CLOSURE-AF: Worse Outcomes With LAAO Driven by Results in Women

Older women with atrial fibrillation (AF), but not their male counterparts, fared worse with left atrial appendage occlusion (LAAO) than with best medical care, which mostly included direct oral anticoagulant (DOAC) therapy, according to a sex-specific analysis of the CLOSURE-AF trial.

The main results of the trial, released in November 2025 and later published in the New England Journal of Medicine, not only failed to show that LAAO was noninferior to medical therapy for the primary endpoint of stroke, systemic embolism, major bleeding, or cardiovascular/unexplained death, but also demonstrated significantly worse outcomes among patients who underwent the procedure.

New data presented recently by Ingo Eitel, MD (University Heart Center Lübeck, Germany), co-principal investigator of CLOSURE-AF, at the European Society of Cardiology Congress 2026 in Munich, Germany, show that only women had poorer outcomes with LAAO, primarily related to an increased rate of CV/unexplained death.

The reason is unclear, Eitel said during a late-breaking science session, noting that clinical outcomes were generally similar between women and men overall, with female patients actually having a lower incidence of stroke. There were no major differences between sexes in terms of procedural success or periprocedural complications.

It’s possible that contemporary medical therapy is particularly beneficial in women, he indicated. “Probably women have a dedicated protection . . . from systemic anticoagulation with DOACs, for example.”

Overall, “we clearly have to conclude that sex may matter when we select for left atrial appendage occlusion procedures,” Eitel said, adding that “of course this is a substudy, it’s exploratory findings, [and] we have to be cautious.”

Nevertheless, physicians “probably have to think twice” about whether LAAO is a better option than DOAC therapy in a frail, elderly woman who doesn’t have a contraindication to oral anticoagulation, he said.

We haven’t proven beyond a shadow of a doubt that these procedures are equivalent for every single patient. Christine Albert

Christine Albert, MD (Mass General Brigham Heart & Vascular Institute, Boston, MA), who co-chaired the session at which Eitel presented the results, said the sex-related difference between LAAO and medical therapy in the risk of CV/unexplained death was puzzling.

“It’s lacking a mechanism to completely understand that,” she told TCTMD.

A few possibilities came up during a discussion that followed Eitel’s presentation, including a potentially higher risk of heart failure in women receiving LAAO and problems with device sizing in women versus men, but Eitel indicated that their data did not support those explanations.

“It’s really an unknown cause of why [the women] would have more death,” Albert said. “They are older, they are frail, and it just makes you want to pause a little bit when you see a patient like that. Is left atrial appendage occlusion really appropriate, especially if it’s somebody who you think can tolerate a [DOAC]?”

Sex in CLOSURE-AF

Explaining the rationale for delving into potential sex-based differences, Eitel pointed to prior data showing potentially higher lifetime risks of stroke and thromboembolic events, and greater susceptibility to bleeding, in women versus men. In addition, women have made up only about one-third of the randomized populations of LAAO studies, indicating a need for more information on the impact of the procedure in this group.

CLOSURE-AF included 888 patients with AF who had elevated risks of both stroke and bleeding who were randomized to LAAO or physician-directed best medical care, which included consideration of DOACs in those who were eligible. Overall, the 343 female participants (38.6% of the cohort), tended to have a higher risk profile compared with men. Women were older (80.5 vs 78.2 years) and had a lower body weight (70 vs 85 kg), higher CHA₂DS₂-VASc score (6.0 vs 5.0), and lower estimated glomerular filtration rate (44 vs 51 mL/min/1.73 m₂).

When considering all patients, regardless of which trial arm they were in, women and men had similar rates of the primary composite outcome (Gray’s P = 0.811) and CV/unknown death (Gray’s P = 0.27) through 6 years of follow-up. The incidence of stroke was lower in women (Gray’s P = 0.033).

A major sex-based difference emerged when looking at the impact of LAAO versus medical therapy. The procedure increased the rate of the primary endpoint in women (58.7% vs 35.1%; adjusted HR 1.66; 95% CI 1.13-2.46) but not in men (51.1% vs 47.8%; adjusted HR 1.07; 95% CI 0.80-1.44), with a significant P value of 0.03 for the interaction. 

For the individual components of the composite endpoint, there was a significant interaction between sex and the treatment effect only for CV/unexplained death (P = 0.03); LAAO increased the risk in women (HR 1.80) but not in men (HR 0.99). Risk of all-cause death also appeared to be higher with LAAO versus medical therapy in women only, although the interaction was not significant (P = 0.07).

These sex differences were consistent across subgroups defined by age, renal function, body weight, thromboembolic risk, and bleeding risk.

Albert noted that the overall CLOSURE-AF results contrast with those from CHAMPION-AF and OPTION, which yielded a more positive outlook for LAAO.

“We haven’t proven beyond a shadow of a doubt that these procedures are equivalent for every single patient,” she said. “So I do think it’s useful to have these data [from CLOSURE-AF]. And it’s also going to be useful to look at the other trials.”

At this point, most physicians continue to individualize the choice between LAAO and DOAC therapy, Albert added.