Katy Cooper

Prevalence of complementary and alternative medicine (CAM) use by the general population: a systematic review and update

Objectives:  To update previous systematic reviews of 12‐month prevalence of complementary and alternative medicine (CAM) use by general populations; to explore trends in CAM use by national populations; to develop and apply a brief tool for assessing methodological quality of published CAM‐use prevalence surveys.

Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis

BackgroundFebrile neutropenia (FN) occurs following myelosuppressive chemotherapy and is associated with morbidity, mortality, costs, and chemotherapy reductions and delays. Granulocyte colony-stimulating factors (G-CSFs) stimulate neutrophil production and may reduce FN incidence when given prophylactically following chemotherapy.MethodsA systematic review and meta-analysis assessed the effectiveness of G-CSFs (pegfilgrastim, filgrastim or lenograstim) in reducing FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. G-CSFs were compared with no primary G-CSF prophylaxis and with one another. Nine databases were searched in December 2009. Meta-analysis used a random effects model due to heterogeneity.ResultsTwenty studies compared primary G-CSF prophylaxis with no primary G-CSF prophylaxis: five studies of pegfilgrastim; ten of filgrastim; and five of lenograstim. All three G-CSFs significantly reduced FN incidence, with relative risks of 0.30 (95% CI: 0.14 to 0.65) for pegfilgrastim, 0.57 (95% CI: 0.48 to 0.69) for filgrastim, and 0.62 (95% CI: 0.44 to 0.88) for lenograstim. Overall, the relative risk of FN for any primary G-CSF prophylaxis versus no primary G-CSF prophylaxis was 0.51 (95% CI: 0.41 to 0.62). In terms of comparisons between different G-CSFs, five studies compared pegfilgrastim with filgrastim. FN incidence was significantly lower for pegfilgrastim than filgrastim, with a relative risk of 0.66 (95% CI: 0.44 to 0.98).ConclusionsPrimary prophylaxis with G-CSFs significantly reduces FN incidence in adults undergoing chemotherapy for solid tumours or lymphoma. Pegfilgrastim reduces FN incidence to a significantly greater extent than filgrastim.

Trends in healthcare incident reporting and relationship to safety and quality data in acute hospitals: results from the National Reporting and Learning System

Background: Internationally, there is increasing recognition of the need to collect and analyse data on patient safety incidents, to facilitate learning and develop solutions. The National Patient Safety Agency (NPSA) for England and Wales has been capturing incident data from acute hospitals since November 2003. Objectives: This study analyses patterns in reporting of patient safety incidents from all acute hospitals in England to the NPSA National Reporting and Learning System, and explores the link between reporting rates, hospital characteristics, and other safety and quality datasets. Methods: Reporting rates to the NPSA National Reporting and Learning System were analysed as trends over time, from the point at which each hospital became connected to the system. The relationships between reporting rates and other safety and quality datasets were assessed using correlation and regression analyses. Results: Reporting rates increased steadily over the 18 months analysed. Higher reporting rates correlated with positive data on safety culture and incident reporting from the NHS Staff Survey, and with better risk-management ratings from the NHS Litigation Authority. Hospitals with higher overall reporting rates had a lower proportion of their reports in the “slips, trips and falls” category, suggesting that these hospitals were reporting higher numbers of other types of incident. There was no apparent association between reporting rates and the following data: standardised mortality ratios, data from other safety-related reporting systems, hospital size, average patient age or length of stay. Conclusions: Incident reporting rates from acute hospitals increase with time from connection to the national reporting system, and are positively correlated with independently defined measures of safety culture, higher reporting rates being associated with a more positive safety culture.

Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis

PURPOSE Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer. METHODS Eleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach. RESULTS Across 26 studies evaluating PET or PET/CT (n = 2591 patients), mean sensitivity was 63% (95% CI: 52-74%; range 20-100%) and mean specificity 94% (95% CI: 91-96%; range 75-100%). Across 7 studies of PET/CT (n = 862), mean sensitivity was 56% (95% CI: 44-67%) and mean specificity 96% (90-99%). Across 19 studies of PET-only (n = 1729), mean sensitivity was 66% (50-79%) and mean specificity 93% (89-96%). Mean sensitivity was 11% (5-22%) for micrometastases (≤2 mm; five studies; n = 63), and 57% (47-66%) for macrometastases (>2 mm; four studies; n = 111). CONCLUSIONS PET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla.

Use of a safety climate questionnaire in UK health care: factor structure, reliability and usability

Aim: To explore the factor structure, reliability, and potential usefulness of a patient safety climate questionnaire in UK health care. Setting: Four acute hospital trusts and nine primary care trusts in England. Methods: The questionnaire used was the 27 item Teamwork and Safety Climate Survey. Thirty three healthcare staff commented on the wording and relevance. The questionnaire was then sent to 3650 staff within the 13 NHS trusts, seeking to achieve at least 600 responses as the basis for the factor analysis. 1307 questionnaires were returned (36% response). Factor analyses and reliability analyses were carried out on 897 responses from staff involved in direct patient care, to explore how consistently the questions measured the underlying constructs of safety climate and teamwork. Results: Some questionnaire items related to multiple factors or did not relate strongly to any factor. Five items were discarded. Two teamwork factors were derived from the remaining 11 teamwork items and three safety climate factors were derived from the remaining 11 safety items. Internal consistency reliabilities were satisfactory to good (Cronbach’s alpha ⩾0.69 for all five factors). Conclusions: This is one of the few studies to undertake a detailed evaluation of a patient safety climate questionnaire in UK health care and possibly the first to do so in primary as well as secondary care. The results indicate that a 22 item version of this safety climate questionnaire is useable as a research instrument in both settings, but also demonstrates a more general need for thorough validation of safety climate questionnaires before widespread usage.

Supplemental calcium in the chemoprevention of colorectal cancer: a systematic review and meta-analysis

OBJECTIVE The aim of the review was to assess the evidence for the effectiveness of calcium in reducing the recurrence of adenomas and the occurrence of colorectal cancer among populations at high, intermediate, and low risk of the disease. METHODS A systematic review of randomized controlled trials (RCTs) was performed to compare calcium alone, and with other agents, versus placebo. Nine databases (Cochrane Library, MEDLINE, PreMEDLINE, CINAHL, EMBASE, Web of Science, Biological Abstracts, the National Research Register, and Current Controlled Trials) were searched for published and unpublished trials. Searches were not restricted by either language or date of publication. All searches were completed in January 2010. Database thesaurus and free text terms for calcium and adenomas or colorectal cancer were used to search for trial reports; additional terms were used to search for other agents of interest, such as NSAIDs and folic acid. Search terms consisted of a combination of terms for colorectal cancer (eg, colon or colorectal and neoplasm or cancer or adenoma) and terms for calcium and RCTs. The initial searches were conducted in June 2008, with update searches in January 2010 to identify more recent studies. The reference lists of relevant studies were also searched for additional papers not identified by the search of electronic databases. Studies had to satisfy the following criteria to be included: RCTs about calcium, with or without other chemopreventive agents, in adults with familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer, or a history of colorectal adenomas, or with no increased baseline risk of colorectal cancer. Meta-analysis was performed. For discrete and numerical outcomes, relative risks (RRs) and risk differences were reported with 95% CIs. The random-effects model was used to account for clinical and methodologic variations between trials. RESULTS The original and update searches of electronic databases produced 3835 citations, of which 6 studies (8 papers) met the inclusion criteria. Supplemental calcium had no effect on the number of adenomas in 1 small trial of patients with FAP. Meta-analysis of 3 trials in individuals with a history of adenomas showed a statistically significant reduction in the RR for adenoma recurrence (RR = 0.80 [95% CI, 0.69-0.94], P = 0.006) for those receiving calcium 1200 to 2000 mg/d, but no effect was seen in advanced adenoma (RR = 0.77 [95% CI, 0.501.17], P = NS). Meta-analysis of 2 trials in populations with no increased baseline risk for colorectal cancer suggested that calcium, with or without vitamin D, had no effect on the RR for colorectal cancer (RR = 0.62 [95% CI, 0.11-3.40], P = NS). CONCLUSION Published reports indicated that supplemental calcium was effective for the prevention of adenoma recurrence in populations with a history of adenomas, but no similar effect was apparent in populations at higher or lower risk.

Magnetic Resonance for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis

INTRODUCTION Current methods of identifying axillary node metastases in breast cancer patients are highly accurate, but are associated with several adverse events. This review evaluates the diagnostic accuracy of magnetic resonance imaging (MRI) techniques for identification of axillary metastases in early stage newly diagnosed breast cancer patients. METHODS Comprehensive searches were conducted in April 2009. Study quality was assessed. Sensitivity and specificity were meta-analysed using a bivariate random effects approach, utilising pathological diagnosis via node biopsy as the comparative gold standard. RESULTS Based on the highest sensitivity and specificity reported in each of the nine studies evaluating MRI (n = 307 patients), mean sensitivity was 90% (95% CI: 78-96%; range 65-100%) and mean specificity 90% (95% CI: 75-96%; range 54-100%). Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), mean sensitivity was 98% (95% CI: 61-100%) and mean specificity 96% (95% CI: 72-100%). Across three studies of gadolinium-enhanced MRI (n = 187), mean sensitivity was 88% (95% CI: 78-94%) and mean specificity 73% (95% CI: 63-81%). In the single study of in-vivo proton MR spectroscopy (n = 27), sensitivity was 65% (95% CI: 38-86%) and specificity 100% (95% CI: 69-100%). CONCLUSIONS USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity and may make a useful addition to the current diagnostic pathway. Additional larger studies with standardised methods and standardised criteria for classifying a node as positive are needed. Current estimates of sensitivity and specificity do not support replacement of SLNB with any current MRI technology in this patient group.

Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) for the Assessment of Axillary Lymph Node Metastases in Early Breast Cancer: Systematic Review and Economic Evaluation

BACKGROUND Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning. OBJECTIVES To evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer. DATA SOURCES A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. REVIEW METHODS One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second. RESULTS Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients. LIMITATIONS No included studies directly compared PET and MRI. CONCLUSIONS Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques. FUNDING This study was funded by the Health Technology Assessment programme of the National Institute of Health Research.

Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation

OBJECTIVES To evaluate the clinical effectiveness and incremental cost-effectiveness of amantadine, oseltamivir and zanamivir for seasonal and post-exposure prophylaxis of influenza. DATA SOURCES A MEDLINE search strategy was used and searches were carried out in July 2007. REVIEW METHODS An independent health economic model was developed based on a review of existing cost-effectiveness models and clinical advice.The model draws together a broad spectrum of evidence relating to the costs and consequences associated with influenza and its prevention. Where direct evidence concerning the effectiveness of prophylaxis within specific model subgroups was lacking, the model uses estimates from mixed subgroups or extrapolates from other mutually exclusive subgroups. RESULTS Twenty-six published references relating to 22 randomised controlled trials (RCTs) were included in the clinical effectiveness review, along with one unpublished report. Eight, six and nine RCTs were included for amantadine, oseltamivir and zanamivir respectively. The study quality was variable and gaps in the evidence base limited the assessment of the clinical effectiveness of the interventions. For seasonal prophylaxis, there was limited evidence for the efficacy of amantadine in preventing symptomatic, laboratory-confirmed influenza (SLCI) in healthy adults [relative risk (RR) 0.40, 95% confidence interval (CI) 0.08-2.03]. Oseltamivir was effective in preventing SLCI, particularly when used in at-risk elderly subjects (RR 0.08, 95% CI 0.01-0.63). The preventative efficacy of zanamivir was most notable in at-risk adults and adolescents (RR 0.17, 95% CI 0.07-0.44), and healthy and at-risk elderly subjects (RR 0.20, 95% CI 0.02-1.72). For post-exposure prophylaxis, data on the use of amantadine were again limited: in adolescents an RR of 0.10 (95% CI 0.03-0.34) was reported for the prevention of SLCI. Oseltamivir was effective in households of mixed composition (RR 0.19, 95% CI 0.08-0.45). The efficacy of zanamivir in post-exposure prophylaxis within households was also reported (RR 0.21, 95% CI 0.13-0.33). Interventions appeared to be well tolerated. Limited evidence was available for the effectiveness of the interventions in preventing complications and hospitalisation and in minimising length of illness and time to return to normal activities. No clinical effectiveness data were identified for health-related quality of life or mortality outcomes. With the exception of at-risk children, the incremental cost-utility of seasonal influenza prophylaxis is expected to be in the range 38,000-428,000 pounds per QALY gained (depending on subgroup). The cost-effectiveness ratios for oseltamivir and zanamivir as post-exposure prophylaxis are expected to be below 30,000 pounds per QALY gained in healthy children, at-risk children, healthy elderly and at-risk elderly individuals. Despite favourable clinical efficacy estimates, the incorporation of recent evidence of viral resistance to amantadine led to it being dominated in every economic comparison. CONCLUSIONS All three interventions showed some efficacy for seasonal and post-exposure prophylaxis. However, weaknesses and gaps in the clinical evidence base are directly relevant to the interpretation of the health economic model and rendered the use of advanced statistical analyses inappropriate. These data limitations should be borne in mind in interpreting the findings of the review.

Desperately Seeking Dissonance Identifying the Disconfirming Case in Qualitative Evidence Synthesis

Actively seeking the disconfirming or deviant case is properly regarded as a hallmark of trustworthiness in primary qualitative research. The need to subject emergent theory to such testing is no less important within qualitative systematic reviews. There is, as yet, little available guidance on how to implement such strategies. Few researchers have described the practicalities of seeking the disconfirming case. We survey the methodological literature to gain a better understanding of how systematic reviews of qualitative research handle the disconfirming case. We reflect on our own experience from three recent qualitative evidence syntheses. We describe how reviewers might actively manufacture opportunities to identify discrepant or refutational findings. We conclude by outlining possible methods by which a team might integrate active seeking of a disconfirming case within the overall review process.