Richard A. Hansen

The burden of gastrointestinal and liver diseases, 2006.

BACKGROUND:Digestive and liver diseases are a source of significant morbidity, mortality, and health-care costs for the U.S. population. An annual report of the toll of these diseases could be helpful to clinicians, policymakers, and researchers.AIM:To describe the epidemiology of gastrointestinal and liver diseases in the United States using data from privately and publicly held databases.METHODS:We collected data from the National Center for Health Statistics, the National Ambulatory Medical Care Survey, the National Inpatient Sample, the Centers for Disease Control and Prevention, and the National Cancer Institute, as well as proprietary pharmaceutical databases to construct a report on the impact of gastrointestinal and liver diseases on the U.S. population. We compiled information on causes of death, hospitalization, clinic visits, cancer incidence, and mortality and infectious disease incidence from these databases, and extracted data specific to gastrointestinal diseases. Because of the high costs associated with medications used to treat gastrointestinal diseases, we also include in this years report a special section on pharmacoepidemiology and pharmacoeconomics.RESULTS:Colorectal cancer continues to be the leading cause of GI-related death, although the data indicate a downward trend in deaths. Abdominal pain, diarrhea, vomiting, and nausea are the most common GI symptoms precipitating a visit to the physician, and GERD is the most common GI-related diagnosis given in office visits. Chest pain not specified to be cardiac in origin is the most common cause of inpatient admission possibly related to GI disease, with cholelithiasis and pancreatitis following. Americans spend in excess of

Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis

10 billion/yr on proton pump inhibitors (PPIs), and two of the top five selling drugs in the United States are PPIs. Trends in PPI use demonstrate turbulent changes, likely reflecting both new drug entries into the field, as well as drug marketing. The number of PPI prescriptions/yr in the United States has doubled since 1999. Twenty-three drugs used for gastrointestinal diseases are among the top 200 generic drugs used in the United States.CONCLUSIONS:Gastrointestinal and liver diseases are significant contributors to the morbidity, mortality, and health-care expenditures of the U.S. population.

Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder

Context Which disease-modifying antirheumatic drugs (DMARDs) best reduce symptoms, improve function, and prevent radiographic progression in patients with rheumatoid arthritis? Contribution This systematic review of trials that compared DMARDs in adults with rheumatoid arthritis found few direct comparisons of different agents but no important differences among synthetic DMARDs or antitumor necrosis factor drugs. Combination therapy improved response rates and functional outcomes in patients whose monotherapy failed. Numbers and types of short-term adverse events were similar among DMARDs. Implication Of several monotherapies for adults with rheumatoid arthritis, no regimen is clearly superior. Combination therapies improve response rates in some patients previously receiving monotherapy. The Editors Rheumatoid arthritis is an autoimmune disease that affects more than 2 million adults in the United States. Disease onset generally occurs between 30 and 55 years of age, and women are affected more often than men. Disease hallmarks are inflammation of the synovium, progressive bone erosion, joint malalignment and destruction, and subsequent weakness of surrounding tissues and muscles. Presentations range from mild to severe, although the typical patient has a progressive course leading to functional limitations. Treatment aims at controlling pain and inflammation and slowing or arresting the progression of joint destruction. Therapies generally used in the United States include corticosteroids; synthetic disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine; and biological DMARDs, such as abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab. The American College of Rheumatology (ACR) recommends beginning DMARD therapy within 3 months of diagnosis (1). Often, treatment with a single DMARD does not adequately control symptoms, leading clinicians to consider various combination strategies. Experts do not agree about the comparative benefits of different combination therapies. Many questions remain about the risks of these agents across a spectrum of adverse events from relatively minor side effects to severe and possibly life-threatening problems. Given this uncertainty, the Agency for Healthcare Research and Quality (AHRQ) commissioned a systematic review to compare the benefits and safety of rheumatoid arthritis drugs (2). Methods We developed and followed a standardized protocol for all steps of the review. The full technical report (2) describes study methods in detail and gives evidence tables of individual studies. Literature Search We searched MEDLINE, EMBASE, The Cochrane Library, and the International Pharmaceutical Abstracts for studies from 1980 to September 2007. Search terms included Medical Subject Headings or keywords when appropriate. We combined terms for rheumatoid arthritis with 11 drugs of interest (corticosteroid, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, etanercept, infliximab, adalimumab, abatacept, anakinra, and rituximab). We limited electronic searches to studies involving adults and humans and studies in English. We manually searched reference lists of review articles and letters to the editor. In addition, we searched the Center for Drug Evaluation and Research database (September 2007) to identify unpublished research submitted to the U.S. Food and Drug Administration. In early to mid-2006, the Oregon Scientific Resource Center invited pharmaceutical manufacturers to submit dossiers on all published and unpublished studies on a specific drug. Five companies (Abbott, Amgen, Bristol-Myers Squibb, Centocor, and Genentech) provided dossiers. Study Selection Two persons, each blinded to the others results, independently reviewed titles, abstracts, and sometimes full text to identify studies meeting preestablished criteria. To assess efficacy regarding symptoms, quality of life, functional capacity, and radiographic progression, we included head-to-head controlled trials and prospective cohort studies comparing any of the therapies. For harms (specific adverse events, rates of adverse events, and discontinuation attributable to adverse events) and subgroups, we also examined data from retrospective observational studies and placebo-controlled trials. For efficacy and harm data, we selected studies with 100 or more participants and at least 12 weeks of follow-up. Finally, if we found no evidence about efficacy from direct head-to-head comparison studies, we included evidence from fair- or good-quality meta-analyses that indirectly compared placebo-controlled trial data across drugs. Data Abstraction and Quality Assessment Trained reviewers abstracted each study by using a Web-based system (SRS 4.0, TrialStat, Ottawa, Ontario, Canada). A senior reviewer read each abstracted article and evaluated completeness of data extraction. We recorded intention-to-treat results if available. We assessed the internal validity (quality) of trials on the basis of predefined criteria from the U.S. Preventive Services Task Force (rating of good, fair, or poor) (3) and the National Health Service Centre for Reviews and Dissemination (4). Elements of internal validity for trials included randomization, allocation concealment, similarity of compared groups at baseline, intention-to-treat analysis, and overall and differential loss to follow-up. To assess the quality of observational studies, we used criteria outlined by Deeks and colleagues (5). Items assessed included sample selection, adjustment for confounders, methods of outcomes assessment, length of follow-up, and statistical analysis. Data Synthesis We primarily synthesized the literature qualitatively; we reported some quantitative syntheses from fair- to good-quality meta-analyses. Drug comparisons that were not quantitatively analyzed in meta-analyses had insufficient data or noncomparable study samples and did not merit additional quantitative analyses. We examined data within 3 main drug classes (corticosteroids, synthetic DMARDs, and biological DMARDs) and between drug classes and combination therapies. Strength of Evidence Ratings We rated the strength of the available evidence in a 3-part hierarchy (high, moderate, and low) (2) based on a modified Grading of Recommendations, Assessment, Development, and Evaluation approach (6, 7). Grades reflect the strength of evidence for a given comparison with respect to specific outcomes, such as 20% improvement in ACR response criteria (ACR 20), radiographic changes, or adverse events. Role of the Funding Source Agency for Healthcare Research and Quality staff participated in formulating initial study questions and reviewed methods, data analysis, and the draft report. The funding source did not participate in the literature search, determination of study eligibility, or evaluation of individual studies. Results Characteristics of Reviewed Studies We identified 2395 citations (Figure). Working from 635 articles retrieved for full review, we included 143 published articles reporting on 101 studies (Table 1). Of the 101 included studies, 49 (48.5%) were supported by pharmaceutical companies, 20 (19.8%) by governmental or independent funds, and 11 (10.9%) by a combination of pharmaceutical and governmental funding. We could not determine the source of support for 21 (20.8%) studies. Table 1. Summary of Head-to-Head Reviewed Studies, by Drug Comparison* Figure. Study flow diagram. Numbers of included articles and included studies differ because some studies have multiple publications. RCT = randomized, controlled trial. Comparative Effectiveness and Harms We found few fair- or good-quality head-to-head trials for each drug comparison (Table 1). Most trials were efficacy trials in highly selected populations with few comorbid conditions. Most trials used ACR 20, disease activity scores to measure clinical improvement, and Sharp or Sharpvan der Heijde scores to measure radiologic progression of the disease. Trials examining quality of life used the Health Assessment Questionnaire (HAQ) or Medical Outcomes Study Short Form 36 (SF-36). Table 2 summarizes results. Table 2. Summary of Comparative Findings on Efficacy and Harms of Rheumatoid Arthritis Drugs Monotherapy versus Monotherapy Synthetic DMARDs One good systematic review that included a meta-analysis of 2 trials suggested that more patients receiving methotrexate achieved ACR 20 at 1 year than did patients receiving leflunomide (odds ratio, 1.43 [95% CI, 1.15 to 1.77]). The ACR 20 benefit was lower and more uncertain at 2 years (odds ratio, 1.28 [CI, 0.98 to 1.67]) (8). However, patients receiving methotrexate showed less improvement in health-related quality of life than did patients receiving leflunomide (odds ratio for SF-36 physical component, 3.00 [CI, 5.41 to 0.59]). Radiographic outcomes over 2 years seemed similar. For leflunomide versus sulfasalazine, data are limited to 1 trial (9) involving 358 participants with 2-year follow-up (10, 11). Leflunomide yielded more patients achieving ACR 20, ACR 50, and greater improvement in functional capacity (ACR 20, 82% vs. 60% [P= 0.008]; ACR 50, 52% vs. 25% [P= 0.040]; HAQ, 0.50 vs. 0.29 [P 0.030]). Radiographic changes were similar for the 2 drugs (Larsen score change at 2 years, 0.010 for either drug) (9). Three trials involving 479 participants and lasting up to 52 weeks compared methotrexate with sulfasalazine and found similar response rates in ACR 20, disease activity scores, or functional capacity (1214). Two trials included patients with disease for longer than 1 year and used a lower dose of weekly methotrexate (7.5 mg) than that generally used in the United States (13, 14). The overall attrition rate for these studies ranged from 19% to 28.5%. We found no statistically significant differences in frequency of serious adverse events for leflunomide, methotrexate, and sulfasalazine in 3 efficacy trial

Comparison of Methods to Assess Medication Adherence and Classify Nonadherence

Context The relative benefits and harms of newer, second-generation antidepressants are sometimes confusing. Contribution In this review of 46 head-to-head randomized trials, the authors generally found no major differences in the numbers of adults with major depression who responded to second-generation antidepressants, such as selective serotonin reuptake inhibitors, bupropion, duloxetine, mirtazapine, and venlafaxine. The overall incidence of adverse events appeared similar across drugs, although types of adverse events varied. Cautions Trials were funded by industry and had variable quality and follow-up duration. Implications Second-generation antidepressants generally have similar benefits but different possible harms for adults with major depression. The Editors Major depressive disorder is a serious disabling illness that affects more than 16% of adults in the United States at some point in their lifetime (1). In 2000, the economic burden of depressive disorders in the United States was estimated to be

Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians.

83.1 billion (2). Current practice guidelines for the treatment of major depressive disorder recommend pharmacotherapy, psychotherapy, psychotherapy plus pharmacotherapy, or electroconvulsive therapy. In most cases, pharmacotherapy is first-line treatment for major depressive disorder. Moreover, it is a practical tool for primary care physicians, who prescribe the majority of antidepressants in the United States (3). Pharmacologic treatment for major depressive disorder includes first-generation antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) and second-generation antidepressants. Second-generation medications include selective serotonin reuptake inhibitors (SSRIs); selective norepinephrine reuptake inhibitors; and other drugs that selectively affect the activity of neurotransmitters, such as serotonin, norepinephrine, and dopamine. In general, the efficacy of first- and second-generation antidepressant medications is similar (4-6). However, first-generation antidepressants often cause multiple side effects that many patients find intolerable (7-9), and the risk for harm when taken in overdose or in combination with certain medications is high. Because of their relatively favorable side effect profile, the second-generation antidepressants play a prominent role in the management of patients with major depressive disorder. Reviews have compared the efficacy and tolerability of newer second-generation antidepressants with those of placebo or older treatments (6, 10, 11) but did not evaluate comparative evidence for second-generation antidepressants. We therefore sought to systematically evaluate comparative data on the efficacy, effectiveness, and tolerability of commonly prescribed second-generation antidepressants. Specifically, we conducted a systematic review and meta-analysis of comparative evidence for 6 SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) and 4 other second-generation antidepressants (bupropion, duloxetine, mirtazapine, and venlafaxine). From here on, we refer to these agents collectively as antidepressants. We examine the role of these agents in the initial treatment of ambulatory adult patients with major depressive disorder. Methods Key Questions Key questions designed to address the comparative efficacy, effectiveness, safety, and tolerability of antidepressants guided our research. A consortium of 12 state Medicaid programs, the Canadian Coordinating Office for Health Technology Assessment, the California HealthCare Foundation, and key experts formulated the questions and provided funding for this research. Literature Search To identify articles relevant to each key question, we searched MEDLINE, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts. To capture articles relevant to the scope of our topic, our searches covered 1980 through 28 February 2005. We manually searched reference lists of relevant review articles and letters to the editor. Pharmaceutical manufacturers were invited to submit dossiers, including citations, as outlined by the Drug Effectiveness Review Project (12). We requested unpublished studies from the U.S. Food and Drug Administration, but this agency did not release unpublished data. Study Selection Two persons independently reviewed titles and abstracts. If both reviewers agreed that a trial did not meet preestablished eligibility criteria (Appendix Table), we excluded it. To assess efficacy and effectiveness, we included head-to-head trials comparing one antidepressant with another. We defined effectiveness trials as those that were conducted in primary care settings, had an adequate duration of follow-up (3 months), had minimal inclusion and exclusion criteria (so that participants represented the general population), assessed health outcomes rather than intermediate outcomes, and had an adequate sample size to determine a minimally important difference (from a patients perspective) on a health-related quality of life instrument (13). To assess safety and tolerability, we included head-to-head trials, placebo-controlled trials, and observational studies with large samples (>100 patients) lasting at least 1 year. We required a larger sample size for observational studies because we wanted primarily to detect adverse events that were not frequent enough to be apparent in smaller trials. Data Abstraction and Quality Assessment Trained reviewers abstracted data from each study, and a senior reviewer read each abstracted article and evaluated completeness of data extraction. We recorded intention-to-treat results if they were available. We assessed the internal validity (quality) of trials by using predefined criteria from the U.S. Preventive Services Task Force (ratings of good, fair, or poor) (14) and the National Health Service Centre for Reviews and Dissemination (15). Elements of internal validity assessment included randomization, allocation concealment, similarity of compared groups at baseline, use of intention-to-treat analysis, and overall and differential loss to follow-up. We defined loss to follow-up as the number of persons who underwent randomization but did not complete the study (16), independent of the reason and whether intention-to-treat analysis was used. We rated studies as poor if they had more than 40% overall loss to follow-up or more than 15 percentage points of differential loss to follow-up between study groups. Data Synthesis We first qualitatively summarized the studies. When more than 3 head-to-head trials compared the same treatments, we did quantitative analyses. In these, the primary outcome measure was treatment response, defined as 50% or greater improvement on the Hamilton Rating Scale for Depression (HAM-D) or the MontgomeryAsberg Depression Rating Scale from baseline to study end. The relative benefit reflects the ratio of benefits or risks in one treatment group compared with another. When treatment effects differed between studies, we explored potential reasons for these differences. For each meta-analysis, we tested for heterogeneity of treatment effects by using I2 statistics. If no heterogeneity was detected, we applied both a random-effects and a fixed-effects model. We report the results of the more conservative random-effects models (17) because the validity of tests of heterogeneity can be limited with a small number of component studies. To estimate possible publication bias caused by the tendency of published studies to be positive, we used funnel plots, the Begg adjusted rank correlation test (18), and the Egger regression approach (19). However, because these tests have low statistical power when the number of trials is small (20), undetected bias may still be present. All statistical analyses were conducted by using StatsDirect Statistical Software, version 2.3.8 (StatsDirect, Ltd., Sale, United Kingdom). We calculated the mean incidence and 95% CIs for specific adverse events reported in included trials. Because assessment and reporting of adverse events varied greatly among trials, this evidence should be interpreted with caution. Role of the Funding Sources The funding sources contributed to the development of the key questions but had no role in the conduct or reporting of the study or in the decision to submit the manuscript for publication. Results We found 820 unduplicated citations. Manual review of the reference lists of pertinent review articles produced another 74 articles. Although 6 pharmaceutical companies submitted dossiers, no included studies stemmed from the dossiers. Therefore, 894 citations were included in our database (Appendix Figure). Forty-six randomized, controlled trials compared the effectiveness or efficacy of one SSRI or other antidepressant with that of another in the treatment of major depressive disorder (Tables 1 and 2). (Complete evidence tables are available at www.ohsu.edu/drugeffectiveness/reports/final.cfm or from the authors.) Most studies were efficacy trials and received a rating of fair for internal validity; some trials rated fair may have fulfilled all quality criteria but did not report methods to an extent that answered all of our questions. We considered 2 trials from Europe (21, 22) and 1 trial from the United States (23) conducted in primary care settings to be effectiveness trials. Sixty percent of included trials were less than 12 weeks in duration. The samples consisted mostly of persons younger than 60 years of age; samples consisted of persons 60 years of age or older in 6 trials (13%) and children or adolescents younger than 18 years of age in 3 trials (7%). Although sponsorship did not influence our quality rating, it may have influenced reporting. About 85% of trials in our review were sponsored by a pharmaceutical company, and an additional 11% had at least 1 author affiliated with a pharmaceutical company. The remaining 4% of included studies

Comparative risk for harms of second-generation antidepressants : a systematic review and meta-analysis.

Background: Medication adherence is suboptimal, and clinicians and researchers struggle with identifying nonadherent patients. Various measures of medication adherence exist, but there is controversy regarding which measures provide acceptable data and how nonadherence should be defined. Objective: To assess agreement among patient self-report, pharmacy refill, and electronic adherence measures and compare the sensitivity and specificity of different cut-points for defining nonadherence. Methods: Data were analyzed from 2 similarly designed randomized controlled trials that assessed a pharmacists intervention to improve medication adherence among patients with hypertension or heart failure. For each participant, adherence was measured by patient self-report, prescription refill records, and electronic lids on medication containers. Agreement among measures was assessed using Spearmans correlation coefficient rho. Correlation coefficients were compared by patient characteristics using Fishers Z transformation, The sensitivity and specificity of different cut-points for defining nonadherence were calculated. Results: Median adherence was 84% for self-report, 86% for electronic, and 91% for prescription refill adherence measurement. Refill and electronic adherence demonstrated the best agreement among measures (rho = 0.48). Age, depression, and other comorbid conditions influenced agreement among measures. Measures were generally in agreement, regardless of how nonadherence was defined. A cut-point of 80% illustrated a fair balance between sensitivity and specificity for all measures. Conclusions: All measures provided similar estimates of overall adherence, although refill and electronic measures were in highest agreement. In selection of a measure, practitioners should consider population and disease characteristics, since measurement agreement could be influenced by these and other factors. The commonly used, clinically based cut-point of 80% had a reasonable balance between sensitivity and specificity in studies of adherence in patients with heart failure or hypertension.

Efficacy and Safety of Inhaled Corticosteroids in Patients With COPD: A Systematic Review and Meta-Analysis of Health Outcomes

Major depressive disorder (MDD) is the most prevalent axis I disorder, affecting more than 16% of U.S. adults during their lifetime (1). In 2000, the economic burden of depressive disorders was an estimated

Meta-analysis of Major Depressive Disorder Relapse and Recurrence With Second-Generation Antidepressants

83.1 billion (2), more than 30% of which was attributable to direct medical expenses. Pharmacotherapy dominates the medical management of MDD. Since the mid-1980s, second-generation antidepressants have gradually replaced tricyclic antidepressants and monoamine oxidase inhibitors as first-line medications, primarily because of their lower toxicity in overdose and similar general efficacy (3). These newer treatments include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, and other second-generation drugs (Table 1). Table 1. Second-Generation Antidepressants Approved for Use in the United States To date, only 2 systematic reviews have assessed the comparative efficacy and harms of second-generation antidepressants (3, 4). These studies reported no substantial differences in efficacy or harms among agents. However, because of a lack of direct head-to-head comparisons, assessments in both studies were primarily qualitative. Consequently, uncertainties persist about the differences among the drugs for which sufficient head-to-head evidence is lacking. We systematically assessed evidence on the comparative benefits and harms of second-generation antidepressants for the acute, continuation, and maintenance phases of treatment of MDD; subsyndromal depression; and dysthymia and the comparative efficacy and effectiveness for such accompanying symptoms as anxiety, insomnia, or neurovegetative symptoms. We also sought to determine whether efficacy, effectiveness, and harms differed among subgroups of patients on the basis of age, sex, race or ethnicity, or comorbid conditions. To our knowledge, this is the first meta-analysis of second-generation antidepressants to assess quantitatively all possible comparisons among drugs in this class. We update findings of an earlier report on these pharmaceuticals (5) for the Agency for Healthcare Research and Quality. Methods An open process (described at www.effectivehealthcare.ahrq.gov) involving the public, the Agency for Healthcare Research and Qualitys Scientific Resource Center for Effective Health Care program, and various stakeholder groups produced key questions. We followed a standardized protocol for all review steps (5). Data Sources We searched MEDLINE, EMBASE, PsychLit, Cochrane Central Register of Controlled Trials, and International Pharmaceutical Abstracts from 1980 to April 2007. We used Medical Subject Heading terms when available and keywords when appropriate. We combined terms for depressive disorders with a list of 12 specific second-generation antidepressantsbupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, and venlafaxineand their specific trade names. We limited electronic searches to adult 19 + years, human, and English language. We manually searched reference lists of pertinent review articles and letters to the editor and used the Center for Drug Evaluation and Research database (up to April 2007) to identify unpublished research submitted to the U.S. Food and Drug Administration. The Scientific Resource Center invited pharmaceutical manufacturers to submit dossiers on completed research for each drug. We received dossiers from 3 pharmaceutical companies (Eli Lilly and Company, Indianapolis, Indiana; GlaxoSmithKline, Philadelphia, Pennsylvania; and Wyeth, Madison, New Jersey). Study Selection Two persons independently reviewed abstracts and relevant full-text articles. To assess efficacy or effectiveness regarding response, speed of onset, remission, maintenance of remission, and quality of life, we included head-to-head controlled trials of at least 6 weeks duration that compared 1 drug with another. Because head-to-head evidence was lacking for many comparisons, we included placebo-controlled trials for indirect comparison models. To assess harms (specific adverse events, rates of adverse events, and discontinuations attributable to adverse events), we also examined data from observational studies with at least 100 participants and follow-up of at least 12 weeks. To assess differences of benefits and harms in subgroups and patients with accompanying symptoms, we reviewed both head-to-head and placebo-controlled trials. We included meta-analyses if we found them to be relevant for a key question and of good or fair methodological quality (6). If both reviewers agreed that a study did not meet eligibility criteria, we excluded it. We also excluded studies that met eligibility criteria but were reported only as an abstract. Investigators resolved disagreements about inclusion or exclusion by consensus or by involving a third reviewer. Data Extraction and Quality Assessment We used a structured, Web-based data abstraction form (SRS 4.0, TrialStat, Ottawa, Ontario, Canada) onto which trained reviewers abstracted data from each study and assigned an initial quality rating. A senior reviewer read each abstracted article, evaluated completeness of data abstraction, and confirmed the quality rating. Investigators resolved disagreements by discussion and consensus or by consulting an independent party. We assessed the internal validity (quality) of trials on the basis of predefined criteria and applied ratings of good, fair, or poor (5, 7, 8). Primary elements of quality assessment included randomization and allocation concealment, similarity of compared groups at baseline, blinding, use of intention-to-treat analysis, and overall and differential loss to follow-up. To assess observational studies, we used criteria involving selection of case patients or cohorts and control participants, adjustment for confounders, methods of outcomes assessment, length of follow-up, and statistical analysis (9). We rated studies with a fatal flaw in 1 or more categories as poor quality (Appendix Table 1) and did not include them in our analyses for this review unless no other head-to-head evidence was available. To identify effectiveness studies, we used a tool that distinguishes efficacy trials from effectiveness studies on the basis of certain elements of study design (10). Such studies have greater generalizability of results than efficacy trials because they enroll less selected study populations, use treatment modalities that mimic clinical practice, and assess health outcomes along with adverse events. Lacking clear definitions about the equivalence of dosages among second-generation antidepressants in the published literature, we developed a roster of low, medium, and high dosages for each drug based on the interquartile dosing range (5). We used this roster, which does not indicate dosing equivalence, to detect gross inequalities in dosing that could affect comparative efficacy and effectiveness. Appendix Table 1. Characteristics of Studies with Poor Internal Validity Data Synthesis If data were sufficient, we conducted meta-analyses of head-to-head comparisons. Efficacy outcomes included the relative benefit of achieving response (more than 50% improvement from baseline), which reflects the ratio of benefits in one treatment group to benefits in another, and the weighted mean difference of changes on the Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale. For each meta-analysis, we conducted a test of heterogeneity (I 2 index) and applied both random- and fixed-effects models. We report the random-effects results because the results from both models were very similar in all meta-analyses. We assessed publication bias by using funnel plots and the Begg adjusted rank correlation test (11) based on the Kendall coefficient. Because no head-to-head evidence was available for the majority of drug comparisons, we conducted adjusted indirect comparisons (5). We employed meta-regressions of placebo-controlled trials by using individual drugs as covariates. When the number of trials was insufficient for meta-regressions, we used modified network meta-analysis (12). Evidence suggests that indirect comparisons agree with head-to-head trials if component studies are similar and treatment effects are expected to be consistent in patients included in different trials (13), although these assumptions are usually not verifiable. All statistical analyses used StatsDirect Statistical Software program, version 2.3.8 (StatsDirect, Sale, United Kingdom); Stata, version 9.1 (StataCorp, College Station, Texas); and SAS, version 9.1 (SAS Institute, Cary, North Carolina). Rating the Strength of Evidence We rated the strength of the available evidence for specific key questions and outcomes in a 3-part hierarchy (high, moderate, and low) (5) by using a modified GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach (14, 15) that incorporates 4 key elements: study design, study quality, consistency of results, and directness (availability of data on outcomes or populations of interest). Role of Funding Source The Agency for Healthcare Research and Quality participated in formulating the key questions and reviewed and commented on planned methods and data analysis. The Agency had no role in study selection, quality ratings, or interpretation and synthesis of the evidence, although staff reviewed interim and final evidence reports and distributed them for external peer review by outside experts. Results We identified 2318 citations from searches and reviews of reference lists (Figure 1). Of the 203 included studies (Appendix Tables 2 to 11), 140 (69.0%) were financially supported by pharmaceutical companies and 19 (9.3%) by governmental agencies or independent funds. For 44 (21.7%) studies, we could not determine the funding source. Figure 1. Study f

Functional outcomes of drug treatment in Alzheimer's disease: A systematic review and meta-analysis.

Background: Evidence indicates that only minor differences in efficacy exist among second-generation antidepressants for the treatment of major depressive disorder (MDD). However, a comprehensive assessment of both benefits and harms is crucial to evaluate the net benefit.Objective: To review systematically the comparative harms of second-generation antidepressants for the treatment of MDD in adults by including both experimental and observational evidence.Data sources: We searched MEDLINE®, EMBASE, PsychLit, The Cochrane Library and the International Pharmaceutical Abstracts from 1980 to April 2007. We manually searched reference lists of pertinent review articles and explored the Center for Drug Evaluation and Research database to identify unpublished research.Study selection: Eligible study designs were trials and observational studies comparing one drug of interest with another.Data extraction: Two persons independently reviewed abstracts and full-text articles. One investigator extracted relevant data. A senior reviewer checked data for completeness and accuracy.Data synthesis: We included 104 experimental and observational studies. If data were sufficient, we conducted meta-analyses of randomized controlled trials on the relative risk of specific adverse events. Findings indicate that the spectrum of adverse events is similar. The frequency of specific adverse events, however, differed across drugs. Venlafaxine was associated with a significantly higher rate of nausea and vomiting than selective serotonin reuptake inhibitors. Compared with other drugs, paroxetine frequently led to more sexual adverse effects and bupropion to fewer such effects; mirtazapine and paroxetine was associated with more weight gain and sertraline with a higher rate of diarrhoea. Overall, however, these differences did not lead to different discontinuation rates. The evidence is insufficient to draw conclusions about rare but severe adverse events.Conclusions: Adverse event profiles are similar among second-generation antidepressants. However, different frequencies of specific adverse events might be clinically relevant and influence the choice of a treatment.

Biologics for the treatment of juvenile idiopathic arthritis: a systematic review and critical analysis of the evidence

PURPOSE We wanted to review systematically the efficacy, effectiveness, and safety of inhaled corticosteroids with respect to health outcomes in patients with chronic obstructive pulmonary disease (COPD). METHODS We searched MEDLINE, EMBASE, The Cochrane Library, and the International Pharmaceutical Abstracts to identify relevant articles. We limited evidence to double-blinded randomized controlled trials (RCTs) for efficacy, but we also reviewed observational evidence for safety. Outcomes of interest were overall mortality, exacerbations, quality of life, functional capacity, and respiratory tract symptoms. When possible, we pooled data to estimate summary effects for each outcome. RESULTS Thirteen double-blinded RCTs determined the efficacy of an inhaled corticosteroid compared with placebo; 11 additional studies assessed the safety of inhaled corticosteroid treatment in patients with asthma or COPD. Overall, COPD patients treated with inhaled corticosteroids experienced significantly fewer exacerbations than patients taking placebo (relative risk [RR] = 0.67; 95% CI, 0.59–0.77). No significant difference could be detected for overall mortality (RR = 0.81; 95% CI, 0.60–1.08). Evidence on quality of life, functional capacity, and respiratory tract symptoms is mixed. Adverse events were generally tolerable; pooled discontinuation rates did not differ significantly between inhaled corticosteroid and placebo treatment groups (RR = 0.92; 95% CI, 0.74–1.14). Observational evidence, however, indicates a dose-related risk of cataract and open-angle glaucoma. Severe adverse events, such as osteoporotic fractures, are rare; the clinical importance of the additional risk is questionable. CONCLUSIONS Overall, the risk-benefit ratio appears to favor inhaled corticosteroid treatment in patients with moderate to severe COPD. Existing evidence does not indicate a treatment benefit for patients with mild COPD.