EchoCRT Revisited: A Role for CRT Despite Narrow QRS Complex?

The Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) trial was a disappointment: After it was halted in 2013 due to futility and possible harm, cardiologists essentially abandoned the goal of extending the use of CRT to the broader range of heart failure patients beyond the minority who had wide QRS intervals and met established guidelines for this lifesaving therapy.

But now, a team of researchers led by Cleveland Clinic electrophysiologist Niraj Varma, MD, PhD, has taken a second look at the EchoCRT data. They’ve identified a subgroup of patients with QRS duration of less than 130 ms who may actually benefit from CRT — specifically, those with a high ratio of QRS duration to left ventricular end-diastolic volume (QRSd:LVEDV ratio). Dr. Varma presented their findings in an Aug. 27 late-breaking science session at the European Society of Cardiology 2017 Congress in Barcelona.

The new data come from a post hoc analysis of EchoCRT, so Dr. Varma notes that they require validation in a prospective trial before any recommendations will change. But he says they offer an exciting hint that “the door is not shut” on the idea of widening the application of CRT to a broader group of heart failure patients.

“The original EchoCRT trial included a range of patients,” he explains. “Most deteriorated with CRT, but we discovered a significant minority that improved. Perhaps CRT should be directed to this subgroup of patients who might derive a survival benefit that they would otherwise be denied.”

Indeed, if the findings pan out, an additional 20 percent of heart failure patients might qualify for CRT in addition to the roughly 25 percent who are currently eligible by virtue of long QRS duration. “That’s a big deal,” Dr. Varma observes.

Essentials of EchoCRT

EchoCRT enrolled adult patients from 115 centers worldwide, including Cleveland Clinic. All patients had the following characteristics:

• New York Heart Association class III or IV heart failure on optimized medical therapy
• Left ventricular ejection fraction (LVEF) of 35 percent or less
• QRS duration of less than 130 ms
• Echocardiographic evidence of left ventricular dyssynchrony

At the time the study was terminated in March 2013, a total of 821 patients had undergone successful implantation of a device for CRT with a defibrillator. Of those, 404 were randomized to have the CRT capability turned on and the other 405 to keep it turned off.

Over a mean of 19.4 months, the primary outcome — a composite of death from any cause or first hospitalization for worsening heart failure — had occurred in 28.7 percent of the group with CRT on versus 25.2 percent of those with CRT off, a nonsignificant difference. Of concern, significantly more patients died in the group with CRT on (11.1 percent) than in the group with it off (6.4 percent).

Deeper dive based on QRSd:LVEDV ratio

In the new analysis, Dr. Varma and colleagues included the metric of LV size into patient stratification and divided the EchoCRT subjects by quartiles of QRSd:LVEDV ratio.

On multivariable analysis, those in the top quartile (Q4) (i.e., with the largest ratio) improved with CRT: The primary outcome occurred in 20.9 percent of patients with CRT on versus 28.3 percent of those with CRT off. In contrast, among patients in the lower three quartiles (Q1-Q3), the primary outcome occurred at a significantly higher rate in those with CRT on (31.7 percent) than in those with it off (24.8 percent). Thus CRT had opposite effects in these two patient groups, and the difference was statistically significant (P = .046 on test for interaction).

Structural remodeling followed suit. For patients with available echo data six months after device implantation, the mean increase in LVEF from baseline was comparable among all QRSd:LVEDV quartiles in patients with CRT off, whereas it was significantly greater in patients in Q4 than in patients in Q1-Q3 among enrollees with CRT on (6.1 percent vs. 3.9 percent; P = .048).

A pre-CRT electrocardiogram from the type of patient found to potentially benefit from CRT in the new analysis — a 56-year-old woman with nonischemic cardiomyopathy, NYHA class III heart failure, QRS duration of 122 ms and an LVEF of 30 percent. The image at the top of this post is a post-CRT radiograph from the same patient showing functional recovery with ventricular remodeling (LVEF of 58 percent).

Building on prior work, and looking ahead

The idea of incorporating LV volume into the CRT equation arose from prior work in which Dr. Varma was investigating sex-specific differences in CRT response. As detailed here, he found that women had a high probability of CRT response at QRS durations of 135 to 150 ms, equivalent to the response among men at 150 to 175 ms.

These sex differences persisted after QRS duration was normalized for body surface area, but they disappeared with normalization for either LV mass or end-diastolic volume. That led to the notion that the extent of LV remodeling is important — in addition to QRS duration and morphology — when evaluating both women and men as candidates for CRT.

Now that he’s found further support for this concept by applying it to the EchoCRT data, Dr. Varma hopes to begin a prospective trial of CRT focused on the high QRSd:LVEDV ratio subgroup. There’s already some work in this area in Japan, where the population’s smaller body size correlates with smaller LV volumes. “A QRS duration of 130 ms has different implications for someone from the U.S. versus Tokyo,” he notes, “though we don’t completely understand the interactions of body size and LV size in heart failure.”

For now, Dr. Varma says he’s “very happy that the hypothesis was sustained and the formula worked in this large trial. It’s exciting because it potentially benefits a very large number of heart failure patients.”