Evaluation of the comparative effectiveness of mineralocorticoid receptor antagonists in patients with chronic heart failure
Nuritdinov N.A.1*, Khamraev A.A.2
1Tashkent Medical Academy, Tashkent, Uzbekistan
2Tashkent Medical Academy, Tashkent, Uzbekistan
ABSTRACT
Purpose. To study the comparative efficacy of mineralocorticoid receptor antagonists (MCRA) on left ventricular diastolic function in patients with chronic heart failure (CHF).
Material and methods. We examined 131 patients with coronary heart disease (CHD) with functional class I-III (FC) CHF (according to NYHA). Patients were randomized into groups according to FC CHF data, according to the classification of the New York Heart Association according to the six-minute walk test (6MWT). The group of patients with FC I consisted of 31 patients, FC II - 51 and FC III - 49 patients.
Results. The study revealed that in patients with CHF, clinical disorders of diastolic function were initially identified in 98 (74.8%) patients with CHF. Long-term complex treatment of CHF patients with the inclusion of MCRA, along with a significant increase in exercise tolerance, improvement of the clinical condition of patients, contributed to the improvement of LV diastolic function - a decrease in the number of patients with LVDD to 58%, an improvement in the quality of life of patients, which were more pronounced in the group of patients taking eplerenone. In both groups, a positive dynamic of the structure of the CHF FC was achieved: the number of CHF patients with FC III decreased due to an increase in the proportion of patients with FC I-II.
Conclusion. Long-term complex treatment of CHF patients with the inclusion of MCRA, along with a significant increase in exercise tolerance, improvement of the clinical condition of patients, contributed to an improvement in LV diastolic function - a decrease in the number of patients with LVDD to 58%, and an improvement in the quality of life of patients.
Keywords
chronic heart failure, diastolic dysfunction, aldosterone, norepinephrine, mineralocorticoid receptor antagonists.
Introduction
Chronic heart failure (CHF), despite the progress achieved in recent years in prevention and treatment, occupies a leading place in the structure of morbidity and mortality in the world. In the world, 1-2% of the adult populations of developed countries have heart failure and CHF occurs in the active period of life that is, in patients aged 40-60 years and is characterized by a frequent cause of hospitalization, deterioration in the quality of life and disability of patients, high mortality rates [9,10]. There is evidence that violations of the diastolic function of the heart usually precede a decrease in the pumping function of the left ventricle and is a predictor of a poor prognosis, the prevalence of which is 40-60% [6,8]. A number of scientific studies are underway in the world aimed at diagnosing, early detection and achieving high efficiency in approaches to the tactics of treating patients with CHF.
In the development of approaches to the early diagnosis of CHF, it is important to study the relationship between clinical and hemodynamic, cardiac remodeling, neurohumoral parameters and the state of the diastolic function of the heart [4]. When analyzing the progression of CHF, it is of interest to study the diastolic function of the left ventricle, since diastolic markers more accurately reflect the systolic functional state of the myocardium and its reserve (ability to carry out the load), and also more reliably than other hemodynamic parameters can be used to assess the quality of life and the effectiveness of therapeutic measures [1, 3]. In the pathogenesis of CHF, an important role is played by the activation of the sympathetic–adrenal and renin-
angiotensin-aldosterone systems (SAS and RAAS) [7,13]. Improving the criteria for early diagnosis of diastolic heart function in CHF, predicting the progression and course of the disease taking into account them, optimizing modern approaches to differentiated pharmacotherapy of CHF taking into account diastolic dysfunction of the left ventricle is one of the urgent tasks today [2, 11].
Purpose
To study the comparative efficacy of MCRA - spirinolactone and eplerenone on left ventricular diastolic function in patients.
Methods
We examined 131 patients with ischemic heart disease (CHD) with functional class I-III (FC) CHF (according to NYHA). Patients were randomized into groups according to FC CHF data, according to the classification of the New York Heart Association according to the six-minute walk test (6MWT). The group of patients with FC I consisted of 31 patients, FC II - 51 and FC III - 49 patients. To compare the data obtained, a group of healthy individuals (control group) in the amount of 20 people, comparable in gender and age with the main group, was examined. The survey did not include patients with complex arrhythmias, acute cerebrovascular accidents, diabetes mellitus, chronic obstructive pulmonary diseases, and liver and kidney diseases.
All patients underwent an electrocardiogram, a complex of clinical, functional and biochemical examinations. The clinical condition of the patients was assessed according to 6MWT, the scale of the assessment clinical condition (SACC) of the patient’s, modified by V.Yu. Mareev (2000).
Quality of life indicators were studied using the Minnesota questionnaire at baseline and after 6 months of follow-up. The diastolic function of the heart and the processes of remodeling were studied by echocardiography (EchoCG) with Doppler imaging. The standard therapy included:
angiotensin-converting enzyme (ACE) inhibitors - 84%, angiotensin receptor antagonists (ARA) - 16%, beta-blockers - 100%, loop diuretics - 36%, spirinolactone - 41%, eplerenone - 35%, antiplatelet agents 94%, nitrates 28%, statins 89%.
To assess the comparative effectiveness of MCRA, the patients were divided into 2 groups: the first group (I) consisted of 51 patients with FC II (26) and FC III CHF (25 patients) who took spirinolactone for 6 months against the background of standard therapy; the second group (II) - 49 patients with FC II (25) and FC III CHF (24 patients) - eplerenone. The dose of spirinolactone was titrated up to 25-50 mg per day (the average dose of the drug was 31.5 ± 10.6), eplerenone was also titrated up to 25-50 mg per day (the average dose of the drug was 29.4 ± 11.5). The groups were randomized for age, sex, and comorbidity.
Data Analysis
For statistical data processing, the Microsoft Office Excel - 2013 software package was used, including the use of built-in statistical processing functions using the STATISTICA-6.0 program.
We used the methods of variational parametric and nonparametric statistics with the calculation of the arithmetic mean of the studied indicator (M), standard deviation (SD), standard error of the mean (m), relative values (frequency,%), the statistical significance of the obtained measurements when comparing the mean values was determined by the criterion Student's t (t) with the calculation of the error probability (P) when checking the normal distribution (by the
kurtosis criterion) and the equality of the general variances (F is the Fisher test). When comparing groups by qualitative characteristics, we used the χ2 criteria. To study the relationship between quantitative variables, correlation analysis was used with the calculation of the Pearson's linear correlation coefficient. The level of reliability p <0.05 was taken as statistically significant changes.
Results
According to the results of the study, disorders of diastolic function were initially identified in 74.8% (98 patients) of patients with CHF. At the same time, grade I (impaired relaxation) was recorded in 38.9% (51 patients), grade II - (pseudonormal) in 21.4% (28), grade III (restrictive) - in 14.5% (19) patients. An analysis of the grades of diastolic dysfunction depending on the CHF FC showed that in patients with CHF FC I, diastolic dysfunction was identified in 58.1% (18) patients, while only grade I (impaired relaxation) was identified - in 12 patients ( 38.7%) and grade II - (pseudonormal) in 6 patients (19.4%). In patients with FC II CHF, DD was detected in 39 patients (76.5%): grade I (impaired relaxation) - in 22 (43.1%) patients, grade II - (pseudonormal) in 10 (19.6%) patients, grade type III (restrictive) - in 7 (13.7%) patients.
In patients with FC III CHF, DD was detected in 81.6% (40 patients) of patients: grade I (impaired relaxation) - in 17 (34.7%) patients, grade II - (pseudonormal) - in 11 (22.4 %) and grade III (restrictive) - in 12 (24.5%) patients.
Disorders of LV diastolic function covered both speed and time parameters of diastole. In the examined patients with CHF, a change in the indicator of the maximum rate of early LV filling (E), a significant decrease in the time of isovolumetric relaxation of the LV (IVRT) and the time of deceleration of the flow rate in the phase of early LV filling (DT, ms) are associated with the progression of CHF and an increase in the FC of the disease. The analysis of indicators depending on the FC of CHF showed that the maximum speed of early filling E of the LV with I, II, III FC was 48.9 ± 8.42, 62.1 ± 7.42 and 71.2 ± 9.03 m / s. The time of isovolumetric relaxation of the LV - IVRT was 108.5 ± 11.2, 94.6 ± 14.3 and 80.1 ± 16.4 ms with a significant decrease in patients with FC II and III CHF by 12.8% (p < 0.05) and 26.2% (p <0.01), respectively, compared with the indicators of FC I of CHF. The time of deceleration of the flow rate in the phase of early LV filling (DT, ms) in patients with FC I, II, III was 212.2 ± 13.25, 184.4 ± 21.91 and 168.3 ± 29.54 ms, respectively. Significant decrease in patients with II and III FC CHF by 12.8% (p <0.05) and 26.2% (p <0.01), respectively, compared with the indicators of FC I CHF.
Thus, the analysis of the types of diastolic dysfunction showed the predominance of relaxation disorders in 38.9% of patients with CHF, an increase in the number of patients with DD and an increase in the number of patients with a restrictive grade of diastolic dysfunction with an increase in the FC of CHF.
Analysis of diastolic function indices in patients of the first and second groups after 6 months of treatment showed an improvement in LV diastolic function.
In patients with FC I CHF after 6 months of treatment, there was an improvement in the indicators of LV diastolic function, which was expressed in a decrease in the E indicator by 12.2% and an increase in A by 14.5%. The E / A ratio were 0.97 ± 0.21. There was a significant improvement in the indicators of the time of isovolumetric relaxation of the LV (IVRT) and the time of deceleration of the flow rate in the phase of early filling of the LV (DT), and these indicators were 194.5 ± 56.7 ms and 88.6 ± 12.6 ms (p <0.05), respectively.
In patients of group II with the inclusion of spirinolactone in the standard of treatment, the diastolic function indicators of peak E decreased by 10.4% (p <0.05) and peak A by 11.5% (p
<0.02), which was accompanied by an improvement in IVRT and DT by 7.6 and 11.7% (p
<0.05). These indicators in patients with FC III CHF also changed significantly, amounting to 14.8 (p <0.01) and 12.4% (p <0.05), respectively. The E / A ratio were 1.31 ± 0.18. IVRT and DT indicators improved by 9.9 (p <0.05) and 13.1% (p <0.01).
In group II patients with FC II CHF, there was a decrease in peak E by 12.6% (p <0.01) and peak A by 12.1% (p <0.05), and IVRT and DT were 89.17 ± 10.14 (p <0.05) and 173.42 ± 14.27 (p
<0.01) ms. In patients with FC III CHF, peak E improved by 13.9% (p <0.01), and A by 14.9% (p
<0.01), which was accompanied by a significant decrease in the E / A ratio. The E / A ratio was 1.12 ± 0.13. IVRT and DT scores improved by 10.9% (p <0.05) and 14.6% (p <0.05) compared to baseline.
Assessment of LV diastolic function in patients with CHF in the course of treatment showed a positive change in the structure of LV diastolic function, and after 6 months of treatment, diastolic dysfunction was detected in 76 (58%) patients. Of these, 33.6% (44 patients) had grade I (impaired relaxation), 14.5% (19) patients had grade II (pseudonormal), and 9.9% (13) patients had grade III (restrictive) DD. LV.
Analysis of LV DD after 6 months of treatment according to FC CHF showed that in patients with FC I CHF grade I was detected in 8 (25.8%) patients; grade II - in 2 (6.5%) patients. In patients of group I with CHF II FC, LVDD was found in 20 patients (76.9%), of which type I in 12 (46.2%) patients, grade II in 5 (19.2%) patients, and grade III in 3 (11.5%) patients. After six months of treatment with the inclusion of spirinolactone in the treatment standards, the incidence of LV DD was 18 (69.2%), with grade I found in 11 (42.3%) patients, grade II in 4 (15.4%) and grade III in 3 (11.5%) patients. In patients with FC III CHF, LV DD was initially detected in 20 (80%) of 25, of which grade I in 8 (32%) patients, grade II and grade III in 6 (24%), respectively, in groups. When analyzing the data obtained, it was revealed that after treatment, LVDD was determined in 19 (76%) patients, including grade I in 8 (32%) patients, grade II in 6 (24%) and grade III in 5 (20%) patients.
In patients with CHF II FC II group LVDD was detected in 19 patients (76%) of them, grade I in 10 (40%) patients, grade II in 5 (20%) patients and grade III in 4 (16%) patients. After six months of treatment with the inclusion of eplerenone in the treatment standards, LV DD was observed in 13 (50%) patients: grade I in 9 (36%) patients, grade II in 3 (12%) and grade III in 1 (4%) patients. In patients of this group with FC III CHF, LV DD was detected in 20 (83.3%) of 24, of which grade I in 9 (37.5%) patients, grade II in 5 (20.8%) and grade III in 6 (25%) patients.
Analysis of these parameters after treatment showed that LVDD occurred in 16 (66.6%) versus 20 (83.3%), while grade I was found in 8 (33.3%) patients, grade II and grade III in 4 (16, 7%) patients by groups, respectively.
Analysis of the dynamics of structural and geometric parameters in the examined patients with long-term standard therapy with the inclusion of spirinolactone and eplerenone showed an improvement in the structural and geometric parameters of the LV. The decrease in volumetric indicators of EDV and CSV was accompanied by an improvement in the EF in both groups.
In patients with I FC CHF of the first group after 6 months of treatment, the sum of points on the SACC 2.5 ± 0.2 points, respectively, was lower than the baseline values (p <0.001).
In patients with FC II CHF of the first group, after 6 months of treatment, there was also a positive dynamic of the SACC index, the sum of points on the SACC was 3.1 ± 0.3 points (p
<0.001), respectively. In group II patients, this indicator was 2.9 ± 0.3 versus 7.9 ± 1.08 points at baseline, respectively. In patients with FC III in the spirinolactone group, the sum of points on the SACC decreased by 25.4% and amounted to 6.6 ± 0.4 points (p <0.01), respectively; in the eplerenone group after 6 months of treatment - 5.6 ± 0.5 points, respectively (p <0.001),
respectively. The data obtained showed a significant improvement in the indicators of the clinical course of the disease in both groups. This was accompanied by an increase in exercise tolerance in patients with CHF II-III FC with an increase in the 6NWT distance by 20.4% (p <0.01) and 28.9% (p <0.001) compared with the initial values in group I patients and by 23.6 and 31.3% (p
<0.001), respectively, in group II patients. Thus, long-term complex treatment of CHF patients with the inclusion of MCRA, along with a significant increase in exercise tolerance, improvement of the clinical condition of patients, contributed to an improvement in LV diastolic function - a decrease in the number of patients with LVDD to 58%, an improvement in the quality of life of patients, which were more pronounced in the group of patients taking eplerenone. In both groups, a positive dynamic of the structure of the CHF FC was achieved: the number of CHF patients with FC III decreased due to an increase in the proportion of patients with FC I-II.
Discussions
LVDD often precedes a violation of systolic function and can lead to the appearance of CHF even in cases where the indicators of central hemodynamics (ejection fraction - EF, stroke volume, cardiac output, and cardiac index) have not yet changed [14]. The main pathogenetic factors that contribute to the development of DD include myocardial fibrosis, its hypertrophy, ischemia, as well as an increase in afterload in arterial hypertension. The most important consequence of the interaction of these factors is an increase in the concentration of calcium ions in cardiomyocytes, a decrease in LV myocardial compliance, impaired relaxation of the heart muscle, a change in the normal ratio of early and late LV filling, and an increase in end-diastolic volume (EDV) [2]. Disorders of diastolic function were initially identified in 80.9% (115 patients) of patients with CHF. At the same time, grade I (impaired relaxation) was recorded in 40.5% (53 patients), grade II - (pseudonormal) in 25.9% (34), grade III (restrictive) - in 14.5%
(19) patients. Analysis of the grades of diastolic dysfunction depending on the CHF FC showed that in patients with CHF FC I, diastolic dysfunction was identified in 76% (38) patients, while only grade I (delayed relaxation) was identified - in 16 patients (43, 2%), grade II - (pseudonormal) in 8 patients (21.6%). In patients with FC II CHF, DD was detected in 80% (80 patients) of patients: grade I (impaired relaxation) - in 21 (42.9%) patients, grade II - (pseudonormal) in 14 (28.6%) patients, grade III (restrictive) - in 6 (12.2%) patients. In patients with FC III CHF, DD was detected in 81.2% (60 patients) of patients: grade I (impaired relaxation) - in 13 (35.6%) patients, grade II - (pseudonormal) in 12 (26.7%) and grade III (restrictive) - in 13 (28.8%) patients.
The restrictive grade of impaired LV diastolic filling is the most important predictor of cardiovascular mortality and maladaptive LV remodeling. It has been proven that FC according to NYHA, exercise tolerance and QOL in CHF patients are highly correlated with restrictive diastolic dysfunction [11]. Identification of the restrictive type of DD regardless of the state of systolic function and other adaptive and compensatory mechanisms in CHF indicates a more severe course of CHF [12].
Early diagnosis of CHF and LV dysfunction, and therefore early initiation of treatment for this group of patients, is the key to success in improving the prognosis and prevention of mortality from heart failure. Multicenter studies EMPHASIS and EMPHASIS-HF have demonstrated that the use of MCRA in patients with CHF reduces the risk of overall mortality and sudden death [5, 15].
Conclusion
Long-term complex treatment of CHF patients with the inclusion of MCRA, along with a significant increase in exercise tolerance, improvement of the clinical condition of patients, contributed to an improvement in LV diastolic function - a decrease in the number of patients with LVDD to 58%, an improvement in the quality of life of patients.
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