The NORDIC-CSP trial is an investigator-initiated, blinded, nordic RCT aimed at evaluating whether using direct pacing of the HIS bundle (HIS)-pacing or left bundle branch (LBB) pacing is superior to conventional biventricular pacing in reducing the incidence of the composite endpoint of death and non-planned HF hospitalization. The study will be conducted in the 4 CRT-centres in Denmark and 6-8 centres from countries Sweden, Norway and Finland.

In this investigator-initiated, blinded, nordic RCT, we will investigate conduction system pacing (CSP) in heart failure (HF) patients. We hypothesized that Cardiac Resynchronization Therapy (CRT) by HIS-pacing or LBB-pacing is superior compared to conventional biventricular (BIV)-CRT in reducing the incidence of the composite endpoint (Death and HF-hospitalization) in patients with symptomatic HF, with LVEF ≤ 35% and indication for CRT.

The Study is a collaboration between CRT centers in the Nordic countries with experience in CSP.

Randomization:

Randomization is conducted electronically using the CRF on the day of device implantation. A computer algorithm will randomly assign patients 1:1 to either the conventional method BIV-CRT or to "the new method" HIS/LBB-CRT.

Randomization will be stratified by the presence of a) true LBBB, b) other bundle branch block (BBB) and c) RV pacing. This will be performed by randomizing in blocks of 10 for LBBB and RV pacing/other bundle branch blocks. Block-randomization is used to ensure that each center includes a similar number of patients for each treatment arm.

The implanting physician is aware of group allocation to provide the correct treatment. Only the implanting physician can access this information in the CRF. The patients and study per-sonnel involved in end-point adjudication as well as all personnel performing imaging analy-sis are blinded to randomization. Follow-up is identical in the two treatment groups. All fol-low-up personnel are blinded to treatment assignment.

Implantation:

The RV electrode is preferentially placed in an RV septal position unless factors related to lead stability, electrical values, and defibrillation vector favor an apical position (at the discretion of the implanting physician). The atrial electrode is positioned at the preference of the implanting physician. With successful implantation of a lead for HIS- or LBB-pacing the physician may prefer to not implant a RV-lead to the septum. In that case, there is no need for a CRT pacemaker and a dual-chamber pacemaker can be implanted instead.

In the HIS-LBB group, CSP is performed according to current recommendations13. The leads allowed to implant in the HIS-LBB position are the ones that have received CE-approval for this indication.

Both HIS-pacing or LBB-pacing can be attempted as first approach at the physician's discretion using available leads both stylet-driven or non-stylet driven and if necessary, guiding from an electrophysiology catheter is used.

HIS-pacing: An approximate ratio of 1:4 between A and V with a clear His deflection is iden-tified and His-capture confirmed. If the threshold for capture of His and the left bundle branches is too high (> 2 V at 1 ms duration) assessed by the operator, the lead should be replaced. If it is not possible to achieve selective or non-selective HIS pacing with bundle branch block correction at a threshold below or equal to 2 V at 1 ms in duration, an attempt to implant the electrode to achieve direct left bundle branch pacing (LBBP) is performed instead.

LBB-pacing: LBB-pacing is performed by moving the sheath a few centimeter further towards the apex of the right ventricle, ensuring contact to the septum. The electrode is screwed into the septum at an angle of -10⁰ to 40⁰ while monitoring current-of-injury (COI), impedance and pacing configuration (gradual emergence of a terminal R-wave in lead V1) until the left bundle branch area is activated and a right-sided bundle branch block pattern is obtained. The operator must attempt to confirm left conduction system capture by identify-ing one or more of the following criteria:

• Fixation beats (PVC´s identical to the paced QRS-complex,)
• Identification of LBB-potentials (> 15 ms before sensed QRS) and capture with RBBB-pattern during unipolar pacing on the LBB-lead. (Not in LBBB patients)
• Transition of QRS patterns during threshold testing:

ns-LBBP to s-LBBP : splitting of EGM and/or V1 RWPT (Rigth wave peak time)¬ by > 10 ms ns-LBBP to LVSP : V6 RWPT¬ by ≥ 15 ms V6 RWPT < 80 ms (LBBB, IVCD RBBB+fascicular block, wide escape rhythm, asystole) V6 -V1 interpeak interval > 44 ms QRS transition to s-LBBP during programmed stimulation

Or one of the following criteria considered likely to represent left conduction system capture:

V6 RWPT < 100 ms (LBBB, IVCD, RBBB + fascicular block, wide escape rhythm, asystole V6 -V1 interpeak interval > 33 ms QRS transition to LVSP during programmed stimulation V6 RWPT prolongation by 10-14 ms during threshold test

If the operator is not succesful, after several attempts, obtaining conduction system capture LVseptal capture (LVSP) can be accepted, with identification of a clearly defined R´ in V1. If only deep septal pacing can be obtained the lead can be left in place or removed at the op-erators discretion and an LV-lead has to be implanted to obtain either BIV-CRT or LOT-CRT.

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Cross-over between intervention arms If neither HIS-pacing nor LBB-pacing is obtainable (none of the abovementioned criteria are met or Left Ventricular septal pacing cannot be obtained), the sheath is switched to a CS sheath instead and an LV electrode is placed as in a conventional CRT procedure. Finally, an atrial electrode is placed if there is not already a usable atrial electrode in place. In all pa-tients, signs of left conduction system capture identified are registered in the CRF.

In the BIV-CRT group, the LV lead is placed in the branch judged to be most suitable, prefer-entially in a posterolateral (2-5 o'clock in the mitral annulus), and mid-ventricular or basal, non-apical position (figure 2), after taking into consideration lead stability, pacing threshold and threshold for phrenic nerve stimulation. In general, multipolar (quadripolar) LV leads are used as first choice but the implanting physician may use a bipolar LV lead if a multipolar lead cannot be implanted. Balloon occlusion venography to visualize the CS and side branches is performed in all patients with a BIV-CRT. Supplementary selective venography may be used to visualize CS branches.

If it is not possible to place a LV -lead due to the anatomical conditions (lack of access to CS, lack of available side bundle branches or only possible to pace in the vena cordis media or vena cordis anterior) or due to unacceptable electrical measurements (best pacing threshold > 4 V at 1,0 msec, or phrenic nerve capture < 2 x lowest pacing threshold), the sheath is in-stead switched to a HIS sheath and electrode placement to the HIS bundle or LBB area is attempted using available sheaths and guide from electrophysiology catheter as outlined above. Again, it is up to the physician whether HIS- or LBB-pacing is attempted first. If it is not possible to achieve selective or non-selective HIS pacing with bundle branch block cor-rection at a threshold below or equal to 2.5 V at 1 ms in duration, an attempt is done to im-plant the electrode further into the ventricle and achieve direct left bundle branch pacing (LBB-CRT) instead. Finally, an atrial electrode is placed if there is not already a usable atrial lead in place. If it is not possible to place either an LV electrode, a HIS electrode or an elec-trode for LBB pacing, the attending physician must decide whether there is any indication for implantation of a transthoracic LV-lead.

Follow-up:

Clinical- and device check-ups are scheduled after 3-, 6- and 12 months, and annually thereafter according .This means that patients are in fact following the current standard regime after CRT-implantation with similar examinations including standard blood tests. However, in addition the patients will be asked to fill out questionnaires, that is the MLHFQ and PRO Questionnaires at baseline and 12 months. Remote monitoring is established for all pa-tients. Echocardiographic follow-ups are scheduled after 6- and 24 months. A 6MWT is per-formed 6 months. At each follow-up visit, medication is recorded and a ECG-12 is obtained upon patient arrival.

All patients are followed for a minimum of 2 years.

Inclusion Criteria:

• ≥18 years of age,
• LVEF ≤ 35%,
• NYHA Class II-IV (IV only outpatients),
• optimized in medical treatment (OMT)

AND one of the following:

. LBBB according to AHA/ACC/HRS Scientific Statement from 2009 and ≥130ms or

• LBBB-like intraventricular conduction delay (IVCD) > 150ms or RV paced QRS and indication for upgrade to CRT (> 40% RV pacing) OR
• ≥18 years of age,
• LVEF ≤ 40 %
• pacing indicated by AV-block and, thus, expected large percentage of ventricular pacing.

Exclusion Criteria:

• recent acute myocardial infarction (AMI)
• coronary artery bypass graft (CABG) (<3 months)
• life expectancy <2 years, patients in hemodialysis
• treatment with a cardiac implantable electronic device (CIED) is contraindicated.
• Patients are excluded with regards to the MRI sub study if eGFR > 35 ml/min, in case or contrast allergy or certain metal implants.

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