Conduction system pacing and atrioventricular node ablation in heart failure: The PACE‐FIB study design

Abstract

Aims

Atrial fibrillation (AF) worsens the prognosis of patients with heart failure (HF). Successful treatments are still very scarce for those with permanent AF and preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction. In this study, the long‐term benefits and safety profile of heart rate regularization through left‐bundle branch pacing (LBBP) and atrioventricular node ablation (AVNA) will be explored in comparison with pharmacological rate‐control strategy.

Methods and results

The PACE‐FIB trial is a multicentre, prospective, open‐label, randomized (1:1) clinical study that will take place between March 2022 and February 2027. A total of 334 patients with HFpEF/HFmrEF and permanent AF will receive either LBBP followed by AVNA (intervention arm) or optimal pharmacological treatment for heart rate control according to European guideline recommendations (control arm). All patients will be followed up for a minimum of 36 months. The primary outcome measure will be the composite of all‐cause mortality, HF hospitalization, and worsening HF at 36 months. Other secondary efficacy and safety outcome measures such as echocardiographic parameters, functional status, and treatment‐related adverse events, among others, will be analysed too.

Conclusion

LBBP is a promising stimulation mode that may foster the clinical benefit of heart rate regularization through AV node ablation compared with pharmacological rate control. This is the first randomized trial specifically addressing the long‐term efficacy and safety of this pace‐and‐ablate strategy in patients with HFpEF/HFmrEF and permanent AF.

Introduction

Atrial fibrillation in patients with heart failure

Concomitant heart failure (HF) and atrial fibrillation (AF) are found in up to 6% of patients with New York Heart Association (NYHA) class I, and 15 to 35% of those with classes II to IV. ¹ , ² , ³ , ⁴ The presence of AF in these patients is associated with a worse prognosis compared with those in sinus rhythm, ¹ , ² , ⁵ regardless of their ejection fraction (EF), ⁶ although the prevalence of AF is higher in patients with HF and preserved [left ventricular EF (LVEF) ≥ 50%; HFpEF] or mildly reduced (LVEF = 41–49%; HFmrEF) EF than those with reduced EF. Moreover, in patients with HFpEF and AF, mortality risk increases independently of heart rate (HR). ⁷ Restoring and maintaining sinus rhythm rather than an HR control strategy alone has shown significant benefits in HF patients, ⁸ , ⁹ but the efficacy of rhythm control strategies is limited in a relatively large subgroup of these patients in whom permanent AF must be assumed.

Current treatment for heart failure and atrial fibrillation

Treatment recommendations for HF with reduced EF (LVEF ≤40% HFrEF) are broad and well‐defined. ¹⁰ However, only sodium‐glucose co‐transporter 2 (SGLT2) inhibitors have shown prognostic benefits in patients with HFpEF or HFmrEF. ¹¹ , ¹² , ¹³ Until recently, diuretics have been the mainstay of treatment to control congestion and alleviate symptoms in HFpEF. In addition, other drugs such as angiotensin‐receptor blockers and mineralocorticoid receptor antagonists may be considered, although there is very little robust evidence, especially in patients with permanent AF. ¹⁰ Lenient [resting HR ≤ 110 beats per minute (bpm)] instead of strict (resting HR ≤ 80 bpm) rate control is currently recommended as first‐line treatment in these patients. ¹⁴ , ¹⁵ Combination of rate‐controlling drugs when a single drug does not achieve the target resting HR and the addition of digoxin/digitoxin or amiodarone are to be considered before cardiac resynchronization therapy pacemaker (CRT‐P), defibrillator (CRT‐D) or pacemaker implantation followed by atrioventricular (AV) node ablation (AVNA). ¹⁶

Mechanisms and deleterious effects of irregular heartbeat in patients with heart failure

Constant beat‐to‐beat irregularity due to permanent AF decreases cardiac output and worsens haemodynamic performance. ¹⁷ , ¹⁸ , ¹⁹ Several root causes have been suggested, such as failure to adapt cardiac contractility for each heartbeat due to incomplete compensation by the Frank‐Starling mechanism, ventricular mechanical inefficiency due to low cardiac filling and reduced myocardial perfusion and coronary blood flow, as well as other vasomotor and neurohormonal factors. ¹⁷ , ¹⁸ , ¹⁹ Moreover, irregular rhythm is associated with altered sarco/endoplasmic reticulum ATPase 2a pump (SERCA) and phospholamban (PLB) proteins expression, leading to a decrease in the amplitude of intramyocardial calcium currents and an increase in cell oxidation and peroxidation. ²⁰ , ²¹

The impact of these deleterious effects has been shown in randomized clinical trials and long‐term observational studies of patients who underwent AVNA and permanent pacing. In these studies, haemodynamic and clinical outcomes, including NYHA functional class, activity, and quality of life scores, use of diuretics, hospital readmission, worsening HF, and mortality, among others, improved upon rhythm regularization. ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷

A collateral effect of AVNA is the prevention of episodes of rapid ventricular response (RVR) that not infrequently occur in patients with adequate baseline HR control, especially in the context decompensated HF and aggravating such episodes.

Cardiac stimulation modes: advantages of left‐bundle branch pacing

Right ventricular apical (RVA) pacing can cause ventricular dilatation and left ventricular (LV) systolic dysfunction due to pacing‐induced ventricular dyssynchrony. ²⁸ , ²⁹ This may be overcome by more physiological cardiac stimulation modes such as CRT (biventricular pacing) or different modalities of conduction system pacing (CSP) at different locations of the His‐Purkinje system [His‐bundle pacing (HBP) or left‐bundle branch pacing (LBBP)]. ²³ , ²⁴ , ²⁵ , ²⁶ , ³⁰ , ³¹ The APAF‐CRT trial with elderly patients with HF, permanent AF and a broad range of EF values showed a significant reduction of a composite of all‐cause mortality, HF hospitalizations (HFH) and worsening HF in patients treated with AVNA and CRT compared with pharmacological rate control. ²⁷ The observed benefit led to early termination of recruitment, which yielded a small population with EF > 35% to obtain definitive conclusions among patients with preserved or only modestly reduced LV function. ³² Other studies have reported significant improvement in echocardiographic parameters, NYHA functional class, and reduced use of diuretics after AVNA and HBP in patients with normal LV function and AF. ²⁵ , ²⁶ , ²⁸

HBP simultaneously stimulates both His bundle branches and provides a physiological contraction pattern with intra and interventricular synchrony. However, several technical weaknesses restrict its wide application, including a higher capture threshold (which reduces the battery life of pacemaker generators) and significant increase in threshold during follow‐up, which may lead to loss of capture in some cases. ³³ , ³⁴

LBBP, targeting the left branch of the His bundle, has appeared as a physiological pacing alternative and is associated with reduced long‐term HFH and mortality compared with RVA pacing. ³⁵ Furthermore, LBBP achieves more favourable pacing parameters (lower and more stable capture threshold) as well as shorter procedural and fluoroscopy durations. ³⁰ Specifically among patients undergoing subsequent AVNA, LBBP leads to higher success rates and decreased incidence of acute and chronic lead‐related complications compared with HBP. ³⁶ Recent observational data and a small randomized clinical trial have suggested that LBBP may be superior to conventional biventricular pacing even in patients with CRT indication. ³¹ , ³⁷ , ³⁸ , ³⁹ This may potentially influence outcomes of patients with HFmrEF following AVNA.

Study rationale and aim

The beneficial effects of LBBP in patients with permanent AF and HFpEF or HFmrEF remain unsettled to date. Hence, the purpose of the PACE‐FIB trial is to assess the long‐term patient prognosis of heart rhythm regularization by CSP (LBBP) and AVNA in this patient population compared with optimal pharmacological HR control.

PACE‐FIB trial design

Study design

PACE‐FIB is a multicentre, prospective, open‐label, randomized (1:1) clinical study on LBBP and subsequent AVNA in Spain. It has been notified to the Spanish Agency of Medicines and Medical Devices (AEMPS), registered on https://www.clinicaltrials.gov with unique identifier NCT05029570 and is being conducted in accordance with the Declaration of Helsinki ethical standards ⁴⁰ and the rules and regulations of the approving Ethics Committee (EC) at the core hospital (Clinical Research EC of Hospital Universitario 12 de Octubre, CEI 21‐454, Madrid, Spain; approved on 12/08/2021). Patient data are handled according to the current General Data Protection Regulation 2016/679 of the European Parliament (EU‐GDPR) and the Council of 27 April 2016 on Personal Data Protection, the Spanish Organic Law 3/2018 of 5 December 2018 on Personal Data Protection and Guarantee of Digital Rights, and the 41/2002 Law of 14 November 2002 on Patient Autonomy and Rights and Obligations in terms of information and clinical documentation.

Participants and study settings

Eligible participants are adults aged 18 or older with HF with NYHA functional Status II to IV, permanent AF with resting HR ≤110 bpm and LVEF >40% (i.e. HFmrEF or HFpEF) measured by the Simpson's method of disks summation in either echocardiogram or cardiac magnetic resonance imaging within the three months prior to inclusion. ⁴¹ , ⁴² In the event of disparities between different techniques or repeated exams in this period, the lower LVEF value would be considered. Other inclusion criteria are at least one HFH or worsening HF (requiring intravenous diuretics and/or inotropes) during the previous year, basal N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels ≥900 pg/mL in the 30 days prior to enrolment, capacity to understand the nature of the study and providing signed informed consent using the EC‐approved consent form. Exclusion criteria are severe frailty (Clinical Frailty Scale ⁴³ ≥7) or comorbidity reducing life expectancy to <12 months, acute HF at enrolment or systolic blood pressure <80 mmHg in the absence of inotropic agents, severe chronic kidney disease [estimated glomerular filtration rate (eGFR) < 20 mL/1.73m²], severe mitral or aortic valvular heart disease, anaemia (haemoglobin <10 g/dL), morbid obesity (body mass index ≥35), severe chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease ⁴⁴ ≥3), presence of a clinical indication for pacemaker of implantable cardioverter‐defibrillator implantation, obstructive hypertrophic cardiomyopathy, infiltrative cardiomyopathy (amyloidosis, sarcoidosis, Fabry disease, or others), simultaneous participation in a different trial, pregnancy or expected pregnancy, and breastfeeding during 18 months after enrolment. No sex‐ or ethnicity‐based criteria will be applied.

The following events are considered study withdrawals: cardiac surgery (coronary artery bypass grafting, valve surgery or pulmonary vein isolation) or cardiac transplant during the study period, residential relocation far away from the centre where the device was implanted, invalidation of the informed consent, investigator's decision to exclude a patient, and patient's decision to withdraw their consent to participate in the study. In these cases, patients may allow the analysis of their cumulative data until withdrawal.

The study took place in 16 Spanish tertiary centres since March 2022, and it is planned to end in May 2027 (inclusive). Patient recruitment started in March 2022 and will finish in February 2024 (inclusive). The patient follow‐up period will be 36 months (until February 2027 for the last recruited patient). For those reaching it before the study completion, additional follow‐up visits every 6 months will continue until February 2027 (Figure  1 ).

Figure 1.

Intervention scheme and visit schedule. The flow chart summarizes the study interventions and the number and frequency of follow‐up visits from patient allocation to study completion. Patients in the intervention arm will be subject to AVNA and CSP (LBBP). Patients in the control arm will receive optimal rate control pharmacological treatment. Duration of patient follow‐up: 36 months minimum. After that, patients will be followed up every 6 months until the end of the study. *ECG and clinical variables will be registered during every visit. If necessary, pharmacological treatment in the control arm will be adjusted to reach optimal resting HR (≤110 bpm). AVNA, atrioventricular node ablation; bpm, beats per minute; CSP, conduction system pacing; d, days; ECG, electrocardiogram; HR, heart rate; LBBP, left‐bundle branch pacing; mo, months; TTE, transthoracic echocardiogram; VVI, ventricular demand pacing; VVIR, rate‐responsive VVI.

Interventions

Patients are assessed for eligibility during the first visit (baseline visit). Included patients are randomly allocated to either pharmacological HR control strategy (control arm) or CSP (LBBP) and subsequent AVNA (intervention arm) (Figure  1 ).

Control arm

Within 60 days after the baseline visit (Visit 1), resting HR is determined by electrocardiogram (ECG). HR control strategy for these patients will be based on the ESC pharmacological treatment algorithm ¹⁶ to maintain resting HR below 110 bpm and achieve the highest possible clinical stability for the patient and the best prognosis. Within 10–20 days after Visit 1 (Visit 2), treatment adherence and tolerance are assessed by telephone visit, and it may be adjusted if necessary. Follow‐up Visit 3 is scheduled 22–40 days after Visit 1. According to the ECG, HR control treatment is fine‐tuned if resting HR is >110 bpm. Within 25–50 days after Visit 3 (Visit 4), telephone treatment follow‐up will be carried out by telephone as the previous one. The subsequent visits (Visits 5–10) are scheduled every 6 months (±30 days) for 36 months. During this follow‐up period, a 24 h Holter ECG or routine transthoracic echocardiogram (TTE) is performed every other visit. Moreover, treatment may be optimized in Visits 5–10 if resting HR is >110 bpm (Figure  1 ).

Intervention arm

Patients in the intervention arm will not receive medication specifically aimed at HR control. However, they will receive pharmacological treatment according to their HF status and other comorbidities. This may potentially include the use of beta‐blockers or calcium‐channel blockers for other indications such as angina, hypertension, or HF when appropriate.

At Visit 1, patients undergo single‐chamber pacemaker implantation with lead implantation aimed at LBB capture using dedicated CSP sheaths according to current standard practice. Implant recommendations and optimization guidance are summarized in Figure 2 . The pacemaker is initially programmed to operate in ventricular demand (VVI) pacing mode and at a 40 bpm minimal rate until AVNA is performed. Following device implantation, the position of the electrode is confirmed by posteroanterior and lateral chest X‐ray (Figure  1 ).

Figure 2.

Optimization of pacemaker programming. Recommendations for pacing fulfilling LBB capture criteria followed by AVNA are shown. AVNA, atrioventricular node ablation; LBB, left‐bundle branch; LBBp, LBB potential; LVAT, left‐ventricular activation time; Stim‐LVAT, interval from stimulation to left‐ventricular activation time; RBBB, right‐bundle branch block; V6RWPT, V6 R‐wave peak time.

Suture and staple removal and early surveillance of pacemaker will take place during Visit 2. Specifically, device functioning (electrogram amplitude detection, signal stability, impedance, and threshold, among others) is checked, with special attention to the detection of potential early implantation‐related adverse events (AE).

In Visit 3, after pacemaker interrogation to ensure adequate pacemaker performance, AVNA is performed via transfemoral venous access according to standard protocols in each centre. It is strongly advised not to discontinue anticoagulant treatment. In any case, bridging therapy using LMWHs is not recommended. Ultrasound‐guided venous cannulation is also strongly recommended. Primary target for ablation is the compact AV node, aiming to preserve a stable escape rhythm. Afterwards, the pacemaker is reinterrogated and programmed at rate‐responsive VVI (VVIR) mode with minimum HR of 80 bpm (Figure  1 ).

During Visit 4, a minimum rate of 60 bpm is set. The maximum rate depends on the age and physical condition of the patient, not exceeding 130 bpm. Follow‐up Visits 5–10 alternate 24‐h Holter ECG with routine TTE and pacemaker surveillance. If necessary, minimum rate and rate response values may be adjusted according to exercise tolerance and HR histograms (Figure  1 ).

Variable description and outcome measures

Demographic data, patients' medical history related to cardiovascular (CV) health and relevant comorbidities are collected during the baseline visit. Clinical parameters and echocardiographic variables related to the primary and secondary outcome measures are collected by the investigators and their teams during the follow‐up visits (Figure  1 ) using an electronic case report form (eCRF): Deaths, hospital admissions, LVEF (assessed by the Simpson's method of disks summation in either echocardiogram or cardiac magnetic resonance imaging ⁴¹ ), end‐diastolic and end‐systolic volumes, mitral regurgitation degree, NYHA class, ⁴⁵ eGFR, HR and levels of brain natriuretic peptide (BNP) and NT‐proBNP (Table  1 ). Electric parameters registered at 200 mm/s in Visits 1, 3, and 10 (including here the stimulated qRS features and LVAT), together with all pacemaker surveillance measurements will be stored in the eCRF as anonymized digital imaging files and will be subsequently analysed by the core lab. (Serious) AE (SAE/AE), (serious) adverse device effects (SADE/ADE), unanticipated serious adverse device effects (USADE), and device deficiencies (DD) will be also reported using the eCRF according to ISO 14155:2020 standard ‘Clinical investigation of medical devices for human subjects‐ Good clinical practice’ (Table  S1 ). ⁴⁶

Table 1.

Study outcome measures (efficacy and safety) with time points and definitions

Outcome measures	Time frame	Variable description
Primary efficacy outcome
Composite of all‐cause mortality, HFH, and worsening HF	36 months	Number and percentage of deaths due to any cause, hospitalized subjects due to HF decompensation and/or subjects presenting an episode of HF, which will be diagnosed by symptoms, signs, imaging techniques and/or analytical criteria and require unexpected medical attention and intravenous diuretic therapy.
Secondary efficacy outcomes
All‐cause mortality	36 months	Number and percentage of deaths due to any cause.
CV mortality	36 months	Number and percentage of deaths due to CV causes.
All‐cause hospitalization	36 months	Number and percentage of hospitalized subjects due to any cause.
HFH	36 months	Number and percentage of hospitalized subjects due to HF decompensation.
Worsening HF	36 months	Number and percentage of subjects presenting an episode of HF, which will be diagnosed by symptoms, signs, imaging techniques and/or analytical criteria and require unexpected medical attention and intravenous diuretic therapy.
Unplanned CV hospitalization	36 months	Number and percentage of hospitalized subjects due to unexpected CV causes.
LVEF	36 mo	Assessed by Simpson's method of disks summation.
LV dimension	36 months	Mean change in end‐diastolic and end‐systolic volumes.
Mitral regurgitation	36 months	Mean change in mitral regurgitation degree.
Functional status	36 months	Number and percentage of subjects in each NYHA class.
Renal function	12 months	Mean change in eGFR.
Natriuretic peptides	12 months	Mean change in NT‐proBNP or BNP.
Secondary safety outcomes
AE after pacemaker implantation	30 days	Number and percentage of subjects suffering one of the following events during the first 30 days after pacemaker implantation: Death, cardiac tamponade, perforation requiring cardiac surgery, pneumothorax, haemothorax, device infection, endocarditis, femoral artery pseudoaneurysm, femoral arteriovenous fistula and lead displacement and haematoma related to pacemaker implantation that require re‐intervention.
AE after AV node ablation	30 days	Number and percentage of subjects suffering one of the following events during the first 30 days after AV node ablation: Death, cardiac tamponade, perforation requiring cardiac surgery, puncture site vascular complications requiring vascular surgery.

Abbreviations: AE, adverse event; AV, atrioventricular; BNP, brain natriuretic peptide; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HFH, heart failure hospitalization; HR, heart rate; LV, left ventricular; LVEF, left ventricular ejection fraction; NT‐proBNP, basal N‐terminal pro‐BNP; NYHA, New York Heart Association.

The eCRF is linked to an internet database to which only designated personnel have access. Clinical study monitors are in charge of contrasting data entries in every participating centre and confirm that all investigators adhere to the study protocol, ISO 14155:2020 standard, the US Food and Drug Administration (FDA) Code of Federal Regulation (CFR) [21 CFR Parts 50 (Informed Consent), 54 (Financial Disclosure), 56 (Institutional Review Board) and 812 (Investigational Device Exemption)], local laws, and ethical principles that have their origin in the Declaration of Helsinki. In addition, all events related to the primary and secondary outcome measures are reviewed by the data monitoring committee, composed of three medical experts in the electrophysiology and HF fields and not directly participating in the study.

The study's primary outcome measure is the composite of all‐cause mortality, HFH, and worsening HF (i.e. unplanned HF hospitalizations or urgent visits requiring intravenous diuretics and/or inotropics) during a 36 month follow‐up period in both arms. Other secondary efficacy and safety outcome measures are described in Table 1 .

Sample size

Results from several observational studies and one single randomized clinical trial point towards a survival benefit and improved HF prognosis associated with AVNA and physiological stimulation, both in patients with LVEF ≤40% and LVEF >40%. ²⁵ , ²⁶ , ²⁷ Although no study has specifically addressed the effect of this strategy in patients with LVEF >40%, we anticipated an incidence of the primary outcome of 30% ²⁷ and 15% ²⁶ in the control and intervention arms, respectively. Therefore, to detect differences between study arms with a 5% significance level and a power of 80%, a sample size of 152 patients per group (304 patients in total) is necessary. Assuming a dropout rate of 10%, 167 patients will be included in each arm (334 patients in the study sample), with no minimum or maximum number of patients per centre. A 24 month inclusion period was estimated to recruit this number of patients.

Interim analysis and stopping guidelines

The study may be halted prematurely for benefit if the interim analysis, which will be performed after recruiting 50% of the estimated sample size, shows significant superiority of either arm regarding the primary outcome, that is, if the percentage of patients in the composite of all‐cause mortality, HFH, and worsening HF is significantly lower. Other stopping rules include the withdrawal of >10% of patients from the study (withdrawal of the informed consent or due to medical reasons) and not having recruited >50% of the total patient sample after 24 months.

Randomization

Before starting patient recruitment, the random allocation sequence will be generated by the biostatistics team with SAS® PROC PLAN and will subsequently be included in the eCRF. The four‐patient block design and stratification by centre will ensure a correct balance between the study arms (1:1). Data from patients that fulfil the eligibility criteria are uploaded by the investigators to the eCRF. Then, patients are automatically assigned to either arm according to the previously generated random allocation list.

Statistical methods

Data will be presented by descriptive‐univariate statistics. Qualitative variables will be described by absolute and relative frequencies. Measures of central tendency and dispersion will be used for quantitative variables. An intention to treat approach will be applied to analyse the primary efficacy outcome, although a pre‐specified analysis per treatment received will be performed assuming that some patients may swap study arms, especially from the pharmacological approach (control arm) to the AVNA and stimulation one (intervention arm). A second pre‐specified outcome measure will consider cardiac stimulation outcomes, according to fulfilment of conduction system capture criteria and paced qRS [qRS <135 ms and LV activation time (LVAT) ≤80 ms (successful capture) vs. qRS >135 ms and LVAT >80 ms (not successful)].

Other pre‐specified subgroup analyses will be performed to test the following hypotheses: (i) patients in the intervention arm with pacing fulfilling LBB capture criteria are associated with better clinical and echocardiographic prognosis than those with LV septal pacing with no LBB capture; (ii) AVNA in patients with recent (4 weeks) CSP implant is an efficacious and safe procedure; (iii) the pharmacological rate control strategy does not prevent CV hospitalizations, emergency visits and episodes of fast ventricular rate despite frequent dose adjustments; (iv) electric parameters related to the stimulation of the conduction system and measured in each participating centre (capture threshold, impedance, stimulated qRS width and LVAT) are stable during a 3 year follow‐up period. These parameters will be compared with those collected in the core laboratory by using the electrocardiographic and endocavitary registry at 200 mm/s, which will be included in every eCRF; and (v) both patients with HFmrEF and HFpEF benefit from this strategy.

Discussion

AVNA followed by the best possible stimulation seems a promising strategy for patients with HF and permanent AF. Recent studies have suggested a superiority in clinical and echocardiographic results of CSP over conventional biventricular pacing through CRT in a variety of scenarios including patients with conventional indication for CRT, ³¹ patients with failed CRT implantation or non‐response to CRT, ⁴⁷ or patients having undergone AVNA. ⁴⁸ Among the different CSP modes, evidence points to a higher safety and long‐term performance of LBBP over HBP in patients with HF and permanent AF. ³⁶ Consequently, a randomized controlled trial evaluating the benefit of CSP (prioritizing LBB pacing) and subsequent AVNA over current first‐line therapy is of interest in a prevalent population as that of HF patients with mildly reduced of preserved systolic function and permanent AF.

A potential limitation of the study is the use of different commercially available pacemakers and leads. No device bias is expected because this study aims to assess the advantages of the AVNA procedure followed by CSP, and all devices have shown high implantation success rates and adequate long‐term performance.

Conclusions

HR regularization through AVNA with subsequent stimulation seems a promising strategy in patients with HF and permanent AF. However, the role of CSP in this scenario and, more specifically, for patients with HFpEF and HFmrEF remains to be established. The PACE‐FIB trial is the first large‐scale study specifically addressing it while comparing LBBP and AVNA interventions to regulate heart rhythm with pharmacological HR control. Hence, it may significantly contribute to redefining and broadening the limited therapeutic strategies for this subset of patients.

Declaration of Interest

IFL has received honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Medtronic and participated on Data Safety Monitoring Board and Advisory Board for Abbott.

DRM and FAY have received honoraria for lectures and educational events from Medtronic and research funding from Medtronic and Biotronik.

Conflict of interest

None declared.

Funding information

The study has received funding from the Spanish Heart Rhythm Association and the Spanish Ministry of Science and Innovation through the Carlos III Institute for Healthcare, without interfering with the study design, preparation of this article or the decision to submit it for publication.

Supporting information

Table S1. Definition of safety endpoints. AE, adverse event; ADE, adverse device effect; CIP, clinical investigation plan; DD, device deficiencies; SAE, serious adverse event; SADE, adverse device effect; USADE, unanticipated serious adverse device effects.

Rodríguez Muñoz, D. , Crespo‐Leiro, M. G. , Fernández Lozano, I. , Zamorano Gómez, J. L. , Peinado Peinado, R. , Manzano Espinosa, L. , de Juan Bagudá, J. , Marco del Castillo, Á. , Arribas Ynsaurriaga, F. , and Salguero Bodes, R. (2023) Conduction system pacing and atrioventricular node ablation in heart failure: The PACE‐FIB study design. ESC Heart Failure, 10: 3700–3709. 10.1002/ehf2.14488.