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Bisoprolol Plasma Residual Concentrations in Chronic Heart Failure (PREVALENT)

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ClinicalTrials.gov Identifier: NCT03644446
Recruitment Status : Unknown
Verified July 2018 by University Hospital, Caen.
Recruitment status was:  Recruiting
First Posted : August 23, 2018
Last Update Posted : August 23, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital, Caen

Brief Summary:
This study evaluate the dosage of bisoprolol plasma residual concentrations in chronic heart failure with mild to reduced ejection fraction adult patients by dose and renal function.

Condition or disease Intervention/treatment
Heart Failure With Reduced Ejection Fraction Biological: Bisoprolol plasma residual concentration dosage

Detailed Description:

The clinical relevance of bisoprolol plasma residual concentration in the management of HF medical therapy and the impact of renal function on reaching the maximum tolerated dose has never been studied. The investigators will perform an observational study to answer this issue.

In this study, there will be no changes of the doses of bisoprolol, whatever the bisoprolol plasma concentration, with the exception of vital threatening concentrations. This study is a pilot study.

Participants will be consecutive ambulatory chronic heart failure patients followed at the CHU de Caen, treated with maximum tolerated dose of bisoprolol with mild to reduced ejection fraction. Participants can benefit of the other heart failure recommended treatment at the exception of ivabradine that would confound the bisoprolol effect on heart rate. Participants will be subsequently studied by renal function.

Patients will be followed at one year with the electronic health record of the CHU de Caen for clinical events.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 81 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 1 Year
Official Title: Bisoprolol Plasma Residual Concentrations for the Optimization of Drug Management in Heart Failure With Mild to Reduced Ejection Fraction
Actual Study Start Date : November 2, 2017
Estimated Primary Completion Date : November 2, 2019
Estimated Study Completion Date : November 2, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Group/Cohort Intervention/treatment
Bisoprolol 5mg
Chronic heart failure with mild to reduced ejection fraction adult patients with bisoprolol intakes at 5mg (patient's maximum tolerated dose), stable, with a left ventricular ejection fraction < 50%. Consecutive patients at the CHU de Caen.
Biological: Bisoprolol plasma residual concentration dosage
Bisoprolol plasma residual concentration dosage will be subsequently studied by renal function (altered if creatinine clearance < 30mL/min, mild altered between 30-60mL/min, normal > 60mL/min as estimated by the CKD-EPI formula)

Bisoprolol 7.5mg
Chronic heart failure with mild to reduced ejection fraction adult patients with bisoprolol intakes at 7.5mg (patient's maximum tolerated dose), stable, with a left ventricular ejection fraction < 50%. Consecutive patients at the CHU de Caen.
Biological: Bisoprolol plasma residual concentration dosage
Bisoprolol plasma residual concentration dosage will be subsequently studied by renal function (altered if creatinine clearance < 30mL/min, mild altered between 30-60mL/min, normal > 60mL/min as estimated by the CKD-EPI formula)

Bisoprolol 10mg
Chronic heart failure with mild to reduced ejection fraction adult patients with bisoprolol intakes at 10mg (patient's maximum tolerated dose), stable, with a left ventricular ejection fraction < 50%. Consecutive patients at the CHU de Caen.
Biological: Bisoprolol plasma residual concentration dosage
Bisoprolol plasma residual concentration dosage will be subsequently studied by renal function (altered if creatinine clearance < 30mL/min, mild altered between 30-60mL/min, normal > 60mL/min as estimated by the CKD-EPI formula)




Primary Outcome Measures :
  1. Bisoprolol residual plasma concentration by dose and renal function [ Time Frame: At the time of inclusion ]
    Bisoprolol plasma residual concentrations will be performed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) with simple precipitation of proteins with acetonitrile, as described by Liu et al. The quantification will be in positive mode by multiple reaction monitoring with the following transitions: 326 to 116 for bisoprolol and 256 to 167 for diphenhydramine (control). Bisoprolol concentrations will be expressed in µg/L.


Secondary Outcome Measures :
  1. Clinical parameters at the time of inclusion [ Time Frame: At the time of inclusion ]
    Heart rate in beats per minute (bpm). Heart rate will be studied as a continous outcome and as a dichotomous outcome for efficacy. The efficacy parameter cutoff is a heart rate < 70bpm.

  2. Clinical parameters at the time of inclusion [ Time Frame: At the time of inclusion ]
    Systolic and diastolic blood pressure (in mmHg)

  3. Clinical parameters at the time of inclusion [ Time Frame: At the time of inclusion ]
    Tolerance : presence of any new symptom that requires a dose lowering or discontinuation of bisoprolol (dichotomous outcome) or symptomatic orthostatic hypotension

  4. Clinical parameters at the time of inclusion [ Time Frame: At the time of inclusion ]
    Tolerance : presence of a symptomatic orthostatic hypotension (dichotomous outcome) that is defined as a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with blood pressure from the sitting or supine position.

  5. Biological assessment [ Time Frame: At the time of inclusion ]
    Routine biological evaluation : creatinine (in µmol/L)

  6. Biological assessment [ Time Frame: At the time of inclusion ]
    Routine biological evaluation : Brain Natriuretic Peptide (in pg/mL)

  7. Biological assessment [ Time Frame: At the time of inclusion ]
    Galectin-3 (in ng/mL)

  8. Clinical outcomes at one year [ Time Frame: At one year follow-up ]
    Heart failure symptoms worsening (dichotomous variable)

  9. Clinical outcomes at one year [ Time Frame: At one year follow-up ]
    Hospitalization for heart failure (dichotomous variable)

  10. Clinical outcomes at one year [ Time Frame: At one year follow-up ]
    Death from any cause (dichotomous variable)

  11. Clinical outcomes at one year [ Time Frame: At one year follow-up ]
    Bisoprolol dose modification (categorical variable : dose increased, dose decreased, dose unchanged and quantitative analysis of mean change between bisoprolol inclusion dose and bisoprolol dose at one year).


Biospecimen Retention:   Samples Without DNA
One blood sample for each patient at the time of inclusion.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Consecutive ambulatory chronic HFrEF patients followed at the CHU de Caen, treated with maximum tolerated dose of bisoprolol. Patients can benefit of other HFrEF recommended treatment at the exception of ivabradine that would confound the bisoprolol effect on heart rate. Patients will be subsequently studied by renal function (altered if creatinine clearance < 30mL/min, mild altered between 30-60mL/min, normal > 60mL/min as estimated by the CKD-EPI formula) and bisoprolol dose (5, 7.5 or 10mg).
Criteria

Inclusion Criteria:

  • Consecutive ambulatory patients with chronic heart failure with mild to reduced ejection fraction (LVEF < 50%) at the CHU de Caen
  • Aged 18 y.o. or older
  • With a stable heart failure (see exclusion criteria)
  • At the maximum tolerated dose of bisoprolol for at least one week (maximum dose reached without adverse tolerance event: orthostatic hypotension, symptomatic bradycardia, fatigue related to the treatment)

Exclusion Criteria:

  • Unstable HF, that are patients who presented in the last 3 months before inclusion an hospitalization for any cardiovascular event including HF, new onset or worsening of HF or coronary artery disease symptoms
  • Patient refusing to participate
  • Patients with a non maximum tolerated dose of bisoprolol
  • Patients with ivabradine intakes
  • Body weight < 60kg or > 100kg
  • Severe liver insufficiency
  • Pregnancy
  • Liberty deprived patients

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03644446


Locations
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France
Alexandre Joachim Recruiting
Caen, Basse Normandie, France, 14000
Contact: Joachim Alexandre, MD    +33231064670    alexandre-j@chu-caen.fr   
Sponsors and Collaborators
University Hospital, Caen
Additional Information:

Publications:
Epidemiology, aetiology, and prognosis of heart failure -- McMurray and Stewart 83 (5): 596 -- Heart [Internet]. [cited 2016 May 3];Available from: http://heart.bmj.com/content/83/5/596.short
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K; ESC Committee for Practice Guidelines (CPG). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008 Oct;29(19):2388-442. doi: 10.1093/eurheartj/ehn309. Epub 2008 Sep 17. Review. Erratum in: Eur Heart J. 2010 Apr;12(4):416. Dosage error in article text. Eur Heart J. 2010 Mar;31(5):624. Dosage error in article text.
McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology, Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, McDonagh T, Sechtem U, Bonet LA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H, Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C, Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012 Aug;14(8):803-69. doi: 10.1093/eurjhf/hfs105. Erratum in: Eur J Heart Fail. 2013 Mar;15(3):361-2.

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Responsible Party: University Hospital, Caen
ClinicalTrials.gov Identifier: NCT03644446    
Other Study ID Numbers: DC-2016-2725
First Posted: August 23, 2018    Key Record Dates
Last Update Posted: August 23, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Caen:
Bisoprolol
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Bisoprolol
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action