Effect of treatment gaps in elderly patients with dementia treated with cholinesterase inhibitors.

OBJECTIVE: To determine the effect of treatment gaps on the risk of institutionalization or death among community-dwelling elderly patients treated with cholinesterase inhibitors (ChIs). METHODS: A survival analysis was conducted among a cohort of community-dwelling elderly patients (age 66+) newly treated with ChIs identified in the Quebec drug claims databases (Régie de l'Assurance Maladie du Québec [RAMQ]) between January 1, 2000, and December 31, 2007. Treatment nonpersistence during the year following ChI initiation was defined as treatment discontinuation or gaps of at least 6 weeks. To account for reverse causality, Cox proportional hazard modeling was conducted only among patients who did not discontinue treatment, in order to assess the association between treatment nonpersistence and institutionalization or death. RESULTS: Among the 24,394 elderly ChI users, 4,108 (16.8) experienced a treatment gap during the year following ChI treatment initiation while 596 (2.4%) discontinued their treatment within the first 3 months (early stoppers) and 4,038 (16.6%) after 3 months of treatment (late stoppers). Of all treated patients, 4,409 (18.1%) were institutionalized or died during follow-up. In patients who did not stop their treatment, the risk of institutionalization or death appeared lower in patients who experienced a treatment gap (hazard ratio 0.91; 95% confidence interval 0.86-0.96). CONCLUSIONS: Our results suggest that, contrary to what was previously reported in clinical trials, treatment gaps do not compromise the outcome of patients treated with ChIs in a real-life setting.

Impact of antidepressants on the risk of suicide in patients with depression in real-life conditions: a decision analysis model.

BACKGROUND: The impact of antidepressant drug treatment (ADT) on the risk of suicide is uncertain. The aim of this study was to determine in a real-life setting whether ADT is associated with an increased or a reduced risk of suicide compared to absence of ADT (no-ADT) in patients with depression. METHOD: A decision analysis method was used to estimate the number of suicides prevented or induced by ADT in children and adolescents (10-19 years old), adults (20-64 years old) and the elderly (65 years) diagnosed with major depression. The impact of gender and parasuicide history on the findings was explored within each age group. Sensitivity analyses were used to assess the robustness of the models. RESULTS: Prescribing ADT to all patients diagnosed with depression would prevent more than one out of three suicide deaths compared to the no-ADT strategy, irrespective of age, gender or parasuicide history. Sensitivity analyses showed that persistence in taking ADT would be the main characteristic influencing the effectiveness of ADT on suicide risk. CONCLUSIONS: Public health decisions that contribute directly or indirectly to reducing the number of patients with depression who are effectively administered ADT may paradoxically induce a rise in the number of suicides.

Channelling of COX-2 inhibitors to patients at higher gastrointestinal risk but not at lower cardiovascular risk: the Cox2 inhibitors and tNSAIDs description of users (CADEUS) study.

PURPOSE: To describe the characteristics of users of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective non-steroidal anti-inflammatory drugs (tNSAIDs) in France. METHODS: Between 1 August 2003 and 31 July 2004, patients who received at least one dispensing of celecoxib, rofecoxib or tNSAIDs were randomly sampled with a 1:1:2 target ratio within the French National Healthcare Insurance database. Patients and prescribers were asked to fill a questionnaire on socio-demographic characteristics, NSAID indication and use and previous medical history. For each respondent, healthcare resources used in the 6 months before inclusion were extracted from the database. Multivariate logistic regression was used to study the determinants of a first COX-2 inhibitor dispensing. RESULTS: Of the 45 217 patients included, 13 065 COX-2 inhibitors and 13 553 tNSAID users had prescriber data. Ninety seven per cent of COX-2 inhibitor prescriptions were for 'rheumatological' indications, whereas 37% of tNSAIDs use was for benign diseases (n = 2643) or analgesia (n = 2318). Among patients with rheumatological indications (n = 4730) and a first COX-2 inhibitor (n = 2427) or tNSAID (n = 2303) dispensing, multivariate analysis of factors associated with COX-2 inhibitors dispensing showed that, compared to new tNSAID users, new COX-2 inhibitor users were older, more often female, on sick leave or unemployed. COX-2 use was also associated with previous gastrointestinal history and previous gastroprotective agent dispensing, but not with previous cardiovascular (CV) history. CONCLUSION: The choice of NSAID depended largely on indication and on previous gastrointestinal history, in line with the recommendations of the French health authorities. Possible knowledge of CV risk associated with COX-2 inhibitors did not influence prescribing.

The CADEUS study: methods and logistics.

PURPOSE: At the request of the French Health authorities, a study called CADEUS (COX-2 inhibitors and NSAIDs: description of users) aimed to describe the users of cyclo-oxygenase (COX)-2 inhibitors and traditional non-selective non-steroidal anti-inflammatory drugs (tNSAIDs). We report here the methodology, logistics and study design performances. METHODS: CADEUS is a cohort study designed to include 40,000 patients randomly sampled monthly in the French National Healthcare Insurance database, who received at least one dispensation of celecoxib, rofecoxib or tNSAIDs (1:1:2), from September 2003 to August 2004. Patients and prescribers were asked to fill a questionnaire on indication, medical history, risk factors and hospitalizations since drug acquisition. There was no reminder. For each respondent, healthcare resources used for the 6 months before and after inclusion were extracted from the database. Response rate, response delay, responders and non-responders characteristics were assessed. RESULTS: Of the 222,879 patients and their prescribers contacted, 20.8% patients and 32.6% prescribers responded. Median response delay was 16 days for patients and 17 days for physicians. Factors associated with patient response were age, cohort, type of prescriber and period of inclusion. CONCLUSION: This is the first study of this design in France, combining data from a claims database and direct patient and prescriber questionnaires.

Persistency of use of COX-2-specific inhibitors and non-specific non-steroidal anti-inflammatory drugs (NSAIDs) in Quebec.

The effectiveness of pharmacological therapies is dependent in part on patient persistency with the prescribed therapeutic regimen. In the case of non-specific non-steroidal anti-inflammatory drugs (NSAIDs), effectiveness is often compromised by undesirable side-effects, poor compliance or discontinuation of therapy. While patterns of utilization of non-specific NSAIDs have been investigated, few data are available on the patterns of persistency for cyclooxygenase (COX)-2-specific inhibitors. This study used a provincial health-care system database in Quebec, Canada, to determine the duration of treatment in new users of COX-2-specific inhibitors and non-specific NSAIDs over the first 3 months of treatment, and to characterize the factors associated with treatment persistency. Results demonstrate that the median duration of treatment was longer among patients initially prescribed COX-2-specific inhibitors (30 days and 23 days for celecoxib and rofecoxib respectively) than in those prescribed non-selective NSAIDs (10 days). Although the percentage of patients remaining on COX-2-specific drugs declined over the course of treatment, few patients on either celecoxib or rofecoxib switched drugs, either to the other COX-2-specific inhibitor or to non-specific NSAIDs. Factors associated with persistent drug use were: COX-2-specific inhibitors, age, and the use of gastroprotective agents either at treatment initiation or during follow-up. Dosage, chronic disease score and prescriber's specialty were only marginally associated with persistency. Prior use of gastroprotective agents was associated with lower persistency. Although the limitations of this study, which included lack of information on the indication for the prescription and the reason for switch or discontinuation, preclude definite conclusions regarding patterns of use of these drugs, the data suggest that the use of COX-2-specific inhibitors may result in increased persistency with treatment.

A case-control analysis of nonsteroidal anti-inflammatory drugs and Alzheimer's disease: are they protective?

In many studies of nonsteroidal anti-inflammatory drugs (NSAIDs) and Alzheimer's disease (AD), the exposure to NSAIDs was concurrent with AD or based on self (or surrogate) report. We conducted a case-control analysis of the Québec participants in the Canadian Study of Health and Aging who received a diagnosis of AD (cases) or were found to be cognitively unimpaired on screening (controls). Information on drug use was obtained from the Québec Provincial Pharmaceutical Services Database. There was no significant difference in the proportion of cases and controls who had received any NSAID prescriptions in the 3 years prior to the onset of symptoms of dementia; amongst NSAID users, there was no difference in mean dose or duration. Our findings, using a measure of drug use prior to symptom onset and not subject to recall bias, do not support a protective effect for NSAIDs.

High daily doses of benzodiazepines among Quebec seniors: prevalence and correlates.

BACKGROUND: Use of high daily doses of benzodiazepines is generally contraindicated for seniors. While both patient and physician factors may influence the use of high daily doses, previous research on the effect of patient factors has been extremely limited. The objectives of this study were to determine the one year prevalence of use of high daily doses of benzodiazepines, and examine physician and patient correlates of such use among Quebec community-dwelling seniors. METHODS: Patient information for 1423 community-dwelling Quebec seniors who participated in the Canadian Study of Health and Aging was linked to provincial health insurance administrative data bases containing detailed information on prescriptions received and prescribers. RESULTS: The standardized one year period prevalence of use of high daily doses of benzodiazepines was 7.9%. Use of high daily doses was more frequent among younger seniors and those who had reported anxiety during the previous year. Patients without cognitive impairment were more likely to receive high dose prescriptions from general practitioners, while those with cognitive impairment were more likely to receive high dose prescriptions from specialists. CONCLUSION: High dose prescribing appears to be related to both patient and physician factors.

Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer's disease drug trials.

Drug therapies for Alzheimer's disease (AD) have been evaluated in clinical trials over the past 2 decades. Systematic reviews of AD drug trials can shed more light on the efficacy of pharmaceutical interventions. The modified Jadad scale can be used to assess the quality of trial reports that are candidates for inclusion in these systematic reviews. The interrater reliability of the modified Jadad scale was examined during such a review. Three blinded reviewers rated the quality of 42 AD drug trial reports: the intraclass correlation coefficient was 0.90. The modified Jadad scale appears to be a useful tool for AD research because of the very good interrater reliability. Also, it is composed of items that are well suited to the specific disease characteristics of AD. Further research should focus on the validity of this instrument.

Evaluation of the Confusion Assessment Method (CAM) as a screening tool for delirium in the emergency room.

The objective of this study was to compare the results of the Confusion Assessment Method (CAM) obtained by a trained non-physician interviewer to those obtained by a geriatrician, among a sample of elderly patients seen in an emergency room. A group of 110 elderly patients (> or =66 years) were evaluated in the emergency room by a lay interviewer. The geriatrician conducted an interview in the presence of the lay interviewer. Subsequently, the geriatrician and the lay interviewer completed a CAM checklist independently. Kappa statistics, sensitivity, specificity, positivity predictive value (PPV), and negative predictive value (NPV) for the geriatrician's and lay interviewer's results with the CAM diagnostic algorithm were compared. The kappa coefficient was 0.91, the sensitivity 0.86, the specificity 1.00, the PPV 1.00, and the NPV 0.97. In conclusion, the CAM used by a trained lay interviewer in the emergency room is sensitive, specific, reliable and easy to use for the identification of patients with delirium. The under-recognition and under-treatment of delirium is a major health issue and has important clinical and financial implications. The implementation of systematic screening in populations at risk could increase the rate of early detection and lead to the appropriate management of delirious patients.

Do patient factors alter the relationship between physician characteristics and use of long-acting benzodiazepines?

Despite known hazards associated with their use, long-acting benzodiazepines are frequently used in the treatment of older adults. While such use has been linked to physician characteristics, the effect of patient factors has not been considered. To investigate this, data from 1423 Quebec community-dwelling subjects of the Canadian Study of Health and Aging were linked to records of prescriptions billed to the provincial health insurance program during the year following study entry. The standardized one-year period prevalence of any use of long-acting benzodiazepines was 12.2%. Among benzodiazepine users, long-acting benzodiazepine use was more common among male patients and patients of earlier graduating prescribers and specialist prescribers. However, the effect of the latter two factors were modified by patient self-reported anxiety. This study demonstrates that consideration of patient factors may be necessary to obtain an accurate estimate of the association between at least some physician factors and use of long-acting benzodiazepines.

Long-term continuous use of benzodiazepines by older adults in Quebec: prevalence, incidence and risk factors.

OBJECTIVE: To determine the prevalence and incidence of long-term use of benzodiazepines and to assess patient-, prescriber-, and drug-related risk factors. DESIGN: Cohort study. PARTICIPANTS: 1,423 community-dwelling older adults in Quebec who participated in the Canadian Study of Health and Aging (CSHA1). MEASUREMENTS: Patient characteristics were obtained from the CSHA1 database. These were linked to provincial health insurance data to ascertain benzodiazepine use and prescriber characteristics. MAIN OUTCOME MEASURE: Use of benzodiazepines for at least 135 of the first 180 days following initiation of use. RESULTS: Twelve-month prevalence of long-term continuous use, standardized by age and gender to the Quebec population, was 19.8%. Twelve-month cumulative incidence of long-term continuous use was 1.9%. Older patients were more likely to proceed to long-term continuous use. CONCLUSIONS: Risk of long-term continuous use of benzodiazepines seems to increase with age. This association was found to be independent of gender, health status, anxiety, cognitive status, benzodiazepine type, and physician characteristics.

Under-reporting of adverse drug reactions. Estimate based on a spontaneous reporting scheme and a sentinel system.

OBJECTIVE: Spontaneous reporting is the most common method used in pharmacovigilance and the best one to generate signals on new or rare adverse drug reactions (ADRs). Under-reporting is a major drawback of this system. The objective of this study was to quantify the extent of under-reporting in general practice and to assess the factors which influence it. METHODS: Details of ADRs collected through a short intensive survey were compared with primary care spontaneous reports received by the Castilla y Leon Regional Pharmacovigilance Centre during a 12-month reference period. The survey was undertaken by a random sample of 146 general practitioners (GPs), providing care to 149,487 people. The pharmacovigilance centre received reports concerning the whole regional population (2.5 million) covered by primary health care. The under-reporting coefficient (U) was estimated as the ratio between the number of effects observed by physicians in the survey and those spontaneously reported to the pharmacovigilance centre. RESULTS: The overall under-reporting rate was 1144 [95% confidence interval (CI): 928-1409]. Under-reporting was greater for psychiatric (2119; 945-4752) and gastrointestinal (1946; 1424-2659) disorders. Severe effects were more reported (U = 605; 151-2431) than moderate (863; 473-1575) and mild (1209; 973-1503) ones. The under-reporting rate was lower for drugs recently marketed (706; 406-1230) and slightly lower for unlabelled effects (1031; 641-1657). CONCLUSION: The under-reporting rate of ADRs is considerable, though not homogeneous for the different cases. This should be taken into account when comparing adverse effects (AEs) for different drugs. Under-reporting seems to be positively selective, as it involves mainly the less severe and better-known effects, preserving the value of spontaneous reporting for signal detection.

Temporal trends in spontaneous reporting of unlabelled adverse drug reactions.

AIMS: Trends in spontaneous reporting during the first years on the market were analyzed from a sample of selected drugs, with special attention to unlabelled effects. METHODS: Ten drugs were selected giving rise to approximately 100 spontaneous reports each during the first 4 years of marketing. Case reports were identified from the national pharmacovigilance database. A bibliographical score assigned at the time of reporting was used to identify unlabelled effects. Results were expressed as reporting rates. RESULTS: The average reporting rate peaked during the first year of marketing (54.6 per million treatment-months; s.d.: 62.8), then progressively decreased during the following years. Unlabelled effects effects represented 63% of all the spontaneous reports during the first year. CONCLUSIONS: Unlabelled adverse effects represent a high proportion of spontaneous reports during the early years of marketing.

Determinants of initiation and suboptimal use of anti-ulcer medication: a study of the Quebec older population.

OBJECTIVES: To describe the use of anti-ulcer medication in the Quebec older population; to examine determinants of initiation, suboptimal use, and switches between products. DESIGN: Population-based retrospective cohort study. SETTING: Universal health program for older adults in Quebec. PARTICIPANTS: 5000 users and 5000 non-users of anti-ulcer medications were selected randomly. Use was defined as the presence in the 1991 prescription database of an anti-ulcer prescription. Among users, 1697 (34%) were new users and were considered as the exposure group. Subjects were followed for 365 days after inclusion. MEASUREMENTS: Measured were patient's age, gender, prescribed duration of anti-ulcer medication, concomitant medications, and gastrointestinal diagnostic procedures. RESULTS: A total of 17% of new users had unusually short courses; 18% were long-term users. There was no difference in duration for omeprazole compared with other anti-ulcer medications. First-time use of NSAIDs was the strongest predictor of initiation of anti-ulcer medication (odds ratio = 3.21; 95% CI, 2.66-3.88). Twenty-six percent of users switched brands. Only 9.5% of new users underwent a diagnostic procedure before initiation of therapy, and 49% of long-term users ever underwent such procedure. CONCLUSION: Despite a relatively homogeneous recommended duration of therapy, patterns of use of anti-ulcer medication among older people are highly variable, and treatment is often not accompanied by a diagnostic procedure.

Under-reporting of adverse drug reactions in general practice.

AIMS: In post-marketing setting, spontaneous reporting by physicians is a mode of surveillance of adverse effects associated with drug use. The objective of this study was to quantitatively assess under-reporting of adverse drug reactions (ADRs) in general practice. METHODS: A random sample of 100 general practitioners (GPs) practising in the region of the Bordeaux pharmacovigilance centre were surveyed to obtain data on adverse effects observed. Overall, 81 GPs agreed to record during 3 non-consecutive working days any effect they believed to be associated with drug use. The types of effects, regardless of their seriousness and labelling, and the drugs suspected were characterized and compared to spontaneous reports received from GPs by the Bordeaux pharmacovigilance centre during the reference period. RESULTS: The average number of ADRs observed per day per GP was 1.99. The estimate of the under-reporting coefficient (U) was 24,433 (95% confidence interval: 20,702-28,837) which indicates that, as a whole, GPs might be expected to report only 1 out of every 24,433 ADRs to the pharmacovigilance centre. Under-reporting was lowest for serious and unlabelled effects (U = 4610; 95% CI: 2514-8454) and for drugs marketed recently (U = 12,802; 95% CI: 8174-20,050). CONCLUSIONS: Adverse effects due to drugs are part of GPs routine activities. According to the observed trend in under-reporting, there appears to be a selection process which indicates that spontaneous reporting in general practice is not conducive to an exhaustive description of the safety profile of a drug. However, our findings are consistent with greater efficacy of spontaneous reporting in detecting serious and unlabelled effect.

Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group.

BACKGROUND: Recently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. METHODS: In a case-control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. RESULTS: The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used to a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs. CONCLUSIONS: The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.

Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.

OBJECTIVE: To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. DESIGN: Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. SETTING: Hospital and community based case-control and cohort studies. MAIN OUTCOME MEASURES: (a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. RESULTS: 12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. CONCLUSIONS: The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs.

Comparing the toxicity of two drugs in the framework of spontaneous reporting: a confidence interval approach.

Spontaneous reporting remains the most frequently used technique in post-marketing surveillance. Decision-making usually depends on comparisons between the number of adverse drug reactions (ADRs) reported for two drugs on the basis of an equivalent number of prescriptions. The validity of such comparisons is expected to be jeopardized by probable underreporting ADR cases. This problem is accentuated when it cannot be assumed that the magnitude of underreporting is the same for the both drugs. Differences in reporting ratios can overemphasize, cancel, or reverse the conclusions of a statistical comparison based on the number of reports. We propose a single method for (1) calculating confidence intervals for relative risks estimated in the context of spontaneous reporting and (2) deriving the range of reporting ratios for which the conclusion of the statistical comparison remains statistically valid.

False-positives in spontaneous reporting: should we worry about them?

Spontaneous reporting remains the most used and, undoubtedly, the most cost-effective approach for the identification of adverse drug reactions (ADRs). Most of the limitations of this method are well recognised but the possibility of receiving false-positive reports of coincidental drug-event associations has received little attention. In this paper we propose a method based on the Poisson distribution for computing the maximum number of reports of an ADR that could be expected to be reported coincidentally. Three parameters are required: (i) the background risk of the event in the reference population, (ii) the total number of patients treated with the drug considered and, (iii) the proportion of cases that have been reported to the pharmacovigilance system. For most empirical situations occurring in the post-marketing surveillance setting, the expected number remains low and only a maximum of one to three cases could be accepted as possibly coincidental. For rare adverse events such as agranulocytosis or toxic epidermal necrolysis, coincidental associations are so unlikely that a number of reports greater than three constitutes a strong warning and requires further investigation. These findings suggest that for rare events, reports of coincidental drug-event associations are too unlikely to be considered as an important limitation of spontaneous reporting.