Gut Microbiota Modulation With Synbiotics After Acute Coronary Syndrome

Official title

Gut Microbiota Modulation With Synbiotics as Secondary Prevention After Acute Coronary Syndrome: A Randomized-Controlled Trial Pilot Study

Overview

Acute coronary syndrome (ACS) remains one of the leading causes of morbidity and mortality worldwide despite major advances in acute management and secondary prevention. Gut dysbiosis has been described as linked to cardiovascular events. Modulating the gut microbiota through symbiotics-a combination of probiotics and prebiotics-represents a promising, low-risk and widely accessible strategy to influence these pathways and contribute to the enhancement of cardiovascular prevention, with regards to the global burden as well as health costs. The SYMBIO-ACS study is therefore designed to assess the effects of a symbiotic intervention on TMAO levels and identify new cardiometabolic biomarkers in patients following ACS, providing essential pilot data for future larger-scale preventive trials.

Detailed description

Modulating the gut microbiota through symbiotics-a combination of probiotics and prebiotics-represents a promising, low-risk and widely accessible strategy to influence these pathways and contribute to the enhancement of cardiovascular prevention, with regards to the global burden as well as health costs. Symbiotics may reduce TMAO levels, decrease systemic inflammation, and support metabolic regulation. However, evidence in post-ACS patients remains limited, and controlled clinical trials addressing mechanistic biomarkers are needed. The SYMBIO-ACS study is therefore designed to assess the effects of a symbiotic intervention on TMAO levels and identify new cardiometabolic biomarkers in patients following ACS, providing essential pilot data for future larger-scale preventive trials.

The aim of the study is to detect a 50% TMAO reduction (and a difference of 1 to 2 μmol/L) with gut modulation with symbiotics after acute coronary syndrome, and identify other relevant anthropometric and biomarkers Design: Prospective monocentric randomized-control trial with superiority design.

Population: Outpatient cardiology clinic or emergency department of the hospital of Biel in Switzerland.

Protocol:

Patients diagnosed with an ACS (less than one week ago) will be identified by doctors of the cardiology department of the Biel Spital Zentrum (Switzerland) both in the ambulatory consultation and emergency department, where cardiologist act as consultants. They will be informed on the study and if wished be given a 48 hours reflection before agreeing with the consent form. All patients, regardless of our study, will be offered the best-guideline directed medical therapy (according to either performed PCI or conservative treatment) with implantation of lifestyle measures (advice with brochure on the Mediterranean diet, physical activity, and tobacco cessation). Then, they will be randomized 1:1 with a software (stratification for age, sex, vegetarian diet and cardiovascular risk factors (cardiovascular risk factors (hypertension, mellitus diabetes, dyslipidemia)) to receive a 10 week daily symbiotic supplementation or the standard therapy alone (no placebo).

At maximum one week after diagnosis of ACS, patients in the intervention group will be provided with the adequate number of capsules for the duration of the study (2 per day, for 10 weeks, giving 140 capsules per patient) with clear instructions.

All included patients will as well be given a study ID number, the anonymization is guaranteed.

Assessement(demographics, anthropometric and laboratory, questionnaire) will be directly asked by the investigators or found in the medical record of the patient. For all the required analysis in addition to the routine laboratory parameters, a sample 2 x 5ml of native blood is planned as supplement to routine analysis. These supplementary analyses will be undergone in a specialized extern laboratory in Inselspital the department of biomedical research linked to Inselspital (University of Bern, CH).

The same measures (anthropometric and plasmatic) will be routinely repeated after 10 weeks of intervention and retrieved in the patient medical record, and again at one year, still in the context of usual follow-up appointments.

A questionnaire will be given as well at inclusion, 10 weeks and 1 year (Redcap link send per mail/post in case of outpatient care setting, or under paper form if wished by the patient or better suited because lack of internet access). The 7-item Seattle Angina Questionnaire (SAQ-7) and the Life's Essential 8 (LE8) are planned to be used.

Statistics:

80 patients (40 per arm). Number of patients required to obtain a 50% reduction in TMAO levels and a 1 to 2 μmol/L difference (classic formula for calculating the sample size for a comparison of means between two groups (two-tailed test, α = 0.05, power = 90%), and estimated baseline of 5-6 μmol/L and a standard deviation of 2,0 to 2,5 μmol/L in post-ACS, considering a compensation for 10% foreseen losses.

Primary between-group comparison of change in plasma TMAO levels using an analysis of covariance (ANCOVA) model adjusted for baseline TMAO and relevant covariates (age, sex, renal function, vegetarian diet and cardiovascular risk factors (hypertension, mellitus diabetes, dyslipidemia)).

Secondary and exploratory outcomes, including inflammatory markers

Interventions

• Dietary supplement Pro-B (Bionaturis),
  10 weeks supplementation with Pro-B symbiotics (BioNaturis, Swizterland) 10 weeks supplementation with Pro-B Kaps, 9,6 x 109 CFU per day of Lactococcus lactis, Lactobacillus helveticus, Streptococcus thermophilus, Lactobacillus rhamnosus and Bifidobacterium longum plus 120 mg per day of fructooligosaccharides and vitamin B complex)
• Other Guideline-Directed Medical Therapy (GDMT)
  GDMT for Aacute coronary syndrome

Primary outcome measures

• TMAO [Time frame: At inclusion, 10 weeks and 1 year]

Secondary outcome measures (12)

• Height [Time frame: At inclusion, 10 weeks and 1 year]
• Weight [Time frame: At inclusion, 10 weeks and 1 year]
• BMI [Time frame: At inclusion, 10 weeks and 1 year]
• Systolic Blood pressure [Time frame: At inclusion, 10 weeks and 1 year]
• hsCRP [Time frame: At inclusion, 10 weeks and 1 year]
• HbA1c [Time frame: At inclusion, 10 weeks and 1 year]
• SCFA and bile acids profile [Time frame: At inclusion, 10 weeks and 1 year]
• LPS [Time frame: At inclusion, 10 weeks and 1 year]
• Lipid profile (LDL, High total/HDL-cholesterol and LDL/HDL-cholesterol) [Time frame: At inclusion, 10 weeks and 1 year]
• Malondialdehyde [Time frame: At inclusion, 10 weeks and 1 year]
• Total antioxidant capacity [Time frame: At inclusion, 10 weeks and 1 year]
• Imidazole propionate [Time frame: At inclusion, 10 weeks and 1 year]

Eligibility criteria

Inclusion criteria

• Informed Consent as documented by signature
• Adult patients capable of providing discernment informed consent
• Recent (< 1 week) diagnosis of acute coronary syndrome as defined in the last 2023 ESC guidelines and the Fourth universal definition of myocardial infarction, including unstable angina or myocardial infarction with or without ST-elevation, managed either with best guideline-directed medical therapy or percutaneous coronary intervention.

• Myocardial injury: Elevated cardiac troponins (cTn) value above the 99th percentile URL. The injury is considered acute if there is a rise and/or fall of cTn values.
• Unstable angina: Myocardial ischaemia at rest or on minimal exertion in the absence of acute cardiomyocyte injury/necrosis. Prolonged (>20 min) angina at rest; new onset of severe angina; angina that is increasing in frequency, longer in duration, or lower in threshold; or angina that occurs after a recent episode of MI
• Type 1 myocardial infarction: Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL and with at least one of the following: Symptoms of acute myocardial ischaemia; New ischaemic ECG change; Development of pathological Q waves; Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology;Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy
• Mastering French or German or capacity to be helped with adequate translation

Exclusion criteria

• Contraindications to symbiotics as listed in Section 3.5.5, that is: immunocompromised individuals, intensive care patients (or critical state), severe valvulopathiesvalvular heart diseases, endocarditis antecedent, known allergy, chronic intestinal diseases or risk factors for small intestine bacterial overgrowth (SIBO) (severe malabsorption or history of digestive surgery), or severe comorbidities (see under)
• Severe hepatic or renal dysfunction (defined as eGFR <30 mL/min/1,73 m², dialysis or Child-Pugh score class C)
• Limited life expectancy (<1 year) or progressive malignant disease
• Type 2 myocardial infarction: Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL, and evidence of an imbalance between myocardial oxygen supply and demand unrelated to acute coronary athero-thrombosis, requiring at least one of the following: Symptoms of acute myocardial ischaemia; New ischaemic ECG changes; Development of pathological Q waves; Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology.
• Ongoing pre/probiotic supplementation
• Chronic antibiotherapy or within less than 3 months
• Women who are pregnant or breast feeding
• Intention to become pregnant during the course of the study
• Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases (Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential)
• Known or suspected non-compliance, drug or alcohol abuse, dement patients not living in assisted nurse facility care or without supervised treatment administration
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant,
• Previous enrolment into the current study,
• Enrolment of the investigator, his/her family members, employees and other dependent persons

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

Open label

Primary purpose

Prevention

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07411287 · BE202601 · Ongoing

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗