Outcomes in Octogenarians and the Effect of Comorbidities After Intact Abdominal Aortic Aneurysm Repair in the Netherlands: A Nationwide Cohort Study

This paper examined retrospectively the outcomes of octogenarians that underwent either open surgical repair or endovascular repair for an intact abdominal aortic aneurysm in an obligatory nationwide registry, re ﬂ ecting daily clinical practice in the Netherlands. The study showed that besides an increased age, comorbidities were clearly associated with impaired peri-operative survival after both open surgical and endovascular repair. Objective: Age is an independent risk factor for mortality after both elective open surgical repair (OSR) and endovascular aneurysm repair (EVAR). As a result of an ageing population, and the less invasive nature of EVAR, the number of patients over 80 years (octogenarians) being treated is increasing. The mortality and morbidity following aneurysm surgery are increased for octogenarians. However, the mortality for octogenarians who have either low or high peri-operative risks remains unclear. The aim of this study was to provide peri-operative outcomes of octogenarians vs. non-octogenarians after OSR and EVAR for intact aneurysms, including separate subanalyses for elective and urgent intact repair, based on a nationwide cohort. Furthermore, the in ﬂ uence of comorbidities on peri-operative mortality was examined. Methods: All patients registered in the Dutch Surgical Aneurysm Audit (DSAA) undergoing intact AAA repair between 2013 and 2018, were included. Patient characteristics and peri-operative outcomes (peri-operative mortality, and major complications) of octogenarians vs. non-octogenarians for both OSR and EVAR were compared using descriptive statistics. Multivariable logistic regression analyses were used to examine whether age and the presence of cardiac, pulmonary, or renal comorbidities were associated with mortality. Results: This study included 12 054 EVAR patients (3 015 octogenarians), and 3 815 OSR patients (425 octogenarians). Octogenarians in both the EVAR and OSR treatment groups were more often female and had more comorbidities. In both treatment groups, octogenarians had signi ﬁ cantly higher mortality rates following intact repair as well as higher major complication rates. Mortality rates of octogenarians were 1.9% after EVAR and 11.8% after OSR. Age (cid:2) 80 and presence of cardiac, pulmonary, and renal comorbidities were associated with mortality after EVAR and OSR. Conclusion: Because of the high peri-operative mortality rates of octogenarians, awareness of the presence of comorbidities is essential in the decision making process before offering aneurysm repair to this cohort, especially when OSR is considered.


INTRODUCTION
In the last decade, endovascular aneurysm repair (EVAR) has become the preferred treatment for many patients with an intact abdominal aortic aneurysm (AAA), 1 because of its lower peri-operative risks. Age is a known independent risk factor for post-operative mortality after both elective open surgical repair (OSR) and EVAR. 2 As a result of an ageing population, 3 the number of patients over 80 years (octogenarians) who qualify for elective AAA repair is increasing. 4,5 However, the mortality and morbidity after AAA surgery for octogenarians is increased, 6e9 which is important in the decision making process of when and how to intervene in this usually frailer population.
In current literature that reports on octogenarians, metaanalyses that include mainly observational studies have not described outcomes with details for octogenarians, 7e9 while RCTs barely enrolled patients over 80 years. 6 Peri-operative mortality of octogenarians after primary AAA repair in 11 countries was assessed by the Vascunet collaboration. However, the morbidity of these patients was not described. 4 Therefore, there is a paucity of real life clinical data concerning mortality and morbidity after AAA surgery for octogenarians. Moreover, published studies scarcely report on the peri-operative mortality of subgroups of octogenarians with either low or high peri-operative risks. The recent ESVS guideline state that it is reasonable to consider elective AAA repair of octogenarians with reasonable life expectancy and quality of life after informing them of the pros and cons of different treatment strategies including conservative treatment. 10 However, no statements were made on which octogenarians have high peri-operative risks. The aim of this study was to provide peri-operative mortality and major complication rates of octogenarians vs. non-octogenarians following intact AAA repair. This was assessed following both open surgical and endovascular aneurysm repair including separate subanalyses for elective and urgent intact repair using a nationwide prospective registry. Furthermore, which octogenarians have low and high peri-operative risks was identified, examining the influence of age and the presence of comorbidities on peri-operative mortality.

Data sources and study design
The dataset was retrieved from the Dutch Surgical Aneurysm Audit (DSAA), a nationwide prospective and compulsory quality registry that registers all patients undergoing aortic aneurysm surgery in the Netherlands. The DSAA was initiated in 2013, and includes all patients who underwent surgical repair of an infrarenal or juxtarenal AAA without previous aortic surgery. Since 2016, patients undergoing revisional aneurysm surgery and/or patients undergoing thoracic or thoraco-abdominal aortic aneurysm repair have been registered as well. Data verification took place through a random sample of hospitals. 11 The data were analysed retrospectively and reported following the STROBE guidelines. 12

Participants
For this study, all patients who were registered in the DSAA undergoing primary repair (EVAR or OSR) for an intact AAA between January 2013 and December 2018 were included for analysis, provided that sex, date of birth, date of surgery, survival status at the time of discharge or 30 days postoperatively were registered. Data analyses were performed on an anonymised dataset. Ethical approval was not needed according to Dutch law.

Definitions
Patients were considered octogenarians when turning 80 years old or older in the year of surgery. EVAR procedures followed by immediate conversion were categorised by intention to treat. Intact aneurysm repairs included pooled data of both elective repair and urgent intact AAA repair. "Cardiac comorbidity" was defined as the use of diuretic or digoxin, antianginal or antihypertensive therapy, peripheral oedema, warfarin therapy, raised jugular venous pressure, or cardiomegaly. 13 "Abnormality on ECG" was defined as atrial fibrillation, ischaemia or any other ECG abnormalities. 13 Because of possible confounding caused by the variables "Cardiac comorbidity" and "Abnormality on ECG", it was decided to combine these variables into the variable "Cardiac comorbidity including abnormality on ECG" in the analyses. "Pulmonary comorbidity" was defined as dyspnoea on exertion, limiting dyspnoea, dyspnoea at rest, or visible consolidations or fibrosis on chest imaging. 13 "Renal comorbidity" was defined as an eGFR < 60 mL/min/1.73m 2 , which is categorised as "chronic kidney disease" by the International Society of Nephrology. 14 The eGFR was estimated using the CKD-EPI equation 15 and the variables "creatinine", "sex", and "age".

Outcomes
All outcomes of octogenarians were compared with the results of non-octogenarians. The primary outcome was peri-operative mortality, which was defined as intraoperative mortality, mortality 30 days after surgery, or during admission (in hospital mortality). The secondary outcomes were peri-operative major complications ( 30 days), defined as either an intra-operative or post-operative complications that needed a re-intervention, induced prolonged stay, or caused death 16 and the peri-operative mortality in patients with and without comorbidities. Furthermore, subgroup analyses were performed to compare outcomes of octogenarians and non-octogenarians treated in elective and urgent intact settings.

Statistical methods
Descriptive analysis was performed using t tests for parametrically distributed data, chi square tests and Fisher exact tests. Baseline characteristics, as well as peri-operative outcomes, were compared between octogenarians and non-octogenarians undergoing either EVAR or OSR. Missing values were shown as separate categories. A p value of <.05 was considered statistically significant.
To investigate whether age ! 80 was associated with peri-operative mortality, multivariable logistic regression analyses were performed for both EVAR and OSR. Patient and aneurysm related variables, based on the V(p)-POSSUM predictive score, 13,17 that were potential confounders and available in the DSAA were included as covariates: age !80, sex, pulmonary comorbidity, cardiac comorbidity including results of last pre-operative electrocardiogram, renal comorbidity, pre-operative haemoglobin, urgency, location, and diameter of the aneurysm. Factors with a p value of <.10 in univariable analysis were selected for multivariable analysis. Finally, the perioperative mortality rates of octogenarians and nonoctogenarians with no comorbidities, cardiac comorbidity (including abnormality on the ECG), pulmonary comorbidity, and renal comorbidity were shown.

Missing data
The data for this study contained some variables with missing values. If patients with any missing data had been excluded from the analyses, information on 2 477 (19.1%) patients including 538 octogenarians who underwent EVAR and 685 (18.0%) patients including 74 octogenarians who underwent OSR would have been lost. To prevent such loss of information, a state of the art method of multiple imputation using chained equations (MICE) was used. 18 Missing data were imputed separately for EVAR and OSR patients. The outcome peri-operative mortality was not imputed, and the following variables were used in the imputation process: age, sex, cardiac and pulmonary comorbidity, results of the last electrocardiogram, haemoglobin, creatinine, diameter, location, urgency, perioperative mortality, pre-and post-operative complications, length of ICU stay, length of hospital stay, re-intervention, and re-admission. Twenty-five completed datasets were generated (each with 10 iterations) for both EVAR and OSR patients. 18 Values that were imputed were compared with values that were observed using scatter and density plots. For the multivariable regression models, the results of the imputed datasets were combined to produce a final result using Rubin's rules. 18 For comparison, multivariable regression analyses using the subsets of complete cases were performed.
All analyses were performed using R version 3.6.1.
Patient characteristics, aneurysm morphology, and operative data Patient characteristics, aneurysm morphology, and operative data comparing octogenarians and non-octogenarians who received either EVAR or OSR are shown in Table 1.
In both groups, octogenarians were more often female, had larger aneurysm diameters, and more often had pulmonary and renal comorbidity compared with younger patients. In the EVAR group and after multiple imputation in the OSR group, octogenarians suffered more often from cardiac comorbidity. In both the EVAR and OSR groups, octogenarians were more often treated for urgent intact aneurysms compared with non-octogenarians.

Peri-operative outcomes
Mortality. As shown in Table 2, octogenarians had statistically significantly higher peri-operative mortality rates than non-octogenarians after surgery for all intact AAA. The odds ratio for peri-operative mortality in octogenarians compared with non-octogenarians was 2. Major complications. Table 2 shows that octogenarians more often developed major complications compared with non-octogenarians following both intact EVAR and OSR, as well as following elective and urgent intact repair. Major octogenarian complication rates in the intact setting were 12.4% after EVAR and 28.0% after OSR.

Associations with mortality
After univariable analyses, the factor "location" (EVAR) was not selected for multivariable analysis because of a p value > .10 ( Table 3). The factor "age ! 80" was statistically significantly associated with higher mortality rates after adjusting for confounding factors after both EVAR and OSR (Tables 3 and 4). Sensitivity analysis involving multivariable analysis using complete cases showed a similar association of "age ! 80", with mortality after EVAR (OR Observed comorbidities and corresponding peri-operative mortality Only 317 (10.5% in original data; 12.0% in imputed data) and 42 (9.9% in original data; 12.8% in imputed data) octogenarians undergoing EVAR and OSR had no comorbidities, respectively (Table 5). Observed peri-operative mortality rates following intact AAA repair in patients with no comorbidity, cardiac, pulmonary, or renal comorbidity are shown in Table 5. After EVAR, the mortality rates of octogenarians with a cardiac, pulmonary, or renal comorbidity reached 2.4%, 4.2%, or 2.5%, respectively, while octogenarians with no comorbidities had a rate of 0.4% (all percentages are based on imputed data). After OSR, the mortality rates of octogenarians with cardiac, pulmonary, or renal comorbidity reached 13.4%, 13.6%, and 14.8%, while octogenarians with no comorbidities had a mortality rate of 3.8% (based on imputed data).

DISCUSSION
The octogenarians in this study were at risk of significantly higher peri-operative mortality and major complication rates after both EVAR and OSR for intact AAA compared with younger patients. Furthermore, the effect of comorbidities in this age group was more pronounced and was clearly associated with impaired survival. In octogenarians, mortality after OSR exceeded 10%, especially when comorbidities were present. After EVAR, octogenarians with pulmonary comorbidities had a mortality rate of approximately 4%. In contrast, mortality was 1.9% for all octogenarians in the EVAR group. Surgical risk is at the heart of clinical (shared) decision making, especially when prophylactic surgery is performed on asymptomatic patients such as in elective AAA care. 19 To inform patients appropriately before undergoing high risk surgery, robust data are needed concerning morbidity and mortality. The DSAA is a mandatory national verified quality registry, set up to monitor and improve the quality of AAA care by providing benchmarked information to vascular surgeons. Since 2013, all patients undergoing primary abdominal aortic aneurysm surgery in the Netherlands have been registered, providing objective, real world data.
Because of its scale and in contrast to other published studies, it enables relevant subanalyses such as the analysis described in this paper. 8,9 Additionally, local data on outcomes of octogenarians could be valuable to inform patients and family accurately, for example because of a potential hospital related volume outcome relationship for OSR. 20 Since 2019, a specific dashboard called the Codman Dashboard has enabled all Dutch vascular surgeons to analyse their registered outcomes of particular subgroups. 21 This study describes a mortality rate of 11.8% for all octogenarians after OSR, and this seems to exceed the yearly rupture risks of smaller aneurysms. Moreover, octogenarians with comorbidities have mortality rates > 10% after OSR, in contrast to the mortality rate of 3.6% in the (small) group of octogenarians without comorbidities (12.8% of all octogenarians in this cohort, based on imputed data). In the literature, a mortality rate of 7.5% for octogenarians who were treated electively by OSR was described in a meta-analysis. 7 For intact aneurysm repair, a mortality rate of 9.5% for octogenarians was described in an international study by Budtz-Lilly et al., which combined the results of 11 vascular registries, 4 similar to the results from the present study. However, mortality rates in these studies were rarely specified for either high or low risk octogenarians. 22 In previous studies that examined the safety of surveillance for small aneurysms up to 5.5 cm, 30 day operative mortality rates of only 5.5% 23 and 2.1% 24 were described. This poses the question of whether operative mortality rates exceeding these numbers are acceptable, in particular in elderly patients undergoing preventive aneurysm repair at relatively small diameters that are at low risk of rupture.
After EVAR, this study reports a mortality rate of 1.9% for octogenarians. This is in line with the previously mentioned international study by Budtz-Lilly et al., which reported a mortality rate of 1.8% of octogenarians after EVAR. Metaanalyses that included older studies have described mortality rates for octogenarians of 3.7% 9 and 4.6% 7 after EVAR. The impact of improved device technology (lower profile devices), peri-operative management including better anaesthetic techniques, 25 and cardioprotective medication 26 might play a role in improved survival of octogenarians in this study compared with the metaanalyses with older data. 4 In the present study, a perioperative mortality rate of 4.2% was observed for octogenarians with a pulmonary comorbidity. This mortality rate was low compared with the mortality rate of 7.3% reported in the EVAR-2 study in patients who were considered not physically fit enough to undergo OSR. 27 Apart from the mortality rates following intact AAA repair, other outcomes for octogenarians are important as well and could assist in the clinical decision making process. First, to deal with the heterogeneity in the group of intact AAA repairs, subanalyses were performed for elective and urgent intact repair including adjustment for urgent intact repair in the multivariable analyses. Furthermore, in the present study, major complication rates were examined. As expected, octogenarians had higher major complication rates compared with non-octogenarians. Obviously, other outcome parameters, such as quality of life, 28 re-intervention rate, 6 long term outcomes, 29 and costs, 30 are also important to consider in the clinical decision making process for octogenarians, but these are not captured in the DSAA registry.
In this study, no association between aneurysm size and mortality was found in OSR patients, which might suggest that postponing OSR does not result in higher mortality rates. Remarkably, in EVAR patients, aneurysm size was associated with mortality. The diameter threshold for elective abdominal aneurysm repair is based on both perioperative risk and the risk of rupture. However, the risk of rupture according to aneurysm diameter was not investigated. In the literature, little is known about the diameters of ruptured aneurysms between octogenarians and nonoctogenarians. 31 In studies up to 2010, the mean annual risk of rupture of a 5 cm aneurysm was 0.6% in men and 2.9% in women. It is stated that the mean diameter of ruptured aneurysms in all patients has increased during the last decade, possibly because of increased statin therapy. 26 A previous study demonstrated that some patients with severe comorbidities and large aneurysms could be managed conservatively with acceptable results for long periods (7 e 76 months). 32 Therefore, the question remains of whether the diameter threshold at which to intervene should be increased for octogenarians because of a much higher peri-operative risk, in particular when octogenarians experience comorbidities and OSR is considered to be the treatment modality.
Despite the relatively large number of octogenarians in this cohort, this study has some limitations. First, the DSAA includes only patients who were considered fit enough to undergo surgery, which was a clinical decision by the surgeon. Because of this selection bias, predictions of mortality Data are presented as n (%) unless stated otherwise. * Peri-operative mortality including intra-operative, 30 day, and in hospital mortality. y Major complication: post-operative death or a peri-or post-operative complication leading to a re-intervention or prolonged hospital stay.  rates based on the number of comorbidities of octogenarians who could be incorporated in the decision making process could not be made, as the decision to perform surgery had already been made. Therefore, the reported peri-operative outcomes of octogenarians in this study will probably be better than peri-operative outcomes of all octogenarians with an intact AAA. Second, information bias might have taken place, as age was calculated as the year of surgery minus the year of birth. This calculation included some patients of age 79 in the group "octogenarians", which might have led to an underestimation of the outcomes of octogenarians. Furthermore, this was a retrospective study of a retrieved dataset from the DSAA, a prospectively maintained national quality registry. As this audit is not designed purely for scientific research, information on some potential confounders such as peripheral artery obstructive disease, 33 type of anaesthetic, anatomical details, surgeon experience, or frailty were not available. It would be interesting to examine the influence of frailty, as it has been reported that frailty is associated with age as well as with peri-operative mortality. 34 Furthermore, Joseph et al. stated that a frailty index was better for predicting mortality compared with age in emergency general surgery in the elderly, 35 while age was a predictor of mortality in vascular studies that did not report on frailty. 36,37 Another limitation of this study is that the specific categories in the groups cardiac and pulmonary comorbidity were potentially not equally weighted between octogenarians and nonoctogenarians, which might have caused heterogeneity in the groups of octogenarians vs. non-octogenarians and thus, these groups were not compared. Finally, the dataset had some missing data and thus, for multivariable logistic regression analyses and analyses stratified for the presence of comorbidities, missing data were imputed using multiple imputation. Sensitivity analyses using complete cases were performed for the multivariable analyses that examined the association of age ! 80 with mortality, with similar results.
In conclusion, age ! 80 and comorbidities are significantly associated with mortality after endovascular and open repair for abdominal aortic aneurysms. Mortality after OSR in octogenarians is exceedingly high, especially in the presence of comorbidities. Reported observed rates in this study can be used by everyone involved in the decision making process considering optimal care for aneurysm patients. More research focused on optimal treatment thresholds for elective AAA repair in both low and high risk subgroups of octogenarians is needed. For now, awareness of the presence of comorbidities is key in the decision making process.

CONFLICTS OF INTEREST
HV: consultant for Medtronic, WL Gore, Terumo, Endologix, and Arsenal AAA.