Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy.

PURPOSE: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

The IMI PROTECT project: purpose, organizational structure, and procedures.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

Multi-centre, multi-database studies with common protocols: lessons learnt from the IMI PROTECT project.

PURPOSE: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. METHODS: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. RESULTS: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10 years and different types of cancer. CONCLUSIONS: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

Case-only designs for studying the association of antidepressants and hip or femur fracture.

PURPOSE: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. METHODS: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. RESULTS: Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. CONCLUSION: Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Antiepileptic drug use in seven electronic health record databases in Europe: a methodologic comparison.

OBJECTIVE: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries due to use of different type of data sources, time periods, population distribution, and methodologic differences. This study aimed to measure prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, The Netherlands, the United Kingdom, and Germany using a standardized methodology and to investigate sources of variation. METHODS: Analyses on the annual prevalence of AEDs were stratified by sex, age, and AED. Overall prevalences were standardized to the European 2008 reference population. RESULTS: Prevalence of any AED varied from 88 per 10,000 persons (The Netherlands) to 144 per 10,000 in Spain and Denmark in 2001. In all databases, prevalence increased linearly: from 6% in Denmark to 15% in Spain each year since 2001. This increase could be attributed entirely to an increase in "new," recently marketed AEDs while prevalence of AEDs that have been available since the mid-1990s, hardly changed. AED use increased with age for both female and male patients up to the ages of 80 to 89 years old and tended to be somewhat higher in female than in male patients between the ages of 40 and 70. No differences between databases in the number of AEDs used simultaneously by a patient were found. SIGNIFICANCE: We showed that during the study period of 2001-2009, AED prescribing increased in five European Union (EU) countries and that this increase was due entirely to the newer AEDs marketed since the 1990s. Using a standardized methodology, we showed consistent trends across databases and countries over time. Differences in age and sex distribution explained only part of the variation between countries. Therefore, remaining variation in AED use must originate from other differences in national health care systems.

Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom.

BACKGROUND: Atopic dermatitis (AD) has been associated with an increased risk of lymphoma. OBJECTIVES: To assess the risk of lymphoma associated with AD and use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI) in a database allowing medical record validation. METHODS: We conducted a nested-case control study using the United Kingdom-based The Health Improvement Network (THIN) database. We excluded patients with established risk factors for lymphoma. Cases of lymphoma were identified and classified after review of the medical records and hospital discharge files. RESULTS: In the study population of 3,500,194 individuals, we identified 2738 cases of lymphoma (1722 non-Hodgkin lymphoma [NHL], 466 Hodgkin disease, 550 indeterminate cases; overall, 188 had cutaneous involvement) and 10,949 matched controls. AD was associated with an increased lymphoma risk (odds ratio [OR], 1.83; 95% CI, 1.41-2.36). In patients with AD referred to a dermatologist, the OR further increased (OR, 3.72; 95% CI, 1.40-9.87). We did not find any cases of lymphoma in TCI users; however, the number of patients exposed to TCI was insufficient to study any possible association between lymphoma and these drugs. TCS use was associated with an increased lymphoma risk (OR, 1.46; 95% CI, 1.33-1.61). The risk increase was dependent on TCS potency (OR for high-potency TCS, 1.80; 95% CI, 1.54-2.11). The increased risk involved both Hodgkin disease and NHL, especially NHL with skin involvement (OR for high-potency TCS, 26.24; 95% CI, 13.49-51.07). CONCLUSION: Our results show an association between lymphoma-especially skin lymphoma-and use of TCS. The risk increased with duration of exposure and potency of TCS.

Topical treatments with pimecrolimus, tacrolimus and medium- to high-potency corticosteroids, and risk of lymphoma.

BACKGROUND/AIMS: A potential risk of lymphoma associated with the use of topical calcineurin inhibitors is debated. We assessed the risk of lymphoma among patients treated with topical pimecrolimus, tacrolimus or corticosteroids. METHODS: We conducted a cohort study using health insurance claims data. Cohorts of initiators of topical pimecrolimus, tacrolimus and corticosteroids, along with cohorts of persons with untreated dermatitis and randomly sampled enrollees were identified from January 2002 to June 2006. Lymphomas were identified using insurance claims and adjudicated by medical records review. We adjusted for confounders by propensity score matching. RESULTS: Among 92,585 pimecrolimus initiators contributing 121,289 person-years of follow-up, we identified 26 lymphomas yielding an incidence of 21/100,000 person-years. This incidence of lymphoma was similar to that among tacrolimus users (rate ratio, RR = 1.16; 95% confidence interval, CI = 0.74-1.82) as well as corticosteroid users (RR = 1.15; 95% CI = 0.49-2.72). All three topical treatments were associated with an increased risk of lymphoma compared with the general population (RR(Pim) = 2.89; RR(Tac) = 2.82; RR(Cort) = 2.10) suggesting increased detection of preexisting lymphomas. CONCLUSION: This study did not find an increased risk of lymphoma among initiators of topical pimecrolimus relative to other topical agents during an average follow-up of 1.3 years. Longer-term studies may be needed.

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA.

INTRODUCTION: Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce. OBJECTIVE: This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice. METHODS: This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders. RESULTS: We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4-4.5]. The incidence was higher in Black [6.2 (95% CI 3.1-12.5)] than in non-black [2.9 (95% CI 2.1-4.1)] patients, higher in women [5.2 (95% CI 3.4-7.9)] than in men [2.3 (95% CI 1.5-3.6)], and greatest in the first 30 days of ACEI therapy. CONCLUSIONS: The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.

Characteristics of early sacubitril/valsartan patients and considerations for studies in electronic health record data.

AIM: We examined characteristics of early sacubitril/valsartan users in a large US electronic health records database. PATIENTS & METHODS: We identified three cohorts of patients with heart failure (HF): sacubitril/valsartan patients with a prior HF diagnosis; patients with HF with reduced ejection fraction; and patients with HF treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a ß-blocker. RESULTS: Sacubitril/valsartan patients were younger than patients in the other cohorts; the mean age of sacubitril/valsartan patients increased by 2 years in the first 15 months of marketing. Most sacubitril/valsartan patients had prior use of HF treatment. CONCLUSION: Overall, sacubitril/valsartan patients resembled those in the HF with reduced ejection fraction cohort, and commonly used other drugs for HF.

Statins and the risk of pneumonia: a population-based, nested case-control study.

STUDY OBJECTIVE: To determine if the use of statins affects pneumonia-related outpatient visits, hospitalizations with survival, and deaths. DESIGN: Population-based, retrospective, nested case-control analysis. DATA SOURCE: United Kingdom-based General Practice Research Database. PARTICIPANTS: The study population (134,262 patients aged > or = 30 yrs) consisted of 55,118 patients who took statins and/or fibrates, 29,144 patients with hyperlipidemia not taking lipid-lowering agents, and 50,000 randomly selected patients without hyperlipidemia and without lipid-lowering treatment. MEASUREMENTS AND MAIN RESULTS: We identified 1253 patients with pneumonia and matched them with 4838 control subjects based on age, sex, general practice, and index date. After adjusting for comorbidity and frequency of visits to general practitioners, we calculated the risks (odds ratios with 95% confidence intervals) of uncomplicated pneumonia, hospitalization for pneumonia with survival, and fatal pneumonia in participants who used statins compared with those who did not. Current statin users had a significantly reduced risk of fatal pneumonia (adjusted odds ratio 0.47, 95% confidence interval 0.25-0.88) and slightly but not significantly reduced risks of uncomplicated pneumonia and pneumonia hospitalization with survival. Recent or past statin use and fibrate use at any time were not associated with a reduced risk of pneumonia. CONCLUSION: Current use of statins was associated with a reduced risk of pneumonia. The risk reduction was particularly strong in the subgroup of patients with fatal pneumonias.

Age-related differences in the prevalence of potential drug-drug interactions in ambulatory dyslipidaemic patients treated with statins.

BACKGROUND AND OBJECTIVE: Elderly patients may be at higher risk of drug-drug interactions (DDIs) because of polypharmacy. This study evaluated age-specific differences in the prevalence of clinically relevant potential DDIs (pDDIs) in ambulatory dyslipidaemic patients treated with an HMG-CoA reductase inhibitor (statin). We hypothesised that elderly patients are at higher risk for pDDIs because of the presence of more drugs and drugs with a higher potential for DDIs in this age group. METHODS: A total of 2742 dyslipidaemic ambulatory patients treated with a statin were included in this cross-sectional study. Drug treatment was screened for clinically relevant pDDIs using an electronic drug interaction program (DRUG-REAX System). RESULTS: The study sample consisted of 483 (17.6%) patients aged < or = 54 years, 732 (26.7%) aged 55-64 years, 924 (33.7%) aged 65-74 years and 603 (22.0%) patients aged > or = 75 years. Patients > or =75 years had significantly more pharmacologically active substances prescribed than patients aged < or =54 years (mean 5.8 vs 3.8, respectively; p < 0.001). Cardiovascular diseases such as coronary heart disease, heart failure or arrhythmias were also significantly more prevalent in patients aged > or = 75 years than in younger patients. The overall prevalence of pDDIs increased significantly from 7.9% in those aged < or = 54 years to 18.4% in patients aged > or = 75 years (p < 0.001). The frequency of both pDDIs associated with statins and non-statin pDDIs increased with age. Risk factors for pDDIs in patients aged > or = 75 years were arrhythmias, heart failure and the number of pharmacologically active substances prescribed. The more frequent prescription of cardiovascular drugs with a high potential for pDDIs (e.g. amiodarone and digoxin) in patients aged > or = 75 years was mainly responsible for the observed increases in statin and non-statin pDDIs in this age group. CONCLUSIONS: Compared with younger patients, elderly dyslipidaemic patients are at a higher risk for clinically relevant pDDIs, mainly because of a higher number of drugs prescribed. In addition, patients aged > or = 75 years were prescribed more drugs with a high potential for DDIs, especially drugs used for the treatment of arrhythmias and heart failure. The risk for adverse reactions associated with pDDIs may often be reduced by dose adjustment, close monitoring or selection of an alternative drug.

Angioedema Among Hypertensive Patients Treated with Aliskiren or Other Antihypertensive Medications in the United States.

BACKGROUND: A non-interventional study suggested that use of angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren was associated with an angioedema risk three times that of beta-blockers (BBs). OBJECTIVE: The aim was to assess angioedema incidence rates (IRs) and the relative angioedema risk of aliskiren compared to other antihypertensive drugs (AHDs). METHODS: A cohort study in hypertensive patients with an AHD prescription between 2007 and 2012 was conducted using data from the US PharMetrics Plus™ claims database. Angioedema was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code 995.1. Additionally, a nested case-control analysis was conducted to assess the relative angioedema risk of aliskiren or other AHDs versus BBs. RESULTS: A total of 3,090,114 patients were included (aliskiren n = 30,720). There were 15,744 angioedema events (IR 2.28/1000 person-years; 95% confidence interval (CI) 2.24-2.32). Aliskiren IRs were: any aliskiren 2.58 (2.08-3.17), aliskiren monotherapy 1.71 (0.74-3.37), aliskiren fixed-dose combination (FDC) 1.27 (0.41-2.96), and aliskiren free-standing combination (FSC) 2.93 (2.31-3.66). The case-control analysis included 15,100 angioedema cases and 60,400 controls; the angioedema risk for both aliskiren monotherapy and FDC was not significantly different from BBs [adjusted odds ratio (adjOR) 0.99 (95% CI 0.45-2.20) and 1.06 (0.40-2.76)]; aliskiren FSC was associated with an increased angioedema risk [adjOR 3.29 (2.42-4.48)], mainly driven by concomitant ACEI use [adjOR 7.03 (4.10-12.05)]. CONCLUSIONS: The IR and risk of angioedema in patients with aliskiren monotherapy or FDC are comparable to BBs. The higher IR and risk of angioedema identified in the aliskiren FSC group may largely be driven by the concomitant use of ACEIs.

The prevalence of potential drug-drug interactions in patients with heart failure at hospital discharge.

BACKGROUND/OBJECTIVE: Pharmacotherapy for heart failure is complex and, due to polypharmacy, is associated with a large risk of potential drug-drug interactions (DDIs). The objective of the present study was to assess the prevalence of potential DDIs in the medication of hospitalised heart failure patients and to evaluate their clinical relevance. STUDY DESIGN/METHODS: The medication of 400 patients was retrospectively analysed for potential DDIs at hospital admission and discharge using a computerised drug interaction program. Main inclusion criteria were the diagnosis of heart failure and a minimum of two drug prescriptions at discharge. RESULTS: In the study population of 400 heart failure patients (median age 79 years, 55.5% men), the median number of drugs per patient was lower at admission than at discharge (6 [interquartile range {IQR} 4-9] vs 8 [IQR 6-10]; p < 0.001). At hospital admission, a total of 863 potential DDIs were detected in 272 patients (68.0%; 95% CI 63.4, 72.6). At discharge, 1171 potential DDIs were detected in 355 patients (88.8%; 95% CI 85.7, 91.8). This corresponds with a significant increase in the median number of potential DDIs per patient from admission to discharge (1.5 [IQR 0-3] vs 3 [IQR 1-4]; p < 0.001). Of the 1171 potential DDIs at discharge, 432 (36.9%) were prevalent at admission and 739 (63.1%) resulted from a medication change during the hospital stay. Of these 739 new potential DDIs, the severity of the potential adverse effect was rated as 'major' in 190 (25.7%) patients, 'moderate' in 482 (65.2%) and 'minor' in 67 (9.1%). The 190 potential DDIs with major severity were recorded in a total of 145 patients (36.3%; 95% CI 31.5, 41.0%). Hyperkalaemia was the most prevalent potential adverse effect of major severity (n = 93) and the combination of an ACE inhibitor with a potassium-sparing diuretic was recorded in 64 (16.0%) patients. CONCLUSIONS: The study shows that hospitalisation of patients with heart failure results in an increase in the number of drugs prescribed per patient and, thereby, also in the number of potentially interacting drug combinations per patient. Although electronic drug interaction programs are a valuable tool to check for potential DDIs, the clinical relevance of most potential DDIs can only be judged by assessment of the individual patient.

Prevalence of potentially inappropriate medication use in elderly patients: comparison between general medical and geriatric wards.

BACKGROUND AND OBJECTIVE: Inappropriate drug use is one of the risk factors for adverse drug reactions in the elderly. We hypothesised that, in elderly patients, geriatricians are more aware of potentially inappropriate medications (PIMs) and may replace or stop PIMs more frequently compared with internists. We therefore evaluated and compared the prevalence of PIMs as well as anticholinergic drug use throughout hospital stay in elderly patients admitted to a medical or geriatric ward. METHODS: In this retrospective cross-sectional study, 800 patients aged > or =65 years admitted to a general medical or geriatric ward of a 700-bed teaching hospital in Switzerland during 2004 were included. PIMs were identified using the Beers criteria published in 2003. The prevalence of anticholinergic drug use was assessed based on drug lists published in the literature. RESULTS: The prevalence of use of PIMs that should generally be avoided was similar in medical and geriatric inpatients both at admission (16.0% vs 20.8%, respectively; p = 0.08) and at discharge (13.3% vs 15.9%, respectively; p = 0.31). In contrast to medical patients, the reduction in the prevalence of use of PIMs between admission and discharge in geriatric patients reached statistical significance (p < 0.05). Overall, the three most prevalent inappropriate drugs/drug classes were amiodarone, long-acting benzodiazepines and anticholinergic antispasmodics. At admission, the prevalence of use of PIMs related to a specific diagnosis was not significantly different between patients hospitalised to a medical or a geriatric ward (14.0% vs 17.5%, respectively; p = 0.17), as compared with the significant difference evident at hospital discharge (11.7% vs 23.7%, respectively; p < 0.001). This was largely because of a higher prescription rate of platelet aggregation inhibitors in combination with low-molecular-weight heparins and benzodiazepines in patients with a history of falls and syncope. The proportions of patients taking anticholinergic drugs in medical and geriatric patients at admission (13.0% vs 17.5%, respectively; p = 0.08) and discharge (12.2% vs 16.5%, respectively; p = 0.10) were similar. CONCLUSION: Inappropriate drug use as defined by the Beers criteria was common in both medical and geriatric inpatients. Compared with internists, geriatricians appear to be more aware of PIMs that should generally be avoided, but less aware of PIMs related to a specific diagnosis, and of the need to avoid anticholinergic drug use. However, the results of this study should be interpreted with caution because some of the drugs identified as potentially inappropriate may in fact be beneficial when the patient's clinical condition is taken into consideration.

Corticosteroid-associated tendinopathies: an analysis of the published literature and spontaneous pharmacovigilance data.

INTRODUCTION AND OBJECTIVE: Corticosteroids may cause tendinopathies, an adverse effect that is not well known and characterised, although it was initially described more than 40 years ago. This study was conducted in order to characterise the important aspects of this adverse reaction, such as the role played by routes of corticosteroid administration, therapy duration, comedication, cumulative corticosteroid dose and underlying disease. STUDY DESIGN AND METHODS: Published case reports of tendinopathies that were associated with corticosteroid use were identified by a comprehensive literature search using the databases MEDLINE, Pharm-line, EMBASE, ToxFile, Adis Inpharma, International Pharmaceutical Abstracts, Drug Information Fulltext and PASCAL. The reference lists of all pertinent articles were cross-referenced to retrieve additional cases. Spontaneous reports were requested from the Uppsala Monitoring Centre (the WHO Collaborating Centre for International Drug Monitoring). Information of published and spontaneous reports was analysed with regard to age, sex, underlying disease, individual corticosteroids, equivalent corticosteroid dose, latency time, cumulative dose, route of administration, comedication and type of tendinopathy. RESULTS: We included and analysed 73 published case reports and case series involving 133 patients and 191 spontaneous reports of corticosteroid-associated tendinopathies. The proportion of women with tendinopathies was 50.8% and 41.0%, respectively. The mean age (+/- standard deviation) of patients with a tendinopathy was 50 +/- 17 years and 61 +/- 16 years, respectively. The predominant routes of administration were oral (33% of published cases and 47% of spontaneous cases) and intra-articular (35% of the published cases or parenteral (7% of the spontaneous cases). There were isolated cases of tendinopathy after inhaled or topical (i.e. ocular, cutaneous, nasal) corticosteroid use. Tendinopathies that were reported in the literature cases consisted mainly of tendon ruptures (93%), predominantly of the Achilles tendon. Of the spontaneous cases, 31% had a rupture and the remaining cases had a tendinitis or an unspecified tendon disorder. CONCLUSION: Oral and parenteral applications, especially intra-articular use, were the most prevalent routes of administration in cases with corticosteroid-associated tendinopathies. However, topical application has also been rarely associated with tendinopathies. Future pharmacoepidemiological studies should further address this issue to quantify the risk of corticosteroid-associated tendinopathies.

Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy.

BACKGROUND: Drug-drug interactions (DDIs) are a well known risk factor for adverse drug reactions. HMG-CoA reductase inhibitors ('statins') are a cornerstone in the treatment of dyslipidaemia and patients with dyslipidaemia are concomitantly treated with a variety of additional drugs. Since DDIs are associated with adverse reactions, we performed a cross-sectional study to assess the prevalence of potentially critical drug-drug and drug-statin interactions in an outpatient adult population with dyslipidaemia. METHODS: Data from patients with dyslipidaemia treated with a statin were collected from 242 practitioners from different parts of Switzerland. The medication list was screened for potentially harmful DDIs with statins or other drugs using an interactive electronic drug interaction program. RESULTS: We included 2742 ambulatory statin-treated patients (mean age +/- SD 65.1 +/- 11.1 years; 61.6% males) with (mean +/- SD) 3.2 +/- 1.6 diagnoses and 4.9 +/- 2.4 drugs prescribed. Of those, 190 patients (6.9%) had a total of 198 potentially harmful drug-statin interactions. Interacting drugs were fibrates or nicotinic acid (9.5% of patients with drug-statin interactions), cytochrome P450 (CYP) 3A4 inhibitors (70.5%), digoxin (22.6%) or ciclosporin (cyclosporine) [1.6%]. The proportion of patients with a potential drug-statin interaction was 12.1% for simvastatin, 10.0% for atorvastatin, 3.8% for fluvastatin and 0.3% for pravastatin. Additionally, the program identified 393 potentially critical non-statin DDIs in 288 patients. CONCLUSIONS: CYP3A4 inhibitors are the most frequent cause of potential drug interactions with statins. As the risk for developing rhabdomyolysis is increased in patients with drug-statin interactions, clinicians should be aware of the most frequently observed drug-statin interactions and how these interactions can be avoided.

Current use of nonsteroidal antiinflammatory drugs and the risk of acute myocardial infarction.

STUDY OBJECTIVE: To evaluate the risk of acute myocardial infarction during current exposure to nonsteroidal antiinflammatory drugs (NSAIDs). DESIGN: Retrospective case-control analysis. SETTING: General practice offices. SUBJECTS: A total of 8688 case patients, aged 89 years or younger, with a first-time acute myocardial infarction and 33,923 control subjects matched on age, sex, calendar time, and general practice attended. INTERVENTION: The United Kingdom General Practice Research Database was searched for potential cases of first-time acute myocardial infarction between January 1995 and April 2001. Control subjects without acute myocardial infarction were identified at random. MEASUREMENTS AND MAIN RESULTS: Exposure to NSAIDs was assessed, and 650 case patients and 2339 control subjects were found to be currently taking NSAIDs. After adjusting for various risk factors for acute myocardial infarction (e.g., hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, body mass index, smoking), the relative risk (expressed as odds ratio [OR]) of acute myocardial infarction was 1.07 (95% confidence interval [CI] 0.96-1.19) for subjects with current NSAID exposure compared with those not taking NSAIDs. The adjusted OR for current diclofenac use was 1.23 (95% CI 1.00-1.51), for current ibuprofen use 1.16 (95% CI 0.92-1.46), and for current naproxen use 0.96 (95% CI 0.66-1.38) compared with those not taking NSAIDs. Current aspirin use combined with current NSAID use was associated with a statistically significant risk reduction (adjusted OR 0.74, 95% CI 0.57-0.97), compared with nonuse of NSAIDs and aspirin. Current use of aspirin together with current use of ibuprofen yielded an adjusted OR of 0.69 (95% CI 0.42-1.15). CONCLUSIONS: Our results provide additional evidence that the risk of first-time acute myocardial infarction during current use of NSAIDs is not materially altered. We found no evidence for a reduced cardioprotective effect of aspirin with concomitant NSAID use.

Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction.

BACKGROUND: Systemic inflammation has been shown to be associated with an increased risk of acute myocardial infarction (AMI). However, the effect of the use of nonsteroidal anti-inflammatory drugs (NSAIDs) on the risk of AMI has not yet been well defined. We therefore studied the risk of AMI during NSAID exposure and after the cessation of NSAID therapy. METHODS: We conducted a large case-control analysis on the British General Practice Research Database. The study included 8688 cases with a first-time AMI between 1995 and 2001 and 33 923 controls, matched to cases on age, sex, calendar time, and general practice attended. RESULTS: After adjusting for hypertension, hyperlipidemia, diabetes mellitus, ischemic heart disease, rheumatoid arthritis, systemic lupus erythematosus, acute chest infection, body mass index, smoking, and aspirin use, the risk of AMI was 1.52 (95% confidence interval [CI], 1.33-1.74) for subjects who stopped taking NSAIDs 1 to 29 days prior to the index date, compared with nonusers. The risk was highest in subjects with rheumatoid arthritis or systemic lupus erythematosus (adjusted OR, 3.68 [95% CI, 2.36-5.74]) and for subjects who discontinued therapy with NSAIDs after previous long-term use (adjusted OR, 2.60 [95% CI, 1.84-3.68]). Current and past NSAID use (discontinued therapy >/=60 days prior to the index date) were not associated with an increased risk of AMI (adjusted OR, 1.07 [95% CI, 0.96-1.19] and 1.05 [95% CI, 0.99-1.12], respectively). CONCLUSION: Our findings suggest that the risk of AMI is increased during several weeks after the cessation of NSAID therapy.