Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Implementing the national invasive cervical cancer audit: a local perspective.

OBJECTIVE: To monitor the effectiveness of the cervical screening programme and identify suboptimal management in order to improve patient care. DESIGN: Retrospective study. SETTING: A university hospital serving a population of 1 million people. POPULATION: All women diagnosed with a cervical cancer between 2003 and 2006. METHODS: Analysis of data from invasive cervical cancer reviews. MAIN OUTCOME MEASURE: Categorisation of cervical cancer cases according to the Invasive Cervical Cancer Audit classification. RESULTS: Eighty-seven women were diagnosed with cervical cancer during the 3-year study period. The 'lapsed attender' group accounted for the greatest number of cases (30%), followed by screen detected (26%), interval cancers (13%), never attended (12%), lost to follow-up (10%) and never invited (9%). Women who had never attended for cytology presented with higher stage disease, stage-II or above, compared with the screen-detected cases: 60% were stage II or above, compared with 13.0%, Chi-square P = 0.018. The most frequently identified screening programme problem was patient compliance, which was determined to be the principle contributing factor in 39 cases (45%) and a secondary factor in a further ten cases. CONCLUSIONS: The categorisation of cervical cancer cases has the potential of yielding invaluable information for improving programme effectiveness. Patient compliance is the greatest challenge to the screening programme, and the need for regular screening and adherence to follow-up regimens needs to be reinforced in order to maximise the efficacy of the national screening programme.

Comparison between transcutaneous bilirubinometry and total serum bilirubin measurements in preterm infants <35 weeks gestation.

BACKGROUND: Neonatal hyperbilirubinaemia is a common treatable cause of brain injury. The treatment for this condition is phototherapy. The decision whether to use phototherapy is currently dependent upon serum bilirubin assay results. However, repeated blood sampling is not only traumatic but may also be a cause of anaemia in neonates. We evaluated a transcutaneous bilirubin assay method to determine whether it was suitable for routine use in preterm infants. METHODS: One hundred and eighty-three transcutaneous bilirubin measurements were taken contemporaneously with blood samples for laboratory measurement of serum bilirubin. The study was carried out with informed parental consent and approval by the local research ethics committee. RESULTS: The transcutaneous bilirubin method (BiliChek) exhibited a consistent positive bias compared with the laboratory bilirubin assay. Consequently, for a given detection rate, the transcutaneous method had a higher screen positive rate, i.e. more neonates would be given phototherapy if transcutaneous bilirubin results were used to decide. There was a margin of safety in the transcutaneous bilirubin assay calibration. CONCLUSION: The BiliChek transcutaneous bilirubin assay is a safe alternative to laboratory bilirubin assay in deciding whether to give preterm neonates phototherapy.

Targeting treatment using calculated cardiovascular disease risk: effective? A shot in the dark? Or is it time to change the paradigm?

BACKGROUND: The current paradigm for cardiovascular risk screening is one of screen and treat; i.e. a risk calculation is used to screen the population to determine who should receive therapy. This is marginally effective with somewhere between 199 and 999 people receiving lipid-lowering therapy and consequently being exposed to the drug-related risk without receiving any benefit. HYPOTHESIS: New evidence suggests that a diagnostic test could be applied to decide which patients will benefit from treatment. CONCLUSION: Changing the paradigm from 'screen and treat' to 'screen, diagnose and treat' could save large amounts of money by avoiding drugs and could prevent many people from being exposed to side effects.

The copper/caeruloplasmin ratio in routine clinical practice in different laboratories.

BACKGROUND: The diagnosis of copper deficiency and excess states is challenging. It was hoped that the non-caeruloplasmin-bound ("free") copper would reduce this difficulty; however, it has its own problems. The copper/caeruloplasmin ratio has been advocated as an alternative index of copper status, especially as it would not need gender-derived or age-derived reference intervals. However, there are no comparative data for different populations using different assays. METHOD: Independent paired copper and caeruloplasmin data were retrospectively obtained for three laboratories. From these data, the copper/caeruloplasmin ratio was calculated, and descriptive statistics for the populations and methods were obtained. The relationship between the copper/caeruloplasmin ratio and both copper and caeruloplasmin were also investigated for the three laboratories. RESULTS: All three datasets displayed a non-Gaussian distribution. The Burton median was statistically different from the two other medians, which did not differ significantly from each other. The regression lines for both copper and caeruloplasmin with the ratio differed from each other. CONCLUSION: The copper/caeruloplasmin ratio behaves differently depending on the laboratory, the population studied, or both. Thus, cut-offs in the literature are not transferable. Each laboratory should therefore derive its own cut-offs.

Risk assessment for prevention of morbidity and mortality: lessons for pressure ulcer prevention.

Medicine has changed from being a reactive process that attempts to alleviate disease only when it is clinically evident to a proactive one in which it is hoped that early intervention may reduce the impact of disease or even it developing at all. In moving the focus of treatment, this inevitably means that a greater number of individuals with lesser disease burdens are treated. The logical end-point of this process is to provide preventative measures for the entire population but this can only be done if the economic costs and negative effects of treatment are out-weighed by the benefits. In the case of pressure ulcers, it is self-evident that prevention is extremely beneficial to patients. However, the cost of some of the equipment used for prevention can be high, and therefore, the balance between the optimum level of provision, the purposes of prevention and the available funding becomes critical. Consequently a screening mechanism to better match susceptible patients with resources is essential. There are, however, many problems with such screening techniques. By looking at other specialties, we can see that it is vital to know the natural history of the disease: PSA testing reveals many men who would have died never having known they had prostate cancer, thus giving them years of worry and morbidity they would probably not previously have suffered; cardiovascular risk screening is so imprecise that risk estimates are of questionable utility; antenatal Down's syndrome risk screening is prone to data-related problems that can unexpectedly reduce the effectiveness of the test. In pressure ulcer screening, there are many tools currently in use, but few (possibly none) are really effective. Finally, this paper details some suggestions for future research to combine risk tests that may offer a prospect for improving ulcer risk screening tools.

Median parameters for Down's syndrome screening should be calculated using a moving time-window method.

BACKGROUND: In Down's syndrome screening, the change in analyte concentrations in maternal serum with advancing gestational age is compensated for by converting concentration to multiples of the median (MoM) by using a mathematical equation describing the expected relationship. However, owing to assay drifts and shift, the equation may be incorrect, leading to deviation of the observed MoM distribution from the ideal MoM distribution. The NHS Fetal Anomaly Screening Programme has produced standards limiting acceptable deviation, and has provided the Down's Syndrome Screening Quality Assurance Service (DQASS) to monitor it. DQASS recommends monitoring by cumulative sum plot. METHODS: Down's screening data for 61,368 consecutive samples (12 October 2004 to 31 December 2007) was evaluated using different median assignment techniques. RESULTS: A change in the paradigm for median equation derivation is described, which significantly improves the probability that medians will be correct at any point in time. CONCLUSION: Software developers need to change the way medians are derived in their programmes.

Evaluation of Down's syndrome screening population data sets by simulation: analyser-specific parameters may be superior to meta-analysis-derived parameters.

OBJECTIVE: Choice of parameter sets used to calculate Down's syndrome risks is complicated. Published population statistics were compared with assay-specific parameters to optimise screening efficiency. DESIGN: Weight-corrected Gaussian population statistics for alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE(3)), expressed as log(10) multiples of median (MoM) were established for a Belgian cohort of 748 unaffected pregnancies. Using Cuckle's method and Access-specific data, Down's syndrome parameters were tailored to the Belgian cohort. Correlated marker triplets for affected and unaffected pregnancies were modelled and combined with maternal age to calculate term risks for Trisomy 21. Receiver-Operator-Curve (ROC) analysis was performed to identify the optimally-performing population set. RESULTS: Log-normal distributions for the Access markers had geometric mean MoM values close to zero and standard deviation values equal to 0.1460 (AFP), 0.2185 (HCG) and 0.1317 (uE(3)). Correlation between AFP and other markers was significant (p < 0.001). Correlation between HCG and uE(3) was not significant (p = 0.4818). The median ratio between the lowest and highest risk outcomes for the test MoM set was 4.3. Areas under ROC curves differed significantly (p < 0.001) between the models and the analyser-assay specific parameters resulted in the largest area. At a 1 in 250 threshold, sensitivity and specificity were 69% and 96%. At false-positive rates (1-specificity) = 5%, sensitivity was 72.5%. CONCLUSION: Population parameters significantly affect risk outcome and hence screening performance. Highest efficiency may be obtained with parameters tailored to an assay-specific population model. Consequently models from literature, without knowledge of the assay/analyser combination may lead to suboptimal performance.

The use and understanding of CA125 as a tumor marker for ovarian cancer: a questionnaire-based survey.

The aim of this study was to assess the level of understanding of the role of the tumor marker CA125 in ovarian cancer among doctors of different grades specializing in obstetrics and gynecology (O&G), medicine, surgery, and primary care (general practitioners [GPs]). The study involves a questionnaire-based survey. Two hundred and fifty-nine questionnaires were distributed. An overall response rate of 47.1% was achieved. All grades of doctors and all major specialties were represented. There was a significant difference in the level of self-reported CA125 ordering between the medical specialties, O&G being the most frequent users and primary care the least (P < 0.001), and between the grade of doctors, senior house officers/preregistration house officers and GPs less than consultants and middle grade doctors (P < 0.001). Electronic literature was the first source of advice for the majority of respondents (38.5%). The knowledge of false-positive causes for a raised CA125 was low in medicine, surgery, and primary care specialties, as was the awareness of the sensitivity and specificity of CA125 in epithelial and nonepithelial ovarian cancers. The role of CA125 in ovarian cancer is poorly understood, especially among doctors working outside O&G. Guidelines should be developed to aid clinicians from all specialties in the most appropriate application of CA125 in their practice. Substantial cost savings could be made by the introduction of clear protocol-driven ordering in an attempt to reduce the number of inappropriate tests performed.

The relationship between serum copper and ceruloplasmin in routine clinical practice.

INTRODUCTION: The biochemical assessment of copper status is not easy when investigating deficient and excess states. Most clinicians request copper and ceruloplasmin and assume that the results provided by their local laboratory are comparable with data in the literature. AIMS AND METHODS: We decided to obtain paired copper and ceruloplasmin values retrospectively from the laboratory information systems from three different hospital laboratories to see how the relationships compared. Descriptive statistics and the relationship between caeruloplasmin and copper were obtained. RESULTS: Our data shows differences in the relationship (slope, intercept and correlation co-efficient) between copper and ceruloplasmin; this is especially the case at the clinical cut-off of a ceruloplasmin concentration of 200 mg/l. CONCLUSION: Differing methods or populations may be contributing to the differences between the data sets. We therefore recommend that local cut-offs are derived for the investigation of copper deficiency and excess states.

Best practice in primary care pathology: review 6.

This sixth best practice review examines four series of common primary care questions in laboratory medicine: (1) laboratory monitoring in hypertension and heart failure abnormalities; (2) markers of inflammatory joint disease; (3) laboratory investigation of chronic diarrhoea; and (4) mumps and chickenpox. The review is presented in question-answer format, referenced for each question series. The recommendations represent a precis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus based rather than evidence based. They will be updated periodically to take account of new information.

Best practice in primary care pathology: review 3.

This best practice review examines four series of common primary care questions in laboratory medicine: (i) "minor" blood platelet count and haemoglobin abnormalities; (ii) diagnosis and monitoring of anaemia caused by iron deficiency; (iii) secondary hyperlipidaemia and hypertriglyceridaemia; and (iv) glycated haemoglobin and microalbumin use in diabetes. The review is presented in question-answer format, referenced for each question series. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards, but form a guide to be set in the clinical context. Most of the recommendations are based on consensus rather than evidence. They will be updated periodically to take account of new information.

Best practice in primary care pathology: review 4.

This fourth best practice review examines four series of common primary care questions in laboratory medicine are examined in this review: (1) safety monitoring for three common drugs; (2) use of prostate-specific antigen; (3) investigation of vaginal discharge; and (4) investigation of subfertility. The review is presented in question-answer format, referenced for each question series. The recommendations represent a precis of the guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most of them are consensus based rather than evidence based. They will be updated periodically to take account of new information.

Weight correction of MoM values: which method?

BACKGROUND: Adjusting maternal serum markers for maternal weight is considered to be a standard practice when screening for pregnancies associated with Down's syndrome. The choice of model for taking maternal weight into account is, however, rarely explicitly evaluated. METHOD: The relationship between the maternal serum markers alphafetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE3), determined with the Beckman Coulter access reagents and maternal weight was investigated in a cohort of 752 Belgian women being screened for pregnancy associated with Down's syndrome. Two different models (the log-linear equation and the linear-reciprocal equation) were used to determine the relationship between the serum markers and maternal weight. RESULTS: A significant relationship between log(10) multiples of median (MoM) values and weight (kg) was obtained for all markers, and the log-linear model had higher coefficients of determination (r(2)) when compared with the linear-reciprocal model. Weight correction with either method achieved the optimum effect that the correction factor for a woman with a population median weight of 65.5 kg was not significantly different from 1. Simulated weight-corrected MoM values with the two approaches were compared and variation was estimated. The mean difference between the weight-corrected MoM values calculated by the two methods was 7.8% (SD 4.3%) for AFP, 14.0% (4.4%) for HCG and 5.9% (3.2%) for uE3. This resulted in a difference in risk estimate of 1.66-5.34% for Down's syndrome owing to weight correction algorithm differences in women of median weight. CONCLUSION: The log-linear weight correction approach was shown to be marginally more effective by a goodness-of-fit analysis. Differences in weight-corrected MoM values estimated with the two approaches are highly significant (p<0.0001, Wilcoxon's paired sample test), but the effect on risk calculation was not significant. It was observed that the changes in risk became significant the more the MoM correction factors deviated from 1.

Adjusting copper concentrations for caeruloplasmin levels in routine clinical practice.

BACKGROUND: An investigation on copper metabolism usually includes the measurement of serum levels of copper and caeruloplasmin. Using these levels, some laboratories derive levels of non-caeruloplasmin-bound copper (NCC); however, a considerable number of patients may show negative values, which is not physiologically possible. AIM: To derive an equation for adjusted copper in a manner similar to that widely accepted for adjusted calcium. METHODS: A linear regression equation for the relationship between caeruloplasmin and copper was used: [copper] (micromol/l) = 0.052x[caeruloplasmin] (mg/l). An equation for copper adjusted for caeruloplasmin was derived using this equation and the reference interval of 10-25 micromol/l for copper. RESULTS: The derived equation was [adjusted copper] (micromol/l) = [total copper] (micromol/l)+0.052x[caeruloplasmin] (mg/l)+17.5 (micromol/l). The adjusted copper concentrations on the 2.5th and 97.5th centiles were 12.7 and 21.5 micromol/l, respectively, with the population having a gaussian distribution. The relationship between NCC and the adjusted copper concentrations is linear and independent of caeruloplasmin concentration. CONCLUSION: Calculation of copper adjusted for caeruloplasmin uses the same variables as those for NCC. Accordingly, the problems that are caused by the lack of specificity of caeruloplasmin immunoassays are the same as those identified for NCC. This calculation, however, overcomes the negative values that are found in a considerable minority of patients with NCC, as well as age and sex differences in the caeruloplasmin reference interval. As the concept is already familiar to non-laboratory healthcare professionals in the form of calcium adjusted for albumin, this method is potentially less confusing than that for NCC.