Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) (RATE-AF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02391337
Recruitment Status : Completed
First Posted : March 18, 2015
Results First Posted : June 16, 2021
Last Update Posted : June 18, 2021
Sponsor:
Information provided by (Responsible Party):
University of Birmingham

Brief Summary:

Atrial fibrillation is a common heart rhythm disturbance, causing important discomfort for patients, a high risk of stroke, frequent hospital admissions and a two-fold increase in death. The number of patients with this condition are expected to double in the next 20 years. Medications to control heart-rate are used in the majority of patients, although the choice of agent is often guided by local preference rather than evidence from controlled trials. Despite the fact that patients with atrial fibrillation have high rates of other cardiac conditions such as heart failure, clinicians have insufficient evidence to personalise the use of different therapies. This feasibility study will allow us to develop a range of methods that can characterise patients according to the pumping and relaxing function of the heart, the burden of symptoms and to identify new blood markers. In this way, the investigators hope to improve clinical practice guidelines, allowing doctors to prescribe appropriate treatments for the right patients.

The research will be focused around a randomised trial of two medication strategies, providing much-needed data on the comparison of digoxin and beta-blockers (two commonly-used drugs in patients with atrial fibrillation). It will also allow us to identify the best way to record patient-reported quality of life and develop robust techniques to determine heart function using non-invasive imaging, facilitating the conduct of a large-scale clinical trial. The key objectives of the research programme are to define the optimal medications for patients with atrial fibrillation and identify the most valid, reproducible and cost-effective methods to examine patients. The ultimate aim of the project is to improve clinical outcomes in atrial fibrillation, benefiting patients, the National Health Service and the global community.


Condition or disease Intervention/treatment Phase
Permanent Atrial Fibrillation Drug: Bisoprolol Drug: Digoxin Phase 4

Detailed Description:

Atrial fibrillation (AF) is an increasingly common cardiac condition that leads to a substantial burden on quality-of-life (QoL), an increased risk of cardiovascular events, hospitalisation and death, and significant healthcare costs for the NHS. In addition to anti-coagulation and considerations for rhythm control therapy, most patients with AF are in need of pharmacological control of heart rate. This aspect of care has not received stringent investigation, with treatment guidelines based on small crossover studies and observational data rather than robust controlled trials. Beta-blocker monotherapy remains the first-line option in the current NICE AF guidelines consultation document, with digoxin only for sedentary patients, although this recommendation is based on 'very low-quality evidence'. The benefit of different rate-control therapies on symptoms and other intermediate outcomes (such as left-ventricular ejection fraction [LVEF] and diastolic function) are unknown, as are their effects on clinical events such as hospitalisation. This situation is unacceptable in light of the potential benefits and risk of different rate-control options in AF. It also limits our ability to personalise treatment according to patient characteristics.

The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial is informed by a number of in-depth systematic reviews of management and clinical outcomes in AF patients. Taken together, this information provides a sound basis to plan a major randomised controlled trial (RCT). However as trials of rate-control in AF have typically been small or uncontrolled, further information is needed before designing a trial that can assess clinical outcomes. The RATE-AF trial will allow us to define appropriate primary and secondary outcome measures and their standard deviation in a contemporary population of patients with permanent AF. This information will allow us to estimate sample size, determination of recruitment, retention and adherence policies, and to ascertain the best methods of obtaining adverse event data and reliable economic costs for a larger trial assessing cardiovascular outcomes and hospitalization. The RATE-AF trial will also be the largest RCT of its kind, allowing us to compare the effect of beta-blockers and digoxin on QoL as initial rate-control therapy in patients with permanent AF. The long-term aim of the research is to answer key questions about how to initiate therapy, stratified by relevant patient characteristics such as systolic and diastolic cardiac function, baseline symptoms and concurrent medication. The research will also define the patho-physiological mechanisms underlying AF-related symptoms, left-ventricular function and their association with adverse clinical outcomes, and to identify clinical markers for the response to different rate control therapy.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 161 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluating Different Rate Control Therapies in Permanent Atrial Fibrillation: A Prospective, Randomised, Open-label, Blinded Endpoint Feasibility Pilot Comparing Digoxin and Beta-blockers as Initial Rate Control Therapy
Actual Study Start Date : December 20, 2016
Actual Primary Completion Date : April 15, 2019
Actual Study Completion Date : September 16, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Beta-blocker
In Group B, oral bisoprolol will be commenced at either 1.25mg, 2.5mg or 5mg according to the treatment schedule and uptitrated, as required, to 15mg daily. Recommended additional therapy in this arm includes diltiazem. Use of digoxin is explicitly discouraged but will not terminate participation in the study. If intolerance to bisoprolol occurs, investigators will be advised to try an alternate beta-blocker of their choosing (typically carvedilol, nebivolol, or metoprolol) at equivalent dosage.
Drug: Bisoprolol
Drug intervention

Active Comparator: Digoxin
In Group A, the maintenance dose of oral digoxin will be either 62.5mcg or 125mcg according to the pre-defined treatment schedule and uptitrated, as required, to 250mcg daily. A single loading dose of four tablets (250 or 500mcg according to target maintenance dose) will be prescribed in digoxin-naïve participants, where necessary. Recommended additional therapy in this arm includes the calcium-channel blocker diltiazem. Use of beta-blockers is explicitly discouraged but will not terminate participation in the study.
Drug: Digoxin
Drug intervention




Primary Outcome Measures :
  1. Patient Reported Quality of Life (SF-36) [ Time Frame: Primary outcome at 6 months timepoint. ]

    Patient-reported outcomes as assessed by the SF-36 questionnaire physical component score.

    The physical component score ranges from 0-100 where higher value indicates better outcome.



Secondary Outcome Measures :
  1. Left Ventricular Ejection Fraction [ Time Frame: 12 months ]
    The above parameters will be measured using echocardiography and diastolic indices

  2. Diastolic Function- Measured by the E/e'. [ Time Frame: 12 months ]

    The above parameters will be measured using echocardiography and diastolic indices.

    E/e' - the ratio between early mitral inflow velocity and mitral annular early diastolic velocity.


  3. B-type Natriuretic Peptide (BNP) at 6 Months. [ Time Frame: 6 months ]
    B-type natriuretic peptide (BNP) at 6 months.

  4. Composite Functional Status Measures- 6 Minute Walking Distance at 12 Months. [ Time Frame: 12 months ]
    Composite functional status measures- 6 minute walking distance at 12 months.

  5. Patient Reported Outcomes- (AFEQT) at 12 Months. [ Time Frame: 12 months ]
    As assessed using the AFEQT overall score at 12 months. The range for AFEQT overall score is from 0= complete disability to 100=no disability.

  6. Patient Reported Outcomes (SF36) Version 2 at 12 Months. [ Time Frame: 12 months ]
    As assessed using the SF-36 version 2 global and specific scores at 12 months. All domains presented are between 0 to 100 scale where the higher score indicates better outcomes.

  7. Patient Reported Outcomes (EQ-5D-5L) [ Time Frame: 12 months ]

    As assessed using the EQ-5D-5L summary index questionnaires at both 6 and 12 months.

    The range for summary index is from -0.594=worst score to 1=best score


  8. Ambulatory Heart-rate. [ Time Frame: Within 12 months ]
    24 hour ambulatory heart-rate.


Other Outcome Measures:
  1. Cardiovascular Events [ Time Frame: 12 months ]
    Number of Participants with hospital admissions for cardiovascular events.

  2. Drug Discontinuation Rate [ Time Frame: 12 months ]
    the number and extent to which patients discontinue trial drugs

  3. Drug Discontinuation Rate Within 12 Months. [ Time Frame: 12 months ]
    Number of participants requiring drug discontinuation due to adverse reactions.

  4. Hospital Admission Rate [ Time Frame: 12 months ]
    A composite of adverse clinical events

  5. Retention of Participants [ Time Frame: 12 months ]
    Convenience, compliance and cross-over data

  6. Preferred Outcome Measures for This Cohort of Patients [ Time Frame: 12 months ]
    Establish which are the best measures for these patients

  7. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [ Time Frame: 12 months ]
    SF-36 physical function score at 6 and 12 months

  8. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [ Time Frame: 12 months ]
    SF-36 overall score at 6 and 12 months

  9. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [ Time Frame: 12 months ]
    AFEQT overall score at 6 and 12 months

  10. Population-specific Standard Deviations to Enable Sample Size Calculation for a Future Trial Powered to Detect a Difference in Hospital Admissions. [ Time Frame: 12 months ]
    LVEF and E/e scores at 6 and 12 months

  11. Number of Participants With Unplanned Hospital Admissions. [ Time Frame: During the 12 month follow-up period. ]
    Number of Participants with Unplanned Hospital Admissions.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult patients aged 60 years or older, able to provide informed written consent
  2. Permanent AF, characterised (at time of randomisation) as a physician decision for rate-control with no plans for cardioversion, anti-arrhythmic medication, or ablation therapy
  3. Symptoms of breathlessness (New York Heart Association Class II or more)
  4. Able to provide written, informed consent

Exclusion Criteria:

  1. Established indication for beta-blocker therapy, e.g. survived myocardial infarction in the last 6 months
  2. Known contraindications for therapy with beta-blockers or digoxin, e.g. a history of severe bronchospasm that would preclude use of beta-blockers, or known intolerance to these medications
  3. Baseline heart rate <60 bpm
  4. Known intolerance of beta-blockers or digoxin
  5. A history of severe bronchospasm (e.g. due to asthma) that would preclude use of beta-blockers
  6. Baseline heart rate <60 bpm
  7. History of second or third-degree heart block
  8. Supraventricular arrhythmias associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome) or a history of ventricular tachycardia or fibrillation
  9. Planned pacemaker implantation, pacemaker-dependent rhythm or history of atrioventricular node ablation
  10. Decompensated heart failure (evidenced by need for intravenous inotropes, vasodilators or diuretics) within 14 days prior to randomisation
  11. A current diagnosis of hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
  12. Received or on waiting list for heart transplantation
  13. Initiation of cardiac resynchronization therapy (with/without defibrillator) within 6 months prior to randomisation
  14. Intravenous infusions for heart failure (inotropes, vasodilators or diuretics) within 7 days prior to randomisation
  15. A current diagnosis of hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
  16. Received or on waiting list for heart transplantation
  17. Receiving renal replacement therapy
  18. Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation
  19. Severe, concomitant non-cardiovascular disease (including malignancy) that is expected to reduce life expectancy

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): NCT02391337


Locations
Layout table for location information
United Kingdom
City Hospital
Birmingham, West Midlands, United Kingdom
Queen Elizabeth Hospital
Birmingham, West Midlands, United Kingdom
Sponsors and Collaborators
University of Birmingham
Investigators
Layout table for investigator information
Principal Investigator: Dipak Kotecha, MBChB PhD MRCP University of Birmingham
  Study Documents (Full-Text)

Documents provided by University of Birmingham:
Study Protocol  [PDF] July 25, 2019
Statistical Analysis Plan  [PDF] December 17, 2019

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT02391337    
Other Study ID Numbers: UBCCS_RATEAF
First Posted: March 18, 2015    Key Record Dates
Results First Posted: June 16, 2021
Last Update Posted: June 18, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Birmingham:
Atrial fibrillation
Quality of life
Left ventricular ejection fraction
Diastolic function
Echocardiography
Beta-blockers
Digoxin
Additional relevant MeSH terms:
Layout table for MeSH terms
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Digoxin
Bisoprolol
Anti-Arrhythmia Agents
Cardiotonic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents