Showing papers in "Pharmacoepidemiology and Drug Safety in 2007"

The new Swedish Prescribed Drug Register—Opportunities for pharmacoepidemiological research and experience from the first six months

Abstract: The new Swedish Prescribed Drug Register-Opportunities for pharmacoepidemiological research and experience from the first six months.

Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research

Abstract: Background The Health Improvement Network (THIN) is a new medical records database that contains records from general practices some of which have or continue to participate in the General Practice Research Database (GPRD) and others that never participated in GPRD. We sought to replicate in THIN well-established associations from the medical literature and to compare results from the GPRD practices to the non-GPRD practices within THIN. Methods Using THIN data from 1986–2003, we conducted case-control studies of associations between diseases (e.g., hypertension and stroke) and between diseases and drugs (e.g., aspirin and colon cancer). Conditional logistic regression was used to calculate odds ratios adjusted for potential confounders. Differences between GPRD and non-GPRD practices were assessed by testing for a statistical interaction by practice type in each outcome-exposure association. Results We observed the expected positive associations (p < 0.05) of stroke with hypertension and diabetes mellitus; of myocardial infarction with hypertension, hypercholesterolemia, obesity, and smoking; and of peptic ulcer disease with aspirin, NSAIDs, and potassium. We observed the expected negative associations (p < 0.05) of colorectal cancer with aspirin, NSAIDs, and cox-2 inhibitors. The expected protective effect of aspirin use for myocardial infarction was not observed. In all cases, the results obtained from the GPRD practices were similar to the results obtained from the non-GPRD practices, only being statistically different for the associations of myocardial infarction with diabetes and aspirin use. Conclusions THIN data that are collected outside of the GPRD appear as valid as the data collected as part of the GPRD. Copyright © 2006 John Wiley & Sons, Ltd.

Immortal time bias in observational studies of drug effects

Abstract: Purpose Recent observational studies suggest that various drugs are remarkably effective at reducing morbidity and mortality. These cohort studies used a flawed approach to design and data analysis which can lead to immortal time bias. We describe the bias from 20 of these studies and illustrate it by showing that unrelated drugs can be made to appear effective at treating cardiovascular disease (CVD). Methods The illustration used a cohort of 3315 patients, with chronic obstructive pulmonary disease (COPD), identified from the Saskatchewan Health databases, hospitalised for CVD and followed for up to a year. We used the biased approach to assess the effect of two medications, namely gastrointestinal drugs (GID) and inhaled beta-agonists (IBA), both unknown to be effective in CVD, on the risk of all-cause mortality. We also estimated these effects using the proper person-time approach. Results Using the inappropriate approach, the rates ratios of all-cause death were 0.73 (95%CI: 0.57–0.93), with IBA and 0.78 (95%CI: 0.61–0.99), with GID. These rate ratios became 0.98 (95%CI: 0.77–1.25) and 0.94 (95%CI: 0.73–1.20), respectively, with the proper person-time analysis. Conclusions Several recent observational studies used a flawed approach to design and data analysis, leading to immortal time bias, which can generate an illusion of treatment effectiveness. Observational studies, with surprising beneficial drug effects should be re-assessed to account for this source of bias. Copyright © 2007 John Wiley & Sons, Ltd.

Hospitalisations and emergency department visits due to drug–drug interactions: a literature review

Abstract: Purpose Our objective was to evaluate the incidence of adverse patient outcomes due to drug–drug interactions (D–DIs), the type of drugs involved and the underlying reason. As a proxy for adverse patient outcomes, emergency department (ED) visits, hospital admissions and re-hospitalisations were assessed. Methods A literature search in the Medline and Embase database (1990–2006) was performed and references were tracked. An overall cumulative incidence was estimated by dividing the sum of the cases by the sum of the study populations. Results Twenty-three studies were found assessing the relationship between D–DIs and ED-visits, hospitalisations or re-hospitalisations. The studies with a large study size showed low incidences and vice versa. D–DIs were held responsible for 0.054% of the ED-visits, 0.57% of the hospital admissions and 0.12% of the re-hospitalisations. In the elderly population, D–DIs were held responsible for 4.8% of the admissions. Drugs most often involved were NSAIDs and cardiovascular drugs. The reasons for admissions or ED-visits, which were most often found were GI-tract bleeding, hyper- or hypotension and cardiac rhythm disturbances. Conclusion This review provides information on the overall incidence of D–DIs as a cause of adverse patient outcomes, although there is still uncertainty about the impact of D–DIs on adverse patient outcomes. Our results suggest that a limited number of drugs are involved in the majority of cases and that the number of reasons for admission as a consequence of D–DIs seems to be modest. Copyright © 2006 John Wiley & Sons, Ltd.

Trends in psychotropic medication use among U.S. adults

Abstract: Purpose To examine trends and prevalence of prescription psychotropic medication use among noninstitutionalized US adults. Methods Prescription medication data from the third National Health and Nutrition Examination Survey (NHANES; 1988–1994; n = 20 050) and the 1999–2002 NHANES (n = 12 060), two nationally representative cross-sectional health examination surveys, were examined for persons aged ≥17 years. Results The age-adjusted prevalence of psychotropic medication use increased from 6.1% in 1988–1994 to 11.1% in 1999–2002 (p < 0.001). This was due to more than a three-fold increase in antidepressant use (2.5%, 1988–1994 vs. 8.1%, 1999–2002 (p < 0.001)). Significant increases between time periods for antidepressant use were seen for all age, gender, and race-ethnic groups although increases were less pronounced for males than females and non-Hispanic blacks and Mexican Americans than non-Hispanic whites. Prevalence of use remained relatively constant from 1988–1994 to 1999–2002 for anxiolytic/sedative/hypnotic (ASH) medications (3.5–3.8%), antipsychotics (0.8–1.0%), and antimanic agents (0.3–0.4%). The age-adjusted prevalence of multiple psychotropic medication use increased from 1.2% in 1988–1994 to 3.1% in 1999–2002 (p < 0.001). Conclusions Psychotropic medication use among US adults increased since 1988–1994, specifically of antidepressants. Increases varied by gender and race-ethnicity indicating under-utilization for non-Hispanic blacks and Mexican Americans compared to non-Hispanic whites for both males and females. Published in 2007 by John Wiley & Sons, Ltd.

Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations.

Abstract: Background Exposure to Benzodiazepines (BZD) during foetal life has been suggested to contribute to neonatal morbidity and some congenital malformations, for example, orofacial clefts. Here we aimed to study the neonatal outcome and congenital malformations in neonates whose mothers reported use of BZD and/or hypnotic benzodiazepine receptor agonists (HBRA) during pregnancy. Methods In the Swedish Medical Birth Register we identified 1979 infants whose mothers (n = 1944) reported use of BZD and/or HBRA in early pregnancy. An additional 401 infants were studied, born to 390 mothers who were prescribed such drugs during late pregnancy. Neonatal outcome including congenital malformations after exposure was compared with that of all births (n = 873 879). Results An increased risk for preterm birth and low birth weight was detected in the exposed population. The rate of relatively major congenital malformations was moderately increased among infants exposed in early pregnancy (adjusted OR = 1.24, 95%CI 1.00-1.55), not explained by known teratogenic maternal co-medication. A higher than expected number of infants with pylorostenosis or alimentary tract atresia (especially small gut) was found. This was, however, based on only seven infants for each group of malformation without association to any specific BZD or HBRA. The earlier proposed increased risk for orofacial clefts was not confirmed in our study. Conclusions Maternal use of BZD and/or HBRA may increase the risk for preterm birth and low birth weight and cause neonatal symptoms, but does not appear to have a strong teratogenic potential. The tentative association with pylorostenosis and alimentary tract atresia needs confirmation. Copyright (C) 2007 John Wiley & Sons, Ltd. (Less)

Relationship between therapeutic use and abuse of opioid analgesics in rural, suburban, and urban locations in the United States

Abstract: SUMMARY Purpose The goal of these studies was to determine the relationship between prescribed use of opioid analgesics and their non-medically related use (abuse) at a regional level across the country. Methods To gather information about prescription drug abuse, we asked 233 drug abuse treatment specialists to provide us Quarterly reports on the number of cases of prescription opioid analgesic abusers who used opioid analgesics to get high in the past 30 days. Results and Conclusions We found that there was a very strong correlation between therapeutic exposure to opioid analgesics, as measured by prescriptions filled, and their abuse. There were, however, geographical loci that represented outliers in which abusewas disproportionately high relative to therapeutic use (>95th percentile), most of which were invery small urban, suburban, and rural areas. The rank order of abuse shows that buprenorphine products, extended release (ER) oxycodone and methadone are the most intensely abused prescription opioid analgesics, with hydrocodone the least abused, when the data are corrected for degree of exposure, i.e., cases/1000 persons filling a prescription. If, on the other hand, one uses the number of cases/100000 population, hydrocodone ranked as high as ER oxycodone and all other drugs grouped together at very low levels of abuse. Since the latter conclusion ignores therapeutic exposure, we conclude that the rate of abuse of highly efficacious opioid analgesics is best expressed as cases of abuse/1000 persons filling a prescription, which yields the best possible estimate of the risk-benefit ratio of these drugs. Copyright # 2007 John Wiley & Sons, Ltd. key words—risk management; risk-benefit; post-marketing surveillance; drug abuse; drug diversion; opioid analgesics;

Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy.

Abstract: Purpose To evaluate risks for perinatal complications and congenital defects among infants exposed in utero to antidepressants. Methods We identified 2201 women who were prescribed an antidepressant during pregnancy and who delivered an infant within one of five large managed care organizations (HMO). Prescription drug dispensings and inpatient and outpatient diagnoses were obtained from automated databases at each HMO. Antidepressants were categorized into tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), and medication timing was assessed by trimester. Rates of congenital anomalies or perinatal complications were compared to infants whose mothers were not prescribed antidepressants during pregnancy. Results Infants exposed to SSRIs or TCAs during pregnancy had a significant increase in preterm delivery risk. Fullterm infants exposed to SSRIs during the third trimester had an increased risk for respiratory distress syndrome, endocrine and metabolic disturbances, hypoglycemia, temperature regulation disorders, and convulsions. Third-trimester exposure to TCAs was also associated with an increased risk for respiratory distress syndrome, endocrine and metabolic disturbances, and temperature regulation disorders. There were 182 infants exposed to Paroxetine, and these infants did not have an increased risk of cardiac septal defects. Conclusions SSRIs and TCAs did not show a consistent link with congenital anomalies. Paroxetine exposure was not linked with an increased risk for cardiovascular anomalies, although our study power to detect a moderate increase in risk was limited. Infants exposed to antidepressants were at increased risk for preterm delivery. Both SSRIs and TCAs used during the third trimester appeared to increase the risk for perinatal complications and their use should be managed carefully among pregnant women with depression. Copyright © 2007 John Wiley & Sons, Ltd.

Paroxetine in the first trimester and the prevalence of congenital malformations.

Abstract: Purpose To refine a preliminary analysis identifying a possibly increased prevalence of malformations among infants born to women exposed to paroxetine in the first trimester. Methods This study used data from UnitedHealthcare, a large U.S. insurer, using datasets originally for a study of bupropion in pregnancy. We identified women with a live-born delivery between January 1995 and September 2004. We classified women according to their first trimester mono- or mono/polytherapy exposure to paroxetine and other antidepressants. We confirmed malformation cases by medical record abstraction. We calculated the adjusted odds ratios (AORs) through logistic regression. Results For paroxetine, there were 815 infants among 791 women exposed as monotherapy, and 1020 infants among 989 women exposed as mono- or polytherapy. For other antidepressants, there were 4198 infants among 4072 women exposed as monotherapy, and 4936 infants among 4767 women exposed as mono- or polytherapy. AORs for all congenital malformations associated with paroxetine were 1.89 (95%CI 1.20–2.98) for monotherapy, and 1.76 (95%CI 1.18–2.64) for mono- or polytherapy. AORs for cardiovascular malformations associated with paroxetine were 1.46 (95%CI 0.74–2.88) for monotherapy, and 1.68 (95%CI 0.95–2.97) for mono- or polytherapy. Conclusions These more detailed paroxetine findings confirm previous findings of analyses of these data among women exposed to all types of antidepressants. The present findings are consistent with other recent results suggesting the possibility of a modestly increased occurrence of congenital malformations following first trimester exposure to paroxetine compared to other antidepressants. Copyright © 2007 John Wiley & Sons, Ltd.

Reliability evaluation of the adapted National Coordinating Council Medication Error Reporting and Prevention (NCC MERP) index

Abstract: Purpose Adapted National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Index criteria were used in a study undertaken to evaluate commercial computerized provider order entry (CPOE) system impact on community hospital medication errors. This article describes: (1) adaptation of the Index, (2) classification criteria and processes used to assess the adapted Index, and (3) inter-rater reliability results. Methods A random sample of 130 (17%) of 2251 medication safety events (MSEs) were classified based on event type, that is, adverse drug event (ADE) or potential ADE (PADE); preventability, that is, ‘yes’ or ‘no,’ and outcome severity. Event outcome severity was categorized using adapted Index categories E–I (ADEs) and B–D (PADEs). Decision rules were used for rule-based classification, while an MSE Case Review Panel used judgment-based classification when decision rules did not apply. Inter-rater reliability for both classification approaches was assessed with kappa coefficients, percentage agreement, and confidence intervals (CI). Results Level of agreement was substantial for both rule-based and judgment-based MSE classification for event type (6 = 0.70–0.90), preventability (6 = 0.67–0.82), and decision rule application (6 = 0.79). Rule-based agreement for ADE and PADE severity was almost perfect for discrete (6 = 0.83–0.84) and combined (6 = 0.87–0.90) Index categories. Judgment-based agreement was substantial for discrete (6 = 0.63–0.67) and combined (6 = 0.66–0.84) Index categories. Conclusions The adapted Index yielded substantial agreement for event type, preventability, and severity. Adaptation of the Index to support classification of non-preventable ADEs was an important improvement. Copyright © 2007 John Wiley & Sons, Ltd.

Application of lag-time into exposure definitions to control for protopathic bias.

Abstract: Purpose To control for protopathic bias, some studies have incorporated the concept of lag-time into their exposure definition (time period before the index date that was not considered in assessing exposure). The objective of this study was to introduce a procedure to identify the best lag-time to be applied in studies where control for protopathic bias is required. Methods We used data from a case-control study carried out to assess the association between exposure to proton pump inhibitors (PPIs) and risk of gastric cancer, using RAMQ databases. Exposure was defined as the number of defined daily doses of PPIs dispensed during the 5-year period prior to the index date (divided into four quartiles). Thirty-one different lag-times were applied (0–30 months) based on 1-month intervals. Logistic regression was used to estimate the matched odds ratio (OR) for each lag-time. The change point in the ln(ORs) was identified by applying a two-compartmental model and a segmented regression model. Results A trend of decreasing ORs was found with the application of an increasing lag-time. As an illustration, the ORs for the 1st quartile of defined daily doses, when applying the 31 different lag-times, ranged between 3.52 when applying a 0 lag-time and 0.97 when applying a 30 months lag-time. Applying the two methods for the different lag-times showed that the ORs stabilized at around 6 months. Conclusion For the purpose of controlling for protopathic bias in pharmacoepidemiological studies, we have provided a method to assess the most appropriate lag-time that should be applied for the assessment of drug exposure. Copyright © 2007 John Wiley & Sons, Ltd.

Attitudes, beliefs and knowledge concerning antibiotic use and self-medication: a comparative European study

Abstract: Purpose Although the relevance of cultural factors for antibiotic use has been recognized, few studies exist in Europe. We compared public attitudes, beliefs and knowledge concerning antibiotic use and self-medication between 11 European countries. Methods In total, 1101 respondents were interviewed on their attitudes towards appropriateness of self-medication with antibiotics and situational use of antibiotics, beliefs about antibiotics for minor ailments, knowledge about the effectiveness of antibiotics on viruses and bacteria and awareness about antibiotic resistance. To deal with the possible confounding effect of both use of self-medication and education we performed stratified analyses, i.e. separate analyses for users and non-users of self-medication, and for respondents with high and low education. The differences between countries were considered relevant when regression coefficients were significant in all stratum-specific analyses. Results Respondents from the UK, Malta, Italy, Czech Republic, Croatia, Israel and Lithuania had significantly less appropriate attitudes, beliefs or knowledge for at least one of the dimensions compared with Swedish respondents. The Dutch, Austrian and Belgian respondents did not differ from Swedish for any dimension. Conclusions The most pronounced differences were for awareness about resistance, followed by attitudes towards situational use of antibiotics. Awareness about antibiotic resistance was the lowest in countries with higher prevalence of resistance. Copyright (C) 2007 John Wiley & Sons, Ltd.

Bupropion in pregnancy and the prevalence of congenital malformations.

Abstract: Purpose Reports from the GlaxoSmithKline Bupropion Pregnancy Registry suggested an increase in cardiovascular defects following exposure to bupropion during pregnancy. We conducted a study of congenital malformations among infants born to women exposed to bupropion during their first trimester. Methods The study used data from UnitedHealthcare between January 1995 and September 2004. We calculated the prevalence of all congenital malformations and cardiovascular malformations associated with bupropion exposure in the estimated first trimester (1213 infants), compared with (1) other antidepressant exposure in the first trimester (4743 infants) and (2) bupropion exposure outside the first trimester (1049 infants). Malformation cases were confirmed through medical record abstraction. We calculated adjusted odds ratios (AORs) using the GEE form of logistic regression. Results For all congenital malformations, the prevalence associated with bupropion first trimester was 23.1 per 1000 infants. The AORs were 0.95 (95%CI 0.62–1.45) and 1.00 (95%CI 0.57–1.73) in comparison to other antidepressants (prevalence 23.2 per 1000) and bupropion outside the first trimester (prevalence 21.9 per 1000), respectively. For cardiovascular malformations, the prevalence associated with bupropion first trimester was 10.7 per 1000 infants. The AORs were 0.97 (95%CI 0.52–1.80) and 1.07 (95%CI 0.48–2.40) in comparison to other antidepressants (prevalence 10.8 per 1000) and bupropion outside the first trimester (prevalence 9.5 per 1000), respectively. Conclusions Results do not support a hypothesis of a teratogenic effect of first trimester bupropion exposure. The prevalence of malformations associated with bupropion exposure in the first trimester was not increased relative to the comparison groups. Copyright © 2006 John Wiley & Sons, Ltd.

Early detection of adverse drug events within population-based health networks: application of sequential testing methods.

Abstract: Purpose Active surveillance of population-based health networks may improve the timeliness of detection of adverse drug events (ADEs). Active monitoring requires sequential analysis methods. Our objectives were to (1) evaluate the utility of automated healthcare claims data for near real-time drug adverse event surveillance and (2) identify key methodological issues related to the use of healthcare claims data for real-time drug safety surveillance. Methods We assessed the ability to detect ADEs using historical data from nine health plans involved in the HMO Research Network's Center for Education and Research on Therapeutics (CERT). Analyses were performed using a maximized sequential probability ratio test (maxSPRT). Five drug-event pairs representing known associations with an ADE and two pairs representing ‘negative controls’ were analyzed. Results Statistically significant (p < 0.05) signals of excess risk were found in four of the five drug-event pairs representing known associations; no signals were found for the negative controls. Signals were detected between 13 and 39 months after the start of surveillance. There was substantial variation in the number of exposed and expected events at signal detection. Conclusions Prospective, periodic evaluation of routinely collected data can provide population-based estimates of medication-related adverse event rates to support routine, timely post-marketing surveillance for selected ADEs. Copyright © 2007 John Wiley & Sons, Ltd.

Antibiotic use in ambulatory care in Europe (ESAC data 1997-2002): trends, regional differences and seasonal fluctuations

Abstract: Purpose The ESAC project (European Study on Antibiotic Consumption) aims to collect antibiotic-use data through a European network of national surveillance systems. This paper reports on the retrospective data collection in ambulatory care for the period 1997–2002. Methods Valid data of antibiotic consumption of 24 European countries for 2002 and of 18 countries for the entire 6-year period was classified according to the Anatomical Therapeutic Chemical Classification (ATC) and expressed in defined daily dose (DDD) per 1000 inhabitants per day (DID). Overall and subgroup comparison of antibiotic consumption over time as well as between geographical clusters was performed. Results Total use of antibiotics in Europe remained at a median level of 20 DID in the period 1997–2002 with a wide variation between countries ranging from 9.8 DID in The Netherlands to 32.2 DID in France. A substantial increase in subclass consumption of co-amoxiclav and fluoroquinolones was noted while the use of narrow-spectrum penicillins, erythromycin, quinolones and sulfonamides decreased. Total consumption as well as seasonal fluctuations showed remarkable geographical clustering with low consumption and low variation between summer and winter in the North, high consumption patterns in the South and a mixed model in the East. Conclusions Within the ESAC project, valid time series of antibiotic-use data are publicly available now, enabling to improve the study of determinants of use, the evaluation of governmental antibiotic consumption policies and the investigation of the associated emergence of antibiotic resistance. Copyright © 2006 John Wiley & Sons, Ltd.

Reporting of adverse drug reactions: predictors of under-reporting in Malaysia.

Abstract: Background Malaysia like many other countries worldwide uses spontaneous reporting systems as a mean of collecting data on suspected adverse drug reaction (ADR). However, compared to other countries, which use the system, the reporting rate in Malaysia is very low. Why some physicians do not report ADRs is not well understood. Objective To identify factors, which would predict physicians' failure to send ADR reports. Design and Setting Face-to-face interview using a structured questionnaire involving physicians working at the University of Malaya Medical Centre, Malaysia. Results About a third of the physicians in the Centre participated. Sixty-five of the 415 approached refused to participate. A high proportion of the respondents (81.4%) indicated that they had suspected an ADR but did not report it, while about 40% of the respondents were not aware of the existence of the national reporting system in Malaysia. Logistic regression modelling identified the variable ‘ADR considered to be too trivial or too well known to report’ as the strongest predictor of not reporting, followed by physicians' category and uncertainty that the reaction had been definitely caused by a drug. Conclusion Important predictor variables, which limit physicians from reporting ADR in Malaysia, were related to uncertainty of types of reaction to report, lack of awareness about the existence, function and purpose of national ADR reporting. The findings could be useful for planning strategies to improve the reporting rate. Copyright © 2006 John Wiley & Sons, Ltd.

Data mining for signals in spontaneous reporting databases: proceed with caution.

Abstract: Purpose To provide commentary and points of caution to consider before incorporating data mining as a routine component of any Pharmacovigilance program, and to stimulate further research aimed at better defining the predictive value of these new tools as well as their incremental value as an adjunct to traditional methods of post-marketing surveillance. Methods/Results Commentary includes review of current data mining methodologies employed and their limitations, caveats to consider in the use of spontaneous reporting databases and caution against over-confidence in the results of data mining. Conclusions Future research should focus on more clearly delineating the limitations of the various quantitative approaches as well as the incremental value that they bring to traditional methods of pharmacovigilance. Copyright © 2006 John Wiley & Sons, Ltd.

A quantitative approach to benefit-risk assessment of medicines - part 1: the development of a new model using multi-criteria decision analysis.

Abstract: Purpose One of the most important uses of benefit-risk assessment pertains to approval of new medicines by regulatory authorities and the subsequent review of these products during their life-cycle when new safety and/or efficacy data becomes available. At present, there exist no validated, well-accepted models for benefit-risk assessment that have the appropriate degree of sophistication, and as a consequence no models are widely used by regulatory authorities or industry. The aim of the study was therefore to develop a new model for benefit-risk assessment of medicines using multi-criteria decision analysis (MCDA). Methods The MCDA methodology was used for a systematic approach to assess the benefit risk ratio of medicines. The reasons for adopting this approach were (1) taking multiple benefit and risk criteria into account, (2) making a judgement on the evidence and potential uncertainty because of the incompleteness of evidence, and (3) making trade-offs of the benefits against risks. Results It was demonstrated through a seven-step approach how MCDA is used to construct the model. Ten benefit and ten risk criteria were identified to form a value tree. Then fixed scales were established for all criteria and options on the criteria were scored. Weights were assigned for each criteria using swing-weighting. Finally sensitivity analysis was carried. Conclusions This novel approach based on MCDA has the potential for being applied as a new tool for judging and deciding on the benefits and risks, thereby helping regulators and industry in the development and approval of new medicines and their adequate use. Copyright (C) 2007 John Wiley & Sons, Ltd.

Coronary heart disease outcomes in patients receiving antidiabetic agents.

Abstract: Background There is conflicting evidence on the reduction of cardiovascular risk in diabetic patients treated with oral antidiabetic agents. Objectives To compare the risk of myocardial infarction (MI) and coronary revascularization (CR) in type 2 diabetic patients treated with rosiglitazone, metformin, or sulfonylurea. Methods Using data from a large US insurer, we created propensity-matched cohorts. We identified hospitalizations for MI or CR. We calculated incidence rates and 95% confidence intervals for the outcomes and estimated risks from Cox proportional hazards models. Results We identified 26,931 initiators of monotherapy, 4,086 initiators of dual-therapy, and 2,346 initiators of combination with insulin therapy. There was no difference between the risk of the composite outcome with rosiglitazone monotherapy compared to metformin monotherapy (HR 1.07, 95% CI: 0.85, 1.34), and similarly with rosiglitazone monotherapy compared to sulfonylurea monotherapy (HR 0.82, 95% CI: 0.67, 1.02). There was no difference in the risk of outcome with rosiglitazone in combination with insulin therapy compared to other oral antidiabetic agents in combination with insulin (HR 0.88, 95% CI: 0.59, 1.32). Overall, there was little difference in the risk of the composite outcome or of the individual outcomes of MI and CR comparing rosiglitazone therapies to non-rosiglitazone therapies (HR for composite outcome 0.93, 95% CI: 0.80, 1.10). Conclusions The results from the monotherapy and the dual-therapy comparisons, though not individually significant, are consistent in suggesting that the risk of cardiovascular outcome events in patients using rosiglitazone may lie between the risks associated with sulfonylureas (higher incidence) and metformin (lower incidence). Copyright © 2007 John Wiley & Sons, Ltd.

Pharmacists' attitudes towards the reporting of suspected adverse drug reactions in Norway.

Abstract: Background In Scandinavian countries, pharmacists have not reported adverse drug reactions (ADRs), either due to legislative restrictions or because of lack of tradition. From 1 January 2005, Norwegian pharmacists have been encouraged by the Norwegian Medicines Agency to take a larger role in the reporting of ADRs. Objective To explore pharmacists' attitudes towards pharmacovigilance and their experiences with ADR reporting, to evaluate the effect of an educational programme and to compare these findings to the attitudes in a control group. Methods From September 2004, pharmacies in two of Norway's five health regions were invited to attend a 3-month ADR reporting study, and 39 pharmacies were recruited. One pharmacist from each pharmacy participated in a 1 day pre-study educational programme and a 1 day post-study evaluation meeting. Pharmacists involved in the study answered a questionnaire (A) regarding their attitudes to ADR reporting (active group). A control group answered the same questionnaire. One reminder was sent. The active group evaluated the study by answering questionnaire A once more and an evaluation questionnaire (B). Qualitative aspects of ADR reporting were discussed with the active group post-study. Results The response rate for questionnaire A was 97% (n = 158) in the active group, 74% (n = 184) in the control group and the response rate for questionnaire A and B post-study was 68% (n = 105) in the active group. Pharmacists in the active group had more positive attitudes to ADR reporting after taking part in the study than the control group (p < 0.001). Lack of time, confidence and knowledge of reporting rules could potentially prevent them from reporting ADRs. Conclusions The pharmacists had positive attitudes towards pharmacovigilance, but very little experience with reporting. The educational programme clarified their role and increased their knowledge about the reporting requirements. Copyright © 2006 John Wiley & Sons, Ltd.

Risk factors for statin‐associated rhabdomyolysis

Abstract: Purpose To identify and characterize risk factors for rhabdomyolysis in patients prescribed statin monotherapy or statin plus fibrate therapy. Methods A nested case-control study was conducted within a cohort of 252 460 new users of lipid-lowering medications across 11 geographically dispersed U.S. health plans. Twenty-one cases of rhabdomyolysis confirmed by medical record review were compared to 200 individually matched controls without rhabdomyolysis. A conditional logistic regression model was applied to evaluate the effects of age, gender, comorbidities, concurrent medication use, dosage, and duration of statin use on the development of rhabdomyolysis. Results Statin users 65 years of age and older have four times the risk of hospitalization for rhabdomyolysis than those under age 65 (odds ratio (OR) = 4.36, 95% confidence interval (CI): 1.5,14.1). We also observed a joint effect of high statin dosage and renal disease (p = 0.022). When these two variables were added to the model with age, we obtained an OR of 5.73 for dosage (95%CI: 0.63, 52.6) and 6.26 for renal disease (95%CI: 0.46, 63.38). Although not statistically significant, we did observe a greater than twofold increase in risk for rhabdomyolysis among females (OR = 2.53, 95%CI: 0.91, 7.32). Conclusions Findings of this study indicate that older age is a risk factor for rhabdomyolysis among statin users. Although the evidence is not as strong, high statin dosage, renal disease, and female gender may be additional risk factors. Patients at higher risk of developing rhabdomyolysis should be closely monitored for signs and symptoms of the disease. Copyright © 2006 John Wiley & Sons, Ltd.

Cancer risks in thiazolidinedione users compared to other anti‐diabetic agents

Abstract: Purpose We conducted three nested case-control studies to evaluate the risk of breast, colon, and prostate cancers developing in patients exposed to thiazolidinediones (TZDs) compared with other anti-diabetic agents. Methods Cancer cases were matched to five controls by age, gender, calendar year, and time in the database from a cohort of 1 26 971 diabetic patients taking anti-diabetic medication in the US Integrated Healthcare Information Services database. Five hundred thirteen breast cancer cases were matched with 2557 controls, 408 cases of colon cancer were matched with 2027 controls and 643 cases of prostate cancer were matched with 3176 controls. Exposure to an anti-diabetic agent within 90 days preceding the index date was defined as recent exposure and at any time during the follow-up was defined as ever exposed. Results The adjusted odds ratios and 95%CI of cancer from ever exposure to TZDs compared to oral monotherapy, oral dual therapy, oral triple therapy, insulin monotherapy, insulin and oral therapy and all non-TZD anti-diabetic agents were, respectively for breast cancer: 0.91 (0.69–1.20), 0.80 (0.56–1.14), 0.87 (0.32–2.35), 1.27 (0.61–2.67), 0.71 (0.36–1.37), 0.89 (0.68–1.15); for colon cancer: 1.06 (0.80–1.40), 1.12 (0.77–1.63), 1.73 (0.39–7.78), 4.46 (1.05–19.00), 1.06 (0.50–2.26) 1.03 (0.80–1.32) and for prostate cancer: 1.08 (0.85–1.37), 0.89 (0.66–1.21); 0.82 (0.33–2.06); 1.80 (0.79–4.07), 1.10 (0.55–2.18), 1.04 (0.83–1.31). Results for exposure within 90 days of the date of the cancer were similar. Conclusions Our findings suggest that the effect of TZDs on the likelihood of development of the cancers studied (colon, prostate and breast) appears to be neutral and do not support a beneficial or deleterious effect of TZD on the cancers studied. Copyright © 2006 John Wiley & Sons, Ltd.

Using prescription claims data for drugs available over-the-counter (OTC)

Abstract: Purpose Many pharmacoepidemiologic studies use automated prescription claims data to estimate the association between exposure and disease. One limitation of automated data, when studying drugs that are also available via retail, is that over-the-counter (OTC) exposure is missed. The purpose of this study is to quantify the effect of misclassification of OTC use in research that uses prescription claims data as the sole source of exposure information. Methods We conducted a sensitivity analysis in the context of studies of non-steroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer. The following factors were widely varied to examine the impact on the validity of the effect estimate for NSAIDs and colorectal cancer: (1) the overall prevalence of NSAID exposure in the population, (2) the proportion of NSAID exposure due to OTC use (the prevalence of missed NSAID exposure in studies of prescription claims), and (3) the true risk ratio (RRtrue). We graphed the RR that would be observed (RRobserved) as a function of overall prevalence of NSAID use and the prevalence of NSAID use that is OTC exposure. Results We found that when the true RR ranges from 0.25 to 0.75, missing OTC drug exposure is not a large source of bias in those situations in which the overall prevalence of drug use is relatively low (less than 35%) and the proportion of drug use that is OTC exposure is as high as 80%. Conclusion Results from our sensitivity analysis indicate that, in many circumstances, prescription claims data can give valid estimates of association even though some of the drugs are available OTC. Copyright © 2007 John Wiley & Sons, Ltd.

A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes

Abstract: Background Recent studies have raised concerns about potential increased cardiovascular (CV) risk in type 2 diabetes patients treated with some peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists. Objective To ascertain the risk of hospitalization for acute myocardial infarction (AMI) in type 2 diabetes patients treated with pioglitazone relative to rosiglitazone. Methodology Using data covering 2003–2006 from a large health care insurer in the US, a retrospective cohort study was conducted in patients who initiated treatment with pioglitazone or rosiglitazone. The hazard ratio (HR) of incident hospitalization for AMI after initiation of treatment with these drugs was estimated from multivariate Cox's proportional hazards survival analysis; similarly, the HR was ascertained for hospitalization for the composite endpoint of AMI or coronary revascularization (CR). Results A total of 29 911 eligible patients were identified in the database; 14 807 in the pioglitazone and 15 104 in the rosiglitazone group. Baseline demographics, medical history, and dispensed medications were generally well balanced between groups. The unadjusted HR for hospitalization for AMI was 0.82, 95%CI: 0.67–1.01. After adjustment for baseline covariates the HR was 0.78, 95%CI: 0.63–0.96. The adjusted HR for the composite of AMI or CR was 0.85, 95%CI: 0.75–0.98. Conclusion This retrospective cohort study showed that pioglitazone, in comparison with rosiglitazone, is associated with a 22% relative risk reduction of hospitalization for AMI in patients with type 2 diabetes. Copyright © 2007 John Wiley & Sons, Ltd.

Trends in potentially inappropriate prescribing amongst older UK primary care patients.

Abstract: Purpose To examine trends in UK primary care prescribing of medications potentially inappropriate for older people in the context of published international data. Methods Analysis of routinely collected anonymised computerised patient records in 131 UK general practices (approximately 162 000 registered patients annually aged ≥65 years) providing data to the DIN-LINK database between 1994 and 2003. In each year, we identified patients prescribed drugs classified by the 2003 Beers criteria as potentially inappropriate for older people. Results The level of potentially inappropriate prescribing remained steady over time: in 2003 32.2% of patients received any Beers drug, and 20.5% received a drug categorised as potentially “high risk”; percentages had been 32.9% and 21.4% respectively in 1994. In 2003, co-proxamol (93.7/1000 patients), benzodiazepines (52.4/1000 patients) and amitriptyline (45.4/1000, mainly at low doses) were the most frequently prescribed potentially inappropriate drugs. If co-proxamol (now being withdrawn) and low-dose amitriptyline (appropriate for neuropathic pain) are excluded, 24.8% of patients still received a potentially inappropriate prescription in 2003. Conclusions Prescription of potentially inappropriate medication, particularly benzodiazepines, to older people remains at a high level in the UK. Levels were higher than those seen in published data from the Netherlands, however the low rate of co-proxamol prescribing in the Netherlands explains much, but not all, of the difference. Future international comparisons, based on more careful delineation of the criteria, may play a valuable role in pharmaco-vigilance and can identify areas where regulation of prescribing may reduce risks to older patients. Copyright © 2006 John Wiley & Sons, Ltd.

Laboratory monitoring of potassium and creatinine in ambulatory patients receiving angiotensin converting enzyme inhibitors and angiotensin receptor blockers.

Abstract: Purpose Serum potassium and creatinine monitoring is recommended for patients prescribed angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). Much has been written about hyperkalemia associated with these drugs; little is known about laboratory monitoring patterns. The purpose of this retrospective cohort study was to assess creatinine and potassium monitoring and characteristics associated with monitoring among patients dispensed ACEi or ARB. Methods This study was conducted in 10 United States health maintenance organizations. Study patients (n = 52 906) were aged 18 or older with dispensings of ACEi or ARB for at least 1 year. Serum potassium and creatinine monitoring were assessed from administrative data and medical records. Results More than two-thirds (68.4%) of patients received laboratory monitoring. Likelihood of monitoring increased with age (adjusted odds ratio [OR] 2.10; 95% confidence interval [95%CI] 1.93, 2.28 [individuals ≥ 80 compared to 9 outpatient visits (OR 1.46; 95%CI 1.39, 1.54), hospitalization (OR 1.15; 95%CI 1.06, 1.25), concomitant medications (potassium [OR 2.01; 95%CI 1.84, 2.20], diuretics [OR 1.54; 95%CI 1.47, 1.61], digoxin [OR 1.15; 95%CI 1.01, 1.30]), and comorbidities (diabetes [OR 1.68; 95%CI 1.61, 1.75], heart failure [OR 1.73; 95%CI 1.57, 1.90], chronic kidney disease [OR 2.95; 95%CI 2.48. 3.51]). Conclusions Nearly one-third of patients dispensed ACEi or ARB did not undergo laboratory monitoring at least yearly. Though patients at increased risk of hyperkalemia were more likely to be monitored, many remained unmonitored. Copyright © 2006 John Wiley & Sons, Ltd.

All-cause mortality associated with atypical and typical antipsychotics in demented outpatients.

Abstract: Purpose To estimate the association between use of typical and atypical antipsychotics and all-cause mortality in a population of demented outpatients. Methods The study cohort comprised all demented patients older than 65 years and registered in the Integrated Primary Care Information (IPCI) database, during 1996–2004. First, mortality rates were calculated during use of atypical and typical antipsychotics. Second, we assessed the association between use of atypical and typical antipsychotics and all-cause mortality through a nested case-control study in the cohort of demented patients. Each case was matched to all eligible controls at the date of death by age and duration of dementia. Odds ratios were estimated through conditional logistic regression analyses. Results The crude mortality rate was 30.1 (95%CI: 18.2–47.1) and 25.2 (21.0–29.8) per 100 person-years (PY) during use of atypical and typical antipsychotics, respectively. No significant difference in risk of death was observed between current users of atypical and typical antipsychotics (OR = 1.3; 95%CI: 0.7–2.4). Both types of antipsychotics were associated with a significantly increased risk of death as compared to non-users (OR = 2.2, 1.2–3.9 for atypical antipsychotics; OR=1.7, 1.3–2.2 for typical antipsychotics). Conclusions Conventional antipsychotic drug should be included in the FDA's Public Health advisory, which currently warns only of the increased risk of death with the use of atypical antipsychotics in elderly demented persons. Copyright © 2006 John Wiley & Sons, Ltd.

Antidepressant drugs: prevalence, incidence and indication of use in general practice of Southern Italy during the years 2003-2004.

Abstract: Purpose To estimate 1-year prevalence, 1-year incidence and indication of use of antidepressant (AD) drug treatment in general practice of Southern Italy during the years 2003–2004. Methods Among 142 346 individuals registered in the lists of 119 general practitioners of Southern Italy, we identified users of different AD types: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. Annual prevalence of AD use was measured as the number of individuals receiving at least one AD prescription in the years 2003–2004, divided by the number of patients registered in the general practitioner (GP) lists. One-year incidence of AD treatment was calculated as the number of new users of AD, divided by the number of total patients free from AD prescriptions in the previous year. Results Overall, 1-year prevalence of AD use was 5.08 (95% confidence interval (CI): 4.97–5.20) per 100 inhabitants in the year 2003, with a 20% increase in 2004 (6.00, 5.88–6.13). Prevalence of SSRI use markedly increased from 3.80 (3.73–3.90) in 2003 to 4.51 (4.40–4.61) in 2004. The incidence rates of SSRI, TCA and other antidepressant use were 2.11 (2.03–2.19), 0.38 (0.35–0.41) and 0.53 (0.49–0.57) respectively. Depressive disorders were the main indication of use of any AD user (mostly for SSRI users), followed by anxious disturbances. Conclusions SSRIs, particularly those recently marketed, have been increasingly used during the last years, mainly to treat affective disorders. Copyright © 2006 John Wiley & Sons, Ltd.

Statins and fracture risk. A systematic review

Abstract: Purpose To summarize current evidence on statin use and fracture risk and to explore potential sources of heterogeneity among study results. Methods A computerized search was conducted on MEDLINE, EMBASE, and the Cochrane databases using the keywords HMG-CoA reductase inhibitor, osteoporosis, and fractures. A meta-analysis was performed to summarize results of studies identified. Results Statin use was associated with a 23% lower fracture risk (OR = 0.77, 95%CI: 0.66–0.90). An effect of statins was found in case-control (OR = 0.62, 0.45–0.85, n = 6) and cohort (OR = 0.77, 0.59–1.00, n = 8) studies, but not in post hoc analyses of randomized trials (OR = 1.03, 0.91–1.16, n = 4). A reduced risk with statin use was found for fractures of the hip (OR = 0.58, 0.46–0.74, n = 16), spine (OR = 0.65, 0.48–0.88, n = 8) and other sites (OR = 0.77, 0.60–1.00, n = 7), and both in women (OR = 0.80, 0.66–0.96, n = 11) and men (OR = 0.62, 0.36–1.08, n = 3). Among the observational studies that also evaluated the effect of other lipid-lowering drugs, no reduced fracture risk was found for these agents (OR = 0.96, 0.85–1.09, n = 10). The test for heterogeneity was significant for study results of statin use versus no-use (p < 0.01). Meta-regression analyses suggested that study design might partly account for the heterogeneity. There was an indication of publication bias by examining Begg's plot, although Egger's test was not significant (p = 0.13). Conclusions Current evidence does not support an effect of statins in preventing fractures given (i) the lack of association in randomized trials, (ii) the heterogeneity among observational studies, (iii) the potential residual confounding, and (iv) the potential publication bias. Copyright © 2007 John Wiley & Sons, Ltd.

Guidelines for submitting adverse event reports for publication

Abstract: medical products that include herbal and complementary medicines, vaccines, and other biologicals and devices is important for postmarketing surveillance. Publication lends credence to important signals raised in these adverse event reports. Unfortunately, deficiencies in vital information in published cases can often limit the value of such reports by failing to provide enough details for either (i) a differential diagnosis or provisional assessment of cause-effect association, or (ii) a reasonable pharmacological or biological explanation. Properly described, a published report of one or more adverse events can provide a useful signal of possible risks associated with the use of a drug or medical product which might warrant further exploration. A review conducted by the Task Force authors found that many major journals have minimal requirements for publishing adverse event reports, and some have none at all. Based on a literature review and our collective experience in reviewing adverse event case reports in regulatory, academic, and industry settings, we have identified information that we propose should always