Determination of Drug Levels for Pharmacotherapy of Heart Failure

Phase 4

Not yet recruiting

• Conditions: Cardiovascular Diseases; Heart Failure With Reduced Ejection Fraction
• Interventions: Drug: Nebivolol; Drug: Valsartan and Sacubitril; Drug: Carvedilol; Drug: Bisoprolol; Drug: Metoprolol; Drug: Spironolactone

• Registration Number: NCT06035978
• Lead Sponsor: University Hospital Ostrava

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2023-09-06
• Study First Submitted QC: 2023-09-06
• Study First Posted: 2023-09-13
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-17
• Last Update Posted: 2024-01-18
• Study Start: 2024-03
• Primary Completion: 2026-04
• Study Completion: 2026-04

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 100

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Patients with Heart Failure with Reduced Ejection Fraction	Valsartan and Sacubitril	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).
Patients with Heart Failure with Reduced Ejection Fraction	Nebivolol	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).
Patients with Heart Failure with Reduced Ejection Fraction	Bisoprolol	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).
Patients with Heart Failure with Reduced Ejection Fraction	Carvedilol	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).
Patients with Heart Failure with Reduced Ejection Fraction	Spironolactone	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).
Patients with Heart Failure with Reduced Ejection Fraction	Metoprolol	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).

Primary Outcome Measures

Name	Time	Method
Determination of the rate of significance between the serum concentration of the used medicinal products and the dose of this medicinal product	24 month	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).

Secondary Outcome Measures

Name	Time	Method
Clinical indicator - Minnesota Living With Heart Failure Questionnaire	24 month	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.
Clinical indicator - NT-proBNP concentration	24 month	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.
Clinical indicator - 6-minute walk test	24 month	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).
Clinical indicator - Echocardiographic examination	24 month	Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - echocardiographic examination.
Clinical indicator - The hospitalization for HFrEF	24 month	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).
Clinical indicator - The length of survival	24 month	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).
Non-adherence to treatment	24 month	Determination the number of patients in whom non-adherence to treatment will be demonstrated.
Adverse effects	24 month	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.

Trial Locations

Locations (1)

University Hospital Ostrava; 🇨🇿 Ostrava, Czech Republic, Czechia