A.C.G. Egberts

Adverse drug events in hospitalized patients A comparison of doctors, nurses and patients as sources of reports

AbstractObjective: This study investigated the relative value of adverse drug events reported by doctors, nurses and patients. Methods: The study was conducted on a total of four wards: the paediatric and internal medicine wards (including geriatric patients) of two peripheral hospitals in the Netherlands. Adverse drug events were collected by spontaneous reporting (doctor and nurse reports) and by daily ward visits, during which the patients were interviewed by a hospital pharmacist (patient reports). Criteria for relative value of the reported adverse drug events were the number of potentially serious reactions, the number of reactions not mentioned in the patient information leaflet and the number of reactions reported to new drugs (5 years or less on the Dutch market). No formal causality assessment was applied. Results: Over a period of 2 months in 1996 (Hospital I) and 2 months in 1997 (Hospital II) a total of 620 patients were included in the study and adverse drug events were reported in 179 (29%) of these cases. Doctors reported a statistically significant larger number of serious (26% of all doctor reports; odds ratio (OR) 3.2; confidence interval (CI) 1.2–8.7) and unknown (39%; OR 2.5; CI 1.0–6.0) adverse drug events than patients themselves during the daily ward visit. Doctors also reported more serious and unknown adverse drug events than nurses. Adverse reactions to new drugs were reported during the daily ward visit only (8% of all daily ward visit reports). Conclusion: This study reconfirms that doctors are the main source for reports of serious and unknown adverse drug events in hospitalized patients. However, patients themselves seem to report more adverse reactions to new drugs (during the daily ward visit). By focusing on patients using new drugs, the daily ward visit might become cost-effective. This needs to be explored in future studies.

Frequency of and Risk Factors for Preventable Medication-Related Hospital Admissions in the Netherlands

BACKGROUND Medication-related problems that lead to hospitalization have been the subject of many studies, many of which were limited to 1 hospital or lacked patient follow-up. Furthermore, little information exists on potential risk factors associated with preventable medication-related hospitalizations. METHODS A prospective multicenter study was conducted to determine the frequency and patient outcomes of medication-related hospital admissions. A case-control design was used to determine risk factors for potentially preventable admissions. All unplanned admissions in 21 hospitals were assessed during 40 days. Controls were patients admitted for elective surgery. Cases and controls were followed up until hospital discharge. The frequency of medication-related hospital admissions, potential preventability, and outcomes were assessed. For potentially preventable medication-related admissions, risk factors were identified in the case-control study. RESULTS Almost 13,000 unplanned admissions were screened, of which 714 (5.6%) were medication related. Almost half (46.5%) of these admissions were potentially preventable, resulting in 332 case patients matched with 332 controls. Outcomes were favorable in most patients. The main determinants of preventable medication-related hospital admissions were impaired cognition (odds ratio, 11.9; 95% confidence interval, 3.9-36.3), 4 or more comorbidities (8.1; 3.1-21.7), dependent living situation (3.0; 1.4-6.5), impaired renal function (2.6; 1.6-4.2), nonadherence to medication regimen (2.3; 1.4-3.8), and polypharmacy (2.7; 1.6-4.4). CONCLUSIONS Adverse drug events are an important cause of hospitalizations, and almost half are potentially preventable. The identified risk factors provide a starting point for preventing medication-related hospital admissions.BACKGROUND Fox-Fordyce disease (FFD) or apocrine miliaria is a rare condition with features that are characteristic clinically but not histopathologically. It is traditionally described as a condition that shows infundibular plugging, acanthosis, parakeratosis, spongiosis, and a nonspecific infiltrate. The so-called retention vesicle, which reputedly involves the apocrine duct, is often difficult to find. Recently, 4 uncontrolled observations were described (infundibular dyskeratotic cells, vacuolar alteration, cornoid lamella-like parakeratosis, and perifollicular foamy macrophages). In this study, we evaluated both established and new histopathologic criteria for the diagnosis of FFD and searched for other meaningful findings. OBSERVATIONS Most established features were observed in both patients with FFD and control patients. All cases occurred during 1995 through 2005. No unequivocal retention vesicle was identifiable in any case. Infundibular vacuolar change and cornoid lamella-like parakeratosis were not corroborated as being diagnostically meaningful. Few dyskeratotic cells were seen in some patients with FFD and in control patients. Perifollicular foam cells were noted in most patients with FFD but not among control patients. These cells expressed CD68 but lacked expression of carcinoembryonic antigen, gross cystic disease fluid protein 15, and periodic acid-Schiff with diastase digestion. Perifollicular mucin, fibrosis, and mast cells in the infiltrate were also observed. CONCLUSIONS The established histopathologic attributes of FFD are nonspecific, and a retention vesicle is difficult to find even in level sections. In contrast, perifollicular foam cells are a distinct, relatively consistent, and specific feature of FFD. We contend that perifollicular foam cells represent a useful hallmark of FFD.

The Risk of Cancer in Users of Statins

PURPOSE Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication. METHODS Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies. RESULTS In the study base, 3129 patients were identified and matched to 16976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91). CONCLUSION This observational study suggests that statins may have a protective effect against cancer.

Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study

Objective: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. Design and setting: Nested case–control study within a cohort of patients (⩾ 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. Patients: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430–436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. Main outcome measure: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. Results: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose–response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). Conclusions: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes.

Psychoactive substance use and the risk of motor vehicle accidents

The driving performance is easily impaired as a consequence of the use of alcohol and/or licit and illicit drugs. However, the role of drugs other than alcohol in motor vehicle accidents has not been well established. The objective of this study was to estimate the association between psychoactive drug use and motor vehicle accidents requiring hospitalisation. A prospective observational case-control study was conducted in the Tilburg region of The Netherlands from May 2000 to August 2001. Cases were car or van drivers involved in road crashes needing hospitalisation. Demographic and trauma related data was collected from hospital and ambulance records. Urine and/or blood samples were collected on admission. Controls were drivers recruited at random while driving on public roads. Sampling was conducted by researchers, in close collaboration with the Tilburg police, covering different days of the week and times of the day. Respondents were interviewed and asked for a urine sample. If no urine sample could be collected, a blood sample was requested. All blood and urine samples were tested for alcohol and a number of licit and illicit drugs. The main outcome measures were odds ratios (OR) for injury crash associated with single or multiple use of several drugs by drivers. The risk for road trauma was increased for single use of benzodiazepines (adjusted OR 5.1 (95% Cl: 1.8-14.0)) and alcohol (blood alcohol concentrations of 0.50-0.79 g/l, adjusted OR 5.5 (95% Cl: 1.3-23.2) and >or=0.8 g/l, adjusted OR 15.5 (95% Cl: 7.1-33.9)). High relative risks were estimated for drivers using combinations of drugs (adjusted OR 6.1 (95% Cl: 2.6-14.1)) and those using a combination of drugs and alcohol (OR 112.2 (95% Cl: 14.1-892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No increased risk for road trauma was found for drivers exposed to cannabis. The study concludes that drug use, especially alcohol, benzodiazepines and multiple drug use and drug-alcohol combinations, among vehicle drivers increases the risk for a road trauma accident requiring hospitalisation.

The Effect of Computerized Physician Order Entry on Medication Prescription Errors and Clinical Outcome in Pediatric and Intensive Care: A Systematic Review

CONTEXT. Pediatric and intensive care patients are particularly at risk for medication errors. Computerized physician order entry systems could be effective in reducing medication errors and improving outcome. Effectiveness of computerized physician order entry systems has been shown in adult medical care. However, in critically ill patients and/or children, medication prescribing is a more complex process, and usefulness of computerized physician order entry systems has yet to be established. OBJECTIVE. To evaluate the effects of computerized physician order entry systems on medication prescription errors, adverse drug events, and mortality in inpatient pediatric care and neonatal, pediatric or adult intensive care settings. METHODS. PubMed, the Cochrane library, and Embase up to November 2007 were used as our data sources. Inclusion criteria were studies of (1) children 0 to 18 years old and/or ICU patients (including adults), (2) computerized physician order entry versus no computerized physician order entry as intervention, and (3) randomized trial or observational study design. All studies were validated, and data were analyzed. RESULTS. Twelve studies, all observational, met our inclusion criteria. Eight studies took place at an ICU: 4 were adult ICUs, and 4 were PICUs and/or NICUs. Four studies were pediatric inpatient studies. Meta-analysis showed a significant decreased risk of medication prescription errors with use of computerized physician order entry. However, there was no significant reduction in adverse drug events or mortality rates. A qualitative assessment of studies revealed the implementation process of computerized physician order entry software as a critical factor for outcome. CONCLUSIONS. Introduction of computerized physician order entry systems clearly reduces medication prescription errors; however, clinical benefit of computerized physician order entry systems in pediatric or ICU settings has not yet been demonstrated. The quality of the implementation process could be a decisive factor determining overall success or failure.

Safety-Related Regulatory Actions for Biologicals Approved in the United States and the European Union

CONTEXT Biologicals are a relatively new class of medicines that carry specific risks (eg, immunogenicity). However, limited information is available on the nature and timing of safety problems with their use that were identified after approval. OBJECTIVE To determine the nature, frequency, and timing of safety-related regulatory actions for biologicals following approval in the United States and/or the European Union. DESIGN AND SETTING Follow-up of a group of biologicals approved in the United States and/or European Union between January 1995 and June 2007. Vaccines, allergenic products, and products for further manufacture and transfusion purposes were excluded. MAIN OUTCOME MEASURES Nature, frequency, and timing of safety-related regulatory actions defined as (1) dear healthcare professional letters (United States) and direct healthcare professional communications (European Union), (2) black box warnings (United States), and (3) safety-related marketing withdrawals (United States and European Union) issued between January 1995 and June 2008. RESULTS A total of 174 biologicals were approved (136 in the United States and 105 in the European Union, of which 67 were approved in both regions). Eighty-two safety-related regulatory actions (46 dear healthcare professional letters, 17 direct healthcare professional communications, 19 black box warnings, and no withdrawals) were issued for 41 of the 174 different biologicals (23.6%). The probability of a first safety-related regulatory action, derived from Kaplan-Meier analyses, was 14% (95% confidence interval [CI], 9%-19%) 3 years after approval and 29% (95% CI, 20%-37%) 10 years after approval. Biologicals first in class to obtain approval had a higher risk for a first safety-related regulatory action compared with later approved products in that class (12.0/1000 vs 2.9/1000 months, respectively; hazard ratio, 3.7 [95% CI, 1.5-9.5]). Warnings mostly concerned the classes general disorders and administration site conditions, infections and infestations, immune system disorders and neoplasms benign, malignant, and unspecified. CONCLUSIONS The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect (infections). Because the biologicals first to be approved in a class were more likely to be subjected to regulatory action, close monitoring is recommended.

Causal or Casual? The Role of Causality Assessment in Pharmacovigilance

SummaryAs with any other study method, ‘spontaneous reporting’ in pharmacovigilance is a process of data acquisition, assessment, presentation and interpretation. The provision of information (i.e. of interpreted data) concerning previously unknown, or otherwise important adverse drug reactions is a major goal. The assessment of case reports in spontaneous reporting takes place in 2 steps: first the assessment of each case individually, and secondly the interpretation of the aggregated data. The latter step is only completed for a minority of case reports, such as when actions or measures are deemed necessary.Uncertainty in case reports regarding the involvement of the suspected drugs is an inherent drawback of spontaneous reporting. Standardised case-causality assessment has become a routine at pharmacovigilance centres around the world. It aims at a decrease in ambiguity of the data and plays a role in data exchange and the prevention of erroneous conclusions. A variety of systems for standardised causality assessment have been developed, ranging from short questionnaires to comprehensive algorithms. Since none of the available assessment systems has been validated (i.e. shown to consistently and reproducibly produce a fair approximation of the truth), causality assessment has only limited scientific value. Causality assessment neither eliminates nor quantifies uncertainty but, at best, categorises it in a semiquantitative way.Routine causality assessment is usually part of the first step in case assessment, and is based on a general system that is intended for all reactions and all drugs. During the subsequent phase of aggregated assessment, causality assessment is likely to be repeated and the use of a specific aetiological-diagnostic system may be more appropriate. It may be recommended to restrict case-causality assessment to selected case reports that are likely to play an active role in pharmacovigilance and to use specific systems, adapted to the reaction or problem involved.It is an inherent limitation of spontaneous reporting that, with the exception of rare proof-positive case reports, conclusive evidence cannot usually be produced. Standardised causality assessment has not really changed this situation. As a rule, confirmation of the connection between a drug and an adverse reaction requires further analytical or experimental study.

Principles of Signal Detection in Pharmacovigilance

SummaryAdverse drug effects are manifold and heterogenous. Many situations may hamper the signalling (i.e. the detection of early warning signs) of adverse effects and new signals often differ from previous experiences.Signals have qualitative and quantitative aspects. Different categories of adverse effects need different methods for detection. Current pharmacovigilance is predominantly based on spontaneous reporting and is mainly helpful in detecting type B effects (those effects that are often allergic or idiosyncratic reactions, characteristically occurring in only a minority of patients and usually unrelated to dosage and that are serious, unexpected and unpredictable) and unusual type A effects (those effects that are related to the pharmacological effects of the drug and are dosage-related). Examples of other sources of signals are prescription event monitoring, large automated data resources on morbidity and drug use (including record linkage), case-control surveillance and follow-up studies. Type C effects (those effects related to an increased frequency of ‘spontaneous’ disease) are difficult to study, however, and continue to pose a pharmacoepidemiological challenge.Seven basic considerations can be identified that determine the evidence contained in a signal: quantitative strength of the association, consistency of the data, exposure response relationship, biological plausibility, experimental findings, possible analogies and the nature and quality of the data. A proposal is made for a standard signal management procedure at pharmacovigilance centres, including the following steps: signal delineation, literature search, preliminary inventory of data, collection of additional information, consultation with the World Health Organization Centre for International Drug Monitoring and the relevant drug companies, aggregated data assessment and a report in writing. A better understanding of the conditions and mechanisms involved in the detection of adverse drug effects may further improve strategies for pharmacovigilance.

Use of antiepileptic drugs and risk of fractures Case–control study among patients with epilepsy

Objective: To study the association between use of antiepileptic drugs (AEDs) and risk of fractures. Methods: The authors obtained data from the General Practice Research Database (GPRD). A case–control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. Results: The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system. Conclusions: Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.