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Excess Mortality for Abdominal Aortic Aneurysms and the Potential of Strict Implementation of Cardiovascular Risk Management: A Multifaceted Study Integrating Meta-Analysis, National Registry, and PHAST and TEDY Trial Data

Open AccessPublished:November 28, 2022DOI:https://doi.org/10.1016/j.ejvs.2022.11.019

      Objective

      Previous studies imply a profound residual mortality risk following successful abdominal aorta aneurysm (AAA) repair. This excess mortality is generally attributed to increased cardiovascular risk. The aim of this study was (1) to quantify the excess residual mortality for patients with AAA, (2) to evaluate the cross sectional level of cardiovascular risk management, and (3) to estimate the potential of optimised cardiovascular risk management to reduce the excess mortality in these patients.

      Methods

      Excess mortality was estimated through a systematic review and meta-analysis, and through data from the Swedish National Health Registry. Cardiovascular risk profiles were individually assessed during eligibility screening of patients with AAA for two multicentre pharmaceutical AAA stabilisation trials. The potential of full implementation of cardiovascular risk management was estimated through the validated Second Manifestations of ARTerial disease (SMART) risk scores algorithm.

      Results

      The meta-analysis showed a similarly impaired survival for patients who received early repair (small AAA) or regular repair (≥ 55 mm), and a further impaired survival for patients under surveillance for a small AAA. Excess mortality was further quantified using Swedish population data. The data revealed a more than quadrupled and doubled five year mortality rate for women and men who had their AAA repaired, respectively. Evaluation of the level of risk management of 358 patients under surveillance in 16 Dutch hospitals showed that the majority of patients with AAA did not meet therapeutic targets set for risk management in high risk populations, and indicated a more pronounced prevention gap in women. Application of the SMART risk score algorithm predicted that optimal implementation of risk management guidelines would reduce the 10 year risk of major adverse cardiovascular events from 43% to 14%.

      Conclusion

      Independent of the rupture risk, AAA is associated with a worryingly compromised life expectancy with a particularly poor prognosis for women. Optimal implementation of cardiovascular risk prevention guidelines is predicted to profoundly reduce cardiovascular risk.

      Keywords

      While the primary concern with abdominal aortic aneurysms (AAAs) is rupture, and rupture risk is now adequately managed by screening and preventive aneurysm repair, a meta-analysis and evaluation of National data for Sweden shows that AAA disease is associated with a disquieting quadrupled (women) and doubled (men) five years residual mortality. This excess mortality may largely reflect the sharply increased cardiovascular risk. Cross sectional evaluation of the level of risk management of patients with AAA participating in the Pharmaceutical Aneurysm Stabilisation Trial (PHAST) and Pharmaceutical Aneurysm Stabilisation Trial (TEDY) trial shows that cardiovascular risk is generally, and particularly in women, suboptimally managed. Conclusions from a validated risk score algorithm stress the relevance of strict adherence to the guidelines for cardiovascular risk management for extremely high risk patients in managing patients with AAA.

      Introduction

      Rupture risk in abdominal aortic aneurysm (AAA) is now effectively managed by screening programmes and elective repair. Worryingly, the disease remains associated with a profound excess mortality
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      and prevailing cardiovascular risk management guidelines classify patients with AAA as “at very high risk” patients.
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      Notwithstanding, it is consistently concluded that the management of patients with AAA remains essentially rupture prevention focused, and that the accompanying excess cardiovascular risk, and the residual mortality risk receive less attention, or are in fact ignored.
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      • Bown M.J.
      • et al.
      Patients with small abdominal aortic aneurysm are at significant risk of cardiovascular events and this risk is not addressed sufficiently.
      The aim of this multifaceted study was threefold: (1) to provide an estimate of the residual mortality risk for patients with AAA; (2) to assess the level of cardiovascular risk management in patients with AAA in daily practice; and (3) to estimate the potential impact of a full implementation of the current cardiovascular prevention guidelines. The research strategy and the methodologies used in this study are summarised in Table 1.
      Table 1Summary of the structure of this multifaceted study on excess mortality in patients with abdominal aortic aneurysms (AAA)
      Study facetsApproachStrategy
      Aim 1: Estimation of the excess mortality of patients with AAA(A) Systematic review and meta-analysisRelative survival of

      (1) Patients under surveillance for a small AAA

      (2) Patients receiving early (<55 mm) repair

      (3) Patients who had regular elective AAA repair (>55 mm)
      (B) National (Swedish) registry dataStandardised excess five years mortality rate for patients with AAA (2006–2010 interval)
      Aim 2: Inventory of the level of cardiovascular risk management in patients with AAAAssessment of the level of risk management in patients with AAA participating in the PHAST
      • Meijer C.A.
      • Stijnen T.
      • Wasser M.N.J.M.
      • Hamming J.F.
      • Van Bockel J.H.
      • Lindeman J.H.N.
      Doxycycline for stabilization of abdominal aortic aneurysms.
      and TEDY
      • Golledge J.
      • Pinchbeck J.
      • Tomee S.M.
      • Rowbotham S.E.
      • Singh T.P.
      • Moxon J.V.
      • et al.
      Efficacy of telmisartan to slow growth of small abdominal aortic aneurysms: a randomized clinical trial.
      trial in 14 centres in The Netherlands
      Prescription status of hypertensives and lipid lowering medication. Assessment of blood pressure and plasma lipid profiles
      Aim 3: Impact of full implementation of the current cardiovascular prevention guidelinesEstimation of the additional impact of strict implementation of risk management on 10 year cardiovascular riskApplication of the European Society of Cardiology SMART risk estimation tool
      • Kristensen M.L.
      • Christensen P.M.
      • Hallas J.
      The effect of statins on average survival in randomised trials, an analysis of end point postponement.
      ,
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • Juni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      on the population inventoried in aim 2
      PHAST = Pharmaceutical Aneurysm Stabilisation Trial; TEDY = TElmisartan in the management of abDominal aortic aneurysm; SMART = Second Manifestations of ARTerial disease.

      Materials and methods

      This multifaceted study is based on three pillars (Table 1). The first pillar evaluates the excess mortality risk of patients with AAA, the second pillar assesses the cross sectional level of cardiovascular risk management of patients with AAA, and the final third pillar estimates the potential of full implementation of prevailing cardiovascular prevention guidelines. Reporting of the observational data was in accordance with the STROBE (Strengthening The Reporting of OBservational Studies in Epidemiology) checklists for observational data.

      Aim 1. Estimation of the excess mortality of patients with abdominal aortic aneurysm

      Systematic literature review of long term survival of patients with abdominal aortic aneurysm

      Survival estimates for patients with AAA who had their larger (> 55 mm) aneurysm repaired were estimated on the basis of a previously published systematic review and meta-analysis of survival following respectively endovascular aneurysm repair (EVAR) or open repair performed by this group.
      • Bulder R.M.A.
      • Bastiaannet E.
      • Hamming J.F.
      • Lindeman J.H.N.
      Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.
      Because the meta-analysis showed similar survival following open or endovascular repair,
      • Bulder R.M.A.
      • Bastiaannet E.
      • Hamming J.F.
      • Lindeman J.H.N.
      Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.
      data were now pooled to obtain survival estimates for patients who had their larger AAA repaired.
      Additional systematic reviews and meta-analyses were performed in order to estimate survival for patients with small (i.e., less than 55 mm) aneurysms. A first meta-analysis estimated post-repair survival of patients who underwent repair of a small aneurysm. The second analysis focused on patients under surveillance for a small AAA. Eligible studies were identified through a search using PubMed, Embase, Web of Science, and Cochrane central (the detailed search strategy is available in Supplementary File S1). The key inclusion criterion for the studies was the availability of long term survival data (at least one year survival) for patients with a small infrarenal AAA (< 5.5 cm). Excluded were studies involving ruptured or thoracic, mycotic or inflammatory aneurysms, or that studied medical stabilisation of their AAA (such as the Pharmaceutical Aneurysm Stabilisation Trial [PHAST] and TElmisartan in the management of abDominal aortic aneurysm [TEDY] trial),
      • Meijer C.A.
      • Stijnen T.
      • Wasser M.N.J.M.
      • Hamming J.F.
      • Van Bockel J.H.
      • Lindeman J.H.N.
      Doxycycline for stabilization of abdominal aortic aneurysms.
      ,
      • Golledge J.
      • Pinchbeck J.
      • Tomee S.M.
      • Rowbotham S.E.
      • Singh T.P.
      • Moxon J.V.
      • et al.
      Efficacy of telmisartan to slow growth of small abdominal aortic aneurysms: a randomized clinical trial.
      as well as articles that were not available in full text or English literature, as well as editorials, letters, comments, or reviews. The final search update was performed on 6 July 2021. The systematic review was not registered.
      The search strategy for the additional systematic review has been reported earlier.
      • Bulder R.M.A.
      • Bastiaannet E.
      • Hamming J.F.
      • Lindeman J.H.N.
      Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.
      For the current study, the specific components for surgical repair (EVAR or open repair) or surveillance strategies were omitted because this limited the search. Two authors reviewed the titles and abstracts for eligibility. When eligibility was unclear, full texts were reviewed. The screening process is summarised in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
      Data extracted from the identified studies were inclusion criteria, characteristics of study population, duration of follow up, and overall survival at one, three, five, and 10 years when available. The overall survival was extracted from Kaplan–Meier graphs. In short, Kaplan–Meier graphs were magnified and printed on A3 paper. Survival was retrieved by reading the intersection point of lines drawn on the tick marks of the y axis (survival) vs. x axis (time points of one, three, five, and 10 years).
      • Kristensen M.L.
      • Christensen P.M.
      • Hallas J.
      The effect of statins on average survival in randomised trials, an analysis of end point postponement.
      When authors presented their results in multiple studies, only the most recent publication was included in the meta-analysis.
      To evaluate the risk of bias and quality of study the Cochrane Collaboration’s tool (for randomised trials) or ROBINS-I tool (for non-randomised trials) was used for assessing risk of bias.
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • Juni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      ,
      • Sterne J.A.C.
      • Hernán M.A.
      • Reeves B.C.
      • Savović J.
      • Berkman N.D.
      • Viswanathan M.
      • et al.
      ROBINS-I: a tool for assessing risk of bias in non-randomized studies of interventions.
      Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.
      • Granholm A.
      • Alhazzani W.
      • Møller M.H.
      Use of the GRADE approach in systematic reviews and guidelines.

      Standardised excess mortality of patients with abdominal aortic aneurysm

      Since conclusions from the meta-analyses are summarised as relative survival estimates (relative survival) and are thus influenced by the baseline risk, more tangible risk estimates of additional relevance were considered. Standardised excess mortality, expressed as the number of observed deaths in a specific subpopulation divided by the number of expected deaths, is a strategy that provides a more qualitative estimate of the risks associated with a particular condition. Standardised excess mortality was estimated for the Swedish population using the National Patient Registry (NPR). Data for patients diagnosed with a repaired AAA were used to estimate the AAA associated standardised excess (residual) mortality. The NPR has a positive predictive value up to 96%, and covers all hospital associated care events and outpatient specialist care events based on the person specific identity numbers in Sweden, a country with 9.8 million inhabitants in 2015.
      • Bulder R.M.A.
      • Talvitie M.
      • Bastiaannet E.
      • Hamming J.F.
      • Hultgren R.
      • Lindeman J.H.N.
      Long-term prognosis after elective abdominal aortic aneurysm repair is poor in women and men: the challenges remain.
      Data were available for the 2000 – 2015 interval. Case identification was based on the registered diagnosis (intact AAA, International Classification of Diseases 9 or 10 codes). Standardised excess mortality was estimated for 2006 – 2010, representing the most recent interval for which five years survival was available. Patients with a diagnosis of ruptured AAA were excluded.
      Standardised excess mortality was estimated by comparing the observed five years mortality of patients with an AAA with that of the corresponding (matched for age, sex, and year) Swedish general population.
      • Bastiaannet E.
      • Liefers G.J.
      • de Craen A.J.
      • Kuppen P.J.
      • van de Water W.
      • Portielje J.E.
      • et al.
      Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients.
      National life tables (Statistics Sweden

      Statistics Sweden. National life tables. Available at: https://www.scb.se/en/ [Accessed 17 January 2023].

      ) were used to estimate the expected five years mortality rate. The excess mortality rate was calculated by dividing the observed number of deaths of patients with AAA by the expected number of deaths for the corresponding general population for the index period.
      • Bastiaannet E.
      • Liefers G.J.
      • de Craen A.J.
      • Kuppen P.J.
      • van de Water W.
      • Portielje J.E.
      • et al.
      Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients.
      Use of the registry data was approved by the Regional Ethics Review Board in Stockholm and complies with the Declaration of Helsinki. For this population based study, informed consent was not required, and data handling followed the requirements of the EU data protection laws.

      Aim 2. Inventory of the level of cardiovascular risk management in patients with abdominal aortic aneurysm

      The level of risk management in patients under surveillance for a small AAA was inventoried in patients participating in the PHAST
      • Meijer C.A.
      • Stijnen T.
      • Wasser M.N.J.M.
      • Hamming J.F.
      • Van Bockel J.H.
      • Lindeman J.H.N.
      Doxycycline for stabilization of abdominal aortic aneurysms.
      and TEDY
      • Golledge J.
      • Pinchbeck J.
      • Tomee S.M.
      • Rowbotham S.E.
      • Singh T.P.
      • Moxon J.V.
      • et al.
      Efficacy of telmisartan to slow growth of small abdominal aortic aneurysms: a randomized clinical trial.
      trials in The Netherlands. Study protocols of both trials were approved by the Medical Ethical Review Board of the Leiden University Medical Centre and by the local review boards of the 16 participating centres. Written informed consent was obtained from all participants.
      The PHAST trial tested the effectiveness of 18 months of doxycycline therapy or placebo in inhibiting AAA growth. The trial included 286 Dutch patients with an AAA measuring between 35 mm and 50 mm. The PHAST study was completed in June 2011 and has been reported previously.
      • Meijer C.A.
      • Stijnen T.
      • Wasser M.N.J.M.
      • Hamming J.F.
      • Van Bockel J.H.
      • Lindeman J.H.N.
      Doxycycline for stabilization of abdominal aortic aneurysms.
      The TEDY trial is an international randomised controlled trial testing the effect of telmisartan on aneurysm growth in patients with small AAAs (diameter 35 – 49 mm).
      • Golledge J.
      • Pinchbeck J.
      • Tomee S.M.
      • Rowbotham S.E.
      • Singh T.P.
      • Moxon J.V.
      • et al.
      Efficacy of telmisartan to slow growth of small abdominal aortic aneurysms: a randomized clinical trial.
      The 72 Dutch patients participating in the trial were included in this inventory.
      This study is based on data collected at the eligibility screening for the PHAST and TEDY trials. For both trials, data with respect to current medication and smoking habits were collected during the eligibility screening and baseline visit. Moreover, standardised measurements were performed of height, weight, and systolic and diastolic blood pressure. Serum blood samples were analysed for lipid spectrum (low density lipoprotein [LDL], high density lipoprotein [HDL], total cholesterol, and triglycerides), the levels of creatinine, alanine transaminase, and (for TEDY only) glycated haemoglobin. The cholesterol/HDL ratio was estimated on the basis of total cholesterol and HDL levels, and the Modification of Diet in Renal Disease formula was used to estimate glomerular filtration rate.
      • Levey A.S.
      • Bosch J.P.
      • Lewis J.B.
      • Greene T.
      • Rogers N.
      • Roth D.
      A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in Renal Disease Study Group.
      All blood samples were analysed in a certified laboratory (the Department of Clinical Chemistry, Leiden University Medical Centre).

      AIM 3. The potential of full implementation of the current cardiovascular prevention guidelines

      The Second Manifestations of ARTerial disease (SMART) risk score,
      • Dorresteijn J.A.
      • Visseren F.L.
      • Wassink A.M.
      • Gondrie M.J.
      • Steyerberg E.W.
      • Ridker P.M.
      • et al.
      Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.
      an online tool offered by the European Society of Cardiology,

      European Society of Cardiology. The Smart Risk Score. Available at: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score [Accessed 27 September 2022].

      estimates 10 year risk of recurrent vascular events in patients with manifest cardiovascular disease. The tool was used to estimate the cardiovascular risk, and the anticipated risk reduction through optimised risk management (relative risk reduction and number needed to treat) for each individual AAA patient participating in the PHAST or TEDY trial. Optimised targets were systolic blood pressure < 140 mmHg, LDL < 1.8 mmol/L, cessation of smoking, or a combination of the different targets.
      • Kristensen M.L.
      • Christensen P.M.
      • Hallas J.
      The effect of statins on average survival in randomised trials, an analysis of end point postponement.
      ,
      • Higgins J.P.
      • Altman D.G.
      • Gotzsche P.C.
      • Juni P.
      • Moher D.
      • Oxman A.D.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      Missing values were considered as missing at random.

      Statistical analyses

      Meta-analysis and survival analyses were performed using Stata/SE, version 12.0 (StataCorp, College Station, TX, USA). I2 statistics were used to estimate heterogeneity.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      A value of > 50% was considered to indicate significant heterogeneity.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      Relative survival for studies included in the meta-analysis was achieved by calculating the observed expected ratios and their 95% confident intervals followed by transformation to their natural logarithms. Pooled observed expected ratios were estimated for patients undergoing elective surgical repair (EVAR and open repair) and those with a small aneurysm using the random effects model of DerSimonian and Laird.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials revisited.
      Relative survival for patients in the Swedish National Patients Registry was calculated by dividing the observed survival of the study population and the expected survival of a general population matched for age, sex, and year of operation.
      • Bulder R.M.A.
      • Bastiaannet E.
      • Hamming J.F.
      • Lindeman J.H.N.
      Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.
      Descriptive statistics regarding the levels of risk management were performed using SPSS (version 25, IBM, Amsterdam, The Netherlands). Continuous data are presented as mean (standard deviation [SD]) or as median (interquartile range). Differences between groups were estimated using the independent t test. Categorical data are presented as percentages and tested using the chi square statistic. A p value of < .050 was considered to be statistically significant.

      Results

      Aim 1. Estimation of the excess mortality of patients with abdominal aortic aneurysm

      Systematic literature review of long term survival of patients with abdominal aortic aneurysm

      Survival estimates for patients with a smaller AAA (< 5.5 cm) were based on a systematic review of reported survival data. A literature search identified 2 345 articles, of which 18 articles met inclusion criteria.
      • Powell J.T.
      • Brown L.C.
      • Forbes J.F.
      • Fowkes F.G.
      • Greenhalgh R.M.
      • Ruckley C.V.
      • et al.
      Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial.
      • Lederle F.A.
      • Wilson S.E.
      • Johnson G.R.
      • Reinke D.B.
      • Littooy F.N.
      • Acher C.W.
      • et al.
      Aneurysm Detection and Management Veterans Affairs Cooperative Study Group. Immediate repair compared with surveillance of small abdominal aortic aneurysms.
      • Ouriel K.
      • Clair D.G.
      • Kent K.C.
      • Zarins C.K.
      Positive Impact of Endovascular Options for treating Aneurysms Early (PIVOTAL) Investigators. Endovascular repair compared with surveillance for patients with small abdominal aortic aneurysms.
      • Cao P.
      • De Rango P.
      • Verzini F.
      • Parlani G.
      • Romano L.
      • Cieri E.
      • et al.
      Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial.
      • Sahal M.
      • Prusa A.M.
      • Wibmer A.
      • Wolff K.S.
      • Lammer J.
      • Polterauer P.
      • et al.
      Elective abdominal aortic aneurysm repair: does the aneurysm diameter influence long-term survival?.
      • Keith Jr., C.J.
      • Passman M.A.
      • Gaffud M.J.
      • Novak Z.
      • Pearce B.J.
      • Matthews T.C.
      • et al.
      Comparison of outcomes following endovascular repair of abdominal aortic aneurysms based on size threshold.
      • Golledge J.
      • Parr A.
      • Boult M.
      • Maddern G.
      • Fitridge R.
      The outcome of endovascular repair of small abdominal aortic aneurysms.
      • LeCroy C.J.
      • Passman M.A.
      • Taylor S.M.
      • Patterson M.A.
      • Combs B.R.
      • Jordan Jr., W.D.
      Should endovascular repair be used for small abdominal aortic aneurysms?.
      • Hallett Jr., J.W.
      • Naessens J.M.
      • Ballard D.J.
      Early and late outcome of surgical repair for small abdominal aortic aneurysms: a population-based analysis.
      • Ouriel K.
      • Srivastava S.D.
      • Sarac T.P.
      • O'hara P.J.
      • Lyden S.P.
      • Greenberg R.K.
      • et al.
      Disparate outcome after endovascular treatment of small versus large abdominal aortic aneurysm.
      • Schlösser F.J.
      • Tangelder M.J.
      • Verhagen H.J.
      • van der Heijden G.J.
      • Muhs B.E.
      • van der Graaf Y.
      • et al.
      Growth predictors and prognosis of small abdominal aortic aneurysms.
      • Wang G.J.
      • Carpenter J.P.
      EVAR in small versus large aneurysms: does size influence outcome?.
      • Bayazit M.
      • Göl M.K.
      • Işcan H.Z.
      • Ulus T.
      • Taşdemir O.
      • Bayazit K.
      Is surgery justifiable for treatment of small abdominal aortic aneurysms?.
      • Hye R.J.
      • Janarious A.U.
      • Chan P.H.
      • Cafri G.
      • Chang R.W.
      • Rehring T.F.
      • et al.
      Survival and reintervention risk by patient age and preoperative abdominal aortic aneurysm diameter after endovascular aneurysm repair.
      • Mehta A.
      • O'Donnell T.F.X.
      • Trestman E.
      • Schutzer R.
      • Bajakian D.
      • Morrissey N.
      • et al.
      The variable impact of aneurysm size on outcomes after open abdominal aortic aneurysm repairs.
      • Jeon-Slaughter H.
      • Krishnamoorthi H.
      • Timaran D.
      • Wall A.
      • Ramanan B.
      • Banerjee S.
      • et al.
      Effects of abdominal aortic aneurysm size on mid- and long-term mortality after endovascular aneurysm repair.
      • Davis F.M.
      • Jerzal E.
      • Albright J.
      • Kazmers A.
      • Monsour A.
      • Bove P.
      • et al.
      Variation in the elective management of small abdominal aortic aneurysms and physician practice patterns.
      • Jones D.W.
      • Deery S.E.
      • Schneider D.B.
      • Rybin D.V.
      • Siracuse J.J.
      • Farber A.
      • et al.
      Differences in patient selection and outcomes based on abdominal aortic aneurysm diameter thresholds in the Vascular Quality Initiative.
      The screening process is summarised in the PRISMA flow diagram in Figure 1. Four of the included articles were randomised controlled trials (22%)
      • Powell J.T.
      • Brown L.C.
      • Forbes J.F.
      • Fowkes F.G.
      • Greenhalgh R.M.
      • Ruckley C.V.
      • et al.
      Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial.
      • Lederle F.A.
      • Wilson S.E.
      • Johnson G.R.
      • Reinke D.B.
      • Littooy F.N.
      • Acher C.W.
      • et al.
      Aneurysm Detection and Management Veterans Affairs Cooperative Study Group. Immediate repair compared with surveillance of small abdominal aortic aneurysms.
      • Ouriel K.
      • Clair D.G.
      • Kent K.C.
      • Zarins C.K.
      Positive Impact of Endovascular Options for treating Aneurysms Early (PIVOTAL) Investigators. Endovascular repair compared with surveillance for patients with small abdominal aortic aneurysms.
      • Cao P.
      • De Rango P.
      • Verzini F.
      • Parlani G.
      • Romano L.
      • Cieri E.
      • et al.
      Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial.
      and 14 were retrospective studies (78%).
      • Sahal M.
      • Prusa A.M.
      • Wibmer A.
      • Wolff K.S.
      • Lammer J.
      • Polterauer P.
      • et al.
      Elective abdominal aortic aneurysm repair: does the aneurysm diameter influence long-term survival?.
      • Jones D.W.
      • Deery S.E.
      • Schneider D.B.
      • Rybin D.V.
      • Siracuse J.J.
      • Farber A.
      • et al.
      Differences in patient selection and outcomes based on abdominal aortic aneurysm diameter thresholds in the Vascular Quality Initiative.
      All included studies are summarised in Supplementary Table S1. This meta-analysis incorporated 20 364 patients: 18 500 (91%) treated by surgical repair of a small AAA, and 1 864 (9%) under surveillance for small AAA. GRADE assessment showed a moderate certainty of evidence for all 10 year survival outcomes due to the long follow up length, loss to follow up, and correlation with mortality. For all other outcomes (one, three, five year survival), certainty of evidence was classified as high. Full GRADE assessment and evidence profiles per outcome are illustrated in Supplementary Table S2.
      Figure 1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram depicting search and study selecting processes in this systematic review of long term survival of patients with small abdominal aortic aneurysms (AAA).
      Survival estimates for patients with larger (> 5.5 cm) AAA shown in Table 1 reflect the aggregated data for 131 925 patients included in an earlier meta-analysis of long term survival following open or endovascular repair of a larger AAA.
      • Bulder R.M.A.
      • Bastiaannet E.
      • Hamming J.F.
      • Lindeman J.H.N.
      Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.
      Survival data were transformed to relative survival in order to correct for variances in age and sex in the study cohorts, for putative age differences between patients with small and larger AAA, and for regional and time related differences in life expectancy. Relative survival estimates are summarised in Table 2. Relative survival estimates were similar for patients with a small AAA who received early repair, and for patients who had their larger AAA repaired (5 years relative survival: 84%, 95% CI 79 – 90%; and 90%, 95% CI 88 – 91% respectively), and worse for patients under surveillance for a small AAA (70%, 95% CI 60 – 82%).
      Table 2Relative survival of patients with abdominal aortic aneurysms (AAA) included in this systematic review and meta-analysis of the available literature, including a total of 18 studies and 20 364 patients. Relative survival reflects the observed survival of the study population divided by the expected survival of the reference population (i.e., general population matched for age, sex year of operation, and country). A relative survival of 100% respectively. 50% reflects a survival equal to, respectively one half of that of the reference population
      Follow up – yRelative survival – %
      Small AAA (<5.5 cm)AAA (>5.5 cm)
      Intervention (n = 18 500)Surveillance (n = 1 864)Intervention (n = 131 925)
      197 (96–97)100 (100–100)
      397 (96–97)98 (96–99)94 (94–95)
      584 (79–90)70 (60–82)90 (88–91)
      1062 (49–80)
      10 year survival data only available for two studies (n = 1 197).21,26
      65 (62–68)
      10 year survival data only available for two studies (n = 1 224).21,36
      76 (71–82)
      Data are presented as median (95% confidence interval).
      10 year survival data only available for two studies (n = 1 197).
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ,
      • Cao P.
      • De Rango P.
      • Verzini F.
      • Parlani G.
      • Romano L.
      • Cieri E.
      • et al.
      Comparison of surveillance versus aortic endografting for small aneurysm repair (CAESAR): results from a randomised trial.
      10 year survival data only available for two studies (n = 1 224).
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ,
      • Hye R.J.
      • Janarious A.U.
      • Chan P.H.
      • Cafri G.
      • Chang R.W.
      • Rehring T.F.
      • et al.
      Survival and reintervention risk by patient age and preoperative abdominal aortic aneurysm diameter after endovascular aneurysm repair.

      Standardised excess mortality of patients with abdominal aortic aneurysm

      Because most studies included in the above meta-analyses report aggregated normalised data, and consequently lack sex and age specific information as well as reference values, a second, more granular survival analysis of five year survival data of all patients with an intact AAA was performed for the Swedish AAA population (Table 3). Data are presented as standardised excess mortality as this provides both reference data (included in the table as “Expected mortality for the age/sex matched population”) and a more direct estimate of the AAA associated excess mortality. Results in Table 3 clearly illustrate the profound residual impact of AAA disease on five year survival, with a quadrupled (for females) and more than doubled (for males) five year mortality risk for patients under 80 with an AAA (Table 3).
      Table 3Rupture censored five years excess mortality for 11 351 patients with abdominal aortic aneurysms (AAA; both small and large) included in the Swedish National Registry between 2006 and 2010
      Data at five yearsMales (n = 8 940)Females (n = 2 411)
      <70 y70–79 y≥80 y<70 y70–79 y≥80 y
      Patients with AAA at risk – n
      Number of patients with AAA at risk represents the number of patients with AAA in the Swedish national registry.
      3 3323 6911 9175841 042785
      Observed mortality in the AAA population545 (16.4)1 258 (34.1)1 245 (64.9)109 (18.7)426 (40.1)521 (66.4)
      Expected mortality for the age and sex matched population
      Expected mortality = anticipated mortality based on the number at risk, and the mortality for the age and sex matched Swedish general population (this number reflects the reference population).
      216 (6.5)617 (16.7)707 (36.9)23 (3.9)108 (10.4)199 (25.4)
      Excess mortality for patients with AAA
      Excess mortality = observed mortality minus expected mortality.
      329 (9.9)641 (17.4)538 (28.1)86 (14.7)318 (30.5)322 (41.0)
      Excess mortality rate for patients with AAA
      Excess mortality rate = observed mortality divided by the expected mortality.
      2.522.041.764.743.762.62
      Data are presented as n (%).
      Number of patients with AAA at risk represents the number of patients with AAA in the Swedish national registry.
      Expected mortality = anticipated mortality based on the number at risk, and the mortality for the age and sex matched Swedish general population (this number reflects the reference population).
      Excess mortality = observed mortality minus expected mortality.
      § Excess mortality rate = observed mortality divided by the expected mortality.

      Aim 2. Inventory of the level of cardiovascular risk management in patients with abdominal aortic aneurysm

      This evaluation included 358 patients from 16 different hospitals in The Netherlands. The mean ± SD age of these patients was 70.3 ± 7.4 years, and 89% were male. Further characteristics of the patient cohort are presented in Table 4.
      Table 4Baseline characteristics of the 358 patients with small abdominal aortic aneurysms included in the Pharmaceutical Aneurysm Stabilisation Trial (PHAST) and TElmisartan in the management of abDominal aortic aneurysm (TEDY) trial
      Baseline characteristicsPatients with small AAA (n = 358)
      Male318 (88.8)
      Female40 (11.2)
      Body mass index >25 kg/m2
       Male124 (39)
       Female10 (25)
      Smoking
       Never30 (8.4)
       Current125 (34.9)
       Former203 (56.7)
      Pack years42.5 ± 27.4
      Systolic blood pressure – mmHg144.4 ± 19.9
      Diastolic blood pressure – mmHg83.5 ± 8.9
      Low density lipoprotein cholesterol – mmol/L2.66 ± 1.03
      Total cholesterol – mmol/L4.63 ± 1.06
      Triglycerides – mmol/L1.93 ± 1.16
      HDL cholesterol – mmol/L1.12 ± 0.34
      Total cholesterol/HDL ratio4.44 ± 1.51
      Glycated haemoglobin – mmol/mole39.7 ± 5.2
      eGFR – mL/min/1.73 m2
      Modification of diet in renal disease formula.
       Male73.3 ± 18.1
       Female68.1 ± 16.3
      Alanine transaminase – U/L26.3 ± 13.4
      Data are presented as n (%) or mean ± standard deviation. eGFR= estimated glomerular filtration rate; HDL = high density lipoprotein.
      Modification of diet in renal disease formula.
      The mean ± SD body mass index (BMI) of male and female patients was 27.4 ± 3.6) kg/m2, and 25.8 kg/m2, respectively, and 23% and 19% of the patients were classified as obese (BMI > 30 kg/m2). Among men, 32.7% were a current smoker, 58.8% a former smoker, and 8.5% had never smoked. Women had worse smoking habits than men: 52.5% were classified as current smokers, 40% former smokers, and 7.5% had never smoked (χ2 = 6.25, p < .050).
      Plasma LDL cholesterol and systolic blood pressure frequency distributions are summarised in Figure 2. Mean ± SD systolic and diastolic blood pressure was 144 ± 20.1 and 83 ± 9.1 mmHg and 149±18 and 84 ± 7.8 mmHg for men and women, respectively. Thirty-eight per cent and 29% of the male and female patients with AAA had a normal blood pressure without use of antihypertensives. Sixty-three per cent of the patients reported use of antihypertensive medication. Of those prescribed antihypertensives, 57% (males) and 73% (females) had a systolic blood pressure above 140 mmHg. Diastolic blood pressure exceeded 85 mmHg in 69% of patients (similar for both sexes).
      Figure 2
      Figure 2Distribution of (A) low density lipoprotein (LDL) cholesterol levels (mmol/L) and (B) systolic blood pressure in patients with a small (<50 mm) abdominal aortic aneurysm participating in Pharmaceutical Aneurysm Stabilisation Trial (PHAST) and TElmisartan in the management of abDominal aortic aneurysm (TEDY) trials (n = 358). Red bars depict individuals with LDL levels or systolic blood pressure above the target levels for high risk patients (1.8 mmol/L and 140 mmHg, respectively). Note the different scales used in A and B.
      Seventy per cent of the patients used lipid lowering medication (statins). Cholesterol levels were lower in those using vs. not using statins; (mean ± SD LDL cholesterol, 2.33 ± 0.88 vs. 3.5 ± 0.91 mmol/L; total cholesterol levels, 4.3 ± 0.92) vs. 5.46 ± 0.96 mmol/L, both p < .001. Of patients receiving statin treatment 18% of males and 11% of females were on target with an LDL level of < 1.8 mmol/L.
      Plasma HDL and triglycerides levels were similar between statin and non-statin users: 1.1 ± 0.4 and 2.0 ± 1.3; and 1.1 ± 0.3 and 1.8 ± 0.8, respectively.

      AIM 3. The potential of full implementation of the current cardiovascular prevention guidelines

      The SMART risk tool
      • Dorresteijn J.A.
      • Visseren F.L.
      • Wassink A.M.
      • Gondrie M.J.
      • Steyerberg E.W.
      • Ridker P.M.
      • et al.
      Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.
      ,

      European Society of Cardiology. The Smart Risk Score. Available at: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score [Accessed 27 September 2022].

      was applied to estimate 10 year cardiovascular risk and theoretically modifiable 10 year cardiovascular risk (treatment gap) for the 304 AAA patients for whom a full risk profile was available. Predicted individual 10 years cardiovascular risk ranged from 17% to 91% (mean predicted 10 years risk, 43%). The potential impacts of the different risk reduction interventions on cardiovascular risk (smoking cessation, lipid lowering (LDL < 1.8 mmol/L), and blood pressure control (systolic blood pressure < 140 mmHg) on the estimated 10 years cardiovascular risk are summarised in Table 5. Based on the SMART risk estimation tool,
      • Dorresteijn J.A.
      • Visseren F.L.
      • Wassink A.M.
      • Gondrie M.J.
      • Steyerberg E.W.
      • Ridker P.M.
      • et al.
      Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.
      ,

      European Society of Cardiology. The Smart Risk Score. Available at: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score [Accessed 27 September 2022].

      it is estimated that if optimised risk management were fully implemented in the 304 patients with AAA, this would result in 29 ± 11.3% (mean ± SD) reduction in 10 years risk of cardiovascular events. It was further concluded that full implementation of risk management would result in a 10 years cardiovascular risk that is approximately 14% higher than that of the general population.
      Table 5Estimated risk reductions achieved by implementing cardiovascular risk management guidelines in 358 patients with a small aneurysm under surveillance in 16 hospitals in The Netherlands using the Second Manifestations of ARTerial disease (SMART) risk scores (estimated 10 year risk of cardiovascular event)
      Treatment targetMenWomen
      nEstimated 10 year risk reductionnEstimated 10 year risk reduction
      Estimated impact on patients not on target
      n = number of patients not on target.
       Systolic blood pressure <140 mmHg1398.2 (5.3–14.5)2110.8 (6.1–15.9)
       LDL cholesterol < 1.8 mg/dL2256.1 (3.1–11.3)307.7 (4.2–12.8)
       Smoking cessation9016.6 (11.5–16.4)1813.0 (10.8–17.3)
       Systolic blood pressure <140 mmHg + LDL cholesterol <1.8 mg/dL11816.9 (10.6–22.6)1914.9 (12.9–20.2)
       Systolic blood pressure <140 mmHg + smoking cessation4322.9 (16.5–26.7)1320.6 (16.6–31.2)
       LDL cholesterol <1.8 mg/dL + Smoking cessation7719.9 (15.5–26.1)1616.6 (14.0–24.1)
       Systolic blood pressure <140 mmHg + LDL cholesterol <1.8 mg/dL + Smoking cessation3627.0 (21.9–35.2)1224.4 (21.5–34.8)
      Estimated overall impact (full cohort)
       Systolic blood pressure <140 mmHg2701.6 (0.0–9.1)345.6 (0.0–11.5)
       LDL cholesterol <1.8 mg/dL2704.9 (1.7–9.9)346.4 (3.1–11.2)
       Smoking cessation2700.0 (0.0–11.5)349.0 (0–13.5)
       Systolic blood pressure <140 mmHg + LDL cholesterol <1.8 mg/dL2706.8 (0.6–16.6)3414.4 (8.8–20.5)
       Systolic blood pressure <140 mmHg + Smoking cessation2700.0 (0.0–12.6)3410.2 (0.0–20.1)
       LDL cholesterol <1.8 mg/dL + smoking cessation2707.2 (1.8–16.1)3413.7 (5.4–19.1)
       Systolic blood pressure <140 mmHg + LDL cholesterol <1.8 mg/dL + smoking cessation2707.0 (0.6–18.5)3418.3 (8.8–25.6)
      Data are presented as median (interquartile range). LDL = low density lipoprotein.
      n = number of patients not on target.

      Discussion

      The meta-analyses of reported survival data for patients with AAA included in this study, and a comparison of survival data of Swedish patients with AAA with that of the general Swedish population show an extreme impact of AAA disease on life expectancy. This excess mortality appears largely independent of rupture risk, and is assumed to relate to a sharply increased cardiovascular risk.
      • Bath M.F.
      • Saratzis A.
      • Saedon M.
      • Sidloff D.
      • Sayers R.
      • Bown M.J.
      • et al.
      Patients with small abdominal aortic aneurysm are at significant risk of cardiovascular events and this risk is not addressed sufficiently.
      ,
      • Kaasenbrood L.
      • Boekholdt S.M.
      • van der Graaf Y.
      • Ray K.K.
      • Peters R.J.
      • Kastelein J.J.
      • et al.
      Distribution of estimated 10-year risk of recurrent vascular events and residual risk in a secondary prevention population.
      ,
      • Sidloff D.A.
      • Saratzis A.
      • Thompson J.
      • Katsogridakis E.
      • Bown M.J.
      Editor’s Choice – Infra-renal aortic diameter and cardiovascular risk: making better use of abdominal aortic aneurysm screening outcomes.
      Systematic evaluation of the levels of risk management in patients under surveillance for small AAA shows that, for the majority of patients, the level of management does not meet the targets for high risk cardiovascular patients.
      • Piepoli M.F.
      • Hoes A.W.
      • Agewall S.
      • Albus C.
      • Brotons C.
      • Catapano A.L.
      • et al.
      2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
      Estimation of the theoretical therapeutic gap through the SMART risk score
      • Dorresteijn J.A.
      • Visseren F.L.
      • Wassink A.M.
      • Gondrie M.J.
      • Steyerberg E.W.
      • Ridker P.M.
      • et al.
      Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.
      ,

      European Society of Cardiology. The Smart Risk Score. Available at: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score [Accessed 27 September 2022].

      illustrated the profound potential of strict implementation of cardiovascular risk management in patients with AAA.
      While the primary focus in AAA management is on rupture prevention, a meta-analysis of patient survival following elective open or endovascular repair shows a profound residual mortality risk for patients who had had their AAA repaired.
      • Bulder R.M.A.
      • Bastiaannet E.
      • Hamming J.F.
      • Lindeman J.H.N.
      Meta-analysis of long-term survival after elective endovascular or open repair of abdominal aortic aneurysm.
      Extension of this evaluation to patients with a small (< 55 mm) AAA in the meta-analyses performed herein show an equal excess mortality for patients who underwent early repair, and an even worse prognosis for those under surveillance. Although the latter may reflect the (slight) rupture risk of small AAA, any conclusion is interfered with by medical decision making (selection bias). To be more specific: the surveillance population also includes patients deemed unfit or non-eligible for AAA repair, and or those who did not meet the inclusion criteria for randomised controlled trials. Consequently, it is likely that frail patients and other patients with an anticipated compromised life expectancy are asymmetrically represented in surveillance studies.
      The relative survival analysis is based on aggregated survival information

      Human Mortality Database. University of California BU, and Max Planck Institute for Demographic Research (Germany). Available at: www.mortality.org or www.humanmortality.de [Accessed 17 January 2023].

      from the meta-analyses and provides an estimate of exposure related deaths (i.e., in this study, disease specific mortality of patients with AAA).
      • Sarfati D.
      • Blakely T.
      • Pearce N.
      Measuring cancer survival in populations: relative survival vs cancer-specific survival.
      It corrects for general interfering factors such as differences in age at the time of surgery, sex, population, and year of data collection (index years). Consequently, while this provides a global and robust overall survival estimate, age and sex specific information (women!) is lacking. To overcome this information gap, an additional analysis of Swedish national data was performed. In this analysis it was decided to apply standardised five years mortality rates rather than relative survival, as these provide more tangible reflections of AAA associated mortality.
      • Bastiaannet E.
      • Liefers G.J.
      • de Craen A.J.
      • Kuppen P.J.
      • van de Water W.
      • Portielje J.E.
      • et al.
      Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients.
      This national evaluation not only confirmed the profound disease specific excess mortality observed in the meta-analysis data, but also revealed an extreme sex disparity and an age effect with a reduced excess mortality in older patients. The observed mitigation of excess mortality with increasing age presumably relates to increases in competitive deaths,
      • Berry S.D.
      • Ngo L.
      • Samelson E.J.
      • Kiel D.P.
      Competing risk of death: an important consideration in studies of older adults.
      selective loss of vulnerable patients during ageing, and or confounding by indication (e.g., frail, older patients may not be referred for evaluation of their AAA). The observed quadrupled five year mortality for women under 80 years provides a worrying quantification of the acknowledged poorer outcomes for female patients with AAA.
      • Bulder R.M.A.
      • Talvitie M.
      • Bastiaannet E.
      • Hamming J.F.
      • Hultgren R.
      • Lindeman J.H.N.
      Long-term prognosis after elective abdominal aortic aneurysm repair is poor in women and men: the challenges remain.
      ,
      • Tomee S.M.
      • Lijftogt N.
      • Vahl A.
      • Hamming J.F.
      • Lindeman J.H.N.
      A registry-based rationale for discrete intervention thresholds for open and endovascular elective abdominal aortic aneurysm repair in female patients.
      Persistently compromised survival following AAA repair (and thus minimisation of rupture risk) implies that the excess mortality in the AAA population is largely independent of rupture risk.
      • Greenhalgh R.M.
      • Brown L.C.
      • Powell J.T.
      • Thompson S.G.
      • Epstein D.
      United Kingdom ETI
      Endovascular repair of aortic aneurysm in patients physically ineligible for open repair.
      This observation is supported by Danish population based data that reported a 2.4 fold increase in all cause mortality for the 11 094 patients with AAA who underwent acute or elective open repair.
      • Bahia S.S.
      • Vidal-Diez A.
      • Seshasai S.R.
      • Shpitser I.
      • Brownrigg J.R.
      • Patterson B.O.
      • et al.
      Cardiovascular risk prevention and all-cause mortality in primary care patients with an abdominal aortic aneurysm.
      The excess profound residual mortality rate is largely attributed to increased cardiovascular risk.
      • Eldrup N.
      • Budtz-Lilly J.
      • Laustsen J.
      • Bibby B.M.
      • Paaske W.P.
      Long-term incidence of myocardial infarct, stroke, and mortality in patients operated on for abdominal aortic aneurysms.
      ,
      • Bath M.F.
      • Saratzis A.
      • Saedon M.
      • Sidloff D.
      • Sayers R.
      • Bown M.J.
      • et al.
      Patients with small abdominal aortic aneurysm are at significant risk of cardiovascular events and this risk is not addressed sufficiently.
      In fact, cardiovascular death accounts for approximately 50% of all deaths in Swedish patients with an AAA, with neoplasm-related deaths being the second most common cause of death (approximately 20 – 25% of all deaths).
      • Bulder R.M.A.
      • Talvitie M.
      • Bastiaannet E.
      • Hamming J.F.
      • Hultgren R.
      • Lindeman J.H.N.
      Long-term prognosis after elective abdominal aortic aneurysm repair is poor in women and men: the challenges remain.
      The increased cardiovascular risk is well acknowledged, and patients with AAA are categorised as being very high risk in the current AAA and cardiovascular risk management guidelines,
      • Piepoli M.F.
      • Hoes A.W.
      • Agewall S.
      • Albus C.
      • Brotons C.
      • Catapano A.L.
      • et al.
      2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
      ,
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor’s Choice – European Society for Vascular Surgery (ESVS) 2019 clinical practice guidelines on the management of abdominal aorto-iliac artery aneurysms.
      and classify for intensified cardiovascular risk management accordingly.
      Conclusions from the national, cross sectional inventory of the levels of risk management presented herein show that, while the great majority of patients with AAA receive some form of risk management, the overall level of risk management achieved does generally not meet the criteria for high risk patients.
      • Piepoli M.F.
      • Hoes A.W.
      • Agewall S.
      • Albus C.
      • Brotons C.
      • Catapano A.L.
      • et al.
      2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
      It is unlikely that these observations are specific for the Dutch health system. In fact, multiple reports indicate suboptimal pharmaceutical risk management and smoking cessation in patients with AAA and conclude that the majority of patients with AAA are undertreated and or insufficiently monitored.
      • Bahia S.S.
      • Vidal-Diez A.
      • Seshasai S.R.
      • Shpitser I.
      • Brownrigg J.R.
      • Patterson B.O.
      • et al.
      Cardiovascular risk prevention and all-cause mortality in primary care patients with an abdominal aortic aneurysm.
      ,
      • Saratzis A.
      • Dattani N.
      • Brown A.
      • Shalhoub J.
      • Bosanquet D.
      • Sidloff D.
      • et al.
      Multi-centre study on cardiovascular risk management on patients undergoing AAA surveillance.
      An alarming observation is the more pronounced prevention gap in women. Although the number of women in the inventory in this study is limited, data indicate that women present with worse cardiovascular risk profiles than men. This poorer level of risk management in women is not an isolated observation for AAA patients: a Dutch evaluation of medical therapy adherence following STEMI (ST segment elevation myocardial infarction) and non-STEMI concluded that treatment adherence was lower in women,
      • Eindhoven D.C.
      • Hilt A.D.
      • Zwaan T.C.
      • Schalij M.J.
      • Borleffs C.J.W.
      Age and gender differences in medical adherence after myocardial infarction: women do not receive optimal treatment – The Netherlands claims database.
      and similar real world conclusions were also reached in other cohort studies.
      • Rea F.
      • Mella M.
      • Monzio Compagnoni M.
      • Cantarutti A.
      • Merlino L.
      • Mancia G.
      • et al.
      Women discontinue antihypertensive drug therapy more than men. Evidence from an Italian population-based study.
      • Spencer-Bonilla G.
      • Chung S.
      • Sarraju A.
      • Heidenreich P.
      • Palaniappan L.
      • Rodriguez F.
      Statin use in older adults with stable atherosclerotic cardiovascular disease.
      • Toth P.P.
      • Granowitz C.
      • Hull M.
      • Anderson A.
      • Philip S.
      Long-term statin persistence is poor among high-risk patients with dyslipidemia: a real-world administrative claims analysis.
      Available evidence suggests that patients with AAA would benefit from optimised management (treat to target), and in this context AAA screening could be considered a two edged sword by also identifying patients at a high cardiovascular risk. The report by Bahia et al. indicated superior five years survival for patients with AAA receiving statins, antiplatelet agents, or antihypertensive medication compared with patients not receiving either one of these therapeutic agents.
      • Bahia S.S.
      • Vidal-Diez A.
      • Seshasai S.R.
      • Shpitser I.
      • Brownrigg J.R.
      • Patterson B.O.
      • et al.
      Cardiovascular risk prevention and all-cause mortality in primary care patients with an abdominal aortic aneurysm.
      Similarly, multiple studies have shown that irrespective of the repair status, statin therapy is associated with superior survival in patients with AAA.
      • Cheng W.
      • Jia X.
      • Li J.
      • Cheng W.
      • Liu Z.
      • Lin Z.
      • et al.
      Relationships of statin therapy and hyperlipidemia with the incidence, rupture, postrepair mortality, and all-cause mortality of abdominal aortic aneurysm and cerebral aneurysm: a meta-analysis and systematic review.
      ,
      • O'Donnell T.F.X.
      • Deery S.E.
      • Shean K.E.
      • Mittleman M.A.
      • Darling J.D.
      • Eslami M.H.
      • et al.
      Statin therapy is associated with higher long-term but not perioperative survival after abdominal aortic aneurysm repair.
      However, it is unclear whether these observations relate to a superior risk management or non-exclusively reflect confounding, caused by an association between therapy compliance and superior survival.
      • Hartz A.
      • He T.
      Why is greater medication adherence associated with better outcomes.
      In an effort to estimate the bridgeable prevention gap for patients with AAA (what would be gained by strict implementation of cardiovascular risk management?), the SMART risk score tool was applied.
      • Dorresteijn J.A.
      • Visseren F.L.
      • Wassink A.M.
      • Gondrie M.J.
      • Steyerberg E.W.
      • Ridker P.M.
      • et al.
      Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.
      ,

      European Society of Cardiology. The Smart Risk Score. Available at: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score [Accessed 27 September 2022].

      Outcomes from the algorithm illustrated the profound potential of optimal cardiovascular risk management, with an average 25% reduction in 10 years cardiovascular risk. Notwithstanding, the data also indicate persistence of considerable residual risk.
      All in all, these data illustrate the need and theoretical potential of optimised cardiovascular risk management in patients with AAA. Although the relative undermanagement may obviously relate to poor patient compliance or adherence,
      • Eindhoven D.C.
      • Hilt A.D.
      • Zwaan T.C.
      • Schalij M.J.
      • Borleffs C.J.W.
      Age and gender differences in medical adherence after myocardial infarction: women do not receive optimal treatment – The Netherlands claims database.
      • Rea F.
      • Mella M.
      • Monzio Compagnoni M.
      • Cantarutti A.
      • Merlino L.
      • Mancia G.
      • et al.
      Women discontinue antihypertensive drug therapy more than men. Evidence from an Italian population-based study.
      • Spencer-Bonilla G.
      • Chung S.
      • Sarraju A.
      • Heidenreich P.
      • Palaniappan L.
      • Rodriguez F.
      Statin use in older adults with stable atherosclerotic cardiovascular disease.
      • Toth P.P.
      • Granowitz C.
      • Hull M.
      • Anderson A.
      • Philip S.
      Long-term statin persistence is poor among high-risk patients with dyslipidemia: a real-world administrative claims analysis.
      or a lack of accurate disease knowledge,
      • Tomee S.M.
      • Gebhardt W.A.
      • de Vries J.P.
      • Hamelinck V.C.
      • Hamming J.F.
      • Lindeman J.H.
      Patients' perceptions of conservative treatment for a small abdominal aortic aneurysm.
      underuse also involves iatrogenic aspects. In fact, an inventory of statin underuse identified a lack of awareness among care providers to be a preventable and major cause (i.e., more than half of patients eligible for statin therapy but not on treatment reported never being offered a statin by their doctor).
      • Bradley C.K.
      • Wang T.Y.
      • Li S.
      • Robinson J.G.
      • Roger V.L.
      • Goldberg A.C.
      • et al.
      Patient-reported reasons for declining or discontinuing statin therapy: insights from the PALM registry.
      This observation may particularly apply to patients with AAA for whom the primary focus is surgical (i.e., management of rupture risk and the adequacy of repair). In this respect, it is concluded that patients with AAA perceive their disease as a “bodily” defect and not as a health condition with an associated risk.
      • Nicolajsen C.W.
      • Sogaard M.
      • Eldrup N.
      • Mikkelsen R.B.L.
      • Hojen A.A.
      Abdominal aortic aneurysm – disease or a defect – patients’ perceptions of aortic aneurysm in the presence of multimorbidity.
      Hence, interventions aimed at mitigating the extreme cardiovascular risk presumably also need to address a gap in health self efficacy.

      Limitations

      The inventory of the level of risk management was performed in patients participating in the TEDY or PHAST trials. Participants in clinical trials generally tend to be “healthier” and more motivated than general patient populations, as a consequence the data may overestimate the level of risk management. Along these lines, use of an angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist was an exclusion criterion in the TEDY trial. Since these groups of antihypertensives are considered second line antihypertensive treatment, patients with severe hypertension may be under represented in the trial. Detailed data on antiplatelet therapy were not available for patients in the PHAST study, and this therapy was therefore not incorporated as a variable in the cardiovascular risk profiles and was excluded from SMART risk analysis as a potential cardiovascular risk modifier.
      The SMART risk score is a validated tool for the calculation of individual cardiovascular risk of several vascular patient groups in clinical practice.
      • Dorresteijn J.A.
      • Visseren F.L.
      • Wassink A.M.
      • Gondrie M.J.
      • Steyerberg E.W.
      • Ridker P.M.
      • et al.
      Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score.
      ,

      European Society of Cardiology. The Smart Risk Score. Available at: https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score [Accessed 27 September 2022].

      Although the tool is validated, differences between populations are observed.
      • Alabas O.A.
      • Gale C.P.
      • Hall M.
      • Rutherford M.J.
      • Szummer K.
      • Lawesson S.S.
      • et al.
      Sex differences in treatments, relative survival, and excess mortality following acute myocardial infarction: national cohort study using the SWEDEHEART registry.
      Finally, although the SMART risk model provides a risk estimate for recurrent cardiovascular events, it is unclear whether the risk reductions will translate to improved long term survival of patients with AAA and reduce their excess mortality.

      Conclusions

      Independent of rupture risk, AAA is associated with a more than doubled (men) or quadrupled (women) five year mortality risk, a risk that far exceeds the mortality risk of patients with a previous myocardial infarction.
      • Kaasenbrood L.
      • Bhatt D.L.
      • Dorresteijn J.A.N.
      • Wilson P.W.F.
      • D’Agostino Sr., R.B.
      • Massaro J.M.
      • et al.
      Estimated life expectancy without recurrent cardiovascular events in patients with vascular disease: the SMART-REACH model.
      This non-aneurysmal, residual excess risk is largely amendable by cardiovascular risk prevention. Conclusions from this study suggest that cardiovascular risk management should be considered equal to or even more relevant than rupture prevention, and the level of risk management should be included as a quality parameter for the management of patients with AAA. The extremely poor outcomes for female patients with AAA are particularly worrying. Considering the traditional focus on male patients with AAA, studies focusing on female patients are urgently required.

      Conflict of interest

      J.S. Matsumura: Grant support to University of Wisconsin from Abbott, Cook, Medtronic, Gore, Endologix.

      Funding

      None.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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      Linked Article

      • Cardiovascular Risk in Individuals with an Abdominal Aortic Aneurysm: Time to Focus on the Forest, not the Tree
        European Journal of Vascular and Endovascular Surgery
        • Preview
          Male sex, smoking, and hypercholesterolaemia are associated with abdominal aortic aneurysm (AAA);1–3 those with an AAA are therefore at high cardiovascular risk.1,2 Lindeman et al. performed an in depth analysis of the association between cardiovascular risk and AAA in three separate “pillars”:1 excess mortality risk in those with AAA; current cardiovascular risk management in patients with an AAA; potential for the full implementation of cardiovascular prevention guidelines. Their findings are important for current clinical practice.
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