British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease.

Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams.

Exploring the perspectives of selectors and collecters of trial outcome data: an international qualitative study.

INTRODUCTION: Selecting and collecting data to support appropriate primary and secondary outcomes is a critical step in designing trials that can change clinical practice. In this study, we aimed to investigate who contributes to the process of selecting and collecting trial outcomes, and how these people are involved. This work serves two main purposes: (1) it provides the trials community with evidence to demonstrate how outcomes are currently selected and collected, and (2) it allows people involved in trial design and conduct to pick apart these processes to consider how efficiencies and improvements can be made. METHODS: One-with-one semi-structured interviews, supported by a topic guide to ensure coverage of key content. The Framework approach was used for thematic analysis of data, and themes were linked through constant comparison of data both within and across participant groups. Interviews took place between July 2020 and January 2021. Participants were twenty-nine international trialists from various contributor groups, working primarily on designing and/or delivering phase III pragmatic effectiveness trials. Their experience spanned various funders, trial settings, clinical specialties, intervention types, and participant populations. RESULTS: We identified three descriptive themes encompassing the process of primary and secondary outcome selection, collection, and the publication of outcome data. Within these themes, participants raised issues around the following: 1) Outcome selection: clarity of the research question; confidence in selecting trial outcomes and how confidence decreases with increased experience; interplay between different interested parties; how patients and the public are involved in outcome selection; perceived impact of poor outcome selection including poor recruitment and/or retention; and use of core outcome sets. 2) Outcome collection: disconnect between decisions made by outcome selectors and the practical work done by outcome collectors; potential impact of outcome measures on trial participants; potential impact on trial staff workload; and use of routinely collected data. 3) Publication of outcome data: difficulties in finding time to write and revise manuscripts for publication due to time and funding constraints. Participants overwhelmingly focused on the process of outcome selection, a topic they talked about unprompted. When prompted, participants do discuss outcome collection, but poor communication between selectors and collectors at the trial design stage means that outcome selection is rarely linked with the data collection workload it generates. DISCUSSION: People involved in the design and conduct of trials fail to connect decisions around outcome selection with data collection workload. Publication of outcome data and effective dissemination of trial results are hindered due to the project-based culture of some academic clinical trial research.

A good use of time? Providing evidence for how effort is invested in primary and secondary outcome data collection in trials.

BACKGROUND: Data collection is a substantial part of trial workload for participants and staff alike. How these hours of work are spent is important because stakeholders are more interested in some outcomes than others. The ORINOCO study compared the time spent collecting primary outcome data to the time spent collecting secondary outcome data in a cohort of trials. METHODS: We searched PubMed for phase III trials indexed between 2015 and 2019. From these, we randomly selected 120 trials evaluating a therapeutic intervention plus an additional random selection of 20 trials evaluating a public health intervention. We also added eligible trials from a cohort of 189 trials in rheumatology that had used the same core outcome set. We then obtained the time taken to collect primary and secondary outcomes in each trial. We used a hierarchy of methods that included data in trial reports, contacting the trial team and approaching individuals with experience of using the identified outcome measures. We calculated the primary to secondary data collection time ratio and notional data collection cost for each included trial. RESULTS: We included 161 trials (120 phase III; 21 core outcome set; 20 public health), which together collected 230 primary and 688 secondary outcomes. Full primary and secondary timing data were obtained for 134 trials (100 phase III; 17 core outcome set; 17 public health). The median time spent on primaries was 56.1 h (range: 0.0-10,746.7, IQR: 226.89) and the median time spent on secondaries was 190.7 hours (range: 0.0-1,356,832.9, IQR: 617.6). The median primary to secondary data collection time ratio was 1.0:3.0 (i.e. for every minute spent on primary outcomes, 3.0 were spent on secondaries). The ratio varied by trial type: phase III trials were 1.0:3.1, core outcome set 1.0:3.4 and public health trials 1.0:2.2. The median notional overall data collection cost was £8015.73 (range: £52.90-£31,899,140.70, IQR: £20,096.64). CONCLUSIONS: Depending on trial type, between two and three times as much time is spent collecting secondary outcome data than collecting primary outcome data. Trial teams should explicitly consider how long it will take to collect the data for an outcome and decide whether that time is worth it given importance of the outcome to the trial.

PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations.

CLINICAL QUESTION: 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? CURRENT PRACTICE: 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. RECOMMENDATIONS: 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. HOW THIS GUIDELINE WAS CREATED: 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. THE EVIDENCE: 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/. UNDERSTANDING THE RECOMMENDATIONS: 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.