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2.  Predictors of persistent pain after breast cancer surgery: a systematic review and meta-analysis of observational studies 
Background:
Persistent pain after breast cancer surgery affects up to 60% of patients. Early identification of those at higher risk could help inform optimal management. We conducted a systematic review and meta-analysis of observational studies to explore factors associated with persistent pain among women who have undergone surgery for breast cancer.
Methods:
We searched the MEDLINE, Embase, CINAHL and PsycINFO databases from inception to Mar. 12, 2015, to identify cohort or case–control studies that explored the association between risk factors and persistent pain (lasting ≥ 2 mo) after breast cancer surgery. We pooled estimates of association using random-effects models, when possible, for all independent variables reported by more than 1 study. We reported relative measures of association as pooled odds ratios (ORs) and absolute measures of association as the absolute risk increase.
Results:
Thirty studies, involving a total of 19 813 patients, reported the association of 77 independent variables with persistent pain. High-quality evidence showed increased odds of persistent pain with younger age (OR for every 10-yr decrement 1.36, 95% confidence interval [CI] 1.24–1.48), radiotherapy (OR 1.35, 95% CI 1.16–1.57), axillary lymph node dissection (OR 2.41, 95% CI 1.73–3.35) and greater acute postoperative pain (OR for every 1 cm on a 10-cm visual analogue scale 1.16, 95% CI 1.03–1.30). Moderate-quality evidence suggested an association with the presence of preoperative pain (OR 1.29, 95% CI 1.01–1.64). Given the 30% risk of pain in the absence of risk factors, the absolute risk increase corresponding to these ORs ranged from 3% (acute postoperative pain) to 21% (axillary lymph node dissection). High-quality evidence showed no association with body mass index, type of breast surgery, chemotherapy or endocrine therapy.
Interpretation:
Development of persistent pain after breast cancer surgery was associated with younger age, radiotherapy, axillary lymph node dissection, greater acute postoperative pain and preoperative pain. Axillary lymph node dissection provides the only high-yield target for a modifiable risk factor to prevent the development of persistent pain after breast cancer surgery.
doi:10.1503/cmaj.151276
PMCID: PMC5047835  PMID: 27402075
3.  Patient values and preferences on transcatheter or surgical aortic valve replacement therapy for aortic stenosis: a systematic review 
BMJ Open  2016;6(9):e014327.
Objective
To investigate patients' values and preferences regarding aortic valve replacement therapy for aortic stenosis.
Setting
Studies published after transcatheter aortic valve insertion (TAVI) became available (2002).
Participants
Adults with aortic stenosis who are considering or have had valve replacement, either TAVI or via surgery (surgical aortic valve replacement, SAVR).
Outcome measures
We sought quantitative measurements, or qualitative descriptions, of values and preferences. When reported, we examined correlations between preferences and objective (eg, ejection fraction) or subjective (eg, health-related quality of life) measures of health.
Results
We reviewed 1348 unique citations, of which 2 studies proved eligible. One study of patients with severe aortic stenosis used a standard gamble study to ascertain that the median hypothetical mortality risk patients were willing to tolerate to achieve full health was 25% (IQR 25–50%). However, there was considerable variability; for mortality risk levels defined by current guidelines, 130 participants (30%) were willing to accept low-to-intermediate risk (≤8%), 224 (51%) high risk (>8–50%) and 85 (19%) a risk that guidelines would consider prohibitive (>50%). Study authors did not, however, assess participants' understanding of the exercise, resulting in a potential risk of bias. A second qualitative study of 15 patients identified the following factors that influence patients to undergo assessment for TAVI: symptom burden; expectations; information support; logistical barriers; facilitators; obligations and responsibilities. The study was limited by serious risk of bias due to authors' conflict of interest (5/9 authors industry-funded).
Conclusions
Current evidence on patient values and preferences of adults with aortic stenosis is very limited, and no studies have enrolled patients deciding between TAVI and SAVR. On the basis of the data available, there is evidence of variability in individual values and preferences, highlighting the importance of well-informed and shared decision-making with patients facing this decision.
Trial registration number
PROSPERO CRD42016041907.
doi:10.1136/bmjopen-2016-014327
PMCID: PMC5051506  PMID: 27687903
GRADE; Shared decision making; TAVI; aortic stenosis
4.  Multivariable fractional polynomial interaction to investigate continuous effect modifiers in a meta-analysis on higher versus lower PEEP for patients with ARDS 
BMJ Open  2016;6(9):e011148.
Objectives
A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes.
Setting
Pooled data from three randomised trials in intensive care identified by a systematic review.
Participants
2299 patients with acute lung injury requiring mechanical ventilation.
Interventions
Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy.
Outcome measures
Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure−PEEP)) and body mass index (BMI).
Results
We found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m2, we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings.
Conclusions
MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS.
Study registration number
CRD42012003129.
doi:10.1136/bmjopen-2016-011148
PMCID: PMC5020750  PMID: 27609843
ARDS; acute lung injury; treatment interaction; multivariable fractional polynomials; IPD meta-analysis
5.  Which Surgical Treatment for Open Tibial Shaft Fractures Results in the Fewest Reoperations? A Network Meta-analysis 
Background
Open tibial shaft fractures are one of the most devastating orthopaedic injuries. Surgical treatment options include reamed or unreamed nailing, plating, Ender nails, Ilizarov fixation, and external fixation. Using a network meta-analysis allows comparison and facilitates pooling of a diverse population of randomized trials across these approaches in ways that a traditional meta-analysis does not.
Questions/purposes
Our aim was to perform a network meta-analysis using evidence from randomized trials on the relative effect of alternative approaches on the risk of unplanned reoperation after open fractures of the tibial diaphysis. Our secondary study endpoints included malunion, deep infection, and superficial infection.
Methods
A network meta-analysis allows for simultaneous consideration of the relative effectiveness of multiple treatment alternatives. To do this on the subject of surgical treatments for open tibial fractures, we began with systematic searches of databases (including EMBASE and MEDLINE) and performed hand searches of orthopaedic journals, bibliographies, abstracts from orthopaedic conferences, and orthopaedic textbooks, for all relevant material published between 1980 and 2013. Two authors independently screened abstracts and manuscripts and extracted the data, three evaluated the risk of bias in individual studies, and two applied Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria to bodies of evidence. We included all randomized and quasirandomized trials comparing two (or more) surgical treatment options for open tibial shaft fractures in predominantly (ie, > 80%) adult patients. We calculated pooled estimates for all direct comparisons and conducted a network meta-analysis combining direct and indirect evidence for all 15 comparisons between six stabilization strategies. Fourteen trials published between 1989 and November 2011 met our inclusion criteria; the trials comprised a total of 1279 patients surgically treated for open tibial shaft fractures.
Results
Moderate confidence evidence showed that unreamed nailing may reduce the likelihood of reoperation compared with external fixation (network odds ratio [OR], 0.38; 95% CI, 0.23–0.62; p < 0.05), although not necessarily compared with reamed nailing (direct OR, 0.74; 95% CI, 0.45–1.24; p = 0.25). Only low- or very low-quality evidence informed the primary outcome for other treatment comparisons, such as those involving internal plate fixation, Ilizarov external fixation, and Ender nailing. Method ranking based on reoperation data showed that unreamed nailing had the highest probability of being the best treatment, followed by reamed nailing, external fixation, and plate fixation. CIs around pooled estimates of malunion and infection risk were very wide, and therefore no conclusive results could be made based on these data.
Conclusion
Current evidence suggests that intramedullary nailing may be superior to other fixation strategies for open tibial shaft fractures. Use of unreamed nails over reamed nails also may be advantageous in the setting of open fractures, but this remains to be confirmed. Unfortunately, these conclusions are based on trials that have had high risk of bias and poor precision. Larger and higher-quality head-to-head randomized controlled trials are required to confirm these conclusions and better inform clinical decision-making.
Level of Evidence
Level I, therapeutic study.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-015-4224-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-015-4224-y
PMCID: PMC4457757  PMID: 25724836
6.  Long-term Impact of Mode of Delivery on Stress Urinary Incontinence and Urgency Urinary Incontinence: A Systematic Review and Meta-analysis 
European Urology  2016;70(1):148-158.
Context
Stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) are associated with physical and psychological morbidity, and large societal costs. The long-term effects of delivery modes on each kind of incontinence remain uncertain.
Objective
To investigate the long-term impact of delivery mode on SUI and UUI.
Evidence acquisition
We searched Medline, Scopus, CINAHL, and relevant major conference abstracts up to October 31, 2014, including any observational study with adjusted analyses or any randomized trial addressing the association between delivery mode and SUI or UUI ≥1 yr after delivery. Two reviewers extracted data, including incidence/prevalence of SUI and UUI by delivery modes, and assessed risk of bias.
Evidence synthesis
Pooled estimates from 15 eligible studies demonstrated an increased risk of SUI after vaginal delivery versus cesarean section (adjusted odds ratio [aOR]: 1.85; 95% confidence interval [CI], 1.56–2.19; I2 = 57%; risk difference: 8.2%). Metaregression demonstrated a larger effect of vaginal delivery among younger women (p = 0.005). Four studies suggested no difference in the risk of SUI between spontaneous vaginal and instrumental delivery (aOR: 1.11; 95% CI, 0.84–1.45; I2 = 50%). Eight studies suggested an elevated risk of UUI after vaginal delivery versus cesarean section (aOR: 1.30; 95% CI, 1.02–1.65; I2 = 37%; risk difference: 2.6%).
Conclusions
Compared with cesarean section, vaginal delivery is associated with an almost twofold increase in the risk of long-term SUI, with an absolute increase of 8%, and an effect that is largest in younger women. There is also an increased risk of UUI, with an absolute increase of approximately 3%.
Patient summary
In this systematic review we looked for the long-term effects of childbirth on urinary leakage. We found that vaginal delivery is associated with an almost twofold increase in the risk of developing leakage with exertion, compared with cesarean section, with a smaller effect on leakage in association with urgency.
Take Home Message
We found that over the long term, vaginal delivery is associated with an almost twofold increase in the risk of developing leakage with exertion, compared with cesarean section, with a smaller effect of leakage in association with urgency.
doi:10.1016/j.eururo.2016.01.037
PMCID: PMC5009182  PMID: 26874810
Cesarean section; Vaginal delivery; Vacuum; Forceps; Instrumental delivery; Stress urinary incontinence; Urgency urinary incontinence; Systematic review
7.  Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials 
PLoS Medicine  2016;13(6):e1002046.
Background
Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees.
Methods and Findings
We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner’s right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements.
Conclusions
Publication agreements constraining academic authors’ independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.
In a document analysis of trial protocols and publications, Erik von Elm and colleagues investigate the potential impact of publication agreements between industry sponsors and academic investigators.
Author Summary
Why Was This Study Done?
Many randomized trials are designed and sponsored by for-profit companies that contract academic investigators to recruit and manage patients.
Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, in particular with respect to trial publication.
Besides evidence from a small sample, it was unclear how often trial protocols included publication agreements between industry and academic investigators, whether these agreements constrained the investigators’ publication rights, and how consistent such agreements stated in trial protocols were with those reported in corresponding publications.
What Did the Researchers Do and Find?
We investigated publication agreements in 647 randomized trial protocols approved in 2000–2003 by six research ethics committees in Switzerland, Canada, and Germany, and in 388 corresponding journal publications.
Seventy percent of protocols mentioned an agreement on publication rights between industry and academic investigators; in 86% of those agreements, industry retained the right to disapprove or at least review manuscripts before publication.
Seventy-four percent of agreements documented in protocols were not mentioned in corresponding journal articles.
What Do These Findings Mean?
Publication agreements constraining academic investigators’ independence are incompletely reported in publications; this may compromise the scientific evidence base established by randomized clinical trials.
More transparency on publication constraints is warranted.
Half of the included journal articles were published before 2008, leaving open the possibility that these findings do not reflect current reporting practice.
doi:10.1371/journal.pmed.1002046
PMCID: PMC4924795  PMID: 27352244
8.  Comparative Effectiveness of Phosphate Binders in Patients with Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis 
PLoS ONE  2016;11(6):e0156891.
Background
Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been linked to poor health outcomes, including diminished quality and length of life. This condition is characterized by high phosphate levels and requires phosphate-lowering agents—phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on patient-important outcomes in patients with CKD-MBD.
Methods
Data sources included MEDLINE and EMBASE Trials from 1996 to February 2016. We also searched the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD, randomized them to receive calcium (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet, placebo or no treatment, and reported effects on all-cause mortality, cardiovascular mortality or hospitalization at ≥4 weeks follow-up. We performed network meta-analyses (NMA) for all cause-mortality for individual agents (seven-node analysis) and conventional meta-analysis of calcium vs. NCBPBs for all-cause mortality, cardiovascular mortality and hospitalization. In the NMAs, we calculated the effect estimates for direct, indirect and network meta-analysis estimates; for both NMA and conventional meta-analysis, we pooled treatment effects as risk ratios (RR) and calculated 95% confidence intervals (CIs) using random effect models. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each paired comparison.
Results
Our search yielded 1190 citations, of which 71 RCTs were retrieved for full review and 15 proved eligible. With 13 eligible studies from a prior review, we included 28 studies with 8335 participants; 25 trials provided data for our quantitative synthesis. Results suggest higher mortality with calcium than either sevelamer (NMA RR, 1.89 [95% CI, 1.02 to 3.50], moderate quality evidence) or NCBPBs (conventional meta-analysis RR, 1.76 [95% CI, 1.21 to 2.56, moderate quality evidence). Conventional meta-analysis suggested no difference in cardiovascular mortality between calcium and NCBPBs (RR, 2.54 [95% CI, 0.67 to 9.62 low quality evidence). Our results suggest higher hospitalization, although non-significant, with calcium than NCBPBs (RR, 1.293 [95% CI, 0.94 to 1.74, moderate quality evidence).
Discussion/Conclusions
Use of calcium results in higher mortality than either sevelamer in particular and NCBPBs in general (moderate quality evidence). Our results raise questions about whether administration of calcium as an intervention for CKD- MBD remains ethical. Further research is needed to explore the effects of different types of phosphate binders, including novel agents such as iron, on quality and quantity of life.
Systematic Review Registration
PROSPERO CRD-42016032945
doi:10.1371/journal.pone.0156891
PMCID: PMC4898688  PMID: 27276077
9.  Women's Values and Preferences for Thromboprophylaxis during Pregnancy: A Comparison of Direct-choice and Decision Analysis using Patient Specific Utilities 
Thrombosis research  2015;136(2):341-347.
Background
Women with a history of venous thromboembolism (VTE) have an increased recurrence risk during pregnancy. Low molecular weight heparin (LMWH) reduces this risk, but is costly, burdensome, and may increase risk of bleeding. The decision to start thromboprophylaxis during pregnancy is sensitive to women's values and preferences. Our objective was to compare women's choices using a holistic approach in which they were presented all of the relevant information (direct-choice) versus a personalized decision analysis in which a mathematical model incorporated their preferences and VTE risk to make a treatment recommendation.
Methods
Multicenter, international study. Structured interviews were on women with a history of VTE who were pregnant, planning, or considering pregnancy. Women indicated their willingness to receive thromboprophylaxis based on scenarios using personalized estimates of VTE recurrence and bleeding risks. We also obtained women's values for health outcomes using a visual analog scale. We performed individualized decision analyses for each participant and compared model recommendations to decisions made when presented with the direct-choice exercise.
Results
Of the 123 women in the study, the decision model recommended LMWH for 51 women and recommended against LMWH for 72 women. 12% (6/51) of women for whom the decision model recommended thromboprophylaxis chose not to take LMWH; 72% (52/72) of women for whom the decision model recommended against thromboprophylaxis chose LMWH.
Conclusions
We observed a high degree of discordance between decisions in the direct-choice exercise and decision model recommendations. Although which approach best captures individuals’ true values remains uncertain, personalized decision support tools presenting results based on personalized risks and values may improve decision making.
doi:10.1016/j.thromres.2015.05.020
PMCID: PMC4880369  PMID: 26033397
Decision making; Decision support techniques; Venous thromboembolism; Heparin; Pregnancy
10.  Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies 
Background
The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes.
Methods
We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed the effect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalization for heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled data from RCTs and observational studies separately, and used the GRADE approach to rate the quality of evidence.
Results
We identified 25 studies that were eligible for our review; 21 RCTs (n = 18,270) and 4 observational studies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failure between GLP-1 agonists versus control (17/7,441 vs. 19/4,317; odds ratio (OR) 0.62, 95 % confidence interval (CI) 0.31 to 1.22; risk difference (RD) 19 fewer, 95 % CI 34 fewer to 11 more per 1000 over 5 years). Three cohort studies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonists do not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonists were not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjusted hazard ratio 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 % CI 25 fewer to 23 more per 1000 over 5 years) and a case–control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. other anti-hyperglycemic drugs: 1118 cases and 17,626 controls, adjusted OR 0.67, 95 % CI 0.32 to 1.42).
Conclusions
The current evidence suggests that GLP-1 agonists do not increase the risk of heart failure or hospitalization for heart failure among patients with type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-016-0260-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-016-0260-0
PMCID: PMC4863354  PMID: 27169565
Glucagon-like peptide-1 receptor; Heart failure; Type 2 diabetes; Systematic review; Meta-analysis
11.  Living cumulative network meta-analysis to reduce waste in research: A paradigmatic shift for systematic reviews? 
BMC Medicine  2016;14:59.
In a recent research article in BMC Medicine, Créquit and colleagues demonstrate how published systematic reviews in lung cancer provide a fragmented, out-of-date picture of the evidence for all treatments. The results and conclusions drawn from this study, based on cumulative network meta-analyses (NMA) of evidence from randomized clinical trials over time, are quite compelling. The inherent waste of research resulting from incomplete evidence synthesis has wide-reaching implications for a range of target groups including developers of systematic reviews and guidelines and their end-users, health care professionals and patients at the point of care. Building on emerging concepts for living systematic reviews and NMA, the authors propose "living cumulative NMA" as a potential solution and paradigmatic shift. Here we describe how recent innovations within authoring, dissemination, and updating of systematic reviews and trustworthy guidelines may greatly facilitate the production of living NMA. Some additional challenges need to be solved for NMA in general, and for living cumulative NMA in particular, before a paradigmatic shift for systematic reviews can become reality.
Please see related research article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0555-0
doi:10.1186/s12916-016-0596-4
PMCID: PMC4812628  PMID: 27025849
Systematic reviews; Network meta-analysis; Evidence-based medicine; Knowledge translation; Clinical practice guidelines; GRADE
12.  Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies 
Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes.
Design Systematic review and meta-analysis of randomised and observational studies.
Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts.
Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure.
Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach.
Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v 33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.
Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.
doi:10.1136/bmj.i610
PMCID: PMC4772781  PMID: 26888822
13.  The effectiveness and safety of treatments used for acute diarrhea and acute gastroenteritis in children: protocol for a systematic review and network meta-analysis 
Systematic Reviews  2016;5:14.
Background
Acute diarrhea and acute gastroenteritis (AD/AGE) are common among children in low- and middle-income countries (LMIC) and high-income countries (HIC). Supportive therapy including maintaining feeding, prevention of dehydration, and use of oral rehydration solution (ORS), is the mainstay of treatment in all children. Several additional treatments aiming to reduce the episode duration have been compared to placebo, but the differences in effectiveness among them are unknown.
Methods and analysis
We will conduct a systematic review of all randomized controlled trials evaluating the use of zinc, vitamin A, probiotics, prebiotics, synbiotics, racecadotril, smectite, and fermented and lactose-free milk/formula for AD/AGE treatment in children. The primary outcomes are diarrhea duration and mortality. Secondary outcomes are diarrhea lasting 3 or 7 days, stool frequency, treatment failure, hospitalizations, and adverse events. We will search MEDLINE, Ovid EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS through Ovid, as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with the grading of recommendations, assessment, development, and evaluation [GRADE] approach). Results will be summarized narratively and statistically. Subgroup analysis according to HIC vs. LMIC, age, nutrition status, and ROB is planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data is available.
Discussion
This is the first systematic review and network meta-analysis that aims to determine the relative effectiveness of pharmacological and nutritional treatments for reducing the duration of AD/AGE in children. The results will help to reduce the uncertainty of the effectiveness of the interventions, find knowledge gaps, and/or encourage further research for other therapeutic options.
Systematic review registration
PROSPERO registration number: CRD42015023778.
doi:10.1186/s13643-016-0186-8
PMCID: PMC4728803  PMID: 26818403
Diarrhea; Gastroenteritis; Children; Zinc; Probiotics; Smectite; Racecadotril; Yogurt; Lactose intolerance; Network meta-analysis; Systematic review
14.  Do clinicians understand the size of treatment effects? A randomized survey across 8 countries 
Background:
Meta-analyses of continuous outcomes typically provide enough information for decision-makers to evaluate the extent to which chance can explain apparent differences between interventions. The interpretation of the magnitude of these differences — from trivial to large — can, however, be challenging. We investigated clinicians’ understanding and perceptions of usefulness of 6 statistical formats for presenting continuous outcomes from meta-analyses (standardized mean difference, minimal important difference units, mean difference in natural units, ratio of means, relative risk and risk difference).
Methods:
We invited 610 staff and trainees in internal medicine and family medicine programs in 8 countries to participate. Paper-based, self-administered questionnaires presented summary estimates of hypothetical interventions versus placebo for chronic pain. The estimates showed either a small or a large effect for each of the 6 statistical formats for presenting continuous outcomes. Questions addressed participants’ understanding of the magnitude of treatment effects and their perception of the usefulness of the presentation format. We randomly assigned participants 1 of 4 versions of the questionnaire, each with a different effect size (large or small) and presentation order for the 6 formats (1 to 6, or 6 to 1).
Results:
Overall, 531 (87.0%) of the clinicians responded. Respondents best understood risk difference, followed by relative risk and ratio of means. Similarly, they perceived the dichotomous presentation of continuous outcomes (relative risk and risk difference) to be most useful. Presenting results as a standardized mean difference, the longest standing and most widely used approach, was poorly understood and perceived as least useful.
Interpretation:
None of the presentation formats were well understood or perceived as extremely useful. Clinicians best understood the dichotomous presentations of continuous outcomes and perceived them to be the most useful. Further initiatives to help clinicians better grasp the magnitude of the treatment effect are needed.
doi:10.1503/cmaj.150430
PMCID: PMC4695351  PMID: 26504102
15.  Cinacalcet versus standard treatment for chronic kidney disease: a protocol for a systematic review and meta-analysis 
Systematic Reviews  2016;5:2.
Background
Chronic kidney disease-mineral and bone disorders (CKD-MBD) have been associated with poor health outcomes, including diminished quality and length of life. Standard management for CKD-MBD includes phosphate-restricted diet, active vitamin D, vitamin D analogs, and phosphate binders. Persistently elevated parathyroid hormone (PTH) levels may require the addition of Cinacalcet hydrochloride (cinacalcet) which sensitizes calcium receptors on the parathyroid glands. The objective of this systematic review is to compare the effect of cinacalcet versus standard treatment in patients with CKD-MBD.
Methods/design
Data sources will include MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and Web of Science from 1996 to June 2015. Teams of two reviewers will, independently and in duplicate, screen titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstract data and assess risk of bias in eligible trials. We will calculate the effect estimates (risk ratios or mean differences) and 95 % confidence intervals, as well as statistical measures of variability in results across studies using random effect models for patient-important and intermediate outcomes. We will use the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence about estimates of effect on an outcome-by-outcome basis. We will present our results with a GRADE summary table.
Discussion
Our review will explore the effect of cinacalcet versus standard treatment in patients with CKD-MBD. The results of this systematic review will help guide management of this patient population, and identify targets for future research.
Systematic review registration
PROSPERO CRD42015020318http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020318.
doi:10.1186/s13643-015-0177-1
PMCID: PMC4700665  PMID: 26729302
Chronic kidney disease; Mineral and bone disorders; Secondary hyperparathyroidism; Calcimimetic agents
16.  Prognosis after surgical replacement with a bioprosthetic aortic valve in patients with severe symptomatic aortic stenosis: systematic review of observational studies 
The BMJ  2016;354:i5065.
Objective To determine the frequency of survival, stroke, atrial fibrillation, structural valve deterioration, and length of hospital stay after surgical replacement of an aortic valve (SAVR) with a bioprosthetic valve in patients with severe symptomatic aortic stenosis.
Design Systematic review and meta-analysis of observational studies.
Data sources Medline, Embase, PubMed (non-Medline records only), Cochrane Database of Systematic Reviews, and Cochrane CENTRAL from 2002 to June 2016.
Study selection Eligible observational studies followed patients after SAVR with a bioprosthetic valve for at least two years.
Methods Reviewers, independently and in duplicate, evaluated study eligibility, extracted data, and assessed risk of bias for patient important outcomes. We used the GRADE system to quantify absolute effects and quality of evidence. Published survival curves provided data for survival and freedom from structural valve deterioration, and random effect models provided the framework for estimates of pooled incidence rates of stroke, atrial fibrillation, and length of hospital stay.
Results In patients undergoing SAVR with a bioprosthetic valve, median survival was 16 years in those aged 65 or less, 12 years in those aged 65 to 75, seven years in those aged 75 to 85, and six years in those aged more than 85. The incidence rate of stroke was 0.25 per 100 patient years (95% confidence interval 0.06 to 0.54) and atrial fibrillation 2.90 per 100 patient years (1.78 to 4.79). Post-SAVR, freedom from structural valve deterioration was 94.0% at 10 years, 81.7% at 15 years, and 52% at 20 years, and mean length of hospital stay was 12 days (95% confidence interval 9 to 15).
Conclusion Patients with severe symptomatic aortic stenosis undergoing SAVR with a bioprosthetic valve can expect only slightly lower survival than those without aortic stenosis, and a low incidence of stroke and, up to 10 years, of structural valve deterioration. The rate of deterioration increases rapidly after 10 years, and particularly after 15 years.
doi:10.1136/bmj.i5065
PMCID: PMC5040922  PMID: 27683072
17.  Transcatheter versus surgical aortic valve replacement in patients with severe aortic stenosis at low and intermediate risk: systematic review and meta-analysis 
The BMJ  2016;354:i5130.
Objective To examine the effect of transcatheter aortic valve implantation (TAVI) versus surgical replacement of an aortic valve (SAVR) in patients with severe aortic stenosis at low and intermediate risk of perioperative death.
Design Systematic review and meta-analysis
Data sources Medline, Embase, and Cochrane CENTRAL.
Study selection Randomized trials of TAVI compared with SAVR in patients with a mean perioperative risk of death <8%.
Review methods Two reviewers independently extracted data and assessed risk of bias for outcomes important to patients that were selected a priori by a parallel guideline committee, including patient advisors. We used the GRADE system was used to quantify absolute effects and quality of evidence.
Results 4 trials with 3179 patients and a median follow-up of two years were included. Compared with SAVR, transfemoral TAVI was associated with reduced mortality (risk difference per 1000 patients: −30, 95% confidence interval −49 to −8, moderate certainty), stroke (−20, −37 to 1, moderate certainty), life threatening bleeding (−252, −293 to −190, high certainty), atrial fibrillation (−178, −150 to −203, moderate certainty), and acute kidney injury (−53, −39 to −62, high certainty) but increased short term aortic valve reintervention (7, 1 to 21, moderate certainty), permanent pacemaker insertion (134, 16 to 382, moderate certainty), and moderate or severe symptoms of heart failure (18, 5 to 34, moderate certainty). Compared with SAVR, transapical TAVI was associated higher mortality (57, −16 to 153, moderate certainty, P=0.015 for interaction between transfemoral versus transapical TAVI) and stroke (45, −2 to 125, moderate certainty, interaction P=0.012). No study reported long term follow-up, which is particularly important for structural valve deterioration.
Conclusions Many patients, particularly those who have a shorter life expectancy or place a lower value on the risk of long term valve degeneration, are likely to perceive net benefit with transfemoral TAVI versus SAVR. SAVR, however, performs better than transapical TAVI, which is of interest to patients who are not candidates for transfemoral TAVI.
Systematic review registration PROSPERO CRD42016042879
doi:10.1136/bmj.i5130
PMCID: PMC5040923  PMID: 27683246
18.  Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial 
The BMJ  2016;355:i5351.
Objective To determine whether low intensity pulsed ultrasound (LIPUS), compared with sham treatment, accelerates functional recovery and radiographic healing in patients with operatively managed tibial fractures.
Design A concealed, randomized, blinded, sham controlled clinical trial with a parallel group design of 501 patients, enrolled between October 2008 and September 2012, and followed for one year.
Setting 43 North American academic trauma centers.
Participants Skeletally mature men or women with an open or closed tibial fracture amenable to intramedullary nail fixation. Exclusions comprised pilon fractures, tibial shaft fractures that extended into the joint and required reduction, pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures >7.5 cm in length, concomitant injuries that were likely to impair function for at least as long as the patient’s tibial fracture, and tibial fractures that showed <25% cortical contact and >1 cm gap after surgical fixation. 3105 consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599 were eligible and 501 provided informed consent and were enrolled.
Interventions Patients were allocated centrally to self administer daily LIPUS (n=250) or use a sham device (n=251) until their tibial fracture showed radiographic healing or until one year after intramedullary fixation.
Main outcome measures Primary registry specified outcome was time to radiographic healing within one year of fixation; secondary outcome was rate of non-union. Additional protocol specified outcomes included short form-36 (SF-36) physical component summary (PCS) scores, return to work, return to household activities, return to ≥80% of function before injury, return to leisure activities, time to full weight bearing, scores on the health utilities index (mark 3), and adverse events related to the device.
Results SF-36 PCS data were acquired from 481/501 (96%) patients, for whom we had 2303/2886 (80%) observations, and radiographic healing data were acquired from 482/501 (96%) patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control groups (mean difference 0.55, 95% confidence interval −0.75 to 1.84; P=0.41) or for the interaction between time and treatment (P=0.30); minimal important difference is 3-5 points) or in other functional measures. There was also no difference in time to radiographic healing (hazard ratio 1.07, 95% confidence interval 0.86 to 1.34; P=0.55). There were no differences in safety outcomes between treatment groups. Patient compliance was moderate; 73% of patients administered ≥50% of all recommended treatments.
Conclusions Postoperative use of LIPUS after tibial fracture fixation does not accelerate radiographic healing and fails to improve functional recovery.
Study registration ClinicalTrialGov Identifier: NCT00667849
doi:10.1136/bmj.i5351
PMCID: PMC5080447  PMID: 27797787
19.  Reporting missing participant data in randomised trials: systematic survey of the methodological literature and a proposed guide 
BMJ Open  2015;5(12):e008431.
Objectives
We conducted a systematic survey of the methodological literature to identify recommended approaches for how and what randomised clinical trial (RCT) authors should report on missing participant data and, on the basis of these approaches, to propose guidance for RCT authors.
Methods
We defined missing participant data (MPD) as missing outcome data for trial participants. We considered both categorical and continuous outcome data. We searched MEDLINE and the Cochrane Methodology Register for articles in which authors proposed approaches to reporting MPD from RCTs. We selected eligible articles independently and in duplicate and extracted data in duplicate. Using an iterative process of discussion and revisions, we used the findings to develop guidance.
Results
Of 10 501 unique citations identified, 13 articles reporting on 10 approaches proved eligible. The identified approaches recommend reporting the following aspects (from most to least frequently recommended): number of participants with MPD (n=10), reasons for MPD (n=7), methods used to handle MPD in the analysis (n=4), flow of participants (n=3), pattern of missingness (eg, whether at random) (n=3), differences in rates of MPD between trial arms (n=2), differences between participants with and without MPD (n=2), results of any sensitivity analyses (n=2), implication of MPD on interpreting the results (n=2) and methods used to prevent missing data (n=1). We propose a guide with nine items related to reporting the number, reasons, patterns, analytical methods and interpretation of MPD.
Conclusions
Most identified approaches invite trial authors to report the extent of MPD and the underlying reasons. Fewer approaches focus on reporting missingness patterns, methods for handling MPD and implications of MPD on results. Our proposed guidance could help RCT authors to better report, and readers to better identify participants with missing data.
doi:10.1136/bmjopen-2015-008431
PMCID: PMC4710817  PMID: 26719310
EPIDEMIOLOGY; Missing participant data; Randomized clinical trials; Systematic reviews
20.  Patients’ values and preferences of the expected efficacy of hip arthroscopy for osteoarthritis: a protocol for a multinational structured interview-based study combined with a randomised survey on the optimal amount of information to elicit preferences 
BMJ Open  2014;4(10):e005536.
Introduction
Symptomatic hip osteoarthritis (OA) is a disabling condition with up to a 25% cumulative lifetime risk. Total hip arthroplasty (THA) is effective in relieving patients’ symptoms and improving function. It is, however, associated with substantial risk of complications, pain and major functional limitation before patients can return to full function. In contrast, hip arthroscopy (HA) is less invasive and can postpone THA. However, there is no evidence regarding the delay in the need for THA that patients would find acceptable to undergoing HA. Knowing patients’ values and preferences (VP) on this expected delay is critical when making recommendations regarding the advisability of HA. Furthermore, little is known on the optimal amount of information regarding interventions and outcomes needed to present in order to optimally elicit patients’ VP.
Methods and analysis
We will perform a multinational, structured interview-based survey of preference in delay time for THA among patients with non-advanced OA who failed to respond to conservative therapy. We will combine these interviews with a randomised trial addressing the optimal amount of information regarding the interventions and outcomes required to elicit preferences. Eligible patients will be randomly assigned (1 : 1) to either a short or a long format of health scenarios of THA and HA. We will determine each patient's VP using a trade-off and anticipated regret exercises. Our primary outcomes for the combined surveys will be: (1) the minimal delay time in the need for THA surgery that patients would find acceptable to undertaking HA, (2) patients’ satisfaction with the amount of information provided in the health scenarios used to elicit their VPs.
Ethics and dissemination
The protocol has been approved by the Hamilton Integrated Research Ethics Board (HIREB13-506). We will disseminate our study findings through peer-reviewed publications and conference presentations, and make them available to guideline makers issuing recommendations addressing HA and THA.
doi:10.1136/bmjopen-2014-005536
PMCID: PMC4202002  PMID: 25326208
Patients' values and preference; Total Hip Arthroplasty; Hip Arthroscopy; Patient Written Information; Decision Making
21.  Strategic use of new generation antidepressants for depression: SUN(^_^) D protocol update and statistical analysis plan 
Trials  2015;16:459.
Background
SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan.
Results
We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken.
Conclusion
This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results.
Trial registration
ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).
doi:10.1186/s13063-015-0985-6
PMCID: PMC4606498  PMID: 26466684
23.  Minimally important difference estimates and methods: a protocol 
BMJ Open  2015;5(10):e007953.
Introduction
Patient-reported outcomes (PROs) are often the outcomes of greatest importance to patients. The minimally important difference (MID) provides a measure of the smallest change in the PRO that patients perceive as important. An anchor-based approach is the most appropriate method for MID determination. No study or database currently exists that provides all anchor-based MIDs associated with PRO instruments; nor are there any accepted standards for appraising the credibility of MID estimates. Our objectives are to complete a systematic survey of the literature to collect and characterise published anchor-based MIDs associated with PRO instruments used in evaluating the effects of interventions on chronic medical and psychiatric conditions and to assess their credibility.
Methods and analysis
We will search MEDLINE, EMBASE and PsycINFO (1989 to present) to identify studies addressing methods to estimate anchor-based MIDs of target PRO instruments or reporting empirical ascertainment of anchor-based MIDs. Teams of two reviewers will screen titles and abstracts, review full texts of citations, and extract relevant data. On the basis of findings from studies addressing methods to estimate anchor-based MIDs, we will summarise the available methods and develop an instrument addressing the credibility of empirically ascertained MIDs. We will evaluate the credibility of all studies reporting on the empirical ascertainment of anchor-based MIDs using the credibility instrument, and assess the instrument's inter-rater reliability. We will separately present reports for adult and paediatric populations.
Ethics and dissemination
No research ethics approval was required as we will be using aggregate data from published studies. Our work will summarise anchor-based methods available to establish MIDs, provide an instrument to assess the credibility of available MIDs, determine the reliability of that instrument, and provide a comprehensive compendium of published anchor-based MIDs associated with PRO instruments which will help improve the interpretability of outcome effects in systematic reviews and practice guidelines.
doi:10.1136/bmjopen-2015-007953
PMCID: PMC4606423  PMID: 26428330
MID; Minimally Important Difference; Patient Reported Outcome; Systematic Survey; Protocol
24.  Reporting, handling and assessing the risk of bias associated with missing participant data in systematic reviews: a methodological survey 
BMJ Open  2015;5(9):e009368.
Objectives
To describe how systematic reviewers are reporting missing data for dichotomous outcomes, handling them in the analysis and assessing the risk of associated bias.
Methods
We searched MEDLINE and the Cochrane Database of Systematic Reviews for systematic reviews of randomised trials published in 2010, and reporting a meta-analysis of a dichotomous outcome. We randomly selected 98 Cochrane and 104 non-Cochrane systematic reviews. Teams of 2 reviewers selected eligible studies and abstracted data independently and in duplicate using standardised, piloted forms with accompanying instructions. We conducted regression analyses to explore factors associated with using complete case analysis and with judging the risk of bias associated with missing participant data.
Results
Of Cochrane and non-Cochrane reviews, 47% and 7% (p<0.0001), respectively, reported on the number of participants with missing data, and 41% and 9% reported a plan for handling missing categorical data. The 2 most reported approaches for handling missing data were complete case analysis (8.5%, out of the 202 reviews) and assuming no participants with missing data had the event (4%). The use of complete case analysis was associated only with Cochrane reviews (relative to non-Cochrane: OR=7.25; 95% CI 1.58 to 33.3, p=0.01). 65% of reviews assessed risk of bias associated with missing data; this was associated with Cochrane reviews (relative to non-Cochrane: OR=6.63; 95% CI 2.50 to 17.57, p=0.0001), and the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (OR=5.02; 95% CI 1.02 to 24.75, p=0.047).
Conclusions
Though Cochrane reviews are somewhat less problematic, most Cochrane and non-Cochrane systematic reviews fail to adequately report and handle missing data, potentially resulting in misleading judgements regarding risk of bias.
doi:10.1136/bmjopen-2015-009368
PMCID: PMC4593136  PMID: 26423858
EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS

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