Treatment Adherence in a Randomized Controlled Trial of Pirfenidone in HFpEF: Determinants and Impact on Efficacy.

OBJECTIVES: Medication adherence in patients with heart failure with preserved ejection fraction is unclear. This study sought to evaluate treatment adherence in the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial. METHODS AND RESULTS: Adherence was evaluated through pill counts and diary cards. Univariable and multivariable regression models were used to assess the relationship between adherence and baseline characteristics. Instrumental variable regression was used to estimate the causal effect of pirfenidone treatment duration on myocardial fibrosis. Complete adherence data were available in 54 of 80 participants completing the trial. Mean adherence to study medication was 94.7% and 96.9% in the pirfenidone and placebo groups, respectively. Each additional day of treatment with pirfenidone resulted in a significant decrease in myocardial extracellular volume (-0.004%; 95% confidence interval: -0.007% to -0.001%; P = 0.007). Associations with adherence included older age, higher symptom burden, lower body weight, and smaller right ventricular size. CONCLUSION: Adherence to study medication in the PIROUETTE trial was very high among patients for whom complete adherence data were available. Importantly, each additional day of treatment reduced myocardial fibrosis. Potential predictors of adherence were identified. Implementation of improved methods for assessing adherence is required.

From Paris to Montreal: disease regression is common during long term follow-up of paediatric Crohn's disease.

Introduction: Paediatric Crohn's disease (PCD) often presents with extensive and a frequent pan-enteric phenotype at onset. However, its long term evolution into adulthood, especially since the widespread use of biological agents, is not well characterised. We conducted a single centre cohort study of all PCD patients transitioned to adult care to assess the long term disease evolution in the era of biologic therapy.Methods: We conducted a retrospective observational, study of all PCD patients who were subsequently transferred to the care of an adult gastroenterology unit and had a minimum follow up of 2 years. We examined the case notes for evolution of disease location and behaviour. Disease location and behaviour was characterised using Paris classification at diagnosis and Montreal classification at last follow-up. In addition, we examined variables associated with complicated disease behaviour and the need for CD related intestinal resection.Results: In total, 132 patients were included with a median age at diagnosis of 13 (IQR 11-14) and a median follow up of 11 years (range 4-14). At diagnosis, 23 (17.4%), 39 (29.6%) and 70 (53%) patients had ileal, colonic and ileocolonic disease respectively. In addition, 31 (23.5%) patients had L4a or L4b disease at diagnosis (proximal or distal to the ligament of treitz respectively) and 13 patients (9.8%) had both whilst 27 (20.4%) patients had perianal disease. At diagnosis, 27 (20.4%) patients had complicated disease behaviour but 83 (62.9)% of patients had an extensive 'pan-enteric' phenotype. Of these patients only 55 (66.3%) retained the pan-enteric phenotype at last follow-up (p = .0002). Disease extension was noted in 25 (18.9%) of patients and regression was noted in 47 (35.6%) of patients, whereas upper GI disease was noted in significantly fewer patients at last follow-up (21, 15.9%) (p = .0001). More patients had complicated disease behaviour (46 patients, 34.9%, p = .0018) at last follow-up. There was a high exposure to both thiopurines 121 (91.7%) and biologics 84 (63.6%). The cumulative probability (95% CI) of surgery was 0.05 (0.02, 0.11) at 1 year, 0.17 (0.11, 0.24) at 3 years and 0.22 (0.15, 0.30) at 5 years. Neither disease location nor behaviour were associated with the need for intestinal resectional surgery.Conclusions: Over the course of an extended follow-up period, there appeared to be changes in both disease location and behaviour in PCD. Interestingly, a significant proportion of patients had disease involution which may be related to a high rate of exposure to thiopurines and biologics. We were unable to identify any variables associated with complicated disease course or the need for intestinal surgery.

Clinical effectiveness of a web-based peer-supported self-management intervention for relatives of people with psychosis or bipolar (REACT): online, observer-blind, randomised controlled superiority trial.

BACKGROUND: The Relatives Education And Coping Toolkit (REACT) is an online supported self-management toolkit for relatives of people with psychosis or bipolar designed to improve access to NICE recommended information and emotional support. AIMS: Our aim was to determine clinical and cost-effectiveness of REACT including a Resource Directory (RD), versus RD-only. METHODS: A primarily online, observer-blind randomised controlled trial comparing REACT (including RD) with RD only (registration ISRCTN72019945). Participants were UK relatives aged > = 16, with high distress (assessed using the GHQ-28), and actively help-seeking, individually randomised, and assessed online. Primary outcome was relatives' distress (GHQ-28) at 24 weeks. Secondary outcomes were wellbeing, support, costs and user feedback. RESULTS: We recruited 800 relatives (REACT = 399; RD only = 401) with high distress at baseline (GHQ-28 REACT mean 40.3, SD 14.6; RD only mean 40.0, SD 14.0). Median time spent online on REACT was 50.8 min (IQR 12.4-172.1) versus 0.5 min (IQR 0-1.6) on RD only. Retention to primary follow-up (24 weeks) was 75% (REACT n = 292 (73.2%); RD-only n = 307 (76.6%)). Distress decreased in both groups by 24 weeks, with no significant difference between the two groups (- 1.39, 95% CI -3.60, 0.83, p = 0.22). Estimated cost of delivering REACT was £62.27 per person and users reported finding it safe, acceptable and convenient. There were no adverse events or reported side effects. CONCLUSIONS: REACT is an inexpensive, acceptable, and safe way to deliver NICE-recommended support for relatives. However, for highly distressed relatives it is no more effective in reducing distress (GHQ-28) than a comprehensive online resource directory. TRIAL REGISTRATION: ISRCTN72019945 prospectively registered 19/11/2015.

Usage Metrics of Web-Based Interventions Evaluated in Randomized Controlled Trials: Systematic Review.

BACKGROUND: The evaluation of web-based interventions (defined as an intervention that can be downloaded or accessed on the internet through a web browser) in randomized controlled trials (RCTs) has increased over the past two decades. Little is known about how participants' use of the intervention is measured, reported, and analyzed in these studies. OBJECTIVE: This study aimed to review the evaluation of web-based interventions in RCTs, assessing study characteristics and the methods used to record, and adjust for, intervention usage. METHODS: A systematic review of the literature was undertaken to identify all published reports of RCTs that involved a web-based intervention. A random sample of 100 published trials was selected for detailed data extraction. Information on trial characteristics was extracted, including whether web usage data were recorded, and if so, the methods used to gather these data and whether these data were used to inform efficacy analyses. RESULTS: A PubMed search identified 812 trials of web-based interventions published up to the end of 2017 and demonstrated a growing trend over time. Of the 100 studies reviewed, 90 studies collected web usage data, but more than half (49/90, 54%) of these studies did not state the method used for recording web usage. Only four studies attempted to check on the reliability of their web usage data collection methods. A total of 39% (35/90) studies reported patterns or levels of web intervention use, of which 21% (19/90) studies adjusted for intervention use in their outcome analysis, but only two of these used appropriate statistical methods. CONCLUSIONS: Trialists frequently report a measure of web-based intervention usage but do not always report the collection method or provide enough detail on their analysis of web usage. Appropriate statistical methods to account for intervention use are rarely used and are not well reported even in the very few trials in which they are used. The number of trialists who attempt to check on the reliability of their web usage collection methods is extremely low.

DIABRISK-SL trial: further consideration of age and impact of imputations.

Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality worldwide. Early interventions may help to delay or prevent onset of cardiometabolic endpoints of clinical importance to T2DM patients.Wijesuriya et al. (BMC Med 15:146, 2017) published results of a randomised controlled trial in Sri Lanka testing the effect of two lifestyle modification programmes of varying intensity in participants aged 5-40 years with risk factors for T2DM. The intervention measured the impact of the two programmes on the primary composite endpoint consisting of various predictors of cardiometabolic disease. The authors concluded that the more intensive programme significantly reduced the incidence of predictors of cardiometabolic disease. Further, they delivered a large-scale intervention with restricted resources with widespread acceptance as demonstrated by the high uptake rate. However, we believe that further analysis is required to fully understand the potential for benefit, particularly in relation to age, retention and missing data.

Brief report: length of ileal resection correlates with severity of bile acid malabsorption in Crohn's disease.

PURPOSE: Bile acid malabsorption (BAM) is a common cause of diarrhoea in Crohn's disease (CD) patients with ileal resection. BAM is usually diagnosed by selenium-labelled homotaurocholic acid test (75SeHCAT) but its availability is limited. Consequently, a large proportion of patients either remain undiagnosed or subject to empirical therapy. There is a paucity of studies examining the correlation between length of ileal resection and severity of BAM, which will be of use to clinicians with no recourse to diagnostic testing for BAM. METHODS: We tested the correlation between length of resected ileum and percentage retention on 75SeHCAT of all CD patients with a prior surgical resection who underwent 75SeHCAT testing. Response to treatment with bile salt sequestrant and 75SeHCAT retention values was tested using Fisher's exact test. RESULTS: A total of 91 patients were identified with a median age of 47 (IQR 21-80). The median length of resected ileum was 24 cm (range 15-165 cm) with a median of 1 resection (range 1-4). Overall, 88 patients (97%) had 75SeHCAT retention values of < 10% and 85 (93%) had retention of < 5%. There was a modest correlation between 75SeHCAT retention and length of ileal resection (Spearman's rho - 0.392, P = 0.0001). Data on response to treatment was available for 57 (63%) patients, of who 38 (67%) responded to bile salt sequestrant. There was no difference in 75SeHCAT retention values between responders and non-responders. CONCLUSIONS: There was a modest correlation between length of ileal resection and severity of BAM as defined by 75SeHCAT retention values. Response to bile salt sequestrant therapy was not dependent on 75SeHCAT retention values.

Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial.

BACKGROUND: The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis. METHODS: The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31phosphorus magnetic resonance spectroscopy. DISCUSSION: PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566). CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566.

Concurrent immunomodulator therapy is associated with higher adalimumab trough levels during scheduled maintenance therapy.

INTRODUCTION: Combination therapy with infliximab and immunomodulators is superior to monotherapy, resulting in better outcomes and higher trough levels of infliximab. The role of concurrent immunomodulatory therapy on adalimumab trough levels has not been adequately investigated. We evaluated the impact of concomitant immunomodulation on adalimumab trough levels in patients on scheduled maintenance therapy. METHOD: We conducted a prospective observational, cross-sectional study of all inflammatory bowel disease patients on maintenance therapy who had adalimumab trough levels measured between January 2013 and January 2016. Drug level and anti-drug antibody measurements were performed on sera using a solid phase assay. Pairwise comparison of means was used to compare trough levels in patients with and without concomitant immune modulator therapy. RESULTS: In total, 79 patients were included. Twenty-three patients (29.1%) were on weekly dosing whereas 56 (70.9%) were on alternate weeks. Median adalimumab trough levels were comparable in patients with and without clinical remission (6.8 µg/ml (IQR 5.6-8.1) versus 6.7 µg/ml (IQR 3.9-8.1), respectively. Patients with an elevated faecal calprotectin >250 µg/g had lower adalimumab trough levels (median 6.7, IQR 3.9-8) compared to patients with faecal calprotectin <250 µg/g (median 7.7, IQR 6.1-8.1) though this did not achieve statistical significance (p = .062). Median adalimumab trough levels among patients on concurrent immunomodulators was 7.2 µg/ml (IQR 5.7-8.1) compared to those not on concurrent immunomodulator, 6.1 µg/ml (IQR 2.7-7.7, p = .0297). CONCLUSION: Adalimumab trough levels were significantly higher in patients on concurrent immunomodulators during maintenance therapy. There was a trend towards a lower adalimumab trough level in patients with elevated calprotectin.

A review of Core Outcome Sets (COS) developed for different settings finds there is a subset of outcomes relevant for both research and routine care.

OBJECTIVES: To compare the outcomes selected for the same condition in core outcome sets (COS) for research with those in COS for the routine care setting. METHODS: A sample of COS was created from the most frequent five health areas within previous systematic reviews of COS for research and COS for routine care. Outcomes were extracted and categorised using an outcome taxonomy. Frequency of outcome domains included within COS were analysed in subgroups according to research or care setting, patient involvement in COS development and health area. Matched sets of COS were created, where at least one research COS and one routine care COS exist for the same health condition, to identify the outcomes that were recommended for both settings. A similar process was used for a subset of paired COS matched in scope for both intervention and population as well as health condition. RESULTS: The sample of COS comprised: 246 COS for research only, 76 COS for routine care only and 55 COS for both research and routine care. Across the 18 sets matched by health condition the median number (range) of outcomes included in both research COS and routine care COS was 6 (3-15), with differences noted across health areas. For the 11 paired COS matched by scope and health condition, the corresponding figures were 2 (2-8). Across all settings, COS that did not include patients as participants were less likely to include life impact outcomes. CONCLUSION: Within a given health condition, a small number of core outcomes were found to be relevant for both research and care, offering a meaningful starting point for linking research and real-world evaluation.

The use of healthcare systems data for RCTs.

BACKGROUND: Healthcare systems data (HSD) has the potential to optimise the efficiency of randomised controlled trials (RCTs), by decreasing trial-specific data demands. Therefore, the use of HSD in trials is expected to increase. In 2019, it was estimated that 47% of NIHR-funded trials were planning to use HSD. We aim to understand the extent and nature of its current use and its evolution over time. METHODS: We identified a cohort of RCTs within the NIHR Journals Library that commenced after 2019 and were described as being in progress on 6 June 2022. Details on the source and use of HSD were extracted from eligible RCTs. The use of HSD was categorised according to whether it was used as the sole data source for outcomes and whether the outcomes were primary or secondary. HSD is often insufficient for patient-reported outcomes (PROs). We aimed to determine methods used by trialists for collecting PRO data alongside HSD. RESULTS: Of the 84 eligible studies, 52 (62%) planned to use HSD and 79 (94%) planned to collect PROs. The number of RCTs planning to use HSD for at least one outcome was 28 (54%) with 24 of these planning to use HSD as the sole data source for at least one outcome. The number of studies planning to use HSD for primary and secondary outcomes was 10 (20%) and 21 (40%) respectively. The sources of HSD were National Health Service (NHS) Digital (n = 37, 79%), patient registries (n = 7, 29%), primary care (n = 5, 21%), The Office for National Statistics (ONS) (n = 3, 13%) and other (n = 2, 8%). PROs were collected for 92% of the trials planning to use HSD. Methods for collection of PROs included in-person (n = 26, 54%), online (n = 22, 46%), postal (n = 18, 38%), phone (n = 14, 29%) and app (n = 2, 4%). CONCLUSIONS: HSD is being used in around two thirds of the studies but cannot yet be used to support PRO data collection within the cohort we examined. Comparison with an earlier cohort demonstrates an increase in the number of RCTs planning to use HSD.

Representation of published core outcome sets in practice guidelines.

OBJECTIVES: A core outcome set (COS) is an agreed standardized set of outcomes that should be measured and reported, as a minimum, in specific areas of health or health care. A COS is developed through a consensus process to ensure health care outcomes to be measured are relevant to decision-makers, including patients and health-care professionals. Use of COS in guideline development is likely to increase the relevance of the guideline to those decision-makers. Previous work has looked at the uptake of COS in trials, systematic reviews, health technology assessments and regulatory guidance but to date there has been no evaluation of the use of COS in practice guideline development. The objective of this study was to investigate the representation of core outcomes in a set of international practice guidelines. STUDY DESIGN AND SETTING: We searched for clinical guidelines relevant to ten high-quality COS (with focus on the United Kingdom, Germany, China, India, Canada, Denmark, United States and World Health Organisation). We matched scope between COS and guideline in terms of condition, population and outcome. We calculated the proportion of guidelines mentioning or referencing COS and the proportion of COS domains specifically, or generally, matching to outcomes specified in each guideline populations, interventions, comparators and outcome (PICO) statement. RESULTS: We found 38 guidelines that contained 170 PICO statements matching the scope of the ten COS and of sufficient quality to allow data extraction. None of the guidelines reviewed explicitly mentioned or referenced the relevant COS. The median (range) of the proportion of core outcomes covered either specifically or generally by the guideline PICO was 30% (0%-100%). CONCLUSION: There is no evidence that COS are being used routinely to inform the guideline development process, and concordance between outcomes in published guidelines and those in COS is limited. Further work is warranted to explore barriers and facilitators in the use of COS when developing clinical guidelines.

Study found increasing use of core outcome sets in Cochrane systematic reviews and identified facilitators and barriers.

OBJECTIVES: In 2019, only 7% of Cochrane systematic reviews (SRs) cited a core outcome set (COS) in relation to choosing outcomes, even though a relevant COS existed but was not mentioned (or cited) for a further 29% of SRs. Our objectives for the current work were to (1) examine the extent to which authors are currently considering COS to inform outcome choice in Cochrane protocols and completed SRs, and (2) understand author facilitators and barriers to using COS. STUDY DESIGN AND SETTING: We examined all completed Cochrane SRs published in the last 3 months of 2022 and all Cochrane protocols published in 2022 for the extent to which they: (a) cited a COS, (b) searched for COS, (c) used outcomes from existing COS, and (d) reported outcome inconsistency among included studies and/or noted the need for COS. One investigator extracted information; a second extractor verified all information, discussing discrepancies to achieve consensus. We then conducted an online survey of authors of the included SRs to assess awareness of COS and identify facilitators and barriers to using COS to inform outcome choice. RESULTS: Objective 1: We included 294 SRs of interventions (84 completed SRs and 210 published SR protocols), of which 13% cited specific COS and 5% did not cite but mentioned searching for COS. A median of 83% of core outcomes from cited COS (interquartile range [IQR] 57%-100%) were included in the corresponding SR. We identified a relevant COS for 39% of SRs that did not cite a COS. A median of 50% of core outcomes from noncited COS (IQR 35%-72%) were included in the corresponding SR. Objective 2: Authors of 236 (80%) of the 294 eligible SRs completed our survey. Seventy-seven percent of authors noted being aware of COS before the survey. Fifty-five percent of authors who did not cite COS but were aware of them reported searching for a COS. The most reported facilitators of using COS were author awareness of the existence of COS (59%), author positive perceptions of COS (52%), and recommendation in the Cochrane Handbook regarding COS use (48%). The most reported barriers related to matching of the scope of the COS and the SR: the COS target population was too narrow/broad relative to the SR population (29%) or the COS target intervention was too narrow/broad relative to the SR intervention (21%). Most authors (87%) mentioned that they would consider incorporating missing core outcomes in the SR/update. CONCLUSION: Since 2019, there is increasing consideration and awareness of COS when choosing outcomes for Cochrane SRs of interventions, but uptake remains low and can be improved further. Use of COS in SRs is important to improve outcome standardization, reduce research waste, and improve evidence syntheses of the relevant effects of interventions across health research.

CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy.

Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12-16 weeks to receive 3-g L-citrulline twice daily (n = 24) or placebo (n = 12) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline: - 1.82 95% CI (- 5.86, 2.22) vs placebo: - 5.00 95% CI (- 12.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes < 9 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.Trial Registration EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20).

Outcomes of care during the last month of life: a systematic review to inform the development of a core outcome set.

BACKGROUND: To date, there is a lack of standardization and consensus on which outcomes are central to assess the care provided to patients in the last month of life. Therefore, we aimed to conduct a systematic review to identify relevant outcomes to inform the development of a core outcome set for the best care for the dying person. METHODS: We conducted a systematic review of outcomes reported in the scientific literature about the care for the dying person in the last month of life. We searched for peer-reviewed studies published before February 2022 in four electronic databases. To categorise the outcomes, we employed the taxonomy developed by the "Core Outcome Measures in Effectiveness Trials" collaboration. RESULTS: Out of the 2,933 articles retrieved, 619 were included for analyses. The majority of studies (71%) were retrospective and with data extracted from chart reviews (71%). We extracted 1,951 outcomes in total, from which, after deletion of repeated outcomes, we identified 256 unique ones. The most frequently assessed outcomes were those related to medication or therapeutic interventions and those to hospital/healthcare use. Outcomes related to psychosocial wellbeing were rarely assessed. The closer to death, the less frequently the outcomes were studied. CONCLUSIONS: Most outcomes were related to medical interventions or to hospital use. Only a few studies focused on other components of integrated care such as psychosocial aspects. It remains to be defined which of these outcomes are fundamental to achieve the best care for the dying.

Identification of heart failure hospitalization from NHS Digital data: comparison with expert adjudication.

AIMS: Population-wide, person-level, linked electronic health record data are increasingly used to estimate epidemiology, guide resource allocation, and identify events in clinical trials. The accuracy of data from NHS Digital (now part of NHS England) for identifying hospitalization for heart failure (HHF), a key HF standard, is not clear. This study aimed to evaluate the accuracy of NHS Digital data for identifying HHF. METHODS AND RESULTS: Patients experiencing at least one HHF, as determined by NHS Digital data, and age- and sex-matched patients not experiencing HHF, were identified from a prospective cohort study and underwent expert adjudication. Three code sets commonly used to identify HHF were applied to the data and compared with expert adjudication (I50: International Classification of Diseases-10 codes beginning I50; OIS: Clinical Commissioning Groups Outcomes Indicator Set; and NICOR: National Institute for Cardiovascular Outcomes Research, used as the basis for the National Heart Failure Audit in England and Wales). Five hundred four patients underwent expert adjudication, of which 10 (2%) were adjudicated to have experienced HHF. Specificity was high across all three code sets in the first diagnosis position {I50: 96.2% [95% confidence interval (CI) 94.1-97.7%]; NICOR: 93.3% [CI 90.8-95.4%]; OIS: 95.6% [CI 93.3-97.2%]} but decreased substantially as the number of diagnosis positions expanded. Sensitivity [40.0% (CI 12.2-73.8%)] and positive predictive value (PPV) [highest with I50: 17.4% (CI 8.1-33.6%)] were low in the first diagnosis position for all coding sets. PPV was higher for the National Heart Failure Audit criteria, albeit modestly [36.4% (CI 16.6-62.2%)]. CONCLUSIONS: NHS Digital data were not able to accurately identify HHF and should not be used in isolation for this purpose.

Effectiveness and cost-effectiveness of a web-based cardiac rehabilitation programme for people with chronic stable angina: protocol for the ACTIVATE (Angina Controlled Trial Investigating the Value of the 'Activate your heart' Therapeutic E-intervention) randomised controlled trial.

INTRODUCTION: Chronic stable angina is common and disabling. Cardiac rehabilitation is routinely offered to people following myocardial infarction or revascularisation procedures and has the potential to help people with chronic stable angina. However, there is insufficient evidence of effectiveness and cost-effectiveness for its routine use in this patient group. The objectives of this study are to compare the effectiveness and cost-effectiveness of the 'Activate Your Heart' cardiac rehabilitation programme for people with chronic stable angina compared with usual care. METHODS AND ANALYSIS: ACTIVATE is a multicentre, parallel-group, two-arm, superiority, pragmatic randomised controlled trial, with recruitment from primary and secondary care centres in England and Wales and a target sample size of 518 (1:1 allocation; allocation sequence by minimisation programme with built-in random element). The study uses secure web-based allocation concealment. The two treatments will be optimal usual care (control) and optimal usual care plus the 'Activate Your Heart' web-based cardiac rehabilitation programme (intervention). Outcome assessment and statistical analysis will be performed blinded; participants will be unblinded. Outcomes will be measured at baseline and at 6 and 12 months' follow-up. Primary outcome will be the UK version of Seattle Angina Questionnaire (SAQ-UK), physical limitations domain at 12 months' follow-up. Secondary outcomes will be the remaining two domains of SAQ-UK, dyspnoea, anxiety and depression, health utility, self-efficacy, physical activity and the incremental shuttle walk test. All safety events will be recorded, and serious adverse events assessed to determine whether they are related to the intervention and expected. Concurrent economic evaluation will be cost-utility analysis from health service perspective. An embedded process evaluation will determine the mechanisms and processes that explain the implementation and impacts of the cardiac rehabilitation programme. ETHICS AND DISSEMINATION: North of Scotland National Health Service Research Ethics Committee approval, reference 21/NS/0115. Participants will provide written informed consent. Results will be disseminated by peer-reviewed publication. TRIAL REGISTRATION NUMBER: ISRCTN10054455.

A systematic review of studies reporting the development of core outcome sets for use in routine care.

OBJECTIVES: Core outcome sets (COS) represent the minimum health outcomes to be measured for a given health condition. Interest is growing in using COS within routine care to support delivery of patient-focused care. This review aims to systematically map COS developed for routine care to understand their scope, stakeholder involvement, and development methods. METHODS: Medline (Ovid), Scopus, and Web of Science Core collection were searched for studies reporting development of COS for routine care. Data on scope, methods, and stakeholder groups were analyzed in subgroups defined by setting. RESULTS: Screening 25,301 records identified 262 COS: 164 for routine care only and 98 for routine care and research. Nearly half of the COS (112/254, 44%) were developed with patients, alongside input from experts in registries, insurance, legal, outcomes measurement, and performance management. Research publications were often searched to generate an initial list of outcomes (115/198, 58%) with few searching routine health records (47/198, 24%). CONCLUSION: An increasing number of COS is being developed for routine care. Although involvement of patient stakeholders has increased in recent years, further improvements are needed. Methodology and scope are broadly similar to COS for research but implementation of the final set is a greater consideration during development.

Patient participation impacts outcome domain selection in core outcome sets for research: an updated systematic review.

OBJECTIVES: The importance of including patients, carers, and the public in health research is well recognized, including the need to consider outcomes in health care research that reflect the priorities of patients. Core outcome sets (COS) define the minimum set of outcomes that should be measured and reported in research of a given condition, determined through consensus among key stakeholders. The Core Outcome Measures in Effectiveness Trials Initiative undertakes an annual systematic review (SR) to identify newly published COS to update its online database of COS for research. The objective of this study was to assess the impact of patient participation on COS. STUDY DESIGN AND SETTING: SR methods used in previous updates were applied to identify research studies published or indexed in 2020 and 2021 (conducted as separate reviews) that report development of a COS, regardless of any specifications relating to condition, population, intervention, or setting. Studies were assessed according to published standards for COS development, and core outcomes extracted from study publications were categorized according to an outcome taxonomy and added to an existing database of core outcome classifications of all previously published COS. The effect of patient participation on core domains was examined. RESULTS: Searches identified 56 new studies published in 2020 and 54 in 2021. All studies met all four minimum standards for scope, and 42 (75%) of the 2020 studies and 45 (83%) of the 2021 studies met all three standards for stakeholders involved. However, only 19 (34%) of the 2020 studies and 18 (33%) of the 2021 studies met all four standards for the consensus process. COS that involved patients or their representatives are more likely to include life impact outcomes (239, 86%) than COS without patient participation (193, 62%). Physiological/clinical outcomes are almost always specified at a granular level, whereas life impact outcomes are often described at a higher level. CONCLUSION: This study adds to the body of evidence demonstrating the importance and impact of including patients, carers, and the public in COS development, in particular by demonstrating that the impact of interventions on patients' lives is more likely to be represented in COS that involve patients or their representatives. COS developers are encouraged to pay increased attention to methods and reporting relating to the consensus process. Further work is required to understand the appropriateness and rationale for the discrepancy in granularity levels between outcome domains.

Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study.

Post-COVID-19 condition (also known as long COVID) is a new, complex, and poorly understood disorder. A core outcome set (COS) for post-COVID-19 condition in adults has been developed and agreement is now required on the most appropriate measurement instruments for these core outcomes. We conducted an international consensus study involving multidisciplinary experts and people with lived experience of long COVID. The study comprised a literature review to identify measurement instruments for the core outcomes, a three-round online modified Delphi process, and an online consensus meeting to generate a core outcome measurement set (COMS). 594 individuals from 58 countries participated. The number of potential instruments for the 12 core outcomes was reduced from 319 to 19. Consensus was reached for inclusion of the modified Medical Research Council Dyspnoea Scale for respiratory outcomes. Measures for two relevant outcomes from a previously published COS for acute COVID-19 were also included: time until death, for survival, and the Recovery Scale for COVID-19, for recovery. Instruments were suggested for consideration for the remaining nine core outcomes: fatigue or exhaustion, pain, post-exertion symptoms, work or occupational and study changes, and cardiovascular, nervous system, cognitive, mental health, and physical outcomes; however, consensus was not achieved for instruments for these outcomes. The recommended COMS and instruments for consideration provide a foundation for the evaluation of post-COVID-19 condition in adults, which should help to optimise clinical care and accelerate research worldwide. Further assessment of this COMS is warranted as new data emerge on existing and novel measurement instruments.