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PPI Co-ordinator, Lynne Maddocks, introduces our PPI case studies – real world examples from real world researchers who have used PPI and (sometimes to their surprise!) found it beneficial to their work.
Naltrexone-bupropion (Mysimba®) in management of obesity: a systematic review and meta-analysis of unpublished clinical study reports.
AIMS: To compare the benefits and harms of naltrexone-bupropion using evidence from clinical study reports (CSRs). METHODS: We searched FDA and EMA websites, PubMed, and Clinicaltrials.gov (May 2016) to identify pivotal trials; we then sent a freedom of information request to the EMA (July 2016). We included pivotal, phase III placebo-controlled trials. We assessed the risks of bias using the Cochrane criteria, and the quality of the evidence using GRADE. We used a random-effects model for meta-analyses. RESULTS: Over a 27-month period (July 2016 to August 2018), we received 31 batches of CSR documents containing over 65 000 pages of data from four pivotal trials (n=4536). Significantly more participants who took naltrexone-bupropion achieved ≥5% reduction in body weight: RR=2.1 (1.35 to 3.28, P=0.001, GRADE=low, NNTB =5 (3 to 17); this represents a 2.53 kg (1.85 to 3.21) reduction in baseline body weight compared with placebo. Naltrexone-bupropion had significantly beneficial effects on other cardiovascular risk factors; however, the true effect sizes for these are uncertain because of incomplete outcome data. Naltrexone-bupropion significantly increased the risk of adverse events: RR=1.11 (1.05 to 1.18, P=0.0004, GRADE=low, NNTH =12 (7 to 27); serious adverse events: RR=1.70 (1.38 to 2.1), P<0.00001, GRADE=moderate, NNTH =21 (13 to 38); and discontinuation because of adverse events: RR=1.92 (1.65 to 2.24), P<0.00001, GRADE=moderate, NNTD =9 (8 to 13). CONCLUSIONS: Naltrexone-bupropion significantly reduces body weight by a small amount but significantly increases the risk of adverse events. A rigorous process of post-marketing surveillance is required.
Plaster cast versus functional brace for non-surgical treatment of Achilles tendon rupture (UKSTAR): a multicentre randomised controlled trial and economic evaluation.
BACKGROUND: Patients with Achilles tendon rupture who have non-operative treatment have traditionally been treated with immobilisation of the tendon in plaster casts for several weeks. Functional bracing is an alternative non-operative treatment that allows earlier mobilisation, but evidence on its effectiveness and safety is scarce. The aim of the UKSTAR trial was to compare functional and quality-of-life outcomes and resource use in patients treated non-operatively with plaster cast versus functional brace. METHODS: UKSTAR was a pragmatic, superiority, multicentre, randomised controlled trial done at 39 hospitals in the UK. Patients (aged ≥16 years) who were being treated non-operatively for a primary Achilles tendon rupture at the participating centres were potentially eligible. The exclusion criteria were presenting more than 14 days after injury, previous rupture of the same Achilles tendon, or being unable to complete the questionnaires. Eligible participants were randomly assigned (1:1) to receive a plaster cast or functional brace using a centralised web-based system. Because the interventions were clearly visible, neither patients nor clinicians could be masked. Participants wore the intervention for 8 weeks. The primary outcome was patient-reported Achilles tendon rupture score (ATRS) at 9 months, analysed in the modified intention-to-treat population (all patients in the groups to which they were allocated, excluding participants who withdrew or died before providing any outcome data). The main safety outcome was the incidence of tendon re-rupture. Resource use was recorded from a health and personal social care perspective. The trial is registered with ISRCTN, ISRCTN62639639. FINDINGS: Between Aug 15, 2016, and May 31, 2018, 1451 patients were screened, of whom 540 participants (mean age 48·7 years, 79% male) were randomly allocated to receive plaster cast (n=266) or functional brace (n=274). 527 (98%) of 540 were included in the modified intention-to-treat population, and 13 (2%) were excluded because they withdrew or died before providing any outcome data. There was no difference in ATRS at 9 months post injury (cast group n=244, mean ATRS 74∙4 [SD 19∙8]; functional brace group n=259, ATRS 72∙8 [20∙4]; adjusted mean difference -1∙38 [95% CI -4∙9 to 2∙1], p=0·44). There was no difference in the rate of re-rupture of the tendon (17 [6%] of 266 in the plaster cast group vs 13 [5%] of 274 in the functional brace group, p=0·40). The mean total health and personal social care cost was £1181 for the plaster cast group and £1078 for the functional bract group (mean between-group difference -£103 [95% CI -289 to 84]). INTERPRETATION: Traditional plaster casting was not found to be superior to early weight-bearing in a functional brace, as measured by ATRS, in the management of patients treated non-surgically for Achilles tendon rupture. Clinicians may consider the use of early weight-bearing in a functional brace as a safe and cost-effective alternative to plaster casting. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.
BACKGROUND: There are a growing number of studies using mediation analysis to understand the mechanisms of health interventions and exposures. Recent work has shown that the reporting of these studies is heterogenous and incomplete. This problem stifles clinical application, reproducibility, and evidence synthesis. This paper describes the processes and methods that will be used to develop a guideline for reporting studies of mediation analyses (AGReMA). METHODS/DESIGN: AGReMA will be developed over five overlapping stages. Stage one will comprise a systematic review to examine relevant evidence on the quality of reporting in published studies that use mediation analysis. In the second stage we will consult a group of methodologists and applied researchers by using a Delphi process to identify items that should be considered for inclusion in AGReMA. The third stage will involve a consensus meeting to consolidate and prioritise key items to be included in AGReMA. The fourth stage will involve the production of AGReMA and an accompanying explanation and elaboration document. In the final stage we will disseminate the AGReMA statement via journals, conferences, and professional meetings across multiple disciplines. DISCUSSION: The development and implementation of AGReMA will improve the standardization, transparency, and completeness in the reporting of studies that use mediation analysis to understand the mechanisms of health interventions and exposures.
Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence
<jats:sec><jats:title>Introduction</jats:title><jats:p>Statins reduce the incidence of cardiovascular disease (CVD) and cause few adverse effects. Half of patients prescribed statins discontinue treatment due to perceived intolerance. Placebo-controlled (blinded) n-of-1 trials have shown people with perceived intolerance that the statin does not cause adverse events and most resume treatment. However, blinded n-of-1 trials are impractical to deliver in routine practice. Tackling Statin Intolerance using n-of-1 trials (TaSINI) will test the feasibility of a general practitioner (GP)-delivered behavioural intervention endorsing an unblinded n-of-1 trial to increase adherence to statins relative to usual care.</jats:p></jats:sec><jats:sec><jats:title>Methods and analysis</jats:title><jats:p>TaSINI is a feasibility randomised controlled trial with a nested qualitative substudy. Ninety primary care patients who have discontinued statins due to intolerance or refused treatment will be randomised to an unblinded n-of-1 trial, a blinded n-of-1 trial (positive control) or usual care (negative control). Participants randomised to usual care will be advised to take statin therapy to prevent CVD. In both n-of-1 trial arms, GPs will deliver a behaviourally informed intervention that accessibly explains the benefits of statins, the prevalence of adverse effects and endorse the benefit of experimenting with medication. Participants will alternate between 4 weeks of medication and no medication (unblinded arm) or randomly sorted active and placebo (blinded arm) and will record adherence, symptoms and symptom attributions throughout. After 6 months, GPs will feedback symptom data during active/inactive treatment periods. All participants will be asked if they would like to initiate statin treatment. Measures of feasibility will be met if 4% of invited patients enrol, 50% of participants randomised to n-of-1 trials engage with the experiment and 25% more participants initiate statin in the unblinded n-of-1 arm than in usual care.</jats:p></jats:sec><jats:sec><jats:title>Ethics and dissemination</jats:title><jats:p>This study has been granted ethical approval by North of Scotland Research Ethics Service. The results will be written up for publication and show whether to progress to an effectiveness trial where the primary outcome would be differences in low-density lipoprotein concentration.</jats:p></jats:sec>
Short and long-term clinical effectiveness and cost-effectiveness of a late-phase community-based balance and gait exercise program following hip fracture. The EVA-Hip Randomised Controlled Trial.
The aim of this trial was to evaluate the clinical effectiveness and cost-effectiveness of a home-based exercise program delivered four months following hip-fracture surgery. In the two-armed randomized, single blinded clinical trial we included persons who lived in the catchment area, were 70 years or older, and community-dwelling at time of the fracture. We excluded persons who were unable to walk ten meters prior to the fracture, and those who were bedridden or had medical contraindications for exercise at baseline (ie. four months after the fracture). All participants underwent routine treatment and rehabilitation. The intervention group received additional 20 sessions (10 weeks) structured, home exercise targeting gait and balance, delivered by physiotherapists in primary health care. Gait speed was the primary outcome. Secondary outcomes included physical activity, gait characteristics, cognitive function, activities of daily living, health-related quality of life, and health care costs extracted from hospital and municipality records. In total, 223 participants were included. Four months post surgery 143 were randomized for the exercise trial (70% women, mean age 83.4 (SD 6.1) years, mean gait speed 0.6 (SD 0.2) m/sec). Estimated between group difference in gait speed was 0.09 m/sec (95% CI: 0.04 to 0.14, p<0.001) at posttest and 0.07 m/sec (95% CI: 0.02 to 0.12, p = 0.009) 12 months post surgery. The mean between-group QALY difference was -0.009 (95% CI: -0.061 to 0.038). The mean between-group total cost difference was +242.9 EUR (95% CI: -8397 to 8584). Our findings suggest that gait recovery after hip fracture can be improved by introducing a home-based balance and gait exercise program four months post surgery, without increasing total health care costs. Future research should focus on how to implement gait and balance exercise in comprehensive interventions that increase adherence among the most vulnerable persons and have an effect on daily life activities and patient-centred outcomes. Trial registration: ClinicalTrials.gov NCT01379456.
Factors that modify the association between knee pain and mobility limitation in older women: the Women's Health and Aging Study.
OBJECTIVE: To investigate the influence of pain severity, knee extensor muscle weakness, obesity, depression, and activity on the association between recent knee pain and limitation of usual and fast paced walking, and ability to rise from a chair. METHODS: A cross sectional analysis of 769 older women (mean age 77.8, range 65-101) with physical disability, but no severe cognitive impairment. Severity of knee pain in the past month was classified as none, moderate, or severe. Mobility was measured using timed performance tests. RESULTS: The prevalence of recent knee pain was 53% (408/769). One third of the women with pain reported it to be severe. In general, knee pain was only significantly associated with limited mobility if severe. Obesity, activity and, to a lesser extent, depression intensified the effects of pain. Knee extensor weakness did not. Obesity was a distinctive risk factor in that it substantially increased the risk of mobility limitation, but only in women with pain. In women who had severe pain, activity (walking more than three city blocks in the past week) increased the risk of walking disability more than inactivity. Depression had a minor, but statistically significant effect on walking ability, but not the ability to rise from a chair. CONCLUSION: In older women with recent knee pain, a high pain severity score, obesity, and activity are important factors that increase the risk of mobility limitation.
The impact of the enhanced recovery pathway and other factors on outcomes and costs following hip and knee replacement: routine data study
<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>There is limited evidence concerning the effectiveness of enhanced recovery programmes in hip and knee replacement surgery, particularly when applied nationwide across a health-care system.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objectives</jats:title> <jats:p>To determine the effect of hospital organisation, surgical factors and the enhanced recovery after surgery pathway on patient outcomes and NHS costs of hip and knee replacement.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>(1) Statistical analysis of national linked data to explore geographical variations in patient outcomes of surgery. (2) A natural experimental study to determine clinical effectiveness of enhanced recovery after surgery. (3) A qualitative study to identify barriers to, and facilitators of, change. (4) Health economics analysis to establish NHS costs and cost-effectiveness.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>Data from the National Joint Registry, linked to English Hospital Episode Statistics and patient-reported outcome measures in both the geographical variation and natural experiment studies, together with the economic evaluation. The ethnographic study took place in four hospitals in a region of England.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Qualitative study – 38 health professionals working in hip and knee replacement services in secondary care and 37 patients receiving hip or knee replacement.</jats:p> </jats:sec> <jats:sec id="abs1-6"> <jats:title>Interventions</jats:title> <jats:p>Natural experiment – implementation of enhanced recovery after surgery at each hospital between 2009 and 2011. Enhanced recovery after surgery is a complex intervention focusing on several areas of patients’ care pathways through surgery: preoperatively (patient is in best possible condition for surgery), perioperatively (patient has best possible management during and after operation) and postoperatively (patient experiences best rehabilitation).</jats:p> </jats:sec> <jats:sec id="abs1-7"> <jats:title>Main outcome measures</jats:title> <jats:p>Patient-reported pain and function (Oxford Hip Score/Oxford Knee Score); 6-month complications; length of stay; bed-day costs; and revision surgery within 5 years.</jats:p> </jats:sec> <jats:sec id="abs1-8"> <jats:title>Results</jats:title> <jats:p>Geographical study – there are potentially unwarranted variations in patient outcomes of hip and knee replacement surgery. This variation cannot be explained by differences in patients, case mix, surgical or hospital organisational factors. Qualitative – successful implementation depends on empowering patients to work towards their recovery, providing post-discharge support and promoting successful multidisciplinary team working. Care processes were negotiated between patients and health-care professionals. ‘Good care’ remains an aspiration, particularly in the post-discharge period. Natural experiment – length of stay has declined substantially, pain and function have improved, revision rates are in decline and complication rates remain stable. The introduction of a national enhanced recovery after surgery programme maintained improvement, but did not alter the rate of change already under way. Health economics – costs are high in the year of joint replacement and remain higher in the subsequent year after surgery. There is a strong economic incentive to identify ways of reducing revisions and complications following joint replacement. Published cost-effectiveness evidence supports enhanced recovery pathways as a whole.</jats:p> </jats:sec> <jats:sec id="abs1-9"> <jats:title>Limitations</jats:title> <jats:p>Short duration of follow-up data prior to enhanced recovery after surgery implementation and missing data, particularly for hospital organisation factors.</jats:p> </jats:sec> <jats:sec id="abs1-10"> <jats:title>Conclusion</jats:title> <jats:p>No evidence was found to show that enhanced recovery after surgery had a substantial impact on longer-term downwards trends in costs and length of stay. Trends of improving outcomes were seen across all age groups, in those with and without comorbidity, and had begun prior to the formal enhanced recovery after surgery roll-out. Reductions in length of stay have been achieved without adversely affecting patient outcomes, yet, substantial variation remains in outcomes between hospital trusts.</jats:p> </jats:sec> <jats:sec id="abs1-11"> <jats:title>Future work</jats:title> <jats:p>There is still work to be done to reduce and understand unwarranted variations in outcome between individual hospitals.</jats:p> </jats:sec> <jats:sec id="abs1-12"> <jats:title>Study registration</jats:title> <jats:p>This study is registered as PROSPERO CRD42017059473.</jats:p> </jats:sec> <jats:sec id="abs1-13"> <jats:title>Funding</jats:title> <jats:p>This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in <jats:italic>Health Services and Delivery Research</jats:italic>; Vol. 8, No. 4. See the NIHR Journals Library website for further project information.</jats:p> </jats:sec>
BACKGROUND:The aim was to estimate the prevalence of frailty and relative contribution of physical/balance, nutritive, cognitive and sensory frailty to important adverse health states (falls, physical activity levels, outdoor mobility, problems in self-care or usual activities, and lack of energy or accomplishment) in an English cohort by age and sex. METHODS:Analysis of baseline data from a cohort of 9803 community-dwelling participants in a clinical trial. The sample was drawn from a random selection of all people aged 70 or more registered with 63 general practices across England. Data were collected by postal questionnaire. Frailty was measured with the Strawbridge questionnaire. We used cross sectional, multivariate logistic regression to estimate the association between frailty domains and known correlates and adjusted for age. Some models were stratified by sex. RESULTS:Mean age of participants was 78 years (sd 5.7), range 70 to 101 and 47.5% (4653/9803) were men. The prevalence of overall frailty was 20.7% (2005/9671) and there was no difference in prevalence by sex (Odds Ratio 0.98; 95% Confidence Interval 0.89 to 1.08). Sensory frailty was the most common and this was reported by more men (1823/4586) than women (1469/5056; Odds Ratio for sensory frailty 0.62, 95% Confidence Interval 0.57 to 0.68). Men were less likely than women to have physical or nutritive frailty. Physical frailty had the strongest independent associations with adverse health states. However, sensory frailty was independently associated with falls, less frequent walking, problems in self-care and usual activities, lack of energy and accomplishment. CONCLUSIONS:Physical frailty was more strongly associated with adverse health states, but sensory frailty was much more common. The health gain from intervention for sensory frailty in England is likely to be substantial, particularly for older men. Sensory frailty should be explored further as an important target of intervention to improve health outcomes for older people both at clinical and population level. TRIAL REGISTRATION:ISRCTN71002650.
BACKGROUND: Bayesian adaptive designs can be more efficient than traditional methods for multi-arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi-arm phase III clinical trials and assess potential benefits that these designs offer. METHODS: We constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These designs incorporated response adaptive randomisation (RAR), arm dropping, and early stopping for efficacy or futility. We studied the operating characteristics of the Bayesian designs via simulation. We then virtually re-executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs. RESULTS: We constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original designs target sample size. The virtual executions showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial. CONCLUSIONS: Using CAST as an example, this case study shows how Bayesian adaptive designs can be constructed for phase III multi-arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to better performing arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials. TRIAL REGISTRATION: CAST study registration ISRCTN, ISRCTN37807450. Retrospectively registered on 25 April 2003.
The social sciences have made few direct empirical contributions to the understanding of 'non-specific' benefits of treatment and generally the symbolic healing of indigenous non-Western medicine has received most attention in this field. This paper reports some results of a wider study of neurological clinics in England in which it is shown that a sample attending for headaches experienced considerable improvement in symptoms when followed up 1 year after attendance. Most of this improvement appeared not to be due to any intended treatments received at the clinics but could be attributed to the quality of patients' immediate responses to clinic attendance as assessed from research interviews conducted after their consultations. This relationship between immediate 'satisfied' response and subsequent symptomatic improvement is interpreted in terms of the general levels of expectancy and sense of potential control achieved by obtaining referral to a specialist which directly enhanced recovery in those patients who felt the doctor's actions to be directly relevant to their personal concerns. Disappointment with the doctor reduced the 'non-specific' therapeutic benefits of the hospital referral. The intimate connections of patient satisfaction, treatment received and subsequent outcomes need more careful consideration in social studies of Western medicine. © 1983.
Survey research into patient satisfaction has been responsible for developing a number of related concepts concerning the ways in which patients evaluate the health care that they receive. Recently doubts have been expressed as to the adequacy of this approach for understanding how patients anticipate and respond to medical encounters. This paper reports a study of patients attending neurological outpatient clinics. The results suggest that the conceptual framework deriving from patient satisfaction research provides only partial and sometimes misleading insights into the perspectives of the patients studied. The paper concludes that patients’ varying concerns with regard to their illness need to be more directly considered in explaining different responses to medical consultations. This approach enables a more sensitive evaluation of health care from the patient's point of view. Copyright © 1983, Wiley Blackwell. All rights reserved
Patients consulting neurological outpatient clinics for headaches that were found not to be due to a serious structural lesion were followed up one year afterwards. Considerable improvement in symptoms was found in the sample. This was only partly attributable to any medical treatment received at the clinics or subsequently from a general practitioner. Improvement was associated with previously expressed satisfaction with the clinic consultation, and a nonspecific 'placebo' response is postulated.
A study is reported of patients attending neurological outpatient clinics with a primary symptom of headache not due to structural disease. Patients were interviewed shortly after their hospital visit and one year after the referral and their views about communication from the doctor were obtained. Approximately one-quarter of patients expressed serious critical comments on this subject. No socio-demographic variable predicted this negative response. However, two groups of patients with particular needs were found to be significantly more critical. Otherwise concerns about information in the sample were limited. Dissatisfaction with communication was found to be significantly related to subsequent non-compliance. © 1981.
Patients attending neurological clinics with headaches that aproved not to be due to clearly defined structural disease were interviewed before and after the consultation and approximately one year later. Their expectations of the consultation were ill-formed. About two-thirds of the patients had fears about organic disease although few had psychiatric morbidity. These fears were generally dispelled by the consultation. About one-third of the patients were dissatisfied by the consultation, nearly all by what the neurologist said rather than by what technical procedures he did or did not undertake. Women with a long history of migraine, with significant psychiatric morbidity, and who had initiated the referral themselves were particularly likely to be dissatisfied. Although most patients were still having headaches one year later, visits to the general practitioner for this symptom had greatly declined.