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1.
Kardiologiia ; 61(5): 71-78, 2021 May 31.
Artigo em Russo, Inglês | MEDLINE | ID: mdl-34112078

RESUMO

Senile asthenia syndrome (SAS) is a geriatric syndrome characterized by age-associated decline of the physiological reserve and function in multiple systems, which results in higher vulnerability to effects of endo- and exogenous factors and a high risk of unfavorable outcomes, loss of self-sufficiency, and death. Generally, SAS is observed in elderly patients with comorbidities. In cardiovascular diseases, SAS is associated with a poor prognosis, including a higher incidence of exacerbation and death both during acute events and in chronic disease. However, SAS is often not taken into account in developing diagnostic and therapeutic programs for managing elderly patients with cardiovascular diseases (CVD). This article analyzes available scientific information about SAS, algorithms for SAS diagnosis, and the scales that may be useful in developing individual plans for management of elderly patients with CVD.


Assuntos
Doenças Cardiovasculares , Geriatras , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Prova Pericial , Avaliação Geriátrica , Humanos , Federação Russa/epidemiologia
2.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(9. Vyp. 2): 46-54, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33076645

RESUMO

Sleep-disordered breathing is one of the most common sleep-associated disorders. At the same time, their prevalence tends to increase with age. One of the most common forms of respiratory failure during sleep is obstructive sleep apnea syndrome (OSA), which is characterized by repeated episodes of cessation of breathing or a significant decrease in respiratory flow while maintaining respiratory effort as a result of obstruction of the upper respiratory tract. Drugs have different effects on OSA. There are drugs that worsen OSA, drugs that do not affect OSA, and drugs that improve OSA. Benzodiazepines, opioids, muscle relaxants, and male hormones adversely affect OSA. Also of clinical interest are drugs that do not affect OSA and can even potentially improve respiratory function during sleep. These include anti-inflammatory drugs, diuretics, bronchodilators, acetylcholinesterase inhibitors, antiparkinsonian, decongestant drugs, drugs for intranasal use, topical soft tissue lubricant, female sex hormones. Finally, the effect of a number of drugs on OSA is not definitively established and requires further study (benzodiazepine receptor agonist hypnotics, angiotensin-converting enzyme inhibitors, opiate receptor antagonists, antidepressants, proton-pump inhibitors, TNF-α antagonists, glutamate receptor antagonists, drugs for the treatment of acromegaly, drugs for the treatment of narcolepsy). Raising awareness of doctors of different specialties about the impact of various drugs on OSA can not only prevent the deterioration of respiratory distress during sleep, but also, with a rational individual approach, makes it possible to even improve the quality of sleep and blood saturation, thereby contributing to a more favorable course of OSA and the underlying disease.


Assuntos
Síndromes da Apneia do Sono , Apneia Obstrutiva do Sono , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Masculino , Prevalência , Sono , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/tratamento farmacológico
3.
Kardiologiia ; 60(5): 1121, 2020 Jun 03.
Artigo em Russo | MEDLINE | ID: mdl-32515714

RESUMO

A hypertensive crisis is a sudden increase in blood pressure (BP) to an individually high level associated with clinical symptoms and target organ damage, in which BP must be reduced immediately. Since 2018 in Europe and since 2020 in Russia, an uncomplicated hypertensive crisis is recommended to be considered as a part of malignant (uncontrolled) arterial hypertension. The clinical picture of increased BP in elderly patients is characterized by nonspecific symptoms even in target organ damage. Management of this group of patients requires a physician to know the patient's comorbidities and the drugs taken on a regular basis to minimize development of side effects of the administered drugs and their undesirable interaction with the chronic therapy.


Assuntos
Hipertensão , Idoso , Anti-Hipertensivos , Pressão Sanguínea , Europa (Continente) , Humanos , Federação Russa
4.
Kardiologiia ; 60(3): 126-136, 2020 Jan 20.
Artigo em Russo | MEDLINE | ID: mdl-32375625

RESUMO

Deprescribing is a scheduled withdrawal, dose reduction, or replacement of a medicine with a safer one. Several groups of medicinal products (MPs) are used simultaneously in the treatment of chronic heart failure. This increases the risk of adverse drug reactions, particularly in elderly and senile patients. A systematic search for literature allowed evaluating possibilities of deprescribing for the following pharmaceutic groups: 1) MPs influencing the renin-angiotensin-aldosterone system; 2) beta-blockers; 3) digoxin; and 4) diuretics. Three systematic reviews and several studies were analyzed to determine the most feasible and potentially optimal regimens of deprescribing in CHF. It was established that in CHF, deprescribing has a very limited potential for use due to the documented, obvious effect of some MP groups on prediction and severity of clinical symptoms in CHF patients.


Assuntos
Desprescrições , Insuficiência Cardíaca , Antagonistas Adrenérgicos beta , Idoso , Diuréticos , Insuficiência Cardíaca/terapia , Humanos , Sistema Renina-Angiotensina
5.
Artigo em Russo | MEDLINE | ID: mdl-31464299

RESUMO

Drug-induced delirium is an urgent challenge of modern healthcare, especially in elderly patients, due to the widespread prevalence, associated complications, longer hospitalization period, higher mortality rate. The exact pathogenesis of delirium is unknown, however, a number of studies suggest that it is based on neurotransmitter dysfunction. Thus, drugs that affect the metabolism of these neurotransmitters can lead to the onset of delirium. The Delirium Drug Scale (DDS) and the Anticholinergic Burden scale (ACB) are used to assess the risk of delirium. For patients with an increased risk of delirium, it is recommended to avoid prescribing benzodiazepines, use with caution opiates, dihydropyridines and antagonists of H1-histamine receptors. Non-pharmacological methods are recommended as a first-line treatment of delirium (behavioral approaches, placing the patient in specially equipped delirious rooms, etc.). If non-pharmacological methods have shown to be ineffective or the patient's behavior represents a danger to the life and health of himself and / or others, it is possible to administer antipsychotic drugs.


Assuntos
Antipsicóticos , Benzodiazepinas , Antagonistas Colinérgicos , Delírio , Idoso , Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Antagonistas Colinérgicos/efeitos adversos , Delírio/induzido quimicamente , Hospitalização , Humanos
6.
Artigo em Russo | MEDLINE | ID: mdl-31317906

RESUMO

The review deals with the problem of polypragmasia and associated adverse drug reactions, which is very relevant for the elderly and senile age. Based on the frequent unjustified prescription of antipsychotic drugs in clinical practice and the serious consequences associated with it, especially in elderly people with cognitive impairment, the aim of this review was to analyze the current literature and an evidence base for antipsychotic therapy optimization in elderly. One of the most effective way to decrease drug-associated harm is deprescribing, the planned process of decreasing dose, discontinuation of drug or switching to another one aimed to improve quality of life of the patient. The article describes different types of deprescribing, presents the results of the analysis of literature on deprescribing of antipsychotics in long-term use in elderly patients with dementia. Central to this is the analysis of a systematic review of Cochrane E. Van Leeuwen and co-authors (2018), the leading research in the evidence base of deprescribing. Based on the available literature, the authors make the conclusion about the safety of deprescribing of antipsychotic drugs. The effect of abrupt discontinuation of treatment with antipsychotic drugs was evaluated in available literature. Most of the evidence relates only to residents of nursing homes or to patients in long-term psychogeriatric or geriatric wards (in-patient treatment). However, the evidence base of deprescribing of antipsychotic drugs is small, many studies have methodological limitations, the initial characteristics of the patients included in the study are extremely heterogeneous, methodologies for diagnosing and determining the severity of dementia, types and dosages of antipsychotic drugs, duration of observation periods differed greatly. Attention is drawn to the short duration of observation periods. All of the above dictates the need for specially planned randomized clinical trials, the results of which will develop detailed algorithms for deprescribing antipsychotics.


Assuntos
Antipsicóticos , Demência , Desprescrições , Idoso , Antipsicóticos/uso terapêutico , Demência/tratamento farmacológico , Humanos , Pacientes , Qualidade de Vida , Revisões Sistemáticas como Assunto
8.
Kardiologiia ; 57(5): 5-9, 2017 05.
Artigo em Russo | MEDLINE | ID: mdl-28762913

RESUMO

Primary prevention of cardiovascular events is based on achievement of optimal control of risk factors - arterial hypertension, dyslipidemia, glycemia - in accordance with current recommendations of scientific societies. But most rapidly growing segment of population - elderly and old individuals - have been underrepresented in randomized clinical trials underlying recommendations on primary and secondary prevention. That is why it is problematic to directly apply recommendations to patients from this group of population. In addition, old patients are characterized by accumulation of functional deficits, development of syndrome of senile asthenia ("frailty"), and multimorbidity. Effect of these characteristics on prognosis often exceeds that of risk factors. Other important factor is high susceptibility of old patients to risk of development of unfavorable effects because of both changes of pharmacokinetics and pharmacodynamics of drugs and the need for multiple medicines (polypragmasy). While applying existing recommendations to old people one should recognize limitations of current knowledge on best ways of realization of approaches to prevention of cardiovascular prevention which effectiveness has been proved in younger individuals. Improvement of awareness and development of special skills of physicians involved in management of old patients is required for timely detection of the syndrome of senile asthenia. Special geriatric approaches should be implemented in cooperation with specialists in geriatric medicine.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Prevenção Primária , Prevenção Secundária , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Glicemia , Doenças Cardiovasculares/fisiopatologia , Dislipidemias/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Prognóstico , Fatores de Risco
9.
Kardiologiia ; 56(11): 50-54, 2016 12.
Artigo em Russo | MEDLINE | ID: mdl-28290818

RESUMO

PURPOSE OF THE STUDY: The study of the characteristics and effectiveness of antihypertensive therapy (AHT) in patients aged 65 years and older. MATERIAL AND METHODS: The study included 356 patients, mean age 74,9+/-6,1 years, 80.4% women. The prevalence of arterial hypertension (AH) and the current intake of antihypertensive drugs were evaluated by self-reported patient. RESULTS: The prevalence of hypertension was 88.5%. The predominant variant was isolated systolic hypertension. 51.1% of patients have systolic blood pressure as measured at the reception turned >140 mm Hg in 34.7% of patients >150 mm Hg AHT received 91.6% of patients with hypertension in 65.6% of cases it was combined. Of the various combinations of bicomponent most patients took angiotensin converting enzyme inhibitor in combination with a -adrenoblocker or a diuretic. CONCLUSIONS: The study showed the high prevalence of hypertension and the lack of efficacy in patients AHT elderly seeking outpatient care.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Diuréticos/uso terapêutico , Hipertensão/tratamento farmacológico , Adulto , Fatores Etários , Idoso , Pressão Sanguínea/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Fatores de Risco
10.
Kardiologiia ; 55(7): 14-25, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26688921

RESUMO

UNLABELLED: Simultaneous inhibition of the renin-angiotensin-aldosterone system and the system of degradation of natriuretic peptides can potentially provide unique therapeutic effects in patients with chronic heart failure (CHF) with reduced ejection fraction (EF). Aim of this study was to assess tolerability of therapy with LCZ696--first representative of a class of inhibitors of angiotensin receptor and neutral endopeptidase neprilysin--and to study its pharmacodynamic effects. METHODS: We included into open uncontrolled study 30 patients with stable functional class II-III CHF and EF ≤ 40%. After 24-hour run-in period during which angiotensin converting enzyme inhibitors (ACEI) were withdrawn the patients were given LCZ696 (100 mg/day for 7 days followed by 200 mg/day for 14 days). Other CHF therapy remained unchanged. RESULTS: Transition from therapy with ACEI to LCZ696 was well tolerated. Three patients were excluded because of hyperkalemia ≥ 5mmol/l. After 21 days of treatment elevation of plasma biomarkers of inhibition of neprilysin and angiotensin receptors occurred: cyclic guanosine monophosphate, renin concentration and activity rose 1.38, 3.50, and 2.27 times from baseline level (p < 0.05 for all). After 7 and 21 days of LCZ696 administration we noted significant lowering of NT-proBNP; significant lowering of aldosterone and endothelin-1 in blood plasma, was observed on day 21. CONCLUSION: Administration of LCZ696 to patients with CHF with reduced ejection fraction (EF) was well tolerated and associated with potentially favorable for this category of patients dynamics of biomarkers.


Assuntos
Aminobutiratos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Volume Sistólico/fisiologia , Tetrazóis/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Ecocardiografia Doppler , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
11.
Ter Arkh ; 87(3): 66-70, 2015.
Artigo em Russo | MEDLINE | ID: mdl-26027243

RESUMO

AIM: To provide a detailed analysis of the efficacy and tolerability of Prestance (perindopril A/amlodipine) in a subgroup of 1936 people participating in the Russian observational CONSTANTA program, most cases of whom were given the drug as a substitute for earlier ineffective monotherapy and combination therapy, without using other antihyperterisive agents. SUBJECTS AND METHODS: The analysis included 1936 patients (aged 58.2±7.5 years; 35% men) with uncontrolled hypertension who received angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (AT II) receptor antagonists alone or in conjunction with free or fixed-dose combinations of two-three antihypertensive agents and who were given Prestance to correct antihypertensive therapy, as decided by their doctors. The goal blood pressure (BP) was <140/<90 mm Hg for all the patients. Their treatment lasted three months. RESULTS: At the end of trial, the patients received Prestance (perindopril A/amlodipine) in the following doses: 5/5 mg (15% of the patients), 10/5 mg (39.9%), 5/10 mg (9.8%), 10/10 mg (36.6%). In the analyzed group, the baseline BP was 163.4±13.7/94.6+10,1 mm Hg; heart rate (HR), 74.0±10.9 beats/min; 3 months later, there were decreases in BP to 130.8±10.2/78.5±7.2 mm Hg (as compared to the baseline values; p<0.001) and in HR to 67.9?5.4 beats/min (p<0.01). The mean BP reduction was 32.6±10.8/16.1±7.2 mm Hg. A total of 1607 (83.0%) patients achieved the goal BP while 1520 (78.5%) patients did this without having another antihypertensive therapy. CONCLUSION: To switch hypertensive patients receiving ineffective monotherapy or dual therapy using ACE inhibitors or AT II receptor blockers to fixed-dose perindopril A and amlodipine combination (Prestance) is a rational way of optimizing a therapy regimen in these patients with a wide range of baseline BP levels; moreover, four out of five patients did not need any additional antihypertensive drug.


Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Perindopril/uso terapêutico , Adulto , Idoso , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Perindopril/administração & dosagem , Fatores de Risco , Federação Russa , Resultado do Tratamento
12.
Ter Arkh ; 87(2): 64-69, 2015.
Artigo em Russo | MEDLINE | ID: mdl-25864352

RESUMO

AIM: To estimate changes in treatment adherence and motivation and quality of life in Prestance-treated population of the observational CONSTANTA program. SUBJECTS AND METHODS: The effect of Prestance on treatment adherence and motivation and quality of life was evaluated in 2435 participants of the CONSTANTA program. It included patients with uncontrolled hypertension who generally received angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists alone or in conjunction with free or fixed-dose combinations of 2-3 antihypertensive agents and who were additionally given Prestance to correct antihypertensive therapy, as decided by their doctors. The goal blood pressure (BP) was less than <140/90 mm Hg for all the patients. A modified Morisky- Green questionnaire was used to measure adherence, motivation, and awareness in the patients. Their treatment lasted three months. RESULTS: A total of 1992 (81.8%) patients in the analyzed group achieved the goal BP. When included in the study, 1076 (44.2%) patients were defined as adherent to therapy; the mean adherence index was equal to 3.12 ± 0.86 scores; at 3 months of therapy, the number of adherents increased up to 1997 (82%) and the mean adherence index rose up to 3.6 ± 0.74 scores. With high baseline motivation, its mean score was 1.25 ± 0.79 in 40.1% of the patients; at 3 months the number of the motivated rose up to 70.9% (p < 0.05) and the mean score was as high as 1.75 ± 0.60 (p < 0/05). At baseline, 44.2% of the patients showed a high awareness; its mean score was 1.42 ± 1.12; at 3 months of therapy, both indicators significantly increased up to 82% (p < 0.05) and 2.38 ± 0.80, respectively. CONCLUSION: The well tolerable BP lowering during Prestance therapy is attended by a substantial rise in treatment adherence and motivations in the patients even in the absence of special purposeful measures.


Assuntos
Anlodipino , Anti-Hipertensivos/administração & dosagem , Hipertensão/tratamento farmacológico , Adesão à Medicação/psicologia , Perindopril , Idoso , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anlodipino/farmacologia , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Feminino , Humanos , Hipertensão/psicologia , Masculino , Pessoa de Meia-Idade , Perindopril/administração & dosagem , Perindopril/efeitos adversos , Perindopril/farmacologia , Resultado do Tratamento
13.
Kardiologiia ; 55(12): 11-16, 2015 12.
Artigo em Russo | MEDLINE | ID: mdl-28294759

RESUMO

AIM: to assess effect of -blockers in the characteristics of the central pulse wave and the effect of switching to a fixed bisoprolol/amlodipine (B/A) combination. MATERIAL AND METHODS: Untreated patients (n=28, age 53.6+/-5.7 years, 19 men) with uncomplicated hypertension without diabetes were given bisoprolol 5-10 mg. After 4 weeks at blood pressure (BP) >40/90 mmHg amlodipine (5 mg) was added by switching to a fixed B/A combination. The dose of amlodipine in this combination was increased to 10 mg in order to achieve target BP. The duration of combination therapy was 8 weeks. Analysis of the contour of central pulse wave and measurement of pulse wave velocity between carotid and femoral arteries (PWV) were evaluated before treatment, after monotherapy with bisoprolol, and after therapy with fixed B/A combination. RESULTS: After monotherapy with bisoprolol 5 patients achieved BP control, 23 were switched to a fixed B/A combination. Monotherapy with bisoprolol reduced mainly peripheral BP and increased augmentation index (AI) of aortic pulse pressure, normalized to heart rate of 75 beats/min (AI-75). Switching to a fixed B/A combination resulted in further reduction of peripheral BP and significantly greater lowering of central systolic and pulse pressure, return of AI-75 to baseline values, significant decrease of PWVCA. CONCLUSION: Switching to a fixed B/A combination eliminates the potentially undesirable effects of -blockers on the parameters of the reflected wave, thus resulting in effective lowering of central systolic and pulse BP, and reduction of PWV.


Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bisoprolol/uso terapêutico , Hipertensão/tratamento farmacológico , Anlodipino/farmacologia , Anti-Hipertensivos/farmacologia , Bisoprolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Determinação da Pressão Arterial , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso
14.
Kardiologiia ; 55(2): 21-26, 2015 Feb.
Artigo em Russo | MEDLINE | ID: mdl-28294806

RESUMO

PURPOSE: to study plasma renin activity (PRA) as a predictor of antihypertensive response to addition of diuretic to combination of angiotensin-converting enzyme inhibitor (ACEI) and calcium antagonist (CA). MATERIAL AND METHODS: The study included 72 patients (39% men, mean age 62.0+/-8.3 years) with uncontrolled despite use of ACEI and CA arterial hypertension (AH) without overt associated clinical conditions (AH criteria of national guidelines, 2010). After 4 weeks of therapy with ACE inhibitor (quadropril 6 mg/day) and CA (felodipine 5 mg/day) in all patients who did not reach target level of blood pressure (BP) (clinical BP more or equal 140/90 mm Hg, daytime BP according to ambulatory BP monitoring [ABPM] >135/85 mm Hg) indapamide retard (1.5 mg/day) was added to combination therapy for 6 months. Examination included measurement of baseline and on treatment PRA and repetitive ABPM. RESULTS: More pronounced antihypertensive response was observed in the group of patients with volume dependent AH. Baseline BP was 156.6+/-14.1/86.7+/-1.5 and 151.9+/-17.1/78.0+/-7.8 mm Hg, on treatment level of clinical BP - 126.2+/-10.6/72.5+/-11.6 and 132.2+/-9.1/71.9+/-7.2 mm Hg (p<0.05) in patients with volume dependent and renin dependent AH, respectively. Target clinical BP was achieved in 95 and 80% of patients, respectively (2=10.3; p<0.05). According to ABPM both daytime and nighttime on treatment BP was lower in the group of patients with volume dependent AH (130.0+/-11.0/74.1+/-9.9 vs. 136.5+/-7.3/78.8+/-8.2 mm Hg, p<0.05; and 127.9+/-15.8/71+/-13.5 vs. 132.6+/-13.0/74.5+/-10.2 mm Hg, p<0.05). CONCLUSION: PRA is an independent predictor of antihypertensive response to addition of a diuretic to combination therapy with ACEI and CA.

16.
Kardiologiia ; 55(7): 14-25, 2015 Jul.
Artigo em Russo | MEDLINE | ID: mdl-28294911

RESUMO

Simultaneous inhibition of the renin-angiotensin-aldosterone system and the system of degradation of natriuretic peptides can potentially provide unique therapeutic effects in patients with chronic heart failure (CHF) with reduced ejection fraction (EF). Aim of this study was to assess tolerability of therapy with LCZ696 - first representative of a class of inhibitors of angiotensin receptor and neutral endopeptidase neprilysin - and to study its pharmacodynamic effects. METHODS: We included into open uncontrolled study 30 patients with stable functional class II-III CHF and EF less or equal 40%. After 24-hour run-in period during which angiotensin converting enzyme inhibitors (ACEI) were withdrawn the patients were given LCZ696 (100 mg/day for 7 days followed by 200 mg/day for 14 days). Other CHF therapy remained unchanged. RESULTS: Transition from therapy with ACEI to LCZ696 was well tolerated. Three patients were excluded because of hyperkalemia more or equal 5mmol/l. After 21 days of treatment elevation of plasma biomarkers of inhibition of neprilysin and angiotensin receptors occurred: cyclic guanosine monophosphate, renin concentration and activity rose 1.38, 3.50, and 2.27 times from baseline level (<0.05 for all). After 7 and 21 days of LCZ696 administration we noted significant lowering of NT-proBNP; significant lowering of aldosterone and endothelin-1 in blood plasma was observed on day 21. CONCLUSION: Administration of LCZ696 to patients with CHF with reduced ejection fraction (EF) was well tolerated and associated with potentially favorable for this category of patients dynamics of biomarkers.

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