Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

Everolimus-induced nephrotic syndrome precipitated by interaction with voriconazole in a patient with Hodgkin's lymphoma.

WHAT IS KNOWN AND OBJECTIVES: Everolimus is a small molecule that inhibits the mammalian target of rapamycin (mTOR) and is used for treatment of various solid tumours and renal transplant rejection prophylaxis. Whereas everolimus-induced proteinuria was previously observed in 3%-36% renal transplant recipients, nephrotic syndrome was not reported in cancer patients taking everolimus. However, nephrotic syndrome was reported in patients taking sirolimus. CASE SUMMARY: We report the case of a 32-year-old female with relapsed Hodgkin's lymphoma who was on everolimus for 5 years and developed nephrotic syndrome about 2 months after initiation of voriconazole. She was on 10 mg everolimus once a day and 200 mg voriconazole twice a day orally. Renal biopsy revealed thrombotic microangiopathic vasculopathy and thin basement membrane nephropathy. Discontinuation of everolimus and voriconazole rapidly improved her nephrotic syndrome. WHAT IS NEW AND CONCLUSION: We provide in-depth analysis of the underlying mechanisms of everolimus-induced nephrotic syndrome and hypothesize that voriconazole likely decreased everolimus metabolism. In the era of targeted therapy for cancer, healthcare providers should be aware of the drug-drug interaction between everolimus (as well as tyrosine kinase inhibitors) and cytochrome P450 CYP3A4 inhibitors (ie voriconazole).

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.

Plasma and rectal mucosal oxylipin levels during aspirin and eicosapentaenoic acid treatment in the seAFOod polyp prevention trial.

BACKGROUND: Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months. METHODS: Resolvin (Rv) E1, 15-epi-lipoxin (LX) A4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants. RESULTS: Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15­epi-LXA4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21-1.95] ng/ml at baseline versus 0.95 [0.46-4.06] ng/ml at 6 months [P<0.0001] in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin. CONCLUSION: Analysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15­epi-LXA4. We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation.

The STAMPEDE2 Trial: a Site Survey of Current Patterns of Care, Access to Imaging and Treatment of Metastatic Prostate Cancer.

AIMS: The forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2. MATERIALS AND METHODS: The survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 (177Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging. RESULTS: From 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment. CONCLUSION: There is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial.

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.

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.

Randomized clinical trial of VNUS ClosureFAST radiofrequency ablation versus laser for varicose veins.

BACKGROUND: Endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) are both associated with excellent technical, clinical and patient-reported outcomes for the treatment of varicose veins. The aim of this study was to compare the techniques in a randomized clinical trial. METHODS: Consecutive patients with primary great saphenous vein reflux were randomized to EVLA (980 nm) or RFA (VNUS ClosureFAST) at a single centre. The primary outcome measure was postprocedural pain after 3 days. Secondary outcome measures were quality of life at 6 weeks, determined by the Aberdeen Varicose Vein Questionnaire (AVVQ) and Short Form 12 (SF-12), and clinical improvement assessed by the Venous Clinical Severity Score (VCSS). Analyses were performed on the basis of intention to treat using multivariable linear regression. RESULTS: Some 131 patients were randomized to EVLA (64 patients) or RFA (67). Mean(s.d.) pain scores over 3 days were 26.4(22.1) mm for RFA and 36.8(22.5) mm for EVLA (P = 0.010). Over 10 days, mean(s.d.) pain scores were 22.0(19.8) mm versus 34.3(21.1) mm for RFA and EVLA respectively (P = 0.001). The mean(s.d.) number of analgesic tablets used was lower for RFA than for EVLA over 3 days (8.8(9.5) versus 14.2(10.7); P = 0.003) and 10 days (20.4(22.6) versus 35.9(29.4) respectively; P = 0.001). Changes in AVVQ, SF-12 and VCSS scores at 6 weeks were similar in the two groups: AVVQ (P = 0.887), VCSS (P = 0.993), SF-12 physical component score (P = 0.276) and mental component score (P = 0.449). CONCLUSION: RFA using VNUS ClosureFAST was associated with less postprocedural pain than EVLA. However, clinical and quality-of-life improvements were similar after 6 weeks for the two treatments.

Does EVAR alter the rate of cardiovascular events in patients with abdominal aortic aneurysm considered unfit for open repair? Results from the randomised EVAR trial 2.

OBJECTIVES: To investigate whether endovascular aneurysm repair (EVAR) influences the rate of cardiovascular events (fatal or non-fatal myocardial infarction or stroke) in patients with abdominal aortic aneurysm (AAA) considered unfit for open repair. DESIGN: Randomised controlled trial. MATERIALS: Between 1999 and 2004, 404 patients with large AAA considered unfit for open repair were randomised to EVAR or no surgical intervention across 33 UK hospitals and followed until July 2009. METHODS: The Customised Probability Index was used to determine fitness for each patient and Cox regression was used to compare time to first cardiovascular event between randomised groups and levels of fitness. RESULTS: During an average of 2.8 years of follow-up, 67 first cardiovascular events occurred with a non-significantly higher event rate in the EVAR group compared to the no intervention group (6.6 versus 5.1 events per 100 person years); adjusted hazard ratio 1.42 [95% CI 0.87-2.34], p=0.156. There was no evidence to suggest that the hazard ratio between randomised groups changed with level of fitness (p=0.378). CONCLUSIONS: Cardiovascular event rates were high in these unfit patients and medical therapy was sub-optimal. Events rates were slightly higher in the EVAR group but this was not statistically significant.

Effluent carbonaceous biochemical oxygen demand (CBOD) characterization for modern pulp and paper facilities.

As receiving water quality models are being used to address dissolved oxygen issues requiring an increased degree of resolution, a more refined characterization of effluent CBOD can become an important aspect of the analysis. The selection and use of kinetic models to identify effluent specific parameters can have a significant impact on this characterization. This study modeled effluents from six pulp and paper facilities in order to reassess the kinetic models, the data, and experimental design used for a typical effluent characterization. The dual first order model fit these effluents with significantly less error than the traditional first order model suggesting a significant fraction of the CBOD is slowly degradable. Because the dual first order model produces a more refined characterization of CBOD kinetics than the first order model, it places an increased demand upon the data used to inform the parameter estimates. Therefore, analysis of the precision of the parameter estimates and methods for improving estimation precision via experimental design are also discussed.

The surgical management of 73 vascular malformations and preoperative predictive factors of major haemorrhage--a single centre experience.

OBJECTIVES: In our series of patients with congenital vascular malformations (CVMs) we investigate the preoperative factors for predicting major haemorrhage at surgery and propose an algorithm for their surgical management. DESIGN: This is a partly prospective case series of patients with severe symptoms/complications due to CVMs. MATERIALS AND METHODS: Data were collected on 73 consecutive procedures in 41 patients with CVMs from 1992 to 2006 at a large university hospital and the association of following factors with blood loss during the procedure were investigated: type of procedure, possibility of proximal tourniquet use, lesion flow characteristics, previous history of major haemorrhage with CVM surgery, platelet counts and length of hospital stay. RESULTS: Significantly higher blood loss was associated with debulking surgery (p=0.006) and with previous history of major haemorrhage during CVM surgery, (p=0.041). Blood loss was higher in lesions where proximal tourniquet application was not possible (p=0.093). High-flow lesions were not strongly associated with major blood loss (p=0.288). Major blood loss (>2l) occurred in 16 (20.8%) procedures performed on 11 (26.2%) patients, but this did not prolong hospital stay. CONCLUSION: Surgery can potentially improve morbidity/mortality in patients with life/limb-threatening complications or severe symptoms due to CVMs, providing they are managed in multidisciplinary specialised centres.

Three-dimensional imaging core laboratory of the endovascular aneurysm repair trials: validation of methodology.

OBJECTIVE: The aim of this study was to establish and validate a three-dimensional imaging protocol for the assessment of Computed Tomography (CT) scans of abdominal aortic aneurysms in UK EVAR trials patients. Quality control and repeatability of anatomical measurements is important for the validity of any core laboratory. METHODS: Three different observers performed anatomical measurements on 50 preoperative CT scans of aortic aneurysms using the Vitrea 2 three-dimensional post-imaging software in a core laboratory setting. We assessed the accuracy of intra and inter observer repeatability of measurements, the time required for collection of measurements, 3 different levels of automation and 3 different automated criteria for measurement of neck length. RESULTS: None of the automated neck length measurements demonstrated sufficient accuracy and it was necessary to perform checking of the important automated landmarks. Good intra and limited inter observer agreement were achieved with three-dimensional assessment. Complete assessment of the aneurysm and iliacs took an average (SD) of 17.2 (4.1) minutes. CONCLUSIONS: Aortic aneurysm anatomy can be assessed reliably and quickly using three-dimensional assessment but for scans of limited quality, manual checking of important landmarks remains necessary. Using a set protocol, agreement between observers is satisfactory but not as good as within observers.

Biomarker-guided trials: Challenges in practice.

Biomarker-guided trials have drawn considerable attention as they promise to lead to improvements in the benefit-risk ratio of treatments and enhanced opportunities for drug development. A variety of such designs have been proposed in the literature, many of which have been adopted in practice. Implementing such trial designs in practice can be challenging, and identifying those challenges was the main objective of a workshop organised by the MRC Hubs for Trials Methodology Research Network's Stratified Medicine Working Group in March 2017. Participants reflected on completed and ongoing biomarker-guided trials to identify the practical challenges encountered. Here, the key challenges identified during the workshop including those related to funding, ethical and regulatory issues, recruitment, monitoring of samples and laboratories, biomarker assessment, and data sharing and resources, are discussed. Despite the complexities often associated with biomarker-guided trials, the workshop concluded that they can play an important role in advancing the field of personalised medicine. Therefore, it is important that the practical challenges surrounding their implementation are acknowledged and addressed.

Modelling the long-term cost-effectiveness of endovascular or open repair for abdominal aortic aneurysm.

BACKGROUND: Recent randomized trials have shown that endovascular abdominal aortic aneurysm repair (EVAR) has a 3 per cent aneurysm-related survival benefit in patients fit for open surgery, but it also has uncertain long-term outcomes and higher costs. This study assessed the cost-effectiveness of EVAR. METHODS: A decision model was constructed to estimate the lifetime costs and quality-adjusted life years (QALYs) with EVAR and open repair in men aged 74 years. The model includes the risks of death from aneurysm, other cardiovascular and non-cardiovascular causes, secondary reinterventions and non-fatal cardiovascular events. Data were taken largely from the EVAR trial 1 and supplemented from other sources. RESULTS: Under the base-case (primary) assumptions, EVAR cost 3800 pounds sterling (95 per cent confidence interval (c.i.) 2400 pounds sterling to 5200 pounds sterling) more per patient than open repair but produced fewer lifetime QALYs (mean -0.020 (95 per cent c.i. -0.189 to 0.165)). These results were sensitive to alternative model assumptions. CONCLUSION: EVAR is unlikely to be cost-effective on the basis of existing devices, costs and evidence, but there remains considerable uncertainty.

Do abdominal aortic aneurysm necks increase in size faster after endovascular than open repair?

INTRODUCTION: Progression of aneurysmal disease in the aortic neck poses a threat to durable abdominal aortic aneurysm (AAA) repair. We tested the hypothesis that 2 years after AAA repair the size of the aortic neck increased more after endovascular (EVAR) than open repair. PATIENTS AND METHODS: For a subset of EVAR 1 trial patients, true outer-wall area at three levels of the aortic neck was measured using a Vitrea2 workstation, and rate of change over 2 years analysed. RESULTS: The 67 EVAR patients and 56 open repair patients were well-matched, very similar to the total EVAR 1 cohort. The mean area change over 2 years at the superior mesenteric artery was small for both groups. However at the caudal renal artery (CRA), adjusted regression coefficient was 0.68 cm(2)/y greater after EVAR (p<0.001) and 0.77 cm(2)/y at a level 15 mm distal to it (p<0.001). The area at the CRA of 45 available post-procedure scans showed a large proportion of the increase had occurred by 3 months (mean 4.8 cm(2) to 5.9 cm(2) versus 6.7 cm(2) at 2 years). CONCLUSIONS: The increase in aortic neck size was much greater 2 years after EVAR versus open repair. Further research is ongoing to establish whether the dilatation is progressive after stent-graft placement.

The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease.

BACKGROUND: Uncertainty exists on whether there is adjuvant benefit of percutaneous transluminal angioplasty (PTA) over supervised exercise and best medical therapy in the treatment of intermittent claudication. METHODS: Patients with symptoms of stable mild to moderate intermittent claudication (MIMIC) were randomised in two multi-centre trials, for femoropopliteal and aortoiliac arterial disease, to receive either PTA or no PTA against a background of supervised exercise and best medical therapy and followed up for 24 months. Initial claudication distance (ICD) and absolute walking distance (AWD) on treadmill were compared between randomised groups adjusting for the corresponding measure at baseline. Secondary outcomes included ankle-brachial pressure index (ABPI) and quality of life. FINDINGS: A total of 93 patients were randomised into the femoropopliteal trial (48 into PTA) and 34 into the aortoiliac trial (19 to PTA). The mean (standard deviation, SD) age was 66(9) years for the femoropopliteal trial (63% male) and 63(9) for the aortoiliac trial (65% male). At 24 months, there were significant improvements in both AWD and ICD in the PTA groups for both trials. The adjusted AWD was 38% greater in the PTA group for the femoropopliteal trial (95%; CI 1-90) (p=0.04) and 78% greater in the PTA group for the aortoiliac trial (95%; CI 0-216) (p=0.05). Further benefits were demonstrated for ABPI but not for quality of life. INTERPRETATION: PTA confers adjuvant benefit over supervised exercise and best medical therapy in terms of walking distances and ABPI 24 months after PTA in patients with stable mild to moderate intermittent claudication.

Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms.

BACKGROUND: Two clinical trials, one British and one American, have shown that early, prophylactic elective surgery does not improve five-year survival among patients with small abdominal aortic aneurysms. We report long-term outcomes in the United Kingdom Small Aneurysm Trial. METHODS: We randomly assigned 1090 patients, 60 to 76 years of age, with small abdominal aortic aneurysms (diameter, 4.0 to 5.5 cm) to one of two groups: 563 were assigned to undergo early elective surgery, and 527 were assigned to undergo surveillance by ultrasonography. Patients were followed in the trial until June 1998 and thereafter until August 2001; the mean duration of follow-up was 8 years (range, 6 to 10). RESULTS: The mean duration of survival was 6.5 years among patients in the surveillance group, as compared with 6.7 years among patients in the early-surgery group (P=0.29). The adjusted hazard ratio for death from any cause in the early-surgery group as compared with the surveillance group was 0.83 (95 percent confidence interval, 0.69 to 1.00; P=0.05). The 30-day operative mortality in the early-surgery group (5.5 percent) led to an early disadvantage in terms of survival. The survival curves crossed at three years, and at eight years, mortality in the early-surgery group was 7.2 percentage points lower than that in the surveillance group (P=0.03). There was no evidence that age, sex, or the initial size of the aneurysm modified the hazard ratio or that delayed surgery in the surveillance group increased 30-day postoperative mortality. Death was attributable to a ruptured aneurysm in 19 of the 411 men who died (5 percent) and in 12 of the 85 women who died (14 percent) (P=0.001). The rate of early cessation of smoking was higher in the early-surgery group than in the surveillance group. CONCLUSIONS: Among patients with a small abdominal aortic aneurysm, we found no long-term difference in mean survival between the early-surgery and surveillance groups, although after eight years, total mortality was lower in the early-surgery group. This difference may be attributed in part to beneficial changes in lifestyle adopted by members of the early-surgery group.