Trimetazidine Overview
Trimetazidine is a metabolic modulator approved as second-line add-on therapy for chronic stable angina when first-line agents (beta-blockers or calcium channel blockers) provide inadequate symptom control or are contraindicated, with its unique advantage being the absence of hemodynamic effects. 1, 2, 3
Mechanism of Action
Trimetazidine inhibits mitochondrial 3-ketoacyl-CoA thiolase (3-KAT), the terminal enzyme in fatty acid β-oxidation, forcing cardiac metabolism to shift from fatty acid to glucose utilization 1, 2, 4
This metabolic shift improves oxygen efficiency during ischemia because glucose oxidation requires approximately 10% less oxygen than fatty acid oxidation to produce the same amount of ATP 2, 5
The drug reduces lactate and proton accumulation in ischemic myocardium, decreasing intracellular acidosis and preserving cellular ATP levels 2, 6, 5
Treatment for 3 months increases myocardial high-energy phosphate levels by 33% in heart failure patients 2
Unlike traditional antianginal agents, trimetazidine does not affect heart rate, blood pressure, or the rate-pressure product, making it hemodynamically neutral 1, 2, 7
Guideline Recommendations and Place in Therapy
Current Classification
The European Society of Cardiology (ESC) and American College of Cardiology (ACC) classify trimetazidine as a Class IIb recommendation (Level B evidence) for second-line therapy 1, 2, 3
This represents a downgrade from the 2019 ESC guidelines, which previously gave trimetazidine a Class IIa recommendation, with long-acting nitrates and ranolazine now receiving preferential Class IIa status 3
Treatment Algorithm
First-line therapy:
- Beta-blockers and/or calcium channel blockers remain the foundation of antianginal treatment 3
- Short-acting nitroglycerin for acute symptom relief in all patients 3
When to add trimetazidine:
- Add when inadequate symptom control persists despite optimized doses of beta-blockers and/or calcium channel blockers 2, 3
- Consider as part of initial treatment when first-line agents are contraindicated or poorly tolerated 1, 3
- Particularly useful in patients with contraindications to multiple first-line agents 2, 3
Clinical Efficacy
Meta-analyses demonstrate that trimetazidine significantly improves exercise tolerance, reduces weekly angina episodes, and decreases short-acting nitrate consumption compared to placebo 1
When used as monotherapy at 20 mg three times daily, trimetazidine produces clinical effects broadly similar to nifedipine 40 mg/day and propranolol 120-160 mg/day, but without affecting the rate-pressure product 7
As adjunctive therapy at 60 mg/day, trimetazidine appears more effective than isosorbide dinitrate 30 mg/day when added to propranolol 120 mg/day 7
Meta-analyses suggest benefit as add-on therapy in patients with left ventricular dysfunction and/or heart failure (moderate strength of evidence) 1, 2
Specific Clinical Scenarios Favoring Trimetazidine
Patients with Hypotension or Low Blood Pressure
- Trimetazidine is the preferred antianginal agent in patients with low blood pressure because it exerts no hemodynamic effects 1, 2, 3
- This makes it particularly valuable when beta-blockers and calcium channel blockers would further compromise blood pressure 3
Patients with Bradycardia or Low Heart Rate
- The ESC suggests trimetazidine as a reasonable option for antianginal combination therapy in patients with low heart rate who cannot tolerate rate-lowering agents 1, 3
Patients with Left Ventricular Hypertrophy
- While not specifically indicated for LVH itself, trimetazidine may be considered in LVH patients with chronic stable angina who have hemodynamic limitations preventing use of traditional agents 1
Ischemic Cardiomyopathy
- The ESC recommends trimetazidine as add-on therapy (Class IIb) in ischemic cardiomyopathy patients with inadequate symptom control despite beta-blockers and/or calcium channel blockers 1, 2
Absolute Contraindications
Screen for these before prescribing:
Parkinson's disease, parkinsonism, and related movement disorders (absolute contraindication due to risk of worsening extrapyramidal symptoms) 1, 2, 3
Severe renal impairment with creatinine clearance <30 mL/min (absolute contraindication) 1, 2, 3
Safety Profile and Adverse Effects
Trimetazidine is generally well-tolerated with a safety profile similar to placebo in clinical trials 1, 2, 7
The most frequently reported adverse effects are mild gastrointestinal disturbances and minor headaches, occurring at low incidence 1, 2, 7
The tolerability profile is superior to nifedipine 40 mg/day or propranolol 120-160 mg/day when used as monotherapy 7
Dosing
- Standard dose: 20 mg three times daily (total 60 mg/day) 7, 5
- Can be used as monotherapy or in combination with other antianginal medications 2
Common Pitfalls to Avoid
Do not use trimetazidine as first-line monotherapy when beta-blockers or calcium channel blockers are appropriate and tolerated 3
Always screen for movement disorders before initiating therapy to avoid prescribing in patients with undiagnosed parkinsonism 3
Check renal function before prescribing to identify severe renal impairment 3
In diabetic patients with chronic angina, consider ranolazine instead of trimetazidine for dual benefits on angina and glycemic control 2, 3
Remember that trimetazidine provides no acute symptom relief—patients still require short-acting nitroglycerin for acute anginal episodes 3
Additional Pleiotropic Effects
Trimetazidine demonstrates antioxidant, cytoprotective, and anti-apoptotic activity beyond its anti-ischemic effects 8
Evidence suggests potential benefits in limiting ischemia/reperfusion damage during percutaneous coronary intervention, coronary artery bypass grafting, and thrombolysis 4, 6
The drug may exhibit antiarrhythmic properties and reduce myocardial damage from oxidative stress and inflammation after invasive procedures 6