Two Conduction-System Pacing RCTs Give Conflicting Results

Conduction-system pacing (CSP) was put to the test in two randomized trials of patients requiring cardiac resynchronization therapy (CRT) for left bundle branch block (LBBB)—the HeartSync-LBBP and PhysioSync-HF studies—coming out on top of traditional biventricular (BiV) pacing in one and providing inferior results in the other, according to findings published online last week in JAMA Cardiology.

In the HeartSync-LBBP trial, LBB pacing reduced the risk of all-cause death or heart failure (HF) hospitalization versus BiV pacing, predominantly by lowering the number of hospital admissions, researchers led by Xueying Chen, MD (Zhongshan Hospital, Shanghai, China), report.

Chen previously presented the positive findings about a year ago at the European Heart Rhythm Association Congress, seemingly affirming prior observational studies and a small pilot RCT that had suggested CSP may improve outcomes over BiV pacing—which remains favored in practice guidelines—in CRT-eligible patients with heart failure.

In that context, the negative results of PhysioSync-HF, a noninferiority trial conducted in a similar population of patients with heart failure with reduced ejection fraction (HFrEF), were somewhat surprising. That Brazilian trial, which employed a mix of pacing techniques, showed that CSP failed to meet noninferiority criteria compared with BiV pacing and both increased adverse clinical outcomes and led to a smaller improvement in LVEF, researchers led by André Zimerman, MD, PhD (Hospital Moinhos de Vento, Porto Alegre, Brazil), report.

“We were not expecting the results that we saw there,” senior PhysioSync-HF investigator André d’Avila, MD, PhD (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA), told TCTMD.

He pointed to a couple of possible reasons for the discrepant results between the two trials, including differences in patient populations, the criteria used to determine LBB capture, and operator experience with CSP. Case volume was a major differentiator: in PhysioSync-HF, 42.8% of procedures were performed by operators with fewer than 40 prior CSP cases, whereas in HeartSync-LBBP, all cases were performed by operators with more than 285 prior CSP procedures.

“In Brazil right now, as a community, we should not change the guidelines and tell people coming to a public hospital to get CSP. Actually, they should have CRT [with BiV pacing],” d’Avila said. “It applies for many groups without enough experience to be 100% sure that they’re capturing the left bundle.”

Kenneth Ellenbogen, MD (Virginia Commonwealth University, Richmond), past president of the Heart Rhythm Society and a HeartSync-LBBP co-author, also pointed to operator experience as a key factor that might explain the divergent results of the two trials, questioning whether all patients randomized to CSP in PhysioSync-HF actually received appropriate therapy.

“The bottom line,” he commented to TCTMD, “is that some of the patients in the Brazilian study did not have conduction-system pacing. They just had septal pacing. And pacing someone’s septum who has advanced cardiomyopathy does not make them better—it probably hurts them, makes them worse.” In contrast, the operators performing CSP in China “were really spectacularly good at doing this,” Ellenbogen said.

He noted that CRT using BiV pacing with a coronary sinus lead is backed by 20 years of technology development and that operators required “hundreds and hundreds and hundreds of cases before they actually got pretty good at doing it.”

For CSP, there’s still a lot to learn. “It requires practice and skill and . . . it just is a good lesson for us,” Ellenbogen said of the new trial results.

The Brazilian PhysioSync-HF Trial

PhysioSync-HF, conducted at 14 hospitals in Brazil, included 173 patients (median age 62 years; 49.7% women) with HF who had NYHA class II/III symptoms, an LVEF of 35% or less (median 26% at baseline), and LBBB with a QRS duration of 130 ms or longer. All were treated with maximally tolerated guideline-directed medical therapy. About two-thirds had dilated cardiomyopathy.

In patients randomized to CSP, lead position was in the LBB area in 68.8%, in a deep septal location in 20.0%, and in the His bundle in 2.5%; another 8.8% had LBB area pacing with optimized resynchronization.

The primary outcome, assessed over 12 months of follow-up, was a hierarchical composite of death, HF hospitalizations, urgent HF visits, and change in LVEF, with significantly worse outcomes in the CSP group (OR 2.36; 95% CI 1.37-4.06). CSP failed to demonstrate noninferiority (P =0.99) compared with BiV because the upper bound the confidence interval exceeded 1.20.

The bottom line is that some of the patients in the Brazilian study did not have conduction-system pacing. Kenneth Ellenbogen

The rate of a composite of death, HF hospitalizations, and urgent HF visits occurred in 17.2% of patients treated with CSP and 9.3% of those treated with BiV pacing, a difference that fell just shy of statistical significance (HR 2.35; 95% CI 0.99-5.61). The mortality rate, however, was significantly higher in the CSP group (12.6% vs 4.7%; HR 3.36; 95% CI 1.05-10.71).

Mean LVEF increased in both groups, with a 3.8% greater gain with BiV pacing. On the other hand, there was a 33.1-meter greater increase in 6-minute walk distance and a lower total direct medical cost (by $7,090) in the CSP group. Other secondary outcomes, including QRS duration, quality of life, NYHA class, LV end-diastolic volume, and natriuretic peptide levels, improved to a similar degree in both arms.

In terms of safety, the proportion of patients with at least one procedure-related complication was 11.5% with CSP and 8.1% with BiV pacing; the most frequent issues were lead dislodgements or fractures. All three procedure-related deaths were in patients randomized to CSP, although one occurred after crossover to BiV pacing.

Overall, “these findings do not support the routine use of CSP as the first-line resynchronization strategy in this population,” the researchers say.

The Chinese HeartSync-LBBP Trial

HeartSync-LBBP, conducted at six centers in China, included 200 patients (mean age 64.8 years; 32% women) who had NYHA II-IV symptoms, an LVEF of 35% or less (mean 28.2% at baseline), and LBBB. Most (82.5%) had nonischemic cardiomyopathy.

The initial success of lead implant was high both in patients treated with LBB pacing (98%) and in those treated with BiV pacing (94%; P = 0.28).

The primary endpoint was a composite of all-cause death or HF hospitalization. Through a median follow-up of 36 months, three times longer than in PhysioSync-HF, 8% of patients treated with LBB pacing and 28% of those treated with BiV pacing had a primary event (HR 0.26; 95% CI 0.12-0.57). There was no significant difference in all-cause mortality between the two groups (2.0% vs 5.0%; HR 0.40; 95% CI 0.08-2.04), but LBB pacing led to a lower risk of HF hospitalization (7.0% vs 28.0%; HR 0.23; 95% CI 0.10-0.52).

“These findings might be explained by a greater improvement in electrical synchrony, ventricular remodeling, and consequent higher rate of super response in the LBB pacing group compared with the BiV pacing group,” Chen et al write.

At 6 months, the proportion of patients with an echocardiographic response, defined as at least a 5% increase in LVEF from baseline, was not significantly different between the LBB and BiV pacing groups (86.0% vs 81.0%; P =0.34). Super response (an LVEF increase of at least 15% or improvement to 50% or higher) was more frequent after LBB pacing (55.0% vs 36.0%; P < 0.007).

Both groups of patients had improvements in LVEF, LV end-diastolic diameter, LV end-systolic diameter, and NYHA functional class, with greater benefits observed in the LBB pacing group. Mean paced QRS duration was significantly shorter at implantation and last follow-up with LBB pacing. There were no major complications associated with LBB pacing, with one lead dislodgement and an increase in pacing thresholds in two cases in the BiV group.

Thus, the researchers concluded, LBB pacing “might be an alternative to BiV pacing in this patient population.”

More Definitive Answer Awaits

Due to the dearth of data from large randomized trials, BiV pacing remains the recommended approach for patients requiring CRT. Pacing and CRT guidelines from the European Society of Cardiology, for instance, say that “especially in CRT candidates with LBBB, biventricular pacing has more solid evidence of efficacy and safety, and therefore remains first-line therapy.”

Though HeartSync-LBBP and PhysioSync-HF are the largest trials to compare CSP and BiV pacing so far, they do not provide guideline-changing results, Ellenbogen indicated.

“They’re not definitive trials, they’re relatively small trials, and they don’t answer the question. You have to wait for the results of large-scale clinical trials,” he said, noting that several such studies will be reporting results in the next 2 to 3 years.

In the meantime, the choice between CSP and BiV pacing may come down to the operator’s skill set, Ellenbogen suggested. “If you’re putting a device in a patient who has left bundle branch block, you probably should start out with a coronary sinus lead unless you’re very experienced in putting conduction-system leads in. You have to know what you’re good at and what you’re capable of doing.”

[CSP] should be performed by experts who really know how to do this properly. André d’Avila

An important message from PhysioSync-HF, d’Avila said, is that in the absence of perfect criteria for LBB capture with CSP, a coronary sinus lead should be added during the same procedure. Ideally, he said, CSP “should be performed by experts who really know how to do this properly.”

In an editorial accompanying the two studies, Jens Cosedis Nielsen, MD, PhD (Aarhus University Hospital, Denmark), and colleagues grapple with the conflicting trial results, noting that neither study was powered to detect differences in hard clinical outcomes. No definitive answer can be obtained from these findings, they say, providing a nuanced conclusion.

“In carefully selected patients with truly correctable LBBB, treated by highly experienced operators achieving reliable left bundle branch capture, CSP may offer superior resynchronization and clinical outcomes compared with BiV pacing,” Nielsen et al write. “However, in more heterogeneous populations where CSP is delivered with variable technical success, BiV pacing may be better than CSP.”

They highlight the need for additional RCTs with “adequate follow-up and clinically meaningful endpoints” before CSP can be widely embraced as an alternative to BiV pacing.

“Trials must show,” they argue, “that CSP can prolong life, reduce heart failure hospitalization, and improve functional status and quality of life in broader populations of patients with heart failure and bundle-branch block.”