An interventional study of Pacemaker: AV optimised, His pacing. in Heart Failure, sponsored by Imperial College London. Completed at 15 sites in United Kingdom. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-02-04.
Sponsored by Imperial College London · Not applicable, Interventional, and Treatment
This is a multi-centre, prospective randomised double-blinded cross over study, recruiting a sub-population of patients with heart failure.
All patients will be implanted with a CRT (Cardiac Resynchronisation Therapy) pacemaker with one of the leads positioned on the His bundle in order to obtain direct His-bundle capture. There will be a 2-month run-in period where the device is not active.
A double-blinded cross-over design will then be employed to investigate the effect of His bundle pacing. Patients will be allocated in random order to six month treatment periods in each of the following two states (1) No pacing; (2) AV optimised direct His-bundle pacing. Endpoint measurements will be taken at baseline, 6 months and 12 months post randomisation. Treatment allocation will be blinded to the endpoint assessor and the patient.
126 patients will be needed to detect the expected effect size on the primary endpoint with 90% power. A total of 160 patients will be recruited to allow for patient drop-out.
Patients entering the study will attend for implantation of a CRT pacemaker device with one lead positioned on the His bundle. This will be performed either at the patient's local hospital or at Imperial College NHS healthcare Trust, no later than 4 months after the patient's screening visit.
All patients will be implanted with a Pacemaker or Implantable cardioverter defibrillator (ICD). In all patients a pacing lead will be positioned in the right atrium (typically the right atrial appendage). All patients will have a pacemaker lead positioned on the His bundle in order to obtain direct His-bundle capture. If it is not possible to successfully implant a His-bundle lead with selective direct His bundle capture or non-selective capture with \< 40ms prolongation of the QRS duration, then a lead will be implanted in a lateral branch of the coronary sinus.
In patients who do not have an indication for an Implantable cardioverter defibrillator (ICD) a second ventricular lead will be implanted in a lateral branch of the coronary sinus. If direct His pacing has not been successfully achieved then a further lead will be positioned at the RV apex. In patients who do have an indication for an Implantable cardioverter defibrillator the ICD lead will be positioned in the right ventricle (either RV apex or RV septum).
AV delay optimisation will be performed using acute non-invasive blood pressure acquired using the Finometer device (Finapres Medical systems, Netherlands). The BHF (British Heart Foundation) alternation protocol will be used in order to minimise the effect of background noise.
After implantation of the device there will be a 2 month run-in period prior to randomisation, the device will be programmed not to deliver His bundle pacing therapy during this period.(Back up only pacing and defibrillator function will be enabled).
Two months after patients are implanted with their device, patients will be randomised to either receive active pacing treatment or back up only pacing (pacemaker programmed to VVI 30 bpm). After a further 6 months they will be crossed over to the alternative treatment arm. Treatment allocation will be obtained using an Interactive Web Response System (IWRS) programmed with a randomisation schedule provided by the trial statistician. Appropriate blocking will be used.
5,701 studies on the registry are indexed under Heart Failure; 1,220 are open to participants now.
This study's enrollment of 198 is above the median of 72 across 3,736 interventional studies indexed under Heart Failure.
Browse Heart Failure studies →Imperial College London is the lead sponsor of 825 studies on the registry; 179 are open to participants now.
Of its 9 completed or terminated interventional studies of FDA-regulated products, 6 (67%) have results posted.
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Exclusion Criteria:
Subjects will remain in this arm for 6 months before being crossed-over. See below intervention details.
Device: Pacemaker: AV optimised, His pacing.
Subjects will remain in this arm for 6 months before being crossed-over. The pacemaker will be programmed to VVI 30 bpm. Dynamic AV delay will be programmed off throughout the study.
Direct His bundle pacing: a Medtronic Select Secure 3830 pacing lead will be positioned at the His bundle. If selective direct His bundle pacing cannot be achieved then non-selective His bundle pacing will be accepted. AV delay optimisation: will be performed using acute non-invasive blood pressure acquired using the Finometer device (Finapres Medical systems, Netherlands).
Changes in Exercise Capacity.
Measured using peak oxygen uptake (VO2).
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in Echocardiographic Measurement of Left Ventricular Function (Ejection Fraction)
Measured during echocardiogram.
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in B-type Naturietic Peptide (BNP).
Measured from blood sample. Note: BNP was log-transformed before analysis in the mixed-model and then back transformed for presentation
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in Quality of Life Scores. - Minnesota
Measured using Minnesota Score obtained from the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Score range: 0 to 105, with higher scores indicating a worse outcome with more significant impairment in health-related quality of life
Time frame: Baseline, 6 months and 12 months post randomisation.
Cost Effectiveness Analysis (Using a Custom Designed Resource Utilisation Questionnaire)
The analysis will be based on an intention-to-treat (ITT) principle. The economic evaluation will compare incremental costs and incremental outcomes of the direct His-bundle pacing against the standard medical care. The study will be performed from a societal perspective, which takes all relevant cost-categories and effects into account. The economic evaluation will consist of two parts, a cost-effectiveness analysis (CEA) and a cost utility analysis (CUA). In the CEA the incremental cost-effectiveness ratio (ICER) will be expressed as the incremental costs per point improvement in exercise capacity in peak VO2. The primary outcome measure in the CUA will be Qualitative Adjusted Life Years (QALYs), based on the EQ5D and Minnesota questionnaire scores. NOTE: Cost effectiveness was unable to be completed for HOPE-HF and as such null results are displayed
Time frame: Baseline.
Changes in Percentage Pacing
Measured at completion of periods 1 \& 2 (M6 \& M12) - Percentage of time where device recorded ventricular pacing during each treatment period. Values are recorded across both arms. Results are descriptive and displayed by treatment and by period.
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in Arrythmia Burden (%).
Measured upon completion of run-in (as baseline) and periods 1 \& 2 (M6 \& M12). Device detected Atrial Fibrillation/Supraventricular Tachycardia (AF/SVT) burden recorded as a percentage of time over the 6-month treatment period. Results are descriptive and displayed by treatment and by period.
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in Pacing Thresholds (Volts).
Measured upon completion of run-in and periods 1 \& 2 (BL, M6 \& M12) Results are descriptive and displayed by treatment and by period. Please also note that voltage is presented for both RA Lead and LV Lead.
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in R Wave Amplitude.
Measured from electrocardiogram (ECG).
Time frame: Baseline, 6 months and 12 months post randomisation.
Changes in Lead Impedance (Ohms).
Measured upon completion of run-in and periods 1 \& 2 (BL, M6 \& M12). Results are descriptive and displayed by treatment and by period. Please also note that lead impedance is presented for both RA Lead, HIS-Lead and LV Lead.
Time frame: Baseline, 6 months and 12 months post randomisation.
Fluoroscopy Time During Device Insertion.
Measured by time in minutes.
Time frame: Taken at Device Insertion Visit (2). Baseline measure.
Changes in Quality of Life Scores. - EQ5D Health State Score
Taken from the Visual Analog Scale (VAS) Score from EQ5D Health State Question in EuroQol, 5-dimension, 5-level (EQ5D5L) questionnaire. Score is on a 0-100 scale with 100 representing a better outcome for patients health state.
Time frame: Baseline, 6 months and 12 months post randomisation.
| Milestone | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Run-In Phase (Pre-Randomisation) |
|---|---|---|---|
| Started | 0 | 0 | 183 |
| Completed | 0 | 0 | 167 |
| Not completed | 0 | 0 | 16 |
| Withdrew: Death | 0 | 0 | 3 |
| Withdrew: Physician decision | 0 | 0 | 4 |
| Withdrew: Withdrawal by subject | 0 | 0 | 4 |
| Withdrew: Protocol violation | 0 | 0 | 1 |
| Withdrew: Adverse event | 0 | 0 | 1 |
| Withdrew: Implantation failure | 0 | 0 | 2 |
| Withdrew: Lost to follow-up | 0 | 0 | 1 |
| Milestone | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Run-In Phase (Pre-Randomisation) |
|---|---|---|---|
| Started | 83 | 84 | 0 |
| Completed | 73 | 77 | 0 |
| Not completed | 10 | 7 | 0 |
| Milestone | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Run-In Phase (Pre-Randomisation) |
|---|---|---|---|
| Started | 73 | 77 | 0 |
| Completed | 67 | 69 | 0 |
| Not completed | 6 | 8 | 0 |
Measured using peak oxygen uptake (VO2).
| ml/min/kg | Pacing | No-Pacing |
|---|---|---|
| Changes in Exercise Capacity. | 14.0 (13.0 to 15.0) | 13.7 (12.8 to 14.6) |
Measured during echocardiogram.
| % (LVEF) | Pacing | No-Pacing |
|---|---|---|
| Changes in Echocardiographic Measurement of Left Ventricular Function (Ejection Fraction) | 33.4 (31.2 to 35.7) | 33.0 (31.0 to 34.9) |
Measured from blood sample. Note: BNP was log-transformed before analysis in the mixed-model and then back transformed for presentation
| (ng/L) | Pacing | No-Pacing |
|---|---|---|
| Changes in B-type Naturietic Peptide (BNP). | 323 (242 to 431) | 335 (257 to 436) |
Measured using Minnesota Score obtained from the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Score range: 0 to 105, with higher scores indicating a worse outcome with more significant impairment in health-related quality of life
| scores on a scale | Pacing | No-Pacing |
|---|---|---|
| Changes in Quality of Life Scores. - Minnesota | 30.9 (25.1 to 36.7) | 34.6 (29.8 to 39.3) |
The analysis will be based on an intention-to-treat (ITT) principle. The economic evaluation will compare incremental costs and incremental outcomes of the direct His-bundle pacing against the standard medical care. The study will be performed from a societal perspective, which takes all relevant cost-categories and effects into account. The economic evaluation will consist of two parts, a cost-effectiveness analysis (CEA) and a cost utility analysis (CUA). In the CEA the incremental cost-effectiveness ratio (ICER) will be expressed as the incremental costs per point improvement in exercise capacity in peak VO2. The primary outcome measure in the CUA will be Qualitative Adjusted Life Years (QALYs), based on the EQ5D and Minnesota questionnaire scores. NOTE: Cost effectiveness was unable to be completed for HOPE-HF and as such null results are displayed
No measurements were reported for this outcome.
Measured at completion of periods 1 \& 2 (M6 \& M12) - Percentage of time where device recorded ventricular pacing during each treatment period. Values are recorded across both arms. Results are descriptive and displayed by treatment and by period.
| % (of time over period) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing |
|---|---|---|
| M6 | 90.8 ± 19.42 | 0 ± 0 |
| M12 | 1.4 ± 11.59 | 93.5 ± 16.48 |
Measured upon completion of run-in (as baseline) and periods 1 \& 2 (M6 \& M12). Device detected Atrial Fibrillation/Supraventricular Tachycardia (AF/SVT) burden recorded as a percentage of time over the 6-month treatment period. Results are descriptive and displayed by treatment and by period.
| % (time under AF/SVT burden) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing |
|---|---|---|
| BL (Randomisation) | 0.1 ± 0.52 | 0.3 ± 2.40 |
| M6 | 0.2 ± 0.62 | 0.1 ± 0.46 |
| M12 | 0.4 ± 2.01 | 1.5 ± 11.87 |
Measured upon completion of run-in and periods 1 \& 2 (BL, M6 \& M12) Results are descriptive and displayed by treatment and by period. Please also note that voltage is presented for both RA Lead and LV Lead.
| Volts | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing |
|---|---|---|
| RA Lead - BL | 0.82 ± 0.972 | 0.78 ± 0.510 |
| RA Lead - M6 | 0.82 ± 1.090 | 0.74 ± 0.645 |
| RA Lead - M12 | 0.78 ± 1.034 | 0.79 ± 0.938 |
| LV Lead - BL | 0.78 ± 0.438 | 0.84 ± 0.516 |
| LV Lead - M6 | 0.78 ± 0.452 | 0.73 ± 0.265 |
| LV Lead - M12 | 0.78 ± 0.359 | 0.76 ± 0.280 |
Measured from electrocardiogram (ECG).
No measurements were reported for this outcome.
Measured upon completion of run-in and periods 1 \& 2 (BL, M6 \& M12). Results are descriptive and displayed by treatment and by period. Please also note that lead impedance is presented for both RA Lead, HIS-Lead and LV Lead.
| ohms | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing |
|---|---|---|
| RA Lead Impedance - BL | 460.8 ± 66.7 | 480.8 ± 89.24 |
| RA Lead Impedance - M6 | 475.2 ± 62.44 | 469.1 ± 86.48 |
| RA Lead Impedance - M12 | 452.0 ± 68.38 | 473.7 ± 110.6 |
| His Lead Impedance - BL | 377.9 ± 104.28 | 392.4 ± 97.94 |
| His Lead Impedance - M6 | 326.3 ± 84.24 | 326.8 ± 87.08 |
| His Lead Impedance - M12 | 324.9 ± 87.08 | 330.6 ± 82.68 |
| LV Lead Impedance - BL | 436.5 ± 90.85 | 464.8 ± 101.62 |
| LV Lead Impedance - M6 | 427.8 ± 87.01 | 439.1 ± 109.44 |
| LVLead Impedance - M12 | 425.8 ± 85.06 | 431.2 ± 9.02 |
Measured by time in minutes.
| minutes | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing |
|---|---|---|
| Fluoroscopy Time During Device Insertion. | 16.5 (10 to 27) | 16.0 (10 to 26) |
Taken from the Visual Analog Scale (VAS) Score from EQ5D Health State Question in EuroQol, 5-dimension, 5-level (EQ5D5L) questionnaire. Score is on a 0-100 scale with 100 representing a better outcome for patients health state.
| scores on a scale | Pacing | No-Pacing |
|---|---|---|
| Changes in Quality of Life Scores. - EQ5D Health State Score | 66.3 (61.0 to 71.6) | 64.3 (60.4 to 68.3) |
Collected over AE Data presented was collected during the treatment phase of the study. 12 months in total.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Run-in Period (Pre-Randomisation) | 0/167 (0%) | 25/167 (15%) | 54/167 (32.3%) |
| AV Optimised Direct His-bundle (ARM A at Period 1, ARM B at Period 2) | 6/160 (3.8%) | 25/160 (15.6%) | 75/160 (46.9%) |
| No Pacing (ARM A at Period 2, ARM B at Period 1) | 4/157 (2.5%) | 20/157 (12.7%) | 75/157 (47.8%) |
| Event | Run-in Period (Pre-Randomisation) | AV Optimised Direct His-bundle (ARM A at Period 1, ARM B at Period 2) | No Pacing (ARM A at Period 2, ARM B at Period 1) |
|---|---|---|---|
| Decompensated / Congestive Cardiac FailureCardiac disorders | 3/167 | 3/160 | 8/157 |
| Exacerbation of Heart FailureCardiac disorders | 2/167 | 7/160 | 2/157 |
| His Lead displacementProduct Issues | 5/167 | 1/160 | 0/157 |
| Atrial FibrillationCardiac disorders | 0/167 | 3/160 | 1/157 |
| BreathlessnessCardiac disorders | 3/167 | 0/160 | 1/157 |
| Acute Kidney InjuryRenal and urinary disorders | 1/167 | 0/160 | 2/157 |
| Atrial flutterCardiac disorders | 0/167 | 0/160 | 2/157 |
| LRTIInfections and infestations | 0/167 | 0/160 | 2/157 |
| Community Acquired PneumoniaInfections and infestations | 0/167 | 2/160 | 0/157 |
| Fluid overloadRenal and urinary disorders | 1/167 | 2/160 | 0/157 |
| Event | Run-in Period (Pre-Randomisation) | AV Optimised Direct His-bundle (ARM A at Period 1, ARM B at Period 2) | No Pacing (ARM A at Period 2, ARM B at Period 1) |
|---|---|---|---|
| Chest InfectionInfections and infestations | 3/167 | 9/160 | 6/157 |
| Non-sustained VT EpisodesCardiac disorders | 0/167 | 6/160 | 6/157 |
| Atrial FibrillationCardiac disorders | 6/167 | 4/160 | 5/157 |
| Ventricular Tachycardia EpisodesCardiac disorders | 6/167 | 5/160 | 2/157 |
| Exacerbation of HFCardiac disorders | 1/167 | 3/160 | 5/157 |
| Increased breathlessnessRespiratory, thoracic and mediastinal disorders | 0/167 | 1/160 | 5/157 |
| Chest PainCardiac disorders | 2/167 | 5/160 | 4/157 |
| HaematomaBlood and lymphatic system disorders | 5/167 | 0/160 | 0/157 |
| Polyps in colonGastrointestinal disorders | 0/167 | 1/160 | 4/157 |
| GoutMetabolism and nutrition disorders | 0/167 | 4/160 | 2/157 |
ITT Population
| Age, Continuous(years) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Mean | 70.0 ± 9.03 | 68.0 ± 10.19 | 69.0 ± 9.66 |
| Sex: Female, Male(Participants) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Female | 9 | 7 | 16 |
| Male | 74 | 77 | 151 |
| Race/Ethnicity, Customized(Participants) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Ethnicity — Asian | 10 | 7 | 17 |
| Ethnicity — Black | 3 | 5 | 8 |
| Ethnicity — Mixed | 0 | 2 | 2 |
| Ethnicity — Other Ethnic Group | 2 | 1 | 3 |
| Ethnicity — White | 68 | 69 | 137 |
| Weight(kg) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Mean | 85.22 ± 16.788 | 89.24 ± 17.636 | 87.24 ± 17.286 |
| BMI(kg/m^2) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Mean | 28.498 ± 5.0208 | 29.665 ± 5.5027 | 29.085 ± 5.2853 |
| Diastolic BP(mmHg) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Mean | 69.0 ± 11.22 | 70.8 ± 11.31 | 69.9 ± 11.26 |
| Systolic BP(mmHg) | Arm A: Pacing Followed by No-Pacing | Arm B: No-Pacing Followed by Pacing | Total |
|---|---|---|---|
| Mean | 121.3 ± 19.07 | 121.7 ± 20.24 | 121.5 ± 19.61 |
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Plan to share: Yes — All IPD that underlie results in a publication. The data set will be created as an anonymised data sharing package and will be available post publication of data.
Supporting information: Study protocol, Sap
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Imperial College London