Heart Failure With Left Bundle Branch Block
Conditions
Keywords
AdaptivCRT, aCRT
Brief summary
The purpose of this clinical study is to test the hypothesis that market released Cardiac Resynchronization Therapy (CRT) devices which contain the AdaptivCRT® (aCRT) algorithm have a superior outcome compared to standard CRT devices in CRT indicated patients with normal atrio-ventricular (AV) conduction and left bundle branch block (LBBB).
Interventions
Sponsors
Medtronic Cardiac Rhythm and Heart Failure
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
* Subject is willing to sign and date the study Patient Informed Consent Form. * Subject is indicated for a CRT device according to local guidelines. * Sinus Rhythm at time of enrollment * Complete Left Bundle Branch Block (LBBB) as documented on an ECG (within 30 days prior to enrollment). Strauss Criteria used for LBBB. * Intrinsic, normal AV conduction as documented on an ECG by a PR interval less than or equal to 200ms (within 30 days prior to enrollment). * Left ventricular ejection fraction less than or equal to 35% (documented within 180 days prior to enrollment). * NYHA class II, III or IV (documented within 30 days prior to enrollment) despite optimal medical therapy. Optimal medical therapy is defined as maximal tolerated dose of Beta-blockers and a therapeutic dose of ACE-I, ARB or Aldosterone Antagonist.
Exclusion criteria
* Subject is less than 18 years of age (or has not reached minimum age per local law). * Subject is not expected to remain available for at least 2 years of follow-up visits. * Subject has permanent atrial arrhythmias for which pharmacological therapy and/or cardioversion have been unsuccessful or have not been attempted * Subject is, or previously has been, receiving cardiac resynchronization therapy. * Subject is currently enrolled or planning to participate in a potentially confounding drug or device trial during the course of this study. Co-enrollment in concurrent trials is only allowed when documented pre-approval is obtained from the Medtronic study manager. * Subject has unstable angina, or experienced an acute myocardial infarction (MI) or received coronary artery revascularization (CABG) or coronary angioplasty (PTCA) within 30 days prior to enrollment. * Subject has a mechanical tricuspid heart valve or is scheduled to undergo valve repair or valve replacement during the course of the study. * Subject is post heart transplant (subjects on the heart transplant list for the first time are not excluded). * Subject has a limited life expectancy due to non-cardiac causes that would not allow completion of the study. * Subject is pregnant (if required by local law, women of child-bearing potential must undergo a pregnancy test within seven days prior to device implant). * Subject meets any
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Endpoint of All-cause Mortality and Intervention for Heart Failure Decompensation | from subject randomization until the first occurrence of death or intervention for heart failure decompensation, median follow-up 4.9 years (max. follow-up 8.1 years) | The first occurrence of death or intervention for heart failure decompensation (defined as an event requiring invasive intervention or inpatient hospitalization). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients With Interventions for Heart Failure Decompensation | from subject randomization until the first occurrence of intervention for heart failure decompensation, median follow-up 4.9 years (max. follow-up 8.1 years) | First occurence of intervention for heart failure decompensation is defined as an event requiring invasive intervention or inpatient hospitalization. |
| Clinical Composite Score | CCS at 6 month post randomization | The Clinical Composite Score (CCS) classifies patients according their clinical status at 6 months post randomization into categories Improved, Unchanged, and Worsened. A patient is classified Worsened in case of death, hospitalization for worsening heart failure, worsened NYHA class (using last observation carried forward), or worsened status on the Global Assessment Score. Also patients that exit the study or cross over because of worsening heart failure are classified Worsened. A patient is classified Improved when not Worsened and there is an improvement in NYHA class or Global Assessment Score. Patients that are not Worsened or Improved are Unchanged. |
| Atrial Fibrillation | from subject randomization until the first occurrence of atrial fibrillation lasting >6 hours in one day, median follow-up 4.9 years (max. follow-up 8.1 years) | Occurrence of atrial fibrillation lasting \>6 hours in one day |
| All-cause Mortality | from subject randomization until the occurrence of death, median follow-up 4.9 years (max. follow-up 8.1 years) | All-cause mortality in the aCRT ON group vs the aCRT OFF group |
| Change in Quality of Life Measured by the EQ-5D | from baseline to 24M follow up | The EQ-5D descriptive system comprises the following five dimensions, each describing a different aspect of health: MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN /DISCOMFORT and ANXIETY / DEPRESSION. Each dimension has three levels: no problems, some problems, extreme problems (labelled 1-3). We calculated the EQ-5D summary index by applying a specific formula providing a valuation to the health states (Shaw et al. Medical Care 2005). For the summary index, value 0 represents health that is valued as equal to death and value 1 represents best possible health. |
| All-cause Re-admissions Within 30 Days After a Heart Failure Admission Per 100 Patient Years | from subject randomization until study exit, median follow-up 4.9 years (max. follow-up 8.1 years) | All-cause hospital re-admissions within 30 days after discharge from a heart failure admission are reported as number of cases per 100 patient years |
| Change in Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | from baseline to 24M follow up | The overall summary score of the Kansas City Cardiomyopathy Questionnaire will be analyzed. The KCCQ measures Quality of Life on a 0-100 scale with higher scores indicating better QoL |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, India, Italy, Japan, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Russia, Saudi Arabia, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled between August 2014 and January 2019
Pre-assignment details
After subject enrollment, subjects were first implanted with a Medtronic device compatible with the AdaptivCRT algorithm. After successful implant subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| aCRT ON The aCRT algorithm has been developed to provide RV-synchronized LV pacing when intrinsic AV conduction is normal or BiV pacing otherwise
aCRT ON: CRT device with AdaptivCRT enabled (AdaptivBiV and LV) | 1,810 |
| aCRT OFF Standard CRT
aCRT OFF: CRT device programmed to Nonadaptive CRT | 1,807 |
| Total | 3,617 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 293 | 327 |
| Overall Study | Lost to Follow-up | 182 | 162 |
| Overall Study | Physician Decision | 51 | 53 |
| Overall Study | Withdrawal by Subject | 167 | 169 |
Baseline characteristics
| Characteristic | aCRT ON | aCRT OFF | Total |
|---|---|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 11.1 | 65.2 years STANDARD_DEVIATION 11 | 64.9 years STANDARD_DEVIATION 11 |
| NYHA class NYHA class II | 881 Participants | 867 Participants | 1748 Participants |
| NYHA class NYHA class III | 908 Participants | 912 Participants | 1820 Participants |
| NYHA class NYHA class IV | 21 Participants | 28 Participants | 49 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 782 Participants | 786 Participants | 1568 Participants |
| Sex: Female, Male Male | 1028 Participants | 1021 Participants | 2049 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 293 / 1,810 | 327 / 1,807 |
| other Total, other adverse events | 773 / 1,810 | 785 / 1,807 |
| serious Total, serious adverse events | 1,072 / 1,810 | 1,073 / 1,807 |
Outcome results
Primary
Combined Endpoint of All-cause Mortality and Intervention for Heart Failure Decompensation
The first occurrence of death or intervention for heart failure decompensation (defined as an event requiring invasive intervention or inpatient hospitalization).
Time frame: from subject randomization until the first occurrence of death or intervention for heart failure decompensation, median follow-up 4.9 years (max. follow-up 8.1 years)
Population: All randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| aCRT ON | Combined Endpoint of All-cause Mortality and Intervention for Heart Failure Decompensation | 430 Participants |
| aCRT OFF | Combined Endpoint of All-cause Mortality and Intervention for Heart Failure Decompensation | 470 Participants |
p-value: 0.07795% CI: [0.779, 1.013]Regression, Cox
Secondary
All-cause Mortality
All-cause mortality in the aCRT ON group vs the aCRT OFF group
Time frame: from subject randomization until the occurrence of death, median follow-up 4.9 years (max. follow-up 8.1 years)
Population: All randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| aCRT ON | All-cause Mortality | 293 Participants |
| aCRT OFF | All-cause Mortality | 327 Participants |
p-value: 0.1295% CI: [0.752, 1.032]Regression, Cox
Secondary
All-cause Re-admissions Within 30 Days After a Heart Failure Admission Per 100 Patient Years
All-cause hospital re-admissions within 30 days after discharge from a heart failure admission are reported as number of cases per 100 patient years
Time frame: from subject randomization until study exit, median follow-up 4.9 years (max. follow-up 8.1 years)
Population: All randomized subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| aCRT ON | All-cause Re-admissions Within 30 Days After a Heart Failure Admission Per 100 Patient Years | 1.07 readmissions per 100 patient years |
| aCRT OFF | All-cause Re-admissions Within 30 Days After a Heart Failure Admission Per 100 Patient Years | 0.93 readmissions per 100 patient years |
p-value: 0.5295% CI: [0.75, 1.75]negative binomial regression
Secondary
Atrial Fibrillation
Occurrence of atrial fibrillation lasting \>6 hours in one day
Time frame: from subject randomization until the first occurrence of atrial fibrillation lasting >6 hours in one day, median follow-up 4.9 years (max. follow-up 8.1 years)
Population: All randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| aCRT ON | Atrial Fibrillation | 317 Participants |
| aCRT OFF | Atrial Fibrillation | 316 Participants |
p-value: 0.8995% CI: [0.85, 1.16]Regression, Cox
Secondary
Change in Quality of Life Measured by the EQ-5D
The EQ-5D descriptive system comprises the following five dimensions, each describing a different aspect of health: MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN /DISCOMFORT and ANXIETY / DEPRESSION. Each dimension has three levels: no problems, some problems, extreme problems (labelled 1-3). We calculated the EQ-5D summary index by applying a specific formula providing a valuation to the health states (Shaw et al. Medical Care 2005). For the summary index, value 0 represents health that is valued as equal to death and value 1 represents best possible health.
Time frame: from baseline to 24M follow up
Population: All randomized subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| aCRT ON | Change in Quality of Life Measured by the EQ-5D | Mean index score at 24M | 0.848 score on a scale | Standard Deviation 0.173 |
| aCRT ON | Change in Quality of Life Measured by the EQ-5D | Mean index score change from baseline to 24M | 0.054 score on a scale | Standard Deviation 0.19 |
| aCRT OFF | Change in Quality of Life Measured by the EQ-5D | Mean index score at 24M | 0.862 score on a scale | Standard Deviation 0.173 |
| aCRT OFF | Change in Quality of Life Measured by the EQ-5D | Mean index score change from baseline to 24M | 0.048 score on a scale | Standard Deviation 0.18 |
p-value: 0.7595% CI: [-0.0068, 0.0094]ANCOVA
Secondary
Change in Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ)
The overall summary score of the Kansas City Cardiomyopathy Questionnaire will be analyzed. The KCCQ measures Quality of Life on a 0-100 scale with higher scores indicating better QoL
Time frame: from baseline to 24M follow up
Population: All randomized subjects
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| aCRT ON | Change in Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | Overall summary score mean at 24M | 80.3 score on a scale | Standard Deviation 19.7 |
| aCRT ON | Change in Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | Overall summary score change from baseline to 24M | 16.8 score on a scale | Standard Deviation 21.2 |
| aCRT OFF | Change in Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | Overall summary score mean at 24M | 81.8 score on a scale | Standard Deviation 19 |
| aCRT OFF | Change in Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | Overall summary score change from baseline to 24M | 16.5 score on a scale | Standard Deviation 20.4 |
p-value: 0.8895% CI: [-1.03, 0.89]ANCOVA
Secondary
Clinical Composite Score
The Clinical Composite Score (CCS) classifies patients according their clinical status at 6 months post randomization into categories Improved, Unchanged, and Worsened. A patient is classified Worsened in case of death, hospitalization for worsening heart failure, worsened NYHA class (using last observation carried forward), or worsened status on the Global Assessment Score. Also patients that exit the study or cross over because of worsening heart failure are classified Worsened. A patient is classified Improved when not Worsened and there is an improvement in NYHA class or Global Assessment Score. Patients that are not Worsened or Improved are Unchanged.
Time frame: CCS at 6 month post randomization
Population: All randomized subjects
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| aCRT ON | Clinical Composite Score | Unchanged | 422 Participants |
| aCRT ON | Clinical Composite Score | Worsened | 138 Participants |
| aCRT ON | Clinical Composite Score | Improved | 1250 Participants |
| aCRT OFF | Clinical Composite Score | Unchanged | 387 Participants |
| aCRT OFF | Clinical Composite Score | Worsened | 129 Participants |
| aCRT OFF | Clinical Composite Score | Improved | 1291 Participants |
p-value: 0.1195% CI: [0.768, 1.026]Regression, Logistic
Secondary
Percent of Patients With Interventions for Heart Failure Decompensation
First occurence of intervention for heart failure decompensation is defined as an event requiring invasive intervention or inpatient hospitalization.
Time frame: from subject randomization until the first occurrence of intervention for heart failure decompensation, median follow-up 4.9 years (max. follow-up 8.1 years)
Population: all randomized subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| aCRT ON | Percent of Patients With Interventions for Heart Failure Decompensation | 238 Participants |
| aCRT OFF | Percent of Patients With Interventions for Heart Failure Decompensation | 255 Participants |
p-value: 0.2895% CI: [0.759, 1.082]Regression, Cox