Efficacy of Ivabradine in Patient With Both Persistent Atrial Fibrillation and Heart Failure With Reduce Ejection Fraction

Efficacy of Ivabradine as a Treatment Modality for Both Rate Control and Heart Failure Medication in Patient With Both Persistent Atrial Fibrillation and Heart Failure With Reduce and Mid-range Ejection Fraction

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Previous studies have shown that rate control strategy in AF is non-inferior to rhythm control strategy, in terms of stroke and mortality risk. In addition, rate control strategy is associated with lower risk of hospitalization and non-cardiovascular mortality. Therefore, rate control is an essential strategy to improve quality of life, decrease morbidity and prevent tachycardia-induced cardiomyopathy in AF patients. The recommended rate control agents include beta-blocker, nondihydropyridine calcium-channel blocker (CCB), digoxin and amiodarone. However, in heart failure with reduced ejection fraction patient, the medication of rate control were beta-blocker than digoxin. But several clinical observation study show excess mortality in AF patients. Ivabradine, a If inhibitor, it is well-established that a pacemaker current, If current, is functionally expressed in the sinus node . Previous studies have shown that Ivabradine, If inhibitor, significantly reduces sinus rate and improves prognosis in patients with systolic heart failure. Interestingly, several investigators found that hyperpolarization- activated cyclic nucleotidylated channel 4 current (HCN4), the main isoform of the channel responsible for If current, is also functionally expressed in the Atrioventricular node(AV node). Recent data have shown that inhibition of If current slows AV node conduction in animals and humans. Thus, we want to compare the effect of Ivabradine on ventricular rate with digoxin in this study.

Study Overview

• Status: Unknown
• Conditions: Heart Failure; Atrial Fibrillation; Ivabradine
• Intervention / Treatment: Drug: Ivabradine 5 mg [Corlanor]; Drug: Digoxin 0.25 mg

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Taipei Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 86 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The patient with persistent or permanent atrial fibrillation(24hr ECG) with HFrEF and HFmrEF.
2. After maximal tolerance dose beta-blocker(Bisoprolol 20mg/day，Carvedilol 50mg/day) or intolerant to beta-blocker the resting heart rate from ECG is still faster than 100 or resting heart rate from ECG is greater than 80 but still with symptoms of short of breath and palpitation.
3. Stable heart rhythm medication.(no change of medication in recently one week)
4. Age 20 to 90 years old.
5. The subject must be an adult who can read himself/herself and walk independently.

Exclusion Criteria:

1. Used medication with interaction with digoxin : Clarithromycin, Erythromycin, Azithromycin, ritonavir, lopinavir/ritonavir, Doxycycline, Minocycline, tetracycline。
2. Used medication with interaction with ivabradine: voriconazole, posaconazole, fluconazole, Ombitasvir, Dasabuvir, Carbamazepine, Enzalutamide, Fosphenytoin, Mitotane, Phenobarbital, Phenytoin, Rifampicin
3. Cardiogenic shock.
4. History of symptomatic bradycardia.
5. Renal insufficiency:eGFR<30 ml/min/1.73m2
6. Pregnancy
7. Heart failure due to congenital heart
8. Severe hypotension(<90/50mmHg)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ivabradine; Subject will be randomly assigned to either Ivabradine or Digoxin group. Ivabradine starting dose is 2.5 mg twice daily(BID). ECG will be performed at each visit during the treatment phase and dose will be adjusted based on the heart rate result from the ECG. Total treatment phase is 16 weeks ( 4 months).	Drug: Ivabradine 5 mg [Corlanor]; Starting dose: Ivabradine 2.5mg twice daily (BID) Max Dose: Ivabradine 7.5 mg twice daily (BID)
Active Comparator: Digoxin; Subject will be randomly assigned to either Ivabradine or Digoxin group. Digoxin starting dose is 0.125mg once daily(QD) in estimated Glomerular filtration rate(eGFR)>60， 0.125mg every other day (QOD) in estimated Glomerular filtration rate(eGFR)<60. Dose adjustment will be based on heart rate result from ECG performed at each treatment visit and Digoxin level from blood sample collected from each visit during treatment phase. Total treatment phase is 16 weeks ( 4 months).	Drug: Digoxin 0.25 mg; Starting dose: 0.125mg once daily (QD) in estimated Glomerular filtration rate(eGFR)>60， 0.125mg once every other day (QOD) in estimated Glomerular filtration rate(eGFR)<60 Max dose: 0.25 once daily (QD)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate change	To compare Heart Rate change monitored from 24 hr ECG. Test will be performed at Baseline (screening phase, 4 weeks time between screening/Informed consent and Randomization visit) and treatment completion (Visit 5/Week 16). Total treatment phase is 16 weeks.	24 hr ECG test will be performed at Screening phase and End of Treatment visit(Visit5/Week 16).
6 minute walk test change	To compare 6 minute walking test walking distance change between Randomization visit(Visit 1/Week 0) and treatment completion(Visit 5/Week 16). Total Treatment phase is 16 weeks.	Test will be performed at Randomization visit (V1/Week0) and treatment completion (Visit 5/Week 16).
N-terminal pro-brain natriuretic peptide(NT-Pro BNP) change	To compare NT-Pro BNP change from blood sample collected at Baseline (screening phase, 4 weeks time between screening/informed consent and Randomization visit) and treatment completion (Visit 5/Week 16). Total treatment phase is 16 weeks.	Blood sample will be collected at Screening phase and End of Treatment visit(Visit5/Week 16).
1-10 Borg Rating of Perceived Exertion Scale change	To compare 1-10 Borg Rating of Perceived Exertion Scale change between Randomization visit (Visit1/Week0) and treatment completion (Visit 5/Week 16). Total Treatment phase is 16 weeks. The number 1-10 Borg Rating of Perceived Exertion Scale will be obtained pre and post 6 minutes walk test. The value of 1-10 Borg Rating of Perceived Exertion Scale pre 6 minutes walking test will be compared between Randomization visit (Visit1/Week0) and treatment completion (Visit 5/Week 16), and the same type of comparison will be performed for 1-10 Borg Rating of Perceived Exertion Scale values post 6 minute walk test. Rating score is as below: 0=Rest, 1=really easy, 2=easy, 3=moderate, 4=sort of hard, 5=hard, 6= between 5 and 7, 7=really hard, 8=between 7 and 9, 9=really really hard, 10=Maximal: just like my hardest race. Decrease in score value compared between Randomization visit (Visit1/Week0) and treatment completion (Visit 5/Week 16) represents better outcome.	Borg's score will be tested at Randomization visit (V1/Week0) and treatment completion (Visit 5/Week 16).

Collaborators and Investigators

• Sponsor: Chun-Yao Huang

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: March 11, 2020
• First Posted (Actual): March 13, 2020

Study Record Updates

• Last Update Posted (Actual): March 13, 2020
• Last Update Submitted That Met QC Criteria: March 11, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Failure; Atrial Fibrillation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Digoxin
• Other Study ID Numbers: N201801089

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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