Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials.

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms. METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI). RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes. CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomized trials.

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper.

Measuring the impact of zero-cases studies in evidence synthesis practice using the harms index and benefits index (Hi-Bi).

OBJECTIVES: In evidence synthesis practice, dealing with studies with no cases in both arms has been a tough problem, for which there is no consensus in the research community. In this study, we propose a method to measure the potential impact of studies with no cases for meta-analysis results which we define as harms index (Hi) and benefits index (Bi) as an alternative solution for deciding how to deal with such studies. METHODS: Hi and Bi are defined by the minimal number of cases added to the treatment arm (Hi) or control arm (Bi) of studies with no cases in a meta-analysis that lead to a change of the direction of the estimates or its statistical significance. Both exact and approximating methods are available to calculate Hi and Bi. We developed the "hibi" module in Stata so that researchers can easily implement the method. A real-world investigation of meta-analyses from Cochrane reviews was employed to evaluate the proposed method. RESULTS: Based on Hi and Bi, our results suggested that 21.53% (Hi) to 26.55% (Bi) of Cochrane meta-analyses may be potentially impacted by studies with no cases, for which studies with no cases could not be excluded from the synthesis. The approximating method shows excellent specificity (100%) for both Hi and Bi, moderate sensitivity (68.25%) for Bi, and high sensitivity (80.61%) for Hi compared to the exact method. CONCLUSIONS: The proposed method is practical and useful for systematic reviewers to measure whether studies with no cases impact the results of meta-analyses and may act as an alternative solution for review authors to decide whether to include studies with no events for the synthesis or not.

Validity of data extraction in evidence synthesis practice of adverse events: reproducibility study.

OBJECTIVES: To investigate the validity of data extraction in systematic reviews of adverse events, the effect of data extraction errors on the results, and to develop a classification framework for data extraction errors to support further methodological research. DESIGN: Reproducibility study. DATA SOURCES: PubMed was searched for eligible systematic reviews published between 1 January 2015 and 1 January 2020. Metadata from the randomised controlled trials were extracted from the systematic reviews by four authors. The original data sources (eg, full text and ClinicalTrials.gov) were then referred to by the same authors to reproduce the data used in these meta-analyses. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews were included when based on randomised controlled trials for healthcare interventions that reported safety as the exclusive outcome, with at least one pair meta-analysis that included five or more randomised controlled trials and with a 2×2 table of data for event counts and sample sizes in intervention and control arms available for each trial in the meta-analysis. MAIN OUTCOME MEASURES: The primary outcome was data extraction errors summarised at three levels: study level, meta-analysis level, and systematic review level. The potential effect of such errors on the results was further investigated. RESULTS: 201 systematic reviews and 829 pairwise meta-analyses involving 10 386 randomised controlled trials were included. Data extraction could not be reproduced in 1762 (17.0%) of 10 386 trials. In 554 (66.8%) of 829 meta-analyses, at least one randomised controlled trial had data extraction errors; 171 (85.1%) of 201 systematic reviews had at least one meta-analysis with data extraction errors. The most common types of data extraction errors were numerical errors (49.2%, 867/1762) and ambiguous errors (29.9%, 526/1762), mainly caused by ambiguous definitions of the outcomes. These categories were followed by three others: zero assumption errors, misidentification, and mismatching errors. The impact of these errors were analysed on 288 meta-analyses. Data extraction errors led to 10 (3.5%) of 288 meta-analyses changing the direction of the effect and 19 (6.6%) of 288 meta-analyses changing the significance of the P value. Meta-analyses that had two or more different types of errors were more susceptible to these changes than those with only one type of error (for moderate changes, 11 (28.2%) of 39 v 26 (10.4%) 249, P=0.002; for large changes, 5 (12.8%) of 39 v 8 (3.2%) of 249, P=0.01). CONCLUSION: Systematic reviews of adverse events potentially have serious issues in terms of the reproducibility of the data extraction, and these errors can mislead the conclusions. Implementation guidelines are urgently required to help authors of future systematic reviews improve the validity of data extraction.

Study of natural product adverse events in adult HIV-infected patients in Canada.

INTRODUCTION: Many individuals living with HIV use natural health products (NHPs) in an effort to decrease medication side effects and to enhance overall well-being. METHODS: An active surveillance study of adult patients (≥ 18 years) with HIV was conducted between 2012 and 2014 to detect prescription drug and NHP use and associated adverse events (AEs) in the last month. RESULTS: Of the 167 participants, 85 (50.9%) took prescription medications only, three (1.8%) took NHPs only, 75 (44.9%) took NHPs and prescription medications concurrently, and four (2.4%) took neither. Patients who used both prescription drugs and NHPs concurrently were more than three times more likely to experience an AE compared with those who used prescription drugs only (OR, P = 0.003, 95% CI: 1.47-6.91). CONCLUSIONS: Increased AEs are reported in patients with HIV who combine NHPs and prescription medications, and no serious AEs were reported. Active surveillance was found to be feasible in this clinical setting.

Study of Natural Products Adverse Reactions (SONAR) in Adults with Mental Health Conditions: A Cross-Sectional Study.

INTRODUCTION: Mental illness is a leading cause of non-fatal disease burden worldwide. Natural health products (NHPs) are sought by patients with mental health conditions as a safer and more 'natural' option than conventional pharmacotherapy; however, the possible adverse events (AE) and interactions between NHPs and prescription medicines are not fully known. OBJECTIVES: The aim of this study was to determine (i) the prevalence of adult patients with mental health conditions taking prescription medications only, NHPs only, NHPs and prescription medications concurrently, or neither, (ii) which prescription medications and NHPs are most commonly used, (iii) AEs (serious and non-serious) experienced in the last 30 days for each product use group. METHODS: Mental health clinics in Alberta and Ontario, Canada, were included in an active surveillance study investigating NHP-drug interactions. On their first clinic visit, adult mental health patients were provided with a form inquiring about prescription drug use, NHP use, and any undesirable health events experienced in the last month. Healthcare professionals were also asked to report AEs. RESULTS: A total of 3079 patients were screened at 11 mental health clinics in Alberta and Ontario. In total, 620 AEs were reported in 447 patients (14.9%). The majority of adverse events were seen in patients using both NHPs and prescription medicines (58.8%), followed by patients taking only prescription medicines (37.1%), NHPs only (3.4%) and neither (0.67%). Combining NHPs and prescription medications increases the likelihood of experiencing AEs (OR 2.1; p < 0.001; 95% CI 1.7-2.6). CONCLUSIONS: Adult patients with mental health conditions who are taking both prescription medications and NHPs are more likely to report an adverse event than patients taking prescription drugs or NHPs alone. Polypharmacy increases the likelihood of an adverse event. Active surveillance is feasible and could contribute to enhanced pharmacovigilance.

Utilization of the evidence from studies with no events in meta-analyses of adverse events: an empirical investigation.

BACKGROUNDS: Zero-events studies frequently occur in systematic reviews of adverse events, which consist of an important source of evidence. We aimed to examine how evidence of zero-events studies was utilized in the meta-analyses of systematic reviews of adverse events. METHODS: We conducted a survey of systematic reviews published in two periods: January 1, 2015, to January 1, 2020, and January 1, 2008, to April 25, 2011. Databases were searched for systematic reviews that conducted at least one meta-analysis of any healthcare intervention and used adverse events as the exclusive outcome. An adverse event was defined as any untoward medical occurrence in a patient or subject in healthcare practice. We summarized the frequency of occurrence of zero-events studies in eligible systematic reviews and how these studies were dealt with in the meta-analyses of these systematic reviews. RESULTS: We included 640 eligible systematic reviews. There were 406 (63.45%) systematic reviews involving zero-events studies in their meta-analyses, among which 389 (95.11%) involved single-arm-zero-events studies and 223 (54.93%) involved double-arm-zero-events studies. The majority (98.71%) of these systematic reviews incorporated single-arm-zero-events studies into the meta-analyses. On the other hand, the majority (76.23%) of them excluded double-arm-zero-events studies from the meta-analyses, of which the majority (87.06%) did not discuss the potential impact of excluding such studies. Systematic reviews published at present (2015-2020) tended to incorporate zero-events studies in meta-analyses than those published in the past (2008-2011), but the difference was not significant (proportion difference=-0.09, 95% CI -0.21 to 0.03, p = 0.12). CONCLUSION: Systematic review authors routinely treated studies with zero-events in both arms as "non-informative" carriers and excluded them from their reviews. Whether studies with no events are "informative" or not largely depends on the methods and assumptions applied, thus sensitivity analyses using different methods should be considered in future meta-analyses.

Adverse Events of Mind-Body Interventions in Children: A Systematic Review.

Mind-body interventions (MBIs) are one of the top ten complementary approaches utilized in pediatrics, but there is limited knowledge on associated adverse events (AE). The objective of this review was to systematically review AEs reported in association with MBIs in children. In this systematic review the electronic databases MEDLINE, Embase, CINAHL, CDSR, and CCRCT were searched from inception to August 2018. We included primary studies on participants ≤ 21 years of age that used an MBI. Experimental studies were assessed for whether AEs were reported on or not, and all other study designs were included only if they reported an AE. A total of 441 were included as primary pediatric MBI studies. Of these, 377 (85.5%) did not explicitly report the presence/absence of AEs or a safety assessment. There were 64 included studies: 43 experimental studies reported that no AE occurred, and 21 studies reported AEs. There were 37 AEs found, of which the most serious were grade 3. Most of the studies reporting AEs did not report on severity (81.0%) or duration of AEs (52.4%). MBIs are popularly used in children; however associated harms are often not reported and lack important information for meaningful assessment.

A proposed framework to guide evidence synthesis practice for meta-analysis with zero-events studies.

OBJECTIVE: In evidence synthesis practice, researchers often face the problem of how to deal with zero-events. Inappropriately dealing with zero-events studies may lead to research waste and mislead healthcare practice. We propose a framework to guide researchers to better deal with zero-events in meta-analysis. STUDY DESIGN AND SETTING: We used two dimensions, one with respect to the total events count across all studies in the comparative arms in a meta-analysis, and a second with respect to whether included studies have single or both arms with zero-events, to establish the framework for the classification of meta-analysis with zero-events studies. A dataset from Cochrane systematic reviews was used to evaluate the classification. RESULTS: The proposed framework classifies meta-analysis with zero-events studies into six subtypes. The classification matched well to the large real-world dataset. The applicability of existing methods for zero-events were then presented under each meta-analysis subtype based on this framework, with a 5-step principle to help researchers in evidence synthesis practice. CONCLUSIONS: The proposed framework should be considered by researchers when making decisions on the selection of the synthesis methods in a meta-analysis. It also provides a reasonable basis for the development of methodological guidelines to deal with zero-events in meta-analysis.

Massage therapy for paediatric procedural pain: A rapid review.

BACKGROUND: Pain is a common paediatric problem, and procedural pain, in particular, can be difficult to manage. Complementary therapies are often sought for pain management, including massage therapy (MT). We assessed the evidence for use of MT for acute procedural pain management in children. METHODS: We searched five main databases for (i) primary studies in English, (ii) included children 0 to 18 years of age, (iii) compared MT for procedural pain management to standard care alone or placebo, and (iv) measured pain as the primary or secondary outcome. The data were extracted by one author and verified by a second author. Randomized controlled trials were evaluated using the Cochrane Risk of Bias tool. RESULTS: Eleven paediatric trials of procedural pain in neonatal, burn, and oncology populations, a total of 771 participants, were identified. Eight reported statistically significant reductions in pain after MT compared to standard care. Pain was measured using validated pain scales, or physiologic indicators. The studies were heterogeneous in population, techniques, and outcome measures used. No adverse events associated with MT were identified. CONCLUSION: MT may be an effective nonpharmacologic adjunct for management of procedural pain in children.

Study of Natural products Adverse Reactions (SONAR) in children seen in mental health clinics: a cross-sectional study.

BACKGROUND: Paediatric mental health patients frequently use natural health products (NHP) in addition to prescription medications, but very little is known about adverse events and possible NHP-drug interactions. OBJECTIVE: To determine: (1) the prevalence of paediatric mental health patients taking prescription medications only, NHP only, both NHP and prescription medications concurrently or neither; (2) which prescription medications and NHP are most commonly used in paediatric mental health populations and (3) adverse events experienced in the last 30 days (serious and non-serious). DESIGN: Cross-sectional surveillance study. SETTING: Paediatric mental health clinics. POPULATION/INTERVENTION: On their first clinic visit, paediatric mental health patients were provided with a form inquiring about prescription drug use, NHP use and any undesirable event experienced in the last month. RESULTS: Of the 536 patients included in this study, 23% (n=120) reported taking only prescription medication(s), 21% (n=109) reported only NHP use, 21% (n=112) reported using both NHP and prescription drugs concurrently, and 36% (n=191) reported using neither. Overall, there were 23 adverse events reported; this represents 6.3%, 2.8%, 10.8% and 0.6% of each population, respectively. The majority of patients who experienced an adverse event reported taking more than one NHP or prescription drug. No serious adverse events were reported. CONCLUSION: Nearly half of the paediatric mental health patients in this study were taking NHPs alone or in addition to prescription medications. Active surveillance identified multiple adverse events associated with NHP and prescription drug use; none were serious. Healthcare professionals were encouraged to initiate conversations regarding NHP use.

Adverse events associated with paediatric massage therapy: a systematic review.

INTRODUCTION: Massage therapy (MT) is frequently used in children. No study has systematically assessed its safety in children and adolescents. We systematically review adverse events (AEs) associated with paediatric MT. METHODS: We searched seven electronic databases from inception to December 2018. We included studies if they (1) were primary studies published in a peer-reviewed journal, (2) involved children aged 0-18 years and (3) a type of MT was used for any indication. No restriction was applied to language, year of publication and study design. AEs were classified based on their severity and association to the intervention. RESULTS: Literature searches identified 12 286 citations, of which 938 citations were retrieved for full-text evaluation and 60 studies were included. In the included studies, 31 (51.6%) did not report any information on AEs, 13 (21.6%) reported that no AE occurred and 16 studies (26.6%) reported at least one AE after MT. There were 20 mild events (grade 1) that resolved with minimal intervention, 26 moderate events (grades 2-3) that required medical intervention, and 18 cases of severe AEs (grades 4-5) that resulted in hospital admission or prolongation of hospital stay; of these, 17 AEs were volvulus in premature infants, four of which were ultimately fatal events. CONCLUSION: We identified a range of AEs associated with MT use, from mild to severe. Unfortunately, the majority of included studies did not report if an AE occurred or not, leading to publication bias. This review reports an association between abdominal massage with volvulus without malrotation in preterm infants; it is still to be defined if this is casual or not, but our findings warrant caution in the use of abdominal massage in preterm infants.

Probiotics for paediatric functional abdominal pain disorders: A rapid review.

BACKGROUND: Functional abdominal pain disorders (FAPD) are prevalent in the paediatric population, however, there is currently no consensus regarding best practices for treatment. The use of probiotics is becoming popular to treat FAPD. The goal of this rapid review is to synthesize the best evidence on the use of probiotics in children with FAPD. METHODS: Searches were conducted on five main databases. Randomized controlled trials (RCTs) of probiotic use in children (0 to 18 years) with FAPD were searched. Populations of interest were patients with functional abdominal pain (FAP), irritable bowel syndrome (IBS), and functional dyspepsia (FD), recruited based on Rome criteria. Outcomes of interest were changes in abdominal pain severity, frequency, and duration. FINDINGS: Eleven RCTs with 829 participants with the diagnosis of FAP (n=400), IBS (n=329), FD (n=45), and mixed population (n=55) were included. Of six studies of children with FAP, two (n=103) used Lactobacillus rhamnosus GG (LGG) and reported no significant effects on pain, and four (n=281) used Lactobacillus (L) reuteri DSM 17938, of which three (n=229) reported significant positive effects on either severity or frequency of pain. Of six trials of children with IBS, four (n=219) used LGG, of which three (n=168) reported a positive effect. One (n=48) used bifidobacteria and one used VSL #3 (n=59), both demonstrating positive effects with probiotics. Two studies of FD reported no benefit. No adverse events were attributed to probiotics. CONCLUSIONS: There is preliminary evidence for use of probiotics, particularly LGG, in reducing abdominal pain in children with IBS. There are inconsistent positive effects of other probiotics, including L. reuteri DSM 17938, in reducing pain in patients with FAP, IBS, or FD. More RCTs with rigorous methodology using single or combination probiotics are warranted.

Efficacy of music on sedation, analgesia and delirium in critically ill patients. A systematic review of randomized controlled trials.

PURPOSE: To systematically synthesize randomized controlled trial data on the efficacy of music to provide sedation and analgesia, and reduce incidence of delirium, in critically ill patients. MATERIAL AND METHODS: Relevant databases (Medline, PubMed, Embase, CINAHL, Cochrane, Alt Healthwatch, LILACS, PsycINFO, CAIRSS, RILM) were searched from inception to April 26, 2018. We also searched the reference lists of included publications and for ongoing trials. The selection of relevant articles was conducted by two researchers at two levels of screening. Data collection followed the recommendations from the Cochrane Systematic Reviews Handbook. We used the Cochrane Collaboration's tool for assessing risk of bias. Quality of the evidence was rated according to GRADE. RESULTS: The review identified six adult studies and no neonatal or pediatric studies. A descriptive analysis of study results was performed. Meta-analysis was not feasible due to heterogeneity. One study reported a reduction in sedation requirements with the use of music while the other five did not find any significant differences across groups. CONCLUSIONS: This systematic review revealed limited evidence to support or refute the use of music to reduce sedation/analgesia requirements, or to reduce delirium in critically ill adults, and no evidence in pediatric and neonatal critically ill patients.

Setting a research agenda for pediatric complementary and integrative medicine: A consensus approach.

BACKGROUND: Pediatric use of complementary medicine (CM) is common and offers numerous research questions about diverse therapies and conditions. Although research priorities for pediatric CM have been identified, there was a need to update in light of the rapid evolution of the field. METHODS: Building on previous work, we conducted an international, consensus-based 4-step modified Delphi process to develop and refine a pediatric CM research agenda, including on-line questionnaires and an in-person meeting. Participants included health care professionals, researchers, and educators. RESULTS: We received 376 responses; participants included conventional and CM providers, researchers, educators, administrators, and policy-makers from 15 countries (Australia, Bangladesh, Belgium, Canada, China, Germany, India, Israel, Italy, New Zealand, Norway, Sri Lanka, The Netherlands, United Kingdom, and United States). While it was recognized that each region must set their own priorities based on use, access, and expertise, a "minimum set" for a pediatric CM research agenda was identified. After three rounds of surveys, participants identified the highest priorities for pediatric CM research as: (i) safety of CM therapies for infants, children, and adolescents; (ii) conditions for which CM use is highly prevalent and for which conventional medicine lacks safe, cost-effective therapies; iii) therapies/therapists to be examined for quality and reproducibility of interventions, comparative and cost effectiveness, dose, etc.; and iv) identification of relevant outcomes and outcome measurement tools. CONCLUSIONS: The results of our study identify that "first do no harm" is the leading research priority for pediatric CM research, followed by more research on effectiveness of CM therapies for conditions not safely and effectively treated with conventional care. In order to improve pediatric health care, interdisciplinary collaborative approaches are needed between CM and conventional providers and researchers.

Tool to assess causality of direct and indirect adverse events associated with therapeutic interventions.

OBJECTIVE: To develop and test a tool to assess the causality of direct and indirect adverse events associated with therapeutic interventions. The intervention was one or more drugs and/or natural health products, a device, or practice (professional delivering the intervention). METHODS: Through the assessment of causality of adverse events, we can learn about factors contributing to the harm and consider what modification may prevent its reoccurrence. Existing scales (WHO-UMC, Naranjo and Horn) were adapted to develop a tool (algorithm and table) to evaluate cases of serious harmful events reported through a national surveillance study. We also incorporated a novel approach that assesses indirect harm (caused by the delay in diagnosis/treatment) and the health provider delivering the intervention (practice). The tool was tested, revised and then implemented to assess all reported cases of serious events resulting from use of complementary therapies. The use of complementary therapies was the trigger to report the event. Each case was evaluated by two assessors, out of a panel of five, representing different health care professionals. RESULTS: The tool was used in assessment of eight serious adverse events. Each event was independently evaluated by two assessors. The algorithm facilitated assessment of a serious direct or indirect harm. Assessors agreed in the final score on seven of eight cases (weighted kappa coefficient of 0.75). CONCLUSION: A tool to support the assessment of causality of adverse events was developed and tested. We propose a novel method to assess direct and indirect harms related to product(s), device(s), practice or a combination of the previous. Further research will probably help evaluate this approach across different settings and interventions.

Unfractionated heparin versus low molecular weight heparins for avoiding heparin-induced thrombocytopenia in postoperative patients.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction presenting as a prothrombotic disorder related to antibody-mediated platelet activation. It is a paradoxical immune reaction resulting in thrombin generation in vivo, which leads to a hypercoagulable state and the potential to initiate venous or arterial thrombosis. A number of factors are thought to influence the incidence of HIT including the type and preparation of heparin (unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) and the heparin-exposed patient population, with the postoperative patient population at higher risk.Although LMWH has largely replaced UFH as a front-line therapy, there is evidence supporting a lack of superiority of LMWH compared with UFH regarding prevention of deep vein thrombosis and pulmonary embolism following surgery, and similar frequencies of bleeding have been described with LMWH and UFH. The decision as to which of these two preparations of heparin to use may thus be influenced by harmful effects such as HIT. We therefore sought to determine the relative impact of UFH and LMWH on HIT in postoperative patients receiving thromboembolism prophylaxis. This is an update of a review first published in 2012. OBJECTIVES: The objective of this review was to compare the incidence of heparin-induced thrombocytopenia (HIT) and HIT complicated by venous thromboembolism in postoperative patients exposed to unfractionated heparin (UFH) versus low molecular weight heparin (LMWH). SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (May 2016), CENTRAL (2016, Issue 4) and trials registries. The authors searched Lilacs (June 2016) and additional trials were sought from reference lists of relevant publications. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which participants were postoperative patients allocated to receive prophylaxis with UFH or LMWH, in a blinded or unblinded fashion. Studies were excluded if they did not use the accepted definition of HIT. This was defined as a relative reduction in the platelet count of 50% or greater from the postoperative peak (even if the platelet count at its lowest remained greater than 150 x 109/L) occurring within five to 14 days after the surgery, with or without a thrombotic event occurring in this timeframe. Additionally, we required circulating antibodies associated with the syndrome to have been investigated through laboratory assays. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias. Disagreements were resolved by consensus with participation of a third author. MAIN RESULTS: In this update, we included three trials involving 1398 postoperative participants. Participants were submitted to general surgical procedures, minor and major, and the minimum mean age was 49 years. Pooled analysis showed a significant reduction in the risk of HIT with LMWH compared with UFH (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.07 to 0.73); low-quality evidence. The number needed to treat for an additional beneficial outcome (NNTB) was 59. The risk of HIT was consistently reduced comparing participants undergoing major surgical procedures exposed to LMWH or UFH (RR 0.22, 95% CI 0.06 to 0.75); low-quality evidence. The occurrence of HIT complicated by venous thromboembolism was significantly lower in participants receiving LMWH compared with UFH (RR 0.22, 95% CI 0.06 to 0.84); low-quality evidence. The NNTB was 75. Arterial thrombosis occurred in only one participant who received UFH. There were no amputations or deaths documented. Although limited evidence is available, it appears that HIT induced by both types of heparins is common in people undergoing major surgical procedures (incidence greater than 1% and less than 10%). AUTHORS' CONCLUSIONS: This updated review demonstrated low-quality evidence of a lower incidence of HIT, and HIT complicated by venous thromboembolism, in postoperative patients undergoing thromboprophylaxis with LMWH compared with UFH. Similarily, the risk of HIT in people undergoing major surgical procedures was lower when treated with LMWH compared to UFH (low-quality evidence). The quality of the evidence was downgraded due to concerns about the risk of bias in the included studies and imprecision of the study results. These findings may support current clinical use of LMWH over UFH as front-line heparin therapy. However, our conclusions are limited and there was an unexpected paucity of RCTs including HIT as an outcome. To address the scarcity of clinically-relevant information on HIT, HIT must be included as a core harmful outcome in future RCTs of heparin.

PRISMA harms checklist: improving harms reporting in systematic reviews.

INTRODUCTION: For any health intervention, accurate knowledge of both benefits and harms is needed. Systematic reviews often compound poor reporting of harms in primary studies by failing to report harms or doing so inadequately. While the PRISMA statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) helps systematic review authors ensure complete and transparent reporting, it is focused mainly on efficacy. Thus, a PRISMA harms checklist has been developed to improve harms reporting in systematic reviews, promoting a more balanced assessment of benefits and harms. METHODS: A development strategy, endorsed by the EQUATOR Network and existing reporting guidelines (including the PRISMA statement, PRISMA for abstracts, and PRISMA for protocols), was used. After the development of a draft checklist of items, a modified Delphi process was initiated. The Delphi consisted of three rounds of electronic feedback followed by an in-person meeting. RESULTS: The PRISMA harms checklist contains four essential reporting elements to be added to the original PRISMA statement to improve harms reporting in reviews. These are reported in the title ("Specifically mention 'harms' or other related terms, or the harm of interest in the review"), synthesis of results ("Specify how zero events were handled, if relevant"), study characteristics ("Define each harm addressed, how it was ascertained (eg, patient report, active search), and over what time period"), and synthesis of results ("Describe any assessment of possible causality"). Additional guidance regarding existing PRISMA items was developed to demonstrate relevance when synthesising information about harms. CONCLUSION: The PRISMA harms checklist identifies a minimal set of items to be reported when reviewing adverse events. This guideline extension is intended to improve harms reporting in systematic reviews, whether harms are a primary or secondary outcome.