Sex Differences Diminish With Third-Generation TAVR Device

Among high-risk and intermediate-risk patients, men and women have similar outcomes out to 1 year when treated with a newer-generation TAVR device, according to data from the PARTNER II S3 trial. But a meta-analysis of TAVR trials looking at longer-term outcomes supports the theory that women may—as earlier studies have hinted—still have a survival advantage.

Data from both the PARTNER and PARTNER IIa trials have previously shown better survival in women compared with men. As the authors of one of the new studies say, having the full complement of sizing options and using CT scans as standard of care have likely closed the gap.The earlier PARTNER studies looked at patients who received first- and second-generation devices, whereas the new PARTNER II S3 data include only high- and intermediate-risk patients who received the Sapien 3 valve (Edwards Lifesciences).

“At first I was surprised [by the results], and then I was thinking about it and I couldn’t say the S3 valve itself equalized everyone because that kind of didn’t make sense,” lead author Molly Szerlip, MD (Heart Hospital Baylor Plano, TX), told TCTMD. “We thought that women had a survival advantage, [but] it may have been that men had a disadvantage and once we leveled the playing field it equalized.”

Specifically, Szerlip cited the availability of 29-mm valves as a major player in leveling the field. Having correct valve sizing and preoperative CT, she added, are primarily what separate the PARTNER II S3 from the previous PARTNER trials since the sites and operators remained the same, making experience or learning curve unlikely factors in equalizing outcomes. Another possible factor is demographics, since patients in PARTNER II S3 had lower overall risk than in the prior PARTNER trials.

The study by Szerlip et al was published this week in JACC: Cardiovascular Interventions.

The 1,661 patients were enrolled in the trial between October 2013 and December 2014. Compared with men, women were more likely to experience major vascular complications (7.2% vs 4.2%; P = 0.009), but no more likely to develop bleeding events or acute kidney injury at either 30 days or 1 year. After TAVR, women had smaller valve areas than men, which persisted after indexing for body size (0.85 cm²/m² vs 0.91 cm²/m²; P < 0.0001).

At 30 days and 1 year there were no differences between men and women in the rates of any outcomes, which included all-cause mortality, cardiac mortality, rehospitalization, disabling stroke, MI, permanent pacemaker placement, moderate/severe paravalvular leak, or in the combined endpoint. On multivariable analysis, female sex was not an independent predictor of all-cause mortality at 180 days (HR 1.16; 95% CI 0.77 to 1.75) or between 180 days and 1 year (HR 0.61; 95% CI 0.35 to 1.06).

Sex-Specific Research Still Needed

In an editorial accompanying the paper, Brian R. Lindman, MD, MS, and Robert N. Piana, MD (Vanderbilt University Medical Center, Nashville, TN), say while the PARTNER II S3 trial showed no differences, there is enough suggestion of a difference from other studies to encourage exploration of whether there are factors that can be modified to optimize outcomes for all patients.

“These studies can inform future quality improvement initiatives and point to potential adjunctive therapies or interventions that may be administered in a sex-specific manner but with the overall goal of improving quality of life and survival for both sexes,” Lindman and Piana write.

Szerlip agreed that research into sex-based differences remains important, particularly to see if differences are observed as newer valves are introduced.

Another important issue to keep an eye on, she added, is that women are continuing to have vascular complications no matter how small the sheaths get. “[The complications] didn’t translate into higher mortality, but they are still important and are much more common in women,” she observed. “As we get into lower-risk populations we need to worry about morbidity as well, not just mortality.”

Asked if she was optimistic that the lack of difference will hold long term, Szerlip said only time will tell. “I don’t see why there would be any difference though,” she noted. “With intermediate-risk patients especially, at 3 years there really shouldn’t be a difference at all because their comorbidities are less and their survival should be better in general.”

Looking Longer Term

A second paper in the same issue of the journal attempted to address just that, with researchers reporting 3-year outcomes in a meta-analysis that analyzed TAVR outcomes by gender.

Despite having more bleeding and vascular complications, women had lower all-cause mortality than men (RR 0.86; 95% CI 0.81-0.92). However, women had a greater long-term risk of stroke/TIA than men.

“To our knowledge, our meta-analysis is the first to report that such risk remains significantly higher in women at long-term follow-up (mean follow-up of 1.4 years),” write researchers led by Marwan Saad, MD, PhD (University of Arkansas for Medical Sciences, Little Rock).

The analysis of 17 studies found that women were older but had fewer comorbidities than their male counterparts. Saad and colleagues say the long-term risk of stroke in women compared with men “should be carefully considered and therapies directed at stroke reduction should be implemented.”

Unlike the PARTNER II S3 study, the meta-analysis included only first- and second-generation TAVR devices. But like the PARTNER II S3 investigators, Saad and colleagues say the unavailability of the 29-mm valve could explain some of the better long-term survival after TAVR in women.

“Because TAVR is based on sutureless anchoring of the prosthesis across the annulus, using more balloon-expandable valves in women could have contributed to optimal stent frame expansion and less moderate/severe [aortic insufficiency] compared with men,” they conclude.