Efficacy of Meldonium in the Complex Treatment of Patients with Decompensated Chronic Heart Failure

Chronic heart failure (CHF) of functional class I-IV according to the classification of New York Heart Association (NYHA) according to studies in 22 regions of Russia (EPOHA CHF and EPOHA-OCHF) was 7% (7.9 million people), and severe CHF (II-IV CHF) was mentioned in 4.5% of population (5.1 million people). According to the National Recommendations of the Society of Heart Failure Specialists (CHF), the Russian Society of Cardiology (RSC) and the Russian National Medical Society of Therapists (RNMOT) on the diagnosis and treatment of CHF of the fourth revision, decompensation of CHF is the cause of hospitalization for every second patient with heart and vascular diseases. The basis for the development of CHF is a violation of the structure and/or function of the heart, as a result of which the heart is unable to meet the oxygen requirements of the body at normal filling pressure of the heart, and it is possible only at the cost of increasing the filling pressure of the heart.

Trends in pharmacotherapy of both acute and chronic heart failure, in addition to standard therapy, are aimed at restoring energy imbalance in the conditions of oxygen starvation of the heart muscle, which can be achieved by using cytoprotectors. Mildronate® (3-2,2,2-trimethylhydrazinium propionate) is a well-known metabolic corrector, which leads to a decrease in the cell energy consumption by using glucose oxidation, reducing the penetration of unoxidized fatty acids into the cell and preventing free radical formation, thereby reducing oxidative stress. This mechanism is especially relevant in ischemic myocardium. Thus, the use of Mildronate® reduces manifestations of CHF, improves cardiac contractile function and, consequently, exercise tolerance.
However, clinical studies on the use of Mildronate® in patients with heart failure do not fully answer the question about the effect of the drug on the prognosis and course of CHF, as well as the possibility of use in the acute period of CHF and the effect on the long-term prognosis in patients with CHF.

Materials and Methods

Fifty patients with decompensated CHF (II-III class according to NYHA classification) aged from 61 to 82 (mean, 73.2 ± 5.6) years were examined at Spasokukotsky Clinical Hospital in Moscow in 2018. The first group included 30 patients, 16 men and 14 women aged 73.2 ± 5.6 years with decompensated CHF. These patients were prescribed Mildronate® in an inpatient dose of 1000 mg once daily by IV as an adjunct to traditional baseline therapy and, after discharge from the hospital, 500 mg in capsules twice daily for a follow-up period of up to three months. The second group included 20 patients, 8 men and 12 women, mean age 75.3 ± 5.5 years with decompensated CHF. These patients received only conventional baseline therapy (control group). The study duration was 3 months.

The exclusion criteria were: dyspnea of noncardiogenic genesis; childbearing age in women and pregnancy or lactation; body temperature over 38.5 °C; sepsis or active infection requiring intravenous administration of antimicrobials; clinical manifestations of acute coronary syndrome at present or within 30 days before inclusion; acute heart failure due to significant arrhythmia, acute myocarditis or hypertrophic obstructive, restrictive or constrictive cardiomyopathy; presence of active or recurrent bacterial, fungal or viral infection at inclusion; presence of cancer; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased more than 3-fold; body mass index over 40 kg/m2.

Standard therapy for CHF was prescribed by a research physician and/or an attending physician according to the accepted standard of care. Standard therapy included prescription of ACE inhibitors, diuretic therapy (furosemide, spironolactone), cardiac glycosides (digoxin) when indicated, antihypertensive drugs when indicated, antiaggregant therapy.

Results of the study

Treatment with Mildronate® in patients with decompensated CHF, as well as in the control group, had no significant effect on heart rate, reliable dynamics of blood pressure, both systolic and diastolic (p > 0.05) was not registered. No side effects of the drug were detected in any case. There were no significant changes in general and biochemical blood tests, no significant changes in electrocardiogram (ECG).

During the study period in the standard therapy group we observed a 4.3% (p = 0.1) decrease in LV CER, 5.3% (p = 0.5) decrease in LV MVP by 5% (p = 0.43), the remaining parameters had no clinically significant changes.

The Mildronate® group showed a 2.5% (p = 0.04) decrease in left atrial size, 4.8% (p = 0.07) decrease in LV CER, 7.3% (p = 0.08) decrease in left ventricular MVP, 6.8% (p = 0.4) decrease in LV CAS, 16% (p = 0.3), decrease in MMLV by 9.4% (p = 0.1), increase in ejection fraction by 7.4% (p = 0.1), but these changes did not reach a statistically significant level, which, in our opinion, was due to insufficient sample size.

Compared to the control group, the treatment group with mildronate® showed a marked increase of ejection fraction by 6.8%, a marked decrease of LV EF by 7.4%, LV CEP by 4.5%, and LV CFR by 8% (Table 2). The positive effect of mildronate® treatment was proven in a relatively short-term follow-up of 3 months, but its greater effect is expected after longer duration of treatment.

In dynamics of NT-proBNP on the 1st and 7th days of hospitalization: in standard therapy group – decrease by 32.8%, in Mildronate® group – decrease by 28.3%. In 3 months after hospitalization: in the group of standard therapy – increase of NT-proBNP by 8,9%, in the group of mildronate® – decrease of NT-proBNP by 16,3% (p < 0,0004) compared to NT-proBNP on the 7th day of hospitalization (Table 3, Fig.), which shows positive effect of mildronate® in complex therapy in patients with decompensated CHF, as NT-proBNP level directly indicates such indicator as one-year survival rate of patients.

Discussion

Hypoxia is a typical pathological process that develops due to absolute and/or relative insufficiency of biological oxidation, leading to impaired energy supply of functions and plastic processes in the body. Understanding that coronary heart disease (CHD) is a mismatch between the level of myocardial oxygen consumption and its delivery by coronary blood flow, as well as impaired beta-oxidation of free fatty acids in cardiomyocyte mitochondria with accumulation of under-oxidized products in mitochondria – acylcarnitine and acyl-CoA (acetyl-CoA), has opened the possibility for a new direction of drug action on ischemic myocardium – myocardial cytoprotection.

The ideology of metabolic cardioprotection has been formed for quite a long time. The use of metabolic correctors in treatment regimens of patients with CHF started in 1990s. Metabolic agents specifically affecting metabolic processes in hypoxia are drugs of different chemical classes, their action is mediated by different mechanisms: improvement of blood oxygen-transport function, maintenance of cell energy balance, correction of respiratory chain function and metabolic disorders of tissue and organ cells.

Mildronate® belongs to the group of so-called cytoprotectors – antihypoxants that provide protection and energy supply to various cells of the body under conditions of ischemia and increased stress. Mildronate®, being a structural analog of γ-butyrobetaine (GBB), is a competitive inhibitor of GBB-hydroxylase, the last enzyme in the chain of carnitine biosynthesis in humans and animals.

A number of studies on the efficacy of Mildronate® in the treatment of CHF are cited in the literature. More than 250 clinical studies have been published, evaluating the clinical efficacy of meldronate for a variety of pathological conditions, and the application of this molecule in various fields of clinical medicine continues to be actively studied. Perhaps the most significant experience with its use has been in the treatment of patients with various forms of coronary heart disease.

We studied 60 men with CHD and CHF II-III class with ejection fraction less than 45%. In addition to standard baseline therapy, 30 patients received Mildronate® 1000 mg once daily orally for 4 weeks. The control group consisted of 30 patients receiving only basic therapy. The effect of treatment was evaluated by EchoCG data, six-minute walk test and SF-36 questionnaire to assess quality of life.

Analysis of the results showed that patients receiving Mildronate®, by the end of the treatment course had a marked increase in EF and a decrease in values of end-diastolic and end-systolic volumes of the LV. The degree of increase in exercise tolerance in the group of patients who received Mildronate® was also higher than in patients who received only standard therapy.

The authors concluded that the inclusion of Mildronate® in the complex therapy of CHF allows for a more pronounced positive effect of therapy on hemodynamics, exercise tolerance and quality of life of patients in general.

Natriuretic peptides are a class of related peptides including ANP (atrial natriuretic peptide), BNP, as well as CNP (C-type natriuretic peptide) and DNP (dendroaspis natriuretic peptide). The BNP of interest is synthesized predominantly by the ventricles of the heart, and the stimulating element for increased secretion of this neurohormone is volume overload of the heart chambers. There is evidence that the concentration of brain natriuretic peptides closely correlates with LV size, function and mass, which is of great importance in the diagnosis of CHF and prognosis of these patients. The study of Gabrusenko S.A. et al. studied the interrelation of clinical data, hemodynamic parameters and concentration of natriuretic peptides in 110 patients with hypertrophic cardiomyopathy. It was found that the content of N-terminal atrial natriuretic peptide correlated with the degree of mitral regurgitation and correlated more closely with the transverse size of the left atrium.

Elevated natriuretic peptide concentration is an independent risk factor for the development of decompensation and the likelihood of mortality in patients with CHF. R. Berger et al. followed 452 patients with moderate to severe CHF and LV ejection fraction less than 35% on an outpatient basis for three years. Brain natriuretic peptide concentrations elevated early in the follow-up appeared to be an independent predictor of sudden death: only 1% of patients with peptide levels less than 130 pg/mL died suddenly, whereas among patients with brain natriuretic peptide levels above 130 pg/mL, 19% of patients died suddenly.

In the study, BNP concentrations in 249 patients were compared with an echocardiographic parameter, transmitral diastolic flow. The patients were divided into two groups: the first group – patients with LV diastolic dysfunction, and the second group – with reference indices of LV diastolic function. In the first group, the BNP concentration was 286 ± 31 pg/ml, and in the second group, it was 33 ± 3 pg/ml. It is noteworthy that the highest peptide values were observed in the subgroup of patients with restrictive type of transmitral flow.

The possibility of predicting mortality and decompensation leading to rehospitalization in 132 patients with suspected CHF was assessed. N-terminal brain natriuretic peptide levels of 50 pmol/L or higher and altered EchoCG were found to be independent indicators predicting adverse outcome .

Summarizing the clinical studies of treatment with Mildronate® for CHF, it should be noted that Mildronate®:

1. improves myocardial contractility by echocardiographic indices;
2. increases exercise tolerance;
3. reduces the number of ventricular extrasystoles and does not cause myocardial ischemia during exercise;
4. improves well-being and quality of life of patients;
5. improves vascular endothelial function;
6. can be included in the schemes of combined therapy;
7. has a favorable safety profile;
8. the optimal daily dose of the drug is 1000 mg per day, with a duration of administration of up to 6 weeks.

Conclusion

Mildronate® in outpatient practice is used as a drug with polymodal action and shown both in isolated and combined pathologies of cardiovascular system of ischemic genesis – CHD, CHF. In hospital, the use of Mildronate ® in combination therapy helps to reduce the duration of hospitalization and improves the patient’s prognosis.

The intravenous use of mildronate® at a dose of 1000 mg/day for 7-10 days followed by oral administration at a dose of 1000 mg/day for 3 months in combination therapy in patients with decompensated CHF has a positive effect: it reduces symptoms of CHF, which is accompanied by a decrease in severity of FK CHF and decrease in NT-proBNP level in blood, favorably influencing the prognosis of patients, reducing the risk of repeated hospitalization for decompensated CHF. Low level of NT-proBNP is prognostically favorable sign and associated with lower probability of lethal outcome and higher quality of life in patients with CHF; it has a favorable effect on cardiac structural and functional parameters (the number of patients with unfavorable types of LV remodeling decreases and diastolic heart function improves).

Our clinical comparative study confirms the efficacy, safety and favorable effect of Mildronate® on the disease prognosis in acute decompensation of CHF at the hospital stage and confirms the necessity of its prolongation at the outpatient treatment stage.