Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease.

BACKGROUND: Anti-tumour necrosis factor-alpha agents (anti-TNF) are effective therapies for the treatment of Crohn's disease (CD), but their comparative efficacy is unknown. AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF therapies in CD. METHODS: After screening 506 studies, reviewers extracted information on 10 studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 1.66, 95% CI: 1.17-2.36 and RR: 1.43, 95% CI: 1.17-1.73, respectively) as well as maintenance of remission and response (RR: 1.78, 95% CI: 1.51-2.09 and RR: 1.68, 95% CI: 1.46-1.93, respectively). NMA found nonsignificant trends between infliximab and adalimumab or certolizumab pegol. Among subcutaneous therapies, NMA demonstrated superiority of adalimumab to certolizumab pegol for induction of remission (RR: 2.93, 95% CrI: 1.21-7.75). Sample size calculations suggest that adequately powered head-to-head comparative efficacy trials would require greater than 3000 patients. CONCLUSIONS: All anti-TNF agents are effective for induction and maintenance of response and remission in the treatment of CD. Although adalimumab is superior to certolizumab pegol for induction of remission, there is no evidence of clinical superiority among anti-TNF agents. Head-to-head trials among the anti-TNF agents are impractical in terms of size and cost.

Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.

BACKGROUND: Antibodies against tumour necrosis factor-alpha (anti-TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown. AIM: To perform a network meta-analysis comparing the efficacy of anti-TNF agents in UC. METHODS: After screening 506 studies, reviewers extracted information on seven studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. RESULTS: Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 2.45, 95% CI: 1.72-3.47 and RR: 1.65, 95% CI: 1.37-1.99 respectively) as well as maintenance of remission and response (RR: 2.00, 95% CI: 1.52-2.62 and RR: 1.76, 95% CI: 1.46-2.14 respectively). Individually, infliximab, adalimumab and goliumumab resulted in a higher likelihood of induction and maintenance for both remission and response. NMA found nonsignificant trends in comparisons of the individual agents. The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively. CONCLUSIONS: This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. However, network meta-analysis demonstrates that no single agent is clinically superior to the others and therefore, other factors such as cost, safety, route of administration and patient preference should dictate our choice of anti-TNF agents. A randomised comparative efficacy trial between infliximab and adalimumab in UC is of practical size and should be performed.

Getting heavier, younger: trajectories of obesity over the life course.

CONTEXT: Although recent trends in obesity have been well documented, generational patterns of obesity from early childhood through adulthood across birth cohorts, which account for the recent epidemic of childhood obesity, have not been well described. Such trends may have implications for the prevalence of obesity-associated conditions among population subgroups, including type 2 diabetes. OBJECTIVE: Our objective was to evaluate trajectories of obesity over the life course for the US population, overall and by gender and race. DESIGN, SETTING AND PARTICIPANTS: We conducted an age, period and birth cohort analysis of obesity for US individuals who participated in the National Health and Nutrition Examination Surveys (NHANES) (1971-2006). MAIN OUTCOME MEASURES: Obesity was defined as a body mass index >or=95th percentile for individuals aged 2-16 years or >or=30 kg m(-2) among individuals older than 16 years. Age was represented by the age of the individual at each NHANES, period was defined by the year midpoint of each survey, and cohort was calculated by subtracting age from period. RESULTS: Recent birth cohorts are becoming obese in greater proportions for a given age, and are experiencing a greater duration of obesity over their lifetime. For example, although the 1966-1975 and 1976-1985 birth cohorts had reached an estimated obesity prevalence of at least 20% by 20-29 years of age, this level was only reached by 30-39 years for the 1946-1955 and 1956-1965 birth cohorts, by 40-49 years for the 1936-1945 birth cohort and by 50-59 years of age for the 1926-1935 birth cohort. Trends are particularly pronounced for female compared with male, and black compared with white cohorts. CONCLUSIONS: The increasing cumulative exposure to excess weight over the lifetime of recent birth cohorts will likely have profound implications for future rates of type 2 diabetes, and mortality within the US population.

Consequences of endoscopic inguinal hernioplasty with mesh on subsequent open radical prostatectomy.

AIM: To determine the effect of prior endoscopic hernia repair with prosthetic mesh on subsequent open radical prostatectomy. METHODS: A retrospective study from 1990 to 2004 identified nine patients with preperitoneal mesh placement followed by open radical prostatectomy. Case controls (n = 26) were matched for age, type of operation, year of surgery and pathologic stage of prostatic adenocarcinoma. Outcome variables of operating time, number of pelvic lymph nodes excised, duration of hospital stay, duration of urinary catheterization, recurrence rates, and incidence of complications were compared. Data analysis was performed using Wilcoxon's rank sums test. RESULTS: Intraoperatively, subjective difficulty in dissection was documented in all cases by the performing urologist. Duration of hospital stay was significantly increased by 1.3 days (p < 0.05), as compared to the control group. However, no statistically significant increase in mean operating time (173 vs. 172 min, p = 0.925), number of lymph nodes sampled (4.4 vs. 6.6, p = 0.147), duration of urinary catheterization (22 vs. 19 days, p = 0.925), oncologic recurrence (11 vs. 11% at 6.1 and 4.8 years follow-up), or complications was found. CONCLUSIONS: Prior TEP/TAPP did not increase the morbidity or mortality of subsequent prostate surgery. Despite some subjective operative difficulty, open prostatectomy was safe and feasible in all cases with a comparable oncologic outcome. Mesh-associated inflammation may preclude adequate nodal sampling. While endoscopic hernia repair remains an excellent option to fix unilateral, bilateral, and recurrent herniae, consideration of future prostate surgery is important. Inserting less "inflammatory" mesh or using an open, anterior approach may be prudent in some men at high risk for needing subsequent prostate surgery.

A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria.

No empirical studies have defined the posttransplant survival that would justify expansion of the Milan criteria for liver transplantation of hepatocellular carcinoma. We created a Markov model comparing the survival benefit of transplantation for a patient with >Milan HCC, versus the harm caused to other patients on the waiting list. In the base-case analysis, the strategy of transplanting the patient with >Milan HCC resulted in a 44% increased risk of death and a utility loss of 3 quality-adjusted years of life across the pre- and posttransplant periods for a nationally representative cohort of patients on the waiting list. This harm outweighed the benefit of transplantation for a patient with >Milan HCC having a 5-year posttransplant survival of less than 61%. This survival threshold was most sensitive to geographic variations in organ shortage, with the threshold varying from 25% (Region 3) to >72% (Regions 1, 5, 7 and 9). In conclusion, expansion of the Milan criteria will require demonstrating high survival rates for the newly eligible patients-approximately 61% at 5 years after transplantation. In regions with less severe organ shortage, a more aggressive approach to transplanting these patients may be justified.

Barriers to following dietary recommendations in Type 2 diabetes.

AIMS: To evaluate barriers to following dietary recommendations in patients with Type 2 diabetes. METHODS: We conducted focus groups and surveys in urban and suburban VA and academic medical centres. For the written survey, a self-administered questionnaire was mailed to a random sample of 446 patients with diabetes. For the focus groups, six groups of patients with diabetes (three urban, three suburban) were conducted, with 6-12 participants in each group. The focus groups explored barriers across various types of diabetes self-management; we extracted all comments relevant to barriers that limited patients' ability to follow a recommended diet. RESULTS: The written survey measured the burden of diabetes therapies (on a seven-point rating scale). Moderate diet was seen as a greater burden than oral agents (median 1 vs. 0, P = 0.001), but less of a burden than insulin (median 1 vs. 4, P < 0.001). A strict diet aimed at weight loss was rated as being similarly burdensome to insulin (median 4 vs. 4, P = NS). Despite this, self-reported adherence was much higher for both pills and insulin than it was for a moderate diet. In the focus groups, the most commonly identified barrier was the cost (14/14 reviews), followed by small portion sizes (13/14 reviews), support and family issues (13/14 reviews), and quality of life and lifestyle issues (12/14 reviews). Patients in the urban site, who were predominantly African-American, noted greater difficulties communicating with their provider about diet and social circumstances, and also that the rigid schedule of a diabetes diet was problematic. CONCLUSIONS: Barriers to adherence to dietary therapies are numerous, but some, such as cost, and in the urban setting, communication with providers, are potentially remediable. Interventions aimed at improving patients' ability to modify their diet need to specifically address these areas. Furthermore, treatment guidelines need to consider patients' preferences and barriers when setting goals for treatment.

Projections of demand and capacity for colonoscopy related to increasing rates of colorectal cancer screening in the United States.

BACKGROUND: There is debate about the optimal colorectal cancer screening test, partly because of concerns about colonoscopy demand. AIM: To quantify the demand for colonoscopy with different screening tests, and to estimate the ability of the United States health care system to meet demand. METHODS: We used a previously published Markov model and the United States census data to estimate colonoscopy demand. We then used an endoscopic database to compare current rates of screening-related colonoscopy with those projected by the model, and to estimate the number of endoscopists needed to meet colonoscopy demand. RESULTS: Annual demand for colonoscopy ranges from 2.21 to 7.96 million. Based on current practice patterns, demand exceeds current supply regardless of screening strategy. We estimate that an increase of at least 1360 gastroenterologists would be necessary to meet demand for colonoscopic screening undergone once at age 65, while colonoscopy every 10 years could require 32 700 more gastroenterologists. A system using dedicated endoscopists could meet demand with fewer endoscopists. CONCLUSIONS: Colorectal cancer screening leads to demand for colonoscopy that outstrips supply. Systems to train dedicated screening endoscopists may be necessary in order to provide population-wide screening. The costs and feasibility of establishing this infrastructure should be studied further.

Avoiding pitfalls in chronic disease quality measurement: a case for the next generation of technical quality measures.

The true utility of quality measurement lies in its ability to inspire quality improvement, with resultant enhancements in the processes and outcomes of care. Because quality measurement is expensive, it is difficult to justify using measures that are not likely to lead to important improvements in health. Many current measures of chronic disease technical quality, however, have one or more pitfalls that prevent them from motivating quality improvement reactions. These pitfalls include that: (1) measured processes of care lack strong links to outcomes; (2) actionable processes of care are not measured; (3) measures do not target those at highest risk; (4) measures do not allow for patient exceptions; and (5) intermediate outcome measures are not severity adjusted. To exemplify recent advancements and current pitfalls in chronic disease quality measurement, we examine the evolution of quality measures for diabetes mellitus and discuss the limitations of many currently used diabetes mellitus care measures. We then propose more clinically meaningful "tightly linked" measures that examine clinical processes directly linked to outcomes, target populations with specific diagnoses or intermediate disease outcomes that contribute to risk for poor downstream health outcomes, and explicitly incorporate exceptions. We believe that using more tightly linked measures in quality assessment will identify important quality of care problems and is more likely to produce improved outcomes for those with chronic diseases.

The role of hospital volume in coronary artery bypass grafting: is more always better?

OBJECTIVES: The goal of this study was to determine whether outcomes of nonemergent coronary artery bypass grafting (CABG) differed between low- and high-volume hospitals in patients at different levels of surgical risk. BACKGROUND: Regionalizing all CABG surgeries from low- to high-volume hospitals could improve surgical outcomes but reduce patient access and choice. "Targeted" regionalization could be a reasonable alternative, however, if subgroups of patients that would clearly benefit from care at high-volume hospitals could be identified. METHODS: We assessed outcomes of CABG at 56 U.S. hospitals using 1997 administrative and clinical data from Solucient EXPLORE, a national outcomes benchmarking database. Predicted in-hospital mortality rates for subjects were calculated using a logistic regression model, and subjects were classified into five groups based on surgical risk: minimal (< 0.5%), low (0.5% to 2%), moderate (2% to 5%), high (5% to 20%), and severe (> or =20%). We assessed differences in in-hospital mortality, hospital costs and length of stay between low- and high-volume facilities (defined as > or =200 annual cases) in each of the five risk groups. RESULTS: A total of 2,029 subjects who underwent CABG at 25 low-volume hospitals and 11,615 subjects who underwent CABG at 31 high-volume hospitals were identified. Significant differences in in-hospital mortality were seen between low- and high-volume facilities in subjects at moderate (5.3% vs. 2.2%; p = 0.007) and high risk (22.6% vs. 11.9%; p = 0.0026) but not in those at minimal, low or severe risk. Hospital costs and lengths of stay were similar across each of the five risk groups. Based on these results, targeted regionalization of subjects at moderate risk or higher to high-volume hospitals would have resulted in an estimated 370 transfers and avoided 16 deaths; in contrast, full regionalization would have led to 2,029 transfers and avoided 20 deaths. CONCLUSIONS: Targeted regionalization might be a feasible strategy for balancing the clinical benefits of regionalization with patients' desires for choice and access.

The cost-utility of screening for depression in primary care.

BACKGROUND: Depressive disorders are common in primary care and cause substantial disability, but they often remain undiagnosed. Screening is a frequently proposed strategy for increasing detection of depression. OBJECTIVE: To examine the cost-utility of screening for depression compared with no screening. DESIGN: Nonstationary Markov model. DATA SOURCES: The published literature. TARGET POPULATION: Hypothetical cohort of 40-year-old primary care patients. TIME HORIZON: Lifetime. PERSPECTIVE: Health care payer and societal. INTERVENTIONS: Self-administered questionnaire followed by provider assessment. OUTCOME MEASURES: Costs and quality-adjusted life-years (QALYs). RESULTS OF BASE-CASE ANALYSIS: Compared with no screening, the cost to society of annual screening for depression in primary care patients is $192 444/QALY. Screening every 5 years and one-time screening cost $50 988/QALY and $32 053/QALY, respectively, compared with no screening. From the payer perspective, the cost of annual screening is $225 467. RESULTS OF SENSITIVITY ANALYSES: Cost-utility ratios are most sensitive to the prevalence of major depression, the costs of screening, rates of treatment initiation, and remission rates with treatment. In Monte Carlo sensitivity analyses, the cost-utility of annual screening is less than $50 000/QALY only 2.2% of the time. In multiway analyses, four model variables must be changed to extreme values for the cost-utility of annual screening to fall below $50 000/QALY, but a change in only one variable increases the cost-utility of one-time screening to more than $50 000/QALY. One-time screening is more robustly cost-effective if screening costs are low and effective treatments are being given. CONCLUSIONS: Annual and periodic screening for depression cost more than $50 000/QALY, but one-time screening is cost-effective. The cost-effectiveness of screening is likely to improve if treatment becomes more effective.

Which colon cancer screening test? A comparison of costs, effectiveness, and compliance.

PURPOSE: Recent media reports have advocated the use of colonoscopy for colorectal cancer screening. However, colonoscopy is expensive compared with other screening modalities, such as fecal occult blood testing and flexible sigmoidoscopy. We sought to determine the cost effectiveness of different screening strategies for colorectal cancer at levels of compliance likely to be achieved in clinical practice. METHODS: A Markov decision model was used to examine screening strategies, including fecal occult blood testing alone, fecal occult blood testing combined with flexible sigmoidoscopy, flexible sigmoidoscopy alone, and colonoscopy. The timing and frequency of screening was varied to assess optimal screening intervals. Sensitivity analyses were conducted to assess the factors that have the greatest effect on the cost effectiveness of screening. RESULTS: All strategies are cost effective versus no screening, at less than $20,000 per life-year saved. Direct comparison suggests that the most effective strategies are twice-lifetime colonoscopy and flexible sigmoidoscopy combined with fecal occult blood testing. Assuming perfect compliance, flexible sigmoidoscopy combined with fecal occult blood testing is slightly more effective than twice-lifetime colonoscopy (at ages 50 and 60 years) but is substantially more expensive, with an incremental cost effectiveness of $390,000 per additional life-year saved. However, compliance with primary screening tests and colonoscopic follow-up for polyps affect screening decisions. Colonoscopy at ages 50 and 60 years is the preferred test regardless of compliance with the primary screening test. However, if follow-up colonoscopy for polyps is less than 75%, then even once-lifetime colonoscopy is preferred over most combinations of flexible sigmoidoscopy and fecal occult blood testing. Costs of colonoscopy and proportion of cancer arising from polyps also affect cost effectiveness. CONCLUSIONS: Colonoscopic screening for colorectal cancer appears preferable to current screening recommendations. Screening recommendations should be tailored to the compliance levels achievable in different practice settings.

Estimating the microvascular benefits of screening for type 2 diabetes mellitus.

OBJECTIVE: To define the relative benefits of screening for diabetes and improved treatment programs and ways of improving the efficiency of screening for a population-based cohort derived from the Third National Health and Nutrition Examination Survey (NHANES III). METHODS: A Markov decision model is used to estimate microvascular benefits of glucose control for four different screening and treatment scenarios, including either universal screening or improved glucose control of known diabetic subjects, neither, or both. RESULTS: A population cohort of subjects with recent onset of diabetes (< 5 years) was derived from NHANES III (of whom close to half were unaware that they had diabetes). In this population-based cohort, the total benefit achievable by universal screening and improved treatment (limiting HbA1c to less than 9%) is a reduction of about 30,000 cases of blindness over the lifetime of the cohort. Screening alone results in 7% of this benefit, and improved treatment alone provides 65%. Screening a targeted group of patients with three or more risk factors for developing diabetes would reduce the number of required fasting glucose measurements needed by 82% and provide 50% of the total benefit of screening the entire population with a fasting glucose measurement. CONCLUSIONS: Morbidity from type 2 diabetes can be most effectively reduced by developing ways to modestly improve the glycemic control of known diabetic subjects, particularly those with high A1c's and early onset of disease. Targeting can significantly reduce the number of persons who need to be screened with a fasting blood test while preserving a large component of the benefit of screening.

Are randomized controlled trials sufficient evidence to guide clinical practice in type II (non-insulin-dependent) diabetes mellitus?

Randomized controlled trials (RCTs) are often considered the standard for defining the practice of evidence-based medicine. Taken alone, they are, however, often insufficient to guide clinical care. Randomized controlled trials are clearly the best method to determine whether interventions are efficacious. They have, however, numerous limitations which make them difficult to carry out or limit applicability to routine clinical practice. Although observational studies also have inherent limitations, they provide data which can help to further explain the results of randomized controlled trials. The use of observational studies to frame randomized trials can allow better application of randomized controlled trial results to individual patients and can thus help to optimize delivery of care, inform clinical practice and determine the need for further such trials.

Cost-utility analysis of screening intervals for diabetic retinopathy in patients with type 2 diabetes mellitus.

CONTEXT: Annual eye screening for patients with diabetes mellitus is frequently proposed as a measure of quality of care. However, the benefit of annual vs less frequent screening intervals has not been well evaluated, especially for low-risk patients. OBJECTIVE: To examine the marginal cost-effectiveness of various screening intervals for eye disease in patients with type 2 diabetes, stratified by age and level of glycemic control. DESIGN: Markov cost-effectiveness model. SETTING AND PARTICIPANTS: Hypothetical patients based on the US population of diabetic patients older than 40 years from the Third National Health and Nutrition Examination Survey. MAIN OUTCOME MEASURES: Patient time spent blind, quality-adjusted life-years (QALYs), and costs of annual vs less frequent screening compared by age and level of hemoglobin A1c. RESULTS: Retinal screening in patients with type 2 diabetes is an effective intervention; however, the risk reduction varies dramatically by age and level of glycemic control. On average, a high-risk patient who is aged 45 years and has a hemoglobin A1c level of 11% gains 21 days of sight when screened annually as opposed to every third year, while a low-risk patient who is aged 65 years and has a hemoglobin A1c level of 7% gains an average of 3 days of sight. The marginal cost-effectiveness of screening annually vs every other year also varies; patients in the high-risk group cost an additional $40530 per QALY gained, while those in the low-risk group cost an additional $211570 per QALY gained. In the US population, retinal screening annually vs every other year for patients with type 2 diabetes costs $107510 per QALY gained, while screening every other year vs every third year costs $49760 per QALY gained. CONCLUSIONS: Annual retinal screening for all patients with type 2 diabetes without previously detected retinopathy may not be warranted on the basis of cost-effectiveness, and tailoring recommendations to individual circumstances may be preferable. Organizations evaluating quality of care should consider costs and benefits carefully before setting universal standards.

Normative issues in cost effectiveness analysis.

Cost effectiveness analysis (CEA) and cost-utility analysis are increasingly used to compare competing uses for limited health care resources, informing policy decisions at governmental, payer, and clinical levels of the health system. The authors discuss various methodologic choices in CEA and the normative (value) assumptions and implications of those choices. The treatment of adult onset diabetes is used as a simplified case example to illustrate the choice of perspective, cost inclusion and exclusion, benefit measurement and aggregation, and how these and other aspects of CEA can implicitly influence policy decisions with consequences for individuals and groups. CEA can be a valuable source of information, but it is a poor "technologic fix" for the thorny problem of allocating limited health care resources.

Screening, prevention, counseling, and treatment for the complications of type II diabetes mellitus. Putting evidence into practice.

PURPOSE: To summarise current knowledge of interventions that should improve the care of patients with type II diabetes mellitus. Interventions lie within the realms of preventions, screening, and treatment, all of which are focused on office practice. METHODS: Review of the literature by a multidisciplinary team involved in the care of patients with diabetes, followed by synthesis of the literature into a clinical care guideline. Literature was identified through consultation with experts and a focused MEDLINE search. MAIN RESULTS: An algorithm-based guideline for screening and treatment of the complications of diabetes was developed. The emphasis is on prevention of atherosclerotic disease, and prevention, screening, and early treatment of microvascular disease. Implementation of these practices has the potential to significantly improve quality of life and increase life expectancy in patients with type II diabetes mellitus.