What is CHANGE AFib?
CHANGE AFib is a pragmatic randomized clinical trial investigating whether the early use of dronedarone can improve outcomes in patients with first-detected atrial fibrillation (AFib).
Who is conducting the trial?
CHANGE AFib is a collaboration between the American Heart Association and the Duke Clinical Research Institute with support from Sanofi US.
Why is this trial important?
Although several clinical trials have addressed the optimal treatment strategy for patients with symptomatic and recurrent AFib, we do not yet have support on the best early treatment plan for those who have just been diagnosed. CHANGE AFib seeks to fill this gap in evidence and determine whether we can better deliver early treatment to help improve long-term outcomes in patients with first-detected AFib.
What treatment is being used?
Eligible, first-detected AFib patients, who provide informed consent to participate, will be randomly assigned to one of two different groups. One group of participants will receive the study intervention – dronedarone – in addition to usual care. The second group will receive usual care alone – medicines that they would receive as part of their usual care (as decided by the care team) per routine clinical practice.
The trial is not blinded. This means that both the participants and the study team know to which group the patient has been assigned.
How does a pragmatic clinical trial differ from an explanatory clinical trial?
Pragmatic clinical trials are designed to test the effectiveness of interventions in real-world practice conditions. Explanatory clinical trials test whether an intervention works under ideal situations. The intention of pragmatic clinical trials is to analyze results that can be applied to generalized settings.
Why is the trial using Dronedarone?
Dronedarone is a rhythm control medicine (antiarrhythmic drug) and has been approved by the U.S. Food and Drug Administration (FDA) in certain patients with atrial fibrillation since 2009. In addition, dronedarone:
- is well-tolerated
- is effective in preventing recurrent AFib
- has been shown to reduce cardiovascular hospitalization
- is safe
- post-hoc analyses suggest it performs well in persons with early AFib
What is considered first-detected atrial fibrillation?
First-detected AFib is defined as atrial fibrillation diagnosed in the previous 60 days. Patients will be enrolled in CHANGE AFib during the time they first present at the hospital for AFib.
What is usual care?
Usual care is defined as best-practice, guideline-directed therapy of AFib, including but not limited to (a) stroke prevention therapy, (b) rate-control, and (c) treatment of risk factors. More specifically, oral anticoagulation in those men with a CHA2DS-2VASc score of 2 or greater or women with a CHA2DS-2VASc score of 3 or greater, rate control, and treatment of concomitant cardiovascular conditions (e.g., coronary artery disease or heart failure).
What is CHANGE AFIB trying to accomplish in light of the findings from EAST?
EAST was a landmark and critically important clinical trial that demonstrated the long-term value of rhythm control (predominantly with antiarrhythmic drug therapy). Alongside EAST, there have also been a fair number of trials focused on catheter ablation as first-line therapy for atrial fibrillation. However, none of these trials focused exclusively on patients with first-detected AF, which accounts for 1 out of 5 hospital admissions for atrial fibrillation in US hospitals. These patients often get prescribed oral anticoagulation and an AV nodal blocker and then go on to have several recurrences before they are referred to a cardiovascular specialist or EP or are offered rhythm control. At present, there are no guideline recommendations for rhythm control in patients with first-detected AF.
The goal of CHANGE AFIB is to determine if up-front rhythm control with a well-tolerated antiarrhythmic medication in patients with a first diagnosis of AF can reduce CV hospitalization or death. One might ask why not randomize to ablation or some other form of rhythm control. It would be unlikely for someone with a first occurrence/diagnosis of AF to immediately undergo ablation. However, if rhythm control therapy is initiated with antiarrhythmic drug therapy up front and they continue to have AF despite medical therapy, then they might be referred earlier for other forms of rhythm control. Thus, the hypothesis is that up-front initiation of rhythm control with dronedarone, will reduce CV events in persons with first-detected AF. We believe that this question is relevant even in practices where catheter ablation is considered after symptomatic recurrences. Said another way, we also think that up-front rhythm control will have benefits even in patients who might otherwise have received rhythm control at 3, 6, or 12 months following their first diagnosis.
Finally, in reference back to EAST, if CHANGE AFIB demonstrates improved CV outcomes, there would be two randomized trials demonstrating benefit to early initiation of rhythm control and this would likely lead to a change in the guidelines with stronger advocacy for early initiation of rhythm control.
Is there someone I can contact if I have questions about CHANGE AFib?
What are the requirements for a hospital to participate in the trial?
- Hospitals must participate in the American Heart Association’s Get With The Guidelines® – AFib (GWTG-AFib) Registry
- Hospitals must be research-ready (e.g., have processes and systems for obtaining IRB approval)
- If your hospital is not part of GWTG-AFib and would like to learn more about joining, email email@example.com.
How many hospitals and patients can be a part of the trial?
The trial is targeting 200 U.S. based hospitals to enroll 3,000 patients.
How are data collected for the trial?
Data are collected in the American Heart Association’s Get With The Guidelines® – AFib (GWTG-AFib) Registry.
Will hospitals participating in the trial receive help and support for the duration of the trial?
Yes, a Program Director and Trial Program Manager will actively support all participating hospitals and will be available to address any trial-related questions. Once a site is signed up for the trial, the site can expect in depth training on trial protocols, patient selection, and data entry as well as ongoing support throughout the trial.
My hospital already participates in GWTG-AFib and submits data to the registry; will we have to collect and abstract additional data to participate in the trial?
There will be a minimal amount of additional data collection for the hospitalization episode. You will also collect data at two follow-up points:
- A mid-way time point, approximately 6 months post discharge
- An end-of-study time point at 12 months post discharge
How can a site sign up for CHANGE AFib and how does contracting work?
Sites will complete a Unified Participation Agreement (UPA), the official contract between the American Heart Association and the Participating Site, that allows the site to enroll and have access to AHA’s Get With The Guidelines on the registry platform. Sites already participating in GWTG-AFib with a UPA in place do not need to sign the UPA. Sites enrolled in a GWTG module other than AFib will sign an amendment to their existing UPA.
All sites will need to also sign the individual Participating Site Agreement which complements the UPA and outlines what the Participating Site is responsible for during the CHANGE AFib trial. The Site Agreement details what the CHANGE AFib trial will cover and formally outlines each parties understanding and responsibilities for conducting the trial. A Participating Site is required to sign both the UPA and the Site Agreement in order to participate in the CHANGE AFib trial.
Is IRB oversight necessary?
Does my site need to establish our own IRB?
Some sites participating in CHANGE-AFib may already have their own IRBs to oversee research conducted within the institution or by staff of the institution. Your site may use your own IRB to participate.
For those sites without an IRB, FDA regulations permit an institution without an IRB to arrange for an “outside” IRB to be responsible for initial and continuing review of studies conducted at a non-IRB institution. A central IRB has been established for CHANGE-AFib; AHA and DCRI staff can help a site navigate the process.
Patient Enrollment and Follow Up
Why does the trial exclude persons <60 years of age?
There are two primary reasons for excluding younger patients. First, patients under 60 years of age comprise a small percentage of the GWTG-AFIB population. Second, due to the question of interest in CHANGE AFIB, the study population must be at sufficient risk for cardiovascular events. While patients younger than 60 years of age do occasionally present with AF, they are usually not hospitalized and they have much lower cardiovascular event rates.
What are the patient eligibility inclusion and exclusion criteria?
Participants are eligible to be included in the trial if ALL the following apply:
- Age 60 years or older
- First-detected AFib (defined as AFib diagnosed in the previous 60 days)
- Electrocardiographic documentation of atrial fibrillation
- Estimated life expectancy of at least 1 year
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) of the trial protocol
Participants are excluded from the trial if ANY of the following criteria apply:
- Prior or planned treatment with rhythm control, either catheter ablation or antiarrhythmic drug therapy
- Prior hospitalization for AFib
- Planned cardiothoracic surgery
- New York Heart Association class III or IV heart failure or a hospitalization for heart failure in the last 4 weeks
- Reduced ejection fraction (LVEF ≤40%)
- Permanent atrial fibrillation
- Ineligible for oral anticoagulation, unless CHA2DS2-VASc is less than 3, in women, or 2, in men.
- Bradycardia with a resting heart rate < 50 bpm
- PR interval >280 msec or 2nd degree or 3rd degree atrioventricular block without a permanent pacemaker/cardiac implanted electronic device
- Corrected QT interval ³500 msec
- Severe hepatic impairment
Why are patients being enrolled early with the condition?
There are no randomized clinical trials that address first-detected AFib treatment. Patients are often started on an atrioventricular nodal blocking agent (beta-blocker or non-dihydropyridine calcium channel blocker). The trial is investigating if earlier administration of a well-tolerated antiarrhythmic drug, shown to reduce hospitalization, may result in improved cardiovascular outcomes and quality of life in patients.
How long is the enrollment period?
Patients may be enrolled through Summer 2023.
Can we enroll patients on an outpatient basis?
Get With The Guidelines – Atrial Fibrillation is an inpatient registry, however, outpatient enrollment is not prohibited. If you encounter a person who meets the inclusion and exclusion criteria and has recently been diagnosed with atrial fibrillation in the past 60 days, then they can be enrolled and randomized from clinic or the outpatient setting. If this occurs, there are several important things to keep in mind.
- The redcap database will need to be completed to allow randomization and treatment assignment.
- Their baseline case report form needs to be filled out completely with information from their hospitalization.
- As stated in the protocol, participants must have a new diagnosis within 60 days of randomization as defined in the protocol.
- If a participant is randomized to the intervention (dronedarone) arm they must be contacted within 10 days of the randomization/discharge to confirm that they started their dronedarone prescription.
Does a patient have to be admitted to the hospital to be eligible for CHANGE AFib?
In order to be eligible for CHANGE AFIB, a patient must have had an acute care encounter at the hospital for atrial fibrillation. For eligibility, this is defined as an acute care encounter and discharge from the emergency room, observation unit, or an inpatient admission.
At what point is a Cardioversion allowed after randomization in both the treatment and Usual Care arms?
A cardioversion is allowed at any time during the conduct of the trial (in either arm).
What follow-up is required of enrolled patients?
There are two pre-specified follow-up encounters.
- The first occurs approximately 6 months after randomization (with an eligibility window between 3 and 9 months). This encounter can be either in-person or through virtual assessment. At the 6-month visit, the 6-month follow-up form is completed in the GWTG-AFib registry.
- The second is the final follow-up encounter and occurs 12-months post randomization. Similar to the 6-month encounter, the final visit can be conducted either in-person or through virtual assessment. At the 12-month encounter, the 12-month follow-up form is completed in the GWTG-AFib registry. Patients who withdraw early or experience mortality will also have the final follow-up form completed.
I am a patient recently diagnosed with AFib and want to learn more about my diagnosis. Where can I find this information?
The American Heart Association (AHA) is a great resource for information on AFib. Go to the AHA website to learn about AFib and why it matters. You will also find a variety of tools for you and those helping you manage your health.
How long will patients participate in the trial?
Patients will take part in the trial for approximately 12 months. There will be two follow-up visits. The first will take place between 3- and 9-months after participant enrollment, and the second will take place approximately 12-months after enrollment. These follow-up visits can be performed either virtually or in-person.
Are there any patient benefits for participation?
Patients will not receive direct benefit from taking part in this trial. They, or their insurance, will need to pay for their own dronedarone. The main reason for joining is to help researchers learn about treating patients with newly diagnosed AFib. The results may benefit patients in the future.
What happens if a patient in the intervention group stops taking dronedarone?
Dronedarone is required for patients randomized to the intervention group of the trial. If a patient decides to stop taking dronedarone they will be withdrawn from the trial and no additional data will be collected from them.
Can a patient choose to withdraw from the trial after being enrolled?
Participation in this trial is completely voluntary. We do ask that patients only enroll if they plan to commit to the trial requirements and duration. This commitment will ensure the trial results are as complete as possible. However, it is understood that circumstances can shift and participants may change their mind about participating at any time. Patients choosing to stop participating must let the trial team know in writing. Once this is complete, they will not need to go to any follow-up visits, nor will any additional information be collected.
Can a participant choose which treatment group they wish to be assigned to?
No, all treatment assignments are assigned at random by a computer (i.e., similar to flipping a coin). A patient will have a 50% chance of being assigned to the treatment group and a 50% chance of receiving usual care alone. Neither the participant, nor provider can control which treatment a participant receives.
What are the safety considerations and most common adverse reactions observed with dronedarone?
Dronedarone is subject to a boxed warning regarding increased risk of death, stroke, and heart failure in patients with decompensated heart failure or permanent atrial fibrillation. Please see the label insert for the complete boxed warning. The most common adverse reactions observed with dronedarone were diarrhea, nausea, abdominal pain, vomiting, and weakness or lack of energy. Rare but serious side effects may occur. A detailed list can be found on the label insert.
Insurance approval for Dronedarone may take time. How should insurance delays be handled?
Electronic medical record systems may identify medications approved by insurance. If it is unclear at the time of discharge, dronedarone can be prescribed as soon as possible after discharge.
Participants in the intervention arm will need to be contacted after discharge to confirm that they filled their dronedarone prescription. This will help to identify any issues participants may be having in getting their prescriptions filled. Assistance programs are available for patients with financial difficulties.
Is the expectation that the site Principal Investigator (PI) prescribe dronedarone for the entire 12 months?
The PI does not need to be the physician prescribing dronedarone; however, the PI does need to assume responsibility for the patient, their participation, and the following of the protocol. In the case of dronedarone, this will include oversight to ensure patients are taking the medication as prescribed after discharge and educating any other providers that are working with the patient. The PI may delegate this monitoring to another member of the trial team.
Are there specific labs that need to be drawn, or tests that need to be done on patients in the dronedarone arm during the follow up period?
No, the protocol does not mandate phlebotomy or lab draws beyond those conducted for usual clinical care.
The protocol states, in section 7.3, that loss to follow up needs to be documented. Where should this information be recorded?
Contact attempts should be documented in the participant’s medical record; however, if a site prefers to record this information within the CHANGE AFib follow-up form only, that is acceptable.
Do candidates for CHANGE AFib need to have paroxysmal AFib? Are patients with persistent AFib excluded?
Patients with both paroxysmal and persistent AFib are eligible.
Do patients need to be symptomatic to be eligible for CHANGE AFib?
No, patients do not need to be symptomatic. Eligible patients do need to have first-detected AFib, defined as AFib diagnosed within the previous 60 days.
What is the timeframe for bradycardia, PR interval, and corrected QT interval exclusions?
Providers should evaluate the patient’s most recent ECG(s). These will likely be from the hospital admission.
What if a patient only has a single instance of bradycardia? Should the patient be excluded from the trial?
For a single episode of bradycardia, the site Principal Investigator’s judgment can be used. If there is a transient bradycardia that was reversible, then that would not necessarily exclude patient screening and enrollment if otherwise eligible.
How should patients with a contingency plan for ablation be handled?
Patients with planned ablation at the time of enrollment, or those patients where ablation is highly anticipated are NOT candidates for CHANGE AFib. Recurrent AFib requiring escalation of rhythm control (including ablation) is expected. Patients in the dronedarone arm may continue dronedarone after AFib ablation.