Abdominal aortic aneurysms : sex and gender disparities in surveillance, treatment and outcome

Background: In the field of abdominal aortic aneurysm (AAA), a lot of what is unknown converge in two specific topics: untreated patients and women. Best management strategies related to surveillance, treatment and outcome are all centered around the fact that surgical repair is indicated when the risk of rupture exceeds the risk of adverse surgical outcomes. The difficulty of this risk-benefit balance is a central and recurrent theme in scientific and clinical contexts. In clinical research, surgical outcomes have tended to gain much more attention than the outcomes of patients surgically untreated for their AAA. The scarce representation of women in randomized trials, screening-based materials and also observational efforts has left us with inferior knowledge on best management for women. Many crucial pieces of information related to surgical non-eligibility, rupture risk and mortality lack sex and gendered specification. An overarching example is the scientific uncertainty around the optimal repair threshold for women. The overall aim of this thesis was to increase the scientific understanding of clinical AAA disease and its special implications in women through all the phases of care: surveillance, treatment and outcome.

Methods and Results: In Study I and II, surgically untreated patients were investigated. Study IIII and IV were studies on surgically treated patients. The aim of the population-based Study I was to characterize patients untreated for their AAA. All patients (≥40 years) diagnosed with an AAA in Sweden 2001-2015 were included by identification from the National Patient Register. There were 19 569 patients who never proceeded to surgical repair during the 14-year period (60% of all diagnosed patients in the nationwide population). In this untreated population, the proportion of women was 23%. The comorbid loads of women and men were similar: equally many women and men had two or more concomitant diseases (15.9% vs. 15.3%, p = 0.46). Within 5 years, 798 ruptures occurred, more frequently in women than men (9.7% women vs. 6.9% men, p <0.001). Female sex was an independent risk factor for rupture (HR 1.23, 95% CI 1.07-1.42, p <0.001, while adjusting for age, comorbidities, and disposable income). More women died because of rupture (11.9% vs. 8.7%, p<0.001). In both women and men, mortality was high – median survival was 5 years.

In Study II, the excess surgical non-eligibility in women was under scrutiny in a multicenter design with detailed patient- and aneurysm-related data. From the vascular outpatient clinics of Stockholm (Sweden), Trondheim (Norway) and Graz (Austria), 200 women and 200 men with AAAs in surveillance were consecutively identified (no prior infrarenal repair), starting from Jan 1st 2014. Through manual chart review, every patient was followed-up for 7 years. Women and men had similar median diameters at inclusion and treatment decisions. When applying sex-specific repair thresholds (50 mm women, 55 mm men), fewer women underwent repair (47% vs. 57%). More women were classified as truly untreated (untreated despite AAA reaching threshold, 26% vs. 8%, p <0.001). In a reanalysis with a 55 mm threshold, truly untreated status remained twice as common among women (16% vs. 8%). There were no apparent distinguishing reasons for truly untreated statuses among women: 50% women and men remained truly untreated due to comorbidities alone, and 36% had comorbidities combined with morphological challenges. Imaging analysis showed similar eligibility for endovascular repair in women and men. Among truly untreated women, ruptures were common (18%) and mortality was very high (86%).

In Study III, surgical outcomes were examined in relative survival terms among the 12 907 patients who underwent elective repair. A relative survival analysis compares the survival of a study cohort to that of an age, sex- and year-matched general population. The impact of two major changes in best management, 1) endovascular repair and 2) the cardiovascular recognition of patients as high risk, were investigated in a time-resolved analysis (Period 1: open repair dominated [2001-2004], Period 2: transition-period [2005- 2011], Period 3: endovascular first strategy [2012-2015]). In this treated population, the proportion of women was 17%. Despite declining trends in procedural mortality, the relative survival remained constantly compromised and low for all treated patients. The relative survival of women was worse (4-year relative survival 0.78-0.80 compared to 0.89-0.91 for men, from Period 1 to 3). There was no periodic shift in causes of death: both women and men died mostly of cardiovascular causes (49%).

Study IV was an observational appraisal of the women-specific repair threshold. The association between AAA size at repair (smaller or larger than the threshold for men, 55 mm) and mortality was investigated among all the 1380 women with elective repairs registered in the Swedish National Registry for Vascular Surgery 2008-2022 (35% repairs at small sizes). Mortality rates of women were high (3.5% at 90 days, 6.7% at 1 year, 15.4% at 3 year) with no clear differences in the two size strata. There was no consistent association between AAA size at repair and mortality up to 3 years in multivariate models (logistic regression and propensity score models). Sex discrepancies in mortality exclusively stemmed from high mortality among younger-than-average women undergoing repair.

Conclusions: Untreated status is the dominating status in the AAA care trajectory, a finding often overseen. This population of untreated patients with AAA disease is characterized as having a very high 5-year mortality rate. The disadvantaged situation for women at every step of the care trajectory was elucidated, with high rates of surgical non-eligibility, high rupture rates, high mortality rates due to rupture, and high postoperative mortality. The internal balance between these excess risks in women seems delicate and complex. The surgical non-eligibility in women remains a reality without clear causes, opening up for future studies with broader considerations of patient- and aneurysm-related factors as well as health care equity. The so far chosen strategy of early repair at smaller AAA sizes does not emerge as uncontroversial and does not ameliorate surgical outcomes in women. Something is also leading to relatively worse longevity after repair in women. Going forward, improved health in women with AAA disease will be obtained by proportionate inclusion of women into studies, routine sex- and gender-specific reporting, increasing consideration of patient input and subgroups of women, and database collaborations facilitating women-specific studies.

List of scientific papers

I. Sex Differences in Rupture Risk and Mortality in Untreated Patients with Intact Abdominal Aortic Aneurysms. Talvitie Mareia, Stenman Malin, Leander Karin, Roy Joy, Hultgren Rebecka. J Am Heart Assoc. 2021 Feb;10(5):e019592.
https://doi.org/10.1161/JAHA.120.019592

II. Women with Large Intact Abdominal Aortic Aneurysms Remain Untreated – A Multicentre Sex-Specific Analysis of Surgical Non-Eligibility. Talvitie Mareia, Åldstedt Nyrønning Linn, Stenman Malin, Roy Joy, Cohnert Tina, Hultgren Rebecka. [Submitted]

III. Long-term Prognosis After Elective Abdominal Aortic Aneurysm Repair is Poor in Women and Men: The Challenges Remain. Bulder Ruth, Talvitie Mareia, Bastiaannet Esther, Hamming Jan, Hultgren Rebecka, Lindeman Jan. Ann Surg. 2020 Nov;272(5):773-778.
https://doi.org/10.1097/SLA.0000000000004182

IV. An Observational Analysis of the Women-Specific Threshold for Repair of Abdominal Aortic Aneurysms and The Association with Mortality. Talvitie Mareia, Jonsson Magnus, Roy Joy, Hultgren Rebecka. [Submitted]