Trimetazidine in Angina and Poor Muscle Function: Protocol for a Randomized Controlled Study
Introduction
The aging population faces significant challenges related to declining muscle strength and physical performance. Low handgrip strength (HS) and reduced gait speed (GS) are particularly prevalent among older adults, with studies showing that nearly 10% to 20% of individuals over 60 years old have low HS, and this condition worsens with age. Similarly, nearly 45% of people aged around 70 years old exhibit low GS. Despite the growing need for effective and safe treatments, there is currently no widely accepted medication for addressing low muscle strength or poor physical performance in the elderly.
Trimetazidine (TMZ), a traditional anti-angina drug, has shown potential benefits beyond its primary use. TMZ targets both skeletal and cardiac muscle cells by improving energy metabolism, which could enhance cardiac function and muscle strength, thereby promoting exercise endurance. Previous studies have demonstrated the positive effects of TMZ on physical performance and muscle endurance in patients with ischemic heart disease (IHD) or claudication. However, the role of TMZ in improving muscle function in elderly patients with stable angina has not been thoroughly investigated.
This study aims to evaluate the efficacy and safety of TMZ in elderly patients with stable angina and poor muscle strength or physical performance. The hypothesis is that TMZ can improve muscle strength, physical performance, and muscle endurance in this population. The study protocol outlines a prospective randomized controlled trial designed to test this hypothesis.
Methods
Ethical Approval
The study will be conducted in accordance with the principles of the Declaration of Helsinki and national regulations. The study protocol, version 3.0, dated April 15, 2018, has been approved by the Research Ethics Committee (REC) of the Chinese People’s Liberation Army General Hospital and Zhengzhou Central Hospital, Zhengzhou University. Signed informed consent forms (ICF) will be obtained from all participants before any intervention. Participants will receive both verbal and written information about the study’s nature and duration. Any amendments to the protocol will require fast-track review by the REC, and enrolled patients will receive updated ICFs.
Study Design
The study, titled “TMZ in Angina and Poor Muscle Function (TAP),” is a prospective randomized controlled trial conducted at two centers in China. Fifty-eight eligible patients will be consecutively recruited and randomly assigned to one of two groups: the TMZ group or the control group. Randomization will be performed using the Statistical Package for Social Sciences (SPSS) software, version 22.0, with an initial random seed parameter of 2,000,000. The study will consist of ten blocks, each containing 29 participants.
The TMZ group will receive a dose of 35 mg of oral TMZ (modified release tablets) twice daily with meals for three months, in addition to conventional treatments for angina. The control group will receive only conventional treatments for angina, which may include anti-platelet drugs, beta-blockers, statins, calcium channel blockers, and nitrates. Due to the unavailability of a placebo, blinding is not feasible in this study.
Study Participants
Inclusion criteria for participants are: (1) age over 60 years; (2) confirmed ICF signature; (3) low HS (less than 26.0 kg for men and less than 18.0 kg for women) or low GS (less than 0.8 m/s); (4) stable angina, defined as a history of coronary artery disease (CAD) diagnosed by coronary artery angiography, computed tomography angiography, or treadmill test, with consistent symptoms over the previous three months.
Exclusion criteria include: (1) secondary hypertension; (2) secondary poor muscle strength or physical performance, such as New York Heart Association class III and IV heart failure; (3) recent surgery within the past three months or poor exercise performance due to neurological, musculoskeletal, or pain-related conditions; (4) liver or renal dysfunction; (5) diagnosed thyroid or hematological diseases; (6) unhealed tuberculosis or metastatic advanced tumors; (7) hypersensitivity to TMZ or prior TMZ use within the last three months; (8) inability to cooperate due to other comorbidities.
Participants who do not meet the criteria during follow-up will be required to leave the study. Elimination criteria include misdiagnosis, false inclusion, poor compliance (less than 80% or more than 120%), critical protocol deviations, disposal of medicine before Visit 1, lack of data after randomization, concomitant use of drugs that may improve muscle strength, or withdrawal of ICF.
Sample Size Calculation
The sample size was calculated using a formula based on previous studies, assuming a type 1 error of 0.05, a power of 90%, and a 1:1 case-to-control ratio. The calculated number of participants was 46, but anticipating a 20% drop-out rate and allocation needs for two centers, 58 participants will be sufficient for the study.
TMZ Treatments
TMZ modified release tablets will be administered at a dose of 35 mg twice daily with meals for three months in the TMZ group. All drug packages will be returned to investigators during hospital visits to monitor compliance.
Concomitant Treatments
Concomitant treatments may include anti-platelet drugs, beta-blockers, statins, calcium channel blockers, nitrates, oral anticoagulants, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers.
Planned Visit Schedule
Participants will undergo a systemic muscle function evaluation at baseline, including medical history, physical performance, muscle strength, muscle endurance, a five-question scale for sarcopenia (SARC-F), and blood tests. The intervention will start on Day 1, with follow-up visits at Day 7±2 (Visit 1), Day 30±5 (Visit 2), Day 60±5 (Visit 3), and Day 90±10 (Visit 4). Visit 1 and Visit 3 will be phone calls, while Visit 2 and Visit 4 will be hospital visits.
Physical Performance
Physical performance will be assessed using the 6-minute walking distance (6MWD) and GS. The 6MWD will be calculated based on GS, measured over a 12-meter straight-line distance. The test will be conducted twice, with the quickest time used for calculations.
Muscle Strength
Muscle strength will be measured using a dynamometer for HS and a gauge for pinch strength. The dominant hand will be determined by testing HS for each hand, and the higher of two measurements will be recorded.
Muscle Endurance and Balance Maintenance
Muscle endurance will be assessed using the five times sit-to-stand test (FTSST), and balance maintenance will be evaluated using the tandem standing test (TST). Both tests will be conducted three times, with the best performance recorded.
Other Physical Examinations
Body mass, height, and circumferences (biceps, waist, hip, and calf) will be measured to an accuracy of 0.1 kg or 0.1 cm.
SARC-F
The SARC-F questionnaire will be used to assess sarcopenia, with a total score of four or more indicating the presence of sarcopenia.
Blood Tests
Routine blood tests and biochemical tests will be conducted in the early morning before breakfast.
Outcome Variables
The primary outcome variable will be the change in 6MWD. Secondary outcome variables include changes in muscle strength (HS and pinch strength), GS, muscle endurance (FTSST), balance maintenance (TST), and the frequency of angina per week.
Safety Variables
Safety variables include the occurrence of adverse drug reactions (ADRs) such as headache, dizziness, stomachache, diarrhea, dyspepsia, nausea, vomiting, rash, pruritus, or urticaria. Laboratory indicators, such as liver and renal function, will also be monitored.
Adverse Event Management
Adverse events (AEs) will be recorded and managed according to good medical practice. Serious AEs will be reported to the principal investigator, REC, and the China Food and Drug Administration within 24 hours.
Statistical Analysis
Data will be analyzed using SPSS software, version 22.0. Continuous variables will be checked for normal distribution, and appropriate statistical tests will be applied. A one-sided P value of less than 0.05 will be considered statistically significant.
Discussion
The TAP study is the first multicenter, randomized, controlled trial to investigate the potential of TMZ in improving poor muscle function in patients with stable angina. Previous studies have shown that TMZ can improve exercise endurance in patients with IHD or claudication, but its role in muscle function has not been comprehensively evaluated.
This study focuses on elderly patients with stable angina and poor muscle strength or physical performance, a population that has received less attention in previous research. The daily dose of TMZ modified release tablets used in this study is 70 mg (35 mg twice daily), which is 10 mg higher than the traditional TMZ tablets used in other studies.
Despite the lack of a placebo and the relatively small sample size, this study provides important insights into the potential benefits of TMZ for elderly patients with low muscle strength or poor physical performance. The results may contribute to the development of effective and safe medical treatments for this population.
Funding
This study is supported by a grant from the China Health Promotion Foundation.
doi.org/10.1097/CM9.0000000000000267
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