Screening women aged 65 years or over for abdominal aortic aneurysm: a modelling study and health economic evaluation.

BACKGROUND: Abdominal aortic aneurysm (AAA) screening programmes have been established for men in the UK to reduce deaths from AAA rupture. Whether or not screening should be extended to women is uncertain. OBJECTIVE: To evaluate the cost-effectiveness of population screening for AAAs in women and compare a range of screening options. DESIGN: A discrete event simulation (DES) model was developed to provide a clinically realistic model of screening, surveillance, and elective and emergency AAA repair operations. Input parameters specifically for women were employed. The model was run for 10 million women, with parameter uncertainty addressed by probabilistic and deterministic sensitivity analyses. SETTING: Population screening in the UK. PARTICIPANTS: Women aged ≥ 65 years, followed up to the age of 95 years. INTERVENTIONS: Invitation to ultrasound screening, followed by surveillance for small AAAs and elective surgical repair for large AAAs. MAIN OUTCOME MEASURES: Number of operations undertaken, AAA-related mortality, quality-adjusted life-years (QALYs), NHS costs and cost-effectiveness with annual discounting. DATA SOURCES: AAA surveillance data, National Vascular Registry, Hospital Episode Statistics, trials of elective and emergency AAA surgery, and the NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP). REVIEW METHODS: Systematic reviews of AAA prevalence and, for elective operations, suitability for endovascular aneurysm repair, non-intervention rates, operative mortality and literature reviews for other parameters. RESULTS: The prevalence of AAAs (aortic diameter of ≥ 3.0 cm) was estimated as 0.43% in women aged 65 years and 1.15% at age 75 years. The corresponding attendance rates following invitation to screening were estimated as 73% and 62%, respectively. The base-case model adopted the same age at screening (65 years), definition of an AAA (diameter of ≥ 3.0 cm), surveillance intervals (1 year for AAAs with diameter of 3.0-4.4 cm, 3 months for AAAs with diameter of 4.5-5.4 cm) and AAA diameter for consideration of surgery (5.5 cm) as in NAAASP for men. Per woman invited to screening, the estimated gain in QALYs was 0.00110, and the incremental cost was £33.99. This gave an incremental cost-effectiveness ratio (ICER) of £31,000 per QALY gained. The corresponding incremental net monetary benefit at a threshold of £20,000 per QALY gained was -£12.03 (95% uncertainty interval -£27.88 to £22.12). Almost no sensitivity analyses brought the ICER below £20,000 per QALY gained; an exception was doubling the AAA prevalence to 0.86%, which resulted in an ICER of £13,000. Alternative screening options (increasing the screening age to 70 years, lowering the threshold for considering surgery to diameters of 5.0 cm or 4.5 cm, lowering the diameter defining an AAA in women to 2.5 cm and lengthening the surveillance intervals for the smallest AAAs) did not bring the ICER below £20,000 per QALY gained when considered either singly or in combination. LIMITATIONS: The model for women was not directly validated against empirical data. Some parameters were poorly estimated, potentially lacking relevance or unavailable for women. CONCLUSION: The accepted criteria for a population-based AAA screening programme in women are not currently met. FUTURE WORK: A large-scale study is needed of the exact aortic size distribution for women screened at relevant ages. The DES model can be adapted to evaluate screening options in men. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020444 and CRD42016043227. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Analysis of clinical benefit, harms, and cost-effectiveness of screening women for abdominal aortic aneurysm.

BACKGROUND: A third of deaths in the UK from ruptured abdominal aortic aneurysm (AAA) are in women. In men, national screening programmes reduce deaths from AAA and are cost-effective. The benefits, harms, and cost-effectiveness in offering a similar programme to women have not been formally assessed, and this was the aim of this study. METHODS: We developed a decision model to assess predefined outcomes of death caused by AAA, life years, quality-adjusted life years, costs, and the incremental cost-effectiveness ratio for a population of women invited to AAA screening versus a population who were not invited to screening. A discrete event simulation model was set up for AAA screening, surveillance, and intervention. Relevant women-specific parameters were obtained from sources including systematic literature reviews, national registry or administrative databases, major AAA surgery trials, and UK National Health Service reference costs. FINDINGS: AAA screening for women, as currently offered to UK men (at age 65 years, with an AAA diagnosis at an aortic diameter of ≥3·0 cm, and elective repair considered at ≥5·5cm) gave, over 30 years, an estimated incremental cost-effectiveness ratio of £30 000 (95% CI 12 000-87 000) per quality-adjusted life year gained, with 3900 invitations to screening required to prevent one AAA-related death and an overdiagnosis rate of 33%. A modified option for women (screening at age 70 years, diagnosis at 2·5 cm and repair at 5·0 cm) was estimated to have an incremental cost-effectiveness ratio of £23 000 (9500-71 000) per quality-adjusted life year and 1800 invitations to screening required to prevent one AAA-death, but an overdiagnosis rate of 55%. There was considerable uncertainty in the cost-effectiveness ratio, largely driven by uncertainty about AAA prevalence, the distribution of aortic sizes for women at different ages, and the effect of screening on quality of life. INTERPRETATION: By UK standards, an AAA screening programme for women, designed to be similar to that used to screen men, is unlikely to be cost-effective. Further research on the aortic diameter distribution in women and potential quality of life decrements associated with screening are needed to assess the full benefits and harms of modified options. FUNDING: UK National Institute for Health Research Health Technology Assessment programme.

Strategy of endovascular versus open repair for patients with clinical diagnosis of ruptured abdominal aortic aneurysm: the IMPROVE RCT.

BACKGROUND: Ruptured abdominal aortic aneurysm (AAA) is a common vascular emergency. The mortality from emergency endovascular repair may be much lower than the 40-50% reported for open surgery. OBJECTIVE: To assess whether or not a strategy of endovascular repair compared with open repair reduces 30-day and mid-term mortality (including costs and cost-effectiveness) among patients with a suspected ruptured AAA. DESIGN: Randomised controlled trial, with computer-generated telephone randomisation of participants in a 1 : 1 ratio, using variable block size, stratified by centre and without blinding. SETTING: Vascular centres in the UK (n = 29) and Canada (n = 1) between 2009 and 2013. PARTICIPANTS: A total of 613 eligible participants (480 men) with a ruptured aneurysm, clinically diagnosed at the trial centre. INTERVENTIONS: A total of 316 participants were randomised to the endovascular strategy group (immediate computerised tomography followed by endovascular repair if anatomically suitable or, if not suitable, open repair) and 297 were randomised to the open repair group (computerised tomography optional). MAIN OUTCOME MEASURES: The primary outcome measure was 30-day mortality, with 30-day reinterventions, costs and disposal as early secondary outcome measures. Later outcome measures included 1- and 3-year mortality, reinterventions, quality of life (QoL) and cost-effectiveness. RESULTS: The 30-day mortality was 35.4% in the endovascular strategy group and 37.4% in the open repair group [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.66 to 1.28; p = 0.62, and, after adjustment for age, sex and Hardman index, OR 0.94, 95% CI 0.67 to 1.33]. The endovascular strategy appeared to be more effective in women than in men (interaction test p = 0.02). More discharges in the endovascular strategy group (94%) than in the open repair group (77%) were directly to home (p < 0.001). Average 30-day costs were similar between groups, with the mean difference in costs being -£1186 (95% CI -£2997 to £625), favouring the endovascular strategy group. After 1 year, survival and reintervention rates were similar in the two groups, QoL (at both 3 and 12 months) was higher in the endovascular strategy group and the mean cost difference was -£2329 (95% CI -£5489 to £922). At 3 years, mortality was 48% and 56% in the endovascular strategy group and open repair group, respectively (OR 0.73, 95% CI 0.53 to 1.00; p = 0.053), with a stronger benefit for the endovascular strategy in the subgroup of 502 participants in whom repair was started for a proven rupture (OR 0.62, 95% CI 0.43 to 0.89; p = 0.009), whereas aneurysm-related reintervention rates were non-significantly higher in this group. At 3 years, considering all participants, there was a mean difference of 0.174 quality-adjusted life-years (QALYs) (95% CI 0.002 to 0.353 QALYs) and, among the endovascular strategy group, a cost difference of -£2605 (95% CI -£5966 to £702), leading to 88% of estimates in the cost-effectiveness plane being in the quadrant showing the endovascular strategy to be 'dominant'. LIMITATIONS: Because of the pragmatic design of this trial, 33 participants in the endovascular strategy group and 26 in the open repair group breached randomisation allocation. CONCLUSIONS: The endovascular strategy was not associated with a significant reduction in either 30-day mortality or cost but was associated with faster participant recovery. By 3 years, the endovascular strategy showed a survival and QALY gain and was highly likely to be cost-effective. Future research could include improving resuscitation for older persons with circulatory collapse, the impact of local anaesthesia and emergency consent procedures. TRIAL REGISTRATION: Current Controlled Trials ISRCTN48334791 and NCT00746122. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 31. See the NIHR Journals Library website for further project information.

Parity, breastfeeding and risk of coronary heart disease: A pan-European case-cohort study.

OBJECTIVE: There is uncertainty about the direction and magnitude of the associations between parity, breastfeeding and the risk of coronary heart disease (CHD). We examined the separate and combined associations of parity and breastfeeding practices with the incidence of CHD later in life among women in a large, pan-European cohort study. METHODS: Data were used from European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD, a case-cohort study nested within the EPIC prospective study of 520,000 participants from 10 countries. Information on reproductive history was available for 14,917 women, including 5138 incident cases of CHD. Using Prentice-weighted Cox regression separately for each country followed by a random-effects meta-analysis, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CHD, after adjustment for age, study centre and several socioeconomic and biological risk factors. RESULTS: Compared with nulliparous women, the adjusted HR was 1.19 (95% CI: 1.01-1.41) among parous women; HRs were higher among women with more children (e.g., adjusted HR: 1.95 (95% CI: 1.19-3.20) for women with five or more children). Compared with women who did not breastfeed, the adjusted HR was 0.71 (95% CI: 0.52-0.98) among women who breastfed. For childbearing women who never breastfed, the adjusted HR was 1.58 (95% CI: 1.09-2.30) compared with nulliparous women, whereas for childbearing women who breastfed, the adjusted HR was 1.19 (95% CI: 0.99-1.43). CONCLUSION: Having more children was associated with a higher risk of CHD later in life, whereas breastfeeding was associated with a lower CHD risk. Women who both had children and breastfed did have a non-significantly higher risk of CHD.

Admissible two-stage designs for phase II cancer clinical trials that incorporate the expected sample size under the alternative hypothesis.

Two-stage studies may be chosen optimally by minimising a single characteristic like the maximum sample size. However, given that an investigator will initially select a null treatment effect and the clinically relevant difference, it is better to choose a design that also considers the expected sample size for each of these values. The maximum sample size and the two expected sample sizes are here combined to produce an expected loss function to find designs that are admissible. Given the prior odds of success and the importance of the total sample size, minimising the expected loss gives the optimal design for this situation. A novel triangular graph to represent the admissible designs helps guide the decision-making process. The H0-optimal, H1-optimal, H0-minimax and H1-minimax designs are all particular cases of admissible designs. The commonly used H0-optimal design is rarely good when allowing stopping for efficacy. Additionally, the δ-minimax design, which minimises the maximum expected sample size, is sometimes admissible under the loss function. However, the results can be varied and each situation will require the evaluation of all the admissible designs. Software to do this is provided.

Impact and costs of incentives to reduce attrition in online trials: two randomized controlled trials.

BACKGROUND: Attrition from follow-up is a major methodological challenge in randomized trials. Incentives are known to improve response rates in cross-sectional postal and online surveys, yet few studies have investigated whether they can reduce attrition from follow-up in online trials, which are particularly vulnerable to low follow-up rates. OBJECTIVES: Our objective was to determine the impact of incentives on follow-up rates in an online trial. METHODS: Two randomized controlled trials were embedded in a large online trial of a Web-based intervention to reduce alcohol consumption (the Down Your Drink randomized controlled trial, DYD-RCT). Participants were those in the DYD pilot trial eligible for 3-month follow-up (study 1) and those eligible for 12-month follow-up in the DYD main trial (study 2). Participants in both studies were randomly allocated to receive an offer of an incentive or to receive no offer of an incentive. In study 1, participants in the incentive arm were randomly offered a £5 Amazon.co.uk gift voucher, a £5 charity donation to Cancer Research UK, or entry in a prize draw for £250. In study 2, participants in the incentive arm were offered a £10 Amazon.co.uk gift voucher. The primary outcome was the proportion of participants who completed follow-up questionnaires in the incentive arm(s) compared with the no incentive arm. RESULTS: In study 1 (n = 1226), there was no significant difference in response rates between those participants offered an incentive (175/615, 29%) and those with no offer (162/611, 27%) (difference = 2%, 95% confidence interval [CI] -3% to 7%). There was no significant difference in response rates among the three different incentives offered. In study 2 (n = 2591), response rates were 9% higher in the group offered an incentive (476/1296, 37%) than in the group not offered an incentive (364/1295, 28%) (difference = 9%, 95% CI 5% to 12%, P < .001). The incremental cost per extra successful follow-up in the incentive arm was £110 in study 1 and £52 in study 2. CONCLUSION: Whereas an offer of a £10 Amazon.co.uk gift voucher can increase follow-up rates in online trials, an offer of a lower incentive may not. The marginal costs involved require careful consideration. TRIAL REGISTRATION: ISRCTN31070347; http://www.controlled-trials.com/ISRCTN31070347 (Archived by WebCite at http://www.webcitation.org/5wgr5pl3s).

Diabetes mellitus, fasting glucose, and risk of cause-specific death.

BACKGROUND: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain. METHODS: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies. RESULTS: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths. CONCLUSIONS: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.).

Modelling bias in combining small area prevalence estimates from multiple surveys.

Combining information from multiple surveys can improve the quality of small area estimates. Customary approaches, such as the multiple-frame and statistical matching methods, require individual level data, whereas in practice often only multiple aggregate estimates are available. Commercial surveys usually produce such estimates without clear description of the methodology that is used. In this context, bias modelling is crucial, and we propose a series of Bayesian hierarchical models which allow for additive biases. Some of these models can also be fitted in a classical context, by using a mixed effects framework. We apply these methods to obtain estimates of smoking prevalence in local authorities across the east of England from seven surveys. All the surveys provide smoking prevalence estimates and confidence intervals at the local authority level, but they vary by time, sample size and transparency of methodology. Our models adjust for the biases in commercial surveys but incorporate information from all the sources to provide more accurate and precise estimates.

Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies.

BACKGROUND: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease. METHODS: We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4.56 kg/m(2) higher BMI, 12.6 cm higher waist circumference, and 0.083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios. RESULTS: Individual records were available for 221,934 people in 17 countries (14,297 incident cardiovascular disease outcomes; 1.87 million person-years at risk). Serial adiposity assessments were made in up to 63,821 people (mean interval 5.7 years [SD 3.9]). In people with BMI of 20 kg/m(2) or higher, HRs for cardiovascular disease were 1.23 (95% CI 1.17-1.29) with BMI, 1.27 (1.20-1.33) with waist circumference, and 1.25 (1.19-1.31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1.07 (1.03-1.11) with BMI, 1.10 (1.05-1.14) with waist circumference, and 1.12 (1.08-1.15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of -0.0001, -0.0001, and 0.0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement -0.19%, -0.05%, and -0.05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0.95, 95% CI 0.93-0.97) than for waist circumference (0.86, 0.83-0.89) or waist-to-hip ratio (0.63, 0.57-0.70). INTERPRETATION: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids. FUNDING: British Heart Foundation and UK Medical Research Council.

Estimation of life-years gained and cost effectiveness based on cause-specific mortality.

Cost-effectiveness analysis is usually based on life-years gained estimated from all-cause mortality. When an intervention affects only a few causes of death accounting for a small fraction of all deaths, this approach may lack precision. We develop a novel technique for cost-effectiveness analysis when life-years gained are estimated from cause-specific mortality, allowing for competing causes of death. In the context of randomised trial data, we adjust for other-cause mortality combined across randomised groups. This method yields a greater precision than analysis based on total mortality, and we show application to life-years gained, quality-adjusted life-years gained, incremental costs, and cost effectiveness. In multi-state health economic models, however, mortality from competing causes is commonly derived from national statistics and is assumed to be known and equal across intervention groups. In such models, our method based on cause-specific mortality and standard methods using total mortality give essentially identical estimates and precision. The methods are applied to a randomised trial and a health economic model, both of screening for abdominal aortic aneurysm. A gain in precision for cost-effectiveness estimates is clearly helpful for decision making, but it is important to ensure that 'cause-specific mortality' is defined to include all causes of death potentially affected by the intervention.

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.

Renal function and abdominal aortic aneurysm (AAA): the impact of different management strategies on long-term renal function in the UK EndoVascular Aneurysm Repair (EVAR) Trials.

OBJECTIVE: To investigate the impact of different management policies on renal function in patients with abdominal aortic aneurysm. SUMMARY BACKGROUND DATA: Limited longitudinal data exist on alterations in renal function in patients with abdominal aortic aneurysm. Escalating use of endovascular aneurysm repair (EVAR) with increased use of intensive imaging and contrast agents may have a deleterious effect on renal function. METHODS: Multilevel modeling of estimated Glomerular Filtration Rate (eGFR), measured annually over an average of 3.6 years, was performed on 1194 patients enrolled in the randomized EVAR trials to compare renal function in patients managed with open or endovascular repair or no intervention and investigate, which factors were associated with fast renal decline. RESULTS: For EVAR trial 1, the mean (SD) rate of change in eGFR was -1.13 (1.43) and -1.00 (1.43) mL/min/1.73 m per year for the EVAR and open repair groups, respectively, but this difference was not statistically significant (P=0.208). For EVAR trial 2, the mean (SD) rate of change in eGFR was -0.98 (1.49) and -0.76 (1.30) mL/min/1.73 m per year for the EVAR and no intervention groups, respectively (P=0.087). Faster rates of renal function decline were significantly associated with larger aortic neck diameters (P=0.003) and onset of graft-related complications after EVAR (P=0.001). CONCLUSIONS: In these patients deterioration in renal function was slow, with little evidence to suggest any long-term difference between treatment with EVAR or open repair in fit patients or between EVAR and no intervention in unfit patients. Graft complications and larger neck diameters appear to be associated with faster renal function decline.

Endovascular versus open repair of abdominal aortic aneurysm.

BACKGROUND: Few data are available on the long-term outcome of endovascular repair of abdominal aortic aneurysm as compared with open repair. METHODS: From 1999 through 2004 at 37 hospitals in the United Kingdom, we randomly assigned 1252 patients with large abdominal aortic aneurysms (> or = 5.5 cm in diameter) to undergo either endovascular or open repair; 626 patients were assigned to each group. Patients were followed for rates of death, graft-related complications, reinterventions, and resource use until the end of 2009. Logistic regression and Cox regression were used to compare outcomes in the two groups. RESULTS: The 30-day operative mortality was 1.8% in the endovascular-repair group and 4.3% in the open-repair group (adjusted odds ratio for endovascular repair as compared with open repair, 0.39; 95% confidence interval [CI], 0.18 to 0.87; P=0.02). The endovascular-repair group had an early benefit with respect to aneurysm-related mortality, but the benefit was lost by the end of the study, at least partially because of fatal endograft ruptures (adjusted hazard ratio, 0.92; 95% CI, 0.57 to 1.49; P=0.73). By the end of follow-up, there was no significant difference between the two groups in the rate of death from any cause (adjusted hazard ratio, 1.03; 95% CI, 0.86 to 1.23; P=0.72). The rates of graft-related complications and reinterventions were higher with endovascular repair, and new complications occurred up to 8 years after randomization, contributing to higher overall costs. CONCLUSIONS: In this large, randomized trial, endovascular repair of abdominal aortic aneurysm was associated with a significantly lower operative mortality than open surgical repair. However, no differences were seen in total mortality or aneurysm-related mortality in the long term. Endovascular repair was associated with increased rates of graft-related complications and reinterventions and was more costly. (Current Controlled Trials number, ISRCTN55703451.)

Endovascular repair of aortic aneurysm in patients physically ineligible for open repair.

BACKGROUND: Endovascular repair of abdominal aortic aneurysm was originally developed for patients who were considered to be physically ineligible for open surgical repair. Data are lacking on the question of whether endovascular repair reduces the rate of death among these patients. METHODS: From 1999 through 2004 at 33 hospitals in the United Kingdom, we randomly assigned 404 patients with large abdominal aortic aneurysms (> or = 5.5 cm in diameter) who were considered to be physically ineligible for open repair to undergo either endovascular repair or no repair; 197 patients were assigned to undergo endovascular repair, and 207 were assigned to have no intervention. Patients were followed for rates of death, graft-related complications and reinterventions, and costs until the end of 2009. Cox regression was used to compare outcomes in the two groups. RESULTS: The 30-day operative mortality was 7.3% in the endovascular-repair group. The overall rate of aneurysm rupture in the no-intervention group was 12.4 (95% confidence interval [CI], 9.6 to 16.2) per 100 person-years. Aneurysm-related mortality was lower in the endovascular-repair group (adjusted hazard ratio, 0.53; 95% CI, 0.32 to 0.89; P=0.02). This advantage did not result in any benefit in terms of total mortality (adjusted hazard ratio, 0.99; 95% CI, 0.78 to 1.27; P=0.97). A total of 48% of patients who survived endovascular repair had graft-related complications, and 27% required reintervention within the first 6 years. During 8 years of follow-up, endovascular repair was considerably more expensive than no repair (cost difference, 9,826 pounds sterling [U.S. $14,867]; 95% CI, 7,638 to 12,013 [11,556 to 18,176]). CONCLUSIONS: In this randomized trial involving patients who were physically ineligible for open repair, endovascular repair of abdominal aortic aneurysm was associated with a significantly lower rate of aneurysm-related mortality than no repair. However, endovascular repair was not associated with a reduction in the rate of death from any cause. The rates of graft-related complications and reinterventions were higher with endovascular repair, and it was more costly. (Current Controlled Trials number, ISRCTN55703451.)

Survival models in health economic evaluations: balancing fit and parsimony to improve prediction.

Health economic decision models compare costs and health effects of different interventions over the long term and usually incorporate survival data. Since survival is often extrapolated beyond the range of the data, inaccurate model specification can result in very different policy decisions. However, in this area, flexible survival models are rarely considered, and model uncertainty is rarely accounted for. In this article, various survival distributions are applied in a decision model for oral cancer screening. Flexible parametric models are compared with Bayesian semiparametric models, in which the baseline hazard can be made arbitrarily complex while still enabling survival to be extrapolated. A fully Bayesian framework is used for all models so that uncertainties can be easily incorporated in estimates of long-term costs and effects. The fit and predictive ability of both parametric and semiparametric models are compared using the deviance information criterion in order to account for model uncertainty in the cost-effectiveness analysis. Under the Bayesian semiparametric models, some smoothing of the hazard function is required to obtain adequate predictive ability and avoid sensitivity to the choice of prior. We determine that one flexible parametric survival model fits substantially better than the others considered in the oral cancer example.

C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis.

BACKGROUND: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances. METHODS: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. RESULTS: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality. INTERPRETATION: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation. FUNDING: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

Uncertainty and validation of health economic decision models.

Health economic decision models are based on specific assumptions relating to model structure and parameter estimation. Validation of these models is recommended as an indicator of reliability, but is not commonly reported. Furthermore, models derived from different data and employing different assumptions may produce a variety of results.A Markov model for evaluating the long-term cost-effectiveness of screening for abdominal aortic aneurysm is described. Internal, prospective and external validations are carried out using individual participant data from two randomised trials. Validation is assessed in terms of total numbers and timings of key events, and total costs and life-years. Since the initial model validates well only internally, two further models are developed that better fit the prospective and external validation data. All three models are then extrapolated to a life-time horizon, producing cost-effectiveness estimates ranging from pound1600 to pound4200 per life-year gained.Parameter uncertainty is now commonly addressed in health economic decision modelling. However, the derivation of models from different data sources adds another level of uncertainty. This extra uncertainty should be recognised in practical decision-making and, where possible, specifically investigated through independent model validation.

Extending DerSimonian and Laird's methodology to perform multivariate random effects meta-analyses.

Multivariate meta-analysis is increasingly used in medical statistics. In the univariate setting, the non-iterative method proposed by DerSimonian and Laird is a simple and now standard way of performing random effects meta-analyses. We propose a natural and easily implemented multivariate extension of this procedure which is accessible to applied researchers and provides a much less computationally intensive alternative to existing methods. In a simulation study, the proposed procedure performs similarly in almost all ways to the more established iterative restricted maximum likelihood approach. The method is applied to some real data sets and an extension to multivariate meta-regression is described.

Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.

CONTEXT: Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. STUDY SELECTION: Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTION: Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. DATA SYNTHESIS: Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. CONCLUSION: Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

The rupture rate of large abdominal aortic aneurysms: is this modified by anatomical suitability for endovascular repair?

BACKGROUND: There are no precise estimates of the rate of rupture of large abdominal aortic aneurysms (AAA). There is recent suspicion that anatomic suitability for endovascular repair may be associated with a decreased risk of AAA rupture. METHODS: Systematic literature review of rupture rates of AAA with initial diameter > or =5 cm in patients not considered for open repair, with stratification by size (<6.0 cm and 6.0+ cm), and gender, combined using random-effects meta-analysis. Proportional hazards regression to analyze factors (including gender, diabetes, initial AAA diameter, aneurysm neck, and sac lengths) associated with rupture in patients anatomically suitable for endovascular repair (EVAR 2 trial). RESULTS: Previous studies (2 prospective, 2 retrospective, and 1 mixed) were identified for meta-analysis and patients with elective repair excluded. The pooled rupture rates was 18.2 [95% confidence interval (CI) 13.7-24.1] per 100 person-years. There was a 2.5-fold increase in rupture rates for patients with AAA of 6.0+ cm versus <6.0 cm, rupture rates = 2.54 (95% CI 1.69-3.85). The pooled rupture rates was nonsignificantly higher in women than men, rupture rates = 1.21 (95% CI 0.77-1.90). For EVAR 2 patients with 6+ cm aneurysms the rupture rates was 17.4 [95% CI 12.9-23.4] per 100 person-years significantly lower than the pooled rate from the meta-analysis, rupture rates = 27.0 [95% CI 21.1-34.7] per 100 person-years, P = 0.026. Patients with shorter neck lengths appeared to have a higher rupture rates than those with longer necks, but this was of borderline significance P = 0.10. CONCLUSIONS: Rupture rates of large AAAs reported in different studies are highly variable. There is emerging evidence that patients anatomically suitable for endovascular repair have lower rupture rates.