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Rate Control in Atrial Fibrillation II (RATAFII)

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ClinicalTrials.gov Identifier: NCT02695992
Recruitment Status : Recruiting
First Posted : March 2, 2016
Last Update Posted : March 21, 2019
Sponsor:
Collaborators:
Vestre Viken Hospital Trust
Helse Sor-Ost
Information provided by (Responsible Party):
Sara Reinvik Ulimoen, Asker & Baerum Hospital

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.


Condition or disease Intervention/treatment Phase
Atrial Fibrillation Permanent Atrial Fibrillation Drug: Metoprolol Drug: Diltiazem Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: Rate Control in Atrial Fibrillation II
Study Start Date : February 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Active Comparator: Metoprolol
Metoprolol, extended release tablets. 100 mg daily
Drug: Metoprolol
Dosage 100 mg o.d.
Other Name: Selo-Zok Metoprolol Astra Zeneca depot

Active Comparator: Diltiazem
Diltiazem, extended release tablets. 360 mg daily
Drug: Diltiazem
Dosage 360 mg o.d.
Other Name: Cardizem Diltiazem Uno depot




Primary Outcome Measures :
  1. Levels of NT-proBNP [ Time Frame: 4 weeks ]
    Levels of NT-proBNP will be measured at baseline and after 4 weeks to assess change

  2. Levels of NT-proBNP [ Time Frame: 6 months ]
    Levels of NT-proBNP will be measured after 6 months


Secondary Outcome Measures :
  1. Exercise capacity defined as peak VO2 [ Time Frame: 4 weeks ]
    Exercise capacity will be assessed by cardiopulmonary exercise test at baseline and after 4 weeks to assess change

  2. Exercise capacity defined as peak VO2 [ Time Frame: 6 months ]
    Exercise capacity will be assessed by cardiopulmonary exercise test after 6 months

  3. Ventricular heart rate [ Time Frame: 4 weeks ]
    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. Ventricular heart rate [ Time Frame: 6 months ]
    Ventricular heart rate will be assessed by ECG at rest and during exercise. Will be measured after 6 months.

  5. Other biomarkers [ Time Frame: 4 weeks ]
    Levels of other biomarkers such as hs-troponins, hs-CRP will be measured at baseline and after 4 weeks to assess change

  6. Other biomarkers [ Time Frame: 6 months ]
    Levels of other biomarkers such as hs-troponins, hs-CRP will be measured after 6 months.

  7. Symptoms [ Time Frame: 4 weeks ]
    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.

  8. Symptoms [ Time Frame: 6 months ]
    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.

  9. Quality of life in SF-36 [ Time Frame: 4 weeks ]
    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.

  10. Quality of life in SF-36 [ Time Frame: 6 months ]
    The SF-36 questionnaire assessing quality of life will be filled out at 6 months.

  11. Echocardiographic measures - Standard parasternal long axis and three apical views recordings. [ Time Frame: 4 weeks ]
    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

  12. Echocardiographic measures - Standard parasternal long axis and three apical views recordings. [ Time Frame: 6 months ]
    Will be done in the end expiratory phase with the subjects in supine lateral position. Measured at 6 months.

  13. Echocardiographic measures - Left ventricular dimension, septal and posterior wall thickness. [ Time Frame: 4 weeks ]
    Will be measured as recommended by American Society of Echocardiography. Will be measured at baseline and after 4 weeks to assess change

  14. Echocardiographic measures - Left ventricular dimension, septal and posterior wall thickness. [ Time Frame: 6 months ]
    Will be measured as recommended by American Society of Echocardiography. Measured at 6 months.

  15. Echocardiographic measures - Left ventricular mass. [ Time Frame: 4 weeks ]
    Will be measured as recommended by American Society of Echocardiography. Will be measured at baseline and after 4 weeks to assess change

  16. Echocardiographic measures - Left ventricular mass. [ Time Frame: 6 months ]
    Will be measured as recommended by American Society of Echocardiography. Measured at 6 months.

  17. Echocardiographic measures - Left ventricular and left atrial maximal and minimal volumes. [ Time Frame: 4 weeks ]
    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

  18. Echocardiographic measures - Left ventricular and left atrial maximal and minimal volumes. [ Time Frame: 6 months ]
    Will be calculated by 2D biplane and 4-chamber and 2D long axis views. (ml/m2). Measured at 6 months.

  19. Echocardiographic measures - Left ventricular ejection fraction will also be calculated. [ Time Frame: 4 weeks ]
    Using the modified Simpsons rule. Will be measured at baseline and after 4 weeks to assess change

  20. Echocardiographic measures - Left ventricular ejection fraction will also be calculated. [ Time Frame: 6 months ]
    Using the modified Simpsons rule. Measured at 6 months.

  21. Echocardiographic measures - Transmitral flow and pulmonary venous flow. [ Time Frame: 4 weeks ]
    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

  22. Echocardiographic measures - Transmitral flow and pulmonary venous flow. [ Time Frame: 6 months ]
    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.

  23. Echocardiographic measures - Global and regional longitudinal left ventricular strain. [ Time Frame: 4 weeks ]
    Will be analysed by a semi-automated speckle tracking technique. Will be measured at baseline and after 4 weeks to assess change

  24. Echocardiographic measures - Global and regional longitudinal left ventricular strain. [ Time Frame: 6 months ]
    Will be analysed by a semi-automated speckle tracking technique.Measured at 6 months.

  25. Echocardiographic measures - Left atrial deformation for assessment of global as well as regional left atrial strain. [ Time Frame: 4 weeks ]
    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

  26. Echocardiographic measures - Left atrial deformation for assessment of global as well as regional left atrial strain. [ Time Frame: 6 months ]
    Will be analysed by a semi-automated speckle tracking technique. Characterizing both reservoir and conduit function. Measured at 6 months.


Other Outcome Measures:
  1. Blood pressure [ Time Frame: 4 weeks ]
    Blood pressure will be measured at baseline and after 4 weeks to assess change

  2. Blood pressure [ Time Frame: 6 months ]
    Blood pressure will be measured after 6 months



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02695992


Contacts
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Contact: Sara Reinvik Ulimoen, MD PhD 0047 41511811 sara.ulimoen@gmail.com
Contact: Katrine Enge, MD 0047 91622668 katrine.enge@gmail.com

Locations
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Norway
Vestre Viken Hospital Trust, Baerum Hospital Recruiting
Rud, Akershus, Norway, 1309
Contact: Sara Reinvik Ulimoen, MD PhD    67809400 ext +47    sara.ulimoen@vestreviken.no   
Principal Investigator: Sara Reinvik Ulimoen, MD PhD         
Sub-Investigator: Arnljot Tveit, MD PhD         
Sub-Investigator: Katrine Enge, MD         
Sponsors and Collaborators
Asker & Baerum Hospital
Vestre Viken Hospital Trust
Helse Sor-Ost
Investigators
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Principal Investigator: Sara Reinvik Ulimoen, MD PhD Vestre Viken HF Baerum Hospital

Publications:

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Responsible Party: Sara Reinvik Ulimoen, MD PhD postdoc fellow, Asker & Baerum Hospital
ClinicalTrials.gov Identifier: NCT02695992     History of Changes
Other Study ID Numbers: 240415
2015-001918-98 ( EudraCT Number )
First Posted: March 2, 2016    Key Record Dates
Last Update Posted: March 21, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Sara Reinvik Ulimoen, Asker & Baerum Hospital:
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
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Metoprolol
Diltiazem
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents