AV Block, Heart Failure, Sinus Node Disease
Conditions
Keywords
pacemaker, CRT-P, auto threshold
Brief summary
The purpose of the IVORY Study is to gather data to support global submissions/approvals for some models of the Ingenio device family.
Detailed description
IVORY is a prospective, multi-center, randomized within-patient, single-blinded study to gather data to support Right Atrial Auto Threshold and RYTHMIQ
Interventions
DEVICERAAT
For Pacemaker and CRT-P: Right Atrial Automatic Threshold (RAAT)
DEVICERYTHMIQ
For pacemakers only: RYTHMIQ RYTHMIQ randomized to on at pre-discharge or at 1-month, depending on assignment
Sponsors
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects who are willing and capable of providing informed consent to undergo a device implant and to participate in all testing associated with this clinical study; * Subjects whose age is 18 or above, or of legal age to give informed consent specific to national law; * Subjects indicated for a dual chamber pacemaker or a CRT-P device according to class I or class II indications of the standard ESC or ACC / AHA implant guidelines; * Subjects who are planned to be implanted with all leads intended for a specific device type (dual chamber pacemaker: atrial and right ventricular lead, CRT-P: atrial, right and left ventricular lead) or are already implanted with such leads; * Subjects who receive or are implanted with a bipolar atrial lead.
Exclusion criteria
* Women of childbearing potential who are or might be pregnant at the time of the study (method of assessment upon physician's discretion); * Enrolled in any other concurrent study, with the exception of local mandatory governmental registries and observational studies/registries that are not in conflict or affect * Schedule of procedures for IVORY (i.e. should not cause additional or missed visits); * Programming of devices for IVORY per CIP; * IVORY outcome (i.e. involve medications that could affect the heart rate of the subject); * Conduct of IVORY per GCP / ISO 14 155:2011 / local regulations. * Subjects who live at such a distance from the clinic that travels for FU visits at a study center would be unusually difficult or burdensome for the subject; * Inability or refusal to comply with the FU schedule; * A life expectancy of less than 12 months, per physician discretion; * Subjects who are planned to be programmed to a pacing mode other than DDD / DDDR during the study period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Accuracy of Commanded Right Atrial Automatic Threshold (RAAT) | 3 months post implant | Accuracy was evaluated by the proportion of tests resulting in an RAAT commanded threshold with \|Manual unipolar threshold - commanded threshold\| ≤ 0.5V. Subjects were allowed to contribute multiple paired datasets for this endpoint analysis, one set each from the 1-month and 3-month visits. Paired datasets from the 1-month and 3-month visits were pooled for purposes of endpoint analysis. A paired dataset consisted of the manual unipolar threshold and the commanded threshold obtained at a visit. |
| System-related Complication-free Rate | 90 days post-implant | Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'. This outcome measure was analyzed only for the combined population and both pacemakers and CRT-P devices were pooled for the analysis. The analysis assesses the system-related complication (SRC) -free rate (excluding LV related events for CRT-P subjects) for subjects implanted or attempted to be implanted with a study device through the first 90 days following the implant procedure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Accuracy of Ambulatory RAAT | 3 months post-implant | Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'. This outcome measure was analyzed only for the combined population (pacemaker and CRT-P). Accuracy was evaluated by the proportion of tests resulting in an RAAT ambulatory threshold with \|ambulatory threshold - commanded threshold\| ≤ 1.0V. Subjects were allowed to contribute multiple paired datasets for this endpoint analysis, one set each from the 1-month and 3-month visits. Paired datasets from the 1-month and 3-month visits were pooled for purposes of endpoint analysis. A paired dataset consisted consisted of the ambulatory threshold obtained within 7 days prior to the visit and the commanded threshold obtained at the visit. |
| Appropriate RAAT Test Outcome | 3 months post-implant | Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'. This outcome measure was analyzed only for the combined population (pacemaker and CRT-P). Accuracy was evaluated by the proportion of tests with an appropriate commanded RAAT test outcome. An appropriate RAAT outcome consists of either a device-determined threshold or a code indicating that a threshold could not be determined and representing a condition that is beyond the control of the RAAT feature and could occur as well in manual threshold test, such as atrial fibrillation. |
| RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ On at Pre-Discharge, Off at 1-Month vs. RYTHMIQ Off at Pre-discharge, On at 1-Month | 3 months post implant | Chronic success is assessed by a median relative reduction of RV pacing percent (RVPP) for RYTHMIQ On at Pre-Discharge, Off at 1-Month vs. RYTHMIQ On at Pre-Discharge, Off at 1-Month. All patients received both RYTHMIQ programmed to ON and programmed to OFF in two consecutive periods, where the patient's programming allocation was randomized for the first period. Then a crossover to the alternate setting occurred for the second period once the end of the first period was reached. |
| Percentage of RAAT Threshold Tests With Sufficient RAAT Pace Output Margin | 3 months post implant | This outcome measure was analyzed only for the combined population (Pacemaker and CRT-P). The sufficient pacing output voltage that is able to capture the right atrium was evaluated by the proportion of Right Atrial Automatic Threshold (RAAT) tests with \[RAAToutput ≥ (max(BP,UP) + δ )\] where BP refers to the manual bipolar threshold, UP refers to the manual unipolar threshold, and δ refers to the safety margin of 0.5V. Subjects were allowed to contribute multiple paired datasets for this endpoint analysis, one set each from the 1-month and 3-month visits. Paired datasets from the 1-month and 3-month visits were pooled for purposes of endpoint analysis. A paired dataset consisted of the commanded threshold and the maximum manual threshold (i.e. the maximum of the manual unipolar and manual bipolar thresholds) obtained at a visit. |
Countries
Austria, Belgium, Denmark, France, Germany, Hong Kong, Italy, Malaysia, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
Subjects were recruited from the general patient population indicated for a dual chamber pacemaker or cardiac resynchronization therapy pacemaker implantation at 15 study centers. First enrollment date was in October 2011 and the last subject was enrolled in March 2012.
Pre-assignment details
Of 139 subjects, 132 were implanted with a study device. Of those subjects who were not implanted with a study device 4 signed informed consent, met eligibility criteria and had anesthesia administered in preparation for the surgical procedure but did not receive a study device (classified as 'Attempt') and 3 signed the informed consent, met eligibility criteria but did not undergo an implant (classified as an 'Intent').
Participants by arm
| Arm | Count |
|---|---|
| Pacemaker Subjects receiving a pacemaker study device (implanted or attempted) | 100 |
| CRT-P Subjects receiving a CRT-P study device (implanted or attempted) | 36 |
| Total | 136 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 4 |
| Overall Study | Underwent anaesthesia, but not finally implanted | 0 | 0 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Pacemaker | CRT-P | Total |
|---|---|---|---|
| Age, Continuous | 73.3 years STANDARD_DEVIATION 10.9 | 72.7 years STANDARD_DEVIATION 9.5 | 73.2 years STANDARD_DEVIATION 10.5 |
| Atrial Arrhythmias Atrial Tachycardia/Flutter | 7 Participants | 3 Participants | 10 Participants |
| Atrial Arrhythmias None | 72 Participants | 26 Participants | 98 Participants |
| Atrial Arrhythmias Other Supraventricular Tachycardia | 3 Participants | 0 Participants | 3 Participants |
| Atrial Arrhythmias Paroxysmal Atrial Fibrillation | 18 Participants | 8 Participants | 26 Participants |
| Atrial Arrhythmias Persistent Atrial Fibrillation | 1 Participants | 0 Participants | 1 Participants |
| BMI | 26.3 kg/m^2 STANDARD_DEVIATION 4.1 | 27.2 kg/m^2 STANDARD_DEVIATION 4 | 26.6 kg/m^2 STANDARD_DEVIATION 4.1 |
| Body Surface Area | 1.9 m^2 STANDARD_DEVIATION 0.3 | 1.9 m^2 STANDARD_DEVIATION 0.2 | 1.9 m^2 STANDARD_DEVIATION 0.2 |
| Brady Arrhythmias: 1st Degree AV Block | 12 Participants | 6 Participants | 18 Participants |
| Brady Arrhythmias: 2nd Degree AV Block - Intermittent | 17 Participants | 2 Participants | 19 Participants |
| Brady Arrhythmias: 2nd Degree AV Block - Permanent | 10 Participants | 0 Participants | 10 Participants |
| Brady Arrhythmias: 3rd Degree AV Block - Intermittent | 21 Participants | 3 Participants | 24 Participants |
| Brady Arrhythmias: 3rd Degree AV Block - Permanent | 15 Participants | 4 Participants | 19 Participants |
| Brady Arrhythmias: Bradycardia | 14 Participants | 2 Participants | 16 Participants |
| Brady Arrhythmias: Chronotropic Incompetence | 5 Participants | 0 Participants | 5 Participants |
| Brady Arrhythmias: None | 6 Participants | 20 Participants | 26 Participants |
| Brady Arrhythmias: Sinus Arrest | 7 Participants | 0 Participants | 7 Participants |
| Brady Arrhythmias: Sinus Node Dysfunction | 32 Participants | 1 Participants | 33 Participants |
| Cardiac Disease & Arrhythmia HistorY Chronic Pulmonary Disease | 10 Participants | 4 Participants | 14 Participants |
| Cardiac Disease & Arrhythmia HistorY Diabetes | 23 Participants | 11 Participants | 34 Participants |
| Cardiac Disease & Arrhythmia HistorY Heart Failure | 6 Participants | 23 Participants | 29 Participants |
| Cardiac Disease & Arrhythmia HistorY Hypertension | 64 Participants | 12 Participants | 76 Participants |
| Cardiac Disease & Arrhythmia HistorY None | 25 Participants | 4 Participants | 29 Participants |
| Cardiac Disease & Arrhythmia HistorY Other | 26 Participants | 8 Participants | 34 Participants |
| Cardiac Disease & Arrhythmia HistorY Renal Disease | 5 Participants | 6 Participants | 11 Participants |
| Concomitant Medications ACE Inhibitor | 27 Participants | 18 Participants | 45 Participants |
| Concomitant Medications Angiotensin Receptor Blocker | 26 Participants | 16 Participants | 42 Participants |
| Concomitant Medications Beta Blockers - Class II | 26 Participants | 26 Participants | 52 Participants |
| Concomitant Medications Calcium Channel Blockers - Class IV | 26 Participants | 4 Participants | 30 Participants |
| Concomitant Medications Diuretics | 26 Participants | 27 Participants | 53 Participants |
| Concomitant Medications Other Cardiovascular Medications | 60 Participants | 29 Participants | 89 Participants |
| Concomitant Medications Potassium Channel Blockers - Class III | 4 Participants | 3 Participants | 7 Participants |
| Concomitant Medications Sodium Channel Blockers - Class I | 3 Participants | 0 Participants | 3 Participants |
| CRT-P Indication Class I - EF ≤ 35%, sinus rhythm, NYHA Class III, or ambulatory NYHA Class IV, QRS ≥ 120 ms, OPT | 0 Participants | 19 Participants | 19 Participants |
| CRT-P Indication Class IIa - EF ≤ 35%, NYHA Class III, or ambul. NYHA Class IV, OPT, freq. dependence on vent. pacing | 0 Participants | 4 Participants | 4 Participants |
| CRT-P Indication Class IIb - EF ≤ 35%, NYHA Class I or II, OPT, device implant with anticipated frequent vent. pacing | 0 Participants | 5 Participants | 5 Participants |
| CRT-P Indication Other | 0 Participants | 2 Participants | 2 Participants |
| CRT-P Indication Replacement CRT-P device | 0 Participants | 6 Participants | 6 Participants |
| Etiology Congenital Heart Disease | 2 Participants | 0 Participants | 2 Participants |
| Etiology Hypertrophic Cardiomyopathy | 1 Participants | 0 Participants | 1 Participants |
| Etiology Idiopathic Cardiomyopathy | 3 Participants | 12 Participants | 15 Participants |
| Etiology Ischemic Cardiomyopathy | 10 Participants | 17 Participants | 27 Participants |
| Etiology No Disease (age related) | 80 Participants | 4 Participants | 84 Participants |
| Etiology Valvular Cardiomyopathy | 4 Participants | 3 Participants | 7 Participants |
| LVEF | 55.7 percent STANDARD_DEVIATION 10.5 | 29.2 percent STANDARD_DEVIATION 8.4 | 44.1 percent STANDARD_DEVIATION 16.3 |
| NYHA Class I | 24 Participants | 1 Participants | 25 Participants |
| NYHA Class II | 10 Participants | 8 Participants | 18 Participants |
| NYHA Class III | 2 Participants | 21 Participants | 23 Participants |
| NYHA Class IV | 0 Participants | 3 Participants | 3 Participants |
| NYHA Class Not reported | 64 Participants | 3 Participants | 67 Participants |
| Pacemaker Indication AV Block | 56 Participants | 0 Participants | 56 Participants |
| Pacemaker Indication Brady-Tachy Syndrome | 1 Participants | 0 Participants | 1 Participants |
| Pacemaker Indication Hypersensitive Carotid Sinus Syndrome | 1 Participants | 0 Participants | 1 Participants |
| Pacemaker Indication Other Block (i.e. Chronic Bifascicular Block) | 5 Participants | 0 Participants | 5 Participants |
| Pacemaker Indication Sinus Node Dysfunction | 37 Participants | 0 Participants | 37 Participants |
| QRS Duration | 109 ms STANDARD_DEVIATION 33 | 158 ms STANDARD_DEVIATION 24 | 123 ms STANDARD_DEVIATION 38 |
| Sex: Female, Male Female | 60 Participants | 28 Participants | 88 Participants |
| Sex: Female, Male Male | 40 Participants | 8 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 136 |
| other Total, other adverse events | 24 / 136 |
| serious Total, serious adverse events | 52 / 136 |
Outcome results
Primary
Accuracy of Commanded Right Atrial Automatic Threshold (RAAT)
Accuracy was evaluated by the proportion of tests resulting in an RAAT commanded threshold with \|Manual unipolar threshold - commanded threshold\| ≤ 0.5V. Subjects were allowed to contribute multiple paired datasets for this endpoint analysis, one set each from the 1-month and 3-month visits. Paired datasets from the 1-month and 3-month visits were pooled for purposes of endpoint analysis. A paired dataset consisted of the manual unipolar threshold and the commanded threshold obtained at a visit.
Time frame: 3 months post implant
Population: Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'.~This outcome measure was analyzed only for the combined population. Analysis performed on subjects with paired datasets, each consisting of a commanded RAAT threshold and manual unipolar threshold collected at the 1- and 3-month visits.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAAT Commanded Threshold | Accuracy of Commanded Right Atrial Automatic Threshold (RAAT) | 100 percentage of accurate RAAT tests |
Primary
System-related Complication-free Rate
Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'. This outcome measure was analyzed only for the combined population and both pacemakers and CRT-P devices were pooled for the analysis. The analysis assesses the system-related complication (SRC) -free rate (excluding LV related events for CRT-P subjects) for subjects implanted or attempted to be implanted with a study device through the first 90 days following the implant procedure.
Time frame: 90 days post-implant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAAT Commanded Threshold | System-related Complication-free Rate | 87.5 percentage of subjects free from SRC |
Secondary
Accuracy of Ambulatory RAAT
Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'. This outcome measure was analyzed only for the combined population (pacemaker and CRT-P). Accuracy was evaluated by the proportion of tests resulting in an RAAT ambulatory threshold with \|ambulatory threshold - commanded threshold\| ≤ 1.0V. Subjects were allowed to contribute multiple paired datasets for this endpoint analysis, one set each from the 1-month and 3-month visits. Paired datasets from the 1-month and 3-month visits were pooled for purposes of endpoint analysis. A paired dataset consisted consisted of the ambulatory threshold obtained within 7 days prior to the visit and the commanded threshold obtained at the visit.
Time frame: 3 months post-implant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAAT Commanded Threshold | Accuracy of Ambulatory RAAT | 186 Paired threshold tests |
Secondary
Appropriate RAAT Test Outcome
Arms/Groups are only applicable for the outcome measure 'Secondary Outcome: RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ Programmed to ON vs. RYTHMIQ Programmed to OFF'. This outcome measure was analyzed only for the combined population (pacemaker and CRT-P). Accuracy was evaluated by the proportion of tests with an appropriate commanded RAAT test outcome. An appropriate RAAT outcome consists of either a device-determined threshold or a code indicating that a threshold could not be determined and representing a condition that is beyond the control of the RAAT feature and could occur as well in manual threshold test, such as atrial fibrillation.
Time frame: 3 months post-implant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAAT Commanded Threshold | Appropriate RAAT Test Outcome | 84.7 percentage of approprite RAAT tests |
Secondary
Percentage of RAAT Threshold Tests With Sufficient RAAT Pace Output Margin
This outcome measure was analyzed only for the combined population (Pacemaker and CRT-P). The sufficient pacing output voltage that is able to capture the right atrium was evaluated by the proportion of Right Atrial Automatic Threshold (RAAT) tests with \[RAAToutput ≥ (max(BP,UP) + δ )\] where BP refers to the manual bipolar threshold, UP refers to the manual unipolar threshold, and δ refers to the safety margin of 0.5V. Subjects were allowed to contribute multiple paired datasets for this endpoint analysis, one set each from the 1-month and 3-month visits. Paired datasets from the 1-month and 3-month visits were pooled for purposes of endpoint analysis. A paired dataset consisted of the commanded threshold and the maximum manual threshold (i.e. the maximum of the manual unipolar and manual bipolar thresholds) obtained at a visit.
Time frame: 3 months post implant
Population: Pooled subjects with a sufficient pacing output voltage to capture the right atrium at the 1-month and the 3-month follow-up visits.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RAAT Commanded Threshold | Percentage of RAAT Threshold Tests With Sufficient RAAT Pace Output Margin | 100 Percentage of RAAT w. sufficient output |
Secondary
RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ On at Pre-Discharge, Off at 1-Month vs. RYTHMIQ Off at Pre-discharge, On at 1-Month
Chronic success is assessed by a median relative reduction of RV pacing percent (RVPP) for RYTHMIQ On at Pre-Discharge, Off at 1-Month vs. RYTHMIQ On at Pre-Discharge, Off at 1-Month. All patients received both RYTHMIQ programmed to ON and programmed to OFF in two consecutive periods, where the patient's programming allocation was randomized for the first period. Then a crossover to the alternate setting occurred for the second period once the end of the first period was reached.
Time frame: 3 months post implant
Population: Pacemaker subjects with RYTHMIQ information available for both randomization periods.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RAAT Commanded Threshold | RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ On at Pre-Discharge, Off at 1-Month vs. RYTHMIQ Off at Pre-discharge, On at 1-Month | RYTHMIQ On | 4 Percentage of RV pacing |
| RAAT Commanded Threshold | RYTHMIQ - Median Relative Reduction of RV Pacing Percent (RVPP) for RYTHMIQ On at Pre-Discharge, Off at 1-Month vs. RYTHMIQ Off at Pre-discharge, On at 1-Month | RYTHMIQ Off | 98 Percentage of RV pacing |