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1.  Limitations of free-form-text diagnostic requisitions as a tool for evaluating adherence to appropriate use criteria for transthoracic echocardiography 
Background
Monitoring the adherence to Appropriateness Use Criteria (AUC) has been identified as an important component for the accreditation of echocardiography laboratories. Referral requisitions are a logical tool to rapidly determine the appropriateness of transthoracic echocardiography (TTE) referrals, however data is lacking. We investigated whether standard free-form-text TTE referral requisitions can be used to evaluate AUC adherence.
Methods
Consecutive TTE referral requisitions to the University of Ottawa Heart Institute echocardiography laboratory were reviewed over a four-week period. Indication on the requisition was matched with the relevant indication on the 2011 American College of Cardiology Foundation (ACCF) AUC. Requisitions that did not provide sufficient information to identify the relevant AUC indication were identified as inadequate. For inadequate requisitions, reason for the referral was clarified through medical records and referring physicians.
Results
Of the 1303 requisitions, 26.2% did not provide adequate information to determine adherence to AUC, despite a non-adherence (inappropriate) rate of only 6.1% in the referral population. Indication for referral, physician specialty, outpatient status, and prior echocardiogram were independent predictors of inadequate requisitions (p < 0.001, respectively). The most common reasons for inadequate requisitions were a failure to report: 1) change in clinical status, 2) date of a prior echocardiogram, and 3) type and/or severity of a valve lesion. Inclusion of this information would have decreased the inadequacy rate by 56%.
Conclusion
In a large, academic echocardiography laboratory, over one quarter of free-form-text TTE requisitions are inadequate to evaluate AUC adherence. Structured requisition formats requiring AUC-relevant information are needed to facilitate the practical application of AUC in the echocardiography laboratory.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-7120-13-4) contains supplementary material, which is available to authorized users.
doi:10.1186/1476-7120-13-4
PMCID: PMC4326475  PMID: 25592146
Transthoracic echocardiography; Appropriate use criteria; Diagnostic requisitions
2.  What Guidance Are Researchers Given on How to Present Network Meta-Analyses to End-Users such as Policymakers and Clinicians? A Systematic Review 
PLoS ONE  2014;9(12):e113277.
Introduction
Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users.
Methods
A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines.
Results
Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information.
Conclusions
Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs.
doi:10.1371/journal.pone.0113277
PMCID: PMC4269433  PMID: 25517510
3.  Effect of rapid HIV testing on HIV incidence and services in populations at high risk for HIV exposure: an equity-focused systematic review 
BMJ Open  2014;4(12):e006859.
Objective
To assess the effects of rapid voluntary counselling and testing (VCT) for HIV on HIV incidence and uptake of HIV/AIDS services in people at high risk for HIV exposure.
Design
Cochrane systematic review and meta-analysis.
Data sources
We searched PubMed, EMBASE, AIDSearch, LILACS, Global Health, Medline Africa, PsychInfo, CINAHL, Cochrane CENTRAL, Cochrane HIV/AIDS Group Specialized Register and grey literature from 1 January 2001 to 5 June 2014 without language restriction.
Data selection
We included controlled studies that compared rapid VCT with conventional testing among people at risk for HIV exposure.
Data extraction
Two reviewers extracted data. We used Cochrane risk of bias tool and GRADE criteria: risk of bias, inconsistency, indirectness, imprecision and publication bias. For observational studies we used the Newcastle-Ottawa Scale. We used the PRISMA-Equity reporting guideline.
Results
From 2441 articles, we included 8 randomised controlled trials and 5 observational studies. Rapid VCT was associated with a threefold increase in HIV-testing uptake (relative risk (RR)=2.95 95% CI 1.69 to 5.16) and a twofold increase in the receipt of test results (RR=2.14, 95% CI 1.08 to 4.24). Women accepted testing more often than men in rapid VCT arm, but no differences in effect for age or socioeconomic status. Observational studies also showed rapid VCT led to higher rates of uptake of testing. Heterogeneity was high. A cluster-randomised trial reported an 11% reduction in HIV incidence in intervention communities (RR=0.89, 95% CI=0.63 to 1.24) over 3 years trial.
Conclusions
Rapid VCT in health facilities and communities was associated with a large increase in HIV-testing uptake and receipt of results. This has implications for WHO guidelines. The routine use of rapid VCT may also help avoid human rights violations among marginalised populations where testing may occur without informed consent and where existing stigma may create barriers to testing.
doi:10.1136/bmjopen-2014-006859
PMCID: PMC4267075  PMID: 25510889
HIV Testing; Rapid VCT; HIV Services
4.  Updating the OMERACT Filter: Implications for imaging and soluble biomarkers 
The Journal of rheumatology  2014;41(5):1016-1024.
Objective
The OMERACT Filter provides a framework for the validation of outcome measures for use in rheumatology clinical research. However, imaging and biochemical measures may face additional validation challenges due to their technical nature. The Imaging and Soluble Biomarker Session at OMERACT 11 aimed to provide a guide for the iterative development of an imaging or biochemical measurement instrument so it can be used in therapeutic assessment.
Methods
A hierarchical structure was proposed, reflecting 3 dimensions needed for validating an imaging or biochemical measurement instrument: outcome domain(s), study setting and performance of the instrument. Movement along the axes in any dimension reflects increasing validation. For a given test instrument, the 3-axis structure assesses the extent to which the instrument is a validated measure for the chosen domain, whether it assesses a patient or disease centred-variable, and whether its technical performance is adequate in the context of its application. Some currently used imaging and soluble biomarkers for rheumatoid arthritis, spondyloarthritis and knee osteoarthritis were then evaluated using the original OMERACT filter and the newly proposed structure. Break-out groups critically reviewed the extent to which the candidate biomarkers complied with the proposed step-wise approach, as a way of examining the utility of the proposed 3 dimensional structure.
Results
Although there was a broad acceptance of the value of the proposed structure in general, some areas for improvement were suggested including clarification of criteria for achieving a certain level of validation and how to deal with extension of the structure to areas beyond clinical trials.
Conclusion
General support was obtained for a proposed tri-axis structure to assess validation of imaging and soluble biomarkers; nevertheless, additional work is required to better evaluate its place within the OMERACT Filter 2.0.
doi:10.3899/jrheum.131313
PMCID: PMC4223089  PMID: 24584916
biomarkers; imaging; OMERACT filter; validation framework
5.  Updating the OMERACT Filter: Implications of Filter 2.0 to select outcome instruments through assessment of ‘Truth’: content, face and construct validity 
The Journal of rheumatology  2014;41(5):1000-1004.
Objective
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face and construct validity.
Method
Discussion groups critically reviewed the variety of ways in which case studies of current OMERACT Working Groups complied with the ‘Truth’ component of the Filter and what issues remained to be resolved.
Results
The case studies showed that there is broad agreement on criteria for meeting the ‘Truth’ criteria through demonstration of content, face and construct validity; however several issues were identified that the Filter Working Group will need to address.
Conclusion
These issues will require resolution in order to reach consensus on how ‘Truth’ will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.
doi:10.3899/jrheum.131310
PMCID: PMC4212637  PMID: 24692531
7.  Assessing bias in osteoarthritis trials included in Cochrane reviews: protocol for a meta-epidemiological study 
BMJ Open  2014;4(10):e005491.
Introduction
The validity of systematic reviews and meta-analysis depends on methodological quality and unbiased dissemination of trials. Our objective is to evaluate the association of estimates of treatment effects with different bias-related study characteristics in meta-analyses of interventions used for treating pain in osteoarthritis (OA). From the findings, we hope to consolidate guidance on interpreting OA trials in systematic reviews based on empirical evidence from Cochrane reviews.
Methods and analysis
Only systematic reviews that compare experimental interventions with sham, placebo or no intervention control will be considered eligible. Bias will be assessed with the risk of bias tool, used according to the Cochrane Collaboration’s recommendations. Furthermore, center status, trial size and funding will be assessed. The primary outcome (pain) will be abstracted from the first appearing forest plot for overall pain in the Cochrane review. Treatment effect sizes will be expressed as standardised mean differences (SMDs), where the difference in mean values available from the forest plots is divided by the pooled SD. To empirically assess the risk of bias in treatment benefits, we will perform stratified analyses of the trials from the included meta-analyses and assess the interaction between trial characteristics and treatment effect. A relevant study-level covariate is defined as one that decreases the between-study variance (τ2, estimated as Tau-squared) as a consequence of inclusion in the mixed effects statistical model.
Ethics and dissemination
Meta-analyses and randomised controlled trials provide the most reliable basis for treatment of patients with OA, but the actual impact of bias is unclear. This study will systematically examine the methodological quality in OA Cochrane reviews and explore the effect estimates behind possible bias. Since our study does not collect primary data, no formal ethical assessment and informed consent are required.
Trial registration number
PROSPERO (CRD42013006924).
doi:10.1136/bmjopen-2014-005491
PMCID: PMC4187994  PMID: 25280805
osteoarthritis; meta-analysis; meta-epidemiology; risk of bias
8.  A Microsoft-Excel-based tool for running and critically appraising network meta-analyses—an overview and application of NetMetaXL 
Systematic Reviews  2014;3:110.
Background
The use of network meta-analysis has increased dramatically in recent years. WinBUGS, a freely available Bayesian software package, has been the most widely used software package to conduct network meta-analyses. However, the learning curve for WinBUGS can be daunting, especially for new users. Furthermore, critical appraisal of network meta-analyses conducted in WinBUGS can be challenging given its limited data manipulation capabilities and the fact that generation of graphical output from network meta-analyses often relies on different software packages than the analyses themselves.
Methods
We developed a freely available Microsoft-Excel-based tool called NetMetaXL, programmed in Visual Basic for Applications, which provides an interface for conducting a Bayesian network meta-analysis using WinBUGS from within Microsoft Excel. . This tool allows the user to easily prepare and enter data, set model assumptions, and run the network meta-analysis, with results being automatically displayed in an Excel spreadsheet. It also contains macros that use NetMetaXL’s interface to generate evidence network diagrams, forest plots, league tables of pairwise comparisons, probability plots (rankograms), and inconsistency plots within Microsoft Excel. All figures generated are publication quality, thereby increasing the efficiency of knowledge transfer and manuscript preparation.
Results
We demonstrate the application of NetMetaXL using data from a network meta-analysis published previously which compares combined resynchronization and implantable defibrillator therapy in left ventricular dysfunction. We replicate results from the previous publication while demonstrating result summaries generated by the software.
Conclusions
Use of the freely available NetMetaXL successfully demonstrated its ability to make running network meta-analyses more accessible to novice WinBUGS users by allowing analyses to be conducted entirely within Microsoft Excel. NetMetaXL also allows for more efficient and transparent critical appraisal of network meta-analyses, enhanced standardization of reporting, and integration with health economic evaluations which are frequently Excel-based.
doi:10.1186/2046-4053-3-110
PMCID: PMC4195340  PMID: 25267416
Network meta-analysis; Software; Microsoft Excel; WinBUGS; Systematic review; Health technology assessment
9.  OMERACT endorsement of measures of outcome for studies of acute gout 
The Journal of rheumatology  2013;41(3):569-573.
Objective
To determine the extent to which OMERACT participants agree that instruments that have been used in clinical trials and measure OMERACT core outcome domains in acute gout fulfil the filter requirements of truth, discrimination and feasibility and to determine where future research efforts need to be directed.
Methods
The results of a systematic literature review and analysis of individual-level data from recent clinical studies of acute gout were presented to OMERACT participants. The information was discussed in breakout groups and opinion was defined by subsequent voting in a plenary session. Endorsement was defined as at least 70% of participants voting in agreement with the proposition (where the denominator excluded those participants who did not vote or who voted ‘don’t know’).
Results
The following measures were endorsed for use in clinical trials of acute gout: (1) 5-point Likert scale and/or VAS (0 to 100mm) to measure pain; (2) 4-point Likert scale for joint swelling; (3) 4-point Likert scale for joint tenderness; and (4) 5-point Likert scale for patient global assessment of response to treatment. Measures for the activity limitations domain were not endorsed.
Conclusions
Measures of pain, joint swelling, joint tenderness and patient global assessment in acute gout were endorsed at OMERACT-11. These measures should now be used in clinical trials of acute gout.
doi:10.3899/jrheum.131246
PMCID: PMC4162875  PMID: 24334651
gout; outcome measures; psychometrics
10.  Acute Isolated Dysarthria Is Associated with a High Risk of Stroke 
Cerebrovascular Diseases Extra  2014;4(2):182-185.
Background
Isolated dysarthria is an uncommon presentation of transient ischemic attack (TIA)/minor stroke and has a broad differential diagnosis. There is little information in the literature about how often this presentation is confirmed to be a TIA/stroke, and therefore there is debate about the risk of subsequent vascular events. Given the uncertain prognosis, it is unclear how to best manage patients presenting to the emergency department (ED) with isolated dysarthria. The objective of this study was to prospectively identify and follow a cohort of patients presenting to EDs with isolated dysarthria in order to explore their natural history and risk of recurrent cerebrovascular events. Specifically, we sought to determine early outcomes of individuals with this nonspecific and atypical presentation in order to appropriately expedite their management.
Methods
Patients with isolated dysarthria having presented to 8 Canadian EDs between October 2006 and April 2009 were analyzed as part of a prospective multicenter cohort study of patients with acute neurological symptoms as assessed by emergency physicians. The study inclusion criteria were age ≥18 years, a normal level of consciousness, and a symptom onset <1 week prior to presentation without an established nonvascular etiology. The primary outcome was a subsequent stroke within 90 days of the index visit. The secondary outcomes were the rate of TIA, myocardial infarction, and death. Isolated dysarthria was defined as slurring with imprecise articulation but without evidence of language dysfunction. The overall rate of stroke in this cohort was compared with that predicted by the median ABCD2 score for this group.
Results
Between 2006 and 2009, 1,528 patients were enrolled and had a 90-day follow-up. Of these, 43 patients presented with isolated acute-onset dysarthria (2.8%). Recurrent stroke occurred in 6/43 (14.0%) within 90 days of enrollment. The predicted maximal 90-day stroke rate was 9.8% (based on a median ABCD2 score of 5 for the isolated dysarthria cohort). After adjusting for covariates, isolated dysarthria independently predicted stroke within 90 days (aOR: 3.96; 95% CI: 1.3-11.9; p = 0.014).
Conclusions
The isolated dysarthria cohort carried a recurrent stroke risk comparable to that predicted by the median ABCD2 scores. Although isolated dysarthria is a nonspecific and uncommon clinical presentation of TIA, these findings support the need to view it first and foremost as a vascular presentation until proven otherwise and to manage such patients as if they were at high risk of stroke in accordance with established high-risk TIA guidelines.
doi:10.1159/000365169
PMCID: PMC4176400  PMID: 25298772
Stroke; Transient ischemic attack; Risk stratification; Outcome; Dysarthria
11.  Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial 
Background:
Small studies have yielded divergent results for administration of granulocyte colony-stimulating factor (G-CSF) after acute myocardial infarction. Adequately powered studies involving patients with at least moderate left ventricular dysfunction are lacking.
Methods:
Patients with left ventricular ejection fraction less than 45% after anterior-wall myocardial infarction were treated with G-CSF (10 μg/kg daily for 4 days) or placebo. After initial randomization of 86 patients, 41 in the placebo group and 39 in the G-CSF group completed 6-month follow-up and underwent measurement of left ventricular ejection fraction by radionuclide angiography.
Results:
Baseline and 6-week mean ejection fraction was similar for the G-CSF and placebo groups: 34.8% (95% confidence interval [CI] 32.6%–37.0%) v. 36.4% (95% CI 33.5%–39.2%) at baseline and 39.8% (95% CI 36.2%–43.4%) v. 43.1% (95% CI 39.2%–47.0%) at 6 weeks. However, G-CSF therapy was associated with a lower ejection fraction at 6 months relative to placebo (40.8% [95% CI 37.4%–44.2%] v. 46.0% [95% CI 42.7%–44.3%]). Both groups had improved left ventricular function, but change in left ventricular ejection fraction was lower in patients treated with G-CSF than in those who received placebo (5.7 [95% CI 3.4–8.1] percentage points v. 9.2 [95% CI 6.3–12.1] percentage points). One or more of a composite of several major adverse cardiac events occurred in 8 patients (19%) within each group, with similar rates of target-vessel revascularization.
Interpretation:
In patients with moderate left ventricular dysfunction following anterior-wall infarction, G-CSF therapy was associated with a lower 6-month left ventricular ejection fraction but no increased risk of major adverse cardiac events. Future studies of G-CSF in patients with left ventricular dysfunction should be monitored closely for safety. Trial registration: ClinicalTrials.gov, no. NCT00394498
doi:10.1503/cmaj.140133
PMCID: PMC4119168  PMID: 24934893
12.  Two Chromosome 9p21 Haplotype Blocks Distinguish Between Coronary Artery Disease and Myocardial Infarction Risk 
Circulation. Cardiovascular genetics  2013;6(4):10.1161/CIRCGENETICS.113.000104.
Background
Variants at the 9p21 locus associate with the risk of coronary artery disease (CAD) or myocardial infarction (MI). However, atherosclerotic plaque deposition is distinct from MI (plaque rupture and thrombosis) and recent studies showed no association between these variants and MI in patients with preexisting CAD. We performed haplotype analysis at the 9p21 locus to test whether haplotypes at distinct linkage disequilibrium (LD) blocks predict these phenotypes.
Methods and Results
Using 24 single-nucleotide polymorphisms genotyped in Caucasians without diabetes, we reconstructed haplotypes at the 9p21 locus. Angiographic CAD/MI patients had at least 1 epicardial stenosis > 50% (n=2352) whereas controls were asymptomatic and over age 60 (n=2116). For CAD patients, regression models examined association of haplotypes with initial age of symptomatic CAD, number of diseased vessels, and history of MI. In the case-control study, only haplotypes at one block tagged by rs1333049 associated with CAD more so than MI. These haplotypes also associated with early onset of CAD (β=−0.13 p=1.37*10−4) and disease severity (β=0.1823, p=0.006), but not with prevalent MI among CAD patients. In contrast, haplotypes at another block tagged by rs518394 associated with prevalent MI (β=0.239, p= 2.05*10−4), but remarkably these are inversely associated with disease severity (β=−0.196, p=0.003). This MI association was replicated in the Cleveland Clinic GeneBank premature CAD cohort (n=1385, β=0.207, p= 0.019).
Conclusions
Variants/haplotypes at two blocks are distinguished at 9p21, those at one block predispose to atherosclerosis whereas those at the other predispose to MI among individuals with preexisting CAD.
doi:10.1161/CIRCGENETICS.113.000104
PMCID: PMC3839299  PMID: 23729007
coronary angiography; haplotype; myocardial infarction; atherosclerosis; chromosome 9p21
13.  Chemotherapy regimens for advanced pancreatic cancer: a systematic review and network meta-analysis 
BMC Cancer  2014;14:471.
Background
Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. Recent randomized clinical trials (RCTs) have demonstrated survival benefits for combination therapy compared to gemcitabine alone. However, the comparative benefits and harms of available combination chemotherapy treatments are not clear. We therefore conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer.
Methods
MEDLINE, PubMed, EMBASE, Cochrane Central Registry of Clinical trials and abstracts from major scientific meetings were searched for RCTs published from 2002 to 2013. Key outcomes were overall survival (OS), progression free survival (PFS), and safety including grade 3–4 febrile neutropenia, neutropenia, vomiting, diarrhea, fatigue and sensory neuropathy. Bayesian network meta-analyses were conducted to calculate survival and safety outcomes using gemcitabine (GEM) as the reference comparator. Effect estimates and 95% credible intervals were calculated for each comparison. Mean ranks and the probability of being best were obtained for each treatment analyzed in the network meta-analysis.
Results
The search identified 23 studies involving 19 different treatment regimens and 9,989 patients. FOLFIRINOX, GEM/cisplatin/epirubicin/5FU (PEFG), GEM/NAB-paclitaxel (NAB-P), GEM/erlotinib+/-bevacizumab, GEM/capecitabine, and GEM/oxaliplatin were associated with statistically significant improvements in OS and PFS relative to gemcitabine alone and several other treatments. They were amongst the top ranked for survival outcomes amongst other treatments included. No significant differences were found for other combination chemotherapy treatments. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Overall, combination therapies had greater risk for evaluated grade 3–4 toxicities over gemcitabine alone.
Conclusions
In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to achieve high-quality information on the effectiveness and safety of each treatment. This study suggests that some combination therapies may offer greater benefits in the treatment of advanced pancreatic cancer than others. To more fully elucidate the comparative benefits and harms of different combination chemotherapy regimens, rigorously conducted comparative studies, or network meta-analysis of patient-level data are required.
doi:10.1186/1471-2407-14-471
PMCID: PMC4097092  PMID: 24972449
Advanced pancreatic cancer; Chemotherapy; Gemcitabine; Combination therapy; Randomized clinical trials; Systematic review; Network meta-analysis
14.  Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation 
BMJ Open  2014;4(6):e004301.
Objective
To examine the comparative efficacy and safety of antithrombotic treatments (apixaban, dabigatran, edoxaban, rivaroxaban and vitamin K antagonists (VKA) at a standard adjusted dose (target international normalised ratio 2.0–3.0), acetylsalicylic acid (ASA), ASA and clopidogrel) for non-valvular atrial fibrillation and among subpopulations.
Design
Systematic review and network meta-analysis.
Data sources
A systematic literature search strategy was designed and carried out using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and the grey literature including the websites of regulatory agencies and health technology assessment organisations for trials published in English from 1988 to January 2014.
Eligibility criteria for selecting studies
Randomised controlled trials were selected for inclusion if they were published in English, included at least one antithrombotic treatment and involved patients with non-valvular atrial fibrillation eligible to receive anticoagulant therapy.
Results
For stroke or systemic embolism, dabigatran 150 mg and apixaban twice daily were associated with reductions relative to standard adjusted dose VKA, whereas low-dose ASA and the combination of clopidogrel plus low-dose ASA were associated with increases. Absolute risk reductions ranged from 6 fewer events per 1000 patients treated for dabigatran 150 mg twice daily to 15 more events for clopidogrel plus ASA. For major bleeding, edoxaban 30 mg daily, apixaban, edoxaban 60 mg daily and dabigatran 110 mg twice daily were associated with reductions compared to standard adjusted dose VKA. Absolute risk reductions with these agents ranged from 18 fewer per 1000 patients treated each year for edoxaban 30 mg daily to 24 more for medium dose ASA.
Conclusions
Compared with standard adjusted dose VKA, new oral anticoagulants were associated with modest reductions in the absolute risk of stroke and major bleeding. People on antiplatelet drugs experienced more strokes compared with anticoagulant drugs without any reduction in bleeding risk. To fully elucidate the comparative benefits and harms of antithrombotic agents across the various subpopulations, rigorously conducted comparative studies or network meta-regression analyses of patient-level data are required.
Systematic review registration number
PROSPERO registry—CRD42012002721.
doi:10.1136/bmjopen-2013-004301
PMCID: PMC4054633  PMID: 24889848
CARDIOLOGY; EPIDEMIOLOGY
15.  The Effect of Telephone Support Interventions on Coronary Artery Disease (CAD) Patient Outcomes during Cardiac Rehabilitation: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(5):e96581.
Background
Cardiac rehabilitation is offered to individuals after cardiac events to aid recovery and reduce the likelihood of further cardiac illness. However, patient participation remains suboptimal and the provision of high quality care to an expanding population of patients with chronic heart conditions is becoming increasingly difficult. A systematic review and meta-analysis was conducted to determine the effect of telephone support interventions compared with standard post-discharge care on coronary artery disease patient outcomes.
Methods
The Cochrane Library, MEDLINE, EMBASE, and CINAHL were searched and randomized controlled trials that directly compared telephone interventions with standard post-discharge care in adults following a myocardial infarction or a revascularization procedure were included. Study selection, data extraction and quality assessment were completed independently by two reviewers. Where appropriate, outcome data were combined and analyzed using a random effects model. For each dichotomous outcome, odds ratios (OR) and 95% confidence intervals (CI) were derived for each outcome. For continuous outcomes, weighted mean differences (WMD) and standardized mean differences (SMD) and 95% CI were calculated.
Results
26 studies met the inclusion criteria. No difference was observed in mortality between the telephone group and the group receiving standard care OR 1.12 (0.71, 1.77). The intervention was significantly associated with fewer hospitalizations than the comparison group OR 0.62 (0.40, 0.97). Significantly more participants in the telephone group stopped smoking OR 1.32 (1.07, 1.62); had lower systolic blood pressure WMD −0.22 (−0.40, −0.04); lower depression scores SMD −0.10 (−0.21, −0.00); and lower anxiety scores SMD −0.14 (−0.24, −0.04). However, no significant difference was observed for low-density lipoprotein levels WMD −0.10 (−0.23, 0.03).
Conclusions
Compared to standard post-discharge care, regular telephone support interventions may help reduce feelings of anxiety and depression as well as, improve systolic blood pressure control and the likelihood of smoking cessation.
doi:10.1371/journal.pone.0096581
PMCID: PMC4010507  PMID: 24798429
16.  Clinical characteristics associated with adverse events in patients with exacerbation of chronic obstructive pulmonary disease: a prospective cohort study 
Background:
To assist physicians with difficult decisions about hospital admission for patients with acute exacerbation of chronic obstructive pulmonary disease (COPD) presenting in the emergency department, we sought to identify clinical characteristics associated with serious adverse events.
Methods:
We conducted this prospective cohort study in 6 large Canadian academic emergency departments. Patients were assessed for standardized clinical variables and then followed for serious adverse events, defined as death, intubation, admission to a monitored unit or new visit to the emergency department requiring admission.
Results:
We enrolled 945 patients, of whom 354 (37.5%) were admitted to hospital. Of 74 (7.8%) patients with a subsequent serious adverse event, 36 (49%) had not been admitted after the initial emergency visit. Multivariable modelling identified 5 variables that were independently associated with adverse events: prior intubation, initial heart rate ≥ 110/minute, being too ill to do a walk test, hemoglobin < 100 g/L and urea ≥ 12 mmol/L. A preliminary risk scale incorporating these and 5 other clinical variables produced risk categories ranging from 2.2% for a score of 0 to 91.4% for a score of 10. Using a risk score of 2 or higher as a threshold for admission would capture all patients with a predicted risk of adverse events of 7.2% or higher, while only slightly increasing admission rates, from 37.5% to 43.2%.
Interpretation:
In Canada, many patients with COPD suffer a serious adverse event or death after being discharged home from the emergency department. We identified high-risk characteristics and developed a preliminary risk scale that, once validated, could be used to stratify the likelihood of poor outcomes and to enable rational and safe admission decisions.
doi:10.1503/cmaj.130968
PMCID: PMC3971051  PMID: 24549125
17.  Risk stratification of adult emergency department syncope patients to predict short-term serious outcomes after discharge (RiSEDS) study 
Background
While Canadian ED physicians discharge most syncope patients with no specific further follow-up, approximately 5% will suffer serious outcomes after ED discharge. The goal of this study is to prospectively identify risk factors and to derive a clinical decision tool to accurately predict those at risk for serious outcomes after ED discharge within 30 days.
Methods/Design
We will conduct a prospective cohort study at 6 Canadian EDs to include adults with syncope and exclude patients with loss of consciousness > 5 minutes, mental status changes from baseline, obvious witnessed seizure, or head trauma prior to syncope. Emergency physicians will collect standardized clinical variables including historical features, physical findings, and results of immediately available tests (blood, ECG, and ED cardiac monitoring) prior to ED discharge/hospital admission. A second emergency physician will evaluate approximately 10% of study patients for interobserver agreement calculation of predictor variables. The primary outcome will be a composite serious outcome occurring within 30 days of ED discharge and includes three distinct categories: serious adverse events (death, arrhythmia); identification of serious underlying disease (structural heart disease, aortic dissection, pulmonary embolism, severe pulmonary hypertension, subarachnoid hemorrhage, significant hemorrhage, myocardial infarction); or procedures to treat the cause of syncope. The secondary outcome will be any of the above serious outcomes either suspected or those occurring in the ED. A blinded Adjudication Committee will confirm all serious outcomes. Univariate analysis will be performed to compare the predictor variables in patients with and without primary outcome. Variables with p-values <0.2 and kappa values ≥0.60 will be selected for stepwise logistic regression to identify the risk factors and to develop the clinical decision tool. We will enroll 5,000 patients (with 125 positive for primary outcome) for robust identification of risk factors and clinical decision tool development.
Discussion
Once successfully developed, this tool will accurately risk-stratify adult syncope patients; however, validation and implementation will still be required. This program of research should lead to standardized care of syncope patients, and improve patient safety.
doi:10.1186/1471-227X-14-8
PMCID: PMC4003802  PMID: 24629180
Syncope; Serious outcomes; Prognosis; Arrhythmia; Emergency department; Management
18.  Effect of an intervention to improve the cardiovascular health of family members of patients with coronary artery disease: a randomized trial 
Background:
Family members of patients with coronary artery disease (CAD) have higher risk of vascular events. We conducted a trial to determine if a family heart-health intervention could reduce their risk of CAD.
Methods:
We assessed coronary risk factors and randomized 426 family members of patients with CAD to a family heart-health intervention (n = 211) or control (n = 215). The intervention included feedback about risk factors, assistance with goal setting and counselling from health educators for 12 months. Reports were sent to the primary care physicians of patients whose lipid levels and blood pressure exceeded threshold values. All participants received printed materials about smoking cessation, healthy eating, weight management and physical activity; the control group received only these materials. The main outcomes (ratio of total cholesterol to high-density lipoprotein [HDL] cholesterol; physical activity; fruit and vegetable consumption) were assessed at 3 and 12 months. We examined group and time effects using mixed models analyses with the baseline values as covariates. The secondary outcomes were plasma lipid levels (total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglycerides); glucose level; blood pressure; smoking status; waist circumference; body mass index; and the use of blood pressure, lipid-lowering and smoking cessation medications.
Results:
We found no effect of the intervention on the ratio of total cholesterol to HDL cholesterol. However, participants in the intervention group reported consuming more fruit and vegetables (1.2 servings per day more after 3 mo and 0.8 servings at 12 mo; p < 0.001). There was a significant group by time interaction for physical activity (p = 0.03). At 3 months, those in the intervention group reported 65.8 more minutes of physical activity per week (95% confidence interval [CI] 47.0–84.7 min). At 12 months, participants in the intervention group reported 23.9 more minutes each week (95% CI 3.9–44.0 min).
Interpretation:
A health educator–led heart-health intervention did not improve the ratio of total cholesterol to HDL cholesterol but did increase reported physical activity and fruit and vegetable consumption among family members of patients with CAD. Hospitalization of a spouse, sibling or parent is an opportunity to improve cardiovascular health among other family members. Trial registration: clinicaltrials.gov, no NCT00552591.
doi:10.1503/cmaj.130550
PMCID: PMC3883820  PMID: 24246588
19.  Computed tomographic coronary angiography for patients with heart failure (CTA-HF): a randomized controlled trial (IMAGE HF Project 1-C) 
Trials  2013;14:443.
Background
The prevalence of heart failure (HF) is rising in industrialized and developing countries. Though invasive coronary angiography (ICA) remains the gold standard for anatomical assessment of coronary artery disease in HF patients, alternatives are being sought. Computed tomographic coronary angiography (CTA) has emerged as an accurate non-invasive diagnostic tool for coronary artery disease (CAD) and has been demonstrated to have prognostic value. Whether or not CTA can be used in HF patients is unknown. Acknowledging the aging population, the growing prevalence of HF and the increasing financial burden of healthcare, we need to identify non-invasive diagnostic tests that are available, safe, accurate and cost-effective.
Methods/Design
The proposed study aims to provide insight into the efficacy of CTA in HF patients. A multicenter randomized controlled trial will enroll 250 HF patients requiring coronary anatomical definition. Enrolled patients will be randomized to either CTA or ICA (n = 125 per group) as the first test to define coronary anatomy. The primary outcomes will be collected to determine downstream resource utilization. Secondary outcomes will include the composite clinical events and major adverse cardiac events. In addition, the accuracy of CTA for detecting coronary anatomy and obstruction will be assessed in patients who subsequently undergo both CTA and ICA. It is expected that CTA will be a more cost-effective strategy for diagnosis: yielding similar outcomes with fewer procedural risks and improved resource utilization.
Trial registration
ClinicalTrials.gov, NCT01283659
Team grant #CIF 99470
doi:10.1186/1745-6215-14-443
PMCID: PMC3895694  PMID: 24369097
20.  Routine versus selective cardiac magnetic resonance in non-ischemic heart failure – OUTSMART-HF: study protocol for a randomized controlled trial (IMAGE-HF (heart failure) project 1-B) 
Trials  2013;14:332.
Background
Imaging has become a routine part of heart failure (HF) investigation. Echocardiography is a first-line test in HF given its availability and it provides valuable diagnostic and prognostic information. Cardiac magnetic resonance (CMR) is an emerging clinical tool in the management of patients with non-ischemic heart failure. Current ACC/AHA/CCS/ESC guidelines advocate its role in the detection of a variety of cardiomyopathies but there is a paucity of high quality evidence to support these recommendations.
The primary objective of this study is to compare the diagnostic yield of routine cardiac magnetic resonance versus standard care (that is, echocardiography with only selective use of CMR) in patients with non-ischemic heart failure. The primary hypothesisis that the routine use of CMR will lead to a more specific diagnostic characterization of the underlying etiology of non-ischemic heart failure. This will lead to a reduction in the non-specific diagnoses of idiopathic dilated cardiomyopathy and HF with preserved ejection fraction.
Design
Tertiary care sites in Canada and Finland, with dedicated HF and CMR programs, will randomize consecutive patients with new or deteriorating HF to routine CMR or selective CMR. All patients will undergo a standard clinical echocardiogram and the interpreter will assign the most likely HF etiology. Those undergoing CMR will also have a standard examination and will be assigned a HF etiology based upon the findings. The treating physician’s impression about non-ischemic HF etiology will be collected following all baseline testing (including echo ± CMR). Patients will be followed annually for 4 years to ascertain clinical outcomes, quality of life and cost. The expected outcome is that the routine CMR arm will have a significantly higher rate of infiltrative, inflammatory, hypertrophic, ischemic and ‘other’ cardiomyopathy than the selective CMR group.
Discussion
This study will be the first multicenter randomized, controlled trial evaluating the role of CMR in non-ischemic HF. Non-ischemic HF patients will be randomized to routine CMR in order to determine whether there are any gains over management strategies employing selective CMR utilization. The insight gained from this study should improve appropriate CMR use in HF.
Trial registration
NCT01281384.
doi:10.1186/1745-6215-14-332
PMCID: PMC4016591  PMID: 24119686
Heart failure; Echocardiography; Cardiac magnetic resonance; Randomized controlled trial
21.  An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure 
European Heart Journal  2013;34(46):3547-3556.
Aims
Cardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data.
Methods and results
An individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58–73) years, QRS duration was 160 (146–176) ms, LVEF was 24 (20–28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value.
Conclusion
QRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response.
ClinicalTrials.gov numbers
NCT00170300, NCT00271154, NCT00251251.
doi:10.1093/eurheartj/eht290
PMCID: PMC3855551  PMID: 23900696
Cardiac resynchronization therapy; Morbidity; Mortality; Heart failure
22.  A tutorial on sensitivity analyses in clinical trials: the what, why, when and how 
Background
Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.
The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.
Discussion
In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.
Summary
When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.
doi:10.1186/1471-2288-13-92
PMCID: PMC3720188  PMID: 23855337
Sensitivity analysis; Clinical trials; Robustness
23.  Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial 
Trials  2013;14:218.
Background
Ischemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.
Methods/Design
This paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.
In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.
Discussion
AIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.
Trial registration
NCT01288560
doi:10.1186/1745-6215-14-218
PMCID: PMC3729711  PMID: 23866673
24.  Systematic reviews need to consider applicability to disadvantaged populations: inter-rater agreement for a health equity plausibility algorithm 
Background
Systematic reviews have been challenged to consider effects on disadvantaged groups. A priori specification of subgroup analyses is recommended to increase the credibility of these analyses. This study aimed to develop and assess inter-rater agreement for an algorithm for systematic review authors to predict whether differences in effect measures are likely for disadvantaged populations relative to advantaged populations (only relative effect measures were addressed).
Methods
A health equity plausibility algorithm was developed using clinimetric methods with three items based on literature review, key informant interviews and methodology studies. The three items dealt with the plausibility of differences in relative effects across sex or socioeconomic status (SES) due to: 1) patient characteristics; 2) intervention delivery (i.e., implementation); and 3) comparators. Thirty-five respondents (consisting of clinicians, methodologists and research users) assessed the likelihood of differences across sex and SES for ten systematic reviews with these questions. We assessed inter-rater reliability using Fleiss multi-rater kappa.
Results
The proportion agreement was 66% for patient characteristics (95% confidence interval: 61%-71%), 67% for intervention delivery (95% confidence interval: 62% to 72%) and 55% for the comparator (95% confidence interval: 50% to 60%). Inter-rater kappa, assessed with Fleiss kappa, ranged from 0 to 0.199, representing very low agreement beyond chance.
Conclusions
Users of systematic reviews rated that important differences in relative effects across sex and socioeconomic status were plausible for a range of individual and population-level interventions. However, there was very low inter-rater agreement for these assessments. There is an unmet need for discussion of plausibility of differential effects in systematic reviews. Increased consideration of external validity and applicability to different populations and settings is warranted in systematic reviews to meet this need.
doi:10.1186/1471-2288-12-187
PMCID: PMC3552943  PMID: 23253632
Systematic reviews; Applicability; Health equity; Sex and gender; Socioeconomic status
25.  The implementation of a community-based aerobic walking program for mild to moderate knee osteoarthritis: A knowledge translation randomized controlled trial: Part II: Clinical outcomes 
BMC Public Health  2012;12:1073.
Background
Osteoarthritis (OA) is the most common joint disorder in the world, as it is appears to be prevalent among 80% of individuals over the age of 75. Although physical activities such as walking have been scientifically proven to improve physical function and arthritic symptoms, individuals with OA tend to adopt a sedentary lifestyle. There is therefore a need to improve knowledge translation in order to influence individuals to adopt effective self-management interventions, such as an adapted walking program.
Methods
A single-blind, randomized control trial was conducted. Subjects (n = 222) were randomized to one of three knowledge translation groups: 1) Walking and Behavioural intervention (WB) (18 males, 57 females) which included the supervised community-based aerobic walking program combined with a behavioural intervention and an educational pamphlet on the benefits of walking; 2) Walking intervention (W) (24 males, 57 females) wherein participants only received the supervised community-based aerobic walking program intervention and the educational pamphlet; 3) Self-directed control (C) (32 males, 52 females) wherein participants only received the educational pamphlet. One-way analyses of variance were used to test for differences in quality of life, adherence, confidence, and clinical outcomes among the study groups at each 3 month assessment during the 12-month intervention period and 6-month follow-up period.
Results
The clinical and quality of life outcomes improved among participants in each of the three comparative groups. However, there were few statistically significant differences observed for quality of life and clinical outcomes at long-term measurements at 12-months end of intervention and at 6- months post intervention (18-month follow-up). Outcome results varied among the three groups.
Conclusion
The three groups were equivalent when determining the effectiveness of knowledge uptake and improvements in quality of life and other clinical outcomes. OA can be managed through the implementation of a proven effective walking program in existing community-based walking clubs.
Trial registration
Current Controlled Trials IRSCTNO9193542
doi:10.1186/1471-2458-12-1073
PMCID: PMC3529193  PMID: 23234575
Osteoarthritis; Clinical trial; Walking; Compliance; Adherence; Education; Behavioural intervention; Guidelines implementation; Knowledge translation

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