Women are underrepresented in cardiac resynchronization therapy trials

Abstract

Introduction Current guidelines for cardiac resynchronization therapy (CRT) device implant are the same across both sexes however women have been traditionally underrepresented in randomized controlled trials (RCTs). We aimed to identify if the number of women included in CRT trials is representative of the real‐world burden of heart failure (HF) in women. Methods RCTs evaluating the benefit of CRT in HF patients referenced in the 2012 EHRA/HRS expert consensus statement on CRT in HF were included. Studies were evaluated for gender representation, baseline variables, and gender‐based analysis of outcomes. Results A total of 10 CRT trials including 8107 patients were studied. Of the total patient population in these RCTs, only 23% were women. Analysis of outcomes based on sex was reported only in 5 out of 10 trials. Of these five trials reporting sex‐based outcomes, multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy (MADIT‐CRT) and resynchronization–defibrillation for ambulatory heart failure trial (RAFT) showed a greater benefit in women compared to men. Both MADIT and RAFT trials had a lower ejection fraction (EF) cut‐off in the inclusion criteria (EF ≤ 30%) compared to the studies that did not find gender‐based differences in the outcome (inclusion criteria: EF ≤ 35% or 40%). Additionally, women had less ischemic cardiomyopathy and more left bundle branch block (LBBB) compared to men in these two trials. Conclusion Women are underrepresented in CRT trials; however, they have been shown to derive a greater benefit from CRT compared to men. Appropriate measures should be taken in future studies to enhance the participation of women in clinical trials for more generalizable evidence.

Heart size disparity drives sex-specific response to cardiac resynchronization therapy: a post-hoc analysis of the MORE-MPP CRT trial

“…Importantly, we report results from the largest dataset of female CRT patients ever evaluated so far. (14) Our findings were as follows: CRT response was superior in females in the overall cohort . In the NICM LBBB cohort , female sex was not an independent response predictor. In the NICM LBBB cohort, increasing normalised QRSd is a significant independent response predictor. In the NICM LBBB cohort , CRT response was superior in females at QRSd < 150 ms and the association between normalised QRSd and response is strongest at QRSd <150ms. …”

“…Determining this accurately requires examination of large sample sizes, especially as women represent only 20-30% of the population in CRT trials. (14) Sex-related CRT response disparity may also be explained by differences in cardiac size, (15) that is, that females are relatively smaller than males, and therefore have a greater degree of dyssynchrony at a given QRSd. This is supported by studies that report that females exhibit an improved CRT response compared to males in cohorts with a QRSd <150ms.…”

“…Determining this accurately requires examination of large sample sizes, especially as women represent only 20-30% of the population in CRT trials. (14)…”

Sex‐based differences in cardiac resynchronization therapy upgrade and outcome for patients with pacemaker and new‐onset heart failure

“…A prior somewhat smaller study from the Swedish heart failure registry showed similar results on de novo CRT implants; a lower proportion of CRT use in women, but also equal underutilization for men 12 . Even though women have notoriously been underrepresented in the clinical trials, there is no evidence to support that the CRT effect women should be less favorable than for men 13 . On the contrary, several trials and meta‐analyses have found that (in de novo CRT implants) women have more pronounced reverse remodeling response, quality of life improvement and better survival free of heart failure hospitalization 14–16 .…”

“…12 Even though women have notoriously been underrepresented in the clinical trials, there is no evidence to support that the CRT effect women should be less favorable than for men. 13 On the contrary, several trials and meta-analyses have found that (in de novo CRT implants) women have more pronounced reverse remodeling response, quality of life improvement and better survival free of heart failure hospitalization. [14][15][16] The potential reasons for more favorable response in women are several; in some studies, they had higher percentage of biventricular pacing, and some have suggested that for a given QRS duration women have relatively more LV dyssynchrony amenable to correction.…”