Louise C. Brown

Risk Factors for Aneurysm Rupture in Patients Kept Under Ultrasound Surveillance

OBJECTIVE To investigate risk factors associated with aneurysm rupture using patients randomized into the U.K. Small Aneurysm Trial (n = 1090) or monitored for aneurysm growth in the associated study (n = 1167). SUMMARY BACKGROUND DATA The U.K. Small Aneurysm Trial has shown that ultrasound surveillance is a safe management option for patients with small abdominal aortic aneurysms (4.0 to 5.5 cm in diameter), with an annual rupture rate of 1%. METHODS In the cohort of 2257 patients (79% male), aged 59 to 77 years, 103 instances of abdominal aortic aneurysm rupture were identified during the 7-year period of follow-up (1991-1998). Almost all patients (98%) had initial aneurysm diameters in the range of 3 to 6 cm, and the majority of ruptures (76%) occurred in patients with aneurysms > or =5 cm in diameter. Kaplan-Meier survival and Cox regression analysis were used to identify baseline risk factors associated with aneurysm rupture. RESULTS After 3 years, the annual rate of aneurysm rupture was 2.2% (95% confidence interval 1.7 to 2.8). The risk of rupture was independently and significantly associated with female sex (p < 0.001), larger initial aneurysm diameter (p < 0.001), lower FEV1 (p = 0.004), current smoking (p = 0.01), and higher mean blood pressure (p = 0.01). Age, body mass index, serum cholesterol concentration, and ankle/brachial pressure index were not associated with an increased risk of aneurysm rupture. CONCLUSIONS Within this cohort of patients, women had a threefold higher risk of aneurysm rupture than men. Effective control of blood pressure and cessation of smoking are likely to diminish the risk of rupture.

Meta‐analysis of individual patient data to examine factors affecting growth and rupture of small abdominal aortic aneurysms

Surveillance is a common management strategy for small abdominal aortic aneurysm (AAA) (3·0–5·4 cm in diameter). Individual characteristics, other than diameter, may influence aneurysm growth or rupture rates.

Inhibition of Prostaglandin E2 Synthesis in Abdominal Aortic Aneurysms : Implications for Smooth Muscle Cell Viability, Inflammatory Processes, and the Expansion of Abdominal Aortic Aneurysms

BACKGROUND There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. METHODS AND RESULTS Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E2 (PGE2) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49+/-22 ng/g, 319+/-38 ng/mL, and 22+/-21 ng/mL, respectively. PGE2 inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC50, 23.2+/-3.8 and 23.6+/-4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE2 also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE2. In explants, indomethacin 10 micromol/L or mefenamic acid 10 micromol/L abolished PGE2 secretion and significantly reduced IL-1beta and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P=0.001. CONCLUSIONS The adverse effects of PGE2 on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE2 synthesis could be an effective treatment to curtail aneurysm expansion.

The UK EndoVascular Aneurysm Repair (EVAR) trials: randomised trials of EVAR versus standard therapy.

OBJECTIVE To assess the efficacy of endovascular aneurysm repair (EVAR) against standard alternative management in patients with large abdominal aortic aneurysm (AAA). DESIGN Two national, multicentre randomised trials - EVAR trials 1 and 2. SETTING Patients were recruited from 38 out of 41 eligible UK hospitals. PARTICIPANTS Men and women aged at least 60 years, with an AAA measuring at least 5.5 cm on a computerised tomography scan that was regarded as anatomically suitable for EVAR, were assessed for fitness for open repair. Patients considered fit were randomised to EVAR or open repair in EVAR trial 1 and patients considered unfit were randomised to EVAR or no intervention in EVAR trial 2. INTERVENTIONS EVAR, open repair or no intervention. MAIN OUTCOME MEASURES The primary outcome was mortality (operative, all-cause and AAA related). Patients were flagged at the UK Office for National Statistics with centrally coded death certificates assessed by an Endpoints Committee. Power calculations based upon mortality indicated that 900 and 280 patients were required for EVAR trials 1 and 2, respectively. Secondary outcomes were graft-related complications and reinterventions, adverse events, renal function, health-related quality of life and costs. Cost-effectiveness analyses were performed for both trials. RESULTS Recruitment occurred between 1 September 1999 and 31 August 2004, with targets exceeded in both trials: 1252 randomised into EVAR trial 1 (626 to EVAR) and 404 randomised into EVAR trial 2 (197 to EVAR). Follow-up closed in December 2009 with very little loss to follow-up (1%). In EVAR trial 1, 30-day operative mortalities were 1.8% and 4.3% in the EVAR and open-repair groups, respectively: adjusted odds ratio 0.39 [95% confidence interval (CI) 0.18 to 0.87], p = 0.02. During a total of 6904 person-years of follow-up, 524 deaths occurred (76 AAA related). Overall, there was no significant difference between the groups in terms of all-cause mortality: adjusted hazard ratio (HR) 1.03 (95% CI 0.86 to 1.23), p = 0.72. The EVAR group did demonstrate an early advantage in terms of AAA-related mortality, which was sustained for the first few years, but lost by the end of the study, primarily due to fatal endograft ruptures: adjusted HR 0.92 (95% CI 0.57 to 1.49), p = 0.73. The EVAR procedure was more expensive than open repair (mean difference £1177) and not found to be cost-effective, but the model was sensitive to alternative assumptions. In EVAR trial 2, during a total of 1413 person-years of follow-up, a total of 305 deaths occurred (78 AAA related). The 30-day operative mortality was 7.3% in the EVAR group. However, this group later demonstrated a significant advantage in terms of AAA-related mortality, but this became apparent only after 4 years: overall adjusted HR 0.53 (95% CI 0.32 to 0.89), p = 0.02. Sadly, this advantage did not result in any benefit in terms of all-cause mortality: adjusted HR 0.99 (95% CI 0.78 to 1.27), p = 0.97. Overall, EVAR was more expensive than no intervention (mean difference £10,222) and not found to be cost-effective. CONCLUSIONS EVAR offers a clear operative mortality benefit over open repair in patients fit for both procedures, but this early benefit is not translated into a long-term survival advantage. Among patients unfit for open repair, EVAR is associated with a significant long-term reduction in AAA-related mortality but this does not appear to influence all-cause mortality. TRIAL REGISTRATION Current Controlled Trials ISRCTN 55703451. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 9. See the HTA programme website for further project information.

Rate and predictability of graft rupture after endovascular and open abdominal aortic aneurysm repair: data from the EVAR Trials.

Objective:To assess the rate and factors associated with rupture after endovascular aneurysm repair (EVAR) or open repair (OR) of abdominal aortic aneurysm. Background:Graft rupture after EVAR has been reported, often preceded by graft-related complications. Graft rupture has also been reported after OR. Methods:By July 2009, a total of 848 elective EVARs and 594 elective ORs were performed in the United Kingdom EVAR trials 1 and 2. Patients were followed up for complications, reinterventions, and rupture. The incidence of rupture was explored in relation to baseline anatomy and subsequent complications in a Cox regression analysis. Results:There were no ruptures in the OR patients. A total of 27 ruptures occurred after EVAR during a mean follow-up of 4.8 years: crude rate = 0.7 [95% confidence interval (CI): 0.5–1.0] ruptures per 100 person-years. Eighteen patients (67%) died within 30 days of rupture. Five ruptures occurred in the first 30 postoperative days and 22 after that: crude rates of rupture = 7.2 (95% CI: 3.0–17.4) and 0.6 (95% CI: 0.4–0.9) per 100 person-years, respectively. Previous complications (endoleak type 1, type 2 with sac expansion, type 3, migration or kinking) increased the risk of rupture, adjusted hazard ratio 8.83 (95% CI 3.76–20.76), P < 0.0001. Conclusions:There were no ruptures after OR and a low rate after EVAR. Mortality after graft rupture is high and previous serious complications are significantly associated with the risk of rupture. Few ruptures after EVAR seem to be spontaneous without complications identified during optimal surveillance.

Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness

BACKGROUND Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Surveillance intervals for small abdominal aortic aneurysms: A meta-analysis

IMPORTANCE Small abdominal aortic aneurysms (AAAs [3.0 cm-5.4 cm in diameter]) are monitored by ultrasound surveillance. The intervals between surveillance scans should be chosen to detect an expanding aneurysm prior to rupture. OBJECTIVE To limit risk of aneurysm rupture or excessive growth by optimizing ultrasound surveillance intervals. DATA SOURCES AND STUDY SELECTION Individual patient data from studies of small AAA growth and rupture were assessed. Studies were identified for inclusion through a systematic literature search through December 2010. Study authors were contacted, which yielded 18 data sets providing repeated ultrasound measurements of AAA diameter over time in 15,471 patients. DATA EXTRACTION AAA diameters were analyzed using a random-effects model that allowed for between-patient variability in size and growth rate. Rupture rates were analyzed by proportional hazards regression using the modeled AAA diameter as a time-varying covariate. Predictions of the risks of exceeding 5.5-cm diameter and of rupture within given time intervals were estimated and pooled across studies by random effects meta-analysis. RESULTS AAA growth and rupture rates varied considerably across studies. For each 0.5-cm increase in AAA diameter, growth rates increased on average by 0.59 mm per year (95% CI, 0.51-0.66) and rupture rates increased by a factor of 1.91 (95% CI, 1.61-2.25). For example, to control the AAA growth risk in men of exceeding 5.5 cm to below 10%, on average, a 7.4-year surveillance interval (95% CI, 6.7-8.1) is sufficient for a 3.0-cm AAA, while an 8-month interval (95% CI, 7-10) is necessary for a 5.0-cm AAA. To control the risk of rupture in men to below 1%, the corresponding estimated surveillance intervals are 8.5 years (95% CI, 7.0-10.5) and 17 months (95% CI, 14-22). CONCLUSION AND RELEVANCE In contrast to the commonly adopted surveillance intervals in current AAA screening programs, surveillance intervals of several years may be clinically acceptable for the majority of patients with small AAA.

Use of angiotensin converting enzyme inhibitors is associated with increased growth rate of abdominal aortic aneurysms

OBJECTIVES To evaluate whether either angiotensin converting enzyme (ACE) inhibitors or other classes of antihypertensive drug attenuate or increase growth rates of small infrarenal abdominal aortic aneurysms. METHODS Prospective cohort study of 1701 patients enrolled in the UK Small Aneurysm Trial or associated study at 93 hospitals between 1991 and 1995 and who had at least two ultrasound measurements of aneurysm diameter and baseline drug prescription data recorded. Abdominal aortic aneurysm diameter was measured in the anterior-posterior plane using ultrasound. The mean growth rate was estimated through a mixed-effects linear growth model. RESULTS Mean aneurysm growth rate in 169 patients taking ACE inhibitors at baseline was 3.33 mm/y vs 2.77 mm/y in the remaining 1532 patients, P = .009. The significance of this finding did not alter after adjustment for known confounders. The prescription of any antihypertensive agent and other specific classes of antihypertensive drugs were not found to be associated with aneurysm growth rate. CONCLUSION These results show that patients taking ACE inhibitors have faster aneurysm growth and are in conflict with the observation from a large Canadian data-base that aneurysm patients taking ACE inhibitors are less likely to present with aneurysm rupture. There is an urgent need for a randomized trial to assess whether ACE inhibitors are beneficial or harmful to patients with aneurysms below the threshold size for surgical intervention.

Color duplex ultrasonography is insensitive for the detection of endoleak after aortic endografting: a systematic review.

Purpose: To synthesize the available evidence regarding the diagnostic accuracy of color duplex ultrasonography (CDU) versus the accepted gold-standard of contrast-enhanced computed tomography (CT) for the detection and classification of endoleaks after aortic endografting. Methods: A systematic search of the literature was conducted using electronic bibliographical databases and other means to gather articles published between 1991 and 2004. Articles were scrutinized against inclusion/exclusion criteria that broadly followed the QUA-DAS quality assessment guidelines. The results of diagnostic CDU were expressed for each study as a 2times2 contingency table, and summary statistics (sensitivity/specificity with 95% confidence intervals [CI]) were calculated. Pooled and random effects meta-analyses were performed. Results: Eight published studies and 2 unpublished studies from Charing Cross and St. Georges Hospitals (711 patients, 1355 paired scans performed ≥1 month after endografting) were eligible for inclusion. From meta-analyses, the pooled sensitivity of CDU (versus CT as the gold standard) was 69% (95% CI 52% to 87%) and the specificity of CDU was 91% (95% CI 87% to 95%). These parameters did not appear to vary over time when a smaller dataset of 117 patients with 239 paired scans was used to compare CT and CDU specifically at 3, 12, and 24 months after endografting. Endoleak classification data, which was derived from only 5 small studies, indicated that CDU appeared to have better diagnostic accuracy in detecting type I or type III endoleaks compared with type II endoleaks; however, the data were insufficient for statistical analysis. Conclusions: CDU currently does not have sufficient diagnostic accuracy for the detection of all endoleaks in routine clinical practice. The diagnostic accuracy of CDU may improve if type II endoleaks are ignored.

The influence of thrombus, calcification, angulation, and tortuosity of attachment sites on the time to the first graft-related complication after endovascular aneurysm repair

PURPOSE Endovascular aneurysm repair (EVAR) is associated with high graft-related complication rates during follow-up. Anatomical fit between patient and endograft could be an important factor for successful treatment. Aim was to assess whether extent of thrombus, calcification, angulation, and tortuosity are associated with occurrence of complications after EVAR. MATERIALS AND METHODS Patients in either United Kingdom EVAR trial 1 or 2 were included if they had undergone EVAR within 6 months of randomization and had a preoperative computed tomography (CT) scan of adequate quality in the core laboratory. Three-dimensional CT imaging was used to assess extent of preoperative thrombus, calcification, angulation, and tortuosity in aneurysm neck and iliac segments. Cox regression modeling, adjusted for the variables tested and for known confounding variables, was used to investigate whether these factors were associated with increased rates of reported first complications. RESULTS A total of 217 patients with 53 first graft-related complications were analyzed after a mean follow-up of 3.6 years. Adjusted hazard ratios (95% confidence intervals, P values) for complications per unit increase of variable were 0.96 (0.92-0.99, 0.018) for neck thrombus, 1.06 (1.00-1.12, 0.044) for neck calcification, 1.02 (1.00-1.05, 0.079) for neck angulation, 1.04 (1.01-1.06, 0.011) for common iliac thrombus, 0.96 (0.93-1.00, 0.033) for common iliac calcification, and 5.96 (1.53-23.28, 0.010) for common iliac tortuosity. CONCLUSION Increased neck angulation and calcification and common iliac thrombus and tortuosity are associated with higher rates of graft-related complications after EVAR. Increased neck thrombus and common iliac calcification appear to protect against complications. Careful evaluation of these factors prior to EVAR might lead to lower complication rates.