Sex-Specific Differences in CRT Response: Have We Cracked the Code?

Two new studies on male-female differences in response to cardiac resynchronization therapy (CRT) may well reshape the way patients are selected to receive CRT devices. Both investigations were led by Cleveland Clinic electrophysiologist Niraj Varma, MD, PhD, who refers to his findings as “cracking the code” on sex-specific differences in CRT response.

Growing certainty around CRT advantages in women

One study — a large nationwide cohort analysis of cardiac implantable electronic devices (CIEDs) published in the May 2017 Journal of the American Heart Association — revealed that women account for less than 30 percent of high-voltage implants and fewer than half of low-voltage implants.

Yet the rationale for the lower use in females is questionable, since survival after receiving an implantable cardioverter-defibrillator (ICD) or pacemaker was found to be similar between the sexes over median follow-up of 2.9 years. Moreover, survival was 27 percent higher for women than men among patients receiving CRT defibrillators and 31 percent higher for women than men among those receiving CRT pacemakers.

The study, based on 269,471 patients implanted with CIEDs between October 2008 and November 2011, confirmed observational findings in Cleveland Clinic’s own patient population reported by Dr. Varma two years ago (as detailed in this previous post) — essentially suggesting that women are being overlooked for potentially beneficial therapy.

“There have always been questions about whether women derive the same benefit from implantable devices as men do,” Dr. Varma says. “The idea has been that defibrillators have less effect in women, but the data have been pretty weak. There has been a signal that women may do better with CRT devices, but that hasn’t been clearly defined because so many other factors come into play.”

Now the new study, especially when paired with the Cleveland Clinic-specific study, shows that women do as well as or better than men when offered implantable devices. “Moreover,” notes Dr. Varma, “more women tend to have left bundle branch block (LBBB) with QRS duration less than 150 ms, which are less strong requirements to qualify for CRT under current guidelines. Despite this fact, women with these characteristics have an especially higher probability of CRT response and potentially longer survival.”

Indeed, since 2015, Cleveland Clinic has been encouraging CRT for women with LBBB and QRS duration less than 150 ms despite current guidelines, which don’t differentiate between men and women.

Beyond body size

In further trailblazing work, Dr. Varma and other Cleveland Clinic researchers may have unearthed the explanation for the sex difference in response to CRT by QRS duration. If they’re correct, it suggests another major paradigm shift: The key factor appears to be differences in heart size — as opposed to body surface area or LBBB criteria. This would argue for taking into account the extent of left ventricular (LV) remodeling, in addition to QRS duration and morphology, when evaluating both women and men as potential candidates for CRT.

This proposed explanation comes from a retrospective analysis of 130 Cleveland Clinic patients published online in April 2017 by JACC: Clinical Electrophysiology. All patients — 55 percent of them female — had New York Heart Association functional class III/IV heart failure, nonischemic cardiomyopathy and strictly defined LBBB.

As in Dr. Varma’s earlier studies, the CRT response rate was greater in women than in men — in this case, 90 percent versus 66 percent. Women also had larger remodeling effects, with LV ejection fraction increasing from 21 percent to 37 percent compared with a rise from 17 percent to 25 percent in men. Women had a high probability of CRT response at QRS duration 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. Specifically, the likelihood of CRT response was 66.7 percent among patients below a QRS/LV mass cut point of 0.8 versus 94.8 percent among patients above that cut point.

“Men and women seem to have very different profiles of left ventricular enlargement, and these differences are not directly related to body size,” Dr. Varma says. “The common denominator for predicting CRT effect is QRS duration linked to left ventricular size. In the future, this could be included in guideline criteria regardless of patient sex. We’ve cracked the code.”

Where to go from here?

While it might take some time — and a randomized trial or two — before CRT guidelines are changed to reflect sex differences, the issue is starting to receive worldwide attention. A 90-minute session entitled “Gender Issues in ICD and CRT Therapy” is scheduled for June 18 at the EHRA Europace-Cardiostim 2017 conference in Vienna. “It’s the first time I’ve seen a session on this,” Dr. Varma says.

He’s not speaking at that session — he’s chairing another panel at the meeting — but the Cleveland Clinic data are sure to be discussed. “Everyone I’ve shown these findings to has found them very provocative,” he notes.