Showing papers by "Gordon H. Guyatt published in 2014"

A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis

Abstract: Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly being used to examine the comparative effectiveness of medical interventions. Minimal guidance exists on how to rate the quality of evidence supporting treatment effect estimates obtained from NMA. We present a four-step approach to rate the quality of evidence in each of the direct, indirect, and NMA estimates based on methods developed by the GRADE working group. Using an example of a published NMA, we show that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.

Myocardial Injury after Noncardiac Surgery: A Large, International, Prospective Cohort Study Establishing Diagnostic Criteria, Characteristics, Predictors, and 30-day Outcomes

Abstract: Background Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study's four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated "abnormal" laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors' diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96-5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6-41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Aspirin in Patients Undergoing Noncardiac Surgery

Abstract: The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P = 0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P = 0.04). The primary and secondary outcome results were similar in the two aspirin strata. Conclusions Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.)

Comparison of Weight Loss Among Named Diet Programs in Overweight and Obese Adults: A Meta-analysis

Abstract: low-carbohydrate diets (8.73 kg [95% credible interval {CI}, 7.27 to 10.20 kg] at 6-month follow-up and 7.25 kg [95% CI, 5.33 to 9.25 kg] at 12-month follow-up) and low-fat diets (7.99 kg [95% CI, 6.01 to 9.92 kg] at 6-month follow-up and 7.27 kg [95% CI, 5.26 to 9.34 kg] at 12-month follow-up). Weight loss differences between individual diets were minimal. For example, the Atkins diet resulted in a 1.71 kg greater weight loss than the Zone diet at 6-month follow-up. Between 6- and 12-month follow-up, the influence of behavioral support (3.23 kg [95% CI, 2.23 to 4.23 kg] at 6-month follow-up vs 1.08 kg [95% CI, −1.82 to 3.96 kg] at 12-month follow-up) and exercise (0.64 kg [95% CI, −0.35 to 1.66 kg] vs 2.13 kg [95% CI, 0.43 to 3.85 kg], respectively) on weight loss differed.

Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise

Abstract: Background: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. Methods: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. Results: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. Interpretation: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date.

How to Read a Systematic Review and Meta-analysis and Apply the Results to Patient Care: Users’ Guides to the Medical Literature

Abstract: Clinical decisions should be based on the totality of the best evidence and not the results of individual studies. When clinicians apply the results of a systematic review or meta-analysis to patient care, they should start by evaluating the credibility of the methods of the systematic review, ie, the extent to which these methods have likely protected against misleading results. Credibility depends on whether the review addressed a sensible clinical question; included an exhaustive literature search; demonstrated reproducibility of the selection and assessment of studies; and presented results in a useful manner. For reviews that are sufficiently credible, clinicians must decide on the degree of confidence in the estimates that the evidence warrants (quality of evidence). Confidence depends on the risk of bias in the body of evidence; the precision and consistency of the results; whether the results directly apply to the patient of interest; and the likelihood of reporting bias. Shared decision making requires understanding of the estimates of magnitude of beneficial and harmful effects, and confidence in those estimates.

How to Use a Subgroup Analysis: Users’ Guide to the Medical Literature

Abstract: Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

Prevalence, characteristics, and publication of discontinued randomized trials.

Abstract: Importance The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. Objectives To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. Design and Setting Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. Main Outcomes and Measures Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. Results After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P Conclusions and Relevance In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis

Abstract: Background Fluid resuscitation is the cornerstone of sepsis treatment. However, whether balanced or unbalanced crystalloids or natural or synthetic colloids confer a survival advantage is unclear. Purpose To examine the effect of different resuscitative fluids on mortality in patients with sepsis. Data sources MEDLINE, EMBASE, ACP Journal Club, CINAHL, HealthSTAR, the Allied and Complementary Medicine Database, and the Cochrane Central Register of Controlled Trials through March 2014. Study selection Randomized trials that evaluated different resuscitative fluids in adult patients with sepsis or septic shock and death. No language restrictions were applied. Data extraction Two reviewers extracted data on study characteristics, methods, and outcomes. Risk of bias for individual studies and quality of evidence were assessed. Data synthesis 14 studies (18916 patients) were included with 15 direct comparisons. Network meta-analysis at the 4-node level showed higher mortality with starches than with crystalloids (high confidence) and lower mortality with albumin than with crystalloids (moderate confidence) or starches (moderate confidence). Network meta-analysis at the 6-node level showed lower mortality with albumin than with saline (moderate confidence) and low-molecular-weight starch (low confidence) and with balanced crystalloids than with saline (low confidence) and low- and high-molecular-weight starches (moderate confidence). Limitations These trials were heterogeneous in case mix, fluids evaluated, duration of fluid exposure, and risk of bias. Imprecise estimates for several comparisons in this network meta-analysis contribute to low confidence in most estimates of effect. Conclusion Among patients with sepsis, resuscitation with balanced crystalloids or albumin compared with other fluids seems to be associated with reduced mortality. Primary funding source The Hamilton Chapter of the Canadian Intensive Care Foundation and the Critical Care Medicine Residency Program and Critical Care Division Alternate Funding Plan at McMaster University.

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies

Abstract: Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.

A framework for crafting clinical practice guidelines that are relevant to the care and management of people with multimorbidity.

Abstract: Many patients of all ages have multiple conditions, yet clinicians often lack explicit guidance on how to approach clinical decision-making for such people. Most recommendations from clinical practice guidelines (CPGs) focus on the management of single diseases, and may be harmful or impractical for patients with multimorbidity. A major barrier to the development of guidance for people with multimorbidity stems from the fact that the evidence underlying CPGs derives from studies predominantly focused on the management of a single disease. In this paper, the investigators from the Improving Guidelines for Multimorbid Patients Study Group present consensus-based recommendations for guideline developers to make guidelines more useful for the care of people with multimorbidity. In an iterative process informed by review of key literature and experience, we drafted a list of issues and possible approaches for addressing important coexisting conditions in each step of the guideline development process, with a focus on considering relevant interactions between the conditions, their treatments and their outcomes. The recommended approaches address consideration of coexisting conditions at all major steps in CPG development, from nominating and scoping the topic, commissioning the work group, refining key questions, ranking importance of outcomes, conducting systematic reviews, assessing quality of evidence and applicability, summarizing benefits and harms, to formulating recommendations and grading their strength. The list of issues and recommendations was reviewed and refined iteratively by stakeholders. This framework acknowledges the challenges faced by CPG developers who must make complex judgments in the absence of high-quality or direct evidence. These recommendations require validation through implementation, evaluation and refinement.

Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection

Abstract: BACKGROUND: Prior guidelines stated that trypanocidal therapy should not be used for treating chronic asymptomatic Trypanosoma cruzi infections. However, the recent availability of clinical trials reporting high rates of parasitologic cure in children with early chronic T. cruzi infection have produced changes of these recommendations in some countries. Because of the uncertainty regarding best treatment for this stage of T. cruzi infections, the literature was reviewed systematically for a synthesis of the available evidence. OBJECTIVES: To assess the effects of trypanocidal therapy for chronic asymptomatic T. cruzi infection. SEARCH STRATEGY: We searched The Cochrane Controlled Trials Register (Issue 1, 2000), MEDLINE (start-Nov 1999), EMBASE (start - Feb 2000), LILACS (start - Feb 2000) and the Tropical Diseases Research Division of WHO database (Start - Feb 2000). Reference lists of articles were searched for relevant material. SELECTION CRITERIA: Published RCTs of trypanocidal therapy for people with chronic, asymptomatic T. cruzi infections DATA COLLECTION AND ANALYSIS: Two reviewers independently screened papers for inclusion criteria, quality assessment and data extraction. Forms were used to collect data. Reviewers resolved differences by discussion then a third reviewer if necessary. MAIN RESULTS: Of 43 papers assessed for inclusion, five RCTs (total population=756) met the inclusion criteria. The quality of the trials was rated as low (n=3) or intermediate (n=2). Two RCTs tested benznidazole in school children and three tested different agents in adults. The Odds Ratios and their 95%CI (Fixed models) were: Incidence of ECG abnormalities: 0.41 (0.09, 1.85); Negative seroconversion (AT ELISA): 10.91 (6.07, 19.58); Negative xenodiagnosis during the follow up: 5.37 (3.34, 8.64); Standardised mean reduction of antibody titres: 0.54 (0.31, 0.84). Nitroimidazolic derivatives substantially and significantly modified parasite-related outcomes compared to placebo. Other agents showed borderline or not significant effect. REVIEWER'S CONCLUSIONS: Despite major public health importance, trypanocidal.therapy for chronic asymptomatic T. cruzi infection has been tested in few, small size RCTs which were designed to assess parasitic-related, but not clinical outcomes. Therefore, the potential of trypanocidal therapy to prevent Chagas' disease among asymptomatic, chronically infected subjects is promising, but remains to be evaluated. trypanocidal therapy, particularly nitroimidazolic derivatives given to children or adults with positive xenodiagnosis improve parasite-related outcomes. The large contrast between the burden of Chagas disease and the existing evidence on its prevention points the need to test these or newer agents in more and larger RCTs that include clinical endpoints.

Management of Bell palsy: clinical practice guideline

Abstract: Bell palsy is an idiopathic weakness or paralysis of the face of peripheral nerve origin, with acute onset. It affects 20–30 persons per 100 000 annually, and 1 in 60 individuals will be affected over the course of their lifetime.[1][1],[2][2] The major cause of Bell palsy is believed to be an

Midodrine for orthostatic hypotension and recurrent reflex syncope A systematic review

Abstract: Objective: Symptomatic orthostatic hypotension (SOH) and recurrent reflex syncope (RRS) can be disabling. Midodrine has been proposed in the management of patients with these conditions but its impact on patient important outcomes remains uncertain. We performed a systematic review to evaluate the efficacy and safety of midodrine in patients with SOH and RRS. Methods: We searched multiple electronic databases without language restriction from their inception to June 2013. We included randomized controlled trials of patients with SOH or RRS that compared treatment with midodrine against a control and reported data on patient important outcomes. We graded the quality of evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Results: Eleven trials involving 593 patients were included in this review. Three studies addressed health-related quality of life in patients with RRS, showing improvement with midodrine: risk difference 14% (95% confidence interval [CI] −3.5 to 31.6), very low confidence. Seven studies addressed symptom improvement and provided poolable data showing improvement with midodrine in patients with SOH: risk difference 32.8% (95% CI 13.5–48), low confidence; and RRS: risk difference 63.3% (95% CI 47.6–68.2), very low confidence. Five studies reported syncope recurrence in patients with RRS showing improvement with midodrine: risk difference 37% (95% CI 20.8%–47.4%), moderate confidence. The most frequent side effects in the midodrine arm were pilomotor reactions (33.6%, risk ratio 4.58 [95% CI 2.03–10.37]). Conclusions: Evidence warranting low/moderate confidence suggests that midodrine improves clinical important outcomes in patients with SOH and RRS.

Activity-Based Funding of Hospitals and Its Impact on Mortality, Readmission, Discharge Destination, Severity of Illness, and Volume of Care: A Systematic Review and Meta-Analysis

Abstract: Background: Activity-based funding (ABF) of hospitals is a policy intervention intended to re-shape incentives across health systems through the use of diagnosis-related groups. Many countries are adopting or actively promoting ABF. We assessed the effect of ABF on key measures potentially affecting patients and health care systems: mortality (acute and post-acute care); readmission rates; discharge rate to post-acute care following hospitalization; severity of illness; volume of care. Methods: We undertook a systematic review and meta-analysis of the worldwide evidence produced since 1980. We included all studies reporting original quantitative data comparing the impact of ABF versus alternative funding systems in acute care settings, regardless of language. We searched 9 electronic databases (OVID MEDLINE, EMBASE, OVID Healthstar, CINAHL, Cochrane CENTRAL, Health Technology Assessment, NHS Economic Evaluation Database, Cochrane Database of Systematic Reviews, and Business Source), hand-searched reference lists, and consulted with experts. Paired reviewers independently screened for eligibility, abstracted data, and assessed study credibility according to a pre-defined scoring system, resolving conflicts by discussion or adjudication. Results: Of 16,565 unique citations, 50 US studies and 15 studies from 9 other countries proved eligible (i.e. Australia, Austria, England, Germany, Israel, Italy, Scotland, Sweden, Switzerland). We found consistent and robust differences between ABF and no-ABF in discharge to post-acute care, showing a 24% increase with ABF (pooled relative risk =1.24, 95% CI 1.18–1.31). Results also suggested a possible increase in readmission with ABF, and an apparent increase in severity of illness, perhaps reflecting differences in diagnostic coding. Although we found no consistent, systematic differences in mortality rates and volume of care, results varied widely across studies, some suggesting appreciable benefits from ABF, and others suggesting deleterious consequences. Conclusions: Transitioning to ABF is associated with important policy- and clinically-relevant changes. Evidence suggests substantial increases in admissions to post-acute care following hospitalization, with implications for system capacity and equitable access to care. High variability in results of other outcomes leaves the impact in particular settings uncertain, and may not allow a jurisdiction to predict if ABF would be harmless. Decision-makers considering ABF should plan for likely increases in post-acute care admissions, and be aware of the large uncertainty around impacts on other critical outcomes.

Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications.

Abstract: Objective To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. Design Cohort of protocols of randomised controlled trial and subsequent full journal publications. Setting Six research ethics committees in Switzerland, Germany, and Canada. Data sources 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. Results Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P Conclusions Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Effects of Centrally Acting Angiotensin Converting Enzyme Inhibitors on Functional Decline in Patients with Alzheimer's Disease

Abstract: Background Centrally acting angiotensin converting enzyme inhibitors (CACE-Is) are associated with reduced rates of cognitive decline in patients with dementia. CACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition, suggesting that CACE-Is may positively influence activities of daily living (ADL) in dementia. Objective To compare rates of decline in patients with mild to moderate Alzheimer's disease (AD) receiving CACE-Is to those not currently treated with CACE-Is (NoCACE-I), included in the Doxycycline and Rifampicin for Alzheimer's Disease study (n = 406). Methods Patients were included if baseline and end-point (twelve months apart) scores were available for measures including the Standardized Alzheimer's Disease Assessment Scale - Cognitive Subscale; Quick Mild Cognitive Impairment screen; Clinical Dementia Rating Scale (CDR-SB), and Lawton-Brody ADL Scale. Results There was a significant, 25% difference (median one-point) in the 12-month rate of decline in ADL scores in patients taking CACE-Is (n = 91), compared to the NoCACE-I group (n = 274), p = 0.024. This remained significant after adjusting for age, gender, education, and blood pressure, p = 0.034. When individual CACE-Is were compared to the NoCACE-I group, a significant reduction in the rate of decline in ADLs (median one versus four points), were only observed for perindopril, p = 0.01. The CDR-SB was also reduced (median one-point) for the perindopril compared to the NoCACE-I group, p = 0.04. Conclusion This observational study suggests that CACE-Is, and potentially perindopril in particular, are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior. This suggests that CACE-Is may slow disease progression in AD.

A GRADE Working Group approach for rating the quality of treatment effect estimates from network

Abstract: Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly beingused to examine the comparative effectiveness of medical interventions. Minimal guidance existson how to rate the quality of evidence supporting treatment effect estimates obtained from NMA.We present a four-step approach to rate the quality of evidence in each of the direct, indirect, andNMA estimates based on methods developed by the GRADE working group. Using an example ofa published NMA, w e show that the quality of e vidence suppor ting NMA estimates v aries from highto very low across compar isons , and that quality r atings giv en to a whole netw ork are uninf ormativeand likely to mislead.MiloAPuhan

Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients

Abstract: IMPORTANCE Venous thromboembolism (VTE) is a common complication of acute illness, and its prevention is a ubiquitous aspect of inpatient care. A multicenter blinded, randomized trial compared the effectiveness of the most common pharmocoprevention strategies, unfractionated heparin (UFH) and the low-molecular-weight heparin (LMWH) dalteparin, finding no difference in the primary end point of leg deep-vein thrombosis but a reduced rate of pulmonary embolus and heparin-induced thrombocytopenia among critically ill medical-surgical patients who received dalteparin.

Evidence-based practice is not synonymous with delivery of uniform health care.

Abstract: Current clinical practice is characterized by substantial variation in delivery of health care for the same conditions.1 In turn, clinical variation is considered one of the major drivers of ever-increasing health care costs1 contributing to the estimated 30% of inappropriate or wasteful health care.2 Perhaps as a natural response to this unsatisfactory situation, a widespread and influential school of thought has emerged contending that greater uniformity of clinical practice is desirable.1,3 Advocates maintain that by achieving uniformity in care, practice variation can be decreased, in turn leading to large cost reductions. The suggested mechanism to achieve uniformity in part involves clinician adherence to practice guidelines, which is seen as synonymous with evidence-based practice.3 In this Viewpoint, we explain that this position is based on a misunderstanding of trustworthy guidelines4 and that striving for uniformity of practice as an end is misguided. The first limitation in the drive for uniformity is a failure to appreciate the need for guidelines that achieve a high standard of trustworthiness.4 Flawed guidelines, particularly those that offer strong recommendations when only weak recommendations are warranted, are unlikely to facilitate optimal practice. Advocates for uniformity should highlight the distinction between flawed vs trustworthy guidelines and ensure that only the latter are seen as a guide for clinical practice.4,5 Uniformity of practice means that patients with a similar presentation of underlying condition, severity, and circumstances will receive the same treatment— that is, they will all receive or not receive particular diagnostic tests, medications, or surgical procedures. There are circumstances in which such uniformity is desirable. In particular, when clinicians are confident in the estimates of the effects of health interventions on all outcomes of importance to patients (ie, high-quality evidence is available), the desirable consequences of the one management strategy clearly outweigh its undesirable consequences, and the relative importance patients place on the key outcomes (ie, their values and preferences) are similar across patients. That the recommended intervention is not overly costly, is highly feasible, is acceptable to clinicians and patients, and reduces health disparities further strengthens the case for uniformity of clinical practice. There are many, indeed the majority of, situations in which clinicians and patients make management decisions of importance, but these conditions are not met. For example, the American Board of Internal Medicine’s Choosing Wisely campaign has identified 135 health interventions in which evidence suggests equivalence but not superiority to other options in terms of benefits, harms, and costs.6 Studies directly addressing the relevant questions may not have been undertaken, or if they have, they may be small, poorly designed or implemented, show inconsistent results, be limited by publication bias, or have enrolled idiosyncratic populations of questionable applicability. In these cases, the confidence in the estimate of effects will often be low or very low. In addition, if values and preferences differ widely across patients (which is often if not uniformly the case), the right decision for one patient may be the wrong decision for another. For example, Montori et al7 illustrated how recent guidelines by the American College of Cardiology and the American Heart Association for the use of statins for primary prevention of heart disease do not mandate uniform practice—some patients informed about cardiovascular disease risk reduction will choose the recommended course of action and use statins, but others will not. Organizations that produce guidelines should distinguish between situations in which confidence in effect estimates is high and the balance between desirable and undesirable consequences is clear and when these conditions do not exist. In the former situation the guideline will include strong, definitive recommendations that often warrant uniformity of practice. In the latter, they will issue weak (conditional or contingent) recommendations. The recommended course of action will be right for many patients, but not right for all.5 In this scenario, uniformity of practice will not be appropriate. For example, administration of at least 1 antiplatelet agent and a statin for patients who have experienced a myocardial infarction; a β-blocker and an angiotensin-converting enzyme inhibitor for patients with systolic heart failure; corticosteroids for patients experiencing asthma exacerbation; and curative chemotherapy for patients with large cell lymphoma all warrant strong recommendations. These situations therefore warrant uniform practice, other than in exceptional situations such as drug allergy or severe comorbidities. In each case, clinicians should have high confidence in estimates of effect and in the desirable consequences of the intervention being much greater than the undesirable consequences. In contrast, use of anticoagulants for low-risk patients with atrial fibrillation; indefinite anticoagulation for patients with unprovoked venous thromboembolism; use of corticosteroids for patients with idiopathic pulmonary fibrosis; and chemotherapy for patients with advanced non–small cell lung cancer warrant weak recommendations. In these instances, in which clinicians have either low confidence in VIEWPOINT

Systematic review of percutaneous closure versus medical therapy in patients with cryptogenic stroke and patent foramen ovale.

Abstract: Objectives To provide a comprehensive comparison of patent foramen ovale (PFO) closure versus medical therapy in patients with cryptogenic stroke or transient ischaemic attack (TIA) and demonstrated PFO. Design Systematic review with complete case meta-analysis and sensitivity analyses. Data sources included MEDLINE and EMBASE from 1980 up to May 2013. All randomised controlled trials (RCTs) comparing treatment with percutaneous catheter-based closure of PFO to anticoagulant or antiplatelet therapy in patients with cryptogenic stroke or TIA and echocardiographically confirmed PFO or atrial septal defect (ASD) were eligible. Participants 1967 participants with prior stroke or TIA and echocardiographically confirmed PFO or ASD. Primary outcome measures The primary outcome of interest was recurrence of ischaemic stroke. We utilised data from complete cases only for the primary endpoint and combined data from trials to estimate the pooled risk ratio (RR) and associated 95% CIs calculated using random effects models. Results We identified 284 potentially eligible articles of which three RCTs including 2303 patients proved eligible and 1967 patients had complete data. Of the 1026 patients randomised to PFO closure and followed to study conclusion 22 experienced non-fatal ischaemic strokes, as did 34 of 941 patients randomised to medical therapy (risk ratio (RR) 0.61, 95% CI 0.34 to 1.07; heterogeneity: p=0.34, I2=8%, confidence in estimates low due to risk of bias and imprecision). Analyses for ischaemic stroke restricted to ‘per-protocol’ patients or patients with concomitant atrial septal aneurysm did not substantially change the observed RRs. Complication rates associated with either PFO closure or medical therapy were low. Conclusions Pooled data from three RCTs provides insufficient support that PFO closure is preferable to medical therapy for secondary prevention of cryptogenic stroke in patients with PFO.

Critical-sized defect in the tibia: is it critical? Results from the SPRINT trial.

Abstract: Objectives The purpose of this study was to determine whether the SPRINT definition of a "critical-sized defect" (fracture gap at least 1 cm in length and involving over 50% of the cortical diameter) was accurate, to discern which factors predict reoperation in patients with these defects, and to compare the patient-based outcomes of these patients with patients without a critical defect. Design Therapeutic Cohort Study. Setting Level 1 and level 2 trauma centers. Patients Thirty-seven patients in the SPRINT trial with a critical-sized defect participated. We evaluated these patients for planned and unplanned secondary intervention to gain union. Additionally, we evaluated which other factors predicted the need for reoperation. Finally, the 37 patients with a critical defect were compared with the larger cohort of patients without a defect with respect to demographics, mechanism of injury, fracture characteristics, and patient-based outcome. Intervention Revision surgery for tibial nonunion. Results Of the 37 patients with a large fracture gap, 7 patients had a planned secondary procedure. Of the remaining 30 patients in whom the attending surgeon adopted a "watch and wait" strategy, 14 patients (47%) never required additional surgery to gain union. Additional surgery to gain union was less likely in patients treated with a reamed nail (P = 0.04) and in female patients (P = 0.04). Patients with a critical-sized defect were more likely to have a high-energy mechanism of injury (P = 0.001), AO-OTA fracture type 42 B or C (P Conclusions Tibial diaphyseal defects of >1 cm and >50% cortical circumference healed without additional surgery in 47% of cases. This definition of a critical-sized defect is not "critical." However, as compared with the overall cohort of tibial fractures, patients with these bone defects had a higher rate of reoperation and worse patient-based outcomes. Further investigation is required to determine which factors predict union in this challenging fracture to avoid unnecessary secondary surgery. Level of evidence Prognostic level I. See instructions for authors for a complete description of levels of evidence.

A practical approach to evidence-based dentistry: Understanding and applying the principles of EBD

Abstract: Scientific evidence is a crucial underpinning of clinical practice. Nevertheless, the first series of articles aimed at providing clinicians with guidelines for critically appraising the evidence that informs clinical practices did not appear until 1981.1 Ten years later, the term “evidence-based medicine”2 first appeared in the medical literature. Subsequently, between 1993 and 2000, a group of evidence-based medicine enthusiasts3 published a series of 25 articles that aimed at assisting clinicians in understanding and applying the medical literature to their clinical decision making in a clinical setting.4 The concept of evidence-based medicine soon expanded to other clinical areas. The first article to use the term “evidence-based dentistry” (EBD) was published in 1995 by Richards and Lawrence,5 and since then other articles have been published on the topic.6-11 There is, however, still no guide easily accessible for practicing dentists in the United States that addresses the critical appraisal and use of evidence specifically aimed at clinicians in oral health care fields. A series of articles (Box) will be published in The Journal of the American Dental Association, aimed at providing an overview of the basic concepts of EBD to assist oral health care professionals in making use of evidence to inform their clinical decisions. The series will consist of, in addition to this introductory commentary, six core articles that will address the main topics in EBD. In this introductory commentary, we will define EBD, delineate its principles and outline the main steps in the process of EBD. The first core article will describe how to state questions in a format that facilitates searching for the evidence, and where and how to search for such evidence. In the remaining articles, we will explain how to use literature about therapy and prevention, etiology and prognosis, and diagnosis as well as systematic reviews and clinical practice guidelines.