with recently diagnosed angina (<1 year), weekly angina attacks decreased from 3.75 ± 4.63 to 0.67 ± 1.51, while in those with advanced disease (>9 years), attacks decreased from 5.63 ± 5.24 to 1.32 ± 2.07 3

Place in Therapy

• Current guidelines (AHA/ACC, ESC, NICE) classify trimetazidine as a second-line agent for patients who have contraindications to first-choice agents (beta-blockers, calcium channel blockers, short-acting nitrates), do not tolerate them, or remain symptomatic 1
• Trimetazidine can be used as monotherapy or in combination with other antianginal medications, particularly calcium channel blockers or beta-blockers 1
• European guidelines have categorized trimetazidine as a class IIb recommendation in patients with heart failure with reduced ejection fraction and angina 4

Special Patient Populations

Patients with Hypotension

• Trimetazidine is preferred in patients with low blood pressure (<130/80 mmHg) as it does not exert hemodynamic effects that could further reduce blood pressure 1

Patients with Heart Failure

• Meta-analyses of small studies suggest trimetazidine may be beneficial as add-on therapy in patients with left ventricular dysfunction and/or heart failure 1
• Trimetazidine has shown improved left ventricular function in addition to anginal symptom relief in patients already on beta-blockers 4

Patients with Diabetes

• For patients with diabetes and chronic angina, ranolazine is generally preferred over trimetazidine due to its proven benefits on glycemic control 5

Safety and Adverse Effects

• Trimetazidine is generally well-tolerated with mild adverse effects, primarily gastrointestinal disturbances (nausea, vomiting) and minor headaches 1
• Contraindicated in patients with Parkinson's disease, parkinsonism, and other related movement disorders 1, 5
• Not recommended in patients with severe renal impairment (creatinine clearance <30 ml/min) 1, 5
• Has fewer dropouts due to adverse events compared to some alternative regimens 2

Clinical Decision Algorithm

1. For first-line therapy of stable angina: Use beta-blockers, calcium channel blockers, or short-acting nitrates 1
2. Consider trimetazidine when:
   • Patient has contraindications to first-line agents 1
   • Patient does not tolerate first-line agents 1
   • Patient remains symptomatic despite optimal first-line therapy 1
   • Patient has hypotension (systolic BP <130 mmHg) 1
3. Avoid trimetazidine in:
   • Patients with Parkinson's disease or movement disorders 1, 5
   • Patients with severe renal impairment (CrCl <30 ml/min) 1, 5
4. For patients with diabetes and angina: Consider ranolazine before trimetazidine 5
5. For patients with heart failure and angina: Consider adding trimetazidine to beta-blockers 4