Rationale and design of the early valve replacement in severe asymptomatic aortic stenosis trial.

BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.

Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation. SUMMARY BACKGROUND DATA: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery. METHODS: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months. RESULTS: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group. CONCLUSIONS: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions. TRIAL REGISTRATION: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. METHODS: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450. FINDINGS: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group. INTERPRETATION: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. FUNDING: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

Altering product placement to create a healthier layout in supermarkets: Outcomes on store sales, customer purchasing, and diet in a prospective matched controlled cluster study.

BACKGROUND: Previous product placement trials in supermarkets are limited in scope and outcome data collected. This study assessed the effects on store-level sales, household-level purchasing, and dietary behaviours of a healthier supermarket layout. METHODS AND FINDINGS: This is a prospective matched controlled cluster trial with 2 intervention components: (i) new fresh fruit and vegetable sections near store entrances (replacing smaller displays at the back) and frozen vegetables repositioned to the entrance aisle, plus (ii) the removal of confectionery from checkouts and aisle ends opposite. In this pilot study, the intervention was implemented for 6 months in 3 discount supermarkets in England. Three control stores were matched on store sales and customer profiles and neighbourhood deprivation. Women customers aged 18 to 45 years, with loyalty cards, were assigned to the intervention (n = 62) or control group (n = 88) of their primary store. The trial registration number is NCT03518151. Interrupted time series analysis showed that increases in store-level sales of fruits and vegetables were greater in intervention stores than predicted at 3 (1.71 standard deviations (SDs) (95% CI 0.45, 2.96), P = 0.01) and 6 months follow-up (2.42 SDs (0.22, 4.62), P = 0.03), equivalent to approximately 6,170 and approximately 9,820 extra portions per store, per week, respectively. The proportion of purchasing fruits and vegetables per week rose among intervention participants at 3 and 6 months compared to control participants (0.2% versus -3.0%, P = 0.22; 1.7% versus -3.5%, P = 0.05, respectively). Store sales of confectionery were lower in intervention stores than predicted at 3 (-1.05 SDs (-1.98, -0.12), P = 0.03) and 6 months (-1.37 SDs (-2.95, 0.22), P = 0.09), equivalent to approximately 1,359 and approximately 1,575 fewer portions per store, per week, respectively; no differences were observed for confectionery purchasing. Changes in dietary variables were predominantly in the expected direction for health benefit. Intervention implementation was not within control of the research team, and stores could not be randomised. It is a pilot study, and, therefore, not powered to detect an effect. CONCLUSIONS: Healthier supermarket layouts can improve the nutrition profile of store sales and likely improve household purchasing and dietary quality. Placing fruits and vegetables near store entrances should be considered alongside policies to limit prominent placement of unhealthy foods. TRIAL REGISTRATION: ClinicalTrials.gov NCT03518151 (pre-results).

Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

AIMS: Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF. METHODS AND RESULTS: We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02). CONCLUSION: Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA. CLINICAL TRIAL REGISTRATION: ISRCTN18250790 and ClinicalTrials.gov: NCT02755688.

Weekend specialist intensity and admission mortality in acute hospital trusts in England: a cross-sectional study.

BACKGROUND: Increased mortality rates associated with weekend hospital admission (the so-called weekend effect) have been attributed to suboptimum staffing levels of specialist consultants. However, evidence for a causal association is elusive, and the magnitude of the weekend specialist deficit remains unquantified. This uncertainty could hamper efforts by national health systems to introduce 7 day health services. We aimed to examine preliminary associations between specialist intensity and weekend admission mortality across the English National Health Service. METHODS: Eligible hospital trusts were those in England receiving unselected emergency admissions. On Sunday June 15 and Wednesday June 18, 2014, we undertook a point prevalence survey of hospital specialists (consultants) to obtain data relating to the care of patients admitted as emergencies. We defined specialist intensity at each trust as the self-reported estimated number of specialist hours per ten emergency admissions between 0800 h and 2000 h on Sunday and Wednesday. With use of data for all adult emergency admissions for financial year 2013-14, we compared weekend to weekday admission risk of mortality with the Sunday to Wednesday specialist intensity ratio within each trust. We stratified trusts by size quintile. FINDINGS: 127 of 141 eligible acute hospital trusts agreed to participate; 115 (91%) trusts contributed data to the point prevalence survey. Of 34,350 clinicians surveyed, 15,537 (45%) responded. Substantially fewer specialists were present providing care to emergency admissions on Sunday (1667 [11%]) than on Wednesday (6105 [42%]). Specialists present on Sunday spent 40% more time caring for emergency patients than did those present on Wednesday (mean 5·74 h [SD 3·39] vs 3·97 h [3·31]); however, the median specialist intensity on Sunday was only 48% (IQR 40-58) of that on Wednesday. The Sunday to Wednesday intensity ratio was less than 0·7 in 104 (90%) of the contributing trusts. Mortality risk among patients admitted at weekends was higher than among those admitted on weekdays (adjusted odds ratio 1·10, 95% CI 1·08-1·11; p<0·0001). There was no significant association between Sunday to Wednesday specialist intensity ratios and weekend to weekday mortality ratios (r -0·042; p=0·654). INTERPRETATION: This cross-sectional analysis did not detect a correlation between weekend staffing of hospital specialists and mortality risk for emergency admissions. Further investigation is needed to evaluate whole-system secular change during the implementation of 7 day services. Policy makers should exercise caution before attributing the weekend effect mainly to differences in specialist staffing. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme.

Outcomes and costs of left atrial appendage closure from randomized controlled trial and real-world experience relative to oral anticoagulation.

AIMS: The aim of this study was to analyse randomized controlled study and real-world outcomes of patients with non-valvular atrial fibrillation (NVAF) undergoing left atrial appendage closure (LAAC) with the Watchman device and to compare costs with available antithrombotic therapies. METHODS AND RESULTS: Registry data of LAAC from two centres were prospectively collected from 110 patients with NVAF at risk of stroke, suitable and unsuitable for long-term anticoagulation (age 71.3 ± 9.2 years, CHADS2 2.8 ± 1.2, CHA2DS2-VASc 4.5 ± 1.6, and HAS-BLED 3.8 ± 1.1). Outcomes from PROTECT AF and registry study LAAC were compared with warfarin, dabigatran, rivaroxaban, apixaban, aspirin, and no treatment using a network meta-analysis. Costs were estimated over a 10-year horizon. Uncertainty was assessed using sensitivity analyses. The procedural success rate was 92% (103/112). Follow-up was 24.1 ± 4.6 months, during which annual rates of stroke, major bleeding, and all-cause mortality were 0.9% (2/223 patient-years), 0.9% (2/223 patient-years), and 1.8% (4/223 patient-years), respectively. Anticoagulant therapy was successfully stopped in 91.2% (93/102) of implanted patients by 12 months. Registry study LAAC stroke and major bleeding rates were significantly lower than PROTECT AF results: mean absolute difference of stroke, 0.89% (P = 0.02) and major bleeding, 5.48% (P < 0.001). Left atrial appendage closure achieved cost parity between 4.9 years vs. dabigatran 110 mg and 8.4 years vs. warfarin. At 10 years, LAAC was cost-saving against all therapies (range £1162-£7194). CONCLUSION: Left atrial appendage closure in NVAF in a real-world setting may result in lower stroke and major bleeding rates than reported in LAAC clinical trials. Left atrial appendage closure in both settings achieves cost parity in a relatively short period of time and may offer substantial savings compared with current therapies. Savings are most pronounced among higher risk patients and those unsuitable for anticoagulation.

Exercises to improve function of the rheumatoid hand (SARAH): a randomised controlled trial.

BACKGROUND: Disease-modifying biological agents and other drug regimens have substantially improved control of disease activity and joint damage in people with rheumatoid arthritis of the hand. However, commensurate changes in function and quality of life are not always noted. Tailored hand exercises might provide additional improvements, but evidence is lacking. We estimated the effectiveness and cost-effectiveness of tailored hand exercises in addition to usual care during 12 months. METHODS: In this pragmatic, multicentre, parallel-group trial, at 17 National Health Service sites across the UK we randomly assigned 490 adults with rheumatoid arthritis who had pain and dysfunction of the hands and had been on a stable drug regimen for at least 3 months, to either usual care or usual care plus a tailored strengthening and stretching hand exercise programme. Participants were randomly assigned with stratification by centre. Allocation was computer generated and unmasked to participants and therapists delivering treatment after randomisation. Outcome assessors and all investigators were masked to allocation. Physiotherapists or occupational therapists gave the treatments. The primary outcome was the Michigan Hand Outcomes Questionnaire overall hand function score at 12 months. The analysis was by intention to treat. We calculated cost per quality-adjusted life-year. This trial is registered as ISRCTN 89936343. FINDINGS: Between Oct 5, 2009, and May 10, 2011, we screened 1606 people, of whom 490 were randomly assigned to usual care (n=244) or tailored exercises (n=246). 438 of 490 participants (89%) provided 12 month follow-up data. Improvements in overall hand function were 3·6 points (95% CI 1·5-5·7) in the usual care group and 7·9 points (6·0-9·9) in the exercise group (mean difference between groups 4·3, 95% CI 1·5-7·1; p=0·0028). Pain, drug regimens, and health-care resource use were stable for 12 months, with no difference between the groups. No serious adverse events associated with the treatment were recorded. The cost of tailored hand exercise was £156 per person; cost per quality-adjusted life-year was £9549 with the EQ-5D (£17,941 with imputation for missing data). INTERPRETATION: We have shown that a tailored hand exercise programme is a worthwhile, low-cost intervention to provide as an adjunct to various drug regimens. Maximisation of the benefits of biological and DMARD regimens in terms of function, disability, and health-related quality of life should be an important treatment aim. FUNDING: UK National Institute of Health Research Health Technology Assessment Programme (NIHR HTA), project number 07/32/05.

The EQ-5D-5L health status questionnaire in COPD: validity, responsiveness and minimum important difference.

BACKGROUND: The EQ-5D, a generic health status questionnaire that is widely used in health economic evaluation, was recently expanded to the EQ-5D-5L to address criticisms of unresponsiveness and ceiling effect. AIMS: To describe the validity, responsiveness and minimum important difference of the EQ-5D-5L in COPD. METHODS: Study 1: The validity of the EQ-5D-5L utility index and visual analogue scale (EQ-VAS) was compared with four established disease-specific health status questionnaires and other measures of disease severity in 616 stable outpatients with COPD. Study 2: The EQ-5D-5L utility index and EQ-VAS were measured in 324 patients with COPD before and after 8 weeks of pulmonary rehabilitation. Distribution and anchor-based approaches were used to estimate the minimum important difference. RESULTS: There were moderate-to-strong correlations between utility index and EQ-VAS with disease-specific questionnaires (Pearson's r=0.47-0.72). A ceiling effect was seen in 7% and 2.6% of utility index and EQ-VAS. Utility index decreased (worsening health status) with indices of worsening disease severity. With rehabilitation, mean (95% CI) changes in utility index and EQ-VAS were 0.065 (0.047 to 0.083) and 8.6 (6.5 to 10.7), respectively, with standardised response means of 0.39 and 0.44. The mean (range) anchor estimates of the minimum important difference for utility index and EQ-VAS were 0.051 (0.037 to 0.063) and 6.9 (6.5 to 8.0), respectively. CONCLUSIONS: The EQ-5D-5L is a valid and responsive measure of health status in COPD and may provide useful additional cost-effectiveness data in clinical trials.

Prospective evaluation of a complex public health intervention: lessons from an initial and follow-up cross-sectional survey of the tuberculosis strain typing service in England.

BACKGROUND: The national tuberculosis strain typing service (TB-STS) was introduced in England in 2010. The TB-STS involves MIRU-VNTR typing of isolates from all TB patients for the prospective identification, reporting and investigation of TB strain typing clusters. As part of a mixed-method evaluation, we report on a repeated cross-sectional survey to illustrate the challenges surrounding the evaluation of a complex national public health intervention. METHODS: An online initial and follow-up questionnaire survey assessed the knowledge, attitudes and practices of public health staff, physicians and nurses working in TB control in November 2010 and March 2012. It included questions on the implementation, experience and uptake of the TB-STS. Participants that responded to both surveys were included in the analysis. RESULTS: 248 participants responded to the initial survey and 137 of these responded to the follow-up survey (56% retention). Knowledge: A significant increase in knowledge was observed, including a rise in the proportion of respondents who had received training (28.6% to 67.9%, p = 0.003), and the self-rated knowledge of how to use strain typing had improved ('no knowledge' decreased from 43.2% to 27.4%). Attitudes: The majority of respondents found strain typing useful; the proportion that reported strain typing to be useful was similar across the two surveys (95.7% to 94.7%, p = 0.67). Practices: There were significant increases between the initial and follow-up surveys in the number of respondents who reported using strain typing (57.0% to 80.5%, p < 0.001) and the proportion of time health protection staff spent on investigating TB (2.74% to 7.08%, p = 0.04). CONCLUSIONS: Evaluation of a complex public health intervention is challenging. In this example, the immediate national roll-out of the TB-STS meant that a controlled survey design was not possible. This study informs the future development of the TB-STS by identifying the need for training to reach wider professional groups, and argues for its continuation based on service users' perception that it is useful. By highlighting the importance of a well-defined sampling frame, collecting baseline information, and including all stakeholders, it provides lessons for the implementation of similar services in other countries and future evaluations of public health interventions.

Primum non nocere: shared informed decision making in low back pain--a pilot cluster randomised trial.

BACKGROUND: Low back pain is a common and disabling condition leading to large health service and societal costs. Although there are several treatment options for back pain little is known about how to improve patient choice in treatment selection. The purpose of this study was to pilot a decision support package to help people choose between low back pain treatments. METHODS: This was a single-centred pilot cluster randomised controlled trial conducted in a community physiotherapy service. We included adults with non-specific low back pain referred for physiotherapy. Intervention participants were sent an information booklet prior to their first consultation. Intervention physiotherapists were trained to enhance their skills in shared informed decision making. Those in the control arm received care as usual. The primary outcome was satisfaction with the treatment received at four months using a five-point Likert Scale dichotomised into "satisfaction" (very satisfied or somewhat satisfied) and "non-satisfaction" (neither satisfied nor dissatisfied, somewhat dissatisfied or very dissatisfied). RESULTS: We recruited 148 participants. In the control arm 67% of participants were satisfied with their treatment and in the intervention arm 53%. The adjusted relative risk of being satisfied was 1.28 (95% confidence interval 0.79 to 2.09). For most secondary outcomes the trend was towards worse outcomes in the intervention group. For one measure; the Roland Morris Disability Questionnaire, this difference was clinically important (2.27, 95% confidence interval 0.08 to 4.47). Mean healthcare costs were slightly lower (£38 saving per patient) within the intervention arm but health outcomes were also less favourable (0.02 fewer QALYs); the estimated probability that the intervention would be cost-effective at an incremental threshold of £20,000 per QALY was 16%. CONCLUSION: We did not find that this decision support package improved satisfaction with treatment; it may have had a substantial negative effect on clinical outcome, and is very unlikely to prove cost-effective. That a decision support package might have a clinically important detrimental effect is of concern. To our knowledge this has not been observed previously. Decision support packages should be formally tested for clinical and cost-effectiveness, and safety before implementation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46035546 registered on 11/02/10.

Is brief advice in primary care a cost-effective way to promote physical activity?

AIM: This study models the cost-effectiveness of brief advice (BA) in primary care for physical activity (PA) addressing the limitations in the current limited economic literature through the use of a time-based modelling approach. METHODS: A Markov model was used to compare the lifetime costs and outcomes of a cohort of 100 000 people exposed to BA versus usual care. Health outcomes were expressed in terms of quality-adjusted life years (QALYs). Costs were assessed from a health provider perspective (£2010/11 prices). Data to populate the model were derived from systematic literature reviews and the literature searches of economic evaluations that were conducted for national guidelines. Deterministic and probability sensitivity analyses explored the uncertainty in parameter estimates including short-term mental health gains associated with PA. RESULTS: Compared with usual care, BA is more expensive, incurring additional costs of £806 809 but it is more effective leading to 466 QALYs gained in the total cohort, a QALY gain of 0.0047/person. The incremental cost per QALY of BA is £1730 (including mental health gains) and thus can be considered cost-effective at a threshold of £20 000/QALY. Most changes in assumptions resulted in the incremental cost-effectiveness ratio (ICER) falling at or below £12 000/QALY gained. However, when short-term mental health gains were excluded the ICER was £27 000/QALY gained. The probabilistic sensitivity analysis showed that, at a threshold of £20 000/QALY, there was a 99.9% chance that BA would be cost-effective. CONCLUSIONS: BA is a cost-effective way to improve PA among adults, provided short-term mental health gains are considered. Further research is required to provide more accurate evidence on factors contributing to the cost-effectiveness of BA.

Long-term clinical outcomes and cost-effectiveness of catheter vs thoracoscopic surgical ablation in long-standing persistent atrial fibrillation using continuous cardiac monitoring: CASA-AF randomized controlled trial.

BACKGROUND: Long-term clinical outcomes of catheter ablation (CA) compared to thoracoscopic surgical ablation (SA) to treat patients with long-standing persistent atrial fibrillation (LSPAF) are not known. OBJECTIVE: The purpose of this study was to compare the long-term (36-month) clinical efficacy, quality of life, and cost-effectiveness of SA and CA in LSPAF. METHODS: Participants were followed up for 3 years using implantable loop recorders and questionnaires to assess the change in quality of life. Intention-to-treat analyses were used to report the findings. RESULTS: Of the 115 patients with LSPAF treated, 104 (90.4%) completed 36-month follow-up [CA: n = 57 (95%); SA: n = 47 (85%)]. After a single procedure without antiarrhythmic drugs, 7 patients (12%) in the CA arm and 5 (11%) in the SA arm [hazard ratio 1.22; 95% confidence interval (CI) 0.81-1.83; P = .41] were free from atrial fibrillation/tachycardia (AF/AT) ≥30 seconds at 36 months. Thirty-three patients (58%) in the CA arm and 26 (55%) in the SA arm (hazard ratio 1.04; 95% CI 0.57-1.88; P = .91) had their AF/AT burden reduced by ≥75%. The overall impact on health-related quality of life was similar, with mean quality-adjusted life year estimates of 2.45 (95% CI 2.31-2.59) for CA and 2.32 (95% CI 2.13-2.52) for SA. Estimated costs were higher for SA (mean £24,682; 95% CI £21,746-£27,618) than for CA (mean £18,002; 95% CI £15,422-£20,581). CONCLUSION: In symptomatic LSPAF, CA and SA were equally effective at achieving arrhythmia outcomes (freedom from AF/AT ≥30 seconds and ≥75% burden reduction) after a single procedure without antiarrhythmic drugs. However, SA is significantly more costly than CA. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04280042.

Illustrating potential efficiency gains from using cost-effectiveness evidence to reallocate Medicare expenditures.

OBJECTIVES: The Centers for Medicare & Medicaid Services does not explicitly use cost-effectiveness information in national coverage determinations. The objective of this study was to illustrate potential efficiency gains from reallocating Medicare expenditures by using cost-effectiveness information, and the consequences for health gains among Medicare beneficiaries. METHODS: We included national coverage determinations from 1999 through 2007. Estimates of cost-effectiveness were identified through a literature review. For coverage decisions with an associated cost-effectiveness estimate, we estimated utilization and size of the "unserved" eligible population by using a Medicare claims database (2007) and diagnostic and reimbursement codes. Technology costs originated from the cost-effectiveness literature or were estimated by using reimbursement codes. We illustrated potential aggregate health gains from increasing utilization of dominant interventions (i.e., cost saving and health increasing) and from reallocating expenditures by decreasing investment in cost-ineffective interventions and increasing investment in relatively cost-effective interventions. RESULTS: Complete information was available for 36 interventions. Increasing investment in dominant interventions alone led to an increase of 270,000 quality-adjusted life-years (QALYs) and savings of $12.9 billion. Reallocation of a broader array of interventions yielded an additional 1.8 million QALYs, approximately 0.17 QALYs per affected Medicare beneficiary. Compared with the distribution of resources prior to reallocation, following reallocation a greater proportion was directed to oncology, diagnostic imaging/tests, and the most prevalent diseases. A smaller proportion of resources went to cardiology, treatments (including drugs, surgeries, and medical devices, as opposed to nontreatments such as preventive services), and the least prevalent diseases. CONCLUSIONS: Using cost-effectiveness information has the potential to increase the aggregate health of Medicare beneficiaries while maintaining existing spending levels.

Exploring what lies behind public preferences for avoiding health losses caused by lapses in healthcare safety and patient lifestyle choices.

BACKGROUND: Although many studies have identified public preferences for prioritising health care interventions based on characteristics of recipient or care, very few of them have examined the reasons for the stated preferences. We conducted an on-line person trade-off (PTO) study (N=1030) to investigate whether the public attach a premium to the avoidance of ill health associated with alternative types of responsibilities: lapses in healthcare safety, those caused by individual action or lifestyle choice; or genetic conditions. We found that the public gave higher priority to prevention of harm in a hospital setting such as preventing hospital associated infections than genetic disorder but drug administration errors were valued similar to genetic disorders. Prevention of staff injuries, lifestyle diseases and sports injuries, were given lower priority. In this paper we aim to understand the reasoning behind the responses by analysing comments provided by respondents to the PTO questions. METHOD: A majority of the respondents who participated in the survey provided brief comments explaining preferences in free text responses following PTO questions. This qualitative data was transformed into explicit codes conveying similar meanings. An overall coding framework was developed and a reliability test was carried out. Recurrent patterns were identified in each preference group. Comments which challenged the assumptions of hypothetical scenarios were also investigated. RESULTS: NHS causation of illness and a duty of care were the most cited reasons to prioritise lapses in healthcare safety. Personal responsibility dominated responses for lifestyle related contexts, and many respondents mentioned that health loss was the result of the individual's choice to engage in risky behaviour. A small proportion of responses questioned the assumptions underlying the PTO questions. However excluding these from the main analysis did not affect the conclusions. CONCLUSION: Although some responses indicated misunderstanding or rejection of assumptions we put forward, the results were still robust. The reasons put forward for responses differed between comparisons but responsibility was the most frequently cited. Most preference elicitation studies only focus on eliciting numerical valuations but allowing for qualitative data can augment understanding of preferences as well as verifying results.

GRADE guidance 23: considering cost-effectiveness evidence in moving from evidence to health-related recommendations.

BACKGROUND: This is the 23rd in a series of articles describing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the certainty of evidence and strength of recommendations for systematic reviews, health technology assessments, and clinical guideline development. OBJECTIVES: We outline how resource utilization and cost-effectiveness analyses are integrated into health-related recommendations, using the GRADE Evidence to Decision (EtD) frameworks. STUDY DESIGN AND SETTING: Through iterative discussions and refinement, in-person, and online meetings, and through e-mail communication, we developed draft guidance to incorporate economic evidence in the formulation of health-related recommendations. We developed scenarios to operationalize the guidance. We presented a summary of the results to members of the GRADE Economic Evaluation Project Group. RESULTS: We describe how to estimate the cost of preventing (or achieving) an event to inform assessments of cost-effectiveness of alternative treatments, when there are no published economic evaluations. Evidence profiles and Summary of Findings tables based on systematic reviews of cost-effectiveness analyses can be created to provide top-level summaries of results and quality of multiple published economic evaluations. We also describe how this information could be integrated in GRADE's EtD frameworks to inform health-related recommendations. Three scenarios representing various levels of available cost-effectiveness evidence were used to illustrate the integration process. CONCLUSION: This GRADE guidance provides practical information for presenting cost-effectiveness data and its integration in the development of health-related recommendations, using the EtD frameworks.

Does responsibility affect the public's valuation of health care interventions? A relative valuation approach to health care safety.

OBJECTIVE: Health services often spend more on safety interventions than seems cost-effective. This study investigates whether the public value safety-related health care improvements more highly than the same improvements in contexts where the health care system is not responsible. METHOD: An online survey was conducted to elicit the relative importance placed on preventing harms caused by 1) health care (hospital-acquired infections, drug administration errors, injuries to health care staff), 2) individuals (personal lifestyle choices, sports-related injuries), and 3) nature (genetic disorders). Direct valuations were obtained from members of the public by using a person trade-off or "matching" method. Participants were asked to choose between two preventative interventions of equal cost and equal health benefit per person for the same number of people, but differing in causation. If participants indicated a preference, their strength of preference was measured by using person trade-off. RESULTS: Responses were obtained from 1030 people, reflecting the sociodemographic mix of the UK population. Participants valued interventions preventing hospital-acquired infections (1.31) more highly than genetic disorders (1.0), although drug errors were valued similarly to genetic disorders (1.07), and interventions to prevent injury to health care staff were given less weight than genetic disorders (0.71). Less weight was also given to interventions related to lifestyle (0.65) and sports injuries (0.41). CONCLUSION: Our results suggest that people do not attach a simple fixed premium to "safety-related" interventions but that preferences depend more subtly on context. The use of the results of such public preference surveys to directly inform policy would therefore be premature.

Bayesian meta-analysis on medical devices: application to implantable cardioverter defibrillators.

OBJECTIVES: The aim of this study is to describe and illustrate a method to obtain early estimates of the effectiveness of a new version of a medical device. METHODS: In the absence of empirical data, expert opinion may be elicited on the expected difference between the conventional and modified devices. Bayesian Mixed Treatment Comparison (MTC) meta-analysis can then be used to combine this expert opinion with existing trial data on earlier versions of the device. We illustrate this approach for a new four-pole implantable cardioverter defibrillator (ICD) compared with conventional ICDs, Class III anti-arrhythmic drugs, and conventional drug therapy for the prevention of sudden cardiac death in high risk patients. Existing RCTs were identified from a published systematic review, and we elicited opinion on the difference between four-pole and conventional ICDs from experts recruited at a cardiology conference. RESULTS: Twelve randomized controlled trials were identified. Seven experts provided valid probability distributions for the new ICDs compared with current devices. The MTC model resulted in estimated relative risks of mortality of 0.74 (0.60-0.89) (predictive relative risk [RR] = 0.77 [0.41-1.26]) and 0.83 (0.70-0.97) (predictive RR = 0.84 [0.55-1.22]) with the new ICD therapy compared to Class III anti-arrhythmic drug therapy and conventional drug therapy, respectively. These results showed negligible differences from the preliminary results for the existing ICDs. CONCLUSIONS: The proposed method incorporating expert opinion to adjust for a modification made to an existing device may play a useful role in assisting decision makers to make early informed judgments on the effectiveness of frequently modified healthcare technologies.

Strengthening and stretching for rheumatoid arthritis of the hand (SARAH): design of a randomised controlled trial of a hand and upper limb exercise intervention--ISRCTN89936343.

BACKGROUND: Rheumatoid Arthritis (RA) commonly affects the hands and wrists with inflammation, deformity, pain, weakness and restricted mobility leading to reduced function. The effectiveness of exercise for RA hands is uncertain, although evidence from small scale studies is promising. The Strengthening And Stretching for Rheumatoid Arthritis of the Hand (SARAH) trial is a pragmatic, multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of adding an optimised exercise programme for hands and upper limbs to best practice usual care for patients with RA. METHODS/DESIGN: 480 participants with problematic RA hands will be recruited through 17 NHS trusts. Treatments will be provided by physiotherapists and occupational therapists. Participants will be individually randomised to receive either best practice usual care (joint protection advice, general exercise advice, functional splinting and assistive devices) or best practice usual care supplemented with an individualised exercise programme of strengthening and stretching exercises. The study assessors will be blinded to treatment allocation and will follow participants up at four and 12 months. The primary outcome measure is the Hand function subscale of the Michigan Hand Outcome Questionnaire, and secondary outcomes include hand and wrist impairment measures, quality of life, and resource use. Economic and qualitative studies will also be carried out in parallel. DISCUSSION: This paper describes the design and development of a trial protocol of a complex intervention study based in therapy out-patient departments. The findings will provide evidence to support or refute the use of an optimised exercise programme for RA of the hand in addition to best practice usual care.

Aspirin to target arterial events in chronic kidney disease (ATTACK): study protocol for a multicentre, prospective, randomised, open-label, blinded endpoint, parallel group trial of low-dose aspirin vs. standard care for the primary prevention of cardiovascular disease in people with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burden of CKD worldwide and the low cost of aspirin. METHODS: ATTACK is a pragmatic multicentre, prospective, randomised, open-label, blinded endpoint adjudication superiority trial of aspirin 75 mg daily vs. standard care for the primary prevention of CVD in 25,210 people aged 18 years and over with CKD recruited from UK Primary Care. Participants aged 18 years and over with CKD (GFR category G1-G4) will be identified in Primary Care and followed up using routinely collected data and annual questionnaires for an average of 5 years. The primary outcome is the time to first major vascular event (composite of non-fatal MI, non-fatal stroke and cardiovascular death [excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage]). Deaths from other causes (including fatal bleeding) will be treated as competing events. The study will continue until 1827 major vascular events have occurred. The principal safety outcome is major intracranial and extracranial bleeding; this is hypothesised to be increased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding. DISCUSSION: This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access. TRIAL REGISTRATION: ISRCTN: ISRCTN40920200 . EudraCT: 2018-000644-26 . CLINICALTRIALS: gov: NCT03796156.