Clinical trial NCT02695992: Rate Control in Atrial Fibrillation II
Official title: Rate Control in Atrial Fibrillation II
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atrial Fibrillation
Permanent Atrial Fibrillation
Keywords: 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
Lead sponsor: Asker & Baerum Hospital
Sponsor class: OTHER
Collaborators: name: Vestre Viken Hospital Trust
name: Helse Sor-Ost
First posted: 2016-03-02
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Levels of NT-proBNP
timeFrame: 4 weeks
measure: Levels of NT-proBNP
timeFrame: 6 months
Secondary outcomes:
measure: Exercise capacity defined as peak VO2
timeFrame: 4 weeks
measure: Exercise capacity defined as peak VO2
timeFrame: 6 months
measure: Ventricular heart rate
timeFrame: 4 weeks
measure: Ventricular heart rate
timeFrame: 6 months
measure: Other biomarkers
timeFrame: 4 weeks
measure: Other biomarkers
timeFrame: 6 months
measure: Symptoms
timeFrame: 4 weeks
measure: Symptoms
timeFrame: 6 months
measure: Quality of life in SF-36
timeFrame: 4 weeks
measure: Quality of life in SF-36
timeFrame: 6 months
measure: Echocardiographic measures - Standard parasternal long axis and three apical views recordings.
timeFrame: 4 weeks
measure: Echocardiographic measures - Standard parasternal long axis and three apical views recordings.
timeFrame: 6 months
measure: Echocardiographic measures - Left ventricular dimension, septal and posterior wall thickness.
timeFrame: 4 weeks
measure: Echocardiographic measures - Left ventricular dimension, septal and posterior wall thickness.
timeFrame: 6 months
measure: Echocardiographic measures - Left ventricular mass.
timeFrame: 4 weeks
measure: Echocardiographic measures - Left ventricular mass.
timeFrame: 6 months
measure: Echocardiographic measures - Left ventricular and left atrial maximal and minimal volumes.
timeFrame: 4 weeks
measure: Echocardiographic measures - Left ventricular and left atrial maximal and minimal volumes.
timeFrame: 6 months
measure: Echocardiographic measures - Left ventricular ejection fraction will also be calculated.
timeFrame: 4 weeks
measure: Echocardiographic measures - Left ventricular ejection fraction will also be calculated.
timeFrame: 6 months
measure: Echocardiographic measures - Transmitral flow and pulmonary venous flow.
timeFrame: 4 weeks
measure: Echocardiographic measures - Transmitral flow and pulmonary venous flow.
timeFrame: 6 months
measure: Echocardiographic measures - Global and regional longitudinal left ventricular strain.
timeFrame: 4 weeks
measure: Echocardiographic measures - Global and regional longitudinal left ventricular strain.
timeFrame: 6 months
measure: Echocardiographic measures - Left atrial deformation for assessment of global as well as regional left atrial strain.
timeFrame: 4 weeks
measure: Echocardiographic measures - Left atrial deformation for assessment of global as well as regional left atrial strain.
timeFrame: 6 months
Other outcomes:
measure: Blood pressure
timeFrame: 4 weeks
measure: Blood pressure
timeFrame: 6 months
Locations:
city: Rud
country: Norway
facility: Vestre Viken Hospital Trust, Baerum Hospital
state: Akershus
Study officials:
affiliation: Vestre Viken HF Baerum Hospital
name: Sara Reinvik Ulimoen, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.