Application of the Pareto principle to identify and address drug-therapy safety issues

Purpose

Adverse drug events (ADE) and medication errors (ME) are common causes of morbidity in patients presenting at emergency departments (ED). Recognition of ADE as being drug related and prevention of ME are key to enhancing pharmacotherapy safety in ED. We assessed the applicability of the Pareto principle (～80 % of effects result from 20 % of causes) to address locally relevant problems of drug therapy.

Methods

In 752 cases consecutively admitted to the nontraumatic ED of a major regional hospital, ADE, ME, contributing drugs, preventability, and detection rates of ADE by ED staff were investigated. Symptoms, errors, and drugs were sorted by frequency in order to apply the Pareto principle.

Results

In total, 242 ADE were observed, and 148 (61.2 %) were assessed as preventable. ADE contributed to 110 inpatient hospitalizations. The ten most frequent symptoms were causally involved in 88 (80.0 %) inpatient hospitalizations. Only 45 (18.6 %) ADE were recognized as drug-related problems until discharge from the ED. A limited set of 33 drugs accounted for 184 (76.0 %) ADE; ME contributed to 57 ADE. Frequency-based listing of ADE, ME, and drugs involved allowed identification of the most relevant problems and development of easily to implement safety measures, such as wall and pocket charts.

Conclusions

The Pareto principle provides a method for identifying the locally most relevant ADE, ME, and involved drugs. This permits subsequent development of interventions to increase patient safety in the ED admission process that best suit local needs.     

Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations

Aim and background

To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.

Methods

This was a cross-sectional retrospective study assessing the dose adequacy of drug treatment of 400 cirrhotic patients at hospital admission based on the authors’ own previous studies and standard literature. The prevalence of total and preventable ADRs and of hospitalizations due to preventable ADRs was determined.

Results

Of all 1653 drugs prescribed (median 4 per patient), 336 (20 %) drugs were inadequately dosed in 184 patients. Overall, 210 ADRs (78 % preventable) occurred in 120 patients. Sixty-nine ADRs (33 % of all ADRs) were associated with inadequate drug dosing in 46 patients, of which 68 % were preventable. Nonsteroidal anti-inflammatory drugs and psycholeptics in particular frequently caused preventable ADRs associated with inadequate drug dosing. Inadequate drug dosing was more frequently associated with ADRs than adequate drug dosing, and patients receiving inadequately dosed drugs were more frequently admitted to the hospital due to ADRs. Hospitalization of patients receiving inadequately dosed drugs that caused preventable ADRs resulted in 94 additional hospital days.

Conclusion

In this retrospective study, inadequate drug dosing was associated with an increased frequency of ADRs, hospital admissions and hospital days in cirrhotic patients. We therefore conclude that the careful dosing of critical drugs is important in patients with liver cirrhosis.     

Lecithin-Based Microemulsions for Targeted Delivery of Ceramide AP into the Stratum Corneum: Formulation, Characterizations, and In Vitro Release and Penetration Studies

Purpose

To improve the solubility and penetration of Ceramide AP (CER [AP]) into the stratum corneum that potentially restores the barrier function of aged and affected skin.

Methods

CER [AP] microemulsions (MEs) were formulated using lecithin, Miglyol® 812 (miglyol) and water-1,2 pentandiol (PeG) mixture as amphiphilic, oily and hydrophilic components, respectively. The nanostructure of the MEs was revealed using electrical conductivity, differential scanning calorimeter (DSC) and electron paramagnetic resonance (EPR) techniques. Photon correlation spectroscopy (PCS) was used to measure the sizes and shape of ME droplets. The release and penetration of the CER into the stratum corneum was investigated in vitro using a multi-layer membrane model.

Results

The MEs exhibited excellent thermodynamic stability (>2 years) and loading capacity (0.5% CER [AP]). The pseudo-ternary phase diagrams of the MEs were obtained and PCS results showed that the droplets are spherical in shape and bigger in size. In vitro investigations showed that the MEs exhibited excellent rate and extent of release and penetration.

Conclusions

Stable lecithin-based CER [AP] MEs that significantly enhance the solubility and penetration of CER [AP] into the stratum corneum were developed. The MEs also have better properties than the previously reported polyglycerol fatty acid surfactant-based CER [AP] MEs.     

Large scale implementation of clinical medication reviews in Dutch community pharmacies: drug-related problems and interventions

Background

Research on the benefits of clinical medication reviews (CMRs) performed by pharmacists has been conducted mostly in controlled settings and has been widely published. Less is known of the effects after large scale implementation in community pharmacies. An online CMR tool enabled the systematic registration of drug-related problems (DRPs) and implemented interventions derived from CMRs in daily practice.

Objective

To describe the effects of CMRs on pharmacy practice after large-scale implementation in the Netherlands.

Setting

268 community pharmacies. Pharmacists were trained on CMRs with a patient centred approach.

Method

Retrospective analyses of DRPs, pharmacists’ proposals and implemented interventions recorded between January 1st and September 1st 2012.

Main outcome measure

Frequencies of DRPs, intervention proposals, implemented interventions, and drugs involved.

Results

4,579 CMRs were analysed. On average 2.9 (SD 2.1) DRPs per review were identified. 4,123 (31 %) of the DRPs led to medication changes. Stopping a drug (16 %) was more frequent than starting a drug (8.1 %). Drugs related to cardiovascular risk management, diabetes and osteoporosis were most frequently involved.

Conclusion

This study is the largest analysis of pharmacists-initiated CMRs in the Netherlands to date. The findings demonstrate the potential to reduce medication-related errors through pharmacist involvements in complex pharmacotherapy and the positive impact on the quality of drug therapy through making necessary medication changes. The data also support the need for large-scale implementation of pharmacists-initiated CMRs in the presence of proper training programmes.     

Impact of Ranolazine on Clinical Outcomes and Healthcare Resource Utilization in Patients with Refractory Angina Pectoris

Background

Ranolazine is a novel antianginal medication approved for the treatment of chronic angina. There are only limited data concerning the efficacy of ranolazine in reducing healthcare resource utilization in patients with refractory angina pectoris.

Objective

The primary objective of this analysis was to evaluate the efficacy and safety of ranolazine in refractory angina pectoris. In addition, the impact of ranolazine on healthcare resource utilization was assessed.

Methods

Consecutive patients with refractory angina pectoris treated with ranolazine at two cardiology practices in the state of Nebraska were included in this analysis. The Canadian Cardiovascular Society (CCS) angina class and frequency and type of healthcare resource consumption were determined during the 12 months prior to and the 12 months after initiation of ranolazine.

Results

A total of 150 pts (64 % men) with a mean age of 66 ± 12 years were included in this analysis. All patients had previously undergone coronary revascularization. Nitrates, β-adrenoceptor antagonists (β-blockers), and calcium antagonists (calcium channel blockers) were being used in 83, 97, and 75 % of patients, respectively. During ranolazine treatment, a significant improvement in CCS angina class was observed, with 23 patients improving by one class and no patient experiencing a deterioration in functional class (p = 0.025). A total of 53 side effects occurred in 28 (19 %) patients receiving ranolazine. Of those patients with side effects, four required dose reduction and seven required drug discontinuation. The frequency of clinic visits and emergency room visits was lower during ranolazine treatment, but the differences in frequency were not significant. The number of patients hospitalized and the number of hospitalizations were significantly lower during ranolazine therapy than in the pre-ranolazine study period (p = 0.002).

Conclusion

Ranolazine improved the CCS angina class and reduced hospitalizations over a 12-month follow-up period in a group of patients with difficult-to-treat refractory angina pectoris.     

Recognition of adverse drug events in older hospitalized medical patients

Objective

To assess medical teams’ ability to recognize adverse drug events (ADEs) in older inpatients.

Methods

The study cohort comprised 250 patients aged 65 years or older consecutively admitted to Internal Medicine wards of three hospitals in the Netherlands between April and November 2007. An independent expert team identified ADEs present upon admission or occurring during hospitalization by a structured retrospective patient chart review. For all ADEs identified, the expert team assessed causality, severity, preventability, and recognition by medical teams.

Results

The medical teams did not recognize 19.9 % of all ADEs present upon admission {60.4 ADEs [95 % confidence interval (CI) 51.5–70.8] per 100 hospitalizations} and 20.3 % of all ADEs occurring during the hospital stay [47.2 ADEs (95 % CI 39.4–56.5) per 100 hospitalizations]. Unrecognized ADEs were significantly more often ADEs with possible causality (p=0.014, df=1), ADEs caused by medication errors (p<0.001, df=1), and ADEs not manifesting as new symptoms (p<0.001, df=1). The medical teams did not recognize 23.2 % of mild to moderately severe ADEs and 16.5 % of severe, life-threatening, or fatal ADEs. The recognition of ADEs varied with event type.

Conclusions

The recognition of ADEs by medical teams was substantial for those ADEs with evident causality and with clinically apparent and severe consequences. ADEs mimicking underlying pathologies with a lower severity went unrecognized much more often, as did those resulting only in abnormal laboratory values. Tools to improve the recognition of ADEs by medical teams should, therefore, focus on those ADEs that are more challenging to detect.     

Pilot study to assess the influence of an enhanced medication plan on patient knowledge at hospital discharge

Purpose

This study assessed the effect of providing an enhanced medication plan (EMP) to patients during patient-physician conversation at hospital discharge and evaluated its immediate impact on patient knowledge on pharmacotherapy.

Methods

We observed patient-physician conversations at hospital discharge in three internal medicine wards of the University Hospital Heidelberg before and after the EMP was integrated into the discharge process, and documented how and to what extent physicians provided the patients with drug information. After the conversation, the patients’ knowledge was evaluated by three standardized questions about their pharmacotherapy.

Results

We observed 90 conversations (50 before EMP-implementation, 40 after). In both phases, the conversation duration was 5.6–6 min (p?=?0.56). However, the time spent on drug information increased significantly by 61.7 % after EMP-implementation (+63 s, p?=?0.02). Before implementation, physicians gave at least one drug administration recommendation for 75.1 % of all drugs, compared to 84.6 % after implementation (p?=?0.02). The EMP provided information for almost all drugs (98.9 %; p?p?Conclusion The provision of an EMP improves information transfer and therefore increases the patients’ knowledge of their individual drug treatment without prolonging the overall discharge process.     

Use of the recommended drug combination for secondary prevention after a first occurrence of acute coronary syndrome in France

Purpose

The recommended pharmacotherapy for secondary prevention of acute coronary syndrome (ACS) is long-term treatment with a combination of four therapeutic classes: beta-blockers, antiplatelet agents (including aspirin), statins or other lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The aim of this study was to describe use and persistence of the recommended drug combination after the first occurrence of ACS in France.

Methods

This was a database cohort study of patients with first registration for ACS between 2004 and 2007 in a representative sample of the French healthcare insurance database (Echantillon Généraliste de Bénéficiaires, EGB). The drugs of interest were those recommended. Persistence was assessed for patients dispensed three or all four drug classes within 2 months following ACS. Discontinuation was defined by a gap of more than 6 weeks between two dispensations. The follow-up period was 24 months after ACS occurrence.

Results

Of 2,057 patients with incident ACS, 872 (42.4 %) had at least one dispensation of each of the four recommended drug classes, and 684 (33.3 %) had three of the four classes. Persistence to treatment at 24 months was 57.4 % (95 % CI [54.0-60.6]) for patients with four classes, and 55.5 % (95 % CI [51.6-59.1]) with three classes. Discontinuation of initial combination was higher in patients aged ?≥?65 years at ACS occurrence, those with associated ongoing chronic disease, and in those who did not suffer myocardial infarction.

Conclusions

Post-ACS secondary prevention in France is not optimal, especially in patients who did not have myocardial infarction.     

Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database

Purpose

Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs.

Methods

The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated.

Results

Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a ‘certain’ causality score (I4) and 13 (7.5 %) a ‘likely’ score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded.

Conclusion

This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.     

Off-label use of anticancer drugs in eastern Switzerland: a population-based prospective cohort study

Purpose

Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations.

Methods

We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines.

Results

A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma.

Conclusions

Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.     

Characterisation of non-warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system

Objective

The aim of the study was to analyse non-warfarin-associated bleeding adverse drug events reported to the Norwegian spontaneous reporting system, with characterisation of the bleeding locations, outcome and drug interactions. In addition, concordance in assessments between reporters and evaluators, trend shifts in reporting, and detection of potentially new adverse drug interaction signals were studied.

Methods

Data on bleeding events reported between 1 January 2003 and 31 December 2005 were retrieved from the Norwegian spontaneous reporting system database.

Results

Of 327 case reports of non-warfarin-associated bleeding events, 270 reports (82.6 %) were characterised as serious and 69 (21.1 %) had a fatal outcome. One hundred and eighty-seven bleeds (57.5 %) were gastrointestinal, 57 (17.4 %) were cerebral, and 81 (24.8 %) were from other bleeding sites. The bleeding sites differed with respect to the patient's age, drug use, diagnoses and outcomes. Of drugs associated with bleeding, nonsteroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors (145 reports) and acetylsalicylic acid (128 reports) were most frequently used. Only fibrinolytics were associated with increased mortality. There was a 67.4 % correlation between reporters and evaluators in assessment of drugs associated with bleeding (P?<?0.001), with considerable variation in concordance between drug groups.

Conclusion

Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers.     

Inappropriate crushing information on ward lists: cytotoxic drugs,capsules, and modified release formulations are gravely neglected

Purpose

The aim of this study was to assess the quality of the information sources on the modification of solid medication dosage forms (crushing, suspending) used on the wards of a large university hospital in Germany.

Methods

We performed on-site visits of all 79 wards of the hospital and collected available sources of information on the modification of solid medication dosage forms. To evaluate the quality of such information, we gathered reference information for each listed brand from the respective pharmaceutical company, transferred this information to a knowledge base, and classified it into three categories, i.e., modification not allowed, modification allowed, and modification allowed under certain circumstances.

Results

Twenty-two lists of information on drug modification were identified in the 79 wards. Each list contained errors, and on average 17.0 % (range 8.0–32.3 %) of the brands listed had been withdrawn from the market or the information on crushing and/or suspending was inappropriate. Most of the incorrect information either concerned brands containing ingredients that were potentially hazardous to the staff members who prepared the drugs or referred to special dosage forms such as capsules and modified release formulations (e.g., cytotoxic drugs).

Conclusion

We found that the lists posted on the wards were often outdated and did not take into account the limitations/problems of preparing drugs on the ward. Our results emphasize that lists posted in wards need to be checked regularly and that “ready-to-use” lists from third parties might require adaptation to site-specific conditions in order to protect healthcare staff from exposure to potentially hazardous drugs during drug preparation and ensure safe drug application to the patient.     

Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care

Rationale

Autism spectrum disorders (ASDs) affect 1 % of children, having significant impact on health and social outcomes. Psychotropic medication use by individuals with ASD in the USA increased over time, and polypharmacy occurred in >50 % of those prescribed. In the UK, no psychotropic drugs are approved in ASDs, and little is known about patterns of pharmacological treatment in the ASD population and associated co-morbidities.

Methods

We used The Health Improvement Network, a nationally representative primary care database, to assess the prevalence of ASD diagnoses, psychotropic drug prescribing and neuropsychiatric co-morbidities of 0–24 year olds between 1992 and 2008.

Results

ASD prevalence increased 65-fold from 0.01 % (1992) to 0.50 % (2008). Psychotropic drugs were prescribed to 29 % (1,619/5,651) of the ASD cohort; the most prescribed drugs were sleep medication (9.7 % of prescribed patients), psychostimulants (7.9 %) and antipsychotics (7.3 %). More patients were given psychostimulants and sleep medications over time from 1.5–6.3 % and 2.2–5.9 % respectively. Thirty-seven per cent of the cohort had ≥1 record of a neuropsychiatric co-morbidity, the most common being developmental difficulties and learning disabilities (12.6 %), behavioural, conduct and personality disorders (11.1 %) and attention deficit hyperactivity disorder (7.5 %).

Conclusions

British physicians are more conservative in prescribing practice than American colleagues. However, use of psychostimulants and antipsychotics is much higher in those with ASD than in the general population. Polypharmacy was seen in 34 % of prescribed patients in 2008. Additional studies examining use, efficacy, and long-term safety of antipsychotics and psychostimulants in autistic individuals are warranted.