Antipsychotics in the Treatment of Delirium in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To conduct a systematic review and meta-analysis assessing whether the use of antipsychotic medications in critically ill adult patients with delirium impacts patient-important outcomes. DATA SOURCES: A medical librarian searched Ovid MEDLINE, EMBASE, APA PsycInfo, and Wiley's Cochrane Library as well as clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2023. STUDY SELECTION: Independently and in duplicate, reviewers screened abstracts and titles for eligibility, then full text of qualifying studies. We included parallel-group randomized controlled trials (RCTs) that included critically ill adult patients with delirium. The intervention group was required to receive antipsychotic medications at any dose, whereas the control group received usual care or placebo. DATA EXTRACTION: Reviewers extracted data independently and in duplicate using a piloted abstraction form. Statistical analyses were conducted using RevMan software (version 5.4). DATA SYNTHESIS: Five RCTs ( n = 1750) met eligibility criteria. The use of antipsychotic medications compared with placebo did not increase the number of delirium- or coma-free days (mean difference 0.90 d; 95% CI, -0.32 to 2.12; moderate certainty), nor did it result in a difference in mortality, duration of mechanical ventilation, ICU, or hospital length of stay. The use of antipsychotics did not result in an increased risk of adverse events (risk ratio 1.27; 95% CI, 0.71-2.30; high certainty). Subgroup analysis of typical versus atypical antipsychotics did not identify any subgroup effect for any outcome. CONCLUSIONS: In conclusion, our systematic review and meta-analysis demonstrated with moderate certainty that there is no difference in delirium- or coma-free days when delirious critically ill adults are treated with antipsychotic medications. Further studies in the subset of patients with hyperactive delirium may be of benefit.

Anti-craving medications for alcohol use disorder treatment in the emergency department: A systematic review of direct evidence for SAEM GRACE.

OBJECTIVES: Alcohol-related concerns commonly present to the emergency department (ED), with a subset of individuals experiencing the symptoms of an alcohol use disorder (AUD). As such, examining the efficacy of pharmacological anti-craving treatment for AUD in the ED is of increasing interest. The objective of this systematic review was to evaluate the direct evidence assessing the efficacy of providing anti-craving medications for AUD treatment in the ED. METHODS: A systematic search was conducted according to the patient-intervention-control-outcome question: (P) adults (≥18 years old) presenting to the ED with an AUD (including suspected AUD); (I) anti-craving medications (i.e., naltrexone, acamprosate, gabapentin); (C) no prescription or placebo; (O) reduction of repeat ED visits, engagement in addiction services, reductions in heavy drinking days, reductions in any drinking and amount consumed (or abstinence), and in relapse. Two reviewers independently assessed articles for inclusion and conducted risk of bias assessments for included studies. RESULTS: From 143 potentially relevant articles, 6 met inclusion criteria: 3 clinical trials, and 3 case studies. The clinical trials identified evaluated oral versus extended-release naltrexone, monthly extended-release naltrexone injections, and disulfiram. Both oral and extended-release naltrexone resulted in decreased alcohol consumption. Monthly extended-release naltrexone injections resulted in significant improvements in drinking and quality of life. Although out of scope, the disulfiram studies identified did not result in an improvement in drinking in comparison to no medication. CONCLUSIONS: Overall, there are few studies directly examining the efficacy of anti-craving medications for AUD in the ED, although the limited evidence that exists is supportive of naltrexone pharmacotherapy, particularly extended-release injection formulation. Additional randomized controlled trials are necessary for substantive direct evidence on anti-craving medication initiation in the ED.

Phenobarbital for alcohol withdrawal management in the emergency department: A systematic review of direct evidence for the SAEM GRACE initiative.

OBJECTIVES: Alcohol withdrawal syndrome (AWS) is a commonly presenting condition in the emergency department (ED) and can have severe complications, including mortality. Benzodiazepines are first-line medications for treating AWS but may be unavailable or insufficient. This systematic review evaluates the direct evidence assessing the utility of phenobarbital for treating AWS in the ED. METHODS: A systematic search was conducted and designed according to the patient-intervention-comparator-outcome (PICO) question: (P) adults (≥18 years old) presenting to the ED with alcohol withdrawal; (I) phenobarbital (including adjunctive); (C) benzodiazepines or no intervention; and (O) AWS complications, admission to a monitored setting, control of symptoms, adverse effects, and adjunctive medications. Two reviewers independently assessed articles for inclusion and conducted risk of bias assessments for included studies. RESULTS: From 70 potentially relevant articles, seven studies met inclusion criteria: three retrospective cohort studies, two retrospective chart reviews, and two randomized controlled trials (RCTs), one examining phenobarbital monotherapy and one examining adjunctive phenobarbital. Across the retrospective cohort studies, treatment of AWS with phenobarbital resulted in lower odds of a subsequent ED visit. The retrospective chart reviews indicated that phenobarbital was associated with higher discharge rate compared to benzodiazepine-only treatments. For the two RCTs, phenobarbital did not differ significantly from benzodiazepine for most outcomes, although concomitant treatment with phenobarbital was associated with lower benzodiazepine use and intensive care unit admission. The heterogeneous designs and small number of studies prevented quantitative synthesis. CONCLUSIONS: Relatively few studies provide direct evidence on the utility of phenobarbital for AWS in the ED, but the evidence that exists generally suggests that it is a reasonable and appropriate approach. Additional RCTs and other methodologically rigorous investigations are needed for more definitive direct evidence.

SAEM GRACE: Dopamine antagonists and topical capsaicin for cannabis hyperemesis syndrome in the emergency department: A systematic review of direct evidence.

BACKGROUND: Adults with cannabis hyperemesis syndrome (CHS) are increasingly presenting to the emergency department (ED), and this systematic review will evaluate the direct evidence on the effectiveness of capsaicin and dopamine antagonists in its clinical management. METHODS: A bibliographic search was conducted to address the following population-intervention-control-outcome (PICO) question: (P) adults >18 years old with a diagnosis of acute CHS presenting to the ED; (I) dopamine antagonists (e.g., haloperidol, droperidol) and topical capsaicin; (C) usual care or no active comparator; and (O) symptoms improvement/resolution in ED, ED length of stay, admission rate, ED recidivism, need for rescue medication, and adverse events. This systematic review was conducted in accordance with PRISMA reporting recommendations. RESULTS: From 53 potentially relevant articles, seven articles were included: five observational studies and two randomized controlled trials, including a total of 492 patients. Five of these studies evaluated the efficacy of capsaicin cream (n = 386), and two examined dopamine antagonists (haloperidol, droperidol; n = 106). There was mixed evidence for the efficacy of capsaicin for reducing nausea and emesis. Both studies evaluating dopamine antagonists detected clinical benefit to usual care or no active comparator. CONCLUSIONS: There is limited direct evidence on the efficacy of dopamine antagonists or capsaicin for treating CHS in the ED. Current evidence is mixed for capsaicin and potentially beneficial for dopamine antagonists. Because of the small number of studies, small number of participants, lack of standardization of treatment administration, and risk of bias of the included studies, methodologically rigorous trials on both types of intervention are needed to directly inform ED management of CHS.

Psychosocial interventions addressing suicidality in inpatient psychiatry: a scoping review protocol.

OBJECTIVE: The objective of this review is to provide an overview of the existing literature on psychosocial interventions aimed at addressing suicidality among adults in the context of an inpatient psychiatric admission. INTRODUCTION: For individuals admitted to a psychiatric inpatient unit, their risk of suicide in the period following discharge is significantly higher compared with the prevalence of death by suicide in the general population. During an inpatient admission, there is opportunity for supportive interventions that may lead to reduced risks of suicide. Yet, interventions that directly address suicidality have primarily been studied in outpatient settings. A broader understanding of inpatient interventions will assist clinicians in understanding key considerations when implementing suicide-related interventions in this setting. INCLUSION CRITERIA: Studies involving adult patients (≥18 years) that describe psychosocial interventions aiming to address suicidality in the context of inpatient psychiatry will be considered. Studies that only describe pharmacological interventions will be excluded, as will studies that describe psychosocial interventions initiated in the context of an outpatient setting. METHODS: We will search MEDLINE (Ovid), CINAHL (EBSCO), APA PsycINFO (EBSCOhost), the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science for studies in English and Spanish. Gray literature and materials will also be searched for using Google and websites relevant to the review topic. No date limit will be set. Two independent reviewers will screen titles and abstracts from studies that meet the inclusion criteria and review eligible studies at full text. Data will be extracted and synthesized and then presented in tabular and graphical formats accompanied by a narrative summary. DETAILS OF THE REVIEW AVAILABLE AT: Open Science Framework https://osf.io/5cwhx.

Gastrointestinal recovery after surgery: protocol for a systematic review.

INTRODUCTION: Gastrointestinal recovery after surgery is of worldwide significance. Postoperative gastrointestinal dysfunction is multifaceted and known to represent a major source of postoperative morbidity, however, its significance to postoperative care across all surgical procedures is unknown. The complexity of postoperative gastrointestinal recovery is poorly defined within gastrointestinal surgery, and even less so outside this field. To inform the clinical care of surgical patients worldwide, this systematic review and meta-analysis will aim to characterise the duration of postoperative gastrointestinal recovery that can be expected across all surgical procedures and determine the associations between factors that may affect this. METHODS AND ANALYSIS: MEDLINE, Embase, Cochrane Library and CINAHL will be searched for studies reporting the time to first postoperative passage of stool after any surgical procedure. We will screen records, extract data and assess risk of bias in duplicate. Forest plots will be constructed for time to postoperative gastrointestinal recovery, as assessed by various outcome measures. Because of potential heterogeneity, a random-effects model will be used throughout the meta-analysis. Funnel plots will be used to test for publication bias. Meta-regressions will be undertaken where the outcome is the mean time to first postoperative passage of stool, with potential predictors and confounders being patient characteristics, postoperative outcomes and surgical factors. ETHICS AND DISSEMINATION: This study will not involve human or animal subjects and, thus, does not require ethics approval. The outcomes will be disseminated via publication in peer-reviewed scientific journal(s) and presentations at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42021256210.

Evidence-Based Decision Making 3: Health Technology Assessment.

This chapter begins with a brief introduction to health technology assessment (HTA). HTA is concerned with the systematic evaluation of the consequences of the adoption and use of new health technologies and to improve the evidence on existing technologies. The objective of mainstream HTA is to support evidence-based decision- and policy-making that encourage the uptake of efficient and effective health-care technologies. This chapter provides a basic framework for conducting an HTA, as well as some fundamental concepts and challenges in assessing health technologies. Whether HTA is beneficial-supporting timely access to needed technologies-or detrimental depends on three critical issues: when the assessment is performed; how it is performed; and how the findings are used.

What Influences the Cost Effectiveness of Dabigatran versus Warfarin for Stroke Prevention in Atrial Fibrillation: A Systematic Review.

OBJECTIVES: The introduction of new oral anticoagulants for the prevention of stroke in atrial fibrillation (AF) has changed the clinical management of AF. To inform decision making around dabigatran by identifying factors influencing cost-effectiveness results, we undertook a systematic review of economic evaluations of dabigatran versus warfarin for the prevention of stroke in AF patients. METHODS: A systematic literature search of Ovid Medline and Embase, Wiley's Cochrane Library, HEED, PubMed databases and grey literature was carried out for primary economic evaluations comparing dabigatran versus warfarin in patients with AF. Data on study characteristics, model inputs and results, and sensitivity analyses were abstracted and synthesized qualitatively. RESULTS: Twenty-three economic evaluations were identified and RE-LY was cited in 52% of studies as the source of the efficacy data. Twenty evaluations used Markov modelling, 2 performed discrete event simulation, and 1 was a trial-based evaluation. Eighty-two percent reported base case incremental cost-effectiveness ratios (ICERs) of less than $50,000 USD/QALY. Key variables, including international normalized ratio (INR) control, the cost of monitoring, risk of stroke and bleeding, and age were found to alter the conclusions in only a few studies. Less commonly explored factors included time horizon and cost of long-term care follow-up. CONCLUSIONS: Several factors should be considered when interpreting the results of economic analyses which are based on randomized clinical trial evidence. Real-world data are needed to further assess the clinical and economic consequences of dabigatran relative to warfarin for the prevention of stroke in AF.

Interventions for preventing, delaying the onset, or decreasing the burden of frailty: an overview of systematic reviews.

BACKGROUND: Many systematic reviews have evaluated the effectiveness of interventions to prevent, delay, or decrease frailty symptoms, but no effort has been made to identify, map, and synthesize the findings from reviews across the full spectrum of interventions. Our objectives are to (1) synthesize findings from all existing systematic reviews evaluating interventions for preventing, delaying the onset, or decreasing the burden of frailty symptoms; (2) examine different conceptualizations of frailty that have been used in the development and implementation of interventions; and (3) inform policy by convening a stakeholder dialogue with Canadian health-system leaders. METHODS/DESIGN: We will conduct an overview of systematic reviews to identify and synthesize all of the systematic reviews addressing interventions to preventing, delaying the onset, or decreasing the burden of frailty symptoms. To identify relevant systematic reviews, we will conduct database searches for published and grey literature as well as contact key experts and search reference lists of included reviews. Two reviewers will independently review all search results for inclusion and then conceptually map, extract key findings (including the conceptualization/definition of frailty used) and assess the methodological quality of all included reviews. We will then synthesize the findings by producing a 'gap map' (i.e. mapping reviews in a matrix according to the interventions and outcomes assessed), and narratively synthesize the key messages across reviews related to type of interventions. DISCUSSION: Following the completion of the synthesis, we will use the findings to develop an evidence brief that mobilizes the best available evidence about the problem related to preventing, delaying the onset, or decreasing the burden of frailty symptoms in older adults, policy and programmatic options to address the problem and implementation considerations. The evidence brief will then be used as the input into a stakeholder dialogue, which will engage 18-22 Canadian health-system leaders (including policymakers, health providers, researchers, and other stakeholders) in 'off-the-record' deliberations to inform future actions and policymaking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015022082.

Pulmonary Rehabilitation in Ontario: A Cross-Sectional Survey.

BACKGROUND: Pulmonary rehabilitation (PR) is a comprehensive intervention of exercise training, education, and behaviour change to improve the physical and psychological condition of people with chronic respiratory disorders, such as chronic obstructive pulmonary disease (COPD) and to promote long-term adherence to health-enhancing behaviours. Although PR is considered the standard of care for patients with COPD who remain symptomatic despite bronchodilator therapies, current evidence suggests that only 1.15% of COPD patients across Canada have access to PR facilities for care. OBJECTIVES: The objectives of this study were to identify the number of health care facilities across Ontario providing PR services for patients with COPD, describe the scope of those services, and determine the province's current capacity to provide PR services relative to need, for the province as a whole and by local health integration network (LHIN). METHODS: The Pulmonary Rehabilitation Programs in Ontario (PRO) Survey was a province-wide, descriptive, cross-sectional survey of health care facilities (hospitals, family health teams, and community health centres). It was distributed to 409 facilities to collect information on various aspects of PR services in the province. RESULTS: Between April 2013 and February 2014, 187 facilities responded to the survey (46% response rate). Most responding centres (144) did not offer PR services, and only 43 were full PR sites providing a comprehensive program. Hospital-based programs made up the majority of sites offering full PR services (67%), followed by programs based at family health teams (19%) and community health centres (14%). More than 90% of PR programs are outpatient-based. The average wait time for outpatient PR was 6.9 weeks, and 58% of programs provide services 5 days per week. More than 80% of patients attending PR complete the full program. Across all program types, the total estimated provincial capacity for PR outpatient care is 4,524 patients per year, or 0.66% to 1.78% of patients with COPD, depending on the estimated prevalence of disease. LIMITATIONS: These results are representative of 12 of the 14 LHINs in Ontario due to low response rates in facilities in 2 LHINs. CONCLUSIONS: Although some increase in capacity has occurred since a similar survey in 2005, PR resources in Ontario are insufficient to support the delivery of care to people with COPD in accordance with clinical practice guideline recommendations.

Evidence-based decision-making 3: Health technology assessment.

This chapter begins with a brief introduction to health technology assessment (HTA). HTA is concerned with the systematic evaluation of the consequences of the adoption and use of new health technologies and improving the evidence on existing technologies. The objective of mainstream HTA is to support evidence-based decision- and policy-making that encourage the uptake of efficient and effective health care technologies. This chapter provides a basic framework for conducting an HTA as well as some fundamental concepts and challenges in assessing health technologies. A case study of the assessment of drug eluting stents in Ontario is presented to illustrate the HTA process. Whether HTA is beneficial-supporting timely access to needed technologies-or detrimental depends on three critical issues: when the assessment is performed; how it is performed; and how the findings are used.

Methodological guidance documents for evaluation of ethical considerations in health technology assessment: a systematic review.

Despite the advances made in the development of ethical frameworks for health technology assessment (HTA), there is no clear agreement on the scope and details of a practical approach to address ethical aspects in HTA. This systematic review aimed to identify existing guidance documents for incorporation of ethics in HTA to provide an overview of their methodological features. The review identified 43 conceptual frameworks or practical guidelines, varying in their philosophical approach, structure, and comprehensiveness. They were designed for different purposes throughout the HTA process, ranging from helping HTA-producers in identification, appraisal and analysis of ethical data to supporting decision-makers in making value-sensitive decisions. They frequently promoted using analytical methods that combined normative reflection with participatory approaches. The choice of a method for collection and analysis of ethical data seems to depend on the context in which technology is being assessed, the purpose of analysis, and availability of required resources.

Safety of tissue expander/implant versus autologous abdominal tissue breast reconstruction in postmastectomy breast cancer patients: a systematic review and meta-analysis.

BACKGROUND: Breast reconstruction after mastectomy for breast cancer should be informed by evidence-based knowledge, such as complication rates. The authors compared the safety of tissue expander/implant reconstruction with that of autologous abdominal tissue reconstruction. METHODS: A systematic literature review identified peer-reviewed studies published from January of 2000 to October of 2012 that compared tissue expander/implant against autologous abdominal tissue reconstruction in the MEDLINE, EMBASE, Cochrane Library, PubMed, and ProQuest Dissertations and Theses databases. Two reviewers independently screened all reports and selected the relevant articles using specific inclusion criteria. Data were extracted from the relevant articles using a standardized abstraction form. RESULTS: Fourteen observational studies were identified that included more than 3000 reconstructed breasts. Significant differences were found between these two approaches. The relative risk associated with reconstructive failure favored autologous abdominal tissue (relative risk, 0.14; 95 percent CI, 0.06 to 0.32; I = 0 percent). Surgical-site infection was significantly lower in autologous abdominal tissue reconstruction compared with tissue expander/implant (relative risk, 0.37; 95 percent CI, 0.25 to 0.55; I = 0 percent), although skin or flap necrosis was higher in autologous abdominal tissue reconstruction compared with tissue expander/implant (relative risk, 2.79; 95 percent CI, 1.87 to 4.17). Studies were of low to moderate quality according to the Newcastle-Ottawa scale. CONCLUSIONS: This study suggests that tissue expander/implant reconstruction has a higher risk of reconstructive failure and surgical-site infection compared with autologous abdominal tissue reconstruction. With the lack of long-term safety studies on different approaches to breast reconstruction, additional long-term comparative studies are needed to support evidence-based decision-making. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Cost-effectiveness of catheter ablation for rhythm control of atrial fibrillation.

Objective. The objective of this study is to evaluate the cost-effectiveness of catheter ablation for rhythm control compared to antiarrhythmic drug (AAD) therapy in patients with atrial fibrillation (AF) who have previously failed on an AAD. Methods. An economic model was developed to compare (1) catheter ablation and (2) AAD (amiodarone 200 mg/day). At the end of the initial 12 month phase of the model, patients are classified as being in normal sinus rhythm or with AF, based on data from a meta-analysis. In the 5-year Markov phase of the model, patients are at risk of ischemic stroke each 3-month model cycle. Results. The model estimated that, compared to the AAD strategy, ablation had $8,539 higher costs, 0.033 fewer strokes, and 0.144 more QALYS over the 5-year time horizon. The incremental cost per QALY of ablation compared to AAD was estimated to be $59,194. The probability of ablation being cost-effective for willingness to pay thresholds of $50,000 and $100,000 was estimated to be 0.89 and 0.90, respectively. Conclusion. Based on current evidence, pulmonary vein ablation for treatment of AF is cost-effective if decision makers willingness to pay for a QALY is $59,194 or higher.

Harmonization of reimbursement and regulatory approval processes: a systematic review of international experiences.

A considerable degree of overlap exists between reimbursement and regulatory approval of health technologies, and harmonization of certain aspects is both possible and feasible. Various models to harmonization have been suggested in which a number of practical attempts have been drawn from. Based on a review of the literature, approaches can be categorized into those focused on reducing uncertainty and developing economies of scale in the evidentiary requirements; and/or aligning timeframes and logistical aspects of the review process. These strategies can further be classified based on the expected level of structural and organizational change required to implement them into the existing processes. Passive processes require less modification, whereas active processes are associated with greater restructuring. Attempts so far at harmonization have raised numerous legal and practical issues and these must be considered when introducing a more harmonized framework into the existing regulatory and reimbursement arrangements.

Hyperbaric oxygen therapy for diabetic ulcers: systematic review and meta-analysis.

OBJECTIVES: Approximately 10-15 percent of individuals with diabetes mellitus develop foot ulcers, which precede 85 percent of amputations. Increased oxygen, through the use of hyperbaric oxygen therapy (HBOT), has been suggested to encourage ulcer healing thus reducing the risk of amputation. The objective of this systematic review is to evaluate the efficacy of systemic HBOT for nonhealing ulcers of the lower limb in diabetes patients. METHODS: A systematic search, using controlled and keyword terms focusing on "HBOT" and "lower limb diabetic ulcers," was conducted. Databases searched included Medline, EMBASE, CINAHL, PubMed, Wiley's Cochrane Library, and Biosis. Randomized controlled trials (RCTs) and observational studies were included. Pooled estimates of outcomes were determined when appropriate. RESULTS: Of the 654 citations identified, 157 articles underwent full-text review. Data were abstracted from twelve publications (six RCTs and six comparative observational studies). Pooled analysis of the RCT and observational data showed that treatment with HBOT reduced the risk of major amputation by 60 percent (p = .29) and 61 percent (p = .003) compared with standard wound care, respectively. The RCT data revealed that the relative risk of having an unhealed wound following HBOT was 0.54 (p = .10) and 0.24 (p < .0001) based on observational data. CONCLUSIONS: Due to the limited RCT evidence, it is not possible to conclusively establish the benefits and harms of treating diabetic lower limb ulcers with HBOT. No significant effects on amputation rates were found in the RCT evidence and in the high quality studies, no difference was found.

Cost-effectiveness of pharmaceutical management for osteoarthritis pain: a systematic review of the literature and recommendations for future economic evaluation.

BACKGROUND AND OBJECTIVE: Osteoarthritis (OA) is a highly prevalent and chronic condition characterized by pain and physical disability. Currently, many treatments are available, and they primarily target pain relief. The objectives of this study were to systematically review economic evaluations for pharmaceutical management of OA pain and to provide methodological recommendations for future economic evaluation. METHODS: Published literature was identified by searching the following bibliographic databases: MEDLINE (1948-16 November 2011) with In-Process records and EMBASE (1980-2011 Week 47) via Ovid; The Cochrane Library (Issue 4 of 4, 2011) and the Health Economic Evaluations Database (HEED) via Wiley; and PubMed (for non-MEDLINE records). The main search terms were OA and economic evaluations. Two reviewers independently screened all identified articles and extracted the data from those included in the final review. RESULTS: Twelve articles reporting the cost-effectiveness of various pharmaceuticals were included, with five being trial-based and seven being model-based economic evaluations. The mean health economics quality score of the included articles was 84 (minimum-maximum: 63-99). These evaluations varied in study design, treatments compared, and outcomes measured. CONCLUSION: The existing economic evaluations on pharmaceutical management of OA pain were of acceptable quality. Comparability of economic evaluations could be improved by selecting standard comparators, adopting a longer time horizon, and directly measuring health utilities.

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer.

BACKGROUND: Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3-4 weeks. Less frequent ('de-escalated') treatment may provide similar benefits with improved safety and reduced cost. METHODS: To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.e. every 12-16 weeks) to standard treatment (i.e. every 3-4 weeks), a formal systematic review of the literature was performed. Two individuals independently screened citations and full text articles. Random effects meta-analyses of clinically important outcomes were planned provided homogeneous studies were identified. RESULTS: Five relevant studies (n=1287 patients) were identified. Sample size ranged from 38 to 425. Information on outcomes including occurrence of SREs, bone pain, urinary N-telopeptide concentrations, serum C-telopeptide concentrations, pain medication use and safety outcomes was not consistently available. Two trials were non-inferiority studies, two dose-response evaluations and one was a pilot study. Bone-targeted agents use varied between studies, as did duration of prior therapy. Patient populations were considered heterogeneous in several ways, and thus no meta-analyses were performed. Observations from the included studies suggest there is potential that 3 month de-escalated treatment may provide similar benefits compared to 3-4 weekly treatment and that lower doses of zoledronic acid and denosumab might be equally effective. CONCLUSIONS: Studies comparing standard and de-escalated treatment with bone-targeted agents in breast cancer are rare. The benefits of standard treatment compared to de-escalated therapy on important clinical outcomes remain unclear. Future pragmatic studies must be conducted to determine the merits of this approach.

Canadian cost- utility analysis of intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) is a hematological disorder and can be classified as acute or chronic. The main goal of treatment for acute childhood ITP is the prevention of potentially fatal bleeding complications, the most serious of which is intracranial hemorrhage (ICH). Treatment options for acute childhood ITP include splenectomy, corticosteroids, and blood products such as intravenous immunoglobulin. OBJECTIVES: The objective was to evaluate, from a Canadian perspective, the cost-effectiveness of intravenous immunoglobulin (IVIG) compared to alternative inpatient treatments for acute childhood idiopathic thrombocytopenic purpura (ITP). METHODS: A Markov model with a lifelong time horizon was used to evaluate the costs and quality-adjusted life years (QALYs) for 5 treatments for children hospitalized for ITP: 1) no treatment; 2) IVIG; 3) Anti-D; 4) prednisone; and 5) methylprednisolone. The model predicted the probability of intracranial hemorrhage for each treatment strategy based on the time children spent with platelet counts <20,000µL. The time patients spent with platelet counts <20,000µL with each treatment was estimated by pooling data from published randomized clinical trials. In the basecase analysis, the cohort was assumed to weigh 20kg. Cost and utility model variables were based upon various literature sources. Parameter uncertainty was assessed using probabilistic sensitivity analysis. RESULTS: The treatment strategies that comprised the efficiency frontier were prednisone, Anti-D and IVIG. The incremental cost per QALY was $53,333 moving from prednisone to Anti-D and $53,846 moving from Anti-D to IVIG. Results were sensitive to patient weight. If patient weight is 10kg, IVIG dominates all other strategies and if weight is increased to 30kg, the cost per QALY of IVIG is $163,708. CONCLUSION: Based on common willingness to pay thresholds, IVIG might be considered a cost effective treatment for acute childhood ITP. Cost effectiveness is highly dependent on patient weight.