Conduction-System Pacing CRT Shines vs BiV in Early Studies

Could single-lead pacing systems for the delivery of cardiac resynchronization therapy (CRT) match or even surpass systems with three leads? Perhaps, suggest several new comparative studies, including a small, randomized trial.

Together the studies make a solid case for conduction-system pacing (CSP) as an alternative, at least, to conventional biventricular (BiV) pacing for CRT in suitable patients with heart failure and reduced ejection fraction.

They also seem to validate expectations that CSP would be superior to BiV pacing at improving electrocardiographic (ECG) dyssynchrony, left ventricular (LV) function, and perhaps clinical risk in such patients.

Unlike BiV pacing, CSP as performed in the studies relies on one lead positioned at either the left bundle branch (LBB) or His bundle to directly stimulate the heart's native conduction network. It's considered more physiologic and, in a major advantage, does not directly pace the right ventricle.

Two of the new studies — the 40-patient randomized trial and a prospective registry study 10 times larger — were reported separately at the Heart Rhythm Society (HRS) 2022 Scientific Sessions, held virtually and live in San Francisco. Another registry-based study with 100 patients appeared recently in the literature.

They set the stage, observers say, for larger and more definitive randomized contests between the two pacing strategies that could determine whether CRT is ready for its next big evolutionary step.

CSP "has potential to replace all pacing that we do, both standard brady-pacing, but also resynchronization," Jeffrey Healey, MD, MSc, Hamilton Health Sciences and McMaster University, Ontario, Canada, told theheart.org | Medscape Cardiology.

"Large clinical trials are going to be key to this," Healey said, given the deep randomized-trial history supporting BiV pacing for reversing ventricular dyssynchrony and improving survival in patients who meet the appropriate ECG and LV functional criteria. That exceptionally well-established evidence base extends back more than 2 decades to the MIRACLE and COMPANION trials.

"All Predictions Came True"

The new randomized efficacy comparison, conducted at two centers in China, represents "the first step" in advancing LBB pacing as a viable CRT alternative to BiV pacing in appropriate patients with HF, said Fengwei Zou, MD, Montefiore Medical Center, Bronx, New York, when presenting those findings April 30 at the HRS sessions. The trial, called LBBP-RESYNCH, entered only patients with nonischemic disease and LBB block.

Left ventricular ejection fraction (LVEF) at 6 months, the primary endpoint, climbed significantly from baseline in both CRT groups, but went up a mean 5.7 points further (P = .039) with LBB pacing, with most of the difference evident within the first 3 months.

The trial suggests LBB pacing has the potential to become a first-line CRT strategy "alongside BiV pacing" in nonischemic HF with LBB block, Zou said, with the proviso that it was small and the follow-up short compared to the decade or more individual patients may live with CRT devices.

Baseline LVEF averaged 29.7 and mean QRS duration was 174.6 ms in the 20 men and 20 women randomly assigned to CRT with LBB pacing or BiV pacing. Two patients in the LBB pacing group crossed over to BiV pacing, and the reverse crossover was necessary for four assigned to BiV pacing.

However, analysis was by intention to treat, reported Zou, not a coauthor on the study but who as a presenter was filling in for his father, coprincipal investigator Jiangang Zou, MD, PhD, First Affiliated Hospital of Nanjing Medical University, China.

LVEF Parameter	LBB Pacing Group	BiV Pacing Group
Change in LVEF, LBB Pacing vs BiV Pacing for CRT in LBBP-RESYNCH
Baseline (%)	28.3	31.1
6 months (%)	49.4	46.5
Increase (% points)	21.1*	15.4
*P = .039 vs BiV pacing

The limited pilot study showed significant "amazing trends" favoring LBB-CRT that justify larger, more definitive randomized comparisons with BiV-CRT, agreed Kenneth Ellenbogen, MD, Virginia Commonwealth University Medical Center, Richmond, as the invited discussant for Zou's presentation.

"All the predictions one might have made based on physiology came true; that is, better ejection fraction, decrease in volume of the left ventricle, N-terminal proBNP levels were lower, a trend toward shorter QRS duration, and an increased response rate," said Ellenbogen, who was senior author on possibly the earliest published experience of LBB pacing in HF.

Less Risk for HF Hospitalization

Elsewhere at the HRS sessions, CRT by CSP — either at the LBB or His bundle — outdid BiV-CRT for the primary endpoint of 1-year death or HF hospitalization in a registry study of patients with CRT indications with or without LBB block at four centers in two major American health systems.

The LBB pacing advantage seemed to be driven by a steep reduction in risk for HF hospitalization, reported Pugazhendhi Vijayaraman, MD, Geisinger Heart Institute, Danville, Pennsylvania, April 29 at the HRS sessions. Vijayaraman was also lead author on the study's same-day publication in Heart Rhythm.

Some in the electrophysiology community have been exploring CSP in practice as a first-line CRT approach, despite the long and successful track record of BiV-CRT, because it's more physiologic, but no one knows for certain whether that mechanistic rationale translates into better functional and clinical outcomes, Vijayaraman observed at a press conference on the study.

Still, he said, the "signal is pretty strong." The current study "gives us confidence that we're not making things worse than with the established therapy and are able to improve outcomes on top of what can be achieved with BiV pacing."

Indeed, electrophysiologists "should learn the skills of His-bundle and left bundle-branch pacing" as additional tools for achieving best results from CRT. They wouldn't necessarily be a first approach, he said, but should be available for "patients who are not getting the best biventricular pacing at the time of implant," perhaps because of anatomic limitations or myocardial scarring. In such cases, "we can quickly move over to do conduction-system pacing."

The baseline LVEF averaged 26% in the registry study's 477 patients, 219 of whom received BiV-CRT at one center and 258 in whom CRT was achieved by either His-bundle or LBB pacing at three other centers in a single health system; about one-third of the participants were women.

The rates of death or HF hospitalization were 28.3% and 38.4% for CSP and BiV pacing, respectively, for an adjusted hazard ratio (HR) of 1.52 (95% CI, 1.08 - 2.09; P = .013) for freedom from the primary endpoint. There were no significant differences in all-cause mortality by itself, but the HR for freedom from HF hospitalization was 3.15 (95% CI, 2.07 - 4.79; P < .001) favoring CSP.

The results were similar and arguably more pronounced in favor of CSP among the 227 patients with LBB block: HR of 2.1 (95% CI, 1.24 - 3.52; P = .006) for freedom from the primary outcome and HR of 3.48 (95% CI, 1.73 - 6.98; P < .001) for freedom from HF hospitalization. Echocardiographic responses were also superior with CSP.

Response by Group	CSP (%)	BiV Pacing (%)	P Value
Echocardiographic Responses to CSP vs BiV Pacing for CRT
All patients (n = 442)
Echo response	69	46	<.001
Echo super-response	42	25	<.001
LBB block patients (n = 227)
Echo response	81	51	<.001
Echo super-response	50	29	.005
Echo response, ≥5% LVEF increase; echo super-response, LVEF increase to >50% or by at least 15 absolute percentage points.

Largely consistent echo findings emerged from a recently published registry study of 100 patients successfully implanted with CRT systems, 49 with LBB pacing and 51 with BiV pacing. Pacing thresholds and QRS responses also significantly favored the LBB pacing group in the experience published in the May issue of EP Europace, with lead author Xueying Chen, MD, PhD, Zhongshan Hospital of Fudan University, Shanghai, and Ellenbogen as a coauthor.

Rates of CRT response did not differ significantly between LBB and BiV pacing groups; a response was defined as an absolute increase of more than 5% in LVEF at either 6 months or 1 year. But the rates of super-response — defined here as an absolute increase of more than 20% in LVEF to higher than 50% — were 53.1% and 36.6% for LBB and BiV pacing, respectively, at 6 months (P = .016) and 61.2% and 39.2%, respectively, at 1 year (P = .028).

Following Zou's LBBP-RESYNCH presentation, Ellenbogen proposed that any forthcoming trials pitting CSP-CRT against BiV-CRT enroll "somewhere between 800 to 2000 patients" and look for "long-term improvement in important inarguable outcomes: cardiovascular mortality, heart failure hospitalization, cardiovascular death, and death, and then secondarily look at LV remodeling and ejection fraction."

Such trials, added Mina Chung, MD, Cleveland Clinic, as invited discussant for Vijayaraman's presentation, should include not only patients with current guideline-recommended LVEF of 35% or less, "but let's look at those intermediate LVEFs of 36% to 50%."

Healey discloses receiving honoraria or fees for speaking or consulting from Cypher Pharma, Servier, Boston Scientific, Myokardia, and Bayer Healthcare; serving on a speakers bureau for Bristol-Myers Squibb; and receiving research grants from Boston Scientific, Medtronic, Bristol-Myers Squibb, Pfizer, and Servier. Zou reports no relevant disclosures. Ellenbogen discloses receiving honoraria or fees for speaking or consulting from Boston Scientific, Medtronic, Kestra, Hylomorph, Biotronik, MediLynx, Milestone Pharmaceuticals, Impulse Dynamics, Abbott, Biosense Webster, Sanofi, and Medpace; and royalty income from Elsevier. Vijayaraman discloses receiving honoraria or fees for speaking or consulting from Abbott, Boston Scientific, Medtronic, Biotronik, and Eaglepoint; and receiving research grants from Medtronic. Chen and coauthors declare no conflicts of interest. Chung discloses receiving royalty income from Elsevier.

Heart Rhythm. Published online April 29, 2022. Abstract

Europace. 2022;24:807-816. Full text

Heart Rhythm Society (HRS) 2022: Abstract LB-735-03. Presented April 29, 2022; Abstract LB-733-02, Presented April 30, 2022.

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