Sarah E. McDowell

Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine

Abstract Objective To review the evidence for ethnic differences in susceptibility to adverse drug reactions (ADRs) to cardiovascular drugs. Design Systematic review and meta-analysis. Data sources We searched Medline and Embase to March 2005. Reference lists of identified articles were hand searched for further relevant articles. Review methods Studies were eligible for inclusion if they included at least two ethnic groups and one or more ADRs. We excluded case reports and case series. Results 564 studies contained some description of ethnicity and an ADR, and 132 of them related to cardiovascular therapies. Twenty four studies provided data for ADRs for at least two ethnic groups and were therefore eligible for inclusion. In pooled analyses the relative risk of angio-oedema from angiotensin converting enzyme (ACE) inhibitors in black compared with non-black patients was 3.0 (95% confidence interval 2.5 to 3.7); the relative risk of cough from ACE inhibitors was 2.7 (1.6 to 4.5) in East Asian compared with white patients; and the relative risk of intracranial haemorrhage with thrombolytic therapy was 1.5 (1.2 to 1.9) in black compared with non-black patients. Conclusion Patients from different ethnic groups have different risks for important ADRs to cardiovascular drugs. Ethnic group may therefore be one determinant of harms of a given treatment in the individual patient, either because it acts as a surrogate measure of genetic make up or because cultural factors alter the risk. Data are sparse, and regulators should consider asking for better data before licensing.

Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis

Objective To investigate the overall probability of error in preparing and administering intravenous medicines; to identify at which stage of the process an error is most likely to occur; and to determine the impact of error correction on the error probability. Design Systematic review and random-effects Bayesian conditional independence modelling. Methods Medline and EMBASE were searched for studies on intravenous medicines. The error rates of each stage were extracted. These, expert estimates, and error rates from generic tasks, were used in a Bayesian conditional independence model to find error ‘hot-spots.’ The main outcome measure was the probability of at least one error occurring during intravenous therapy. Results Nine published studies were identified for inclusion in the systematic review and meta-analysis. The overall probability of making at least one error in intravenous therapy was 0.73 (95% credible interval (CrI) 0.54 to 0.90). If error-checking was introduced at each stage of the process, the overall rate fell to 0.22 (95% CrI 0.14 to 0.31). Errors were most likely in the reconstitution step. Removing the reconstitution step by providing preprepared injections would reduce the overall error rate to 0.17 (95% CrI 0.09 to 0.27). Conclusions Intravenous therapy is complex and error-prone. Error-checking at each stage could reduce the error probability. The use of preprepared injections may help by eliminating errors in the reconstitution of drug and diluent. However, it will be important to ensure that benefits are not outweighed by practical disadvantages such as an increase in selection errors.

On the alert: future priorities for alerts in clinical decision support for computerized physician order entry identified from a European workshop

BackgroundClinical decision support (CDS) for electronic prescribing systems (computerized physician order entry) should help prescribers in the safe and rational use of medicines. However, the best ways to alert users to unsafe or irrational prescribing are uncertain. Specifically, CDS systems may generate too many alerts, producing unwelcome distractions for prescribers, or too few alerts running the risk of overlooking possible harms. Obtaining the right balance of alerting to adequately improve patient safety should be a priority.MethodsA workshop funded through the European Regional Development Fund was convened by the University Hospitals Birmingham NHS Foundation Trust to assess current knowledge on alerts in CDS and to reach a consensus on a future research agenda on this topic. Leading European researchers in CDS and alerts in electronic prescribing systems were invited to the workshop.ResultsWe identified important knowledge gaps and suggest research priorities including (1) the need to determine the optimal sensitivity and specificity of alerts; (2) whether adaptation to the environment or characteristics of the user may improve alerts; and (3) whether modifying the timing and number of alerts will lead to improvements. We have also discussed the challenges and benefits of using naturalistic or experimental studies in the evaluation of alerts and suggested appropriate outcome measures.ConclusionsWe have identified critical problems in CDS, which should help to guide priorities in research to evaluate alerts. It is hoped that this will spark the next generation of novel research from which practical steps can be taken to implement changes to CDS systems that will ultimately reduce alert fatigue and improve the design of future systems.

How NICE may be outflanked

We argued a decade ago that the NHS should not have to pay for new drugs unless they are at least as good as older ones, nor for expensive drugs whose benefits are uncertain.1 Since then, the National Institute for Health and Clinical Excellence (NICE) has been created. NICE appraises technologies that are available to the NHS and recommends whether they should be used unreservedly, with restrictions, or not at all.2 Part of its remit is to ensure equity, but equity is not in everyones interests. Here, we consider how individuals or groups with specific interests may seek to outflank NICE. When many people share common resources, it is rational for each individual to increase personal use of the resources. But if all individuals do this, the resources are overexploited and eventually everyone will be ruined. This is termed the tragedy of commons.3 The NHS is a common resource. A patient acts rationally in seeking an expensive treatment that produces a benefit (even if small), because the cost falls almost entirely on others. But the NHS cannot support overexploitation indefinitely. It already spends £10.3bn (€15bn;

Ethnic differences in the risks of adverse reactions to drugs used in the treatment of psychoses and depression: a systematic review and meta-analysis.

19bn) a year on drugs, and costs are rising rapidly.w1 One way to avoid overexploitation is to appoint a guardian to administer the commons. NICE plays this role but faces many challenges. NICE examines the value of drugs only when it is invited to do so by the Department of Health and Welsh Assembly, so it may never review some important aspects of therapeutics. The process is complex, involves many interested parties (stakeholders), and takes around two years to complete.w2 The delays between the initial suggestion and the final determination can allow patterns of treatment of uncertain cost effectiveness to become established. The longer the patterns persist, the harder they …

A systematic review and meta‐analysis of thiazide‐induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation?

Background: Factors such as age, sex and disease state alter a patient’s susceptibility to adverse drug reactions (ADRs). Ethnicity may also alter the risk of an ADR.Objective: To review the evidence for ethnic differences in susceptibility to adverse reactions to drugs used to treat psychoses and depression.Data sources: We searched MEDLINE (from 1951), EMBASE (from 1974), and PsycINFO (from 1950) to March 2006.Study selection: Studies were included if there was a mention of ethnicity, ethnic or racial groups and a description of a procedure to investigate ADRs specifically or a description of ADRs that were a result of drugs in therapeutic use. Studies selected by any two reviewers were retained if they referred to drugs used in the treatment of psychoses and related disorders or antidepressant drugs. Of 124 studies describing ADRs to antipsychotics or antidepressants, 51 reported data from different ethnic groups.Data extraction: Data were extracted independently from those studies selected for inclusion by two reviewers, using a standard data extraction form. Studies were assessed for bias in order to determine the quality of the study.Data synthesis: In a pooled analysis of patients treated with antipsychotics, the relative risk (RR) of tardive dyskinesia in Black compared with White patients was 1.03 (95% CI 0.85, 1.24); the RR of extrapyramidal symptoms in East Asian compared with non-East Asian patients was 1.38 (95% CI 1.11, 1.72); the RR of hyperglycaemia in Black compared with non-Black patients was 1.55 (95% CI 0.95, 2.53); and the RR of diabetes mellitus in non-White compared with White patients was 1.35 (95% CI 0.95, 1.92). It was impossible to perform pooled analysis of data from studies investigating antidepressants due to insufficient data.Conclusions: We found limited evidence of ethnic differences in the risk of ADRs. The clinical implications of these results remain unclear because of confounding factors. Further progress will require improved recruitment of patients from different ethnic groups and an established consensus on how to define ethnicity.

Developing consensus on hospital prescribing indicators of potential harms amenable to decision support

AIMS Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition. METHODS Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken. RESULTS One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m−2. Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) mm and serum potassium of 3.3 (95% CI 3.0, 3.5) mm. Mean urinary sodium concentration was 64 mm (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide. CONCLUSIONS Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7–14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required.

Oversight: a retrospective study of biochemical monitoring in patients beginning antihypertensive drug treatment in primary care

AIMS To develop a list of prescribing indicators specific for the hospital setting that would facilitate the prospective collection of high-severity and/or high-frequency prescribing errors, which are also amenable to electronic clinical decision support. METHODS A two-stage consensus technique (electronic Delphi) was carried out with 20 experts across England. Participants were asked to score prescribing errors using a five-point Likert scale for their likelihood of occurrence and the severity of the most likely outcome. These were combined to produce risk scores, from which median scores were calculated for each indicator across the participants in the study. The degree of consensus between the participants was defined as the proportion that gave a risk score in the same category as the median. Indicators were included if a consensus of 80% or more was achieved. RESULTS A total of 80 prescribing errors were identified by consensus as being high or extreme risk. The most common drug classes named within the indicators were antibiotics (n = 13), antidepressants (n = 8), nonsteroidal anti-inflammatory drugs (n = 6) and opioid analgesics (n = 6). The most frequent error type identified as high or extreme risk were those classified as clinical contraindications (n = 29 of 80). CONCLUSIONS Eighty high-risk prescribing errors in the hospital setting have been identified by an expert panel. These indicators can serve as a standardized, validated tool for the collection of prescribing data in both paper-based and electronic prescribing processes. This can assess the impact of safety improvement initiatives, such as the implementation of electronic clinical decision support.

Dose Omissions in Hospitalized Patients in a UK Hospital

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Guidelines recommend biochemical monitoring of patients treated with antihypertensive agents, although there is little primary evidence for these recommendations. WHAT THIS STUDY ADDS Patients treated for hypertension in general practice often have no biochemical tests before, or in the 6 months after, starting drug treatment. AIMS Guidelines on the management of hypertension have recommended baseline testing of serum electrolyte and creatinine concentrations before treatment since the 1990s. We wished to examine the extent of laboratory monitoring in patients with newly diagnosed hypertension and newly treated with antihypertensive drugs. METHODS We carried out a retrospective analysis of 74,096 patients in the General Practice Research Database (GPRD) aged 18 years and older with newly diagnosed hypertension and prescribed a single antihypertensive agent. We determined the number of patients with a laboratory test for serum electrolyte and creatinine (or urea) concentrations prior to the first antihypertensive drug prescription and in the 6 months after and patient factors associated with subsequent monitoring. RESULTS Thirty-four thousand nine hundred and forty-seven patients (47%) had at least one biochemical test in the 12 months prior to beginning antihypertensive treatment, and 26,946 (36%) had at least one biochemical monitoring test in the 6 months after beginning antihypertensive treatment. Thirteen thousand five hundred and four (18%) had both baseline and monitoring tests. Baseline tests were normal in 11,671 patients (86%), of whom 10,213 (88%) had normal tests at first monitoring. Monitoring was significantly more likely in patients treated with ACE inhibitors than thiazides (adjusted OR 1.90; 95% CI 1.80, 2.00), older patients (adjusted OR 1.23; 95% CI 1.11, 1.36) [individuals aged 80-89 years compared with <40 years], and patients with diabetes mellitus (adjusted OR 2.03; 95% CI 1.91, 2.16). CONCLUSION Biochemical testing at baseline and monitoring after starting treatment is often omitted in newly diagnosed hypertensive patients. When both are tested, one in eight normal results becomes abnormal.

Laboratory monitoring and adverse patient outcomes with antihypertensive therapy in primary care.

AbstractBackground: The omission of charted (prescribed) doses for hospitalized patients is an important problem in the UK. Inappropriate drug omission can clearly lead to harm from lack of therapeutic effect. However, healthcare professionals administering medicines may decide that omission of a dose is appropriate in certain circumstances, e.g. when patients show signs of a possible adverse drug reaction (ADR). Objective: The aim of this study was to characterize dose omissions to understand the factors that influence non-administration of therapy and to determine the proportion of doses that are appropriately omitted due to ADRs. Methods: We used data from a bespoke hospital-wide electronic prescribing and administration system at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. We extracted data on 6.01 million drug ad-ministrations during 2010 and then randomly selected four 7-day periods, concentrating on doses that were charted but not given. Omitted medicines were counted if either there was a charted ‘non-administration’ (i.e. an active acknowledgement of the omitted dose) or there was no charting of that dose (i.e. no record of either administration or omission). Paused medicines were not counted. When a dose was omitted, staff indicated the reasons for non-administration using codes (‘hard coded’) or free text in the electronic system. We used both to compare the contribution of different factors, including ADRs, to the total rates of dose omissions. Results: In the four 7-day periods analysed, 60 763 (12.4%) of the 491 894 charted doses were omitted. The most common code was ‘patient refused drug’ (45.4%). Only 1.6% of doses were omitted for reasons of patient safety, of which 4 in 1000 omissions were coded as directly due to an ADR. Conclusions: Measures to improve the quality of care should seek to reduce dose omissions, but in some cases omission may be rational. Electronic medication administration records allow for detailed analysis of decisions made by healthcare professionals at the point of administration. While dose omissions related to ADRs are uncommon, they are important both for patient safety and for therapeutic decision making.