What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is ...uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19.
The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty).
This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19.
This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline.
This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.
Objective To estimate the benefits and harms of using corticosteroids as an adjunct treatment for sore throat.Design Systematic review and meta-analysis of randomised control trials.Data ...sources Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries up to May 2017, reference lists of eligible trials, related reviews.Study selection Randomised controlled trials of the addition of corticosteroids to standard clinical care for patients aged 5 or older in emergency department and primary care settings with clinical signs of acute tonsillitis, pharyngitis, or the clinical syndrome of sore throat. Trials were included irrespective of language or publication status.Review methods Reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. A parallel guideline committee (BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. Random effects model was used for meta-analyses. Quality of evidence was assessed with the GRADE approach.Results 10 eligible trials enrolled 1426 individuals. Patients who received single low dose corticosteroids (the most common intervention was oral dexamethasone with a maximum dose of 10 mg) were twice as likely to experience pain relief after 24 hours (relative risk 2.2, 95% confidence interval 1.2 to 4.3; risk difference 12.4%; moderate quality evidence) and 1.5 times more likely to have no pain at 48 hours (1.5, 1.3 to 1.8; risk difference 18.3%; high quality). The mean time to onset of pain relief in patients treated with corticosteroids was 4.8 hours earlier (95% confidence interval −1.9 to −7.8; moderate quality) and the mean time to complete resolution of pain was 11.1 hours earlier (−0.4 to −21.8; low quality) than in those treated with placebo. The absolute pain reduction at 24 hours (visual analogue scale 0-10) was greater in patients treated with corticosteroids (mean difference 1.3, 95% confidence interval 0.7 to 1.9; moderate quality). Nine of the 10 trials sought information regarding adverse events. Six studies reported no adverse effects, and three studies reported few adverse events, which were mostly complications related to disease, with a similar incidence in both groups.Conclusion Single low dose corticosteroids can provide pain relief in patients with sore throat, with no increase in serious adverse effects. Included trials did not assess the potential risks of larger cumulative doses in patients with recurrent episodes of acute sore throat.Systematic review registration PROSPERO CRD42017067808.
What is the role of plasma exchange and what is the optimal dose of glucocorticoids in the first 6 months of therapy of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis ...(AAV)? This guideline was triggered by the publication of a new randomised controlled trial.
Existing guideline recommendations vary regarding the use of plasma exchange in AAV and lack explicit recommendations regarding the tapering regimen of glucocorticoids during induction therapy.
The guideline panel makes a weak recommendation against plasma exchange in patients with low or low-moderate risk of developing end stage kidney disease (ESKD), and a weak recommendation in favour of plasma exchange in patients with moderate-high or high risk of developing ESKD. For patients with pulmonary haemorrhage without renal involvement, the panel suggests not using plasma exchange (weak recommendation). The panel made a strong recommendation in favour of a reduced dose rather than standard dose regimen of glucocorticoids, which involves a more rapid taper rate and lower cumulative dose during the first six months of therapy.
A guideline panel including patients, a care giver, clinicians, content experts, and methodologists produced these recommendations using GRADE and in adherence with standards for trustworthy guidelines. The recommendations are based on two linked systematic reviews. The panel took an individual patient perspective in the development of recommendations.
The systematic review of plasma exchange identified nine randomised controlled trials (RCTs) that enrolled 1060 patients with AAV. Plasma exchange probably has little or no effect on mortality or disease relapse (moderate and low certainty). Plasma exchange probably reduces the one year risk of ESKD (approximately 0.1% reduction in those with low risk, 2.1% reduction in those with low-moderate risk, 4.6% reduction in those with moderate-high risk, and 16.0% reduction in those with high risk or requiring dialysis) but increases the risk of serious infections (approximately 2.7% increase in those with low risk, 4.9% increase in those with low-moderate risk, 8.5% increase in those with moderate-high risk, to 13.5% in high risk group) at 1 year (moderate to high certainty). The guideline panel agreed that most patients with low or low-moderate risk of developing ESKD would consider the harms to outweigh the benefits, while most of those with moderate-high or high risk would consider the benefits to outweigh the harms. For patients with pulmonary haemorrhage without kidney involvement, based on indirect evidence, plasma exchange may have little or no effect on death (very low certainty) but may have an important increase in serious infections at 1 year (approximately 6.8% increase, low certainty). The systematic review of different dose regimens of glucocorticoids identified two RCTs at low risk of bias with 704 and 140 patients respectively. A reduced dose regimen of glucocorticoid probably reduces the risk of serious infections by approximately 5.9% to 12.8% and probably does not increase the risk of ESKD at the follow-up of 6 months to longer than 1 year (moderate certainty for both outcomes).
The recommendations were made with the understanding that patients would place a high value on reduction in ESKD and less value on avoiding serious infections. The panel concluded that most (50-90%) of fully informed patients with AAV and with low or low-moderate risk of developing ESKD with or without pulmonary haemorrhage would decline plasma exchange, whereas most patients with moderate-high or high risk or requiring dialysis with or without pulmonary haemorrhage would choose to receive plasma exchange. The panel also inferred that the majority of fully informed patients with pulmonary haemorrhage without kidney involvement would decline plasma exchange and that all or almost all (≥90%) fully informed patients with AAV would choose a reduced dose regimen of glucocorticoids during the first 6 months of therapy.
In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering ...drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug?
Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens.
The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins.
An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation.
A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/.
The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.
In patients with symptomatic severe aortic stenosis but at lower risk of perioperative death, how do minimally invasive techniques compare with open surgery? Prompted by a recent trial, an expert ...panel produced these recommendations based on three linked rapid systematic reviews
Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. According to the GRADE approach, recommendations can be strong or weak and for or against a course of ...action.33 High quality evidence of an effect on surrogate outcomes do not trigger strong recommendations. All tests for relative subgroup effects may be underpowered to detect true differences because the effect sizes are small, especially for mortality. ...we cannot be certain that a true subgroup effect does not exist. Several trials of corticosteroids for pneumonia or acute respiratory distress syndrome have enrolled patients who did not have sepsis; we did not consider these trials. ...clinicians treating these conditions should also consider evidence2324 and guidelines12 applicable to patients who have pneumonia and acute respiratory distress syndrome.
Universally acknowledged standards for trustworthy guidelines include the necessity to ground recommendations in patient values and preferences. When information is limited-which is typically the ...case-guideline panels often find it difficult to explicitly integrate patient values and preferences into their recommendations. Our objective was to develop and evaluate a framework for systematically navigating guideline panels in incorporating patient values and preferences in making recommendations.
In the context of developing a guideline for colorectal cancer screening, we generated an initial framework for creating panel surveys to elicit guideline panelists' views of patient values and preferences and to inform panel discussions on recommendations. With further applications in guidelines of diverse topic areas, we dynamically refined the framework through iterative discussions and consensus.
The finial framework consists of five steps for creating and implementing panel surveys. The surveys can serve three objectives following from the quantitative information regarding patient values and preferences that guideline panels usually require. An accompanying video provides detailed instructions of the survey.
The framework for creating and implementing panel surveys offers explicit guidance for guideline panels considering transparently and systematically incorporating patient values and preferences into guideline recommendations.
To explore guideline panelists’ understanding of panel surveys for eliciting panels’ inferences regarding patient values and preference, and the influence of the surveys on making recommendations.
We ...performed sampling and data collection from all four guideline panels that had conducted the surveys through October 2020. We collected the records of all panel meetings, and interviewed some panelists in different roles. We applied inductive thematic analysis for analyzing and interpreting data.
We enrolled four guideline panels with 99 panelists in total, and interviewed 25 of them. Most panelists found the survey was easy to follow and facilitated the incorporation of patient values and preferences in the tradeoffs between benefits and harms or burdens. The variation of patient preferences and uncertainty regarding patient values and preferences reflected in the surveys helped the panels ponder the strength of recommendations. In doing so, the survey results enhanced a rationale for panels’ decision on the recommendations.
The panel surveys have proved to help guideline panels explicitly consider and incorporate patient values and preferences in making recommendations. Guideline panels would benefit from widespread use of the panel surveys, particularly when primary evidence regarding patient values and preferences is scarce.
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