His-Alternative II: Conduction-System Pacing Holds Up Well in CRT-Treated HFrEF

In patients with heart failure with reduced ejection fraction (HFrEF) who are in sinus rhythm and have an indication for cardiac resynchronization therapy (CRT), conduction-system pacing (CSP) provides results that are noninferior to those obtained with traditional biventricular pacing, data from the randomized His-Alternative II trial show.

The mean reduction in left ventricular end-systolic volume (LVESV) from baseline to 6 months was 35% among patients treated with CSP and 34% among those treated with biventricular pacing, a difference that met criteria for noninferiority with a 10% margin (P = 0.003).

Michael Vinther, MD, PhD (Copenhagen University Hospital - Rigshospitalet, Denmark), presented the findings recently at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany. Various secondary outcomes and safety endpoints were similar in the two groups, he reported.

The findings were published simultaneously online in JACC: Clinical Electrophysiology.

His-Alternative II adds to a growing evidence base on the impact of CSP in the context of CRT for HFrEF, with observational studies and smaller RCTs generally pointing toward results that are at least as good as, if not better than, those seen with biventricular pacing. But not all CSP studies have been positive, and the most recent ESC guidelines on pacing and CRT state that “especially in CRT candidates with LBBB [left bundle branch block], biventricular pacing has more solid evidence of efficacy and safety, and therefore remains first-line therapy.”

Considering the totality of the evidence, including the results of His-Alternative II, Vinther concluded that “conduction-system pacing shows promise as an alternative resynchronization strategy to biventricular pacing, but we do need larger randomized studies with longer follow-up to firmly establish the future role of CRT delivered with conduction system pacing.”

His-Alternative II

Conducted at two centers (one in Denmark and one in England), His-Alternative II included 148 candidates for CRT (mean age about 68 years; 65% men) who were in sinus rhythm and had NYHA class II-IV symptoms, an LVEF of 35% or lower, and either LBBB based on the Strauss criteria or a prior pacemaker with more than 90% right ventricular pacing. Mean LVEF at baseline was 27-28%.

Patients were randomized 2:1 to CSP or biventricular pacing. In the CSP arm, operators were instructed to first try His-bundle pacing (with a threshold < 2.5 V at 1 ms for capturing His with correction of LBBB). If that was not possible, they would attempt LBB pacing. Crossover to biventricular pacing was allowed if CSP was not successful; this occurred in 15% of cases. Only one patient crossed over from biventricular pacing to CSP.

The noninferiority of CSP versus biventricular pacing in terms of the change in LVESV was consistent in an on-treatment analysis. There were no significant differences between the biventricular pacing and CSP arms on several secondary outcomes:

• CRT response, defined at a ≥ 15% reduction in LVESV (79% vs 80%)
• Change in NT-proBNP level (mean -110 vs -72 pmol/L)
• Change in 6-minute walk distance (mean +24 vs +37 m)
• Change in NYHA class (mean -0.6 in each arm)
• Change in Minnesota Living with Heart Failure Questionnaire score (mean -13 vs -16)
• Change in LVEF (mean +14% in both groups)

In the on-treatment analysis, the CRT response rate was 78% with biventricular pacing, 88% with His-bundle pacing, 83% with LBB area pacing, and 40% with deep septal pacing.

Safety did not differ significantly between trial arms, with three deaths among patients treated with biventricular pacing and six among those treated with CSP. There was only one unplanned hospital admission, which was for atrial fibrillation and worsening HF in a patient who received biventricular pacing. No patients had periprocedural complications, with similar rates seen up to 6 months.

Haran Burri, MD (University Hospital of Geneva, Switzerland), the discussant at the Hot Line session, called His-Alternative II an important study, although he pointed out some issues to consider, including the relatively small sample size and the lack of information on how well conduction-system capture held up over time.

He highlighted the “somewhat lenient” definition of LBB area pacing used by the investigators, which was less detailed than the criteria laid out in a European Heart Rhythm Association consensus statement on CSP released in 2023. Burri, who was the lead author of that statement, noted, however, that His-Alternative II began prior to the statement’s publication.

The CRT response rate in the LBB area pacing group is difficult to interpret, he indicated, because it’s unknown whether that pacing was done with or without capture of the conduction system. “That’s important,” he said, “because we know that for heart failure treatment, if you want to get the best results, you need to capture the conduction system of the left side.”

As for the 15% rate of crossover from CSP to biventricular pacing, “some people may think that this is high, but I think it’s very much in line with expectations,” Burri said, pointing to prior registry and RCT findings.

Overall, he said, His-Alternative II “adds to the knowledge that we now have on randomized controlled trials in the domain of CSP and we look forward to the larger trials which are currently [ongoing].” 

Information from those forthcoming studies “I think then will change guidelines,” he added.