Angela Kaminski-Hartenthaler

[GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes].

GRADE requires guideline developers to make an overall rating of confidence in estimates of effect (quality of evidence-high, moderate, low, or very low) for each important or critical outcome. GRADE suggests, for each outcome, the initial separate consideration of five domains of reasons for rating down the confidence in effect estimates, thereby allowing systematic review authors and guideline developers to arrive at an outcome-specific rating of confidence. Although this rating system represents discrete steps on an ordinal scale, it is helpful to view confidence in estimates as a continuum, and the final rating of confidence may differ from that suggested by separate consideration of each domain. An overall rating of confidence in estimates of effect is only relevant in settings when recommendations are being made. In general, it is based on the critical outcome that provides the lowest confidence.

[GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables].

This article is the first of a series providing guidance for the use of the GRADE system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments, and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence has been collected and summarised, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterised as strong or weak (alternative terms: conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarising evidence in succinct, transparent, and informative Summary of Findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADEs approach to formulating questions, assessing quality of evidence, and developing recommendations.

GRADE-Leitlinien: 4. Bewertung der Qualität der Evidenz – Studienlimitationen (Risiko für Bias)

In the GRADE approach, randomised trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of randomised trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently, recognised limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes (e.g., loss to follow-up may be far less for all-cause mortality than for quality of life), a consideration that many systematic reviews ignore. In deciding whether to rate down for risk of bias - whether for randomised trials or observational studies-authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias.

GRADE Leitlinien: 5. Einschätzung der Qualität der Evidenz – Publikationsbias

In the GRADE approach, randomized trials are classified as high quality evidence and observational studies as low quality evidence but both can be rated down if a body of evidence is associated with a high risk of publication bias. Even when individual studies included in best-evidence summaries have a low risk of bias, publication bias can result in substantial overestimates of effect. Authors should suspect publication bias when available evidence comes from a number of small studies most of which have been commercially funded. A number of approaches based on examination of the pattern of data are available to help assess publication bias. The most popular of these is the funnel plot; all, however, have substantial limitations. Publication bias is likely frequent, and caution in the face of early results, particularly with small sample size and number of events, is warranted.

GRADE Leitlinien: 8. Einschätzung der Qualität der Evidenz – Indirektheit☆

Zusammenfassung Direkte Evidenz ergibt sich aus Analysen, die Interventionen von Interesse in relevanten Populationen direkt miteinander vergleichen und hierbei patientenrelevante Zielkriterien messen. Aus vier Grunden kann die Evidenz aber als indirekt bezeichnet werden. Erstens, die Patienten in den Studien konnen von der relevanten Population abweichen (der Begriff Ubertragbarkeit wird oft fur diese Form der Indirektheit verwendet). Zweitens, die untersuchte Intervention (und/oder der Komparator) konnen von den relevanten Interventionen abweichen. Dabei hangen die Entscheidungen hinsichtlich der Indirektheit von Patienten und Intervention vom Verstandnis ab, ob biologische oder soziale Faktoren so wesentlich abweichen, dass substanzielle Differenzen in der Effektgrose zu erwarten sind. Drittens, die Zielkriterien konnen von den primar relevanten Endpunkten abweichen, wenn z.B. Surrogatendpunkte (die selbst nicht relevant sind) mit der Annahme erhoben werden, dass die Veranderung der Surrogate die patientenrelevanten Endpunkte widerspiegelt. Der vierte Typ der Indirektheit unterscheidet sich konzeptionell von den ersten drei. Er liegt vor, wenn zwischen Interventionen gewahlt werden muss, die nicht im direkten Vergleich zueinander untersucht wurden. In solchen Fallen werden fur den Vergleich von Behandlungen spezifische statistische Methoden benotigt, die jedoch zu einer Abwertung der Qualitat von einer oder zwei Stufen fuhren konnen. Eine Herabstufung hangt vom Umfang der Unterschiede zwischen den Patientenpopulationen, den begleitenden Interventionen, der Ergebnismessung und der Studienmethodik der in Frage kommenden Intervention im Vergleich zu einem anderen Komparator ab.Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important to patients. Evidence can be indirect in one of four ways. First, patients may differ from those of interest (the term applicability is often used for this form of indirectness). Second, the intervention tested may differ from the intervention of interest. Decisions regarding indirectness of patients and interventions depend on an understanding of whether biological or social factors are sufficiently different that one might expect substantial differences in the magnitude of effect. Third, outcomes may differ from those of primary interest - for instance, surrogate outcomes that are not themselves important, but measured in the presumption that changes in the surrogate reflect changes in an outcome important to patients. A fourth type of indirectness, which is conceptually different from the first three, occurs when clinicians must choose between interventions that have not been tested in head to head comparisons. Making comparisons between treatments under these circumstances requires specific statistical methods and will be rated down in quality by one or two levels depending on the extent of differences between the patient populations, co-interventions, measurements of the outcome, and the methods of the trials of the candidate interventions against some other comparator.

Ezetimibe-Statin Combination Therapy: Efficacy and Safety as Compared With Statin Monotherapy — a Systematic Review

BACKGROUND To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus. METHODS This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry. RESULTS Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]). CONCLUSION In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect was similar in the two treatment groups.

GRADE Leitlinien: 7. Einschätzung der Qualität der Evidenz – Inkonsistenz

This article deals with inconsistency of relative, rather than absolute, treatment effects in binary/dichotomous outcomes. A body of evidence is not rated up in quality if studies yield consistent results, but may be rated down in quality if inconsistent. Criteria for evaluating consistency include similarity of point estimates, extent of overlap of confidence intervals, and statistical criteria including tests of heterogeneity and I(2). To explore heterogeneity, systematic review authors should generate and test a small number of a priori hypotheses related to patients, interventions, outcomes, and methodology. When inconsistency is large and unexplained, rating down quality for inconsistency is appropriate, particularly if some studies suggest substantial benefit, and others no effect or harm (rather than only large versus small effects). Apparent subgroup effects may be spurious. Credibility is increased if subgroup effects are based on a small number of a priori hypotheses with a specified direction; subgroup comparisons come from within rather than between studies; tests of interaction generate low p-values; and have a biological rationale.

Grade Leitlinien: 15. Von der Evidenz zur Empfehlung – Determinanten, die Richtung und Stärke einer Empfehlung bestimmen☆

In the GRADE approach, the strength of a recommendation reflects the extent to which we can be confident that the composite desirable effects of a management strategy outweigh the composite undesirable effects. This article addresses GRADEs approach to determining the direction and strength of a recommendation. The GRADE describes the balance of desirable and undesirable outcomes of interest among alternative management strategies depending on four domains, namely estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use. Ultimately, guideline panels must use judgment in integrating these factors to make a strong or weak recommendation for or against an intervention.

Ezetimibe-Statin Combination Therapy: Efficacy and Safety as Compared With Statin Monotherapy

BACKGROUND To date, most clinical comparisons of ezetimibe-statin combination therapy versus statin monotherapy have relied entirely on surrogate variables. In this systematic review, we study the efficacy and safety of ezetimibe-statin combination therapy in comparison to statin monotherapy in terms of the prevention of cardiovascular events in hyperlipidemic patients with atherosclerosis and/or diabetes mellitus. METHODS This review is based on a systematic literature search (1995 to July 2015) in PubMed, the Excerpta Medica Database (EMBASE), the Cochrane Library, and the ClinicalTrials.gov registry. RESULTS Nine randomized, controlled trials with data from a total of 19 461 patients were included. Ezetimibe-statin combination therapy was associated with a lower risk of cardiovascular events than statin monotherapy: 33% of the patients treated with ezetimibe and a statin, and 35% of those treated with a statin alone, had a cardiovascular event within seven years (number needed to treat [NNT]: 50 over 7 years). Combination therapy was also significantly more effective in preventing a composite endpoint consisting of death due to cardiovascular disease, nonfatal myocardial infarction, unstable angina pectoris, coronary revascularization, and nonfatal stroke (hazard ratio [HR] 0.94, 95% confidence interval [0,89; 0,99]; p = 0.016). Diabetic patients benefited from combination therapy rather than monotherapy with respect to cardiovascular morbidity (HR 0.87 [0.78; 0.94]). On the other hand, the addition of ezetimibe to statin therapy did not lessen either cardiovascular or overall mortality. Serious undesired events occurred in 38% of the patients taking ezetimibe and a statin nd in 39% of the patients taking a statin alone (relative risk 1.09 [0.77; 1.55]). CONCLUSION In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect was similar in the two treatment groups.

Efficacy and Harms of Second-generation Antidepressants for the Prevention of Seasonal Affective Disorder: a Systematic Review

Introduction Seasonal Affective Disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occur during autumn or winter and remit in spring. Second-generation antidepressants (SGAs) are established interventions to treat acute episodes of SAD. However, little is known about the efficacy and potential harms of these interventions for preventing SAD. Objectives To assess the efficacy and safety of SGAs to prevent SAD and improve patient–centered outcomes in adults with a history of SAD. Methods We searched the Cochrane Depression, Anxiety and Neuorosis Review Groups specialised register, EMBASE, MEDLINE, PsycINFO and the Cochrane Central Register of Controlled Trials. In addition, we searched pharmaceutical industry trials registers via the Internet to identify unpublished trial data. We also conducted grey literature searches and handsearches of pertinent reference lists. Two authors reviewed the evidence, abstracted data, and assessed risk of bias. We pooled data for meta-analysis when participant groups were similar and the studies assessed the same treatments with the same comparator. Results We did not find eligible studies for most comparisons. We included three RCTs comparing bupropion XL with placebo. Statistically significantly fewer patients treated with bupropion experienced the onset of a major depressive episode during winter months. The overall risk of adverse events was similar between treatment groups. However, bupropionn-treated patients had significantly higher risk for headache, insomnia, and nausea. Conclusion The evidence base on SGA treatment to prevent SAD is limited. Future studies are needed to provide a sufficient evidence base for clinical decisionmaking.