Patricia Thieda

A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention.

This systematic review focuses on outcomes of gestational weight gain, specifically birthweight, fetal growth, and postpartum weight retention, for singleton pregnancies with respect to the 1990 Institute of Medicine weight gain recommendations. A total of 35 studies met the inclusion criteria and were reviewed. There was strong evidence to support associations between excessive gestational weight gain and increased birthweight and fetal growth (large for gestational age) as well as inadequate gestational weight gain and decreased birthweight and fetal growth (small for gestational age). There was moderate evidence to support the association between excessive gestational weight gain and postpartum weight retention. Clear clinical recommendations based on this review are challenging because of several limitations in the literature. Improvements in future research include the use of consistent definitions of gestational weight gain and outcomes of interest, assessment of confounders, and better collection of weight and weight gain data.

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

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

Outcomes and costs of community health worker interventions: A systematic review

Objectives:We conducted a systematic review on outcomes and costs of community health worker (CHW) interventions. CHWs are increasingly expected to improve health outcomes cost-effectively for the underserved. Research Design:We searched Medline, Cochrane Collaboration resources, and the Cumulative Index to Nursing and Allied Health Literature for studies conducted in the United States and published in English from 1980 through November 2008. We dually reviewed abstracts, full-text articles, data abstractions, quality ratings, and strength of evidence grades and resolved disagreements by consensus. Results:We included 53 studies on outcomes of CHW interventions and 6 on cost or cost-effectiveness. For outcomes, limited evidence (5 studies) suggests that CHW interventions can improve participant knowledge compared with alternative approaches or no intervention. We found mixed evidence for participant behavior change (22 studies) and health outcomes (27 studies). Some studies suggested that CHW interventions can result in greater improvements in participant behavior and health outcomes compared with various alternatives, but other studies suggested that CHW interventions provide no statistically different benefits than alternatives. We found low or moderate strength of evidence suggesting that CHWs can increase appropriate health care utilization for some interventions (30 studies). Six studies with economic information yielded insufficient data to evaluate the cost-effectiveness of CHW interventions relative to other interventions. Conclusions:CHWs can improve outcomes for underserved populations for some health conditions. The effectiveness of CHWs in many health care areas requires further research that addresses the methodologic limitations of prior studies and that contributes to translating research into practice.

Comparative risk for harms of second-generation antidepressants : 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.

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

OBJECTIVE This meta-analysis reviewed data on the efficacy and effectiveness of second-generation antidepressants for preventing major depression relapse and recurrence during continuation and maintenance phases of treatment, respectively. METHODS MEDLINE, EMBASE, and PsycINFO, the Cochrane Library, and International Pharmaceutical Abstracts were searched for the period of January 1980 through April 2007 for reviews, randomized controlled trials, meta-analyses, and observational studies on the topic. Two persons independently reviewed abstracts and full-text articles using a structured data abstraction form to ensure consistency in appraisal and data extraction. RESULTS Four comparative trials and 23 placebo-controlled trials that addressed relapse or recurrence prevention were included. Results of comparative trials have not demonstrated statistically significant differences between duloxetine and paroxetine, fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine. Pooled data for the class of second-generation antidepressants compared with placebo suggested a relatively large effect size that persists over time. For preventing both relapse and recurrence, the number of patients needed to treat is five (95% confidence interval of 4 to 6). Differences in the length of open-label treatment before randomization, drug type, and trial duration did not affect pooled estimates of relapse rates. Across all trials, 7% of patients randomly assigned to receive active treatment and 5% of patients randomly assigned to receive a placebo discontinued treatment because of adverse events. CONCLUSIONS This review demonstrates the overall benefits of continuation- and maintenance-phase treatment of major depression with second-generation antidepressants and emphasizes the need for additional studies of comparative differences among drugs.

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

Biologics are an important therapeutic option for treating patients with juvenile idiopathic arthritis (JIA). In adults, they are associated with rare but severe adverse events such as serious infections and malignancies. We reviewed systematically the evidence on the efficacy and safety of biologics for the treatment of JIA. We searched electronic databases up to August 2006. We limited evidence to prospective studies for efficacy but included retrospective observational evidence for safety. Outcomes of interest were clinical response, radiographic progression, quality of life, and adverse events. One randomized controlled trial (RCT) and 11 uncontrolled prospective studies provided data on efficacy; three additional studies assessed safety. The only RCT and six uncontrolled trials support the general efficacy of etanercept for the treatment of JIA. Internal and external validity of these studies are limited. The evidence on other biologic agents such as adalimumab, abatacept, anakinra, infliximab, rituximab, and tocilizumab is sparse or entirely missing. Because of the lack of sound long-term safety data, evidence is insufficient to draw firm conclusions about the balance of risks and benefits of any biologic agent for the treatment of JIA. Clinicians have to be aware of the lack of evidence supporting a long-term net benefit when considering biologics for patients with JIA.

Treating the physical symptoms of depression with second-generation antidepressants: A systematic review and metaanalysis

BACKGROUND Approximately two-thirds of patients with depression experience physical pain symptoms. Coexisting pain complicates the treatment of depression and is associated with worse depression outcomes. OBJECTIVE The authors reviewed the effect of newer antidepressants on pain in patients with depression. METHOD The authors searched systematically for trials of second-generation antidepressants that enrolled depression patients and reported pain outcomes, pooling changes on the pain visual-analog scale (VAS), using random-effects models. RESULTS Eight trials were eligible. Pooled analysis of head-to-head trials showed no difference in VAS between duloxetine and paroxetine. Both drugs were superior to placebo. CONCLUSION The authors found insufficient evidence to support the choice of one second-generation antidepressant over another in patients with pain accompanying depression.

The effect of study sponsorship on a systematically evaluated body of evidence of head-to-head trials was modest: secondary analysis of a systematic review

OBJECTIVE The objective of this study was to determine the effect of industry bias in a systematically reviewed body of evidence of head-to-head trials. STUDY DESIGN AND SETTING We limited our analysis to published head-to-head randomized controlled trials of selective serotonin reuptake inhibitors (SSRIs) identified in a comparative effectiveness review. Two reviewers independently determined the status of funding for each trial. We classified drugs into one of two groups: (1) drugs associated with the funding source and (2) drugs not associated with the funding source. To determine the effect of any underlying industry bias, we conducted relative-benefit meta-analyses comparing the response rates of drugs when associated with the funding source with response rates of the same drugs when not associated with the funding source. RESULTS Thirteen out of 20 studies (65%) numerically favored drugs associated with the funding source over drugs used as controls. The pooled response rates of SSRIs, when associated with the funding source, are significantly greater than those of the same SSRIs when not associated with the sponsor (relative benefit=1.07; 95% confidence interval=1.02-1.11). The difference, however, is likely to be not of clinical importance. CONCLUSIONS The effect of industry bias in comparative effectiveness reviews might play a lesser role than in systematic reviews of placebo-controlled trials.

Inadequate reporting of trials compromises the applicability of systematic reviews

BACKGROUND Uncertainty about the applicability of controlled trial findings is an increasing concern for clinicians and policy decision makers. This study aimed to determine whether information reported in studies included in systematic reviews was adequate enough to assess their applicability. METHODS We used the databases of four recently conducted systematic reviews on the comparative efficacy and safety of second-generation antidepressants, inhaled corticosteroids, Alzheimers drugs, and targeted immune modulators. We developed and pilot-tested a questionnaire to assess the adequacy of reporting with respect to seven previously validated criteria of study design that distinguish explanatory from pragmatic studies. For each of the 137 included studies, two reviewers independently assessed the adequacy of reporting. RESULTS Overall, only 12 percent of the included studies provided sufficient information to reliably distinguish explanatory from pragmatic studies. The areas with the greatest lack of reporting were the setting of the study, methods of adverse event assessment, and sample size considerations to determine a minimally important difference from a patient perspective. CONCLUSIONS Substantial shortcomings in reporting exist in aspects of study design important to determine whether a study is applicable to specific populations of interest.

The impact of inclusion criteria in health economic assessments

The debate surrounding whether the findings of efficacy studies are applicable to real-world treatment situations is ongoing. The issue of lack of applicability due to a lack of clinical heterogeneity could be addressed by employing less restrictive inclusion criteria. Given that health economic assessments based on cost-effectiveness measures are required by many governments and insurance providers, the impact of this choice may be far reaching.The objective of this article was to explore the use of a pilot study to examine the impact of inclusion criteria on cost-effectiveness results and clinical heterogeneity. A health economic assessment was conducted using QRISK®2 and simulation modelling of different population groups within the pilot study in Lower Austria. Patients were referred by their family physicians to ‘Active Prevention’ (Vorsorge Aktiv), a community-based lifestyle intervention focused on exercise and nutritional programmes. Cardiovascular risk factors were recorded before and after the intervention and translated to cardiovascular events.As expected, enforcing restrictive inclusion criteria produced stronger and more irrefutable computations — in the expected number of events, the number of deaths, the incremental cost per life-year saved and in the 95% confidence interval. These findings provide insight into the issues surrounding clinical heterogeneity and the need for restrictive inclusion criteria. This is not a full health economic assessment of the intervention.While inclusion criteria provide stronger results by limiting populations to those who would benefit the most, they must be enforced, both within and outside the clinical trial setting. Enforcement has costs, both monetary and arising from unintended negative consequences of enforcement mechanisms. All these considerations will affect the results realized by the payer organization.A pilot study can reveal whether an intervention may be cost effective ‘enough’ without restrictive inclusion criteria and can enable researchers to search for population subgroups in which the intervention remains cost effective. When the pilot study does not indicate sufficiently strong cost-effectiveness results, the broader trade-offs between clinical heterogeneity and the strength of the submission package to the reimbursement agency can be discussed by all parties. Payer concerns about the ability to generalize the results beyond the clinical trial can also be discussed at this time. Applicability then depends on the ability to enforce inclusion criteria similar to those used in the trials in the real world.