Atrial Fibrillation, Atrial Flutter, Embolism, Systemic Arterial, Major Bleeding, Stroke
Conditions
Keywords
Implanted Cardioverter Defibrillator, Cardiac Resynchronization Therapy Defibrillator, Home Monitoring, Oral Anticoagulation
Brief summary
The IMPACT Study will investigate the potential clinical benefit of the combined use of BIOTRONIK Home Monitoring (HM) technology and a predefined anticoagulation plan compared to conventional device evaluation and physician-directed anticoagulation in patients with implanted dual-chamber defibrillators or cardiac resynchronization therapy devices.
Detailed description
Atrial fibrillation (AF) and atrial flutter (AFL) are common cardiac arrhythmias associated with an increased incidence of stroke in patients with additional risk factors. Oral Anticoagulation (OAC) reduces stroke risk, but because these arrhythmias are frequently intermittent and asymptomatic, start of OAC therapy is often delayed until electrocardiographic documentation is obtained. Technological advances in implanted dual-chamber cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices allow early detection and real time verification of AF/AFL with intracardiac electrograms (IEGM) automatically transmitted to the clinicians. Such remote diagnostic capability might be particularly relevant in patients with asymptomatic AF by allowing timely treatment. Compared to conventional periodic, (e.g., quarterly) office device evaluation, daily remote monitoring may prove superior for diagnosis of AF and prophylactic treatment of thromboembolism. The start, stop and restart of OAC based on a predefined atrial rhythm-guided strategy in conjunction with a standard risk-stratification scheme could lead to better clinical outcomes compared with conventional clinical care. The study is designed to demonstrate a risk reduction of both thromboembolism proximate to episodes of documented AF/AFL and bleeding potentiated by chronic OAC in the absence of AF. Verification of this premise would impact the clinical practice, providing evidence to physicians for the use of HM to guide OAC in patients with AF/AFL. The results of this study should demonstrate the clinical value of wireless remote surveillance of the cardiac rhythm and may define the critical threshold of AF/AFL burden warranting OAC or antiarrhythmic drug therapy in patients at risk of stroke
Interventions
DRUGHome Monitoring Guided OAC
Active monitoring for atrial episodes through the automatic HM notifications (email, fax, short message service) is required. If the total duration over 48 consecutive hours reaches the predefined anticoagulation condition, and AF/AFL diagnosis is confirmed using the IEGM online, the site instructs the patient by telephone to start OAC. Clinicians continue to monitor patients using HM, and if freedom from AF/AFL reaches the predefined interval, stop of OAC therapy is requested over the telephone. Following stop of anticoagulation, any recurrence of AF/AFL requires restart of OAC therapy. OAC drugs used: Dabigatran etexilate, Rivaroxaban, Warfarin, other approved VKA
DRUGPhysician-Directed OAC
Patients will receive physician-directed anticoagulation therapy based on conventional criteria. OAC drugs used: Dabigatran etexilate, Rivaroxaban, Warfarin, other approved VKA
Sponsors
Biotronik, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Candidates for implantation of, or already implanted with, a BIOTRONIK Lumax HF-T or DR-T device * Documented P wave mean amplitude ≥ 1.0 mV (sinus rhythm) or ≥ 0.5 mV (AF) at enrollment, if previously implanted * CHADS2 risk score ≥ 1 * Able and willing to follow OAC therapy if the indication develops during the course of the trial * Able to utilize the HM throughout the study Key
Exclusion criteria
* Permanent AF * History of stroke, transient ischemic attack (TIA) or systemic embolism and documented AF or AFL * Currently requiring OAC therapy for any indication * Patients who underwent successful AF ablation (sinus rhythm restored) and have not completed a minimum of 3 months of OAC therapy * Known, current contraindication to use of eligible OAC * Long QT or Brugada syndrome as the sole indication for device implantation * Life expectancy less than the expected term of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | From date of enrollment until date of primary endpoint event, assessed up to study exit, with a mean treatment duration of 2.0 years | The primary endpoint is to demonstrate whether early detection of atrial arrhythmias based on BIOTRONIK Home Monitoring technology combined with a predefined anticoagulation plan in the Home Monitoring Guided OAC group is superior to the Physician-Directed OAC group reflecting conventional care and physician directed treatment of AF in terms of risk reduction of the primary composite endpoint including stroke, systemic embolism, and major bleeding events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Ischemic and Hemorrhagic Stroke | Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years | — |
| Rate of Fatal or Disabling and Non-disabling Stroke | Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years | — |
| Rate of Major Bleeding Events | Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years | — |
| Rates of All-cause Mortality | Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years | — |
| Rate of Cardioembolic and Non-cardioembolic Stroke | Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years | — |
| Change in Quality of Life Score | 1 year | Quality of Life was evaluated using the SF-36 v2 Health Survey. The SF-36 consists of eight scaled scores which correspond to the following sections: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. Responses are recoded per a scoring key with each question having a value from 0 to 100. Scores from items in the same scale are averaged together per the scoring key to create the section and subsection (physical health and mental health) scores. For all reported scores, the lowest possible value is 0 (representing the highest disability) and the highest possible value is 100 (representing no disability). Therefore, a positive change from baseline to 1 year represents an improvement in disability, while a negative change represents a worsening of disability. |
| Mean Ventricular Heart Rate Reduction | 1 year | — |
| Mean Atrial Fibrillation/Atrial Flutter Burden | Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years | — |
Countries
Australia, Canada, Denmark, Germany, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Home Monitoring Guided OAC Home Monitoring is fully enabled and continuous remote surveillance data is available to investigators. Patients will be treated according to a predefined anticoagulation plan, which uses the total duration of AF/AFL combined with patients' CHADS2 score to determine the start, stop, and restart of oral anticoagulation therapy. | 1,357 |
| Physician-Directed OAC In Control (Group 2), Home Monitoring is active for Safety Net alerts, but the remote AF/AFL data is not revealed to the patient or treating physician. These patients receive physician-directed oral anticoagulation therapy consistent with current standards of care. | 1,361 |
| Total | 2,718 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 147 | 140 |
| Overall Study | ICD device explanted | 10 | 17 |
| Overall Study | Lost to Follow-up | 42 | 56 |
| Overall Study | Withdrawal by Subject | 152 | 139 |
Baseline characteristics
| Characteristic | Home Monitoring Guided OAC | Physician-Directed OAC | Total |
|---|---|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 10.8 | 64.2 years STANDARD_DEVIATION 11.5 | 64.4 years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 347 Participants | 368 Participants | 715 Participants |
| Sex: Female, Male Male | 1010 Participants | 993 Participants | 2003 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 135 / 1,357 | 139 / 1,361 |
| serious Total, serious adverse events | 372 / 1,357 | 374 / 1,361 |
Outcome results
Primary
Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed
The primary endpoint is to demonstrate whether early detection of atrial arrhythmias based on BIOTRONIK Home Monitoring technology combined with a predefined anticoagulation plan in the Home Monitoring Guided OAC group is superior to the Physician-Directed OAC group reflecting conventional care and physician directed treatment of AF in terms of risk reduction of the primary composite endpoint including stroke, systemic embolism, and major bleeding events.
Time frame: From date of enrollment until date of primary endpoint event, assessed up to study exit, with a mean treatment duration of 2.0 years
Population: Intent to treat analysis of all enrolled subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Home Monitoring Guided OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 2 Years | 94.8 percentage of participants-Kaplan Meier |
| Home Monitoring Guided OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 4 Years | 90.0 percentage of participants-Kaplan Meier |
| Home Monitoring Guided OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 3 Years | 92.3 percentage of participants-Kaplan Meier |
| Home Monitoring Guided OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 5 Years | 86.8 percentage of participants-Kaplan Meier |
| Home Monitoring Guided OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 1 Year | 97.5 percentage of participants-Kaplan Meier |
| Physician-Directed OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 5 Years | 87.9 percentage of participants-Kaplan Meier |
| Physician-Directed OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 1 Year | 97.7 percentage of participants-Kaplan Meier |
| Physician-Directed OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 2 Years | 95.7 percentage of participants-Kaplan Meier |
| Physician-Directed OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 3 Years | 92.0 percentage of participants-Kaplan Meier |
| Physician-Directed OAC | Composite Primary Endpoint: Kaplan-Meier Estimate of Patients Without a Stroke, Systemic Embolism, or Major Bleed | Kaplan-Meier estimate at 4 Years | 89.4 percentage of participants-Kaplan Meier |
p-value: 0.73295% CI: [0.75, 1.51]Regression, Cox
Secondary
Change in Quality of Life Score
Quality of Life was evaluated using the SF-36 v2 Health Survey. The SF-36 consists of eight scaled scores which correspond to the following sections: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health. Responses are recoded per a scoring key with each question having a value from 0 to 100. Scores from items in the same scale are averaged together per the scoring key to create the section and subsection (physical health and mental health) scores. For all reported scores, the lowest possible value is 0 (representing the highest disability) and the highest possible value is 100 (representing no disability). Therefore, a positive change from baseline to 1 year represents an improvement in disability, while a negative change represents a worsening of disability.
Time frame: 1 year
Population: Subjects with paired baseline and 1 year Quality of Life scores
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Home Monitoring Guided OAC | Change in Quality of Life Score | Physical health summary | 1.3 Scores on a scale | Standard Deviation 8.8 |
| Home Monitoring Guided OAC | Change in Quality of Life Score | Mental health summary | 1.9 Scores on a scale | Standard Deviation 11 |
| Physician-Directed OAC | Change in Quality of Life Score | Physical health summary | 0.9 Scores on a scale | Standard Deviation 8.8 |
| Physician-Directed OAC | Change in Quality of Life Score | Mental health summary | 1.6 Scores on a scale | Standard Deviation 11.2 |
Secondary
Mean Atrial Fibrillation/Atrial Flutter Burden
Time frame: Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Home Monitoring Guided OAC | Mean Atrial Fibrillation/Atrial Flutter Burden | 1.3 percent daily burden | Standard Deviation 8.2 |
| Physician-Directed OAC | Mean Atrial Fibrillation/Atrial Flutter Burden | 1.2 percent daily burden | Standard Deviation 7.4 |
Secondary
Mean Ventricular Heart Rate Reduction
Time frame: 1 year
Population: Subjects with baseline and 1 year ventricular rate information
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Home Monitoring Guided OAC | Mean Ventricular Heart Rate Reduction | 0.07 beats per minute | Standard Deviation 6.31 |
| Physician-Directed OAC | Mean Ventricular Heart Rate Reduction | -0.34 beats per minute | Standard Deviation 5.9 |
Secondary
Rate of Cardioembolic and Non-cardioembolic Stroke
Time frame: Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Home Monitoring Guided OAC | Rate of Cardioembolic and Non-cardioembolic Stroke | Cardiogenic embolism | 9 Participants |
| Home Monitoring Guided OAC | Rate of Cardioembolic and Non-cardioembolic Stroke | Non-cardiogenic | 5 Participants |
| Physician-Directed OAC | Rate of Cardioembolic and Non-cardioembolic Stroke | Cardiogenic embolism | 7 Participants |
| Physician-Directed OAC | Rate of Cardioembolic and Non-cardioembolic Stroke | Non-cardiogenic | 8 Participants |
Secondary
Rate of Fatal or Disabling and Non-disabling Stroke
Time frame: Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Home Monitoring Guided OAC | Rate of Fatal or Disabling and Non-disabling Stroke | Fatal or disabling stroke | 9 Participants |
| Home Monitoring Guided OAC | Rate of Fatal or Disabling and Non-disabling Stroke | Non-disabling stroke | 15 Participants |
| Physician-Directed OAC | Rate of Fatal or Disabling and Non-disabling Stroke | Fatal or disabling stroke | 11 Participants |
| Physician-Directed OAC | Rate of Fatal or Disabling and Non-disabling Stroke | Non-disabling stroke | 19 Participants |
Secondary
Rate of Ischemic and Hemorrhagic Stroke
Time frame: Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Home Monitoring Guided OAC | Rate of Ischemic and Hemorrhagic Stroke | Ischemic stroke | 22 Participants |
| Home Monitoring Guided OAC | Rate of Ischemic and Hemorrhagic Stroke | Hemorrhagic stroke | 3 Participants |
| Physician-Directed OAC | Rate of Ischemic and Hemorrhagic Stroke | Ischemic stroke | 28 Participants |
| Physician-Directed OAC | Rate of Ischemic and Hemorrhagic Stroke | Hemorrhagic stroke | 3 Participants |
Secondary
Rate of Major Bleeding Events
Time frame: Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Home Monitoring Guided OAC | Rate of Major Bleeding Events | 46 Participants |
| Physician-Directed OAC | Rate of Major Bleeding Events | 34 Participants |
Secondary
Rates of All-cause Mortality
Time frame: Study duration from date of enrollment to date of study exit, with mean implant duration of 2.0 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Home Monitoring Guided OAC | Rates of All-cause Mortality | 147 Participants |
| Physician-Directed OAC | Rates of All-cause Mortality | 140 Participants |