What is the role of trimetazidine in patients with Heart Failure with reduced Ejection Fraction (HFrEF) without chest pain?

Trimetazidine in HFrEF Without Chest Pain

Trimetazidine is not recommended as standard therapy for HFrEF patients without angina, as it is not included in any major guideline-directed medical therapy (GDMT) for heart failure and lacks robust evidence for mortality benefit in this population.

Guideline-Directed Medical Therapy Takes Priority

The 2022 AHA/ACC/HFSA guidelines clearly define GDMT for HFrEF, which includes:

• ACE inhibitors, ARBs, or ARNI (Class I, Level A/B-R) 1
• Evidence-based beta-blockers (Class I, Level A) 1
• Mineralocorticoid receptor antagonists (MRAs) (Class I, Level A) 1
• SGLT2 inhibitors (Class I, Level A) 1

Trimetazidine is conspicuously absent from all major heart failure guidelines 1. The European Society of Cardiology guidelines classify trimetazidine only as a Class IIb recommendation specifically for HFrEF patients WITH angina, not for those without chest pain 2.

The Evidence Gap for Trimetazidine in HFrEF

While research suggests potential benefits, the evidence base is fundamentally inadequate:

Study Quality Concerns

• Most studies are small and underpowered: The median study size in meta-analyses is only N=58 patients 3
• Short duration: Mean follow-up is only 6 months 3
• Poor methodology: 68% of studies are open-label (not blinded) 3
• No large pragmatic trials exist to establish definitive efficacy 3

Contradictory Findings

Positive signals from meta-analysis suggest trimetazidine may reduce cardiovascular mortality (OR 0.33) and HF hospitalizations (OR 0.42) 3, with improvements in functional class, 6-minute walk distance, and quality of life 3. It may also improve left ventricular global longitudinal strain 4.

However, a well-designed prospective randomized controlled trial in 45 patients with advanced HFrEF found no significant changes in mortality, exercise capacity, LVEF, or quality of life after 6 months of trimetazidine on top of optimal medical therapy 5.

Clinical Algorithm for HFrEF Without Angina

Step 1: Optimize Proven GDMT First

Before considering any adjunctive therapy, ensure the following are maximized 1:

• ARNI (sacubitril-valsartan) titrated to target dose (97/103 mg twice daily) 1
• Evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) at target doses 1
• MRA (spironolactone or eplerenone) at appropriate doses 1
• SGLT2 inhibitor (empagliflozin or dapagliflozin) 1

Step 2: Address Specific Indications

• Diuretics as needed for congestion 1
• ICD for primary prevention if LVEF ≤35% after ≥3 months of optimal medical therapy 1
• CRT if QRS ≥150 ms with LBBB morphology 1

Step 3: Trimetazidine Consideration (Only If Angina Present)

Do NOT use trimetazidine in HFrEF patients without angina because:

• It lacks guideline support for this indication 1
• Evidence is insufficient and contradictory 5, 3
• Proven GDMT provides substantial mortality benefit (20%+ risk reduction) 1
• Resources should focus on optimizing established therapies 1

Critical Pitfalls to Avoid

Do not substitute trimetazidine for proven GDMT: The magnitude of benefit from ARNI, beta-blockers, and MRAs is well-established (≥20% mortality reduction) 1, whereas trimetazidine's mortality benefit remains unproven in adequately powered trials 5, 3.

Do not use trimetazidine as "add-on" therapy without angina: Even European guidelines restrict its use to HFrEF patients WITH angina symptoms 2. Without angina, there is no guideline-supported rationale for its use.

Recognize the difference between surrogate endpoints and hard outcomes: While trimetazidine may improve functional parameters 3, 4, a well-designed RCT showed no mortality benefit 5, and prioritizing morbidity and mortality outcomes is paramount.

Bottom Line

Focus exclusively on optimizing the four pillars of GDMT (ARNI/ACEi/ARB, beta-blocker, MRA, SGLT2i) in HFrEF patients without angina 1. Trimetazidine should only be considered in HFrEF patients who have concomitant angina despite optimal antianginal therapy, and even then, it remains a second-line agent 2. The evidence does not support its use in non-ischemic symptoms or as routine HFrEF therapy 5, 3.