PRImary care Streptococcal Management (PRISM) study:In vitro study, diagnostic cohorts and a pragmatic adaptive randomised controlled trial with nested qualitative study and cost-effectiveness study

Background: Antibiotics are still prescribed to most patients attending primary care with acute sore throat, despite evidence that there is modest benefit overall from antibiotics. Targeting antibiotics using either clinical scoring methods or rapid antigen detection tests (RADTs) could help. However, there is debate about which groups of streptococci are important (particularly Lancefield groups C and G), and uncertainty about the variables that most clearly predict the presence of streptococci. Objective: This study aimed to compare clinical scores or RADTs with delayed antibiotic prescribing. Design: The study comprised a RADT in vitro study; two diagnostic cohorts to develop streptococcal scores (score 1; score 2); and, finally, an open pragmatic randomised controlled trial with nested qualitative and cost-effectiveness studies. Setting: The setting was UK primary care general practices. Participants: Participants were patients aged ≥ 3 years with acute sore throat. Interventions: An internet program randomised patients to targeted antibiotic use according to (1) delayed antibiotics (control group), (2) clinical score or (3) RADT used according to clinical score. Main outcome measures: The main outcome measures were self-reported antibiotic use and symptom duration and severity on seven-point Likert scales (primary outcome: mean sore throat/difficulty swallowing score in the first 2-4 days). Results: The IMI TestPack Plus Strep A (Inverness Medical, Bedford, UK) was sensitive, specific and easy to use. Lancefield group A/C/G streptococci were found in 40% of cohort 2 and 34% of cohort 1. A five-point score predicting the presence of A/C/G streptococci [FeverPAIN: Fever; Purulence; Attend rapidly (≤ 3 days); severe Inflammation; and No cough or coryza] had moderate predictive value (bootstrapped estimates of area under receiver operating characteristic curve: 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection. In total, 38% of cohort 1 and 36% of cohort 2 scored ≤ 1 for FeverPAIN, associated with streptococcal percentages of 13% and 18%, respectively. In an adaptive trial design, the preliminary score (score 1; n = 1129) was replaced by FeverPAIN (n = 631). For score 1, there were no significant differences between groups. For FeverPAIN, symptom severity was documented in 80% of patients, and was lower in the clinical score group than in the delayed prescribing group (-0.33; 95% confidence interval -0.64 to -0.02; p = 0.039; equivalent to one in three rating sore throat a slight rather than moderately bad problem), and a similar reduction was observed for the RADT group (-0.30; -0.61 to 0.00; p = 0.053). Moderately bad or worse symptoms resolved significantly faster (30%) in the clinical score group (hazard ratio 1.30; 1.03 to 1.63) but not the RADT group (1.11; 0.88 to 1.40). In the delayed group, 75/164 (46%) used antibiotics, and 29% fewer used antibiotics in the clinical score group (risk ratio 0.71; 0.50 to 0.95; p = 0.018) and 27% fewer in the RADT group (0.73; 0.52 to 0.98; p = 0.033). No significant differences in complications or reconsultations were found. The clinical score group dominated both other groups for both the cost/quality-adjusted life-years and cost/change in symptom severity analyses, being both less costly and more effective, and cost-effectiveness acceptability curves indicated the clinical score to be the most likely to be cost-effective from an NHS perspective. Patients were positive about RADTs. Health professionals' concerns about test validity, the time the test took and medicalising self-limiting illness lessened after using the tests. For both RADTs and clinical scores, there were tensions with established clinical experience. Conclusions: Targeting antibiotics using a clinical score (FeverPAIN) efficiently improves symptoms and reduces antibiotic use. RADTs used in combination with FeverPAIN provide no clear advantages over FeverPAIN alone, and RADTs are unlikely to be incorporated into practice until health professionals' concerns are met and they have experience of using them. Clinical scores also face barriers related to clinicians' perceptions of their utility in the face of experience. This study has demonstrated the limitation of using one data set to develop a clinical score. FeverPAIN, derived from two data sets, appears to be valid and its use improves outcomes, but diagnostic studies to confirm the validity of FeverPAIN in other data sets and settings are needed. Experienced clinicians need to identify barriers to the use of clinical scoring methods. Implementation studies that address perceived barriers in the use of FeverPAIN are needed

Use of varenicline for smoking cessation treatment in UK primary care: an association rule mining analysis

BACKGROUND: Varenicline is probably the most effective smoking cessation pharmacotherapy, but is less widely used than nicotine replacement therapy. We therefore set out to identify the characteristics of numerically important groups of patients who typically do, or do not, receive varenicline in the UK. METHODS: We used association rule mining to analyse data on prescribing of smoking cessation pharmacotherapy in relation to age, sex, comorbidity and other variables from 477,620 people aged 16 years and over, registered as patients throughout 2011 with one of 559 UK general practices in The Health Improvement Network (THIN) database, and recorded to be current smokers. RESULTS: 46,685 participants (9.8% of all current smokers) were prescribed any smoking cessation treatment during 2011, and 19,316 of these (4% of current smokers, 41% of those who received any therapy) were prescribed varenicline. Prescription of varenicline was most common among heavy smokers aged 31–60, and in those with a diagnosis of COPD. Varenicline was rarely used among smokers who were otherwise in good health, or were aged over 60, were lighter smokers, or had psychotic disorders or dementia. CONCLUSIONS: Varenicline is being underused in healthy smokers, or in older smokers, and in those with psychotic disorders or dementia. Since varenicline is probably the most effective available single cessation therapy, this study identifies under-treatment of substantial public health significance

The chronicity of self-injurious behaviour: A long-term follow-up of a total population study

Background: Self-injurious behaviour (SIB) is a relatively common problem for people with intellectual disabilities and it is known to be associated with various risk markers, such as degree of disability, sensory impairments, and autism (McClintock et al. 2003). Less is known about its long-term course however. Method: The present study was conducted to examine the quality of life and changes in behaviour for a cohort of 49 people with intellectual disabilities and SIB who were all part of a previous total population study conducted in the south of England by Oliver, Murphy and Corbett (1987). Assessment tools used in the original study, and an additional quality of life measure, the Life Experience Checklist (Ager, 1990), were carried out with informants in the participant's homes or places of day activity. Results: The results show that 84% of the sample continued to self-injure nearly 20 years on, with no significant mean changes in number of topographies or severity of SIB across the group. No one was living in hospital in this study (cf. many individuals in the first survey) but for those who had moved out of hospital, their SIB had not reduced. More people were receiving psychological treatment; more were also receiving anti-convulsant and anti-psychotic medications, though polypharmacy had reduced somewhat. The number of people accessing full-time day activities had decreased substantially, with 44% of people only accessing structured daily activities for 21/2 days per week or less. Conclusions: The results of the study add to the growing evidence of extreme chronicity for SIB and the relative lack of impact of treatment for people in whom self-injury has become well-established. They imply that early intervention is essential if such behaviour is to be eliminated long term

Cost-effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts: economic evaluation alongside a randomised controlled trial (EVerT trial)

Background Plantar warts (verrucae) are extremely common. Although many will spontaneously disappear without treatment, treatment may be sought for a variety of reasons such as discomfort. There are a number of different treatments for cutaneous warts, with salicylic acid and cryotherapy using liquid nitrogen being two of the most common forms of treatment. To date, no full economic evaluation of either salicylic acid or cryotherapy has been conducted based on the use of primary data in a pragmatic setting. This paper describes the cost-effectiveness analysis which was conducted alongside a pragmatic multicentre, randomised trial evaluating the clinical effectiveness of cryotherapy versus 50% salicylic acid of the treatment of plantar warts. Methods A cost-effectiveness analysis was undertaken alongside a pragmatic multicentre, randomised controlled trial assessing the clinical effectiveness of 50% salicylic acid and cryotherapy using liquid nitrogen at 12 weeks after randomisation of patients. Cost-effectiveness outcomes were expressed as the additional cost required to completely cure the plantar warts of one additional patient. A NHS perspective was taken for the analysis. Results Cryotherapy costs on average £101.17 (bias corrected and accelerated (BCA) 95% CI: 85.09-117.26) more per participant over the 12 week time-frame, while there is no additional benefit, in terms of proportion of patients healed compared with salicylic acid. Conclusions Cryotherapy is more costly and no more effective than salicylic acid

The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation

Background: Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease modifying anti-rheumatic drugs (DMARD) such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated.Objective: To assess the clinical and cost-effectiveness of four biologic DMARDs (etanercept, abatacept, adalimumab and tocilizumab - with or without methotrexate where indicated) for the treatment of JIA (systemic or oligoarticular JIA excluded).Data sources: Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and DARE were searched for published studies from inception to May 2015 for English language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence.Review methods: Systematic reviews of clinical-effectiveness, health-related quality of life and cost-effectiveness were undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision analytic model was developed to compare estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base case time horizon was 30 years and the model took a National Health Service (NHS) perspective, with costs and benefits discounted at 3.5%.Results: Four placebo-controlled RCTs met the inclusion criteria for the clinical-effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi) 30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar with fewer disease flares and greater proportions with ACR Pedi 50 and 70 responses among participants randomised to continued biologic DMARD. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that generally ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality of life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratio (ICER) for adalimumab, etanercept and tocilizumab versus methotrexate was £38,127, £32,526 and £38,656 per QALY, respectively. The ICER for abatacept versus methotrexate as a second line biologic was £39,536 per QALY.Limitations: The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs and clinical evidence for specific JIA subtypes is limited.Conclusions: Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA, and an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow- are needed to establish comparative effectiveness. RCTs for JIA subtypes where evidence is lacking are also required.Funding: The National Institute for Health Research Health Technology Assessment programme. <br/

A randomised controlled trial and economic evaluation of intraoperative cell salvage during caesarean section in women at risk of haemorrhage: the SALVO (cell SALVage in Obstetrics) trial

Background Caesarean section is associated with blood loss and maternal morbidity. Excessive blood loss requires transfusion of donor (allogeneic) blood, which is a finite resource. Cell salvage returns blood lost during surgery to the mother. It may avoid the need for donor blood transfusion, but reliable evidence of its effects is lacking. Objectives To determine if routine use of cell salvage during caesarean section in mothers at risk of haemorrhage reduces the rates of blood transfusion and postpartum maternal morbidity, and is cost-effective, in comparison with standard practice without routine salvage use. Design Individually randomised controlled, multicentre trial with cost-effectiveness analysis. Treatment was not blinded. Setting A total of 26 UK obstetric units. Participants Out of 3054 women recruited between June 2013 and April 2016, we randomly assigned 3028 women at risk of haemorrhage to cell salvage or routine care. Randomisation was stratified using random permuted blocks of variable sizes. Of these, 1672 had emergency and 1356 had elective caesareans. We excluded women for whom cell salvage or donor blood transfusion was contraindicated. Interventions Cell salvage (intervention) versus routine care without salvage (control). In the intervention group, salvage was set up in 95.6% of the women and, of these, 50.8% had salvaged blood returned. In the control group, 3.9% had salvage deployed. Main outcome measures Primary – donor blood transfusion. Secondary – units of donor blood transfused, time to mobilisation, length of hospitalisation, mean fall in haemoglobin, fetomaternal haemorrhage (FMH) measured by Kleihauer–Betke test, and maternal fatigue. Analyses were adjusted for stratification factors and other factors that were believed to be prognostic a priori. Cost-effectiveness outcomes – costs of resources and service provision taking the UK NHS perspective. Results We analysed 1498 and 1492 participants in the intervention and control groups, respectively. Overall, the transfusion rate was 2.5% in the intervention group and 3.5% in the control group [adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.42 to 1.01; p = 0.056]. In a planned subgroup analysis, the transfusion rate was 3.0% in the intervention group and 4.6% in the control group among emergency caesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 1.8% in the intervention group and 2.2% in the control group among elective caesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46, suggesting that the difference in effect between subgroups was not statistically significant). Secondary outcomes did not differ between groups, except for FMH, which was higher under salvage in rhesus D (RhD)-negative women with RhD-positive babies (25.6% vs. 10.5%, adjusted OR 5.63, 95% CI 1.43 to 22.14; p = 0.013). No case of amniotic fluid embolism was observed. The additional cost of routine cell salvage during caesarean was estimated, on average, at £8110 per donor blood transfusion avoided. Conclusions The modest evidence for an effect of routine use of cell salvage during caesarean section on rates of donor blood transfusion was associated with increased FMH, which emphasises the need for adherence to guidance on anti-D prophylaxis. We are unable to comment on long-term antibody sensitisation effects. Based on the findings of this trial, cell salvage is unlikely to be considered cost-effective. Future work Research into risk of alloimmunisation among women exposed to cell salvage is needed. Trial registration Current Controlled Trials ISRCTN66118656. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 2. See the NIHR Journals Library website for further project information