Marika J Suttorp

Meta-analysis: surgical treatment of obesity.

Context The effectiveness of surgical therapy in the treatment of obesity is unclear. Contribution Many published studies of obesity surgery have significant limitations, and case series make up much of the evidence. Evidence is complicated by the heterogeneity of procedures studied. However, surgery can result in substantial amounts of weight loss (20 to 30 kg) for markedly obese individuals. One cohort study documented weight loss for 8 years with associated improvements in comorbid conditions, such as diabetes. Complications of surgery appear to occur in about 20% of patients. Implications Those considering surgical treatment for obesity should understand that, although patients who have surgery can lose substantial amounts of weight, the evidence base for these treatments is limited. The Editors The prevalence of obesity in the United States is reaching epidemic proportions. An estimated 30% of individuals met the criteria for obesity in 19992002 (1, 2), and many industrialized countries have seen similar increases. The health consequences of obesity include heart disease, diabetes, hypertension, hyperlipidemia, osteoarthritis, and sleep apnea (3-7). Weight loss of 5% to 10% has been associated with marked reductions in the risk for these chronic diseases and with reducing the incidence of diabetes (8-14). The increasing numbers of obese individuals have led to intensified interest in surgical treatments to achieve weight loss, and a variety of surgical procedures have been used (Figure 1). Bariatric surgery was first performed in 1954 with the introduction of the jejunoileal bypass, which bypasses a large segment of small intestine by connecting proximal small intestine to distal small intestine. With this procedure, weight loss occurs secondary to malabsorption from reduction of upstream pancreatic and biliary contents. However, diarrhea and nutritional deficiencies were common, and this procedure was discontinued because of the complication of irreversible hepatic cirrhosis. With the development of surgical staplers came the introduction of gastroplasty procedures by Gomez in 1981 (15) and Mason in 1982 (16). In these early procedures, the upper portion of the stomach was stapled into a small gastric pouch with an outlet (that is, a stoma) to the remaining distal stomach, which limited the size of the meal and induced early satiety. These procedures were prone to staple-line breakdown or stoma enlargement and were modified in turn by the placement of a band around the stoma (vertical banded gastroplasty). Figure 1. Surgical procedures. The first gastric bypass was reported in 1967 by Mason and Ito (17). It combined the creation of a small gastric pouch with bypassing a portion of the upper small intestine. Additional modifications resulted in the Roux-en-Y gastric bypass (RYGB), a now common operation that involves stapling the upper stomach into a 30-mL pouch and creating an outlet to the downstream small intestine. The new food limb joins with the biliopancreatic intestine after a short distance. This procedure, performed laparoscopically or by using an open approach, generates weight loss by limiting gastric capacity, causing mild malabsorption, and inducing hormonal changes. A second common technique, particularly outside of the United States, is the laparoscopic adjustable gastric band. This device is positioned around the uppermost portion of the stomach and can be adjusted to allow tailoring of the stoma outlet, which controls the rate of emptying of the pouch and meal capacity. Another procedure, preferred by a number of surgeons, is the biliopancreatic bypass, which combines a limited gastrectomy with a long Roux limb intestinal bypass that creates a small common channel (that is, an intestine where food and biliopancreatic contents mix). This procedure can be combined with a duodenal switch, which maintains continuity of the proximal duodenum with the stomach and uses a long limb Roux-en-Y bypass to create a short common distal channel. These latter 2 procedures generate weight loss primarily through malabsorption. Recent worldwide survey data from 2002 and 2003 show that gastric bypass is the most commonly performed weight loss procedure (65.1%) (18). Slightly more than half of gastric bypasses are done laparoscopically. Overall, 24% of cases are laparoscopic adjustable band procedures; 5.4% are vertical banded gastroplasties; and 4.9% are biliopancreatic diversion, with or without the duodenal switch. In California, the number of bariatric cases increased 6-fold between 1996 and 2000 (19), from 1131 cases to 6304; an estimated 140000 procedures were performed in the United States in 2004. With this escalation in the number of procedures, there have been reports of high postoperative complication rates (20-24). Because of these reports and the increasing use of obesity surgery, we were asked to review the literature to estimate the effectiveness of bariatric surgery relative to nonsurgical therapy for weight loss and reduction in preoperative obesity-related comorbid conditions. We were also asked to compare outcomes of surgical techniques. This paper is part of a larger evidence report titled Pharmacological and Surgical Treatment of Obesity, which was prepared for the Agency for Healthcare Research and Quality and is available at www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.19289. Methods Literature Search and Selection We began with an electronic search of MEDLINE on 16 October 2002, followed by a search of EMBASE and subsequent periodic search updates (on 22 May, 2 June, 12 June, and 3 July 2003). We also assessed existing reviews of surgical therapy for obesity (10, 25, 26). Three reviewers independently reviewed the studies, abstracted data, and resolved disagreements by consensus (2 reviewers per study). The principal investigator settled any unresolved disagreements. We focused on studies that assessed surgery and used a concurrent comparison group. This category includes randomized, controlled trials (RCTs); controlled clinical trials; and cohort studies. A brief scan of the literature showed that these types of studies were rare. Therefore, we also elected to include case series with 10 or more patients, since these studies can be used to assess adverse events and could potentially augment the efficacy data from comparative studies. Publication bias is one potential limitation of analyzing the available literature because poor or negative results are not as likely to be reported as are successes or positive results. Extraction of Study-Level Variables We abstracted data from the articles, including number of patients and comorbid conditions, adverse events, types of outcome measures, and time from intervention until outcome. Detailed data were also collected on characteristics of the study samples, including median age, percentage of women, median baseline weight (in kilograms or body mass index [BMI]), percentage of patients with comorbid conditions at baseline (diabetes, hypertension, dyslipidemia, and sleep apnea), percentage of improvement or resolution of preexisting comorbid conditions, and median follow-up time. We also recorded whether the case series studies reported on consecutive patients. Choice of Outcomes The main outcomes of interest were weight loss, mortality, complication rates, and control of obesity-related comorbid conditions. We used the most commonly reported measurement of weight loss, that is, kilograms, which allowed us to include the greatest number of studies. Among 111 surgical studies reporting weight loss, 43 reported weight loss in kilograms or pounds, 17 reported excess weight loss or some variant, 46 reported both of these outcomes, and 5 reported neither. A total of 89 studies had sufficient data to be included in the weight loss analysis. Because weight loss achieves health benefits primarily by reducing the incidence or severity of weight-related comorbid conditions, we also compared the effects on these outcomes. Quality of life, an important outcome in assessing tradeoffs between benefits and risks, was reported infrequently. Statistical Analyses Because we included both comparative studies and case series, we conducted several types of analyses. The vast number of types of surgical procedures and technical variations required that we aggregate those that were clinically similar and identify the comparisons that were of most interest to the clinical audience. On the basis of discussions with bariatric surgeons, we categorized obesity surgery procedures by procedure type (for example, gastric bypass, vertical banded gastroplasty), laparoscopic or open approach, and specific surgical details such as length of Roux limb (see the larger evidence report for details). Analysis of the Efficacy of Surgical Weight Loss We extracted the mean weight loss and standard deviation at 12 postoperative months and at the maximum follow-up time (36 months). These times were chosen because they are clinically relevant and are most commonly reported. Of the 89 weight loss studies, 71 reported baseline BMI (average, 47.1 kg/m2), 16 reported baseline weight in kilograms or pounds (average, 123.3 kg), and 2 did not report either. The average age of patients was 38 years, and more than three quarters were women. For comparative studies that reported a within-study comparison of 2 procedures, a mean difference was calculated. Mean differences were pooled by using a random-effects model, and 95% CIs were estimated; the same method was used to determine a pooled mean weight loss for each group considering all studies combined. However, mean difference in weight loss was not calculated. Analysis of Surgery Mortality We recorded the number of deaths observed and the total number of patients in each procedure group. If the study self-identified the deaths as early or postoperative or as occurring within 30 days of the surgery, we termed these early deaths. If the

Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials

Abstract Objective To assess the relative effectiveness of interventions to prevent falls in older adults to either a usual care group or control group. Table 2 Components of multifactorial falls risk assessment Trial Orthostatic blood pressure Vision Balance and gait Drug review Instrumental activities of daily living or activities of daily living Cognitive evaluation Environmental hazards Other Carpenter 1990w4 No No No No Yes No No Fabacher 1994w13 Yes Yes Yes Yes Yes Yes Yes Assessment of hearing and depression Rubenstein 1990w30 Yes Yes Yes Yes Yes Yes Yes Neurological and musculoskeletal examination, laboratory tests, 24 hour heart monitor Tinetti 1994w37 Yes No Yes Yes No No Yes Muscle strength and range of motion Wagner 1994w39 No Yes No Yes No No Yes Hearing, assessment of alcohol misuse, assessment of physical activity Gallagher 1996w15 Yes Yes Yes Yes Yes Yes Yes List of health problems Coleman 1999w7 No No No Yes No No No Self management skills, health assessment Close 1999w6 Yes Yes Yes Yes Yes Yes Yes Affect, carotid sinus studies (if clinical suspicion) McMurdo 2000w21 Yes Yes No Yes No No No Review of lighting in environment Van Haastregt 2000w38 No No No Yes Yes Yes Yes Physical health, psychosocial functioning Millar 1999w24 Yes Yes No Yes No No No Review of lighting in environment Crome 2000w8* Jensen 2002w17 No Yes Yes Yes Yes Yes Yes Hearing, review of lighting in environment, assistive device (for example, cane, walker), review of use of device, and repair of device if needed See table A on bmj.com for details of references. * No specific components stated. Design Systematic review and meta-analyses. Data sources Medline, HealthSTAR, Embase, the Cochrane Library, other health related databases, and the reference lists from review articles and systematic reviews. Data extraction Components of falls intervention: multifactorial falls risk assessment with management programme, exercise, environmental modifications, or education. Results 40 trials were identified. A random effects analysis combining trials with risk ratio data showed a reduction in the risk of falling (risk ratio 0.88, 95% confidence interval 0.82 to 0.95), whereas combining trials with incidence rate data showed a reduction in the monthly rate of falling (incidence rate ratio 0.80, 0.72 to 0.88). The effect of individual components was assessed by meta-regression. A multifactorial falls risk assessment and management programme was the most effective component on risk of falling (0.82, 0.72 to 0.94, number needed to treat 11) and monthly fall rate (0.63, 0.49 to 0.83; 11.8 fewer falls in treatment group per 100 patients per month). Exercise interventions also had a beneficial effect on the risk of falling (0.86, 0.75 to 0.99, number needed to treat 16) and monthly fall rate (0.86, 0.73 to 1.01;2.7). Conclusions Interventions to prevent falls in older adults are effective in reducing both the risk of falling and the monthly rate of falling. The most effective intervention was a multifactorial falls risk assessment and management programme. Exercise programmes were also effective in reducing the risk of falling.

Meta-analysis : Pharmacologic treatment of obesity

Context The effectiveness of pharmacologic therapy in the treatment of obesity is unclear. Contribution This review of 79 clinical trials involving diet plus the obesity drugs sibutramine, orlistat, fluoxetine, sertraline, bupropion, topiramate, or zonisamide shows that these medications can lead to modest weight reductions of approximately 5 kg or less at 1 year. Available evidence is lacking on the effect of these drugs on long-term weight loss, health outcomes such as cardiovascular events and diabetes, and adverse effects. Implications Those considering pharmacologic treatment for obesity should understand that these drugs can lead to modest weight loss at 1 year, but data on long-term effectiveness and safety are lacking. The Editors Obesity has been defined as excess body fat relative to lean body mass (1) and, in humans, is the result of interactions of the environment with multiple genes. The age-adjusted prevalence of obesity was 30.5% in 19992000 (2). Although it is difficult to precisely estimate the change in prevalence of obesity over time because of changing definitions, nearly all clinical authorities agree that obesity is reaching epidemic proportions (2-13). Obesity is currently defined as a body mass index (BMI) of 30 kg/m2 or greater. Individuals whose BMI falls between 25 kg/m2 and 29.9 kg/m2 are considered overweight. Attempts to meet the body weight goal of the Healthy People 2000 initiative (7)to reduce the prevalence of overweight among adults to less than 20% of the populationdid not succeed. Still, many Americans are trying. According to a national survey (14), about 40% of women and 25% of men reported that they were currently trying to lose weight. However, most weight loss attempts consist of 6 months of loss followed by gradual regain to baseline (15). The health consequences of obesity include some of the most common chronic diseases in our society. Obesity is an independent risk factor for heart disease (16). Type 2 diabetes mellitus, hypertension and stroke, hyperlipidemia, osteoarthritis, and sleep apnea are all more common in obese individuals (17-19). A recent prospective study involving 900000 U.S. adults reported that increased body weight was associated with increased death rates for all cancer combined and for cancer at multiple specific sites (20). Adult weight gain is associated with increased risk for breast cancer in postmenopausal women (21). Weight loss of 5% to 10% can be associated with marked reductions in the risk for these chronic diseases (22). In the Diabetes Prevention Program, weight loss of about 5% to 6% among persons with a BMI of 34 kg/m2, along with increased physical activity, resulted in a 58% reduction in the incidence of diabetes (23). In response to the increase in obesity, pharmaceutical treatments for obesity have become both more numerous and more commonly used. Drugs prescribed for weight loss can be divided into 2 categoriesappetite suppressants and lipase inhibitorson the basis of their putative mechanisms of action. Appetite suppressants can be further subdivided on the basis of the neurotransmitters they are believed to affect. This article, which reviews the available evidence on medications used as obesity treatment in adults (Table 1), is part of a larger evidence report prepared for the Agency for Healthcare Research and Quality titled Pharmacological and Surgical Treatment of Obesity. The larger report is available at www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.19289. Table 1. Prescription Medications Used for Weight Loss Methods Literature Search and Selection Our search for controlled human studies of pharmacologic treatments of obesity began with an electronic search of MEDLINE on 16 October 2002. Subsequently, our librarian conducted current awareness search updates on 22 May, 2 June, 12 June, and 3 July 2003. We also searched the Cochrane Controlled Clinical Trials Register Database and existing systematic reviews. Full details of the search strategy are available in the larger evidence report. To be accepted for analysis, a study of drug therapy had to be a controlled clinical trial that assessed the effect of one of the pharmaceutical agents in humans and reported at least 6-month weight loss outcomes in pounds or kilograms. We made an exception for topiramate, for which most trials reported only percentage of weight loss. Patients in included studies needed to have a BMI of 27 kg/m2 or greater (Appendix Table). The technical expert panel for our evidence report determined which pharmaceutical agents would be included. The panel chose sibutramine, orlistat, phentermine, and diethylpropion, all of which have been approved by the U.S. Food and Drug Administration, as well as other medications being used for weight loss, including fluoxetine, bupropion, sertraline, topiramate, and zonisamide. Extraction of Study-Level Variables and Results Three reviewers, working in groups of 2, extracted data from the same articles and resolved disagreements by consensus. A senior physician resolved any remaining disagreements. We used the Jadad score to evaluate the quality of the studies, using information on study design, method of random assignment, blinding, and withdrawal (34). Jadad scores range from 0 (lowest quality) to 5 (highest quality). We also collected information on withdrawal and dropout rates and calculated the percentage of attrition by dividing the number of patients providing follow-up data by the number of patients initially enrolled. Of the medications we assessed, 3 had up-to-date existing meta-analyses (sibutramine, phentermine, and diethylpropion) and 4 others had a sufficient number of new studies to justify a new meta-analysis (orlistat, fluoxetine, bupropion, and topiramate). However, because heterogeneity was too great for the fluoxetine studies, they are summarized narratively. Selection of Trials for Meta-Analysis The outcome of interest was weight loss between baseline and follow-up. To make our analyses comparable, we stratified them in the same manner as did the recent meta-analysis on sibutramine (35). We defined data collected at 6 months to be data collected at any point between 16 and 24 weeks; likewise, 1-year follow-up data were those collected at any point between 44 and 54 weeks. If a study presented data for 2 or more time points in an interval, for example, 16 and 18 weeks, we chose the longest follow-up measurement for our analysis. Mean Difference For each trial, we extracted the follow-up mean weight loss for the control group, the follow-up mean weight loss for the medication group, and the standard deviation for each group. We then calculated a mean difference for each study, which was the difference between follow-up mean weight loss in the control group versus the medication group. Sensitivity Analyses We conducted sensitivity analyses on 4 study dimensions: Jadad quality score (2 vs. 3), year of publication (1998 or earlier vs. 1999 or later), completion rate (<80% vs. 80% and <70% vs. 70%), and dosage. We tested for differences between subgroups (for example, high-quality vs. lower-quality studies) by conducting a meta-regression analysis using a single dichotomous variable to indicate subgroup membership. We conducted sensitivity analyses to determine the possible impact of dropouts. In these analyses, we assumed that all patients who dropped out had a weight loss of zero. The mean weight loss for a particular study was then recalculated on the basis of the complete sample of both responders and dropouts. We assumed that the standard deviation of weight loss for a study did not change and recalculated the standard error on the basis of the complete sample size. We then conducted a pooled analysis for each medication and follow-up time as performed in the original approach. Meta-Analysis of Weight Loss For the 6-month and 12-month analyses, we estimated a pooled DerSimonianLaird random-effects estimate (36) of the overall mean difference. The mean differences in the individual trials are weighted by both within-study variation and between-study variation in this synthesis. We also report P values derived from the chi-square test of heterogeneity based on the Cochran Q-test (37), and the I2 statistic (38). This latter statistic represents the percentage of study variability that is due to heterogeneity rather than chance and is independent of the number of studies and the effect size metric. Publication Bias We assessed the possibility of publication bias by evaluating a funnel plot. We also conducted an adjusted rank correlation test (39) as a formal statistical test for publication bias. Extraction of Data on Adverse Events We assessed evidence of adverse events from randomized, controlled trials (RCTs) only. We did not include observational studies or case series data. Each trial included in the weight loss analysis was examined to determine whether it reported data on adverse events. Adverse events were recorded as the number of events or the number of people, depending on how the trial chose to report events. Most trials recorded the number of events rather than the number of unique people who experienced the event. Each event was counted as if it represented a unique individual. Because a single individual might have experienced more than 1 event, this assumption may have overestimated the number of people who had an adverse event. Meta-Analysis of Adverse Events For subgroups of events that occurred in 2 or more trials, at least once in the medication group and at least once in the control group, we performed a meta-analysis to estimate the pooled odds ratio and its associated 95% CI. Given that many of the events were rare, we used exact conditional inference to perform the pooling rather than applying the usual asymptotic methods that assume normality. For interpretability, for any significant pooled odds ratio greater than 1 (which indicates that the odds of the adverse

Meta-analysis: chronic disease self-management programs for older adults

Context Do self-management programs improve outcomes of adults with chronic conditions? Contribution This meta-analysis summarizes data from 53 randomized, controlled trials of self-management interventions for adults with diabetes mellitus, hypertension, or osteoarthritis. Self-management helped reduce hemoglobin A1c and blood pressure levels in diabetes and hypertension, respectively, but had minimal effect on pain and function in patients with arthritis. The authors could not identify any self-management program characteristics that predicted successful outcomes. Cautions The authors found evidence of possible publication bias. Implications Self-management programs may improve some outcomes in patients with some chronic diseases, but how to design an optimal program is not yet clear. The Editors Chronic diseases are conditions that are usually incurable. Although often not immediately life-threatening, they place substantial burdens on the health, economic status, and quality of life of individuals, families, and communities (1). In 1995, 79% of noninstitutionalized persons who were 70 years of age or older reported having at least 1 of 7 of the most common chronic conditions affecting this age group: arthritis, hypertension, heart disease, diabetes mellitus, respiratory disease, stroke, and cancer (1). Of these 7 conditions, arthritis is most prevalent, affecting more than 47% of individuals 65 years of age and older (2). Hypertension affects 41% of this population, and 31% of this group has some form of heart disease (of which ischemic heart disease and a history of myocardial infarction are major components). Diabetes mellitus affects approximately 10% of persons 65 years of age and older and increases the risk for other chronic conditions, including ischemic heart disease, renal disease, and visual impairment (2). Enthusiasm is growing for the role of self-management programs in controlling and preventing chronic disease complications (3-5). Despite this enthusiasm, experts do not agree on the definition of what constitutes a chronic disease self-management program, which elements of self-management programs are essential regardless of the clinical condition, or which elements are important for specific conditions. Several recent reviews on chronic disease self-management interventions have been published, including 2 Cochrane collaborations (6-13). Almost all have been disease-specific. One Cochrane review (12) concluded that there was insufficient evidence to assess the benefit of dietary treatment for type 2 diabetes mellitus programs, but exercise programs led to improved hemoglobin A1c values. A second Cochrane review of self-management for hypertension (11) used unpooled results to conclude that a reduction in the frequency of medication dosage increased adherence. There was not, however, consistent evidence of decreased blood pressure. Almost all previous reviews have been disease-specific or addressed specific intervention components within specific disease conditions (14-17). Two recent reviews assessed self-management programs across conditions. The first review provided a qualitative evaluation of self-management interventions across 3 conditions: type 2 diabetes mellitus, arthritis, and asthma (18). This review, which presented an overall optimistic assessment of self-management interventions, did not, however, include a quantitative synthesis of the data, nor did it address the issue of publication bias. The second review quantitatively assessed 71 trials (both randomized and nonrandomized) that included a self-management education program for patients with asthma, arthritis, diabetes mellitus, hypertension, and miscellaneous other conditions. Meta-analysis found statistically significant benefits for some outcomes within conditions. The authors could not detect meaningful differences in the effectiveness of the programs because of the varying intervention characteristics, such as the use of a formal syllabus, the type of program facilitator, the number of program sessions in which patients participated, and the duration of the program (19). In our review, we sought to quantitatively assess chronic disease self-management programs for older adults within and across disease conditions. We used empirical data from the literature to address 2 research questions: First, do chronic disease self-management programs result in improved disease-related outcomes for specific chronic diseases of high prevalence in older adults? Second, if self-management interventions are effective, are there specific components that are most responsible for the effect, within or across disease conditions? To address these questions, we focused on evaluating the effect of self-management programs for the 3 chronic conditions that have been most commonly studied in controlled trials of older adults: osteoarthritis, diabetes mellitus, and hypertension. Methods Conceptual Model Because there is no accepted definition of what constitutes a chronic disease self-management program, we used an intentionally broad definition to avoid prematurely excluding relevant studies. On the basis of a conceptual framework derived from the clinical literature and from discussions with social scientists with expertise in self-management, we defined chronic disease self-management as a systematic intervention that is targeted toward patients with chronic disease. The intervention should help them actively participate in either or both of the following: self-monitoring (of symptoms or of physiologic processes) or decision making (managing the disease or its impact through self-monitoring). We attempted to understand the characteristics particular to chronic disease self-management programs that may be most responsible for their effectiveness. On the basis of the literature and expert opinion, we postulated 5 hypotheses regarding the effectiveness of chronic disease self-management programs that feature the following characteristics: Tailoring. Patients who receive interventions tailored to their specific needs and circumstances are likely to derive more benefit than those receiving interventions that are generic. roup setting. Patients are more likely to benefit from interventions received within a group setting that includes others affected by the same condition than from an intervention provided in some other setting. Feedback. Patients are more likely to derive benefit from a cycle of intervention followed by some form of individual review with the provider of the intervention than from interventions where no such review exists. Psychological emphasis. Patients are more likely to derive benefit from a psychological intervention than from interventions where there is no psychological emphasis. Medical care. Patients who receive interventions directly from their medical providers (physicians or primary care providers) are more likely to derive benefit than those who receive interventions from nonmedical providers. Outcome Measures From the literature, we identified outcomes of interest to include the following: clinical outcomes, such as pain and function for osteoarthritis; measures that have strong links to clinical outcomes, such as hemoglobin A1c levels, fasting blood glucose levels, and patient weight for diabetes and blood pressure for hypertension; and intermediate outcomes, such as knowledge, feeling of self-efficacy, and health behaviors that are postulated to be related to clinical outcomes. Databases for Literature Search We used several databases and published documents to identify existing research and potentially relevant evidence for this report. For our primary source of citation information from 1980 until 1995, we used An Indexed Bibliography on Self-Management for People with Chronic Disease (20), published by the Center for Advancement of Health in association with the Group Health Cooperative of Puget Sound; we obtained any studies not listed in the bibliography (including those published later than 1995) by searching MEDLINE, PsycINFO, and CINAHL. We also used the Cochrane Library (its database of systematic reviews and the central register of controlled trials); the Assessment of Self-Care Manuals, published by the Evidence-based Practice Center at the Oregon Health Sciences University (21); and 77 other previously completed reviews relevant to this project. We retrieved all relevant documents referenced in these publications, and we updated our search in September 2004. Each review discussed at least 1 intervention aimed at chronic disease self-management. We also searched the Health Care Quality Improvement Projects database, maintained by the U.S. Centers for Medicare & Medicaid Services. This database contains reports known as narrative project documents, each of which describes an individual research project conducted by a Medicare Peer Review Organization; most projects in this database are not published elsewhere. Each report includes the projects background, aims, quality indicators, collaborators, sampling methods, interventions, measurement, and results. A complete description of our literature search has been reported elsewhere (22). Article Selection and Data Abstraction Two trained physician reviewers, working independently, conducted the article selection, quality assessment, and data abstraction; disagreements were resolved by consensus or third-party adjudication. Articles were not masked. We included all randomized trials that assessed the effects of an intervention or interventions relative to either a group that received usual care or a control group among the elderly and for our 3 conditions. Most studies compared their intervention with usual care or with a control intervention designed to account for the added attention received in the intervention (such as attending classes on vehicle safety instead of attending classes on self-management). Because our analysis was funded by the Centers for M

Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis

Context Sorting through the proven benefits and harms of the agents available for treating osteoporosis is difficult. Contribution This systematic review of 76 randomized trials and 24 meta-analyses found good evidence that multiple agents, including alendronate, zoledronic acid, and estrogen, prevented vertebral and hip fractures more than placebo. Harms included increased risk for thromboembolic events with raloxifene, estrogen, and estrogenprogestin and increased gastrointestinal symptoms with bisphosphonates. No large trials directly compared 2 or more agents and established superiority of any agent. Implication Available data insufficiently characterize the benefits and harms of various therapies for osteoporosis relative to one another. The Editors Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (1). Approximately 44 million people in the United States are affected by osteoporosis and low bone mass (2). The clinical complications include fractures, disability, and chronic pain. About 54% of women age 50 years or older will have an osteoporotic fracture during their lifetime (3). Furthermore, approximately 4% of patients older than 50 years of age who have a hip fracture die while in the hospital and 24% die within 1 year after the hip fracture (4). The economic burden of osteoporosis is large and growing. Most estimates are based on the cost of fracture alone: A 1995 estimate of costs incurred by osteoporotic fractures in the United States was

Spinal Manipulative Therapy for Low Back Pain: A Meta-Analysis of Effectiveness Relative to Other Therapies

13.8 billion (5). A 2003 review estimated the total costs in the United States at

Pregnancy and fertility following bariatric surgery: a systematic review.

17 billion (6). Although the bulk of these costs were incurred by retired individuals older than age 65 years, direct costs and work loss are significant among employed postmenopausal women (7). The increasing prevalence and cost of osteoporosis have heightened interest in the efficacy and safety of the many agents available to treat the loss of bone mineral associated with osteoporosis. This systematic review, developed under the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care Program, describes the benefits in fracture reduction and the harms from adverse events among and within the various classes of pharmacotherapies for osteoporosis. The agents evaluated were bisphosphonates (alendronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronic acid), calcitonin, estrogen, teriparatide, selective estrogen receptor modulators (raloxifene and tamoxifen), testosterone, and vitamins (vitamin D) and minerals (calcium). Methods We followed a standardized protocol for the review. The full technical report (8) provides detailed methods, evidence tables, and risk estimates for individual studies. The full report also enumerates studies included in the meta-analyses described in this review. Data Sources and Study Selection We searched MEDLINE (1966 to December 2006), the ACP Journal Club database, the Cochrane Central Register of Controlled Trials (no date limits), the Cochrane Database of Systematic Reviews (no date limits), and the Web sites of the National Institute for Health and Clinical Excellence (no date limits) and Health Technology Assessment Programme (January 1998 to December 2006) for materials pertaining to the specified agents, limiting our searches to English-language publications and human studies. We first identified systematic reviews and meta-analyses of trials that reported pooled estimates of the effect of the agents on fracture risk. When such reviews were identified for specific agents, we truncated our searches for randomized trials to include only those published after the last search date used in the review or meta-analysis. We manually searched reference lists of all review articles obtained for any reports of original research not already identified, and we reviewed U.S. Food and Drug Administration (FDA) medical and statistical reviews, scientific information packets from pharmaceutical companies, and additional studies recommended by our technical expert panel and by stakeholders during a public review period. To supplement the information in systematic reviews on estrogen, we reviewed the Womens Health Initiative and Heart and Estrogen/progestin Replacement Study trials, as suggested by our technical expert panel. Finally, we conducted an additional search for large observational studies that reported any of the following adverse events: 1) cardiovascular events (myocardial infarction and stroke); 2) thromboembolic events (pulmonary embolism and venous thromboembolic events); 3) malignant conditions (breast cancer, colon cancer, lung cancer, and osteosarcoma); 4) upper gastrointestinal events (perforations, ulcers, bleeding, and esophageal ulcerations); and 5) osteonecrosis. The search was updated for this paper, but not for the full report, by searching MEDLINE (1 January 2007 to 10 November 2007) for large clinical trials that reported fracture outcomes for the specified agents. For information on efficacy, we selected meta-analyses that reported pooled risk estimates for fracture and randomized trials that compared any of the agents with placebo or with each other and reported fracture outcomes. For information on harms, we selected systematic reviews, randomized trials, and large casecontrol or cohort studies with more than 1000 participants. We also reviewed cases of osteonecrosis at AHRQs request. Data Extraction and Study Quality Two physicians independently abstracted data about study populations, interventions, follow-up, and outcome ascertainment by using a structured form. For each group in a randomized trial, a statistician extracted the sample size and number of persons who reported fractures. Two reviewers, under the supervision of the statistician, independently abstracted information about adverse events. Disagreements were resolved by the statistician or the principal investigator. Adverse events were recorded onto a spreadsheet that identified numbers of participants in each trial group and the description of the adverse event as listed in the original article. Each event was counted as if it represented a unique individual. Because an individual may have experienced more than 1 event within a category of adverse events (for example, both stroke and myocardial infarction), this assumption may have overestimated the number of people who had an adverse event in that category. If a trial report mentioned a particular type of adverse event but did not report data on it, we did not include the trial in that particular events analysis. In other words, we did not assume an occurrence of zero events unless it was specifically reported as such. By taking this approach, we may have overestimated the number of patients for whom a particular adverse event was observed. We used predefined criteria to assess the quality of systematic reviews and randomized trials, based on internal and external validity assessment detailed in the QUOROM (Quality of Reporting of Meta-Analyses) statement (9), and items related to randomization, blinding, and accounting for withdrawals and dropouts (10, 11). Each element is detailed in appendices to the full report (8). For this review, we characterized the overall strength of evidence for estimating fracture risk as good, fair, or weak on the basis of the characteristics previously described, as well as the number of studies, total number of participants across studies, whether fractures were a primary outcome, reproducibility of results across studies, and precision of the CIs surrounding the point estimates. Evidence was classified as good if the total sample size was greater than 1000, the results across all studies were consistent, and the studies were of high methodological quality. Evidence was classified as fair if results were inconsistent across the studies. The evidence was classified as weak if no studies assessed fracture as a primary outcome, the total sample size across studies was less than 500, and the CIs around the point estimates were wide and crossed null. Data Synthesis and Statistical Analysis Comparisons of interest were single agent versus placebo and single agent versus another agent for agents within the same class and across classes. We also compared estrogenprogestin versus placebo or single drugs. Studies that included either calcium or vitamin D in all study groups were classified as comparisons between the other agents in each group; for example, alendronate plus calcium versus risedronate plus calcium would be classified as alendronate versus risedronate. In this review, we summarize data on vertebral, nonvertebral, and hip fractures; data on total, wrist, and humerus fractures are included in the full report (8). The number of people with at least 1 fracture was our primary outcome of interest. Because fractures rarely occurred and zero events were often observed in at least 1 treatment group, we calculated odds ratios (ORs) by using the Peto method (12). Trials with zero events in both groups have an undefined OR. Because fractures are rare events, the OR approximates the relative risk (RR) for fracture. We combined data from multiple study groups in an individual study to calculate a single OR for comparisons of interest. In these instances, the same outcome had been reported for each group, and the individuals in each group were unique. For example, to develop an OR for the risk for vertebral fractures regardless of dose, we combined the participants in the various dose groups and compared them with those in the placebo group. We conducted the meta-analysis by using StatXact PROCs (Cytel, Cambridge, Massachusetts) for SAS software (SAS Institute, Cary, North Carolina). Recognizing that characteristics of the study population may affect risk for fracture, we defined risk groups to categorize the

Efficacy and Comparative Effectiveness of Atypical Antipsychotic Medications for Off-Label Uses in Adults: A Systematic Review and Meta-analysis

Context The role of spinal manipulation in the treatment of low back pain remains controversial, possibly because previous summaries of the evidence have compared spinal manipulation with a combination of traditional therapies rather than with individual therapies. Contribution This meta-analysis of randomized clinical trials found that spinal manipulation was more effective than sham therapy but was no more or less effective than general practitioner care, analgesics, physical therapy, exercise, or back school. Implications While some patients with low back pain may prefer spinal manipulation to traditional therapies, there is no evidence that it achieves better outcomes than standard treatments. The Editors Low back pain is a disabling disorder that greatly affects western society; it is a burden for the individual patient and an additional cost for society because of loss of work and medical expenses (1, 2). Therefore, adequate treatment of low back pain is an important issue for patients, treating clinicians, and health care policymakers. Spinal manipulative therapy is widely used for low back pain. It has been studied in many randomized, controlled trials (RCTs), which are heterogeneous in size, design, and quality of performance. These trials have been summarized in numerous systematic reviews (3). The conclusions of systematic reviews (4-6), which provided input for national guidelines, are partially discordant. None of these reviews has included the larger high-quality trials that have been published over the past few years (7-16). Furthermore, all of these reviews and meta-analyses have considered the treatments to which spinal manipulative therapy is being compared as equivalent, meaning, for example, that no distinction was made among studies comparing spinal manipulative therapy with bed rest and studies comparing spinal manipulative therapy with physical therapy. Only two recent reviews (17, 18) compared spinal manipulative therapy with a homogeneous control group (sham treatment in both reviews). Spinal manipulation has a prominent role in all national guidelines on the management of back pain (19). However, the recommendations in these guidelines vary. In most countries, spinal manipulative therapy is recommended for acute low back pain. However, in the Netherlands, Australia, and Israel, the evidence is interpreted differently (19). Recommendations also vary for chronic low back pain; spinal manipulative therapy is recommended in the Danish and Dutch guidelines but is not recommended or is absent in the other national guidelines. Our goal in this review is to update, improve, and resolve inconsistencies in previous systematic reviews through collaboration with the Cochrane Back Review Group (20). We incorporate relevant clinical variables and combine them with meta-analytic techniques to estimate the effectiveness of spinal manipulative therapy relative to other commonly used therapies (21). By presenting the most current information on this complicated issue, we provide support for individual and collective treatment decisions. Methods Literature Search One reviewer searched the following computerized bibliographic databases without language restrictions (22, 23): MEDLINE from January 1966 to January 2000, EMBASE from January 1988 to January 2000, and CINAHL from January 1982 to January 2000. The highly sensitive Cochrane Collaboration search strategy, which aims to identify all randomized, controlled trials, was used (20, 24). The same reviewer also searched for systematic reviews on low back pain and spinal manipulation (25). Additional specific subject headings and free text words were used to identify papers on low back pain and spinal manipulation (20). The Cochrane Controlled Trial Register was searched (24). Finally, references from retrieved articles were screened. To determine whether a study should be included, the abstracts of all identified papers were assessed by the same reviewer who performed the computerized bibliographic search. If there was any doubt, the full article was retrieved and read independently by both reviewers. Disagreements were resolved by consensus. Literature Selection We included studies that met the following conditions: 1) adult patients with low back pain, regardless of radiation pattern; 2) comparison of manipulation or mobilization for low back pain with another treatment or control [manipulation differs from mobilization in that it focuses on a different range of motion of the involved joint; unless otherwise indicated, spinal manipulative therapy refers to both hands-on treatments in this review; co-interventions were allowed]; 3) at least one clinically relevant outcome measure (pain, global improvement, back painspecific functional status, or generic functional status) [26]; 4) follow-up of at least 1 day; 5) publication as a full report before January 2001. Quality Assessment Quality can be assessed by using different checklists or scales. We used the quality list from the Cochrane Back Review Group (20) to assess methodologic quality. This list contains items relevant to the description, internal validity, and statistical issues of the study (Table 1). Each criterion was rated as positive, negative, or inconclusive (insufficient information presented). Equal weights were applied, resulting in a total score for internal validity of each study, by adding the number of positive criteria (range, 0 to 10); higher scores indicated a lower likelihood of bias. In addition, we scored the list of Jadad and colleagues (27, 28). We used multiple criteria and scales because of the absence of a consensus on a gold standard for quality, especially for interventions such as spinal manipulative therapy, for which true double-blinding is not feasible. Table 1. Criteria for the Methodologic Assessment of Randomized Clinical Trials (Cochrane Back Review Group and Editorial Board Quality List) The articles were not blinded for authors, journal, or year of publication (27) because the two reviewers were familiar with most of the articles from their previous reviews. Included articles were independently assessed for methodologic quality by the two authors. Disagreements were discussed and resolved in a consensus meeting. Data Extraction Data were independently extracted by the two reviewers and checked for accuracy by two other authors. Statistical Analysis We briefly describe the analysis here. The Appendix describes the analysis in detail. We classified studies by the duration of back pain (acute, chronic, mixed, and unsure), presence of leg pain, profession of manipulator, comparison therapy, outcome measured, and follow-up time. Short-term follow-up was less than 6 weeks; for the meta-analysis, we chose the outcome measurement closest to 3 weeks. Long-term follow-up was more than 6 weeks; for the meta-analysis, we chose the outcome measurement closest to 6 months. For each study that had data available for each of the four outcomes (short-term pain, long-term pain, short-term function, and long-term function), we calculated the effect sizes of the changes in outcome between the reference spinal manipulative therapy group and all comparison therapy groups in the study. An effect size is the ratio of the difference in mean outcomes between the spinal manipulative therapy and comparison therapy groups divided by its standard deviation; it is a unitless measure of comparison for results reported by using different measurement scales (for example, pain measured by using a 100-mm visual analogue scale [VAS] or a 7-point pain rating scale). A positive effect size indicates that spinal manipulative therapy was beneficial, that is, function increased or pain decreased, as compared with the alternative therapy. For each outcome, we assessed the degree of heterogeneity in all effect sizes within each back pain stratum by use of a forest plot and chi-square test (29). Ideally, we would have liked to compare spinal manipulative therapy with each different therapy for each outcome within each back pain stratum, but this was not possible because the data were sparse. Therefore, we used available research evidence and the clinical judgment of similar effectiveness of the Editorial Board of the Cochrane Back Review Group to group the comparison therapies into the following clusters of presumed effectiveness: 1. Sham: Used to assess efficacy rather than effectiveness. 2. Conventional general practitioner care and analgesics: Although general practitioners may suggest other therapy for back pain in addition to prescribing medication, empirical evidence shows that 80% of initial visits to primary care providers for back pain result in an analgesic prescription (38); consequently, we considered these two categories sufficiently similar to pool. 3. Physical therapy and exercise: Both are considered to be activating therapies; in general, exercises are often a key component of physical therapy, making up 30%, 33%, and 100% of the treatment delivered in three studies of physical therapy for patients with low back pain (7-10, 39). 4. Traction, corset, bed rest, home care, topical gel, no treatment, diathermy, and minimal massage: Treatments that were considered to lack evidence of benefit or have evidence of harm (40). 5. Back school: Treatments that did not conceptually fit with any other group. For each outcome, we fit a random-effects meta-regression (33) model, in which effect size is the unit of observation, to compare the effect of spinal manipulative therapy with that of alternative therapies while controlling for other variables. The model contained indicator variables for the five alternative therapy clusters and main effects for duration of back pain (chronic, acute, mixed, or unsure). Although we also developed estimates for patients with mixed pain patterns and unsure, we do not present them because the number of studies was too small. We also fit a series of models with increas

Diagnosing and Managing Common Food Allergies: A Systematic Review

CONTEXT Use of bariatric surgery has increased dramatically during the past 10 years, particularly among women of reproductive age. OBJECTIVES To estimate bariatric surgery rates among women aged 18 to 45 years and to assess the published literature on pregnancy outcomes and fertility after surgery. EVIDENCE ACQUISITION Search of the Nationwide Inpatient Sample (1998-2005) and multiple electronic databases (Medline, EMBASE, Controlled Clinical Trials Register Database, and the Cochrane Database of Reviews of Effectiveness) to identify articles published between 1985 and February 2008 on bariatric surgery among women of reproductive age. Search terms included bariatric procedures, fertility, contraception, pregnancy, and nutritional deficiencies. Information was abstracted about study design, fertility, and nutritional, neonatal, and pregnancy outcomes after surgery. EVIDENCE SYNTHESIS Of 260 screened articles, 75 were included. Women aged 18 to 45 years accounted for 49% of all patients undergoing bariatric surgery (>50,000 cases annually for the 3 most recent years). Three matched cohort studies showed lower maternal complication rates after bariatric surgery than in obese women without bariatric surgery, or rates approaching those of nonobese controls. In 1 matched cohort study that compared maternal complication rates in women after laparoscopic adjustable gastric band surgery with obese women without surgery, rates of gestational diabetes (0% vs 22.1%, P < .05) and preeclampsia (0% vs 3.1%, P < .05) were lower in the bariatric surgery group. Findings were supported by 13 other bariatric cohort studies. Neonatal outcomes were similar or better after surgery compared with obese women without laparoscopic adjustable gastric band surgery (7.7% vs 7.1% for premature delivery; 7.7% vs 10.6% for low birth weight, P < .05; 7.7% vs 14.6% for macrosomia, P < .05). No differences in neonatal outcomes were found after gastric bypass compared with nonobese controls (26.3%-26.9% vs 22.4%-20.2% for premature delivery, P = not reported [1 study] and P = .43 [1 study]; 7.7% vs 9.0% for low birth weight, P = not reported [1 study]; and 0% vs 2.6%-4.3% for macrosomia, P = not reported [1 study] and P = .28 [1 study]). Findings were supported by 10 other studies. Studies regarding nutrition, fertility, cesarean delivery, and contraception were limited. CONCLUSION Rates of many adverse maternal and neonatal outcomes may be lower in women who become pregnant after having had bariatric surgery compared with rates in pregnant women who are obese; however, further data are needed from rigorously designed studies.

Prevalence of Symptoms of Bladder Pain Syndrome/Interstitial Cystitis Among Adult Females in the United States

CONTEXT Atypical antipsychotic medications are commonly used for off-label conditions such as agitation in dementia, anxiety, and obsessive-compulsive disorder. OBJECTIVE To perform a systematic review on the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration. DATA SOURCES AND STUDY SELECTION Relevant studies published in the English language were identified by searches of 6 databases (PubMed, EMBASE, CINAHL, PsycInfo, Cochrane DARE, and CENTRAL) from inception through May 2011. Controlled trials comparing an atypical antipsychotic medication (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included. Observational studies with sample sizes of greater than 1000 patients were included to assess adverse events. DATA EXTRACTION Independent article review and study quality assessment by 2 investigators. DATA SYNTHESIS Of 12 228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms. CONCLUSIONS Benefits and harms vary among atypical antipsychotic medications for off-label use. For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common.