Rate Control in Atrial Fibrillation II

Study Overview
=================
Brief Summary
-----------------
The RATAF II study is a randomized, prospective, parallel group study, designed to compare the effects of two different drug regimens for rate control in permanent AF (atrial fibrillation). We will investigate on the difference in effects on exercise capacity, biomarkers (NT-proBNP (N-terminal pro-brain natriuretic peptide), troponins, hs-CRP), heart rate, echocardiographic measurements and symptoms. Our main hypothesis is that six months' treatment with the calcium channel blocker diltiazem will lower NT-proBNP and increase exercise capacity (peak VO2) compared to treatment with the beta blocker metoprolol in permanent AF.

Detailed Description
-----------------
Atrial fibrillation is a common cardiac disease, with increasing incidence and prevalence. There are two main treatment strategies for this arrhythmia, rhythm control and rate control. As rate control is easier to achieve and no major difference in outcome has been found between these two strategies, it is considered a reasonable initial treatment for the majority of AF patients. Reduced exercise capacity is the most prevalent symptom in patients with permanent AF. In the first Rate control in Atrial Fibrillation (RATAF) study, we demonstrated that calcium channel blockers preserved exercise capacity, reduced arrhythmia-related symptoms and lowered levels of NT-proBNP - whereas the beta blockers reduced the exercise capacity, did not reduce arrhythmia-related symptoms and increased NT-proBNP. These findings are relevant to a large proportion of patients with permanent AF, suggesting that calcium channel blockers should be the first drug of choice for rate control in patients without heart failure or coronary heart disease. Our results challenge the current widespread use of beta blockers in this setting. However, as the follow up time in the RATAF study was only 3 weeks, it is not clear if these effects are sustained over time. Furthermore, we do not know the mechanisms for the differential effects on exercise capacity, arrhythmia related symptoms and NT-proBNP levels. In the RATAF II study we will investigate whether the effects on NT-proBNP levels, exercise capacity and symptoms are sustained over time, and explore potential mechanisms that may explain the difference in these effects. The study will provide new insights and results relevant for everyday clinical practice and be of importance for a large and growing group of patients. A total of 240 patients will be included. Eligible patients will be recruited from the out-patient clinics at the participation hospitals and through advertisements in local newspapers. After inclusion and a wash-out period of 14 days free from drugs affecting the heart rate, patients will be examined by echocardiography, 12-lead ECG (electrocardiography), 24h Holter monitoring, maximal cardiopulmonary exercise test and venous blood sampling at rest, at maximal exercise and after recovery. Perceived arrhythmia related symptoms, quality of life and level of physical activity will be assessed using self-administered questionnaires. Participants will be randomized through a computer-generated randomization list, to receive one of the study drug regimens; metoprolol 100 mg o.d. or diltiazem 360 mg o.d. The investigators and study personnel will be blinded with regard to allocated study drug. The participants themselves will know what study drug they are assigned. Also, study personnel not involved in examinations will also be able to acquire knowledge concerning assigned study drug, to ensure the process of dosage in the startup phase, assess adverse events (AE) and side effects throughout the study. Examinations will be repeated after four weeks and six months. All examinations will be performed at the Department of Medical Research, Baerum Hospital to ensure standardized procedures.

Official Title
-----------------
Rate Control in Atrial Fibrillation II

Conditions
-----------------
Atrial Fibrillation, Permanent Atrial Fibrillation

Intervention / Treatment
-----------------
* Drug: Metoprolol
* Drug: Diltiazem


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Above 18 years of age Symptomatic, permanent AF of at least three months duration Resting heart rate ≥80 bpm Signed informed consent Exclusion Criteria: Congestive heart failure Ischemic heart disease Hypotension (Systolic blood pressure <100 mmHg) Treatment with class I or III antiarrhythmic drugs Severe hepatic or renal failure Pregnancy or lactation Hypersensitivity or contradictions to study drugs Atrio-ventricular conduction disturbances Thyrotoxicosis Life limiting disease or substance abuse which may affect participation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metoprolol<br>Metoprolol, extended release tablets. 100 mg daily | Drug: Metoprolol<br>* Dosage 100 mg o.d.<br>* Other names: Selo-Zok Metoprolol Astra Zeneca depot;|
| Active Comparator: Diltiazem<br>Diltiazem, extended release tablets. 360 mg daily | Drug: Diltiazem<br>* Dosage 360 mg o.d.<br>* Other names: Cardizem Diltiazem Uno depot;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of NT-proBNP | Levels of NT-proBNP will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Levels of NT-proBNP | Levels of NT-proBNP will be measured after 6 months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise capacity defined as peak VO2 | Exercise capacity will be assessed by cardiopulmonary exercise test at baseline and after 4 weeks to assess change | 4 weeks | 
| Exercise capacity defined as peak VO2 | Exercise capacity will be assessed by cardiopulmonary exercise test after 6 months | 6 months | 
| Ventricular heart rate | Ventricular heart rate will be assessed by ECG at rest and during exercise. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Ventricular heart rate | Ventricular heart rate will be assessed by ECG at rest and during exercise. Will be measured after 6 months. | 6 months | 
| Other biomarkers | Levels of other biomarkers such as hs-troponins, hs-CRP will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Other biomarkers | Levels of other biomarkers such as hs-troponins, hs-CRP will be measured after 6 months. | 6 months | 
| Symptoms | Symptoms will be assessed using a validated, self-administered questionnaire, the Symptom Checklist - Frequency and Severity (SCL). This will be filled out at baseline and 4 weeks to assess change. | 4 weeks | 
| Symptoms | Symptoms will be assessed using a validated, self-administered questionnaire, the Symptom Checklist - Frequency and Severity (SCL). This will be filled out at 6 months. | 6 months | 
| Quality of life in SF-36 | The SF-36 (Short Form 36 Health Survey) questionnaire assessing quality of life will be filled out at baseline and 4 weeks to assess change. | 4 weeks | 
| Quality of life in SF-36 | The SF-36 questionnaire assessing quality of life will be filled out at 6 months. | 6 months | 
| Echocardiographic measures - Standard parasternal long axis and three apical views recordings. | Will be done in the end expiratory phase with the subjects in supine lateral position. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Standard parasternal long axis and three apical views recordings. | Will be done in the end expiratory phase with the subjects in supine lateral position. Measured at 6 months. | 6 months | 
| Echocardiographic measures - Left ventricular dimension, septal and posterior wall thickness. | Will be measured as recommended by American Society of Echocardiography. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Left ventricular dimension, septal and posterior wall thickness. | Will be measured as recommended by American Society of Echocardiography. Measured at 6 months. | 6 months | 
| Echocardiographic measures - Left ventricular mass. | Will be measured as recommended by American Society of Echocardiography. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Left ventricular mass. | Will be measured as recommended by American Society of Echocardiography. Measured at 6 months. | 6 months | 
| Echocardiographic measures - Left ventricular and left atrial maximal and minimal volumes. | Will be calculated by 2D biplane and 4-chamber and 2D long axis views. (ml/m2). Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Left ventricular and left atrial maximal and minimal volumes. | Will be calculated by 2D biplane and 4-chamber and 2D long axis views. (ml/m2). Measured at 6 months. | 6 months | 
| Echocardiographic measures - Left ventricular ejection fraction will also be calculated. | Using the modified Simpsons rule. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Left ventricular ejection fraction will also be calculated. | Using the modified Simpsons rule. Measured at 6 months. | 6 months | 
| Echocardiographic measures - Transmitral flow and pulmonary venous flow. | Will be assessed by pulsed Doppler. Tissue Doppler imaging-derived indices will be recorded at the base of the septal and lateral mitral annulus. (cm/s). Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Transmitral flow and pulmonary venous flow. | Will be assessed by pulsed Doppler. Tissue Doppler imaging-derived indices will be recorded at the base of the septal and lateral mitral annulus. (cm/s). Measured at 6 months. | 6 months | 
| Echocardiographic measures - Global and regional longitudinal left ventricular strain. | Will be analysed by a semi-automated speckle tracking technique. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Global and regional longitudinal left ventricular strain. | Will be analysed by a semi-automated speckle tracking technique.Measured at 6 months. | 6 months | 
| Echocardiographic measures - Left atrial deformation for assessment of global as well as regional left atrial strain. | Will be analysed by a semi-automated speckle tracking technique. Characterizing both reservoir and conduit function. Will be measured at baseline and after 4 weeks to assess change | 4 weeks | 
| Echocardiographic measures - Left atrial deformation for assessment of global as well as regional left atrial strain. | Will be analysed by a semi-automated speckle tracking technique. Characterizing both reservoir and conduit function. Measured at 6 months. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rate control in atrial fibrillation, Beta blockers, Calcium channel blockers, Permanent atrial fibrillation, Management of atrial fibrillation, Atrial fibrillation and biomarkers, Arrhythmias, cardiac, Heart Diseases, Pathological processes, Diltiazem, Metoprolol, Adrenergic Agents, Adrenergic Antagonists, Adrenergic beta-1 Receptor Antagonists, Adrenergic beta-Antagonists, Anti-Arrhythmia Agents, Antihypertensive Agents, Autonomic Agents, Cardiovascular Agents, Membrane Transport Modulators, Molecular Mechanisms of Pharmacological Action, Neurotransmitter Agents, Peripheral Nervous System Agents, Physiological Effects of Drugs, Sympatholytics, Therapeutic Uses, Vasodilator Agents, Troponins, NT-proBNP, Biomarkers