Resynchronization Pacing May Work Well in Non-LBBB: ENHANCE CRT

May 21, 2018

BOSTON — Cardiac resynchronization therapy (CRT) seemed to improve 12-month clinical outcomes in patients with heart failure (HF) but without left bundle-branch block (LBBB) on their electrocardiograms (ECGs) in a small randomized trial.

On the other hand, the ENHANCE CRT pilot study, conducted solely in such "non-LBBB" patients, did not show an advantage to using an electrophysiologic measure of left ventricular (LV) delay to guide lead placement when implanting the CRT's biventricular lead system.

The study's main purpose had been to compare that targeted approach to the traditional practice of placing the LV lead over the lateral or posterolateral wall.

When CRT was developed for patients with LBBB and a prolonged QRS duration, it seemed right to place the LV lead in one of those lateral positions because the LV wall is among the last regions of the heart to be activated each cycle, explained Jagmeet P. Singh, MD, DPhil, Massachusetts General Hospital, Boston, for theheart.org | Medscape Cardiology.

But the activation sequence is less well understood in non-LBBB patients, who tend not to respond well to CRT, at least when the LV lead is positioned in the usual anatomic-guided way as operators typically do, he said.

Such operators, "even without guidelines for non-LBBB, have been treating them essentially like LBBB," Singh, who had presented ENHANCE CRF here at the Heart Rhythm Society (HRS) 2018 Scientific Sessions, said when interviewed.

First Such Randomized Trial

The trial sought to determine whether mapping a patient's degree of intrinsic LV delay (QLV) in the anterolateral LV wall improved lead placement and CRT outcomes in non-LBBB.  If QLV was increased enough at that site, the LV lead was positioned over the anterolateral instead of the lateral wall. Otherwise, it was placed over the lateral or posterolateral wall, Singh explained.

Lateral or posterolateral lead placement was routine in the non-LBBB patients randomly assigned to standard of care.

ENHANCE CRT is the first head-to-head comparison of LV lead placement guided by electrical delay vs the standard of care, Singh said. As it turned out, both approaches to LV lead placement were associated with significant improvement in patients' clinical composite scores, symptoms, quality of life, and ventricular function.

But neither approach fared better than the other in the primary analysis of this study with 190 patients, all of whom qualified for CRT by clinical, ejection fraction, and QRS criteria.

Patients with LBBB and right bundle-branch block (RBBB) show left- or right-heart conduction delays, respectively. Both the LBBB and RBBB definitions call for a QRS duration of 120 ms or more on the ECG.

Guidelines prefer use of CRT in the presence of LBBB and a QRS of 150 ms or greater and give qualified support for use with QRS of 130 ms or more.

Non-LBBB, but Wide QRS Durations

ENHANCE CRT's non-LBBB patients had RBBB or an intraventricular conduction delay (IVCD). For entry, the study required a QRS of 120 ms or greater, but it was 150 ms or greater in more than half of patients in both lead-placement groups.

Although ENHANCE CRT must be considered a "neutral" study, "from my perspective it was a very positive study," said Michael R. Gold, MD, PhD, Medical University of South Carolina, Charleston, as assigned discussant for Singh's presentation.

"It showed that CRT is an effective therapy in patients with non-LBBB. Particularly in this study — the mean QRS duration was greater than 150 ms."

A number of possible explanations were raised here for why the targeted strategy didn't outperform the standard anatomic approach. Gold proposed several potential reasons, including that the QLV threshold used to assess ventricular delay for lead placement may not have been long enough or that QLV may simply not be a predictor of response to CRT in non-LBBB patients.

"I think the reason for not finding a difference between the two arms is probably because there was some overlap in the final lead locations between both patients," Singh said when interviewed. Lots of patients in the "targeted" arm ended up with leads over the lateral wall, he noted.

That shows anatomic lead positioning is often sufficient, even in non-LBBB, Singh said. "The added value that you get from adding electrical delay over the conventional anatomic approach may not be large enough, or individualized enough, for you to tease out the benefit."

Mostly NYHA Class III

ENHANCE CRT randomly assigned 242 non-LBBB patients implanted with quadripolar-lead, defibrillating CRT systems that were first-time implants or upgrades; 190 were available for the 12-month follow-up.

The total population's mean LV ejection fraction (LVEF) was about 26%; 96% of patients were in NYHA class III heart failure, and the rest were in class IV. About 60% had coronary disease.

Their QRS durations were 120 to 149 ms in 45.8% of cases and longer in the remainder; 60.5% had RBBB and 39.5% had IVCD. Patients with permanent or persistent atrial fibrillation had been excluded.

Clinical composite scores improved by 1 year in 67.2% of the 128 patients with QLV-targeted lead placement and in 72.6% of the 62 who had anatomic lead placement (P = .51). There were no significant differences in the proportions who worsened or showed no change in their clinical composite scores.

In addition, no apparent variation was seen in responses by subgroups, including RBBB vs IVCD, QRS interval, sex, heart failure cause, or LVEF.

Both groups showed significant and similar improvements in LVEF, by 5.8 points in the QLV-guided group and 5.5 points in the anatomy-guided group (both P < .01). That was also true for improvements in scores on the Minnesota Living with Heart Failure Questionnaire, by 17 points and 15.1 points, respectively (both P < .001).

How Consistent With Clinical Trials?

Non-LBBB patients may be passed over for CRT, in part because the major trials didn't emphasize them as a group that would benefit, and the MADIT-CRT trial suggested CRT may increase their mortality, Gold observed.

That finding, he noted, wasn't from a prespecified analysis, and indeed, COMPANION and RAFT were the only major CRT trials to prespecify an analysis of outcomes in non-LBBB patients.

During discussion following his formal ENHANCE CRT presentation, Singh pointed out that the trial included patients in NYHA class III to IV, whereas MADIT-CRT entered patients in milder NYHA class I to II. That makes the latter trial's finding of possible harm in non-LBBB less relevant to the current study.

"I would not make MADIT-CRT conclusive on this, in any way," he said. The question of whether CRT benefits in non-LBBB "is still open," considering its observed positive effects in both arms of the current study.

"I would say we need to reconsider our approach to non-LBBB," he said, and explore whether there might be ways to individualize CRT lead placement even among those patients.

When interviewed, Singh observed that His-bundle pacing may be a promising alternative CRT modality in non-LBBB patients. But he said the underlying myopathy of most such patients may not be ideal for a resynchronization effect from His-bundle pacing.

"The conduction-tissue disease in this population may be more patchy than discrete. As a result of which, if you do His bundle pacing, you may not have the exact uniform response of electrical synchrony as you would expect," he said.

"I'm speculating, but that remains to be seen, and I think having a His-bundle study in this patient population would be very meaningful."

All devices implanted in ENHANCE CRT were from St Jude Medical/Abbott, which sponsored the study. Singh discloses receiving grants or compensation for services from Abbott, Biotronik, Boston Scientific, EBR Systems, Medtronic, Impulse Dynamics USA, and LivaNova. Gold discloses receiving grants or compensation for services from St Jude Medical/Abbott, Boston Scientific, and Medtronic.

Heart Rhythm Society (HRS) 2018 Scientific Sessions. Abstract B-LBCT01-03.  Presented May 10, 2018.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org, follow us on Twitter and Facebook.

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