Ozone Therapy in Refractory Ischemic Heart Disease.

Effectiveness and Cost-effectiveness of Ozone Therapy in Patients With Ischemic Heart Disease Refractory to Medical and Surgical Treatment: Randomized, Triple-blind Clinical Trial

The main objective of this clinical trial is to evaluate the effectiveness and cost-effectiveness of adding ozone therapy to standard management of patients with advanced ischemic heart disease refractory to medical and surgical treatment.

This study will evaluate the potential role of ozone therapy added to the standard management of patients with symptomatic refractory ischemic heart disease, III-IV functional class of the classification of the New York Heart Association (NYHA).

MAIN OBJECTIVES: 1) to evaluate clinical effect and quality of life related to health (HRQOL) of adding O3 to the standard treatment of these patients. 2) to estimate the additional costs of adding O3 to the standard treatment and to evaluate the cost-effectiveness ratio.

SECONDARY OBJECTIVES: 3) To evaluate the evolution of a) biochemical parameters; b) cardiovascular parameters; c) toxicity of O3. 4) Develop and evaluate the acceptability of a shared decision-making (SDM) tool between professionals and patients.

METHODOLOGY: Phase II-III clinical trial, randomized, triple-blind. Sample size: 18 patients.

TREATMENT: All patients will receive their standard treatment + 40 sessions of rectal insufflation:

1. Ozone-Group (n = 9): O3/O2 concentration progressively increased from 10 to 30 µg/ml.
2. Control-placebo-Group (n = 9): O3/O2 Concentration = 0 µg/ml (only O2).

Main Variables: 1) changes in the self-perceived quality of life (Minnesota scale). 2) Direct costs.

Secondary Variables: 1) biochemical parameters; 2) Cardiovascular parameters; 3) Side effects. 4) acceptability of patients to a shared decision-making (SDM) tool.

Length of treatment: 16 weeks.

Follow-up: 16 weeks after completion of O3.

Assessments: 1) Pre-O3 (basal), 2) pos-O3 (end of O3), 3) 4 months pos-O3.

Planned length of clinical trial: 36 months.

Inclusion Criteria:

• Adults with ischemic heart disease, Functional Class III-IV from the NYHA, with symptoms in spite of maximal conventional medical treatment and no suitable to further percutaneous or surgical procedures.
• It should be required clinical diagnosis by the Cardiology Department and confirmation by cardiac catheterization with coronary angiography.
• Ejection Fraction < 40%
• Patients who have signed and dated the study 's specific informed consent.
• Before enrollment, women of childbearing potential should obtain a negative result in the serum or urine pregnancy test at the screening visit, and accept the use of appropriate contraceptive methods at least from the 14 days prior to the first dose of the study drug. up to 14 days after the last one.

Exclusion Criteria:

• Age < 18 or > 85 years old.
• Severe valve disease and/or dynamic left ventricular outflow tract obstruction.
• Pregnancy at the time of enrollment.
• Limited walking ability due to neurologic or orthopedic impairments of the legs
• Those who are incapable to fill in the scales used to measure the quality of life variables
• Cerebral vascular accident (CVA or Transient Ischemic Attack (TIA) within the previous 3 months or carotid stenosis > 80%.
• Acute myocardial infarction (AMI), Percutaneous coronary intervention (PCI) or transmyocardial laser revascularization (TMR or PMR) within the previous 3 months.
• Hemodynamically or clinically unstable patients.
• Severe or limiting pulmonary diseases.
• Specific liver enzymes [Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) > 5 times the upper limit of normal
• Increased creatinine > 3 times the upper limit of normal or Glomerular Filtration Rate (GFR) < 25 ml/min or who are on chronic renal dialysis.
• Severe peripheral vascular disease with rest pain or significant chronic wounds.

Uncontrolled cancer disease or severe active systemic infection or HIV.

• Life expectancy < 4 months
• Contraindication or disability for rectal ozone administration or to attend scheduled treatments.
• Known allergy to ozone.
• Patients who do not meet all the inclusion criteria.