Landiolol for Rate Control in Decompensated Heart Failure Due to Atrial Fibrillation (LARISA)

The study will include patients with acute heart failure with reduced left ventricular ejection fraction (<40%) triggered by atrial fibrillation (AF) with a heart rate of >130/min. Patients in cardiogenic shock, critical state, or patients requiring emergent electric cardioversion during the first 2 hours will be excluded. The patients will be randomized (1:1) to a strategy of initial intensive heart rate control using continuous infusion of landiolol and boluses of digoxin vs. standard approach to the rate control without the use of landiolol. All patients will receive recommended pharmacotherapy of acute heart failure (diuretics, nitrates, inotropes in patients with signs of low cardiac output - preferentially milrinone or levosimendan). The patients will undergo hemodynamic monitoring, laboratory testing, evaluation of symptoms, and quantification of lung water content by ultrasound for 48 hours. The study will test a hypothesis whether patients treated with initial intensive heart rate control with the preferential use of landiolol will achieve faster heart rate control, compensation of heart failure, and relief of heart failure symptoms without causing hypotension or deterioration of heart failure.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation; Acute Heart Failure; Left Ventricular Dysfunction; Atrial Fibrillation Rapid
• Intervention / Treatment: Drug: Intensive heart rate control with landiolol; Drug: Standard approach to heart rate control

Detailed Description

Procedure:

1. Eligible patients with signed consent will be enrolled.
2. Baseline transthoracic echocardiography, laboratory testing, evaluation of subjective dyspnea, lung water by ultrasound, chest x-ray, hemodynamic monitoring (details below)
3. Randomisation 1:1 to standard therapy vs. intensive heart rate control

4. Two hours of therapy with continous hemodynamic monitoring (blood pressure by arterial line, cardiac output and stroke volume non-invasively by bioreactance)

   1. Standard therapy (oral or intravenous beta-blockers other than landiolol while avoiding hypotension or deterioration of hemodynamics, according to the preference of the physician) with a bolus of 250-500mg of digoxin
   2. Intensive heart rate control with the goal to achieve heart rate <115 during the first the hours, preferentially with continuous infusion of landiolol and a bolus of 250-500mg of digoxin. The dose will be titrated according to the actual heart rate and hemodynamic parameters (blood pressure, cardiac index, stroke volume index). If possible, in both groups, electric cardioversion will be preferentially delayed during the first 2 hours. Both groups will receive standard therapy of acute heart failure (diuretics, inotropes if needed-preferentially milrinone or levosimendan, nitrates..)
5. At 2 hours: evaluation of patients subjective dyspnea (primary clinical endpoint), heart rate (primary endpoint), hearth rhythm and hemodynamics
6. After 2 hours, both groups can be treated according to the preference of the physician.
7. Symptoms, heart rate control, hemodynamics and lung congestion will be reevaluated at 12 and 48 hours
8. The study protocol will end after 48 hours.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marek Sramko, MD., PhD.; Phone Number: +420776246127; Email: marek.sramko@ikem.cz

Study Locations

• Czechia
  • Prague, Czechia, 14021
    • Recruiting
    • Institute for Clinical and Experimental Medicine (IKEM)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• acute heart failure with reduced left ventricular ejection (<40%)
• atrial fibrillation with heart rate >130/min lasting presumably >12 hours and presumably contributing to the acute heart failure
• pulmonary congestion detected by auscultation, lung ultrasound or CXR

Exclusion Criteria:

• ongoing type 1. myocardial infarction
• cardiogenic shock
• presumed need for mechanical heart support during the first 48hours of the study
• presumed need for electric cardioversion during the first 2 hours of the study
• medication for heart rate control (beta-blockers, calcium channel blockers, digoxin) or antiarrhythmics introduced <24 hours before the study. Chronic therapy with these will not be a contraindication for the study
• thyreotoxicosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Intensive rate control with landiolol; Intensive heart rate control using landiolol with the goal to achieve HR<115 during the first 2 hours.	Drug: Intensive heart rate control with landiolol; Intensive heart rate control preferably with the use of short-acting betablocker landiolol in combination with digoxin; Other Names: Rapibloc, Amomed Pharma, Austria
ACTIVE_COMPARATOR: Standard therapy; Standard heart rate control with therapy other than landiolol	Drug: Standard approach to heart rate control; Standard heart rate control with intravenous or oral beta-blockers and/or antiarrhythmic in combination with digoxin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate control	Achievement of heart rate <115/min for at least 15 mins	during the first 2 hours
Change in patient-reported symptoms	Change of patient-reported dyspnea evaluated 1-10 visual analog scale (1=unbearable dyspnea, 10=no symptoms)	at 2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Significant change of heart rate	Decrease of heart rate >20% from baseline	During the first 2 hours
Heart rate and heart rhythm	the mean heart rate obtained from three measurements	heart rate measured at hours 2, 12 and 48 of the study protocol
Safety - hypotension	Occurence of hypotension requiring reduction of the dose of betablockers or vasopressors	first 2 hours
Change in cardiac index	Change in cardiac index (L/m2) evaluated noninvasively by bioreactance (Starling SV, Cheetah Medical)	evaluated between baseline and hour 2
Change in stroke volume index	Change in stroke volume index (ml/m2) evaluated noninvasively by bioreactance (Starling SV, Cheetah Medical)	evaluated between baseline and hour 2

Collaborators and Investigators

• Sponsor: Institute for Clinical and Experimental Medicine

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 5, 2020
• Primary Completion (ANTICIPATED): December 31, 2023
• Study Completion (ANTICIPATED): December 31, 2023

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 31, 2020
• First Posted (ACTUAL): January 5, 2021

Study Record Updates

• Last Update Posted (ACTUAL): January 6, 2021
• Last Update Submitted That Met QC Criteria: January 5, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: rate control; landiolol; betablockers
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Failure; Atrial Fibrillation; Ventricular Dysfunction; Ventricular Dysfunction, Left; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Landiolol
• Other Study ID Numbers: LARISA2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No