Value of risk scores in the decision to palliate patients with ruptured abdominal aortic aneurysm.

BACKGROUND: The aim of this study was to develop a 48-h mortality risk score, which included morphology data, for patients with ruptured abdominal aortic aneurysm presenting to an emergency department, and to assess its predictive accuracy and clinical effectiveness in triaging patients to immediate aneurysm repair, transfer or palliative care. METHODS: Data from patients in the IMPROVE (Immediate Management of the Patient With Ruptured Aneurysm: Open Versus Endovascular Repair) randomized trial were used to develop the risk score. Variables considered included age, sex, haemodynamic markers and aortic morphology. Backwards selection was used to identify relevant predictors. Predictive performance was assessed using calibration plots and the C-statistic. Validation of the newly developed and other previously published scores was conducted in four external populations. The net benefit of treating patients based on a risk threshold compared with treating none was quantified. RESULTS: Data from 536 patients in the IMPROVE trial were included. The final variables retained were age, sex, haemoglobin level, serum creatinine level, systolic BP, aortic neck length and angle, and acute myocardial ischaemia. The discrimination of the score for 48-h mortality in the IMPROVE data was reasonable (C-statistic 0·710, 95 per cent c.i. 0·659 to 0·760), but varied in external populations (from 0·652 to 0·761). The new score outperformed other published risk scores in some, but not all, populations. An 8 (95 per cent c.i. 5 to 11) per cent improvement in the C-statistic was estimated compared with using age alone. CONCLUSION: The assessed risk scores did not have sufficient accuracy to enable potentially life-saving decisions to be made regarding intervention. Focus should therefore shift to offering repair to more patients and reducing non-intervention rates, while respecting the wishes of the patient and family.

Lessons learned about prevalence and growth rates of abdominal aortic aneurysms from a 25-year ultrasound population screening programme.

BACKGROUND: This study aimed to assess how the prevalence and growth rates of small and medium abdominal aortic aneurysms (AAAs) (3·0-5·4 cm) have changed over time in men aged 65 years, and to evaluate long-term outcomes in men whose aortic diameter is 2·6-2·9 cm (subaneurysmal), and below the standard threshold for most surveillance programmes. METHODS: The Gloucestershire Aneurysm Screening Programme (GASP) started in 1990. Men aged 65 years with an aortic diameter of 2·6-5·4 cm, measured by ultrasonography using the inner to inner wall method, were included in surveillance. Aortic diameter growth rates were estimated separately for men who initially had a subaneurysmal aorta, and those who had a small or medium AAA, using mixed-effects models. RESULTS: Since 1990, 81 150 men had ultrasound screening for AAA (uptake 80·7 per cent), of whom 2795 had an aortic diameter of 2·6-5·4 cm. The prevalence of screen-detected AAA of 3·0 cm or larger decreased from 5·0 per cent in 1991 to 1·3 per cent in 2015. There was no evidence of a change in AAA growth rates during this time. Of men who initially had a subaneurysmal aorta, 57·6 (95 per cent c.i. 54·4 to 60·7) per cent were estimated to develop an AAA of 3·0 cm or larger within 5 years of the initial scan, and 28·0 (24·2 to 31·8) per cent to develop a large AAA (at least 5·5 cm) within 15 years. CONCLUSION: The prevalence of screen-detected small and medium AAAs has decreased over the past 25 years, but growth rates have remained similar. Men with a subaneurysmal aorta at age 65 years have a substantial risk of developing a large AAA by the age of 80 years.

Sex differences in mortality after abdominal aortic aneurysm repair in the UK.

BACKGROUND: The UK abdominal aortic aneurysm (AAA) screening programmes currently invite only men for screening because the benefit in women is uncertain. Perioperative risk is critical in determining the effectiveness of screening, and contemporary estimates of these risks in women are lacking. The aim of this study was to compare mortality following AAA repair between women and men in the UK. METHODS: Anonymized data from the UK National Vascular Registry (NVR) for patients undergoing AAA repair (January 2010 to December 2014) were analysed. Co-variables were extracted for analysis by sex. The primary outcome measure was in-hospital mortality. Secondary outcome measures included mortality by 5-year age groups and duration of hospital stay. Logistic regression was performed to adjust for age, calendar time, AAA diameter and smoking status. NVR-based outcomes were checked against Hospital Episode Statistics (HES) data. RESULTS: A total of 23 245 patients were included (13·0 per cent women). Proportionally, more women than men underwent open repair. For elective open AAA repair, the in-hospital mortality rate was 6·9 per cent in women and 4·0 per cent in men (odds ratio (OR) 1·48, 95 per cent c.i. 1·08 to 2·02; P = 0·014), whereas for elective endovascular AAA repair it was 1·8 per cent in women and 0·7 per cent in men (OR 2·86, 1·72 to 4·74; P < 0·001); the results in HES were similar. For ruptured AAA, there was no sex difference in mortality within the NVR; however, in HES, for ruptured open AAA repair, the in-hospital mortality rate was higher in women (33·6 versus 27·1 per cent; OR 1·36, 1·16 to 1·59; P < 0·001). CONCLUSION: Women have a higher in-hospital mortality rate than men after elective AAA repair even after adjustment. This higher mortality may have an impact on the benefit offered by any screening programme offered to women.

Meta-analysis of the current prevalence of screen-detected abdominal aortic aneurysm in women.

BACKGROUND: Although women represent an increasing proportion of those presenting with abdominal aortic aneurysm (AAA) rupture, the current prevalence of AAA in women is unknown. The contemporary population prevalence of screen-detected AAA in women was investigated by both age and smoking status. METHODS: A systematic review was undertaken of studies screening for AAA, including over 1000 women, aged at least 60 years, done since the year 2000. Studies were identified by searching MEDLINE, Embase and CENTRAL databases until 13 January 2016. Study quality was assessed using the Newcastle-Ottawa scoring system. RESULTS: Eight studies were identified, including only three based on population registers. The largest studies were based on self-purchase of screening. Altogether 1 537 633 women were screened. Overall AAA prevalence rates were very heterogeneous, ranging from 0·37 to 1·53 per cent: pooled prevalence 0·74 (95 per cent c.i. 0·53 to 1·03) per cent. The pooled prevalence increased with both age (more than 1 per cent for women aged over 70 years) and smoking (more than 1 per cent for ever smokers and over 2 per cent in current smokers). CONCLUSION: The current population prevalence of screen-detected AAA in older women is subject to wide demographic variation. However, in ever smokers and those over 70 years of age, the prevalence is over 1 per cent.

Cost-effectiveness of the National Health Service Abdominal Aortic Aneurysm Screening Programme in England.

BACKGROUND: Implementation of the National Health Service abdominal aortic aneurysm (AAA) screening programme (NAAASP) for men aged 65 years began in England in 2009. An important element of the evidence base supporting its introduction was the economic modelling of the long-term cost-effectiveness of screening, which was based mainly on 4-year follow-up data from the Multicentre Aneurysm Screening Study (MASS) randomized trial. Concern has been expressed about whether this conclusion of cost-effectiveness still holds, given the early performance parameters, particularly the lower prevalence of AAA observed in NAAASP. METHODS: The existing published model was adjusted and updated to reflect the current best evidence. It was recalibrated to mirror the 10-year follow-up data from MASS; the main cost parameters were re-estimated to reflect current practice; and more robust estimates of AAA growth and rupture rates from recent meta-analyses were incorporated, as were key parameters as observed in NAAASP (attendance rates, AAA prevalence and size distributions). RESULTS: The revised and updated model produced estimates of the long-term incremental cost-effectiveness of £5758 (95 per cent confidence interval £4285 to £7410) per life-year gained, or £7370 (£5467 to £9443) per quality-adjusted life-year (QALY) gained. CONCLUSION: Although the updated parameters, particularly the increased costs and lower AAA prevalence, have increased the cost per QALY, the latest modelling provides evidence that AAA screening as now being implemented in England is still highly cost-effective.

Long-term cost-effectiveness analysis of endovascular versus open repair for abdominal aortic aneurysm based on four randomized clinical trials.

BACKGROUND: A number of published economic evaluations of elective endovascular aneurysm repair (EVAR) versus open repair for abdominal aortic aneurysm (AAA) have come to differing conclusions about whether EVAR is cost-effective. This paper reviews the current evidence base and presents up-to-date cost-effectiveness analyses in the light of results of four randomized clinical trials: EVAR-1, DREAM, OVER and ACE. METHODS: Markov models were used to estimate lifetime costs from a UK perspective and quality-adjusted life-years (QALYs) based on the results of each of the four trials. The outcomes included in the model were: procedure costs, surveillance costs, reintervention costs, health-related quality of life, aneurysm-related mortality and other-cause mortality. Alternative scenarios about complications, reinterventions and deaths beyond the trial were explored. RESULTS: Models based on the results of the EVAR-1, DREAM or ACE trials did not find EVAR to be cost-effective at thresholds used in the UK (up to £30,000 per QALY). EVAR seemed cost-effective according to models based on the OVER trial. These results seemed robust to alternative model scenarios about events beyond the trial intervals. CONCLUSION: These analyses did not find that EVAR is cost-effective compared with open repair in the long term in trials conducted in European centres. EVAR did appear to be cost-effective based on the OVER trial, conducted in the USA. Caution must be exercised when transferring the results of economic evaluations from one country to another.

Observations from the IMPROVE trial concerning the clinical care of patients with ruptured abdominal aortic aneurysm.

BACKGROUND: Single-centre series of the management of patients with ruptured abdominal aortic aneurysm (AAA) are usually too small to identify clinical factors that could improve patient outcomes. METHODS: IMPROVE is a pragmatic, multicentre randomized clinical trial in which eligible patients with a clinical diagnosis of ruptured aneurysm were allocated to a strategy of endovascular aneurysm repair (EVAR) or to open repair. The influences of time and manner of hospital presentation, fluid volume status, type of anaesthesia, type of endovascular repair and time to aneurysm repair on 30-day mortality were investigated according to a prespecified plan, for the subgroup of patients with a proven diagnosis of ruptured or symptomatic AAA. Adjustment was made for potential confounding factors. RESULTS: Some 558 of 613 randomized patients had a symptomatic or ruptured aneurysm: diagnostic accuracy was 91·0 per cent. Patients randomized outside routine working hours had higher operative mortality (adjusted odds ratio (OR) 1·47, 95 per cent confidence interval 1·00 to 2·17). Mortality rates after primary and secondary presentation were similar. Lowest systolic blood pressure was strongly and independently associated with 30-day mortality (51 per cent among those with pressure below 70 mmHg). Patients who received EVAR under local anaesthesia alone had greatly reduced 30-day mortality compared with those who had general anaesthesia (adjusted OR 0·27, 0·10 to 0·70). CONCLUSION: These findings suggest that the outcome of ruptured AAA might be improved by wider use of local anaesthesia for EVAR and that a minimum blood pressure of 70 mmHg is too low a threshold for permissive hypotension.

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.

Should the frequency of surveillance for small abdominal aortic aneurysms be reduced?

Different national screening programmes use a variety of surveillance intervals for patients identified with small abdominal aortic aneurysm. An individual patient meta-analysis of >15000 persons with small aneurysm has provided a strong scientific basis for safe surveillance frequency. In many screening programmes the number of surveillance visits for men could be reduced by up to half. The higher rate of aneurysm rupture in women leads to different recommendation for women.

Final follow-up of the Multicentre Aneurysm Screening Study (MASS) randomized trial of abdominal aortic aneurysm screening.

BACKGROUND: The long-term effects of abdominal aortic aneurysm (AAA) screening were investigated in extended follow-up from the UK Multicentre Aneurysm Screening Study (MASS) randomized trial. METHODS: A population-based sample of men aged 65-74 years were randomized individually to invitation to ultrasound screening (invited group) or to a control group not offered screening. Patients with an AAA (3·0 cm or larger) detected at screening underwent surveillance and were offered surgery after predefined criteria had been met. Cause-specific mortality data were analysed using Cox regression. RESULTS: Some 67 770 men were enrolled in the study. Over 13 years, there were 224 AAA-related deaths in the invited group and 381 in the control group, a 42 (95 per cent confidence interval 31 to 51) per cent reduction. There was no evidence of effect on other causes of death, but there was an overall reduction in all-cause mortality of 3 (1 to 5) per cent. The degree of benefit seen in earlier years of follow-up was slightly diminished by the occurrence of AAA ruptures in those with an aorta originally screened normal. About half of these ruptures had a baseline aortic diameter in the range 2·5-2·9 cm. It was estimated that 216 men need to be invited to screening to save one death over the next 13 years. CONCLUSION: Screening resulted in a reduction in all-cause mortality, and the benefit in AAA-related mortality continued to accumulate throughout follow-up. REGISTRATION NUMBER: ISRCTN37381646 (http://www.controlled-trials.com).

Making predictions from complex longitudinal data, with application to planning monitoring intervals in a national screening programme.

When biological or physiological variables change over time, we are often interested in making predictions either of future measurements or of the time taken to reach some threshold value. On the basis of longitudinal data for multiple individuals, we develop Bayesian hierarchical models for making these predictions together with their associated uncertainty. Particular aspects addressed, which include some novel components, are handling curvature in individuals' trends over time, making predictions for both underlying and measured levels, making predictions from a single baseline measurement, making predictions from a series of measurements, allowing flexibility in the error and random-effects distributions, and including covariates. In the context of data on the expansion of abdominal aortic aneurysms over time, where reaching a certain threshold leads to referral for surgery, we discuss the practical application of these models to the planning of monitoring intervals in a national screening programme. Prediction of the time to reach a threshold was too imprecise to be practically useful, and we focus instead on limiting the probability of exceeding the threshold after given time intervals. Although more complex models can be shown to fit the data better, we find that relatively simple models seem to be adequate for planning monitoring intervals.

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.

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

BACKGROUND: 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. METHODS: Individual data were collated from 15 475 people under follow-up for a small aneurysm in 18 studies. The influence of co-variables (including demographics, medical and drug history) on aneurysm growth and rupture rates (analysed using longitudinal random-effects modelling and survival analysis with adjustment for aneurysm diameter) were summarized in an individual patient meta-analysis. RESULTS: The mean aneurysm growth rate of 2.21 mm/year was independent of age and sex. Growth rate was increased in smokers (by 0.35 mm/year) and decreased in patients with diabetes (by 0.51 mm/year). Mean arterial pressure had no effect and antihypertensive or other cardioprotective medications had only small, non-significant effects on aneurysm growth, consistent with the observation that calendar year of enrollment was not associated with growth rate. Rupture rates were almost fourfold higher in women than men (P < 0.001), were double in current smokers (P = 0.001) and increased with higher blood pressure (P = 0.001). CONCLUSION: Follow-up schedules for individuals with a small AAA may need to consider diabetes and smoking, in addition to aneurysm diameter. The differing risk factors for growth and rupture suggest that a lower threshold for surgical intervention in women may be justified. No single drug used for cardiovascular risk reduction had a major effect on the growth or rupture of small aneurysms.

Incidence of cardiovascular events and death after open or endovascular repair of abdominal aortic aneurysm in the randomized EVAR trial 1.

BACKGROUND: The aim was to compare rates of myocardial infarction, stroke and cardiovascular death in patients with a large abdominal aortic aneurysm who had endovascular (EVAR) or open repair to determine whether cardiovascular mortality explains the convergence in survival curves after these procedures. METHODS: Between 1999 and 2004, 1252 patients were randomized to EVAR or open repair in the UK EVAR trial 1. All patients were followed for death, myocardial infarction or stroke until September 2009. Cox regression was used to compare cardiovascular events and deaths between the randomized groups during different time intervals. RESULTS: Over 5 years of follow-up, a total of 187 first non-fatal or fatal cardiovascular events (98 myocardial infarctions and 89 strokes) and 256 cardiovascular deaths occurred. Although the endovascular group had a lower cardiovascular event rate than the open repair group (2·6 versus 3·2 per 100 person-years respectively) this was not statistically significant (adjusted hazard ratio (HR) 0·83, 95 per cent confidence interval 0·62 to 1·10; P = 0·199). Overall, there was little difference in cardiovascular mortality between the randomized groups (adjusted HR 1·06, 0·83 to 1·36; P = 0·638), but a non-significant excess of cardiovascular deaths was apparent in the endovascular group during the 6-24-month interval (adjusted HR 1·44, 0·79 to 2·62; P = 0·237). CONCLUSION: Patients who had EVAR appeared to have a lower subsequent cardiovascular event rate during all time intervals. Cardiovascular mortality was similar between the two groups overall, but more cardiovascular deaths in the EVAR group appeared to contribute to the convergence in all-cause mortality during the first 2 years.

Systematic review and meta-analysis of growth rates of small abdominal aortic aneurysms.

BACKGROUND: Small abdominal aortic aneurysms are usually asymptomatic and managed safely in ultrasound surveillance programmes until they grow to a diameter threshold where intervention is considered. The aim of this study was to synthesize systematically the published data on growth rates for small aneurysms to investigate the evidence basis for surveillance intervals. METHODS: This was a systematic review of the literature published before January 2010, which identified 61 potentially eligible reports. Detailed review yielded 15 studies providing growth rates for aneurysms 3·0-5·5 cm in diameter (14 in millimetres per year, 1 as percentage change per year). These studies included 7630 people (predominantly men) enrolled during 1976-2005. RESULTS: The pooled mean growth rate was 2·32 (95 per cent confidence interval 1·95 to 2·70) mm/year but there was very high heterogeneity between studies; the growth rate ranged from - 0·33 to + 3·95 mm/year. Six studies reported growth rates by 5-mm diameter bands, which showed the trend for growth rate to increase with aneurysm diameter. Simple methods to determine growth rate were associated with higher estimates. Meta-regression analysis showed that a 10-mm increase in aneurysm diameter was associated with a mean(s.e.m.) 1·62(0·20) mm/year increase in growth rate. Neither mean age nor percentage of women in each study had a significant effect. On average, a 3·5-cm aneurysm would take 6·2 years to reach 5·5 cm, whereas a 4·5-cm aneurysm would take only 2·3 years. CONCLUSION: There was considerable variation in the reported growth rates of small aneurysms beyond that explained by aneurysm diameter. Fuller evidence on which to base surveillance intervals for patients in screening programmes requires a meta-analysis based on individual patient data.

Rupture rates of small abdominal aortic aneurysms: a systematic review of the literature.

BACKGROUND: Small aneurysms of the abdominal aorta (3.0-5.5 cm in diameter) often are managed by regular surveillance, rather than surgery, because the risk of surgery is considered to outweigh the risk of aneurysm rupture. The risk of small aneurysm rupture is considered to be low. The purpose of this review is to summarise the reported estimates of small aneurysm rupture rates. METHODS AND FINDINGS: We conducted a systematic review of the literature published before 2010 and identified 54 potentially eligible reports. Detailed review of these studies showed that both ascertainment of rupture, patient follow-up and causes of death were poorly reported: diagnostic criteria for rupture were never reported. There were only 14 studies from which rupture rates (as ruptures per 100 person-years) were available. These 14 published studies included 9779 patients (89% male) over the time period 1976-2006 but only 7 of these studies provided rupture rates specifically for the diameter range 3.0-5.5 cm, which ranged from 0 to 1.61 ruptures per 100 person-years. CONCLUSIONS: Rupture rates of small abdominal aortic aneurysms would appear to be low, but most studies have been poorly reported and did not have clear ascertainment and diagnostic criteria for aneurysm rupture.

Two-stage designs optimal under the alternative hypothesis for phase II cancer clinical trials.

The Simon two-stage optimal design is often used for phase II cancer clinical trials. A study proceeds to the second stage unless the null hypothesis, that the true tumour response rate is below some specified value, is already accepted at the end of stage one. The conventional optimal design, for given type 1 and type 2 error rates, is the one which minimises the expected sample size under the null hypothesis. However, at least some new agents are active, and designs that explicitly address this possibility should be considered. We therefore investigate novel designs which are optimal under the alternative hypothesis, that the tumour response rate is higher than the null hypothesis value, and also designs which allow early stopping for efficacy. We make available, software for identifying the corresponding optimal and minimax designs. Considerable savings in expected sample sizes can be achieved if the alternative hypothesis is in fact true, without sample sizes suffering too much if the null hypothesis is true. We present an example discussing the merits of different designs in a practical context. We conclude that it is relevant to consider optimal designs under a range of hypotheses about the true response rate, and that allowing early stopping for efficacy is always advantageous in terms of expected sample size.

Use of baseline factors to predict complications and reinterventions after endovascular repair of abdominal aortic aneurysm.

BACKGROUND: It is uncertain which baseline factors are associated with graft-related complications and reinterventions after endovascular aneurysm repair (EVAR) in patients with a large abdominal aortic aneurysm. METHODS: Patients randomized to elective EVAR in EVAR Trial 1 or 2 were followed for serious graft-related complications (type 2 endoleaks excluded) and reinterventions. Cox regression analysis was used to investigate whether any prespecified baseline factors were associated with time to first serious complication or reintervention. RESULTS: A total of 756 patients who had elective EVAR were followed for a mean of 3.7 years, by which time there were 179 serious graft complications (rate 6.5 per 100 person years) and 114 reinterventions (rate 3.8 per 100 person years). The highest rate was during the first 6 months, with an apparent increase again after 2 years. Multivariable analysis indicated that graft-related complications increased significantly with larger initial aneurysm diameter (P < 0.001) and older age (P = 0.040). There was also evidence that patients with larger common iliac diameters experienced higher complication rates (P = 0.011). CONCLUSION: Graft-related complication and reintervention rates were common after EVAR in patients with a large aneurysm. Younger patients and those with aneurysms closer to the 5.5-cm threshold for intervention experienced lower rates.