Efficacy of Lipoic Acid on Chronic Ischemic Heart Failure Patients

Official title

Lipoic Acid in Chronic Ischemic Heart Failure: Assessment of Reduction in Major Adverse Cardiovascular Events

Overview

Chronic heart failure is a clinical condition caused by structural heart disease and is characterized by reduced pumping function, fluid retention, and abnormal activation of neurohormonal systems. It represents the advanced stage of many cardiovascular diseases and remains a major global health challenge. Despite progress in medical and interventional therapies, patients with chronic heart failure continue to experience high rates of death, hospitalization, and long-term disability. Ischemic heart failure, which develops as a result of coronary artery disease and prior myocardial infarction, is the most common form of chronic heart failure. Current treatment strategies, including guideline-directed medical therapy and revascularization procedures, can improve symptoms and outcomes but do not fully address the residual risk of adverse cardiovascular events. Therefore, additional therapeutic approaches are needed to further improve long-term prognosis in this population. Abnormal myocardial energy metabolism is a key pathological feature of heart failure. Mitochondria play a central role in energy production, and impaired mitochondrial function contributes to disease progression. Previous studies by our group have identified mitochondrial aldehyde dehydrogenase 2 (ALDH2) as an important regulator of myocardial metabolic homeostasis and cardiac protection under ischemic and stress conditions. Alpha-lipoic acid is a vitamin B-related compound with antioxidant properties and has been widely used in clinical practice for other indications. Increasing evidence suggests that alpha-lipoic acid may also exert protective effects in cardiovascular diseases, potentially through modulation of mitochondrial function. Experimental studies have shown that alpha-lipoic acid can restore ALDH2 activity and improve cardiac function in models of heart failure. Based on these findings, we conducted an exploratory randomized controlled trial between 2019 and 2023 to evaluate the safety and potential efficacy of alpha-lipoic acid in patients with ischemic heart failure. In this multicenter study, patients receiving alpha-lipoic acid showed favorable trends toward reduced risk of death and heart failure-related hospitalization, as well as significant improvements in left ventricular ejection fraction and exercise capacity, without an increase in adverse events. Taken together, prior mechanistic research and early clinical evidence support the hypothesis that alpha-lipoic acid may provide additional benefit when used as adjunctive therapy in patients with chronic ischemic heart failure. The present study is designed to further evaluate whether long-term supplementation with alpha-lipoic acid can reduce major adverse cardiovascular events and improve clinical outcomes in this population.

Interventions

• Drug Alpha-Lipoic Acid (ALA)
  After enrollment, patients received Alpha-Lipoic Acid drug at a dose of 600 mg per day for 24 months.
• Drug placebo
  After enrollment, patients received placebo drug at a dose of 600 mg per day for 24 months.

Primary outcome measures

• Major Adverse Cardiovascular Events (MACE) [Time frame: From enrollment to the end of treatment at 24 months.]
• Hospitalization for Heart Failure [Time frame: From enrollment to the end of treatment at 24 months.]

Secondary outcome measures (10)

• Hospitalization for Heart Failure [Time frame: From enrollment to the end of treatment at 24 months.]
• Non-fatal Stroke [Time frame: From enrollment to the end of treatment at 24 months.]
• Non-fatal Myocardial Infarction [Time frame: From enrollment to the end of treatment at 24 months.]
• All-cause Mortality [Time frame: From enrollment to the end of treatment at 24 months.]
• Change in Left Ventricular Ejection Fraction (LVEF) [Time frame: From enrollment to the end of treatment at 24 months.]
• Change in 6-Minute Walk Distance (6MWD) [Time frame: From enrollment to the end of treatment at 24 months.]
• Change in NT-proBNP Level [Time frame: From enrollment to the end of treatment at 24 months.]
• Change in Quality of Life Score (KCCQ) [Time frame: From enrollment to the end of treatment at 24 months.]
• Unplanned Coronary Revascularization [Time frame: From enrollment to the end of treatment at 24 months.]
• Heart Transplantation [Time frame: From enrollment to the end of treatment at 24 months.]

Eligibility criteria

Inclusion criteria

• Aged 18 years or older and younger than 75 years at the time of enrollment.
• A history of chronic heart failure for more than 3 months, or clinical symptoms of heart failure lasting more than 3 months, diagnosed according to the 2023 European Society of Cardiology guidelines for the diagnosis and treatment of chronic heart failure.
• Left ventricular ejection fraction (LVEF) of 40% or less, as assessed by echocardiography.
• A history of acute myocardial infarction more than 3 months prior to enrollment, diagnosed according to the Fourth Universal Definition of Myocardial Infarction.
• New York Heart Association (NYHA) functional class II to IV, with stable clinical symptoms.
• Receipt of guideline-directed medical therapy for heart failure for at least 2 weeks, without dose adjustment or intravenous therapy during this period. Guideline-directed medical therapy includes: Angiotensin-converting enzyme inhibitors (ACEIs), or Angiotensin receptor blockers (ARBs), or Angiotensin receptor-neprilysin inhibitors (ARNIs), Beta-blockers, and Mineralocorticoid receptor antagonists,unless contraindicated or not tolerated, and prescribed at optimal tolerated doses.
• Ability and willingness to understand the study procedures and provide written informed consent.

Exclusion criteria

• Prior cardiac resynchronization therapy (CRT).
• Severe hepatic dysfunction, defined as liver transaminase levels greater than three times the upper limit of normal, or severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m².
• Presence of uncontrolled malignant arrhythmias or progressively worsening unstable angina.
• Presence of malignancy, lymphoma, leukemia, or other serious diseases with an expected life expectancy of less than 1 year.
• Participation in another investigational drug study within 4 weeks prior to enrollment, or current receipt of any investigational treatment other than the study intervention.
• Pregnant or breastfeeding women.
• Known allergy to vitamin B-related medications.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 21 centers

• The First Affiliated Hospital of USTC (Anhui Provincial Hospital) — Hefei
• Fujian provincial hospital — Fuzhou
• The First Affiliated Hospital, Sun Yat-sen University — Guangzhou
• Luoyang Central Hospital Affiliated to Zhengzhou University — Luoyang
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• Zhongda Hospital, Southeast University — Nanjing
• Affiliated Zhongshan Hospital of Dalian University — Dalian
• The First Affiliated Hospital of Xi'an Jiaotong University — Xi'an
• … and 13 more centers

Identifiers

NCT: NCT07725484 · KY2026037

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗