Bradycardia
Conditions
Keywords
Bradycardia, Sinus Node Dysfunction, Chronotropic incompetence, Pacemaker, Rate adaptive
Brief summary
This is a randomized, prospective, single-blinded, multi-center study involving approximately 1500 patients at 100 centers. The purpose of this study is to demonstrate the effectiveness of Closed Loop Stimulation (CLS) rate adaption technology over both standard rate responsive technology (R) and non-rate responsive mode (DDD) during activities of daily living (ADL).
Detailed description
All patients enrolled in the CLEAR study are implanted with a Cylos pacemaker with Closed Loop Stimulation (CLS) rate adaption technology. Any legally marketed pacing leads may be implanted with the Cylos family of pacemakers. Prior to enrollment, patients provide written informed consent and are screened to ensure they are eligible to participate in the study. Patients enrolled in the study must have been implanted within 45 days prior to enrollment or are being considered for implant. Once enrolled and implanted with the Cylos pacemaker, the first 500 patients have 45 days to complete an ADL Testing visit. At the Activities of Daily Living (ADL) testing visit, each of the first 500 enrolled patients performs a 6-minute walk test, orthostatic test, and sweep test in three pacing modes, CLS (DDD-CLS or VVI-CLS), standard rate response (DDDR or VVIR) and non-rate responsive mode (DDD or VVI). The order of the pacing modes for testing is randomized in a 1:1:1 ratio. The study primarily analyzes the number of ADL repetitions performed during the 6-minute walk and sweep tests, pulse pressure during the orthostatic test, and secondarily analyzes heart rates during all three tests to compare CLS to both rate responsive and non-rate responsive pacing modes. For all enrolled patients, the study collects additional data over a 12-month period. Patients are randomized and their pacemaker programmed to one of three pacing modes, CLS, R, or no-rate response in a 2:1:1 ratio, respectively. The patients are then followed for a period of 12 months after the ADL testing (first 500 enrolled patients) or enrollment (patients 501 through 1500). The study collects the following secondary measures to compare CLS to both rate responsive and non-rate responsive pacing modes: changes in 6-minute walk test distance, quality of life, mode reprogramming, atrial fibrillation (AF) burden, cardiac symptoms, and New York Heart Association (NYHA) classification.
Interventions
Comparison of different pacing modes available on the Cylos pacemaker device. In this intervention group, subjects were programmed to the Closed Loop Stimulation (DDD-CLS or VVI-CLS) pacing mode for the long-term follow-up portion of this study.
DEVICEStandard Rate Adaptive (R) Technology
Comparison of different pacing modes available on the Cylos pacemaker device. In this intervention group, subjects were programmed to the standard are adaptive pacing mode (DDDR or VVIR) for the long-term follow-up portion of this study.
DEVICENon-rate adaptive (DDD) pacing
Comparison of different pacing modes available on the Cylos pacemaker device. In this intervention group, subjects were programmed to the non-rate adaptive pacing mode (DDD or VVI) for the long-term follow-up portion of this study.
Sponsors
Biotronik, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Implanted within the last 45 days or being considered for implant with a BIOTRONIK pacemaker utilizing CLS rate adaptation technology (currently the Cylos family of pacemakers). * Ability to give written informed consent * Geographically stable and able to return for regular follow-ups for 12 months after ADL testing * At least 18 years old
Exclusion criteria
* Patients physically limited and unable to perform all or parts of the ADL testing * Currently enrolled in any other clinical study * Patients with medical reasons that preclude regular participation in the follow-ups
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Performance of Activities of Daily Living Tests (6-minute Walk and Sweep) | within 45 days of enrollment | Six-minute walk test and sweep test results for subjects completing tests in all three pacing modes and requiring at least 80% pacing during both tests in the CLS and R pacing modes. The mean composite of repetitions (six minute walk plus sweep) are presented. |
| Pulse Pressure During Activities of Daily Living Tests (Orthostatic Test) | within 45 days of enrollment | Patients completing the orthostatic test in all three pacing modes and that had at least 80% pacing during the test in the CLS and R pacing modes are included in the analysis. The mean pulse pressure is provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Atrial Fibrillation (AF) Burden | 12 months | AF burden was measured at 12 months as the percentage of total atrial beats that are at or above 160 bpm. |
| Cardiac Symptoms | 12 months | Number of subjects exhibiting each cardiac symptom was determined at the 12 month follow-up visit. |
| Mode Reprogramming | 12 months | Number of subjects with device reprogramming from dual (atrial and ventricular pacing) to single chamber (ventricular pacing only) or from single (ventricular pacing only) to dual chamber (atrial and ventricular pacing) during the 12 month follow-up. |
| Change in 6-minute Walk Test Distance | baseline and 12 months | Change in number of 10 foot repetitions between baseline and 12-month visit were examined. |
| Change in New York Heart Association (NYHA) Class | baseline and 12 months | Number of subjects with improved, no change, or worsened NYHA classification at the 12-month visit, as compared to baseline. NYHA classifications (I to IV) are used to assess the various stages of heart failure, with Class I relating to mild heart failure and Class IV relating to severe heart failure. |
| Change in Quality of Life | baseline and 12 months | Change in Quality of life (QOL) score was determined from baseline to the 12 month follow-up visit. The QOL utilized the physical functioning scale of the SF-36 v2, in which a higher score indicates a better health perception. Best possible score was 57.03 while the worst possible score was 14.94. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CLS Rate Adaptive Pacing Pacemaker programmed with Closed Loop Stimulation (CLS) rate adaptive technology for long-term study follow-up. | 741 |
| Standard Rate Adaptive Pacing Pacemaker programmed with standard rate adaptive technology (R, accelerometer) for long-term study follow-up. | 369 |
| No Rate Adaptive Pacing Pacemaker programmed with no rate adaption (DDD) for long-term study follow-up. | 381 |
| Total | 1,491 |
Baseline characteristics
| Characteristic | CLS Rate Adaptive Pacing | Standard Rate Adaptive Pacing | No Rate Adaptive Pacing | Total |
|---|---|---|---|---|
| Age Continuous | 73.5 years STANDARD_DEVIATION 11.7 | 72.5 years STANDARD_DEVIATION 12 | 72.7 years STANDARD_DEVIATION 12.4 | 73.1 years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 308 Participants | 178 Participants | 190 Participants | 676 Participants |
| Sex: Female, Male Male | 433 Participants | 191 Participants | 191 Participants | 815 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 44 / 741 | 23 / 369 | 19 / 381 |
| serious Total, serious adverse events | 0 / 741 | 0 / 369 | 0 / 381 |
Outcome results
Primary
Performance of Activities of Daily Living Tests (6-minute Walk and Sweep)
Six-minute walk test and sweep test results for subjects completing tests in all three pacing modes and requiring at least 80% pacing during both tests in the CLS and R pacing modes. The mean composite of repetitions (six minute walk plus sweep) are presented.
Time frame: within 45 days of enrollment
Population: Patients requiring at least 80% pacing during both tests in the CLS and accelerometer pacing modes are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Performance of Activities of Daily Living Tests (6-minute Walk and Sweep) | 19.28 repetitions | Standard Deviation 9.7 |
| Standard Rate Adaptive Pacing | Performance of Activities of Daily Living Tests (6-minute Walk and Sweep) | 18.09 repetitions | Standard Deviation 9.36 |
| No Rate Adaptive Pacing | Performance of Activities of Daily Living Tests (6-minute Walk and Sweep) | 18.05 repetitions | Standard Deviation 9.86 |
Comparison: The endpoint will compare the composite percent change in ADL performance for patients while their devices are programmed to CLS and accelerometer pacing modes, using the no rate adaptive pacing mode as the baseline. Null hypothesis: mean composite of percent change for patients with their device programmed to CLS is less than or equal to the mean composite of percent change for the same patients with their device in accelerometer.p-value: 0.00495% CI: [3.24, 15.11]t-test, 2 sided
Primary
Pulse Pressure During Activities of Daily Living Tests (Orthostatic Test)
Patients completing the orthostatic test in all three pacing modes and that had at least 80% pacing during the test in the CLS and R pacing modes are included in the analysis. The mean pulse pressure is provided.
Time frame: within 45 days of enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Pulse Pressure During Activities of Daily Living Tests (Orthostatic Test) | 48.13 mmHg | Standard Deviation 12.35 |
| Standard Rate Adaptive Pacing | Pulse Pressure During Activities of Daily Living Tests (Orthostatic Test) | 50.00 mmHg | Standard Deviation 14.4 |
| No Rate Adaptive Pacing | Pulse Pressure During Activities of Daily Living Tests (Orthostatic Test) | 50.54 mmHg | Standard Deviation 15.23 |
Comparison: The purpose of endpoint was to evaluate the percent change in pulse pressure during test. The null hypothesis was the mean percent change for patients with their device programmed to CLS is greater or equal to the mean percent change for the same patients with their device in accelerometer.p-value: 0.55295% CI: [-6.17, 3.33]t-test, 2 sided
Comparison: The purpose of endpoint was to evaluate the percent change in pulse pressure during test. The null hypothesis was the mean percent change for patients with their device programmed to CLS is greater or equal to the mean percent change for the same patients with their device without rate adaptative pacing.p-value: 0.50595% CI: [-3.8, 7.63]t-test, 2 sided
Secondary
Atrial Fibrillation (AF) Burden
AF burden was measured at 12 months as the percentage of total atrial beats that are at or above 160 bpm.
Time frame: 12 months
Population: Percentage of atrial burden was collected for subjects utilizing dual chamber pacing that completing a 12-month follow-up visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Atrial Fibrillation (AF) Burden | 7.54 percentage of atrial beats | Standard Deviation 20.75 |
| Standard Rate Adaptive Pacing | Atrial Fibrillation (AF) Burden | 5.57 percentage of atrial beats | Standard Deviation 16.81 |
| No Rate Adaptive Pacing | Atrial Fibrillation (AF) Burden | 6.65 percentage of atrial beats | Standard Deviation 19.86 |
Secondary
Cardiac Symptoms
Number of subjects exhibiting each cardiac symptom was determined at the 12 month follow-up visit.
Time frame: 12 months
Population: All subjects answering questions about current cardiac symptoms at the 12-month visit were included in this intention to treat analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Dizzy Spells | 62 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Palpitations | 55 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Fatigue | 120 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Hypotension | 14 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Weakness | 77 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Shortness of Breath | 94 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Syncope | 5 participants |
| CLS Rate Adaptive Pacing | Cardiac Symptoms | Chest Pains | 32 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Hypotension | 7 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Syncope | 6 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Shortness of Breath | 46 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Fatigue | 51 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Dizzy Spells | 31 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Chest Pains | 21 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Weakness | 30 participants |
| Standard Rate Adaptive Pacing | Cardiac Symptoms | Palpitations | 30 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Shortness of Breath | 47 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Hypotension | 9 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Chest Pains | 19 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Syncope | 5 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Fatigue | 54 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Weakness | 30 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Palpitations | 24 participants |
| No Rate Adaptive Pacing | Cardiac Symptoms | Dizzy Spells | 29 participants |
Secondary
Change in 6-minute Walk Test Distance
Change in number of 10 foot repetitions between baseline and 12-month visit were examined.
Time frame: baseline and 12 months
Population: Subjects completing the 6 minute walk at both enrollment and at the 12-month visit were included in intention to treat analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Change in 6-minute Walk Test Distance | 0.03 repetitions | Standard Deviation 3.63 |
| Standard Rate Adaptive Pacing | Change in 6-minute Walk Test Distance | 0.41 repetitions | Standard Deviation 3.36 |
| No Rate Adaptive Pacing | Change in 6-minute Walk Test Distance | 0.27 repetitions | Standard Deviation 3.95 |
Secondary
Change in New York Heart Association (NYHA) Class
Number of subjects with improved, no change, or worsened NYHA classification at the 12-month visit, as compared to baseline. NYHA classifications (I to IV) are used to assess the various stages of heart failure, with Class I relating to mild heart failure and Class IV relating to severe heart failure.
Time frame: baseline and 12 months
Population: Subjects with NYHA classifications at both enrollment and at the 12-month visit were analyzed using intention to treat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Worsened 1 class | 65 participants |
| CLS Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | No change | 341 participants |
| CLS Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Improved 2 classes | 7 participants |
| CLS Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Improved 1 class | 56 participants |
| CLS Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Worsened 2 classes | 1 participants |
| Standard Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | No change | 143 participants |
| Standard Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Improved 2 classes | 0 participants |
| Standard Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Improved 1 class | 25 participants |
| Standard Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Worsened 1 class | 32 participants |
| Standard Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Worsened 2 classes | 1 participants |
| No Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Worsened 2 classes | 0 participants |
| No Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Worsened 1 class | 40 participants |
| No Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Improved 2 classes | 1 participants |
| No Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | No change | 166 participants |
| No Rate Adaptive Pacing | Change in New York Heart Association (NYHA) Class | Improved 1 class | 16 participants |
Secondary
Change in Quality of Life
Change in Quality of life (QOL) score was determined from baseline to the 12 month follow-up visit. The QOL utilized the physical functioning scale of the SF-36 v2, in which a higher score indicates a better health perception. Best possible score was 57.03 while the worst possible score was 14.94.
Time frame: baseline and 12 months
Population: Subjects completing a QOL at both baseline and 12 month follow-up were included in an intention to treat analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Change in Quality of Life | -0.41 score | Standard Deviation 10.38 |
| Standard Rate Adaptive Pacing | Change in Quality of Life | 0.37 score | Standard Deviation 10.38 |
| No Rate Adaptive Pacing | Change in Quality of Life | -0.41 score | Standard Deviation 9.35 |
Secondary
Mode Reprogramming
Number of subjects with device reprogramming from dual (atrial and ventricular pacing) to single chamber (ventricular pacing only) or from single (ventricular pacing only) to dual chamber (atrial and ventricular pacing) during the 12 month follow-up.
Time frame: 12 months
Population: Subjects completing at least one follow-up visit were analyzed using intention to treat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CLS Rate Adaptive Pacing | Mode Reprogramming | Dual to single chamber | 5 participants |
| CLS Rate Adaptive Pacing | Mode Reprogramming | Single to dual chamber | 5 participants |
| Standard Rate Adaptive Pacing | Mode Reprogramming | Dual to single chamber | 2 participants |
| Standard Rate Adaptive Pacing | Mode Reprogramming | Single to dual chamber | 0 participants |
| No Rate Adaptive Pacing | Mode Reprogramming | Dual to single chamber | 1 participants |
| No Rate Adaptive Pacing | Mode Reprogramming | Single to dual chamber | 1 participants |