Tom Walley

Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients

Abstract Objective To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design Prospective observational study. Setting Two large general hospitals in Merseyside, England. Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. Results There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is £466m (€706m,

The clinical effectiveness of central venous catheters treated with anti-infective agents in preventing catheter-related bloodstream infections : A systematic review

847m). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. Conclusion The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.

Involving consumers in a needs-led research programme: a pilot project

Objectives:To assess the clinical effectiveness of central venous catheters (CVCs) treated with anti-infective agents (AI-CVCs) in preventing catheter-related bloodstream infections (CRBSI). Data Sources:MEDLINE (OVID), EMBASE, SCI//Web of Science, SCI/ISI Proceedings, and the Cochrane Library. Study Selection:A systematic review of the literature was conducted using internationally recognized methodology. All included articles were reports of randomized controlled trials comparing the clinical effectiveness of CVCs treated with AI-CVCs with either standard CVCs or another anti-infective treated catheter. Articles requiring in-house preparation of catheters or that only reported interim data were excluded. Data Extraction:Data extraction was carried out independently and crosschecked by two reviewers using a pretested data extraction form. Data Synthesis:Meta-analyses were conducted to assess the effectiveness of AI-CVCs in preventing CRBSI, compared with standard CVCs. Results are presented in forest plots with 95% confidence intervals. Results:Thirty-eight randomized controlled trials met the inclusion criteria. Methodologic quality was generally poor. Meta-analyses of data from 27 trials assessing CRBSI showed a strong treatment effect in favor of AI-CVCs (odds ratio 0.49 (95% confidence interval 0.37–0.64) fixed effects, test for heterogeneity, chi-square = 28.78, df = 26, p = 0.321, I2 = 9.7). Results subgrouped by the different types of anti-infective treatments generally demonstrated treatment effects favoring the treated catheters. Sensitivity analyses investigating the effects of methodologic differences showed no differences to the overall conclusions of the primary analysis. Conclusion:AI-CVCs appear to be effective in reducing CRBSI compared with standard CVCs. However, it is important to establish whether this effect remains in settings where infection-prevention bundles of care are established as routine practice. This review does not address this question and further research is required.

Reporting of adverse drug reactions by nurses

Objectives To describe the methods used for involving consumers in a needs‐led health research programme, and to discuss facilitators, barriers and goals.

Accounting for Noncompliance in Pharmacoeconomic Evaluations

Schemes for spontaneous reporting of adverse drug reactions are important to post-marketing safety surveillance worldwide. In the UK, doctors, dentists, coroners, and pharmacists are allowed to report through the yellow card scheme, but nurses were not until October, 2002. We used a similar programme to assess the role of community and hospital nurses in reporting of adverse drug reactions. The proportion and quality of reports received from nurses was similar to that of those received from doctors: we received reports from one in seven nurses eligible to report, compared with one in eight doctors; 137 of 177 nurse reports and 676 of 984 doctor reports were judged to be appropriate according to regulatory authority criteria (95% CI for difference between proportions 1.4-15.0, z=2.3, p=0.02). Our findings suggest that nurses, who form the largest proportion of health-care staff in the UK, can play a valuable part in improvement of pharmacovigilance.

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses.

Noncompliance with prescribed drug regimens is a widespread phenomenon which results in decreased efficacy and is often associated with increased medical expenditures. Despite this, economic evaluations based on decision-analytic models rarely incorporate noncompliance to allow for the differences in compliance observed between controlled clinical trials and routine clinical practice.This review examines the issues relating to the measurement of noncompliance, and the clinical and economic consequences of noncompliant drug taking behaviour. In order to fully appreciate the clinical (and therefore the economic) consequences of noncompliance, a detailed understanding of the type of noncompliance, the pharmacokinetic and pharmacodynamic properties of the drug and the pathophysiological processes of the diseases being treated is required. These are described in detail, and a classification of drug-disease combinations according to the potential economic impact of the varying forms of noncompliance is set out.Issues are raised to highlight the need for improved modelling of the impact of noncompliance, and to this end, recommendations are made for future analyses. The main points are that compliance should be defined clearly, distinguishing between the various forms of noncompliance, that the assumptions relating to the health status of noncompliers should be explicit and robust, and that sensitivity analysis should be applied appropriately to ascertain the impact of noncompliance on the cost-effectiveness of drug therapies.

Alterations in prescribing by general practitioner fundholders: an observational study.

There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and meta-analyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.

The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation

Abstract Objectives: To compare prescribing in general practices before and after they become fundholders to assess whether this affected prescribing patterns. Design: Analysis of prescribing data (PACT) for one year before and one year after practices become first, second, or third wave fundholders and comparison with practices that were not fundholders during any part of the study. Main outcome measures: Prescribing costs (net ingredient cost per prescribing unit), prescribing volume (items per 1000 prescribing units), net ingredient cost per item, and percentage of generic prescribing. Setting: Former Mersey Regional Health Authority. Subjects: 100 fundholders (20 first wave, 31 second wave, 49 third wave) and 312 non-fundholders. Results: Prescribing costs and volume rose throughout the study in all groups. In all three fundholding waves the rate of increase of prescribing costs was significantly lower than for non-fundholders. Both cost per item and prescribing volume tended to decrease, the former probably because of a significant increase in generic prescribing. Fundholding and non-fundholding practices differed in several respects. Conclusion: Fundholding has altered practice prescribing patterns compared with those of non-fundholders, increasing generic prescribing and reducing the rate of increase of prescribing costs.

The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review.

OBJECTIVE To determine whether testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia leads to improvement in outcomes, is useful in medical, personal or public health decision-making, and is a cost-effective use of health-care resources. DATA SOURCES The following electronic databases were searched for relevant published literature: Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Technology Assessment database, ISI Web of Knowledge, MEDLINE, PsycINFO, NHS Economic Evaluation Database, Health Economic Evaluation Database, Cost-effectiveness Analysis (CEA) Registry and the Centre for Health Economics website. In addition, publicly available information on various genotyping tests was sought from the internet and advisory panel members. REVIEW METHODS A systematic review of analytical validity, clinical validity and clinical utility of CYP testing was undertaken. Data were extracted into structured tables and narratively discussed, and meta-analysis was undertaken when possible. A review of economic evaluations of CYP testing in psychiatry and a review of economic models related to schizophrenia were also carried out. RESULTS For analytical validity, 46 studies of a range of different genotyping tests for 11 different CYP polymorphisms (most commonly CYP2D6) were included. Sensitivity and specificity were high (99-100%). For clinical validity, 51 studies were found. In patients tested for CYP2D6, an association between genotype and tardive dyskinesia (including Abnormal Involuntary Movement Scale scores) was found. The only other significant finding linked the CYP2D6 genotype to parkinsonism. One small unpublished study met the inclusion criteria for clinical utility. One economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants and 28 economic models of schizophrenia were identified; none was suitable for developing a model to examine the cost-effectiveness of CYP testing. CONCLUSIONS Tests for determining genotypes appear to be accurate although not all aspects of analytical validity were reported. Given the absence of convincing evidence from clinical validity studies, the lack of clinical utility and economic studies, and the unsuitability of published schizophrenia models, no model was developed; instead key features and data requirements for economic modelling are presented. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.

Treatment for newly diagnosed hypertension: patterns of prescribing and antihypertensive effectiveness in the UK

BACKGROUND Breast cancer is the most common cancer affecting women in the UK. Tamoxifen (TAM) is considered as the standard of care for many women with oestrogen receptor positive breast cancer. However, wide variability in the response of individuals to drugs at the same doses may occur, which may be a result of interindividual genetic differences (pharmacogenetics). TAM is known to be metabolised to its active metabolites N-desmethyl TAM and 4-hydroxytamoxifen by a number of CYP450 enzymes, including CYP2D6, CYP3A4, CYP2C9, CYP2C19 and CYP2B6. N-desmethyl TAM is further metabolised to endoxifen by CYP2D6. Endoxifen, which is also formed via the action of CYP2D6, is 30- to 100-fold more potent than TAM in suppressing oestrogen-dependent cell proliferation, and is considered an entity responsible for significant pharmacological effects of TAM. Thus, an association between the cytochrome P450 2D6 (CYP2D6) genotype and phenotype (expected drug effects) is believed to exist and it has been postulated that CYP2D6 testing may play a role in optimising an individuals adjuvant hormonal treatment. OBJECTIVES To determine whether or not testing for cytochrome P450 2D6 (CYP2D6) polymorphisms in women with early hormone receptor positive breast cancer leads to improvement in outcomes, is useful for health decision-making and is a cost-effective use of health-care resources. DATA SOURCES Relevant electronic databases and websites including MEDLINE, EMBASE and HuGENet [Centers for Disease Control and Prevention (Office of Public Health Genomics), Human Genome Epidemiology Network] were searched until July 2009. Further studies that became known to the authors via relevant conferences or e-mail alerts from an automatically updated search of the Scopus database were also included as the review progressed, up to March 2010. REVIEW METHODS A systematic review of the clinical effectiveness and cost-effectiveness of CYP2D6 testing was undertaken. As it was not possible to conduct meta-analyses, data were extracted into structured tables and narratively discussed. An exploratory analysis of sensitivity and specificity was undertaken. A review of economic evaluations and models of CYP2D6 testing for patients treated with TAM was also carried out. RESULTS A total of 25 cohorts were identified which examined clinical efficacy (overall survival and relapse/recurrence), adverse events and endoxifen plasma concentrations by genotype/phenotype. Significantly, six cohorts suggest extensive metabolisers (Ems) appear to have better outcomes than either poor metabolisers (PMs) or PMs + intermediate metabolisers in terms of relapse/recurrence; however, three cohorts report apparently poorer outcomes for EMs (albeit not statistically significant). There was heterogeneity across the studies in terms of the patient population, alleles tested and outcomes used and defined. One decision model proposing a strategy for CYP2D6 testing for TAM was identified, but this was not suitable for developing a model to examine the cost-effectiveness of CYP2D6 testing. It was not possible to produce a de novo model because of a lack of data to populate it. CONCLUSION This is a relatively new area of research that is evolving rapidly and, although international consortia are collaborating, the data are limited and conflicting. Therefore, it is not possible to recommend pharmacogenetic testing in this patient population. Future research needs to focus on which alleles (including, or in addition to, those related to CYP2D6) reflect patient response, the link between endoxifen levels and clinical outcomes, and the appropriate pathways for implementation of such pharmacogenetic testing in patient care pathways.