xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06035978</url>
    </required_header>
    <id_info>
      <org_study_id>FNO-HeFa1-BESPISAVA</org_study_id>
      <nct_id>NCT06035978</nct_id>
    </id_info>
    <brief_title>Determination of Drug Levels for Pharmacotherapy of Heart Failure</brief_title>
    <official_title>Use of Determination of Drug Levels to Optimize Pharmacotherapy of Heart Failure</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University Hospital Ostrava</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University Hospital Ostrava</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The aim of this study is to determine whether and how serum concentrations of the used&#xD;
        medicinal products, including their metabolites, correlate with selected clinical indicators&#xD;
        of heart failure (NT-proBNP concentration, 6-minute walk test, quality of life questionnaire,&#xD;
        echocardiographic parameters, hospitalization for HFrEF, length of survival).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The prevalence of chronic heart failure increases with age, and this disease is one of the&#xD;
        most common reasons for hospitalization in the elderly. In order to reduce the number of&#xD;
        exacerbations, the frequency of hospitalizations, morbidity and mortality and improve the&#xD;
        overall quality of life, the treatment strategy should be individually set for each patient,&#xD;
        regularly monitored and reviewed.&#xD;
  &#xD;
        Patients with chronic heart failure show significant differences in the pharmacokinetics of&#xD;
        both cardiovascular and non-cardiovascular drugs. At the same time, they tend to be exposed&#xD;
        to other prescribed medicinal products, and therefore there is an increased risk of drugs&#xD;
        interactions. These findings emphasize the need for comprehensive pharmacokinetic studies in&#xD;
        patients with chronic heart failure, together with the exploration of the potential benefit&#xD;
        of biomarkers suitable for monitoring the clinical status of patients. Pharmacotherapy of&#xD;
        chronic heart failure with reduced ejection fraction (Heart Failure with Reduced Ejection&#xD;
        Fraction - HFrEF) currently consists of beta-blockers together with mineralocorticoid&#xD;
        receptor antagonists, the combination of sacubitril/valsartan drugs and sodium-glucose&#xD;
        transporter 2 inhibitors. Although the recommendation of therapeutic drug monitoring (TDM) in&#xD;
        patients with chronic heart failure has not yet been established, its introduction can serve&#xD;
        as an effective tool for detecting changes in the pharmacokinetics of drugs used,&#xD;
        objectifying drug interactions and ascertaining patient adherence to treatment, thereby&#xD;
        becoming part of safe personalized pharmacotherapy of this disease.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">November 2023</start_date>
    <completion_date type="Anticipated">April 2026</completion_date>
    <primary_completion_date type="Anticipated">April 2026</primary_completion_date>
    <phase>Phase 4</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Determination of the rate of significance between the serum concentration of the used medicinal products and the dose of this medicinal product</measure>
      <time_frame>24 month</time_frame>
      <description>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).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Clinical indicator - NT-proBNP concentration</measure>
      <time_frame>24 month</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinical indicator - 6-minute walk test</measure>
      <time_frame>24 month</time_frame>
      <description>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).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinical indicator - Minnesota Living With Heart Failure Questionnaire</measure>
      <time_frame>24 month</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinical indicator - Echocardiographic examination</measure>
      <time_frame>24 month</time_frame>
      <description>Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - echocardiographic examination.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinical indicator - The hospitalization for HFrEF</measure>
      <time_frame>24 month</time_frame>
      <description>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).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinical indicator - The length of survival</measure>
      <time_frame>24 month</time_frame>
      <description>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).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Adverse effects</measure>
      <time_frame>24 month</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Non-adherence to treatment</measure>
      <time_frame>24 month</time_frame>
      <description>Determination the number of patients in whom non-adherence to treatment will be demonstrated.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">100</enrollment>
    <condition>Cardiovascular Diseases</condition>
    <condition>Heart Failure With Reduced Ejection Fraction</condition>
    <arm_group>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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).</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Nebivolol</intervention_name>
      <description>Nebivolol (Nebilet) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.</description>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <other_name>Nebilet, anatomical-therapeutic-chemical code (ATC) C07AB12</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Valsartan and Sacubitril</intervention_name>
      <description>Valsartan and Sacubitril (Entresto) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.</description>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <other_name>Entresto, ATC C09DX04</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Carvedilol</intervention_name>
      <description>Carvedilol (Dilatrend) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.</description>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <other_name>Dilatrend, ATC C07AG02</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Bisoprolol</intervention_name>
      <description>Bisoprolol (Concor) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.</description>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <other_name>Concor, ATC C07AB07</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Metoprolol</intervention_name>
      <description>Metoprolol (Betaloc ZOK) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.</description>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <other_name>Betaloc ZOK, ATC C07AB02</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Spironolactone</intervention_name>
      <description>Verospiron (Spironolactone) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.</description>
      <arm_group_label>Patients with Heart Failure with Reduced Ejection Fraction</arm_group_label>
      <other_name>Verospiron, ATC C03DA01</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  HFrEF with already established or newly started treatment with the listed medicinal&#xD;
               products&#xD;
  &#xD;
            -  Male and female patients over 18 years of age&#xD;
  &#xD;
            -  Signed Informed Consent with participation in the study&#xD;
  &#xD;
            -  Women of childbearing potential must have a negative serum human chorionic&#xD;
               gonadotropin (hCG) result at baseline and use an acceptable method of contraception&#xD;
               with a home control urine pregnancy test every 3 months throughout the duration of the&#xD;
               study&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Hypersensitivity to the medicinal substance or to any auxiliary substance&#xD;
  &#xD;
            -  Pregnant and breastfeeding women&#xD;
  &#xD;
            -  Additional exclusion criteria for patients taking Bisoprolol, Carvedilol, Metoprolol&#xD;
               succinate or Nebivolol: Unstable or decompensated heart failure belonging to New York&#xD;
               Heart Association (NYHA) group IV according to the New York Heart Association&#xD;
               classification, requiring intravenous inotropic support&#xD;
  &#xD;
            -  Additional exclusion criteria for patients using Bisoprolol, Carvedilol, Metoprolol&#xD;
               succinate or Nebivolol:&#xD;
  &#xD;
            -  - Clinically manifest liver dysfunction&#xD;
  &#xD;
            -  - History of bronchospasm or asthma&#xD;
  &#xD;
            -  - Severe obstructive airways disease&#xD;
  &#xD;
            -  - 2nd and 3rd degree A-V block (unless a permanent pacemaker is implanted)&#xD;
  &#xD;
            -  - severe bradycardia (heart rate &lt;50)&#xD;
  &#xD;
            -  - 2nd and 3rd degree A-V block (unless a permanent pacemaker is implanted)&#xD;
  &#xD;
            -  - severe bradycardia (heart rate &lt;50)&#xD;
  &#xD;
            -  - cardiogenic shock&#xD;
  &#xD;
            -  - sinus node dysfunction syndrome (including sinoatrial block)&#xD;
  &#xD;
            -  - severe hypotension (systolic blood pressure &lt;85 mmHg)&#xD;
  &#xD;
            -  - Prinzmetal angina&#xD;
  &#xD;
            -  - untreated pheochromocytoma&#xD;
  &#xD;
            -  - metabolic acidosis&#xD;
  &#xD;
            -  - severe peripheral arterial circulation disorders&#xD;
  &#xD;
            -  - concurrent intravenous treatment with verapamil or diltiazem&#xD;
  &#xD;
            -  Additional exclusion criteria for patients using Spironolactone:&#xD;
  &#xD;
            -  - anuria&#xD;
  &#xD;
            -  - acute renal failure&#xD;
  &#xD;
            -  - severe renal impairment (estimated glomerular filtration rate &lt;10 ml/min)&#xD;
  &#xD;
            -  - hyperkalemia &gt;5.5 mmol/l&#xD;
  &#xD;
            -  - hyponatremia &lt;125 mmol/l&#xD;
  &#xD;
            -  - Addison's disease&#xD;
  &#xD;
            -  - concurrent use of eplerenone or other potassium-sparing diuretics&#xD;
  &#xD;
            -  - porphyria&#xD;
  &#xD;
            -  Additional exclusion criteria for patients using Sacubitril/Valsartan:&#xD;
  &#xD;
            -  - concomitant use with Angiotensin converting enzyme (ACE) inhibitors&#xD;
  &#xD;
            -  - angioedema related to previous ACE inhibitor treatment or a history of angiotensin&#xD;
               II receptor blockers (ARB) treatment&#xD;
  &#xD;
            -  - hereditary or idiopathic angioedema&#xD;
  &#xD;
            -  - concomitant use with medicinal products containing Aliskiren in patients with&#xD;
               diabetes mellitus or in patients with impaired renal function (eGFR &lt;60 ml/min/1.73&#xD;
               m2)&#xD;
  &#xD;
            -  - severe liver dysfunction, biliary cirrhosis and cholestasis&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Marie Lazárová, MD, Ph.D.</last_name>
      <role>Principal Investigator</role>
      <affiliation>University Hospital Ostrava</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Jiří Hynčica</last_name>
      <phone>0042059737</phone>
      <phone_ext>2587</phone_ext>
      <email>jiri.hyncica@fno.cz</email>
    </overall_contact>
    <location>
      <facility>
        <name>University Hospital Ostrava</name>
        <address>
          <city>Ostrava</city>
          <state>Czech Republic</state>
          <zip>70852</zip>
          <country>Czechia</country>
        </address>
      </facility>
      <contact>
        <last_name>Jiří Hynčica</last_name>
        <phone>0042059737</phone>
        <phone_ext>2587</phone_ext>
        <email>jiri.hyncica@fno.cz</email>
      </contact>
      <investigator>
        <last_name>Marie Lazárová, MD, Ph.D.</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Ivana Kacířová, doc., MD, Ph.D.</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Czechia</country>
    </location_countries>
    <reference>
      <citation>Buda V, Prelipcean A, Cozma D, Man DE, Negres S, Scurtu A, Suciu M, Andor M, Danciu C, Crisan S, Dehelean CA, Petrescu L, Rachieru C. An Up-to-Date Article Regarding Particularities of Drug Treatment in Patients with Chronic Heart Failure. J Clin Med. 2022 Apr 4;11(7):2020. doi: 10.3390/jcm11072020.</citation>
      <PMID>35407628</PMID>
    </reference>
    <reference>
      <citation>Raschi E, Diemberger I, Sabatino M, Poluzzi E, De Ponti F, Potena L. Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction. Expert Opin Pharmacother. 2022 Feb;23(3):303-320. doi: 10.1080/14656566.2022.2027909. Epub 2022 Jan 20.</citation>
      <PMID>35050813</PMID>
    </reference>
    <reference>
      <citation>Pyvovar SM, Rudyk IS. Use of beta-blockers in patients with heart failure - unresolved issues. Pol Merkur Lekarski. 2022 Aug 23;50(298):237-239.</citation>
      <PMID>36086982</PMID>
    </reference>
    <reference>
      <citation>Lee CM, Kang P, Cho CK, Park HJ, Lee YJ, Bae JW, Choi CI, Kim HS, Jang CG, Lee SY. Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes. Arch Pharm Res. 2022 Jun;45(6):433-445. doi: 10.1007/s12272-022-01394-2. Epub 2022 Jun 28.</citation>
      <PMID>35763157</PMID>
    </reference>
    <reference>
      <citation>Fontana V, Turner RM, Francis B, Yin P, Putz B, Hiltunen TP, Ruotsalainen S, Kontula KK, Muller-Myhsok B, Pirmohamed M. Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol. Pharmgenomics Pers Med. 2022 Mar 22;15:249-260. doi: 10.2147/PGPM.S352719. eCollection 2022.</citation>
      <PMID>35356681</PMID>
    </reference>
    <reference>
      <citation>de Denus S, Leclair G, Dube MP, St-Jean I, Zada YF, Oussaid E, Jutras M, Givertz MM, Mentz RJ, Tang WHW, Ferreira JP, Rouleau J, Butler J, Kalogeropoulos AP. Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA-HF trial. Eur J Heart Fail. 2020 Aug;22(8):1451-1461. doi: 10.1002/ejhf.1802. Epub 2020 Apr 1.</citation>
      <PMID>32237012</PMID>
    </reference>
    <reference>
      <citation>Giri P, Joshi V, Giri S, Delvadia P, Jain MR. Simultaneous determination of sacubitrilat and fimasartan in rat plasma by a triple quad liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive mode. Biomed Chromatogr. 2021 Feb;35(2):e4981. doi: 10.1002/bmc.4981. Epub 2020 Sep 18.</citation>
      <PMID>32895916</PMID>
    </reference>
    <reference>
      <citation>Iacoviello M, Pugliese R, Correale M, Brunetti ND. Optimization of Drug Therapy for Heart Failure With Reduced Ejection Fraction Based on Gender. Curr Heart Fail Rep. 2022 Dec;19(6):467-475. doi: 10.1007/s11897-022-00583-w. Epub 2022 Oct 5.</citation>
      <PMID>36197626</PMID>
    </reference>
    <reference>
      <citation>Ritscher S, Georges C, Wunder C, Wallemacq P, Persu A, Toennes SW. Assessment of adherence to diuretics and beta-blockers by serum drug monitoring in comparison to urine analysis. Blood Press. 2020 Oct;29(5):291-298. doi: 10.1080/08037051.2020.1763775. Epub 2020 May 13.</citation>
      <PMID>32400211</PMID>
    </reference>
    <reference>
      <citation>Rea F, Iorio A, Barbati G, Bessi R, Castrichini M, Nuzzi V, Scagnetto A, Senni M, Corrao G, Sinagra G, Di Lenarda A. Patient adherence to drug treatment in a community based-sample of patients with chronic heart failure. Int J Cardiol. 2022 Feb 15;349:144-149. doi: 10.1016/j.ijcard.2021.11.018. Epub 2021 Nov 18. No abstract available.</citation>
      <PMID>34801616</PMID>
    </reference>
    <reference>
      <citation>Sweeney M, Cole GD, Pabari P, Hadjiphilippou S, Tayal U, Mayet J, Chapman N, Plymen CM. Urinary drug metabolite testing in chronic heart failure patients indicates high levels of adherence with life-prolonging therapies. ESC Heart Fail. 2021 Jun;8(3):2334-2337. doi: 10.1002/ehf2.13284. Epub 2021 Mar 11.</citation>
      <PMID>33709563</PMID>
    </reference>
    <reference>
      <citation>Simpson J, Jackson CE, Haig C, Jhund PS, Tomaszewski M, Gardner RS, Tsorlalis Y, Petrie MC, McMurray JJV, Squire IB, Gupta P. Adherence to prescribed medications in patients with heart failure: insights from liquid chromatography-tandem mass spectrometry-based urine analysis. Eur Heart J Cardiovasc Pharmacother. 2021 Jul 23;7(4):296-301. doi: 10.1093/ehjcvp/pvaa071.</citation>
      <PMID>32597982</PMID>
    </reference>
    <reference>
      <citation>Jelinek L, Vaclavik J, Ramik Z, Pavlu L, Benesova K, Jarkovsky J, Lazarova M, Janeckova H, Spurna J, Taborsky M. Directly Measured Adherence to Treatment in Chronic Heart Failure: LEVEL-CHF Registry. Am J Med Sci. 2021 Apr;361(4):491-498. doi: 10.1016/j.amjms.2020.12.004. Epub 2020 Dec 7.</citation>
      <PMID>33781390</PMID>
    </reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 6, 2023</study_first_submitted>
    <study_first_submitted_qc>September 6, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 6, 2023</last_update_submitted>
    <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Cardiovascular Diseases</keyword>
    <keyword>Heart Failure with Reduced Ejection Fraction</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
      <mesh_term>Cardiovascular Diseases</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Metoprolol</mesh_term>
      <mesh_term>Valsartan</mesh_term>
      <mesh_term>Carvedilol</mesh_term>
      <mesh_term>Nebivolol</mesh_term>
      <mesh_term>Bisoprolol</mesh_term>
      <mesh_term>Spironolactone</mesh_term>
      <mesh_term>Sacubitril and valsartan sodium hydrate drug combination</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>There is no plan to share individual participant data with other researchers.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06035978
  org study id: FNO-HeFa1-BESPISAVA
  nct id: NCT06035978
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  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).
  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.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Determination of the rate of significance between the serum concentration of the used medicinal products and the dose of this medicinal product
  time frame: 24 month
  description: 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).
  measure: Clinical indicator - NT-proBNP concentration
  time frame: 24 month
  description: 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.
  measure: Clinical indicator - 6-minute walk test
  time frame: 24 month
  description: 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).
  measure: Clinical indicator - Minnesota Living With Heart Failure Questionnaire
  time frame: 24 month
  description: 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.
  measure: Clinical indicator - Echocardiographic examination
  time frame: 24 month
  description: Determination of a significant dependence between the serum concentration of the used medicinal products and the values of the selected clinical indicator - echocardiographic examination.
  measure: Clinical indicator - The hospitalization for HFrEF
  time frame: 24 month
  description: 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).
  measure: Clinical indicator - The length of survival
  time frame: 24 month
  description: 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).
  measure: Adverse effects
  time frame: 24 month
  description: 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.
  measure: Non-adherence to treatment
  time frame: 24 month
  description: Determination the number of patients in whom non-adherence to treatment will be demonstrated.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  arm group type: Experimental
  description: 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).
  intervention type: Drug
  intervention name: Nebivolol
  description: Nebivolol (Nebilet) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  other name: Nebilet, anatomical-therapeutic-chemical code (ATC) C07AB12
  intervention type: Drug
  intervention name: Valsartan and Sacubitril
  description: Valsartan and Sacubitril (Entresto) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  other name: Entresto, ATC C09DX04
  intervention type: Drug
  intervention name: Carvedilol
  description: Carvedilol (Dilatrend) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  other name: Dilatrend, ATC C07AG02
  intervention type: Drug
  intervention name: Bisoprolol
  description: Bisoprolol (Concor) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  other name: Concor, ATC C07AB07
  intervention type: Drug
  intervention name: Metoprolol
  description: Metoprolol (Betaloc ZOK) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  other name: Betaloc ZOK, ATC C07AB02
  intervention type: Drug
  intervention name: Spironolactone
  description: Verospiron (Spironolactone) tablet will be administered orally to patients according to their clinical condition and the decision of the attending physician.
  arm group label: Patients with Heart Failure with Reduced Ejection Fraction
  other name: Verospiron, ATC C03DA01
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Marie Lazárová, MD, Ph.D.
  role: Principal Investigator
  affiliation: University Hospital Ostrava
  last name: Jiří Hynčica
  phone: 0042059737
  phone ext: 2587
  email: jiri.hyncica@fno.cz
  facility: 
  contact: 
  investigator: 
  investigator: 
  country: Czechia
  citation: Buda V, Prelipcean A, Cozma D, Man DE, Negres S, Scurtu A, Suciu M, Andor M, Danciu C, Crisan S, Dehelean CA, Petrescu L, Rachieru C. An Up-to-Date Article Regarding Particularities of Drug Treatment in Patients with Chronic Heart Failure. J Clin Med. 2022 Apr 4;11(7):2020. doi: 10.3390/jcm11072020.
  PMID: 35407628
  citation: Raschi E, Diemberger I, Sabatino M, Poluzzi E, De Ponti F, Potena L. Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction. Expert Opin Pharmacother. 2022 Feb;23(3):303-320. doi: 10.1080/14656566.2022.2027909. Epub 2022 Jan 20.
  PMID: 35050813
  citation: Pyvovar SM, Rudyk IS. Use of beta-blockers in patients with heart failure - unresolved issues. Pol Merkur Lekarski. 2022 Aug 23;50(298):237-239.
  PMID: 36086982
  citation: Lee CM, Kang P, Cho CK, Park HJ, Lee YJ, Bae JW, Choi CI, Kim HS, Jang CG, Lee SY. Physiologically based pharmacokinetic modelling to predict the pharmacokinetics of metoprolol in different CYP2D6 genotypes. Arch Pharm Res. 2022 Jun;45(6):433-445. doi: 10.1007/s12272-022-01394-2. Epub 2022 Jun 28.
  PMID: 35763157
  citation: Fontana V, Turner RM, Francis B, Yin P, Putz B, Hiltunen TP, Ruotsalainen S, Kontula KK, Muller-Myhsok B, Pirmohamed M. Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol. Pharmgenomics Pers Med. 2022 Mar 22;15:249-260. doi: 10.2147/PGPM.S352719. eCollection 2022.
  PMID: 35356681
  citation: de Denus S, Leclair G, Dube MP, St-Jean I, Zada YF, Oussaid E, Jutras M, Givertz MM, Mentz RJ, Tang WHW, Ferreira JP, Rouleau J, Butler J, Kalogeropoulos AP. Spironolactone metabolite concentrations in decompensated heart failure: insights from the ATHENA-HF trial. Eur J Heart Fail. 2020 Aug;22(8):1451-1461. doi: 10.1002/ejhf.1802. Epub 2020 Apr 1.
  PMID: 32237012
  citation: Giri P, Joshi V, Giri S, Delvadia P, Jain MR. Simultaneous determination of sacubitrilat and fimasartan in rat plasma by a triple quad liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive mode. Biomed Chromatogr. 2021 Feb;35(2):e4981. doi: 10.1002/bmc.4981. Epub 2020 Sep 18.
  PMID: 32895916
  citation: Iacoviello M, Pugliese R, Correale M, Brunetti ND. Optimization of Drug Therapy for Heart Failure With Reduced Ejection Fraction Based on Gender. Curr Heart Fail Rep. 2022 Dec;19(6):467-475. doi: 10.1007/s11897-022-00583-w. Epub 2022 Oct 5.
  PMID: 36197626
  citation: Ritscher S, Georges C, Wunder C, Wallemacq P, Persu A, Toennes SW. Assessment of adherence to diuretics and beta-blockers by serum drug monitoring in comparison to urine analysis. Blood Press. 2020 Oct;29(5):291-298. doi: 10.1080/08037051.2020.1763775. Epub 2020 May 13.
  PMID: 32400211
  citation: Rea F, Iorio A, Barbati G, Bessi R, Castrichini M, Nuzzi V, Scagnetto A, Senni M, Corrao G, Sinagra G, Di Lenarda A. Patient adherence to drug treatment in a community based-sample of patients with chronic heart failure. Int J Cardiol. 2022 Feb 15;349:144-149. doi: 10.1016/j.ijcard.2021.11.018. Epub 2021 Nov 18. No abstract available.
  PMID: 34801616
  citation: Sweeney M, Cole GD, Pabari P, Hadjiphilippou S, Tayal U, Mayet J, Chapman N, Plymen CM. Urinary drug metabolite testing in chronic heart failure patients indicates high levels of adherence with life-prolonging therapies. ESC Heart Fail. 2021 Jun;8(3):2334-2337. doi: 10.1002/ehf2.13284. Epub 2021 Mar 11.
  PMID: 33709563
  citation: Simpson J, Jackson CE, Haig C, Jhund PS, Tomaszewski M, Gardner RS, Tsorlalis Y, Petrie MC, McMurray JJV, Squire IB, Gupta P. Adherence to prescribed medications in patients with heart failure: insights from liquid chromatography-tandem mass spectrometry-based urine analysis. Eur Heart J Cardiovasc Pharmacother. 2021 Jul 23;7(4):296-301. doi: 10.1093/ehjcvp/pvaa071.
  PMID: 32597982
  citation: Jelinek L, Vaclavik J, Ramik Z, Pavlu L, Benesova K, Jarkovsky J, Lazarova M, Janeckova H, Spurna J, Taborsky M. Directly Measured Adherence to Treatment in Chronic Heart Failure: LEVEL-CHF Registry. Am J Med Sci. 2021 Apr;361(4):491-498. doi: 10.1016/j.amjms.2020.12.004. Epub 2020 Dec 7.
  PMID: 33781390
  responsible party type: Sponsor
  mesh term: Heart Failure
  mesh term: Cardiovascular Diseases
  mesh term: Metoprolol
  mesh term: Valsartan
  mesh term: Carvedilol
  mesh term: Nebivolol
  mesh term: Bisoprolol
  mesh term: Spironolactone
  mesh term: Sacubitril and valsartan sodium hydrate drug combination
  sharing ipd: No
  ipd description: There is no plan to share individual participant data with other researchers.