Efficacy and safety of omalizumab in children and adolescents with moderate-to-severe asthma: A systematic literature review.

BACKGROUND: There are limited pediatric data about the use of omalizumab, especially the effectiveness and safety of omalizumab in the real-world management of allergic asthma. OBJECTIVE: The objective of this study was to summarize the safety and efficacy of omalizumab in both randomized clinical trials (RCT) used for U.S. Food and Drug Administration registration and real-world studies (RWS) based on clinical care of children with moderate-to-severe asthma. METHODS: Studies that evaluated omalizumab use in patients <18 years old and with asthma, published between January 2003 and October 2016, were retrieved from medical literature data bases. Assessed outcomes included the following: exacerbation rates, spirometric indices, changes in asthma medication use, asthma control, patient-reported outcomes, and health care resource utilization. RESULTS: A total of five RWS were identified; outcomes reported were compared with three omalizumab RCTs. Overall, the mean rate of annual exacerbations was significantly lower after 6 months to 2 years of treatment with omalizumab in both RCTs and RWS. In two RCTs and three RWS, inhaled corticosteroid use was significantly reduced in patients who used omalizumab. Similar reductions in the use of rescue medication were also observed in the RCTs and RWS on omalizumab. Real-world evidence demonstrated improvement in forced expiratory volume in the first second of expiration (% predicted) in patients treated with omalizumab as well as significant improvement in the level of asthma control observed over 1 year. There also was evidence that omalizumab treatment reduced health care resource utilization, including fewer hospitalizations, emergency department visits, and unscheduled medical visits. Safety outcomes in all five RWS showed no new safety signals and demonstrated that omalizumab was well tolerated. CONCLUSION: Overall, RCT evidence strongly supported omalizumab efficacy and safety as add-on treatment in children 6 to 11 years old with moderate-to-severe persistent allergic asthma. RWS data confirmed these findings in an extended patient population of children and adolescents that is more generalizable to the actual day-to-day management of these patients.

Comparative effectiveness of anti-VEGF agents for diabetic macular edema.

OBJECTIVES: The aim of this study was to evaluate the comparative effectiveness of anti-vascular endothelial growth factor therapy in the treatment of diabetic macular edema (DME). METHODS: Searches focused on reports concerning treatment of DME with aflibercept, bevacizumab, pegaptanib, or ranibizumab published between January 2000 and June 30, 2012, with comparisons to laser photocoagulation, sham injection, or other control (e.g., triamcinolone). Effectiveness was based on best-corrected visual acuity (BCVA), in terms of letters gained. Direct meta-analyses were conducted on BCVA for each anti-vascular endothelial growth factor (VEGF) agent; indirect comparisons also were performed for each anti-VEGF pair. RESULTS: A total of fifteen randomized controlled trials (eleven fair- or good-quality) and eight observational studies were included. No direct comparative studies were identified. Improvement in visual acuity versus control was seen with all agents (range: 4-9 letters); outcomes were consistent across multiple timepoints. Meta-analyses showed no statistically significant and/or consistent differences between agents in BCVA changes or the percentage of patients gaining more than ten letters. No discernible differences in the potential harms of anti-VEGFs, including ocular events, MI, stroke, and other cardiovascular events, as well as death, were noted between aflibercept, pegaptanib, and ranibizumab. Data on harms for bevacizumab were underreported. CONCLUSIONS: All anti-VEGF agents are effective in improving visual acuity in comparison to laser photocoagulation. Evidence is insufficient to distinguish the performance of any single anti-VEGF agent over others. The safety of bevacizumab remains the greatest element of uncertainty.

Biomarker tests for the diagnosis of Alzheimer's disease: Generating evidence to inform insurance coverage determinations.

Outside of their uses in drug development and clinical research trials, the current clinical value of performing any type of formal biomarker testing for the diagnosis or exclusion of Alzheimer's disease (AD) is controversial, and most biomarker tests for AD are not covered by public or private insurers. This situation raises the issue of how insurers determine whether there is "adequate" evidence to justify a positive coverage determination in this area. This article, a focused condensation of a larger white paper, is the product of an initiative led by the Institute for Clinical and Economic Review to convene a multiple-stakeholder AD Diagnostics Policy Development Group composed of patient advocates, clinicians, clinical researchers, manufacturers, and insurers. The larger white paper was the basis for the evidence review presented to the Medicare Evidence Development and Coverage Advisory Committee meeting on January 30, 2013, as part of its deliberations on positron emission tomography-amyloid imaging. Herein we focus on the description of the core elements of what insurers will be looking for in evidence on all potential diagnostic tests for AD. Corresponding research recommendations are also included, framed to serve as a guide for future AD diagnostics research.

Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence.

BACKGROUND: Acute ischemic strokes are associated with poor outcomes and high health care burden. Evidence exists evaluating the use of neurothrombectomy devices in patients receiving currently recommended treatments that may have limited efficacy. PURPOSE: To describe the state of the evidence supporting use of neurothrombectomy devices in the treatment of acute ischemic stroke. DATA SOURCES: MEDLINE, SCOPUS, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Web of Science were searched, without language restrictions, from their inception through May 2010. The MEDLINE and Cochrane Central Register of Controlled Trials searches were updated through November 2010. STUDY SELECTION: Two independent investigators screened citations for human studies of any design or case series or case reports of patients with an acute ischemic stroke that evaluated a neurothrombectomy device and reported at least 1 clinical effectiveness outcome or harm. DATA EXTRACTION: Using standardized protocols, 2 independent investigators extracted information about study characteristics and outcomes, and a third reviewer resolved disagreement. DATA SYNTHESIS: 87 articles met eligibility criteria, including 18 prospective single-group studies, 7 noncomparative retrospective studies, and 62 case series or case reports. Two U.S. Food and Drug Administration (FDA)-cleared devices, the MERCI Retriever (Concentric Medical, Mountain View, California) (40%) and the Penumbra System (Penumbra, Alameda, California) (9%), represented a large portion of the available data. All prospective and retrospective studies provided data on successful recanalization with widely varying rates (43% to 78% with the MERCI Retriever and 83% to 100% with the Penumbra System). Rates of harms, including symptomatic (16 studies; 0% to 10% with the MERCI Retriever and 0% to 11% with the Penumbra System) or asymptomatic (13 studies; 28% to 43% and 1% to 30%, respectively) intracranial hemorrhage and vessel perforation or dissection (11 studies; 0% to 7% and 0% to 5%, respectively), also varied by device. Predictors of harm included older age, history of stroke, and higher baseline stroke severity scores, whereas successful recanalization was the sole predictor of good outcomes. LIMITATIONS: Most available data are from single-group, noncomparative studies. In addition, the patient population most likely to benefit from these devices is undetermined. CONCLUSION: Currently available neurothrombectomy devices offer intriguing treatment options in patients with acute ischemic stroke. Future trials should use a randomized design, with adequate power to show equivalency or noninferiority between competing strategies or devices, and strive to identify populations that are most likely to benefit from use of neurothrombectomy devices. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).

Patient-reported outcomes in moderate-to-severe allergic asthmatics treated with omalizumab: a systematic literature review of randomized controlled trials.

OBJECTIVE: Randomized controlled trials (RCTs) have established the safety and efficacy of omalizumab on clinical parameters, and have also evaluated its impact on patient-reported outcomes (PROs). The purpose of this systematic literature review was to review published data based on PRO endpoints in order to determine the benefit of omalizumab as add-on therapy to inhaled corticosteroids in patients with moderate-to-severe persistent allergic asthma. METHODS: A systematic literature review was conducted of reference databases and recent conferences. RCTs of add-on omalizumab therapy in adults, adolescents, and children with moderate-to-severe persistent asthma were included. Two researchers independently screened and reviewed articles with regards to inclusion and exclusion criteria for relevant studies. RESULTS: Twenty-six trials met the criteria for inclusion. Of these, PRO measures were included in 19 trials to capture the impact of omalizumab on symptoms, 11 assessed patients for health-related quality-of-life (HRQoL), and four evaluated asthma control. Other PROs related to global evaluation of treatment effectiveness and work productivity. Overall, results demonstrated a significant difference across most PROs in favor of omalizumab add-on therapy vs placebo or comparators. CONCLUSIONS: PROs are an integral part of outcome assessment in clinical trials related to asthma. The RCTs reviewed demonstrate that omalizumab treatment improves PROs in patients with moderate-to-severe persistent allergic asthma, particularly symptom control and HRQoL.

Management options for children with attention-deficit/hyperactivity disorder: a regional perspective on value.

Use of comparative effectiveness information in local healthcare decisions can be confounded by variations in practice, barriers to access and population demographics. The New England Comparative Effectiveness Public Advisory Council was convened as a public deliberative panel that considers evidence on the comparative clinical effectiveness and comparative value of a variety of therapeutic interventions. The council is tasked with making summary judgments on the evidence and recommendations for applying the evidence in medical and drug coverage policy, as well as initiating educational efforts for patients and clinicians. The New England Comparative Effectiveness Public Advisory Council met in June 2012 to discuss management options for attention-deficit/hyperactivity disorder, guided by a recent comparative effectiveness review from the Agency for Healthcare Research and Quality and supplementary economic analyses conducted by the Institute for Clinical and Economic Review. This article summarizes the deliberations and reflects on lessons learned regarding use of region-specific economic analyses to guide decision-making.

Evaluating the evidence on comparative effectiveness and value of management options for treatment-resistant depression.

Treatment-resistant depression (TRD) is a debilitating patient condition with significant clinical and economic impact. The introduction of a new treatment approach, repetitive transcranial magnetic stimulation (rTMS), created the opportunity for a multi-stakeholder initiative to examine the comparative clinical effectiveness and comparative value of the different approaches to managing patients with TRD. The New England Comparative Effectiveness Public Advisory Council (CEPAC) convened in December 2011 to discuss the evidence on management options for patients with TRD. The Council voted that rTMS was as good or better than usual care and represented a reasonable value compared with usual care. The votes and deliberation of CEPAC led to first-in-the-nation payer coverage policies allowing patients access to this new treatment option. Regional groups that examine and deliberate on the comparative effectiveness evidence for existing and emerging treatments can have a direct influence on medical policy that accelerates access to innovative treatments.

Patient satisfaction with warfarin- and non-warfarin-containing thromboprophylaxis regimens for atrial fibrillation.

OBJECTIVE: To compare patient-reported limitations, concerns, and burdens in those receiving and not receiving warfarin for thromboprophylaxis in atrial fibrillation (AF). METHODS: We conducted a cross-sectional survey study of patients with AF receiving thromboprophylaxis for stroke prevention. Patients were administered the validated Anti-Clot Treatment Scale (ACTS). Mean scores of patients receiving and not receiving warfarin were compared for each ACTS item, and for the Burden and Benefit subscales. RESULTS: From July 2010 to August 2011, 80 patients with AF were administered the survey, with 65 patients receiving a regimen containing warfarin and 15 patients not receiving a regimen containing warfarin. Six of the 17 individual questions depicting patient- perceived limitations in physical activity due to bleeding, limitations on diet, feelings of inconvenience of occasional aspects of thromboprophylaxis therapy, and frustration, and burden had less favorable scores in the warfarin-managed patients compared with the patients not receiving warfarin (P < 0.05 for all). Mean ACTS Burden scores were more favorable in the no-warfarin group (44.5 ± 6.4) compared with the warfarin group (39.8 ± 8.0; P = 0.003). No difference was seen between the 2 groups on the ACTS Benefits score (11.1 ± 3.4 vs 10.4 ± 3.7; P = 0.38). CONCLUSION: Patients with AF receiving warfarin may have less favorable feelings regarding thromboprophylaxis versus those receiving non-warfarin thromboprophylaxis. Patients report having more limitations and having greater feelings of burden on warfarin.

Predictors of medication adherence in an urban Latino community with healthcare disparities.

Ethnic disparities exist when comparing glycemic control: Latino patients have suboptimal glycemic control as compared to non-Latino whites. A key factor to achieving optimal diabetes management and control is medication adherence. We conducted a nested, cross-sectional retrospective study of data (n = 61) collected from a larger parallel, randomized, longitudinal study conducted at an urban primary care practice examining a culturally tailored community-based peer counselor intervention. Baseline demographic and medication utilization covariates were evaluated for eligibility into the multivariate logistic regression to predict medication adherence. Significant correlates of medication adherence were physician or healthcare team support (OR 12.79, 95% CI 1.04, 157.21), and increasing numbers of medications taken (OR 1.24, 95% CI 1.04, 1.48). Receipt of government benefits was associated with medication non-adherence (OR 0.06, 95% CI 0.01, 0.51). Modifiable factors such as the number of medications and the patient-healthcare team relationship appear to play a role in medication adherence.

Management strategies for attention-deficit/hyperactivity disorder: a regional deliberation on the evidence.

Parents, clinicians, and policymakers require the latest evidence to help inform treatment decisions. The New England Comparative Effectiveness Public Advisory Council (CEPAC) leverages existing federally produced comparative effectiveness research supplemented with additional clinical and economic analyses to deliberate on the latest evidence. At its June 2012 meeting, the CEPAC voted on the evidence for the treatment of attention-deficit/hyperactivity disorder (ADHD) in preschoolers and school-aged children. The CEPAC voted unanimously that parent behavior training was better than usual care (eg, wait-list control) for the preschool population. They also judged it to be of "reasonable value" compared with usual care. The CEPAC also stipulated unanimously that medications are better than usual care (eg, services provided at individual practitioner discretion) for school-aged children in regards to long-term effectiveness and safety. The CEPAC members and clinical experts recommended the increased use of parent behavior training as first-line therapy for preschoolers and emphasized the importance of proper monitoring of and dosing for all children who receive medication for their ADHD symptoms. The ADHD CEPAC meeting demonstrated the important role that a public, transparent deliberation on the latest medical evidence can have in supporting informed decision making and efficient use of health care resources.

Effect of ascorbic acid on inflammatory markers after cardiothoracic surgery.

PURPOSE: The effect of ascorbic acid on inflammatory markers after cardiothoracic surgery (CTS) was studied. METHODS: In this randomized, double-blind, placebo-controlled trial, patients undergoing cardiopulmonary bypass graft surgery or valve replacement surgery from April 2009 through March 2010 at Hartford Hospital were randomized to receive ascorbic acid (2-g loading dose followed by 500 mg every 12 hours) or matching placebo the evening before surgery and for four days postoperatively. Inflammatory mediators were measured preoperatively and on postoperative days 1-4. Intergroup comparisons were performed using two-tailed t tests and Fisher's exact test. Multiple comparisons were conducted using repeated analyses of variance with Bonferroni tests. RESULTS: Of the 62 patients screened, 24 met the study inclusion criteria. Of these, 13 were assigned to receive ascorbic acid and 11 received placebo. Ascorbic acid did not affect the natural course of inflammatory marker rise for C-reactive protein (CRP) concentration, white blood cell (WBC) count, or fibrinogen concentration versus placebo at any evaluated time point (p > 0.05 for all intergroup comparisons). Intragroup analyses demonstrated significant differences among baseline and postoperative measures of all inflammatory mediators (p < 0.05). No significant differences were noted in inflammatory markers between patients undergoing cardiothoracic surgery with or without cardiopulmonary bypass, regardless of treatment group. CONCLUSION: Ascorbic acid did not attenuate the rise in inflammatory markers after CTS when compared with placebo. The use of off-pump surgery did not significantly change the levels of CRP and fibrinogen or the WBC count postoperatively when compared with on-pump surgery with a biocompatible polymer coating.