Kim Peterson

Hypothermia Treatment for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

In this study, we conducted an updated meta-analysis of the effects of hypothermia therapy on mortality, favorable neurologic outcome, and associated adverse effects in adults with traumatic brain injury (TBI) for use by Brain Trauma Foundation (BTF)/American Association of Neurological Surgeons (AANS) task force to develop evidence-based treatment guidelines. Our data sources relied on handsearches of four previous good-quality systematic reviews, which all conducted electronic searches of primarily MEDLINE (OVID), EMBASE, and Cochrane Library. An independent, supplemental electronic search of MEDLINE was undertaken as well (last searched June 2007). Only English-language publications of randomized controlled trials of therapeutic hypothermia in adults with TBI were selected for analysis. Two reviewers independently abstracted data on trial design, patient population, hypothermia and cointervention protocols, patient outcomes, and aspects of methodological quality. Pooled relative risks (RR) and associated 95% confidence intervals (CIs) were calculated for each outcome using random-effects models. In the current study, only 13 trials met eligibility criteria, with a total of 1339 randomized patients. Sensitivity analyses revealed that outcomes were influenced by variations in methodological quality. Consequently, main analyses were conducted based on eight trials that demonstrated the lowest potential for bias (n = 781). Reductions in risk of mortality were greatest (RR 0.51; 95% CI 0.33, 0.79) and favorable neurologic outcomes much more common (RR 1.91; 95% CI 1.28, 2.85) when hypothermia was maintained for more than 48 h. However, this evidence comes with the suggestion that the potential benefits of hypothermia may likely be offset by a significant increase in risk of pneumonia (RR 2.37; 95% CI 1.37, 4.10). In sum, the present studys updated meta-analysis supports previous findings that hypothermic therapy constitutes a beneficial treatment of TBI in specific circumstances. Accordingly, the BTF/AANS guidelines task force has issued a Level III recommendation for optional and cautious use of hypothermia for adults with TBI.

Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis

RationaleRecommended medication prescribing hierarchies for adult attention-deficit hyperactivity disorder (ADHD) vary between different guideline committees. Few trials directly compare competing ADHD medications in adults and provide little insight for clinicians making treatment choices.ObjectiveThe objective of this study was to assess comparative benefits and harms of competing medications for adult ADHD using indirect comparison meta-analysis.Materials and methodsEligible studies were English-language publications of randomized controlled trials comparing ADHD drugs to placebo. Data sources were electronic bibliographic databases, Drugs@FDA, manufacturer data, and reference lists. Two reviewers independently abstracted data on design, internal validity, population, and results. Benefits and harms were compared between drug types using indirect comparison meta-regression (ratio of relative risks).ResultsTwenty-two placebo-controlled trials were included (n = 2,203). Relative benefit of clinical response for shorter-acting stimulants, primarily immediate release methylphenidate, was 3.26 times greater than for patients taking longer-acting stimulants (95% CI 2.03, 5.22) and 2.24 times greater than for patients taking longer-acting forms of bupropion (95% CI 1.23, 4.08). Immediate release methylphenidate is also the only drug shown to reduce ADHD symptoms in adults with substance abuse disorders. Neither non-stimulants nor longer-acting stimulants reduced adverse effects compared to shorter-acting stimulants. Key gaps in evidence were academic, occupational, social functioning, cardiovascular toxicity, and longer-term outcomes, influences of ADHD subtype and/or comorbidities, and misuse/diversion of the drugs.ConclusionsCurrent best evidence supports using immediate release methylphenidate as first-line treatment for most adults with ADHD.

A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia

Although the Food and Drug Administration (FDA) has not approved atypical antipsychotics for use in patients with dementia, they are commonly prescribed in this population. Recent concerns about increased risk of cerebrovascular events and mortality have led to warnings. A systematic review was conducted to assess the benefits and harms of atypical antipsychotics when used in patients with behavioral and psychological symptoms of dementia. Electronic searches (through March 2005) of the Cochrane Library, Medline, Embase, and PsycINFO were supplemented with hand searches of reference lists, dossiers submitted by pharmaceutical companies, and a review of the FDA Website and industry‐sponsored results database. Using predetermined criteria, each study was assessed for inclusion, and data about study design, population, interventions, and outcomes were abstracted. An overall quality rating (good, fair, or poor) was assigned based on internal validity.

Depression drug treatment outcomes in pregnancy and the postpartum period: A systematic review and meta-analysis

OBJECTIVE: To evaluate the comparative benefits and harms in both mother and child of antidepressant treatment for depression in pregnant or postpartum women. DATA SOURCES: MEDLINE, the Cochrane Library, CINAHL, Scopus, ClinicalTrials.gov (inception to July 2013), manufacturers, and reference lists. METHODS OF STUDY SELECTION: Two reviewers independently selected studies of pregnant women with depression comparing antidepressants with each other, placebo or no treatment, or nondrug treatments. Studies making comparisons among women taking antidepressants for any reason and those not taking antidepressants (depression status unknown) were used to fill gaps in the evidence. TABULATION, INTEGRATION, AND RESULTS: Dual study data extraction and quality assessment were used. Six randomized controlled trials and 15 observational studies provided evidence. Low-strength evidence suggested neonates of pregnant women with depression taking selective serotonin reuptake inhibitors had higher risk of respiratory distress than did neonates of untreated women (13.9% compared with 7.8%; P<.001) but no difference in risk of neonatal convulsions (0.14% compared with 0.11%; P=.64) or preterm birth (17% compared with 10%; P=.07). Indirect evidence from studies of pregnant women receiving antidepressants for mixed or unreported reasons compared with pregnant women not taking antidepressants (depression status unknown) suggested future research should focus on congenital anomalies and autism spectrum and attention deficit disorders in the child. In postpartum depression, low-strength evidence suggested symptom response was not improved when sertraline was added to psychotherapy or when cognitive–behavioral therapy was added to paroxetine. Evidence was insufficient for other outcomes, including depression symptoms, functional capacity, breastfeeding, and infant and child development. A serious limitation is the lack of study populations of exclusively depressed pregnant and postpartum women. CONCLUSION: Evidence about the comparative benefits and harms of pharmacologic treatment of depression in pregnant and postpartum women was largely inadequate to allow informed decisions about treatment. Considering the prevalence of depression, filling this gap is essential.

Methods for the Drug Effectiveness Review Project

The Drug Effectiveness Review Project was initiated in 2003 in response to dramatic increases in the cost of pharmaceuticals, which lessened the purchasing power of state Medicaid budgets. A collaborative group of state Medicaid agencies and other organizations formed to commission high-quality comparative effectiveness reviews to inform evidence-based decisions about drugs that would be available to Medicaid recipients. The Project is coordinated by the Center for Evidence-based Policy (CEbP) at Oregon Health & Science University (OHSU), and the systematic reviews are undertaken by the Evidence-based Practice Centers (EPCs) at OHSU and at the University of North Carolina. The reviews adhere to high standards for comparative effectiveness reviews. Because the investigators have direct, regular communication with policy-makers, the reports have direct impact on policy and decision-making, unlike many systematic reviews. The Project was an innovator of methods to involve stakeholders and continues to develop its methods in conducting reviews that are highly relevant to policy-makers. The methods used for selecting topics, developing key questions, searching, determining eligibility of studies, assessing study quality, conducting qualitative and quantitative syntheses, rating the strength of evidence, and summarizing findings are described. In addition, our on-going interactions with the policy-makers that use the reports are described.

US Food and Drug Administration documents can provide unpublished evidence relevant to systematic reviews

OBJECTIVES A key systematic review (SR) methodology is comprehensive searching. The Drug Effectiveness Review Project (DERP) SRs search US Food and Drug Administration (FDA) documents to identify unpublished evidence. This study evaluates the success of those efforts. STUDY DESIGN AND SETTING We examined DERP reports published since 2003 for the use of FDA preapproval and postmarketing documents. We categorized evidence as (1) unique unpublished studies, (2) supplemental unpublished data, or (3) FDA postmarketing data analysis. Three reviewers independently assigned predetermined impact categories (e.g., qualitative or quantitative usage, fills gaps, confirms findings, and alters conclusions), resolving disagreements through consensus. RESULTS Among 114 DERP reports, 19% included unpublished studies and/or supplemental data and 10% included postmarketing analyses. From 175 preapproval documents, 14% provided eligible unpublished studies and 4.0% supplemental unpublished data that helped confirm previous findings, identify important harms, and fill gaps in knowledge about understudied subpopulations, outcomes, and comparisons. Report conclusion statements changed in 9 of 33 instances of premarketing documents compared with 4 of 12 postmarketing analyses. CONCLUSIONS The FDA documents can provide important unpublished evidence for SRs, although in a small proportion of cases. Future research should identify attributes that predict which reviews may benefit most from review of FDA documents.

Decisions to update comparative drug effectiveness reviews vary based on type of new evidence

OBJECTIVE To determine the time to and key factors associated with decision to update comparative effectiveness of reviews of drugs based on periodic scans of new evidence. STUDY DESIGN AND SETTING Based on periodic scans of new evidence, we analyzed 69 decisions on whether to update for 41 comparative effectiveness reviews conducted for the Drug Effectiveness Review Project. We used the Kaplan-Meier product limit method to estimate mean time to update and generalized estimating equation logistic regression to estimate associations between updating decisions and review topic or characteristics of new evidence. RESULTS Mean time to update was 24.9 months. Significant predictors of a decision to update were identification of a new drug (odds ratio [OR]: 5.71; 95% confidence interval [CI]: 1.68-19.44) and the number of new relevant trials (OR: 1.06; 95% CI: 1.03-1.10). Compared with nonpsychiatric topics, psychiatric topics were most rapidly developing (mean new relevant citations: 38.4 vs. 8.2; P=0.0127) and were updated at a faster pace (mean survival time: 10.2 vs. 27.5 months; P<0.0001). CONCLUSION Using periodic scans of new evidence, updating should be considered yearly for rapidly developing topics and biannually for other topics.

Rapid Evidence Review of Bariatric Surgery in Super Obesity (BMI ≥ 50 kg/m2)

Despite accumulating evidence of the important health benefits of bariatric surgery in morbidly obese patients in general, bariatric surgery outcomes are less clear in higher-risk, high-priority populations of patients with BMI ≥ 50 kg/m2. To help the Department of Veterans Affairs (VA) Health Services Research & Development Service (HSR&D) develop a research agenda, we conducted a rapid evidence review to better understand bariatric surgery outcomes in adults with BMI ≥ 50 kg/m2. We searched MEDLINE®, the Cochrane Database of Systematic Reviews, the Cochrane Central Registry of Controlled Trials, and ClinicalTrials.gov through June 2016. We included trials and observational studies. We used pre-specified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO registration number CRD42015025348). All decisions were completed by one reviewer and checked by another. Among 1892 citations, we included 23 studies in this rapid review. Compared with usual care, one large retrospective VA study provided limited evidence that bariatric surgery can lead to increased mortality in the first year, but decreased mortality long-term among super obese veterans. Studies that compared different bariatric surgical approaches suggested some differences in weight loss and complications. Laparoscopic gastric bypass generally resulted in greater short-term proportion of excess weight loss than did other procedures. Duodenal switch led to greater long-term weight loss than did gastric bypass, but with more complications. The published literature that separates the super obese is insufficient for determining the precise balance of benefits and harms of bariatric surgery in this high-risk subgroup. Future studies should evaluate a more complete set of key outcomes with longer follow-up in larger samples of more broadly representative adults.BackgroundDespite accumulating evidence of the important health benefits of bariatric surgery in morbidly obese patients in general, bariatric surgery outcomes are less clear in higher-risk, high-priority populations of patients with BMI ≥ 50 kg/m2. To help the Department of Veterans Affairs (VA) Health Services Research & Development Service (HSR&D) develop a research agenda, we conducted a rapid evidence review to better understand bariatric surgery outcomes in adults with BMI ≥ 50 kg/m2.MethodsWe searched MEDLINE®, the Cochrane Database of Systematic Reviews, the Cochrane Central Registry of Controlled Trials, and ClinicalTrials.gov through June 2016. We included trials and observational studies. We used pre-specified criteria to select studies, abstract data, and rate internal validity and strength of the evidence (PROSPERO registration number CRD42015025348). All decisions were completed by one reviewer and checked by another.ResultsAmong 1892 citations, we included 23 studies in this rapid review. Compared with usual care, one large retrospective VA study provided limited evidence that bariatric surgery can lead to increased mortality in the first year, but decreased mortality long-term among super obese veterans. Studies that compared different bariatric surgical approaches suggested some differences in weight loss and complications. Laparoscopic gastric bypass generally resulted in greater short-term proportion of excess weight loss than did other procedures. Duodenal switch led to greater long-term weight loss than did gastric bypass, but with more complications.ConclusionsThe published literature that separates the super obese is insufficient for determining the precise balance of benefits and harms of bariatric surgery in this high-risk subgroup. Future studies should evaluate a more complete set of key outcomes with longer follow-up in larger samples of more broadly representative adults.

A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab.

BACKGROUND The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of cholesterol-lowering medications that provide significant reductions in lipids but at a large cost relative to statins. With 2 such drugs now on the market, alirocumab and evolocumab, comparing the evidence base for these drugs is necessary for informed decision making. OBJECTIVE To compare the benefits and harms of the PCSK9 inhibitors alirocumab and evolocumab. METHODS The databases Ovid MEDLINE, Cochrane Library, SCOPUS, and ClinicalTrials.gov were used to search for randomized controlled trials of alirocumab or evolocumab with any relevant comparator reporting health outcomes, lipid outcomes, or harms through September 2015, and information was requested from manufacturers. Results were reviewed according to standard review methods. RESULTS The database searches revealed 17 fair- and good-quality trials; however, none had primary health outcomes or directly compared PCSK9 inhibitors. Alirocumab (75 mg to 150 mg subcutaneously every 2 weeks) resulted in significantly greater reductions in low-density lipoprotein cholesterol (LDL-C; -8% to -67%) at 12-24 weeks in patients with (a) heterozygous familial hypercholesterolemia and (b) patients at high or varied cardiovascular (CV) risk who were not at LDL-C goals with statin therapy. The highest strength evidence was for patients with high CV risk not at LDL-C goals. Alirocumab also resulted in high-density lipoprotein cholesterol (HDL-C) increases of 6%-12%. Low- and moderate-strength evidence for adjudicated CV events at 52-78 weeks for a priori analyses indicated no benefit. Low- and moderate-strength evidence also found no differences in harms except possibly slightly more injection-site reactions. Evolocumab (120 mg subcutaneously every 2 weeks to 420 mg every 4 weeks) resulted in significantly greater reductions in LDL-C (-32% to -71%) at 12-52 weeks in patients with heterozygous or homozygous familial hypercholesterolemia, patients intolerant of statins, and patients with varied CV risk not at LDL-C goal with statin therapy. The highest strength evidence was for heterozygous familial hypercholesterolemia and patients not at LDL-C goals. Moderate-strength evidence showed HDL-C increases in the range of 4.5%-6.8%. Harms were not different between groups, except possibly slightly greater overall adverse event reporting. Evidence on adjudicated CV outcomes was insufficient to draw conclusions because of sparseness of events, study limitations, and inability to assess consistency of findings. CONCLUSIONS Alirocumab and evolocumab have evidence of large improvements in lipid levels. The strength of the evidence is greater for alirocumab than evolocumab in patients with high CV risk who were not at LDL-C target goals, while evidence for evolocumab is stronger in patients with heterogeneous familial hypercholesterolemia and patients with varied CV risk who were not at LDL-C target goals. Evidence on adjudicated CV outcomes for a priori analyses is unable to show benefit for alirocumab and is insufficient to draw conclusions for evolocumab. Important questions remain about the comparative effects on long-term health outcomes. DISCLOSURES This project was funded by The Drug Effectiveness Review Project. Project participants reviewed the manuscript but had no role in conducting the work or writing the manuscript. Any comments received from the participants during the course of the review were taken at the discretion of the authors independently. All authors had access to the data and a role in writing the manuscript. McDonagh, Peterson, and Holzhammer declare no conflict of interest or financial interest in any therapy discussed in this article. Fazio declares receiving compensation from Sanofi for a presentation on his science to a group of their advisors and has served as a consultant to MSD, BASF, NHP, Sanofi, Ionis Pharmaceuticals, and Kowa. Study concept and design were primarily contributed by McDonagh, along with Peterson and Holzhammer, with assistance from Fazio. Holzhammer took the lead in data collection, with assistance from McDonagh and Peterson. Data interpretation was performed by McDonagh, Peterson, and Fazio. The manuscript was written by McDonagh, Peterson, and Fazio, with assistance from Holzhammer, and revised by all the authors.

Mortality disparities in racial/ethnic minority groups in the veterans health administration: An evidence review and Map

Background Continued racial/ethnic health disparities were recently described as “the most serious and shameful health care issue of our time.” Although the 2014 US Affordable Care Act-mandated national insurance coverage expansion has led to significant improvements in health care coverage and access, its effects on life expectancy are not yet known. The Veterans Health Administration (VHA), the largest US integrated health care system, has a sustained commitment to health equity that addresses all 3 stages of health disparities research: detection, understanding determinants, and reduction or elimination. Despite this, racial disparities still exist in the VHA across a wide range of clinical areas and service types. Objectives To inform the health equity research agenda, we synthesized evidence on racial/ethnic mortality disparities in the VHA. Search Methods Our research librarian searched MEDLINE and Cochrane Central Registry of Controlled Trials from October 2006 through February 2017 using terms for racial groups and disparities. Selection Criteria We included studies if they compared mortality between any racial/ethnic minority and nonminority veteran groups or between different minority groups in the VHA (PROSPERO# CRD42015015974). We made study selection decisions on the basis of prespecified eligibility criteria. They were first made by 1 reviewer and checked by a second and disagreements were resolved by consensus (sequential review). Data Collection and Analysis Two reviewers sequentially abstracted data on prespecified population, outcome, setting, and study design characteristics. Two reviewers sequentially graded the strength of evidence using prespecified criteria on the basis of 5 key domains: study limitations (study design and internal validity), consistency, directness, precision of the evidence, and reporting biases. We synthesized the evidence qualitatively by grouping studies first by racial/ethnic minority group and then by clinical area. For areas with multiple studies in the same population and outcome, we pooled their reported hazard ratios (HRs) using random effects models (StatsDirect version 2.8.0; StatsDirect Ltd., Altrincham, England). We created an evidence map using a bubble plot format to represent the evidence base in 5 dimensions: odds ratio or HR of mortality for racial/ethnic minority group versus Whites, clinical area, strength of evidence, statistical significance, and racial group. Main Results From 2840 citations, we included 25 studies. Studies were large (n ≥ 10 000) and involved nationally representative cohorts, and the majority were of fair quality. Most studies compared mortality between Black and White veterans and found similar or lower mortality for Black veterans. However, we found modest mortality disparities (HR or OR = 1.07, 1.52) for Black veterans with stage 4 chronic kidney disease, colon cancer, diabetes, HIV, rectal cancer, or stroke; for American Indian and Alaska Native veterans undergoing noncardiac major surgery; and for Hispanic veterans with HIV or traumatic brain injury (most low strength). Author’s Conclusions Although the VHA’s equal access health care system has reduced many racial/ethnic mortality disparities present in the private sector, our review identified mortality disparities that have persisted mainly for Black veterans in several clinical areas. However, because most mortality disparities were supported by single studies with imprecise findings, we could not draw strong conclusions about this evidence. More disparities research is needed for American Indian and Alaska Native, Asian, and Hispanic veterans overall and for more of the largest life expectancy gaps. Public Health Implications Because of the relatively high prevalence of diabetes in Black veterans, further research to better understand and reduce this mortality disparity may be prioritized as having the greatest potential impact. However, other mortality disparities affect thousands of veterans and cannot be ignored.