Reem A. Mustafa

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

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.

The GRADE Working Group clarifies the construct of certainty of evidence

OBJECTIVEnTo clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines.nnnSTUDY DESIGN AND SETTINGnThis work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance.nnnRESULTSnCertainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects.nnnCONCLUSIONnIt is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.

GRADE guidelines 17: assessing the risk of bias associated with missing participant outcome data in a body of evidence

OBJECTIVEnTo provide GRADE guidance for assessing risk of bias across an entire body of evidence consequent on missing data for systematic reviews of both binary and continuous outcomes.nnnSTUDY DESIGN AND SETTINGnSystematic survey of published methodological research, iterative discussions, testing in systematic reviews, and feedback from the GRADE Working Group.nnnRESULTSnApproaches begin with a primary meta-analysis using a complete case analysis followed by sensitivity meta-analyses imputing, in each study, data for those with missing data, and then pooling across studies. For binary outcomes, we suggest usexa0of plausible worst case in which review authors assume that those with missing data in treatment arms have proportionallyxa0higher event rates than those followed successfully. For continuous outcomes, imputed mean values come from other studiesxa0within the systematic review and the standard deviation (SD) from the median SDs of the control arms of all studies.nnnCONCLUSIONSnIf the results of the primary meta-analysis are robust to the most extreme assumptions viewed as plausible, one does not rate down certainty in the evidence for risk of bias due to missing participant outcome data. If the results prove not robust to plausible assumptions, one would rate down certainty in the evidence for risk of bias.

Outcomes of vascular access for hemodialysis: A systematic review and meta-analysis

BACKGROUNDnThe decision about the type and location of a hemodialysis vascular access is challenging and can be affected by multiple factors. We explored the effect of several a priori chosen patient characteristics on access outcomes.nnnMETHODSnWe searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database ofxa0Systematic Reviews, and Scopus through November 13, 2014. We included studies that evaluated patency, mortality, access infection, and maturation of vascular access in adults requiring long-term dialysis. Pairs of reviewers working independently selected the studies and extracted the data. Outcomes were pooled across studies using the random-effects model.nnnRESULTSnTwo hundred studies met the eligibility criteria reporting on 875,269 vascular accesses. Overall, studies appeared to have provided incidence rates at low to moderate risk of bias. The overall primary patency at 2xa0years was higher for fistulas than for grafts and catheters (55%, 40%, and 50%, respectively). Patency was lower in individuals with diabetes, coronary artery disease, older individuals, and in women. Mortality at 2xa0years was highest with catheters, followed by grafts then fistulas (26%, 17%, and 15%, respectively).nnnCONCLUSIONSnThe current evidence remains in support of autogenous access as the best approach when feasible. We provide incidence rates in various subgroups to inform shared decision making and facilitate the conversation with patients about access planning.

Effect of Lowering the Dialysate Temperature in Chronic Hemodialysis: A Systematic Review and Meta-Analysis

BACKGROUND AND OBJECTIVESnLowering the dialysate temperature may improve outcomes for patients undergoing chronic hemodialysis. We reviewed the reported benefits and harms of lower temperature dialysis.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnWe searched the Cochrane Central Register, OVID MEDLINE, EMBASE, and Pubmed until April 15, 2015. We reviewed the reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included all randomized, controlled trials that evaluated the effect of reduced temperature dialysis versus standard temperature dialysis in adult patients receiving chronic hemodialysis. We followed the Grading of Recommendations Assessment, Development and Evaluation approach to assess confidence in the estimates of effect (i.e., the quality of evidence). We conducted meta-analyses using random effects models.nnnRESULTSnTwenty-six trials were included, consisting of a total of 484 patients. Compared with standard temperature dialysis, reduced temperature dialysis significantly reduced the rate of intradialytic hypotension by 70% (95% confidence interval, 49% to 89%) and significantly increased intradialytic mean arterial pressure by 12 mmHg (95% confidence interval, 8 to 16 mmHg). Symptoms of discomfort occurred 2.95 (95% confidence interval, 0.88 to 9.82) times more often with reduced temperature compared with standard temperature dialysis. The effect on dialysis adequacy was not significantly different, with a Kt/V mean difference of -0.05 (95% confidence interval, -0.09 to 0.01). Small sample sizes, loss to follow-up, and a lack of appropriate blinding in some trials reduced confidence in the estimates of effect. None of the trials reported long-term outcomes.nnnCONCLUSIONSnIn patients receiving chronic hemodialysis, reduced temperature dialysis may reduce the rate of intradialytic hypotension and increase intradialytic mean arterial pressure. High-quality, large, multicenter, randomized trials are needed to determine whether reduced temperature dialysis affects patient mortality and major adverse cardiovascular events.

Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis

This article describes conceptual advances of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidance to evaluate the certainty of evidence (confidence in evidence, quality of evidence) from network meta-analysis (NMA). Application of the original GRADE guidance, published in 2014, in a number of NMAs has resulted in advances that strengthen its conceptual basis and make the process more efficient. This guidance will be useful for systematic review authors who aim to assess the certainty of all pairwise comparisons from an NMA and who are familiar with the basic concepts of NMA and the traditional GRADE approach for pairwise meta-analysis. Two principles of the original GRADE NMA guidance are that we need to rate the certainty of the evidence for each pairwise comparison within a network separately and that in doing so we need to consider both the direct and indirect evidence. We present, discuss, and illustrate four conceptual advances: (1) consideration of imprecision is not necessary when rating the direct and indirect estimates to inform the rating of NMA estimates, (2) there is no need to rate the indirect evidence when the certainty of the direct evidence is high and the contribution of the direct evidence to the network estimate is at least as great as that of the indirect evidence, (3) we should not trust a statistical test of global incoherence of the network to assess incoherence at the pairwise comparison level, and (4) in the presence of incoherence between direct and indirect evidence, the certainty of the evidence of each estimate can help decide which estimate to believe.

GRADE Guidelines: 18. How ROBINS-I and other tools to assess risk of bias in non-randomized studies should be used to rate the certainty of a body of evidence.

OBJECTIVEnTo provide guidance on how systematic review authors, guideline developers, and health technology assessment practitioners should approach the use of the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool as a part of GRADEs certainty rating process.nnnSTUDY DESIGN AND SETTINGnThe study design and setting comprised iterative discussions, testing in systematic reviews, and presentation at GRADE working group meetings with feedback from the GRADE working group.nnnRESULTSnWe describe where to start the initial assessment of a body of evidence with the use of ROBINS-I and where one would anticipate the final rating would end up. The GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains: large effects, dose-effect relations, and when plausible residual confounders or other biases increase certainty. They will need to be considered in an assessment of a body of evidence when using ROBINS-I.nnnCONCLUSIONSnThe use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias. Challenges remain, including appropriate presentation of evidence from RCTs and NRSs for decision-making and how to optimally integrate RCTs and NRSs in an evidence assessment.

Cinacalcet versus standard treatment for chronic kidney disease: a systematic review and meta-analysis

Abstract 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, vitamin D and phosphate binders. Persistently elevated parathyroid hormone levels may require the addition of cinacalcet hydrochloride (cinacalcet), which sensitizes calcium receptors in the parathyroid gland. Purpose: The objective of this systematic review is to compare, in patients with CKD-MBD the effect of cinacalcet versus standard treatment on patient-important outcomes, including parathyroidectomy, fractures, hospitalizations due to cardiovascular events, cardiovascular mortality, all-cause mortality, and intermediate outcomes, in particular Kidney Disease Outcome Quality Initiative targets. Methods: Data sources included MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Web of Science from 1996 to June 2015. 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 trials. We calculated 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. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate quality of evidence about estimates of effect on an outcome-by-outcome basis for all outcomes. We presented our results with a GRADE summary table. Results: Twenty-four trials including 8311 CKD patients proved eligible. The results left considerable uncertainty regarding the impact of cinacalcet on reducing fractures (relative risk [RR] 0.59, 95% confidence interval [CI] 0.13–2.60; heterogeneity: pu2009=u20090.03, I2=u200978%; very low quality evidence), and indicated that cinacalcet did not reduce hospitalizations due to cardiovascular events (RR 0.93, 95% CI 0.85–1.02, moderate quality of evidence), cardiovascular mortality (RR 0.95, 95% CI 0.84–1.07; heterogeneity p=u20090.61, high quality evidence) or all-cause mortality (RR 0.96, 95% CI 0.89–1.04; heterogeneity: p=u20090.98, I2=u20090%; moderate quality evidence). Cinacalcet reduced the need for parathyroidectomy (RR 0.30, 95% CI 0.22–0.42; heterogeneity: p=u20090.70, I2=u20090%; absolute effect 55 fewer per 1000 [95% CI 61 fewer to 45 fewer], high quality of evidence). The most common adverse event associated with cinacalcet therapy was gastrointestinal side effects. Cinacalcet increased nausea (RR 2.16, 95% CI 1.46–3.21, absolute effect 158 more per 1000 [95% CI 82 more to 302 more]) and vomiting (RR 2.15, 95% CI 1.66–2.80, absolute effect 63 more per 1000 [95% CI 109 more to 171 more]). Cinacalcet treatment increased the rate of hypocalcemia (RR 6.0, 95% CI 3.65–9.87; heterogeneity: p=u20090.71, I2=u20090%, absolute effect 20 more per 1000 [95% CI 11 more to 36 more], high quality of evidence). Conclusions: In the hands of clinicians participating in these studies, cinacalcet decreased the rate of parathyroidectomy but had no influence on mortality. Patients and clinicians can trade of the benefit of fewer parathyroidectomies against the adverse effects.

Combined general and neuraxial anesthesia versus general anesthesia: a population-based cohort study

PurposeTo determine whether combining spinal or epidural anesthesia with general anesthesia (combined anesthesia) reduces major medical complications of elective surgery compared with general anesthesia alone.MethodsWe conducted a propensity-matched population-based historical cohort study using large healthcare databases from Ontario, Canada. We identified patients undergoing 21 different elective procedures that were amenable to either combined anesthesia or general anesthesia alone in 108 hospitals from 2004 to 2011. We assessed the following four outcomes together as a composite and individually in the 30xa0days following surgery: acute kidney injury, stroke, myocardial infarction, and all-cause mortality.ResultsPrior to matching, we identified 21,701 patients receiving general anesthesia and 8,042 patients receiving combined anesthesia. After matching, our cohort included 12,379 patients. Twenty-eight baseline characteristics were well-matched between the combined (nxa0=xa04,773) and general anesthesia groups (nxa0=xa07,606). Mean patient age was 66xa0yr. Relative to general anesthesia alone, combined anesthesia was not associated with a reduced risk for the composite outcome [104/4,773 (2.2%) vs 162/7,606 (2.1%); odds ratio (OR) 0.97; 95% confidence interval (CI) 0.75 to 1.24] or for any of the four component outcomes when examined separately: acute kidney injury (OR 0.93; 95% CI 0.58 to 1.51), stroke (OR 0.79; 95% CI 0.36 to 1.73), myocardial infarction (OR 1.04; 95% CI 0.69 to 1.57), and all-cause mortality (OR 0.91; 95% CI 0.59 to 1.42).ConclusionThe addition of spinal or epidural anesthesia to general anesthesia was not associated with a reduced risk of major medical complications among 21 different elective procedures when compared with general anesthesia alone.RésuméObjectifDéterminer si la combinaison d’une rachianesthésie ou d’une anesthésie péridurale avec une anesthésie générale (anesthésie combinée) diminue les complications médicales majeures d’une chirurgie programmée comparativement à une anesthésie générale seule.MéthodesNous avons réalisé une étude de cohorte historique basée sur une population appariée pour la propension en utilisant les grandes bases de données de soins de santé de la province d’Ontario (Canada). Nous avons identifié des patients subissant 21 types différents de procédures chirurgicales programmées qui étaient susceptibles de bénéficier d’une anesthésie combinée ou d’une anesthésie générale seule dans 108xa0hôpitaux entre 2004 et 2011. Nous avons évalué les quatre aboutissements suivants ensemble sous forme de critère composite et individuellement, dans les 30xa0jours suivant l’intervention: insuffisance rénale aiguë, accident vasculaire cérébral (AVC), infarctus du myocarde et mortalité toute cause.RésultatsAvant l’appariement, nous avons identifié 21xa0701 patients ayant reçu une anesthésie générale et 8xa0042 patients ayant reçu une anesthésie combinée. Après l’appariement, notre cohorte incluait 12xa0379 patients. Vingt-huit caractéristiques à l’inclusion étaient bien appariées entre les groupes «xa0anesthésie combinéexa0» (nxa0=xa04xa0773) et «xa0anesthésie généralexa0» (nxa0=xa07xa0606). L’âge moyen des patients était de 66xa0ans. Par rapport à l’anesthésie générale seule, l’anesthésie combinée n’a pas été associée à une réduction du risque pour le critère d’évaluation composite [104/4xa0773 (2,2xa0%) contre 162/7xa0606 (2,1xa0%); rapport de cotes (OR) 0,97; intervalle de confiance (IC) à 95xa0%: 0,75 à 1,24] ou à l’un des quatre éléments du critère d’évaluation quand ils étaient calculés séparément: insuffisance rénale aiguë (OR: 0,93; IC à 95xa0%: 0,58xa0à 1,51), AVC (OR: 0,79; IC à 95xa0%: 0,36 à 1,73), infarctus du myocarde (OR: 1,04; IC à 95xa0%: 0,69 à 1,57) et mortalité toute cause (OR: 0,91; IC à 95xa0%: 0,59 à 1,42).ConclusionL’ajout de la rachianesthésie ou de l’anesthésie péridurale à l’anesthésie générale n’a pas été associé à une diminution du risque de complications médicales majeures pour 21xa0procédures chirurgicales électives différentes par rapport à l’anesthésie générale administrée seule.

A methodological survey of the analysis, reporting and interpretation of Absolute Risk ReductiOn in systematic revieWs (ARROW): a study protocol

Background nClinicians, providers and guideline panels use absolute effects to weigh the advantages and downsides of treatment alternatives. Relative measures have the potential to mislead readers. However, little is known about the reporting of absolute measures in systematic reviews. The objectives of our study are to determine the proportion of systematic reviews that report absolute measures of effect for the most important outcomes, and ascertain how they are analyzed, reported and interpreted.