Rate Control in Atrial Fibrillation II (RATAFII)

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.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; Permanent Atrial Fibrillation
• Intervention / Treatment: Drug: Metoprolol; Drug: Diltiazem

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.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Akershus
    • Rud, Akershus, Norway, 1309
      • Vestre Viken Hospital Trust, Baerum Hospital

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metoprolol; Metoprolol, extended release tablets. 100 mg daily	Drug: Metoprolol; Dosage 100 mg o.d.; Other Names: Selo-Zok Metoprolol Astra Zeneca depot
Active Comparator: Diltiazem; Diltiazem, extended release tablets. 360 mg daily	Drug: Diltiazem; Dosage 360 mg o.d.; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood pressure	Blood pressure will be measured at baseline and after 4 weeks to assess change	4 weeks
Blood pressure	Blood pressure will be measured after 6 months	6 months

Collaborators and Investigators

• Sponsor: Asker & Baerum Hospital
• Collaborators: Vestre Viken Hospital Trust; Helse Sor-Ost
• Investigators: Principal Investigator: Sara Reinvik Ulimoen, MD PhD, Vestre Viken HF Baerum Hospital

Publications and helpful links

General Publications

• Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van Veldhuisen DJ, Van den Berg MP; RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363-73. doi: 10.1056/NEJMoa1001337. Epub 2010 Mar 15.
• European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010 Oct;31(19):2369-429. doi: 10.1093/eurheartj/ehq278. Epub 2010 Aug 29. No abstract available. Erratum In: Eur Heart J. 2011 May;32(9):1172.
• Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001 May 9;285(18):2370-5. doi: 10.1001/jama.285.18.2370.
• Ulimoen SR, Enger S, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation. Eur Heart J. 2014 Feb;35(8):517-24. doi: 10.1093/eurheartj/eht429. Epub 2013 Oct 17.
• Ulimoen SR, Enger S, Carlson J, Platonov PG, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation. Am J Cardiol. 2013 Jan 15;111(2):225-30. doi: 10.1016/j.amjcard.2012.09.020. Epub 2012 Oct 27.
• Ulimoen SR, Enger S, Norseth J, Pripp AH, Abdelnoor M, Arnesen H, Gjesdal K, Tveit A. Improved rate control reduces cardiac troponin T levels in permanent atrial fibrillation. Clin Cardiol. 2014 Jul;37(7):422-7. doi: 10.1002/clc.22281. Epub 2014 Apr 3.
• Van Gelder IC, Hobbelt AH, Mulder BA, Rienstra M. Rate control in atrial fibrillation: many questions still unanswered. Circulation. 2015 Oct 27;132(17):1597-9. doi: 10.1161/CIRCULATIONAHA.115.018952. Epub 2015 Sep 17. No abstract available.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): October 1, 2021
• Study Completion (Actual): November 12, 2021

Study Registration Dates

• First Submitted: April 28, 2015
• First Submitted That Met QC Criteria: February 25, 2016
• First Posted (Estimate): March 2, 2016

Study Record Updates

• Last Update Posted (Actual): January 5, 2022
• Last Update Submitted That Met QC Criteria: January 4, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Biomarkers; Physiological Effects of Drugs; Peripheral Nervous System Agents; Heart Diseases; Therapeutic Uses; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Calcium channel blockers; Adrenergic beta-Antagonists; Vasodilator Agents; Sympatholytics; Neurotransmitter Agents; Metoprolol; Cardiovascular Agents; NT-proBNP; Molecular Mechanisms of Pharmacological Action; Adrenergic Agents; Permanent atrial fibrillation; Beta blockers; Diltiazem; Membrane Transport Modulators; Adrenergic Antagonists; Adrenergic beta-1 Receptor Antagonists; Rate control in atrial fibrillation; Management of atrial fibrillation; Atrial fibrillation and biomarkers; Arrhythmias, cardiac; Pathological processes; Troponins
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol; Diltiazem
• Other Study ID Numbers: 240415; 2015-001918-98 (EudraCT Number)

Plan for Individual participant data (IPD)

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