Samantha Johnson

Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer: a systematic review and overview of reviews

BACKGROUND Prophylactic aspirin has been considered to be beneficial in reducing the risks of heart disease and cancer. However, potential benefits must be balanced against the possible harm from side effects, such as bleeding and gastrointestinal (GI) symptoms. It is particularly important to know the risk of side effects when aspirin is used as primary prevention--that is when used by people as yet free of, but at risk of developing, cardiovascular disease (CVD) or cancer. In this report we aim to identify and re-analyse randomised controlled trials (RCTs), systematic reviews and meta-analyses to summarise the current scientific evidence with a focus on possible harms of prophylactic aspirin in primary prevention of CVD and cancer. OBJECTIVES To identify RCTs, systematic reviews and meta-analyses of RCTs of the prophylactic use of aspirin in primary prevention of CVD or cancer. To undertake a quality assessment of identified systematic reviews and meta-analyses using meta-analysis to investigate study-level effects on estimates of benefits and risks of adverse events; cumulative meta-analysis; exploratory multivariable meta-regression; and to quantify relative and absolute risks and benefits. METHODS We identified RCTs, meta-analyses and systematic reviews, and searched electronic bibliographic databases (from 2008 September 2012) including MEDLINE, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, NHS Centre for Reviews and Dissemination, and Science Citation Index. We limited searches to publications since 2008, based on timing of the most recent comprehensive systematic reviews. RESULTS In total, 2572 potentially relevant papers were identified and 27 met the inclusion criteria. Benefits of aspirin ranged from 6% reduction in relative risk (RR) for all-cause mortality [RR 0.94, 95% confidence interval (CI) 0.88 to 1.00] and 10% reduction in major cardiovascular events (MCEs) (RR 0.90, 95% CI 0.85 to 0.96) to a reduction in total coronary heart disease (CHD) of 15% (RR 0.85, 95% CI 0.69 to 1.06). Reported pooled odds ratios (ORs) for total cancer mortality ranged between 0.76 (95% CI 0.66 to 0.88) and 0.93 (95% CI 0.84 to 1.03). Inclusion of the Womens Health Study changed the estimated OR to 0.82 (95% CI 0.69 to 0.97). Aspirin reduced reported colorectal cancer (CRC) incidence (OR 0.66, 95% CI 0.90 to 1.02). However, including studies in which aspirin was given every other day raised the OR to 0.91 (95% CI 0.74 to 1.11). Reported cancer benefits appeared approximately 5 years from start of treatment. Calculation of absolute effects per 100,000 patient-years of follow-up showed reductions ranging from 33 to 46 deaths (all-cause mortality), 60-84 MCEs and 47-64 incidents of CHD and a possible avoidance of 34 deaths from CRC. Reported increased RRs of adverse events from aspirin use were 37% for GI bleeding (RR 1.37, 95% CI 1.15 to 1.62), between 54% (RR 1.54, 95% CI 1.30 to 1.82) and 62% (RR 1.62, 95% CI 1.31 to 2.00) for major bleeds, and between 32% (RR 1.32, 95% CI 1.00 to 1.74) and 38% (RR 1.38, 95% CI 1.01 to 1.82) for haemorrhagic stroke. Pooled estimates of increased RR for bleeding remained stable across trials conducted over several decades. Estimates of absolute rates of harm from aspirin use, per 100,000 patient-years of follow-up, were 99-178 for non-trivial bleeds, 46-49 for major bleeds, 68-117 for GI bleeds and 8-10 for haemorrhagic stroke. Meta-analyses aimed at judging risk of bleed according to sex and in individuals with diabetes were insufficiently powered for firm conclusions to be drawn. LIMITATIONS Searches were date limited to 2008 because of the intense interest that this subject has generated and the cataloguing of all primary research in so many previous systematic reviews. A further limitation was our potential over-reliance on study-level systematic reviews in which the person-years of follow-up were not accurately ascertainable. However, estimates of number of events averted or incurred through aspirin use calculated from data in study-level meta-analyses did not differ substantially from estimates based on individual patient data-level meta-analyses, for which person-years of follow-up were more accurate (although based on less-than-complete assemblies of currently available primary studies). CONCLUSIONS We have found that there is a fine balance between benefits and risks from regular aspirin use in primary prevention of CVD. Effects on cancer prevention have a long lead time and are at present reliant on post hoc analyses. All absolute effects are relatively small compared with the burden of these diseases. Several potentially relevant ongoing trials will be completed between 2013 and 2019, which may clarify the extent of benefit of aspirin in reducing cancer incidence and mortality. Future research considerations include expanding the use of IPD meta-analysis of RCTs by pooling data from available studies and investigating the impact of different dose regimens on cardiovascular and cancer outcomes. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Doctor role modelling in medical education: BEME Guide No. 27

Aim: The aim of this review is to summarise the evidence currently available on role modelling by doctors in medical education. Methods: A systematic search of electronic databases was conducted (PubMed, Psyc- Info, Embase, Education Research Complete, Web of Knowledge, ERIC and British Education Index) from January 1990 to February 2012. Data extraction was completed by two independent reviewers and included a quality assessment of each paper. A thematic analysis was conducted on all the included papers. Results: Thirty-nine studies fulfilled the inclusion criteria for the review. Six main themes emerged from the content of high and medium quality papers: 1) the attributes of positive doctor role models; 2) the personality profiles of positive role models; 3) the influence of positive role models on students’ career choice; 4) the process of positive role modelling; 5) the influence of negative role modelling; 6) the influence of culture, diversity and gender in the choice of role model. Conclusions: This systematic review highlights role modelling as an important process for the professional development of learners. Excellence in role modelling involves demonstration of high standards of clinical competence, excellence in clinical teaching skills and humanistic personal qualities. Positive role models not only help to shape the professional development of our future physicians, they also influence their career choices. This review has highlighted two main challenges in doctor role modelling: the first challenge lies in our lack of understanding of the complex phenomenon of role modelling. Second, the literature draws attention to negative role modelling and this negative influence requires deeper exploration to identify ways to mitigate adverse effects. This BEME review offers a preliminary guide to future discovery and progress in the area of doctor role modelling.

Total hip replacement and surface replacement for the treatment of pain and disability resulting from end-stage arthritis of the hip (review of technology appraisal guidance 2 and 44): systematic review and economic evaluation

BACKGROUND Total hip replacement (THR) involves the replacement of a damaged hip joint with an artificial hip prosthesis. Resurfacing arthroplasty (RS) involves replacement of the joint surface of the femoral head with a metal surface covering. OBJECTIVES To undertake clinical effectiveness and cost-effectiveness analysis of different types of THR and RS for the treatment of pain and disability in people with end-stage arthritis of the hip, in particular to compare the clinical effectiveness and cost-effectiveness of (1) different types of primary THR and RS for people in whom both procedures are suitable and (2) different types of primary THR for people who are not suitable for hip RS. DATA SOURCES Electronic databases including MEDLINE, EMBASE, The Cochrane Library, Current Controlled Trials and UK Clinical Research Network (UKCRN) Portfolio Database were searched in December 2012, with searches limited to publications from 2008 and sample sizes of ≥ 100 participants. Reference lists and websites of manufacturers and professional organisations were also screened. REVIEW METHODS Systematic reviews of the literature were undertaken to appraise the clinical effectiveness and cost-effectiveness of different types of THR and RS for people with end-stage arthritis of the hip. Included randomised controlled trials (RCTs) and systematic reviews were data extracted and risk of bias and methodological quality were independently assessed by two reviewers using the Cochrane Collaboration risk of bias tool and the Assessment of Multiple Systematic Reviews (AMSTAR) tool. A Markov multistate model was developed for the economic evaluation of the technologies. Sensitivity analyses stratified by sex and controlled for age were carried out to assess the robustness of the results. RESULTS A total of 2469 records were screened of which 37 were included, representing 16 RCTs and eight systematic reviews. The mean post-THR Harris Hip Score measured at different follow-up times (from 6 months to 10 years) did not differ between THR groups, including between cross-linked polyethylene and traditional polyethylene cup liners (pooled mean difference 2.29, 95% confidence interval -0.88 to 5.45). Five systematic reviews reported evidence on different types of THR (cemented vs. cementless cup fixation and implant articulation materials) but these reviews were inconclusive. Eleven cost-effectiveness studies were included; four provided relevant cost and utility data for the model. Thirty registry studies were included, with no studies reporting better implant survival for RS than for all types of THR. For all analyses, mean costs for RS were higher than those for THR and mean quality-adjusted life-years (QALYs) were lower. The incremental cost-effectiveness ratio for RS was dominated by THR, that is, THR was cheaper and more effective than RS (for a lifetime horizon in the base-case analysis, the incremental cost of RS was £11,284 and the incremental QALYs were -0.0879). For all age and sex groups RS remained clearly dominated by THR. Cost-effectiveness acceptability curves showed that, for all patients, THR was almost 100% cost-effective at any willingness-to-pay level. There were age and sex differences in the populations with different types of THR and variations in revision rates (from 1.6% to 3.5% at 9 years). For the base-case analysis, for all age and sex groups and a lifetime horizon, mean costs for category E (cemented components with a polyethylene-on-ceramic articulation) were slightly lower and mean QALYs for category E were slightly higher than those for all other THR categories in both deterministic and probabilistic analyses. Hence, category E dominated the other four categories. Sensitivity analysis using an age- and sex-adjusted log-normal model demonstrated that, over a lifetime horizon and at a willingness-to-pay threshold of £20,000 per QALY, categories A and E were equally likely (50%) to be cost-effective. LIMITATIONS A large proportion of the included studies were inconclusive because of poor reporting, missing data, inconsistent results and/or great uncertainty in the treatment effect estimates. This warrants cautious interpretation of the findings. The evidence on complications was scarce, which may be because of the absence or rarity of these events or because of under-reporting. The poor reporting meant that it was not possible to explore contextual factors that might have influenced study results and also reduced the applicability of the findings to routine clinical practice in the UK. The scope of the review was limited to evidence published in English in 2008 or later, which could be interpreted as a weakness; however, systematic reviews would provide summary evidence for studies published before 2008. CONCLUSIONS Compared with THR, revision rates for RS were higher, mean costs for RS were higher and mean QALYs gained were lower; RS was dominated by THR. Similar results were obtained in the deterministic and probabilistic analyses and for all age and sex groups THR was almost 100% cost-effective at any willingness-to-pay level. Revision rates for all types of THR were low. Category A THR (cemented components with a polyethylene-on-metal articulation) was more cost-effective for older age groups. However, across all age-sex groups combined, the mean cost for category E THR (cemented components with a polyethylene-on-ceramic articulation) was slightly lower and the mean QALYs gained were slightly higher. Category E therefore dominated the other four categories. Certain types of THR appeared to confer some benefit, including larger femoral head sizes, use of a cemented cup, use of a cross-linked polyethylene cup liner and a ceramic-on-ceramic as opposed to a metal-on-polyethylene articulation. Further RCTs with long-term follow-up are needed. STUDY REGISTRATION This study is registered as PROSPERO CRD42013003924. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Total Hip Replacement for the Treatment of End Stage Arthritis of the Hip: A Systematic Review and Meta-Analysis

Background Evolvements in the design, fixation methods, size, and bearing surface of implants for total hip replacement (THR) have led to a variety of options for healthcare professionals to consider. The need to determine the most optimal combinations of THR implant is warranted. This systematic review evaluated the clinical effectiveness of different types of THR used for the treatment of end stage arthritis of the hip. Methods A comprehensive literature search was undertaken in major health databases. Randomised controlled trials (RCTs) and systematic reviews published from 2008 onwards comparing different types of primary THR in patients with end stage arthritis of the hip were included. Results Fourteen RCTs and five systematic reviews were included. Patients experienced significant post-THR improvements in Harris Hip scores, but this did not differ between impact types. There was a reduced risk of implant dislocation after receiving a larger femoral head size (36 mm vs. 28 mm; RR = 0.17, 95% CI: 0.04, 0.78) or cemented cup (vs. cementless cup; pooled odds ratio: 0.34, 95% CI: 0.13, 0.89). Recipients of cross-linked vs. conventional polyethylene cup liners experienced reduced femoral head penetration and revision. There was no impact of femoral stem fixation and cup shell design on implant survival rates. Evidence on mortality and complications (aseptic loosening, femoral fracture) was inconclusive. Conclusions The majority of evidence was inconclusive due to poor reporting, missing data, or uncertainty in treatment estimates. The findings warrant cautious interpretation given the risk of bias (blinding, attrition), methodological limitations (small sample size, low event counts, short follow-up), and poor reporting. Long-term pragmatic RCTs are needed to allow for more definitive conclusions. Authors are encouraged to specify the minimal clinically important difference and power calculation for their primary outcome(s) as well CONSORT, PRISMA and STROBE guidelines to ensure better reporting and more reliable production and assessment of evidence.

Adverse events in women and children who have received intrapartum antibiotic prophylaxis treatment : a systematic review.

BackgroundAdverse events from intrapartum antibiotic prophylaxis (IAP) are poorly documented yet essential to inform clinical practice for neonatal group B Streptococcus (GBS) disease prevention. In this systematic review, we appraised and synthesised the evidence on the adverse events of IAP in the mother and/or her child.MethodsWe searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane, and Science Citation Index from date of inception until October 16th 2016. Reference lists of included studies and relevant systematic reviews were hand-searched. We included primary studies in English that reported any adverse events from intrapartum antibiotics for any prophylactic purpose compared to controls. The search was not restricted to prophylaxis for GBS but excluded women with symptoms of infection or undergoing caesarean section. Two reviewers assessed the methodological quality of studies, using the Cochrane Risk of Bias tool, and the Risk of Bias Assessment Tool for Nonrandomised Studies. Results were synthesised narratively and displayed in text and tables.ResultsFrom 2364 unique records, 30 studies were included. Despite a wide range of adverse events reported in 17 observational studies and 13 randomised controlled trials (RCTs), the evidence was inconsistent and at high risk of bias. Only one RCT investigated the long-term effects of IAP reporting potentially serious outcomes such as cerebral palsy; however, it had limited applicability and unclear biological plausibility. Seven observational studies showed that IAP for maternal GBS colonisation alters the infant microbiome. However, study populations were not followed through to clinical outcomes, therefore clinical significance is unknown. There was also observational evidence for increased antimicrobial resistance, however studies were at high or unclear risk of bias.ConclusionsThe evidence base to determine the frequency of adverse events from intrapartum antibiotic prophylaxis for neonatal GBS disease prevention is limited. As RCTs may not be possible, large, better quality, and longitudinal observational studies across countries with widespread IAP could fill this gap.Trial registrationCRD42016037195.

Newborn screening for Tyrosinemia type 1 using succinylacetone – a systematic review of test accuracy

BackgroundTyrosinemia type 1 is an autosomal recessive disorder of amino acid metabolism. Without treatment, death in childhood is common. Treatment with nitisinone and dietary restrictions are associated with improved outcomes; some studies suggest better outcomes when treatment begins at an asymptomatic stage. Newborn screening allows for earlier identification, but there is uncertainty regarding the test accuracy of the current method: succinylacetone measurement in dried blood spots using tandem mass spectrometry.MethodsWe conducted a systematic review of literature published up to January 2016. Two reviewers independently assessed titles, abstracts, full texts, and conducted quality appraisals. A single reviewer extracted data, which was checked by a second reviewer.ResultsTen studies provided test accuracy data: five studies reporting screening experiences and five case–control studies. Sensitivity (29 cases in total) and specificity (34,403 controls in total) were 100% in the case–control studies, but could not be calculated in the studies reporting screening experiences due to a lack of follow-up of screen-negative babies. Positive predictive values in the screening experience studies ranged from 66.7% (2 true positive cases, 1 false positive case from ~500,000 people screened) to 100% (8 true positive cases from 856,671 people screened); negative predictive values could not be calculated. Positive and negative predictive values cannot be calculated from case–control studies.ConclusionsScreening for Tyrosinemia type 1 using tandem mass spectrometry measurement of succinylacetone from dried blood spots appears to be promising. Confirmation of test accuracy data should be obtained from studies that include a two-year follow-up of individuals who screen negative.

Bacterial load and molecular markers associated with early-onset Group B Streptococcus

Background: The natural history of neonatal group B Streptococcus (GBS) is poorly understood. Little is known about the bacterial factors influencing the transmission of GBS from mother to neonate, or the development of invasive early-onset GBS disease (EOGBS) in colonized neonates. We reviewed whether bacterial load and molecular markers are associated with GBS vertical transmission and progression to EOGBS. Methods: We searched Medline, Embase, Cochrane and Web of Science from inception to October 10, 2016, for observational studies in English. We also hand-searched reference lists of relevant publications and experts cross-checked included studies. Two reviewers independently screened studies, extracted data and appraised the quality of included studies using the Quality in Prognosis Studies tool. We conducted random-effects meta-analyses where possible and narratively synthesized the evidence in text and tables. Results: Seventeen studies were included from 1107 records retrieved from electronic databases and publication references. Meta-analyses of 3 studies showed that neonates colonized by serotype III had a higher risk of developing EOGBS than serotype Ia (pooled risk ratio: 1.51, 95% confidence interval: 1.12–2.03) and serotype II (risk ratio: 1.95, 95% confidence interval: 1.10–3.45). Eleven studies showed that in heavily colonized mothers, 2–3 times more neonates were colonized, and in heavily colonized neonates, up to 15 times more neonates had EOGBS, compared with light colonization. Most evidence was published before 2000 and was at risk of bias. Conclusions: Acknowledging the difficulty of natural history studies, well-controlled studies are needed to assess the predictive value of pathogen subtype and heavy load; they may be useful for better-targeted prevention.

Evaluation of pre-symptomatic nitisinone treatment on long-term outcomes in Tyrosinemia type 1 patients: a systematic review

BackgroundTyrosinemia type 1 (TYR1) is a rare autosomal recessive disorder of amino acid metabolism that is fatal without treatment. With medication (nitisinone) and dietary restrictions outcomes are improved. We conducted a systematic review to investigate if treatment with nitisinone following screening provides better long-term outcomes than treatment with nitisinone following symptomatic detection.MethodsWe searched Web of Science, Medline, Pre-Medline, and Embase up to 23rd September 2016 for journal articles comparing clinical outcomes of TYR1 patients receiving earlier versus later nitisinone treatment. Two reviewers independently screened titles and abstracts, assessed full texts, and appraised study quality. Data extraction was performed by a single reviewer and checked by a second.ResultsWe included seven articles out of 470 unique records identified by our search. The seven articles included four studies (three cohort studies and one cross-sectional study). Study sample sizes ranged from 17 to 148. There is consistent evidence that nitisinone is an effective treatment for TYR1, and some evidence that earlier treatment with nitisinone and dietary restrictions within the first one or 2 months of life is associated with reduced need for liver transplantation, lower rates of renal dysfunction, fewer neurological crises, and fewer, shorter hospital admissions compared to later treatment. However, study quality was moderate to weak, with high risk of confounding and applicability concerns to the screening context. We conducted post hoc analyses to address these issues. Results suggested an association between earlier treatment and fewer liver transplants (earlier treatment: 0% of 10–24 patients; later treatment: 25–60% of 4–15 patients), but no impact on neurological crises. We found no effect of treatment timing on mortality in either the primary or post hoc analyses. Post hoc analyses of other health-related outcomes were not possible because of sample size or reporting.ConclusionsThere is some evidence from observational studies that earlier treatment with nitisinone might be beneficial but this is subject to bias. The applicability of our findings to the screening context or clinical practice is limited as not all early-treated patients were identified by screening and late-treated groups included patients born prior to the availability of nitisinone.

OP33 Symptomatic vs pre-symptomatic treatment of tyrosinemia type 1 with nitisinone: a systematic review

Background Tyrosinemia type 1 is a rare autosomal recessive disorder of amino acid metabolism, affecting approximately 1 in 1 00 000 people. Without treatment, death is common in childhood. Treatment with nitisinone is associated with reductions in mortality and morbidity; some studies suggest better outcomes when treatment is initiated before the symptoms of the disorder present. An apparent benefit of earlier versus later treatment has been used to support the implementation of newborn screening for Tyrosinemia type 1, but these studies have not been synthesised or quality appraised. We conducted a systematic review to examine if individuals treated following screen detection of the disorder had better outcomes than those treated following symptomatic detection. Methods Standard systematic review methods were used. Embase, Medline, Pre-Medline, and Web of Science were searched. Participants were individuals with Tyrosinemia type 1. We compared people who received nitisinone following screen detection of the disorder (early treatment) with those who received nitisinone after symptomatic presentation (late treatment). Any reported outcomes were considered. Two reviewers independently screened and assessed records, and conducted quality appraisal (using the Quality Assessment Tool for Quantitative Studies). Data extraction was carried out by one reviewer, and checked by another. A narrative synthesis of results was carried out. Post-hoc comparisons were conducted to address confounding factors and applicability concerns. Results The titles/abstracts of 470 unique records were examined, and 50 full texts assessed. Seven articles were included in the review. Study sample sizes ranged from 17 to 148. Methodological quality of the studies was moderate to weak. There was evidence of associations between early treatment with nitisinone and lower rates of death, liver disease and transplantations, and renal dysfunction. However, posthoc analyses suggested an association between earlier treatment and lower rates of liver transplantation but not mortality (analysis 1) or no differences in outcomes for those treated earlier versus later (analyses 2 and 3). Discussion Evidence from observational studies suggests that treatment with nitisinone initiated during the pre-symptomatic period may be beneficial to people with Tyrosinemia type 1. However, this is subject to bias and applicability concern; the apparent benefits of early treatment may not be present when these issues are addressed. There are several challenges inherent in rare diseases research, including small and heterogeneous populations, lack of appropriate comparator treatments, and limited knowledge about the disease. Our review suggests that alternative research methods or tolerance of lower levels of evidence may be required.