Determination of Drug Levels for Pharmacotherapy of Heart Failure

Study Overview
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Brief Summary
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The aim of this study is to determine whether and how serum concentrations of the used medicinal products, including their metabolites, correlate with selected clinical indicators of heart failure (NT-proBNP concentration, 6-minute walk test, quality of life questionnaire, echocardiographic parameters, hospitalization for HFrEF, length of survival).

Detailed Description
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The prevalence of chronic heart failure increases with age, and this disease is one of the most common reasons for hospitalization in the elderly. In order to reduce the number of exacerbations, the frequency of hospitalizations, morbidity and mortality and improve the overall quality of life, the treatment strategy should be individually set for each patient, regularly monitored and reviewed. Patients with chronic heart failure show significant differences in the pharmacokinetics of both cardiovascular and non-cardiovascular drugs. At the same time, they tend to be exposed to other prescribed medicinal products, and therefore there is an increased risk of drugs interactions. These findings emphasize the need for comprehensive pharmacokinetic studies in patients with chronic heart failure, together with the exploration of the potential benefit of biomarkers suitable for monitoring the clinical status of patients. Pharmacotherapy of chronic heart failure with reduced ejection fraction (Heart Failure with Reduced Ejection Fraction - HFrEF) currently consists of beta-blockers together with mineralocorticoid receptor antagonists, the combination of sacubitril/valsartan drugs and sodium-glucose transporter 2 inhibitors. Although the recommendation of therapeutic drug monitoring (TDM) in patients with chronic heart failure has not yet been established, its introduction can serve as an effective tool for detecting changes in the pharmacokinetics of drugs used, objectifying drug interactions and ascertaining patient adherence to treatment, thereby becoming part of safe personalized pharmacotherapy of this disease.

Official Title
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Use of Determination of Drug Levels to Optimize Pharmacotherapy of Heart Failure

Conditions
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Cardiovascular Diseases, Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Nebivolol
* Drug: Valsartan and Sacubitril
* Drug: Carvedilol
* Drug: Bisoprolol
* Drug: Metoprolol
* Drug: Spironolactone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HFrEF with already established or newly started treatment with the listed medicinal products Male and female patients over 18 years of age Signed Informed Consent with participation in the study Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) result at baseline and use an acceptable method of contraception with a home control urine pregnancy test every 3 months throughout the duration of the study Exclusion Criteria: Hypersensitivity to the medicinal substance or to any auxiliary substance Pregnant and breastfeeding women Additional exclusion criteria for patients taking Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol: Unstable or decompensated heart failure belonging to New York Heart Association (NYHA) group IV according to the New York Heart Association classification, requiring intravenous inotropic support Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol succinate or Nebivolol: - Clinically manifest liver dysfunction - History of bronchospasm or asthma - Severe obstructive airways disease - 2nd and 3rd degree A-V block (unless a permanent pacemaker is implanted) - severe bradycardia (heart rate <50) - 2nd and 3rd degree A-V block (unless a permanent pacemaker is implanted) - severe bradycardia (heart rate <50) - cardiogenic shock - sinus node dysfunction syndrome (including sinoatrial block) - severe hypotension (systolic blood pressure <85 mmHg) - Prinzmetal angina - untreated pheochromocytoma - metabolic acidosis - severe peripheral arterial circulation disorders - concurrent intravenous treatment with verapamil or diltiazem Additional exclusion criteria for patients using Spironolactone: - anuria - acute renal failure - severe renal impairment (estimated glomerular filtration rate <10 ml/min) - hyperkalemia >5.5 mmol/l - hyponatremia <125 mmol/l - Addison's disease - concurrent use of eplerenone or other potassium-sparing diuretics - porphyria Additional exclusion criteria for patients using Sacubitril/Valsartan: - concomitant use with Angiotensin converting enzyme (ACE) inhibitors - angioedema related to previous ACE inhibitor treatment or a history of angiotensin II receptor blockers (ARB) treatment - hereditary or idiopathic angioedema - concomitant use with medicinal products containing Aliskiren in patients with diabetes mellitus or in patients with impaired renal function (eGFR <60 ml/min/1.73 m2) - severe liver dysfunction, biliary cirrhosis and cholestasis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with Heart Failure with Reduced Ejection Fraction<br>Patients with heart failure with reduced ejection fraction, aged 18+, dispensary at the Cardiology Outpatient Clinic for Heart Failure University Hospital Ostrava, who are orally administered tablets one of the evaluated medicinal products or their combination as indicated by the attending physician (Nebivolol, Valsartan and Sacubitril, Carvedilol, Bisoprolol, Metoprolol, Spironolactone). | Drug: Nebivolol<br>* Nebivolol (Nebilet) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.<br>* Other names: Nebilet, anatomical-therapeutic-chemical code (ATC) C07AB12;Drug: Valsartan and Sacubitril<br>* Valsartan and Sacubitril (Entresto) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.<br>* Other names: Entresto, ATC C09DX04;Drug: Carvedilol<br>* Carvedilol (Dilatrend) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.<br>* Other names: Dilatrend, ATC C07AG02;Drug: Bisoprolol<br>* Bisoprolol (Concor) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.<br>* Other names: Concor, ATC C07AB07;Drug: Metoprolol<br>* Metoprolol (Betaloc ZOK) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.<br>* Other names: Betaloc ZOK, ATC C07AB02;Drug: Spironolactone<br>* Verospiron (Spironolactone) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.<br>* Other names: Verospiron, ATC C03DA01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the rate of significance between the serum concentration of the used medicinal products and the dose of this medicinal product | Determination whether the serum concentration of used medicinal products (Nebivolol, Valsartan/Sacubitril, Carvedilol, Bisoprolol, Metoprolol, Spironolactone) is more important than the dose of these medicinal products for compensating health status in patients with chronic heart failure with reduced ejection fraction (HFrEF). | 24 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical indicator - NT-proBNP concentration | Determination of a significant dependence between serum concentration of the used medicinal products and the values of the selected clinical indicator - N-terminal prohormone of natriuretic peptide B (NT-pro BNP), measured in pg/ml. | 24 month | 
| Clinical indicator - 6-minute walk test | Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - 6-minute walking test. The test measures the distance the patient walks 6 minutes in the corridor (in meters). | 24 month | 
| Clinical indicator - Minnesota Living With Heart Failure Questionnaire | Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - Minnesota Living With Heart Failure Questionnaire. The total score could range from 0 to 105, with higher scores indicating more significant impairment in health-related quality of life. | 24 month | 
| Clinical indicator - Echocardiographic examination | Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - echocardiographic examination. | 24 month | 
| Clinical indicator - The hospitalization for HFrEF | Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - the hospitalization for HFrEF (yes/no). | 24 month | 
| Clinical indicator - The length of survival | Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - the length of survival (measured in month). | 24 month | 
| Adverse effects | Determination of the number of patients in whom a significant dependence between the serum concentration of the used medicinal products and the adverse effects of these medicinal products is demonstrated. | 24 month | 
| Non-adherence to treatment | Determination the number of patients in whom non-adherence to treatment will be demonstrated. | 24 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular Diseases, Heart Failure with Reduced Ejection Fraction