What is the role of trimetazidine in the treatment of heart failure with reduced ejection fraction (HFrEF)?

Trimetazidine in Heart Failure with Reduced Ejection Fraction

Trimetazidine is not recommended as part of guideline-directed medical therapy for HFrEF, as it is not included in any major international heart failure guidelines (ESC, ACC/AHA, or HFSA). While research suggests potential benefits, the evidence base consists primarily of small, short-duration trials insufficient to establish its role in standard HFrEF management.

Guideline Status and Recommendations

• Major heart failure guidelines do not include trimetazidine in their treatment algorithms for HFrEF 1.
• The ESC 2012 guidelines, ACC/AHA 2021-2023 updates, and recent HFA consensus statements focus exclusively on four foundational drug classes: ARNI/ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors 1.
• No Class I, IIa, or IIb recommendation exists for trimetazidine in any contemporary HFrEF guideline 1.

Current Evidence Base

Meta-Analysis Findings

• A 2024 systematic review of 28 studies (2,552 patients) found trimetazidine reduced cardiovascular mortality (OR 0.33,95% CI 0.21-0.53) and HF hospitalizations (OR 0.42,95% CI 0.29-0.60) 2.
• The same meta-analysis showed improvements in NYHA functional class (mean difference -0.44), 6-minute walk distance (+109 meters), and quality of life 2.
• An earlier 2011 meta-analysis of 17 trials (955 patients) demonstrated improved LVEF in both ischemic (WMD 7.37%) and non-ischemic HF (WMD 8.72%) 3.

Critical Limitations of Available Evidence

• Studies were predominantly small (median size N=58) with short follow-up (mean 6 months) 2.
• 68% of trials were open-label, introducing significant bias risk 2.
• The 2024 meta-analysis authors explicitly state: "Current evidence supports the potential role of trimetazidine in HFrEF, but this is based on multiple smaller trials of varying quality" 2.

Contradictory Evidence

• A 2022 prospective randomized crossover study of 45 patients with advanced HFrEF found no significant changes in peak VO₂, 6MWT, LVEF, quality of life, mortality, or cardiovascular events after 6 months of trimetazidine 4.
• A 2025 review concluded that "trimetazidine's role in the treatment of heart failure is still not clearly identified, since most studies on this topic were underpowered" 5.

Clinical Context: Established HFrEF Therapy

Proven Guideline-Directed Medical Therapy

• Quadruple therapy (ARNI/ACE inhibitor + beta-blocker + MRA + SGLT2 inhibitor) reduces mortality by 73% over 2 years and extends life expectancy by approximately 6 years in a 55-year-old patient 1.
• Each component has robust evidence from large, multicenter, double-blind randomized trials 1.
• Current gaps in GDMT implementation are substantial: only 1% of eligible patients achieve target doses of all recommended drugs simultaneously 1.

Priority Focus Areas

• Optimizing existing GDMT should be the absolute priority before considering non-guideline therapies 1.
• Target dose achievement for established therapies remains at only 10-30% for most drug classes 1.
• Discontinuation rates for proven therapies are unacceptably high (24-55%) 1.

Practical Considerations

When Trimetazidine Might Be Considered

• Only after maximizing all four pillars of GDMT at target or maximally tolerated doses 1.
• In patients with persistent angina despite optimal beta-blocker therapy, where European guidelines give trimetazidine a Class IIb recommendation specifically for angina relief 5.
• In resource-limited settings where cost is prohibitive for established therapies, though this represents suboptimal care 2.

Common Pitfalls to Avoid

• Do not substitute trimetazidine for any component of GDMT - it lacks the robust mortality benefit of established therapies 1, 2.
• Avoid using trimetazidine as an excuse for clinical inertia in optimizing proven therapies 1.
• Do not rely on open-label trial data when making decisions about mortality-reducing therapies 2.
• Recognize that improved LVEF alone does not guarantee mortality benefit - multiple therapies have improved LVEF without reducing death 2, 4.

Mechanism and Theoretical Rationale

• Trimetazidine inhibits fatty acid β-oxidation, shifting myocardial metabolism toward glucose oxidation 2, 5.
• It possesses antioxidant properties and inhibits cardiac fibrosis 5.
• The metabolic modulation approach is theoretically sound but requires validation in adequately powered trials 2.

Future Directions

• The 2024 meta-analysis authors explicitly recommend "a large pragmatic randomised clinical trial to establish the definitive role of trimetazidine in the management of HFrEF" 2.
• Until such evidence exists, trimetazidine remains investigational for HFrEF and should not displace proven therapies 2, 5.