Atrial Fibrillation (AF)
Conditions
Keywords
Atrial Fibrillation, Quality of Life, Bisoprolol, Diltiazem, Calcium Channel Blockers, Arrhythmias, Cardiac, Clinical Trial, Phase IV, Beta-Blocker
Brief summary
Beta-blockers are generally prescribed for the treatment of atrial fibrillation. Their purpose is to slow the heart rate and thereby reduce the workload on the heart. However, beta-blockers can affect patients' quality of life, for example by reducing physical performance or causing fatigue in daily life. In this study, we aim to determine whether calcium channel blockers can improve the treatment of atrial fibrillation and have a positive impact on the quality of life of patients with atrial fibrillation compared with beta-blockers. We will also investigate how calcium channel blockers affect the physical exercise capacity. In addition, we will monitor potential side effects of both medications and explore whether there are any differences between women and men over the course of the study. Both study medications, the calcium channel blocker diltiazem and the beta-blocker bisoprolol, are approved by authorities and are recommended by the European Society of Cardiology for rate control in atrial fibrillation.
Detailed description
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. Many AF patients present with a rapid ventricular response resulting in a high heart rate (HR). In these patients, it is important to lower the HR. To achieve rate control, several pharmacological agents are available, but beta-blockers (BB) are predominantly used. There is little evidence supporting the preference for BB. Side effects of BB such as fatigue, dizziness, and effort intolerance are widely known. Non-dihydropyridine calcium channel blockers (NDCC) represent an alternative for rate control and might be associated with better quality of life (QoL) than BB in AF patients. This study aims to investigate the impact on the QoL of AF patients who are currently on BB therapy and are switching to NDCC. Both men and women affected by AF and its complications will be enrolled in the study. If this study can show an advantage of NDCC over BB in AF patients, a paradigm shift in the treatment of AF could take place. This could mean an easily implementable potential therapeutic advantage at no supplementary cost for patients and the health care system. Given the very common use of BB in AF patients, the negative impact of this drug on QoL could affect thousands of patients. The investigational medicinal product (IMP) is diltiazem, a NDCC. Diltiazem belongs to the benzothiazepine class and exerts its pharmacological effect through inhibition of L-type calcium channels in atrioventricular nodal tissue, resulting in negative dromotropic effects and effective ventricular rate control in AF. Diltiazem is approved by the authorities and recommended by current guidelines as an alternative to BB for rate control in AF. In the present study, diltiazem is administered orally in a prolonged-release formulation at daily doses of 90 mg, 180 mg, or 360 mg, corresponding to low, normal, or high dose categories. The comparator is bisoprolol, a β1-selective beta-adrenergic receptor blocker. BB are the most frequently prescribed agents for rate control in AF and represent the current standard of care. Bisoprolol is administered orally at daily doses of 2.5 mg, 5 mg, or 10 mg, reflecting standard clinical practice. Patient representatives have been involved in developing our research from the beginning. Their insights have guided our approach to ensure the study addresses real concerns faced by patients affected by AF.
Interventions
Study participants randomized in the experimental intervention group will receive Non-dihydropyridine calcium channel blockers (NDCC) Diltiazem retard for 90 days. Depending on the dosage of the beta-blocker treatment of these patients at baseline, three different dosage options will be used (low, normal, high). Diltiazem capsules of 90mg will be provided, meaning that patients with the low dosage will take one capsule a day (morning), patients with the normal dosage two capsules a day (morning and evening) and patients with the high dosage four capsules a day (2x morning and 2x evening). Based on previous data, we assume that most patients will use the low or normal dosage. The medication Diltiazem 90mg will be over-encapsulated, packed and labelled by a pharmacy specialist.
DRUGControl Intervention
Study patients will receive the beta-blocker (BB) Bisoprolol for 90 days. Depending on the dosage of the BB treatment of these patients at baseline, three different dosage options will be used (low, normal high). Low dosage of Bisoprolol is corresponding to 2.5mg, normal dosage to 5mg and high dosage to 10mg/day. Bisoprolol capsules of 2.5mg will be provided, meaning that patients with the low dosage will take one capsule a day (morning), patients with the normal dosage two capsules a day (morning and evening) and patients with the high dosage four capsules (2x morning and 2x evening). The medication Bisoprolol will be over-encapsulated, packed and labelled by a pharmacy specialist.
Sponsors
University Hospital, Basel, Switzerland
Swiss National Science Foundation
Schweizerische Herzstiftung
Freiwillige Akademische Gesellschaft Basel
Clinical Trial Unit, University Hospital Basel, Switzerland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Besides the participants all members of the study team are blinded.
Intervention model description
Randomized, double-blind, multicenter, controlled, superiority trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented AF * Currently on a stable regimen of BB for at least three weeks * Informed consent as documented by signature
Exclusion criteria
* Left ventricular ejection fraction (LVEF) \<40% * Severe valvular heart disease * Uncontrolled hypertension defined as systolic BP \> 180 mmHg * AV block Type II, AV block type III * Severe bradycardia, defined as a resting heart rate \<40 bpm on ECG * Currently on a NDCC (Diltiazem or Verapamil) * Concomitant rhythm-controlling medication (antiarrhythmic drugs Vaughan Williams classification I and III) * Currently on Ivabradine, Digoxin, Clonidine, Pimozide, Dihydroergotamine, Nifedipine, Lomitapide * History of atrio-ventricular node ablation * Implanted pacemaker or implantable cardioverter defibrillator (ICD) with a right-ventricular pacing burden \>40% * Previous pulmonary vein isolation (PVI) or electric cardioversion within 90 days prior to study enrolment * Established infiltrative myocardial disease, e.g. amyloidosis, constrictive pericarditis, myocarditis, hypertrophic cardiomyopathy * End-stage renal disease, estimated glomerular filtration rate (eGFR) \<15 ml/min/1.73 m2 * Pregnant or breastfeeding women, or women of childbearing potential who do not use a highly effective form of birth control * Expected life expectancy \< 6months * Drug or alcohol abuse * Inability to understand and sign study information and patient informed consent Both women and men will be enrolled, and sex-specific differences in treatment effects will be examined in a subgroup analysis. No vulnerable populations will be included. All participants are capable of judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Atrial-Fibrillation-related Quality of Life | From baseline to 3 months | Change in Atrial-Fibrillation-related Quality of Life between Non-dihydropyridine calcium channel blockers (NDCC) versus continuation of beta-blockers (BB) from baseline to 3 months in patients with Atrial-Fibrillation. The primary outcome uses the AFEQT questionnaire: The AFEQT 20-item questionnaire is a validated, AF-specific QoL tool. It assesses 4 domains: symptoms, daily activities, treatment concerns, and treatment satisfaction. The overall AFEQT score is calculated using the first 3 domains and ranges from 0 = worst to 100 = best QoL. Additionally, for each domain of interest, there is a corresponding subscale score: symptoms, daily activities, treatment concerns, and treatment satisfaction subscale scores. Each subscale ranges from 0 = worst to 100 = best QoL and is scored separately. The AFEQT questionnaire will be done at baseline before the intake of the first study drug and after three months of intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NT-proBNP | At Baseline and after 3 Months | Change in NT-proBNP levels measured at baseline and after 3 months. NT-proBNP is released into the circulation in response to myocardial cell stretch. This biomarker is commonly used to evaluate the degree of heart failure in cardiac patients. Non-fasting blood samples will be taken at baseline before randomization and at the final study visit (4.7ml each). NT-proBNP levels will be measured in the laboratory of the respective study site by using an electrochemiluminescence immunoassay (Elecsys, Roche Diagnostics, Switzerland). Furthermore, if patients provide consent, additional blood samples (serum, plasma and whole blood) will be taken, processed, frozen and stored at -80°C, according to the ethical guidelines concerning biobanking, at the Cardiovascular Research Institute Basel. These samples will be used for future genetic analyses and for the assessment of emerging biomarkers of interest in this context. |
| 6-minute walking test (6MWT) distance | At baseline and after 3 months | Change in 6MWT distance assessed at baseline and after 3 months The 6MWT is a simple test which does not require expensive equipment or advanced training for technicians. The test involves asking the patient to walk the longest distance possible in a set interval of 6 minutes, through a walking course (corridor) preferably 30 meters long. The result of the 6MWT will be entered in the CRF as the distance in meters. In this context, other variables will be assessed, including the Borg Scale after the test and information on whether the test was done with a walking aid or must be terminated earlier. The 6MWT will be done at baseline before randomization and after 3 months of intervention. |
| Peak flow measurement | At baseline and after 3 months | Change in peak flow measured at baseline and at the study end visit after 90 days of study intervention. The patient will perform the test in a standing position. Study personnel will instruct the patient to inhale as deeply as possible and then exhale as forcefully and rapidly as they can. The measurement will be repeated three times, and the results of all three attempts will be recorded in the study database. |
| Hierarchical composite endpoint comprising | Baseline to 3 months | A hierarchical win ratio will be calculated comparing participants between treatment groups using the following pre-specified hierarchy (in order of priority), all assessed as change from baseline to 3 months: * AF-related QoL * 6MWT distance * NT-proBNP |
Countries
Switzerland
Contacts
CONTACTPatrick Badertscher, PD Dr. med.
CONTACTStefanie Aeschbacher, PhD
PRINCIPAL_INVESTIGATORPatrick Badertscher, PD Dr. med.
University Hospital, Basel, Switzerland
Outcome results
None listed