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Background: The AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial demonstrated that rate control and rhythm control strategies result in similar survival and quality of life for patients with atrial fibrillation (AF). Because of superior safety and lower cost, rate control is now the recommended strategy (or the management of most elderly, high-risk AF patients. Objective: To determine the extent to which the AFFIRM trial results have been adopted into actual practice. Methods: We conducted a time-series analysis of 3 population-based cohorts of patients with AF who were 66 years of age or older in Pennsylvania and Ontario. We stratified patients in Ontario by socioeconomic status (SES) and examined changes in quarterly prescription rates for rate control and rhythm controlling medications as well as cardioversion procedures before and after publication of the AFFIRM trial. Results: The publication of the AFFIRM trial resulted in statistically significant reductions in the use of rhythm controlling medications in all 3 cohorts (p < 0.01). The magnitude of these changes in the non-low SES Canadian cohort was approximately 1% per quarter and was greater than the magnitude observed in the other cohorts (p < 0.001). The use of cardioversion procedures also decreased in all study regions (p < 0.01). In contrast, AFFIRM publication was also associated with a small increase in the use of rate controlling medications in Canada (p < 0.01) but not in the US (p = 0.23). Conclusions: Publication of the AFFIRM trial resulted in small but statistically significant changes in the care of patients with AF.

Introduction:Pergolide is an ergot derived dopamine agonist that is widely used for the treatment of Parkinson’s disease. Studies have found an association between pergolide and valvular heart abnormalities although there is still much to be learned about the clinical significance of the valvular changes, who is at risk, and whether there is duration of exposure effect.Objective:To assess the long term risk of hospital admissions for valvular heart disease (VHD) or congestive heart failure (CHF, a clinically overt outcome of VHD) in new users of pergolide compared to new users of levodopa. The secondary objective was to assess whether there are any characteristics that can predict who is at higher risk of developing this outcome.Design:Retrospective, population-based cohort study.Setting:Ontario, Canada.Subjects:Ontario residents aged 66 and older, newly started on treatment with either pergolide or levodopa.Outcomes:Admission to hospital with the most responsible diagnosis of congestive heart failure or valvular heart disease.Results:The risk for admission for valvular heart disease or congestive heart failure were higher in those with 1-4 years exposure to pergolide compared with no exposure to pergolide (VHD: hazard ratio 2.4, p = 0.04; CHF: hazard ratio 1.6, p =0.02). No such pattern was found with exposure to levodopa.Conclusion:Our study demonstrates that treatment with pergolide is associated with a higher risk of hospital admission for valvular heart disease or congestive heart failure and that this risk is greater in those with 1-4 years exposure than in those with less exposure. We did not find an increased risk beyond four years.

OBJECTIVES: To examine current utilization patterns of cholinesterase inhibitor (ChEI) therapy for dementia to determine treatment duration, use in long-term care, how often patients receive these drugs until death, and frequency of switching between the available ChEIs. DESIGN: A population-based healthcare administrative database study. SETTING: Patients aged 66 and older from the Canadian province of Ontario who received a new prescription for a ChEI between June 1, 2000, and December 31, 2002. Patients were followed until discontinuation of ChEI therapy, death, or end of the observation period (March 31, 2005). PARTICIPANTS: Twenty-eight thousand nine hundred and sixty-one patients, including 4,601 residing in long-term care, mean age 80, 63% female. MEASUREMENTS: Information on diagnosis, medical comorbidity, physician visits, and concomitant medication use was obtained. Estimates of duration of continuous use were determined. The percentage of patients who remained on the initial dose prescribed, the proportion who switched to a second ChEI, and the percentage who remained on ChEIs until death were calculated. RESULTS: Patients had on average more than 26 physician visits in the year before ChEI therapy, but only 28% had seen a dementia specialist. Concomitant use of potentially inappropriate medications (strongly anticholinergic medications and benzodiazepines) was noted in 37% of patients. The average length of treatment for all patients was 866 days. Many patients (43%) remained on the initial dose prescribed, 6% switched to another ChEI, and 19% died while on ChEI therapy. CONCLUSION: Elderly patients with dementia are treated for lengthy periods of time with ChEIs in the community and in long-term care facilities. Further research is required to determine whether these utilization patterns are appropriate. It is also unclear whether these results are generalizable to other populations without universal health coverage or drug formulary benefits.

The choice of agents to treat psychotic symptoms in Parkinson's disease is important given the potential for antipsychotics to worsen Parkinsonism. The purpose of this study was to estimate the incidence of psychotic symptoms requiring treatment in individuals with Parkinson's disease after starting dopaminergic medications, and to describe the agents being selected as initial antipsychotic therapy. Using the administrative health care databases of Ontario, Canada, individuals 66 years of age or older with Parkinson's disease who were newly treated with dopaminergic agents were identified. Subsequent prescriptions for antipsychotic medications were then identified. A total of 10,347 older adults were newly started on dopaminergic agents between 1998 and 2003. The Kaplan-Meier estimate for the cumulative probability of requiring an antipsychotic at 7 years was 35%; 499 individuals (4.8%; 5.2/100 person-years) were prescribed an antipsychotic within 1 year of starting dopaminergic therapy. The proportion of initial antipsychotic prescriptions for typical antipsychotics decreased from 56% (42 of 75) in 1998 to 9% (8 of 88) in 2002. Antipsychotic use is common in individuals with Parkinsonism newly treated with dopaminergic medication. Typical antipsychotics are still commonly being chosen as first-line agents for older patients, indicating a need for interventions to improve practice.

OBJECTIVE—To describe recent trends in the proportion of deliveries in women with pregestational diabetes (PGD), their use of services, and diabetes-related obstetrical complications. RESEARCH DESIGN AND METHODS—In this population-based retrospective cohort study, comprehensive administrative data were used to identify all women (with and without PGD) who gave birth in an Ontario, Canada, hospital from 1996 to 2001. Data on maternal complications and interventions were obtained from hospital discharge records; data on use of prenatal services were obtained from fee-for-service claims. RESULTS—The proportion of deliveries in women with PGD increased steadily from 0.8% in 1996 to 1.2% in 2001 (P < 0.001). In 2001, women with PGD were more likely to be diagnosed with shoulder dystocia (adjusted odds ratio 2.00 [95% CI 1.55–2.58]), hypertension (4.13 [3.44–4.96]), and preeclampsia/eclampsia (4.44 [3.43–5.73]) and have higher rates of inductions (1.69 [1.52–1.88]) and caesarean sections (1.78 [1.60–1.98]) than women without PGD. In 2001, 50% of the women with PGD had a visit to a diabetes specialist during pregnancy and only 30% of women had claims for a prenatal retinal examination. Both of these rates have decreased over the study period. CONCLUSIONS—Women with PGD now account for a larger proportion of deliveries. These women continue to have higher obstetrical complication and intervention rates than women without PGD and many do not receive recommended specialty care during pregnancy.

Background: The use of lithium carbonate for the treatment of mood disorders in old age has decreased at a dramatic rate in favor of valproate. Because of lithium's narrow therapeutic range, neurotoxicity can be an important complication in lithium therapy and potentially influence prescription patterns. Therefore, we compared the incidence of delirium in older adults with mood disorders who were newly dispensed either lithium or valproate. Method: Using 4 population-based administrative databases from the province of Ontario, Canada (the Ontario Drug Benefit program, the Canadian Institute for Health Information, the Ontario Health Insurance Plan, and the Registered Persons Data Base), we were able to identify a cohort of mood disorder patients 66 years and older who were newly dispensed lithium or valproate over an 8-year period (1993-2001). Measures were taken to ensure that the sample was composed of mood disorder patients. As a comparator, we included a known deliriogenic drug, benztropine. The main outcome measure was a new diagnosis of delirium on a hospitalization record during 1 year of follow-up. Results: Our study cohort consisted of 2422 new users of lithium and 2918 new users of valproate over an 8-year period. There was no statistically significant difference in the incidence of delirium between lithium (2.8 per 100 person-years) and valproate (4.1 per 100 person-years). Compared with patients who received lithium, patients who received benztropine had a significantly higher risk of delirium (p

Objective The authors sought to determine the incidence of lithium-induced hypothyroidism in a population-based cohort of older adults beginning lithium therapy and thereby to inform clinical guidelines on the frequency of monitoring necessary in this group. Methods The authors conducted a population-based observational cohort study using four administrative databases that contained information on over 1.3 million older adults in Ontario who receive universal healthcare coverage in terms of physician services, drugs, and hospitalizations. Over an 18-month period, they studied adults age ≥65 who were newly prescribed lithium or valproate, monitoring subjects for initiation of T 4 therapy (as a proxy for hypothyroidism) while they continued their lithium use. Results The authors identified 1,705 new users of lithium and 2,406 new users of valproate with similar baseline characteristics. Lithium users were significantly more likely to be treated with T 4 than were valproate users. The rate of T 4 treatment per 100 person-years was 5.65 in the lithium group and 2.70 in the valproate group. Conclusion T 4 treatment was initiated in almost 6% of lithium-treated patients, suggesting the possibility that hypothyroidism developed twice as frequently among these patients as would be expected among a mixed-age population. Increased vigilance and continued monitoring of thyroid functioning for at least 2 years is necessary in older adults beginning lithium therapy.

Objectives: To compare patterns of potentially inappropriate drug therapy prescribing in community-dwelling older adults and nursing home residents in Ontario, Canada. Design: A retrospective cohort study using administrative databases. Setting: Ontario community and nursing home facilities. Participants: All 1,275,619 older adults aged 66 and older in Ontario (1,216,900 community-dwelling and 58,719 nursing home residents) who were dispensed at least one prescription from the comprehensive provincial drug plan in 2001. In Ontario, the provision of clinical pharmacy services is mandated in the nursing home setting. No comparable program exists for older adults in the community setting. Measurements: Potentially inappropriate drug prescribing was compared between community-dwelling and nursing home residents in two categories: those to always avoid and therapies considered rarely appropriate to prescribe. Results: Of the 1,275,619 adults in the cohort, nursing home residents were older (mean age±standard deviation=84.2±7.6 vs 75.0±6.5, P

OBJECTIVE: To evaluate the dose-related benefit of angiotensin-converting enzyme (ACE) inhibitor therapy among older adults with heart failure and to evaluate whether low-dose ACE inhibitor therapy is better than none. DESIGN: Observational cohort study. SETTING: Community-dwelling older adults in Ontario, Canada. PATIENTS/PARTICIPANTS: We identified 16,539 adults 66 years or older who survived 45 days following their first heart failure hospitalization discharge. MEASUREMENT AND MAIN RESULTS: Multivariate techniques including propensity scores were used to study the association between the dose of ACE inhibitor therapy dispensed and 3 outcomes: survival, survival or heart failure rehospitalization, and survival or all-cause hospitalization at 1 year of follow-up. Logistic regression models explored the association between initial dose dispensed and subsequent dose reduction or drug cess-ation. Overall, 10,793 (65.3%) of patients were dispensed ACE inhibitor therapy, with more than a third (3,935; 36.5%) initiated on low-dose therapy. Relative to dispensing of low-dose ACE inhibitor therapy, nonuse was associated with increased mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.02 to 1.22). Dispensing medium-dose therapy provided a benefit similar to low-dose (HR, 0.94; CI, 0.86 to 1.03) and dispensing of high-dose therapy was associated with improved survival benefit (HR, 0.76; CI, 0.68 to 0.85). Relative to dispensing of low-dose ACE inhibitor therapy, dispensing high-dose conferred a benefit (HR, 0.87; CI, 0.80 to 0.95) on the composite outcome of 1-year mortality or heart failure hospitalization and the composite outcome of 1-year mortality or all-cause hospitalization (HR, 0.87; CI, 0.81 to 0.93). Relative to those dispensed low-dose ACE inhibitor therapy, those initially dispensed high-dose therapy were twice as likely to have their subsequent dose reduced or the therapy discontinued (odds ratio, 2.36; CI, 2.07 to 2.69). CONCLUSION: Our findings suggest that when possible, older adults should be titrated to the higher doses of ACE inhibitor therapy evaluated in clinical trials. If older adults cannot tolerate higher doses, then low-dose ACE inhibitor therapy is superior to none. High-dose ACE inhibitor therapy is not as well tolerated as lower doses.

Objectives: To describe the incidence and dose of neuroleptic drug therapy newly dispensed for behavioral disorders to older adults admitted to nursing homes and to determine whether this use is associated with patient characteristics and contact with specialists. Design: A retrospective cohort study using administrative data from a comprehensive and universal drug program. Setting: All licensed nursing homes in Ontario, Canada. Participants: All 19,780 adults aged 66 and older who had no evidence of neuroleptic drug use in the previous year and no history of major psychosis and were newly admitted to a nursing home between April 1, 1998, and March 31, 2000. Measurements: Exposure to neuroleptic drug therapy and initial dose were measured using claims submitted to the Ontario Drug Benefit Program. Results: A prescription for a neuroleptic therapy was dispensed to 17% of older adults with no previous neuroleptic exposure within 100 days and to 24% within 1 year of their nursing home admission. New exposure to a neuroleptic therapy was less likely in women (odds ratio (OR)=0.7, 95% confidence interval (CI)=0.6–0.8) and more likely in residents with dementia (OR=3.5, 95% CI=3.2–3.8). Almost 10% of nursing home residents received an initial dose that exceeded recommended thresholds. Only 14% of those newly exposed had prior contact with a geriatrician or psychiatrist. Conclusion: Incident use of neuroleptics in Ontario nursing homes is substantial. Use of high doses suggests that some physicians may need better information about using these agents, particularly given the rapid adoption of atypical neuroleptic drug therapies.

OBJECTIVES: To compare the prevalence of inappropriate prescribing before and after nursing home admission and to determine which patient and physician characteristics are associated with inappropriate prescribing in the nursing home setting. DESIGN: A pre/post retrospective, cohort study. SETTING: All licensed nursing homes in Ontario, Canada. PARTICIPANTS: Nineteen thousand nine hundred eleven individuals aged 66 and older, newly admitted to nursing homes in Ontario between April 1, 1997, and March 31, 1999. MEASUREMENTS: For each patient in the cohort, a subset of the Beers criteria was used to characterize and compare the prevalence of inappropriate prescribing (as indicated by the prescription of one of 49 inappropriate drugs) before and after nursing home admission. A logistic regression model was used to study the association between inappropriate prescribing and patient and physician characteristics. RESULTS: The proportion of patients receiving a prescription for at least one inappropriate drug decreased from 25.4% before nursing home admission to 20.8% afterward (P < .001). Most patients who had been prescribed an inappropriate agent before nursing home entry had that agent discontinued after admission. The most commonly prescribed inappropriate drugs after nursing home admission were strongly anticholinergic antidepressants (6.4%) and long-half-life benzodiazepines (5.9%). Patients younger than 85 were more likely to receive inappropriate drug therapy (odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.15–1.35) than those aged 85 and older. Other significant predictors were having more than one prescriber (OR = 1.40, 95% CI = 1.29–1.51), having a physician aged 50 or older (OR = 1.14, 95% CI = 1.05–1.23), having a male physician (OR = 1.20, 95% CI = 1.05–1.37), having a nonspecialist physician (OR = 1.23, 95% CI = 1.01–1.49), having a nonurban physician (OR = 1.13, 95% CI = 1.03–1.24), and having a physician practicing outside the greater Ontario metropolitan area (OR = 1.31, 95% CI = 1.19–1.51). CONCLUSIONS: Although a substantial number of nursing home residents receive inappropriate drug therapy, the prevalence of inappropriate prescriptions in our cohort declined after nursing home admission despite an overall increase in drug use. Patient and physician characteristics were associated with inappropriate prescribing. Targeted interventions such as regionally based education programs or drug use restrictions may reduce the prevalence of inappropriate prescribing.

Objectives. We sought to determine whether more comprehensive risk-adjustment models have a significant impact on hospital risk-adjusted mortality rates after coronary artery bypass graft surgery (CABG) in Ontario, Canada. Background. The Working Group Panel on the Collaborative CABG Database Project has categorized 44 clinical variables into 7 core, 13 level 1 and 24 level 2 variables, to reflect their relative importance in determining short-term mortality after CABG. Methods. Using clinical data for all 5,517 patients undergoing isolated CABG in Ontario in 1993, we developed 12 increasingly comprehensive risk-adjustment models using logistic regression analysis of 6 of the Panel’s core variables and 6 of the Panel’s level 1 variables. We studied how the risk-adjusted mortality rates of the nine cardiac surgery hospitals in Ontario changed as more variables were included in these models. Results. Incorporating six of the core variables in a risk-adjustment model led to a model with an area under the receiver operating characteristic (ROC) curve of 0.77. The ROC curve area slightly improved to 0.79 with the inclusion of six additional level 1 variables (p = 0.063). Hospital risk-adjusted mortality rates and relative rankings stabilized after adjusting for six core variables. Adding an additional six level 1 variables to a risk-adjustment model had minimal impact on overall results. Conclusions. A small number of core variables appear to be sufficient for fairly comparing risk-adjusted mortality rates after CABG across hospitals in Ontario. For efficient interprovider comparisons, risk-adjustment models for CABG could be simplified so that only essential variables are included in these models.

Objectives: To examine funding priorities assigned by health ministry officials when choosing between clinical programs that offer similar overall benefits distributed in different ways (e.g. large gains for a few versus small gains for many), and to compare the relative magnitude of any distributional bias to age biases. Methods: A survey consisting of paired hypothetical health care programs was mailed to the 135 most senior officials of the Health Ministry in Ontario, Canada (population 11.5 million). Respondents were asked to assume they were members of a panel allocating a fixed sum of money to one of two programs in each pair. All program descriptions included the number of persons affected each year by a given disease and the average survival gains from the hypothetical programs. Some scenarios also mentioned the side-effects associated with programs and/or the average age of the beneficiaries. Results: Four respondents had retired/died. Of 131 eligible respondents, 80/131 (61%) provided usable responses. Asked to choose between providing large benefits to a few citizens and small benefits to a great many, 23% (95% CI: 14%, 33%) of respondents were unable to decide, but 55.8% (95% CI: 47%, 70%) favored providing large benefits to fewer patients. Eliminating the 23% unable to decide, 47/62 or 76% (CI: 63%, 86%) expressed a distributional preference. With a smaller distributional discrepancy, indecision increased, with 35% of respondents having no preference and the remainder split almost evenly between the two programs. Other scenarios showed that health officials' pro-youth biases were only slightly larger than their distributional preferences and that distributional preferences were magnified when combined with minor differences in average ages of beneficiaries. Conclusions: A substantial minority of health care decision-makers had difficulty choosing between programs with similar overall gains and distributional differences — a result consistent with the utilitarian assumptions of cost-effectiveness analysis. However, when distributional differences were large, decision-makers clearly favored large gains for a few beneficiaries rather than small gains for many. Policy analysts should explicitly weigh distributional issues along with aggregate health gains when addressing resource allocation problems.

Analytical strategies can help deal with potential confounding but readers need to know which strategy is appropriate The previous articles in this series1 2 argued that cohort studies are exposed to selection bias and confounding, and that critical appraisal requires a careful assessment of the study design and the identification of potential confounders. This article describes two analytical strategies—regression and stratification—that can be used to assess and reduce confounding. Some cohort studies match individual participants in the intervention and comparison groups on the basis of confounders, but because matching may be viewed as a special case of stratification we have not discussed it specifically and details are available elsewhere.3 4 Neither of these techniques can eliminate bias related to unmeasured or unknown confounders. Furthermore, both have their own assumptions, advantages, and limitations. Regression uses the data to estimate how confounders are related to the outcome and produces an adjusted estimate of the intervention effect. It is the most commonly used method for reducing confounding in cohort studies. The outcome of interest is the dependent variable, and the measures of baseline characteristics (such as age and sex) and the intervention are independent variables. The choice of method of regression analysis (linear, logistic, proportional hazards, etc) is dictated by the type of dependent variable. For example, if the outcome is binary (such as occurrence of hip fracture), a logistic regression model would be appropriate; in contrast, if the outcome is time to an event (such as time to hip fracture) a proportional hazards model is appropriate. Regression analyses estimate the association of each independent variable with the dependent variable after adjusting for the effects of all the other variables. Because the estimated association between the intervention and outcome variables adjusts …

Although confounding is an important problem of cohort studies, its effects can be minimised to enable valid comparison In cohort studies, who does or does not receive an intervention is determined by practice patterns, personal choice, or policy decisions. This raises the possibility that the intervention and comparison groups may differ in characteristics that affect the study outcome, a problem called selection bias. If these characteristics have independent effects on the observed outcome in each group, they will create differences in outcomes between the groups apart from those related to the interventions being assessed. This effect is known as confounding.1 In the first paper in the series we dealt with the design and use of cohort studies and how to identify selection bias.2 This paper focuses on the definition and assessment of confounders. For a characteristic to be a confounder in a particular study, it must meet two criteria.1 The first is that it must be related to the outcome in terms of prognosis or susceptibility. For example, in the study of the association between antipsychotic use and hip fracture that we considered in the first paper,2 age is known to be related to risk of hip fracture and therefore has the potential to be a confounder. The second criterion that defines a confounder is that the distribution of the characteristic is different in the groups being compared. It can differ in terms of either the mean or the degree of variation or variability in that characteristic. For example, for age to be a confounder in a cohort study, either the average age or the variation in the age in the groups being compared would have to be different. Assessing variation as well as average values is important because groups can have the same average value …

To examine current utilization patterns of cholinesterase inhibitor (ChEI) therapy for dementia to determine treatment duration, use in long-term care, how often patients receive these drugs until death, and frequency of switching between the available ChEIs.A population-based healthcare administrative database study.Patients aged 66 and older from the Canadian province of Ontario who received a new prescription for a ChEI between June 1, 2000, and December 31, 2002. Patients were followed until discontinuation of ChEI therapy, death, or end of the observation period (March 31, 2005).Twenty-eight thousand nine hundred and sixty-one patients, including 4,601 residing in long-term care, mean age 80, 63% female.Information on diagnosis, medical comorbidity, physician visits, and concomitant medication use was obtained. Estimates of duration of continuous use were determined. The percentage of patients who remained on the initial dose prescribed, the proportion who switched to a second ChEI, and the percentage who remained on ChEIs until death were calculated.Patients had on average more than 26 physician visits in the year before ChEI therapy, but only 28% had seen a dementia specialist. Concomitant use of potentially inappropriate medications (strongly anticholinergic medications and benzodiazepines) was noted in 37% of patients. The average length of treatment for all patients was 866 days. Many patients (43%) remained on the initial dose prescribed, 6% switched to another ChEI, and 19% died while on ChEI therapy.Elderly patients with dementia are treated for lengthy periods of time with ChEIs in the community and in long-term care facilities. Further research is required to determine whether these utilization patterns are appropriate. It is also unclear whether these results are generalizable to other populations without universal health coverage or drug formulary benefits.

To estimate the rate of new chronic benzodiazepine use after hospitalization in older adults not previously prescribed with benzodiazepines.Retrospective cohort study using linked, population-based administrative data.Ontario, Canada between April 1, 1992 and March 31, 2005.Community-dwelling seniors who had not been prescribed benzodiazepine drugs in the year before hospitalization were selected from all 1.4 million Ontario residents aged 66 years and older.New chronic benzodiazepine users, defined as initiation of benzodiazepines within 7 days after hospital discharge and an additional claim within 8 days to 6 months. We used multivariate logistic regression to examine for the effect of hospitalization on the primary outcome after adjusting for confounders.There were 405,128 patient hospitalizations included in the cohort. Benzodiazepines were prescribed to 12,484 (3.1%) patients within 7 days of being discharged from hospital. A total of 6,136 (1.5%) patients were identified as new chronic benzodiazepine users. The rate of new chronic benzodiazepine users decreased over the study period from 1.8% in the first year to 1.2% in the final year (P.001). Multivariate logistic regression found that women, patients admitted to the intensive care unit or nonsurgical wards, those with longer hospital stays, higher overall comorbidity, a prior diagnosis of alcoholism, and those prescribed more medications had significantly elevated adjusted odds ratios for new chronic benzodiazepine users. Older individuals had a lower risk for the primary outcome.New benzodiazepine prescription after hospitalization occurs frequently in older adults and may result in chronic use. A systemic effort to address this risky practice should be considered.

Background Excessive prescribing of antipsychotic therapy is a concern owing to their potential to cause serious adverse events. We explored variation in the use of antipsychotic therapy across nursing homes in Ontario, Canada, and determined if prescribing decisions were based on clinical indications. Methods A point-prevalence study of antipsychotic therapy use in 47 322 residents of 485 provincially regulated nursing homes in December 2003. Facilities were classified into quintiles according to their mean antipsychotic prescribing rates. Residents were grouped into those with a potential clinical indication or no identified clinical indication for antipsychotic therapy. Results A total of 15 317 residents (32.4%) were dispensed an antipsychotic agent. The mean rate of antipsychotic prescribing by home ranged from 20.9% in the quintile of facilities with the lowest mean prescribing rates (quintile 1) to 44.3% in facilities with the highest mean prescribing rates (quintile 5). Compared with individuals residing in nursing homes with the lowest mean antipsychotic prescribing rates, those residing in facilities with the highest rates were 3 times more likely to be dispensed an antipsychotic agent (adjusted odds ratio [AOR], 3.0; 95% confidence interval [CI], 2.74-3.19). Similar rates were observed among residents with psychoses with or without dementia (AOR, 2.7; 95% CI, 2.35-3.09) and residents without psychoses or dementia (AOR, 2.9; 95% CI, 2.19-3.81) who had no identifiable indication for an antipsychotic therapy. Conclusion Residents in facilities with high antipsychotic prescribing rates were about 3 times more likely than those in facilities with low prescribing rates to be dispensed an antipsychotic agent, irrespective of their clinical indication.

Background Public insurance plans for pharmaceuticals in Canada differ substantially across provinces in the conditions under which pharmaceuticals are reimbursed. Coxibs provide a good example. Quebec had no restrictions on reimbursement for these drugs. Ontario required physicians to submit the clinical indications for their use on the prescription. British Columbia required physicians to seek and receive prior authorisation from the drug plan. Objective This study compares the effects of different reimbursement policies on coxib, non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs), and gastro-protective agent (GPA) use and cost. Study design Analysis of retrospective time series analysis of all NSAID and GPA administrative claims data from April 1997 through December 2002. Setting Administrative claims data from April 1997 through December 2002 for each of the publicly funded drug plans in Quebec, Ontario, and British Columbia. In addition, we obtained data from BC PharmaNet, which records all dispensed prescriptions in British Columbia. Patients or other participants Senior beneficiaries (≥ 65 years). Main outcome measure We compared the projected total NSAID utilisation in the absence of coxib reimbursement restriction with actual utilisation by province and drug category. Projected utilisation was based on ARIMA modelling and reported as the number of defined daily doses (DDDs) per 100 senior (≥65 years) beneficiaries/month. Results In Ontario, under its “limited use” policy, uptake and steady-state use of coxibs was similar to that in Quebec, where there were no restrictions. In British Columbia, publicly funded use of coxibs was 6% of that in Ontario and Quebec. Despite a shift to private reimbursement, total coxib use in BC was only 50% of use in Ontario and Quebec. The use of all NSAIDS (nsNSAIDS plus coxibs) increased for all provincial drug plans except for BC. The increase and overall rate of total NSAID use was greatest in Ontario. Neither Ontario's nor BC's policies had an impact on use of nsNSAIDs or GPAs. Conclusion Only BC's policy effectively limited publicly funded coxib use. However, there was substantial cost-shifting to out-of-pocket and third party insurance plans in BC.

To describe recent trends in the proportion of deliveries in women with pregestational diabetes (PGD), their use of services, and diabetes-related obstetrical complications.In this population-based retrospective cohort study, comprehensive administrative data were used to identify all women (with and without PGD) who gave birth in an Ontario, Canada, hospital from 1996 to 2001. Data on maternal complications and interventions were obtained from hospital discharge records; data on use of prenatal services were obtained from fee-for-service claims.The proportion of deliveries in women with PGD increased steadily from 0.8% in 1996 to 1.2% in 2001 (P0.001). In 2001, women with PGD were more likely to be diagnosed with shoulder dystocia (adjusted odds ratio 2.00 [95% CI 1.55-2.58]), hypertension (4.13 [3.44-4.96]), and preeclampsia/eclampsia (4.44 [3.43-5.73]) and have higher rates of inductions (1.69 [1.52-1.88]) and caesarean sections (1.78 [1.60-1.98]) than women without PGD. In 2001, 50% of the women with PGD had a visit to a diabetes specialist during pregnancy and only 30% of women had claims for a prenatal retinal examination. Both of these rates have decreased over the study period.Women with PGD now account for a larger proportion of deliveries. These women continue to have higher obstetrical complication and intervention rates than women without PGD and many do not receive recommended specialty care during pregnancy.

The authors sought to determine the incidence of lithium-induced hypothyroidism in a population-based cohort of older adults beginning lithium therapy and thereby to inform clinical guidelines on the frequency of monitoring necessary in this group.The authors conducted a population-based observational cohort study using four administrative databases that contained information on over 1.3 million older adults in Ontario who receive universal healthcare coverage in terms of physician services, drugs, and hospitalizations. Over an 18-month period, they studied adults ageor=65 who were newly prescribed lithium or valproate, monitoring subjects for initiation of T4 therapy (as a proxy for hypothyroidism) while they continued their lithium use.The authors identified 1,705 new users of lithium and 2,406 new users of valproate with similar baseline characteristics. Lithium users were significantly more likely to be treated with T4 than were valproate users. The rate of T4 treatment per 100 person-years was 5.65 in the lithium group and 2.70 in the valproate group.T4 treatment was initiated in almost 6% of lithium-treated patients, suggesting the possibility that hypothyroidism developed twice as frequently among these patients as would be expected among a mixed-age population. Increased vigilance and continued monitoring of thyroid functioning for at least 2 years is necessary in older adults beginning lithium therapy.

Cohort studies can provide valuable information unavailable from randomised trials, but readers need to be alert to possible flaws

To evaluate the representation of frail older adults in randomized controlled trials (RCTs), and to assess consequences of under representation by analyzing drug discontinuation rates.A cohort of older adults newly dispensed donepezil in Ontario between September 2001 and March 2002 was constructed using administrative data. A systematic review of the literature identified RCTs of donepezil. Patients dispensed donepezil were then compared to clinical trial subjects. Discontinuation rates were examined for patients with and without potential contraindications to this drug.There were 6,424 older adults in the Ontario cohort with new claims for donepezil. Ten RCTs evaluating the use of donepezil were identified (n = 3,423). Between 51% and 78% of the Ontario cohort would have been ineligible for RCT enrollment. Patients dispensed donepezil were older (80.3 vs. 73.7 years, p0.001) and more likely to be in long-term care (14.1 vs. 7.1%, p0.001) than RCT subjects. Overall, 27.8% of the Ontario cohort discontinued donepezil within seven months of initial prescription. Discontinuation rates were significantly higher for patients with a history of obstructive lung disease, active cardiovascular disease, or Parkinsonism.Fewer than half of the older adults dispensed donepezil in Ontario would have been eligible to participate in the RCTs that established the efficacy of this drug. Discontinuation rates were higher among patient groups not represented in the trials. Clinicians should carefully assess the potential risks and benefits of such drug therapies for older patients with dementia.

To explore the prescribing of potentially inappropriate drug therapy in Ontario, Canada where there is a restrictive drug formulary relative to the US where there is no single drug formulary. A retrospective, cohort study using an administrative database (Ontario, Canada) compared with published survey results (US). All 1 088 680 community-dwelling adults ≥66 years of age in Ontario, Canada compared with published survey results from 2455 community-dwelling older adults in the US in 1996. Patterns of potentially inappropriate drug prescribing were compared between countries using a list of 33 potentially inappropriate drug therapies. These therapies were classified by an expert panel into three categories: (i) those to always avoid; (ii) those which are rarely appropriate; and (iii) those with only some indications to prescribe. Among the 33 potentially inappropriate drug therapies, 15 (45%) prescribed in the US were not available through Ontario’s drug formulary. Potentially inappropriate drug therapies available through the Ontario Drug Benefit Plan (ODB) and also in the US were frequently prescribed in both Ontario and the US. Differences in prescribing patterns of individual drug therapies were noted between the two countries. Specifically, in the rarely appropriate category, diazepam, a long half-life benzodiazepine, was much more frequently dispensed in Ontario than in the US (3.18% vs 1.37%). In contrast, dextropropoxyphene, an opioid with a poor adverse event profile was more frequently prescribed in the US than in Ontario (6.21% vs 0.74%). Almost half of the potentially inappropriate drug therapies that are available in the US are unavailable from Ontario’s drug formulary. Potentially inappropriate drug therapies that were available through the ODB were frequently prescribed in both countries. Alternative approaches that make information immediately accessible to physicians at the time they make prescribing decisions should be considered to improve prescribing practices.

To compare patterns of potentially inappropriate drug therapy prescribing in community-dwelling older adults and nursing home residents in Ontario, Canada.A retrospective cohort study using administrative databases.Ontario community and nursing home facilities.All 1,275,619 older adults aged 66 and older in Ontario (1,216,900 community-dwelling and 58,719 nursing home residents) who were dispensed at least one prescription from the comprehensive provincial drug plan in 2001. In Ontario, the provision of clinical pharmacy services is mandated in the nursing home setting. No comparable program exists for older adults in the community setting.Potentially inappropriate drug prescribing was compared between community-dwelling and nursing home residents in two categories: those to always avoid and therapies considered rarely appropriate to prescribe.Of the 1,275,619 adults in the cohort, nursing home residents were older (mean age+/-standard deviation=84.2+/-7.6 vs 75.0+/-6.5, P.001), included more women (73.3% vs 57.7%, P.001), had higher comorbidity scores (measured by the number of distinct drug therapies dispensed in the prior year (10.7+/-6.8 vs 7.2+/-5.7, P.001) and Charlson comorbidity scores (1.4+/-1.6 vs 0.9+/-1.5, P.001)) than community-dwelling individuals. Community-dwelling older adults were significantly more likely to be dispensed at least one drug therapy in the always avoid or rarely appropriate category than nursing home residents (3.3% vs 2.3%, P.001). Using a logistic regression model that controlled for age, sex, and comorbidity (number of distinct drug therapies dispensed in the prior year), nursing home residents were close to half as likely to be dispensed one of these potentially inappropriate drug therapies as community-dwelling older adults (odds ratio=0.52, 95% confidence interval=0.49-0.55, P.001).Potentially inappropriate drug therapy in the always avoid and rarely indicated categories is dispensed less often to nursing home residents than to older community-dwelling adults. Clinical pharmacist services, which are mandated in the nursing home setting, may be responsible for these differences in Ontario, Canada.

To describe the incidence and dose of neuroleptic drug therapy newly dispensed for behavioral disorders to older adults admitted to nursing homes and to determine whether this use is associated with patient characteristics and contact with specialists.A retrospective cohort study using administrative data from a comprehensive and universal drug program.All licensed nursing homes in Ontario, Canada.All 19,780 adults aged 66 and older who had no evidence of neuroleptic drug use in the previous year and no history of major psychosis and were newly admitted to a nursing home between April 1, 1998, and March 31, 2000.Exposure to neuroleptic drug therapy and initial dose were measured using claims submitted to the Ontario Drug Benefit Program.A prescription for a neuroleptic therapy was dispensed to 17% of older adults with no previous neuroleptic exposure within 100 days and to 24% within 1 year of their nursing home admission. New exposure to a neuroleptic therapy was less likely in women (odds ratio (OR)=0.7, 95% confidence interval (CI)=0.6-0.8) and more likely in residents with dementia (OR=3.5, 95% CI=3.2-3.8). Almost 10% of nursing home residents received an initial dose that exceeded recommended thresholds. Only 14% of those newly exposed had prior contact with a geriatrician or psychiatrist.Incident use of neuroleptics in Ontario nursing homes is substantial. Use of high doses suggests that some physicians may need better information about using these agents, particularly given the rapid adoption of atypical neuroleptic drug therapies.

Over the past decade, valproic acid (prescribed as divalproex in North America) has been marketed as an alternative to lithium for treating bipolar disorders. For elderly patients, however, there is no clear evidence that valproic acid is more beneficial than lithium. Moreover, the evidence for the superiority of valproic acid in treating bipolar disorders—mixed episodes and rapid cycling—has been challenged in a recent Cochrane review.1 Valproic acid has not benefited patients with manic and psychiatric symptoms in dementia, despite the growing use of the drug in the management of these conditions.2 Recently, the relatively rapid shift in prescription patterns has been questioned.3 We describe trends in the use of lithium and valproic acid in a large population of people over 65. We obtained information on drug use from the Ontario Drug Benefit Program, which provides comprehensive drug benefits to all residents aged 65 or older in Ontario, Canada. …

Summary Background Many older people do not receive β-blocker therapy after myocardial infarction or receive doses lower than those tested in trials, perhaps because physicians fear that β-blockers may precipitate heart failure. We examined the relation between use of β-blockers, the dose used, and hospital admission for heart failure and 1-year survival in a cohort of all older patients surviving myocardial infarction in Ontario, Canada. Methods We collected data on a cohort of 13 623 patients aged 66 years or older who were discharged from hospital after a myocardial infarction and who did not receive β-blocker therapy or received low, standard, or high doses. We used Cox's proportional-hazards models to study the association of dose with admission for heart failure and survival with adjustment for factors including age, sex, and comorbidity. Findings Among 8232 patients with no previous history of heart failure, dispensing of β-blocker therapy was associated with a 43% reduction in subsequent admission for heart failure (adjusted risk ratio 0·57 [95% C*** 0·48–0·69]) compared with patients not dispensed this therapy. Among the 4681 patients prescribed β-blockers, the risk of admission was greater in the high-dose than in the low-dose group (1·53 [1·01·2·31]). Among all 13 623 patients in the cohort, 2326 (17·1%) died by 1 year. Compared with those not dispensed β-blocker therapy, the adjusted risk ratio for mortality was lower for all three doses (low 0·40 [0·34–0·47], standard 0·36 [0·31–0·42], high 0·43 [0·33–0·56]). Interpretation Compared with high-dose β-blocker therapy, low-dose treatment is associated with a lower rate of hospital admission for heart failure and has a similar 1-year survival benefit. Our findings support the need for a randomised controlled trial comparing doses of β-blocker therapy in elderly patients.

Background:Coronary artery disease is a leading cause of heart failure. Statins are efficacious drugs for the primary and secondary prevention of coronary heart disease, but their value in persons with heart failure remains unknown. Methods:We performed a population-based retrospective cohort study involving the entire province of Ontario, Canada, restricting participants to those aged 66 to 85 years who were free of cancer and who survived at least 90 days following hospitalization for newly diagnosed heart failure. The primary study outcome was the risk of death from all causes, nonfatal acute myocardial infarction, or nonfatal stroke among persons newly dispensed statins (n=1146) relative to those who were not (n=27682). Results:Themeanageofallparticipantswas76.5years, and half were women. During the 7-year study period, death, acute myocardial infarction, or stroke occurred in 217statinrecipients(13.6per100person-years)vs12299 nonrecipients (21.8 per 100 person-years; adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.630.83). Most of the benefit from statins was related to a reduction in all-cause mortality (adjusted HR, 0.67; 95% CI,0.57-0.78).Nosignificantreductionwasseenforsubsequent myocardial infarction (adjusted HR, 0.81; 95% CI,0.63-1.03)orstroke(adjustedHR,0.81;95%CI,0.531.25). Conclusions: Statin use is associated with a lower risk of death among seniors newly diagnosed as having congestive heart failure. While statin use has been previously shown to be efficacious in patients with coronary heartdiseaseandstroke,wecouldnotcontrolforallprognosticriskfactorsinthepresentstudy,includingleftventricular ejection fraction and serum lipid levels. Better evidence can direct clinicians about which patients with heart failure might benefit from these drugs. Arch Intern Med. 2005;165:62-67

Objectives. This study was done to compare characteristics and outcomes of patients with acute myocardial infarction participating in two thrombolysis trials with those of nontrial patients at study hospitals and external hospitals. Background. Preferential recruitment of lower risk patients into randomized trials of thrombolysis has been suggested by earlier studies. However, to date there has not been a definitive population-based comparison of characteristics and outcomes for thromblysis trial participants and nonparticipants. Methods. Population-based data on hospital admissions and mortality from acute myocardial infarction for all hospitals in Ontario from 1989 to 1992 were linked to data on trial participants in two distinct thrombolysis studies (GUSTO I and LATE). Included were 1,304 patients entered into GUSTO, 12,657 nonparticipants at GUSTO hospitals, 249 patients entered into LATE, 5,997 nonparticipants at LATE hospitals and 12,299 patients at external hospitals. The main outcomes were differences in age, gender, comorbidity scores, coronary revascularization and survival to hospital discharge. Results. Patients in both GUSTO and LATE were significantly more likely to be

Background Antipsychotic therapy is widely used to treat behavioral problems in older adults with dementia. Cohort studies evaluating the safety of antipsychotic therapy generally focus on a single adverse event. We compared the rate of developing any serious event, a composite outcome defined as an event serious enough to lead to an acute care hospital admission or death within 30 days of initiating antipsychotic therapy, to better estimate the overall burden of short-term harm associated with these agents. Methods In this population-based, retrospective cohort study, we identified 20 682 matched older adults with dementia living in the community and 20 559 matched individuals living in a nursing home between April 1, 1997, and March 31, 2004. Propensity-based matching was used to balance differences between the drug exposure groups in each setting. To examine the effects of antipsychotic drug use on the composite outcome of any serious event we used a conditional logistic regression model. We also estimated adjusted odds ratios using models that included all covariates with a standard difference greater than 0.10. Results Relative to those who received no antipsychotic therapy, community-dwelling older adults newly dispensed an atypical antipsychotic therapy were 3.2 times more likely (95% confidence interval, 2.77-3.68) and those who received conventional antipsychotic therapy were 3.8 times more likely (95% confidence interval, 3.31-4.39) to develop any serious event during the 30 days of follow-up. The pattern of serious events was similar but less pronounced among older adults living in a nursing home. Conclusions Serious events, as indicated by a hospital admission or death, are frequent following the short-term use of antipsychotic drugs in older adults with dementia. Antipsychotic drugs should be used with caution even when short-term therapy is being prescribed.

Background —The Warm Heart Trial randomized 1732 CABG patients to receive warm or cold blood cardioplegia. In the warm cardioplegia patients, nonfatal perioperative cardiac events were significantly decreased and the mortality rate was nonsignificantly decreased (1.4% versus 2.5%, P =0.12). The purpose of the present study was to evaluate the late results of these trial patients. Methods and Results —Randomization was stratified according to surgeon and urgency of the operation. Seven hundred sixty-two patients recruited from 1 of the centers were followed through the hospital clinic for late events. Late survival (including perioperative deaths) at 72 months was nonsignificantly greater in the warm cardioplegia patients (94.5±1.7%, mean±SEM) than in the cold cardioplegia patients (90.9±2.6%). Independent predictors of mortality by Cox proportional hazards model were redo CABG, diabetes mellitus, renal insufficiency, and increasing age. The influence of nonfatal perioperative events (perioperative myocardial infarction according to computerized ECG readings or low output syndrome as determined by an outcome committee) on late survival was also analyzed. Late survival at 84 months was significantly reduced in the group who experienced nonfatal perioperative outcomes (94.5±1.7% versus 84.9±4.5%, P P Conclusions —Effective myocardial protection through either cold or warm blood cardioplegia is essential, because late survival is significantly reduced in patients with nonfatal perioperative cardiac outcomes.

• The DSM-III-R criteria for uncomplicated alcohol withdrawal require the presence of coarse tremor of the hands, tongue, or eyelids plus one of a number of other clinical features. We examined the validity and other characteristics of these items in 137 patients in pure alcohol withdrawal using the reliable and valid Clinical Institute Withdrawal Assessment for Alcohol. The DSM-III-R items of hand tremor amplitude, nausea or vomiting, headache, transient hallucinations, autonomic hyperactivity (increased pulse or sweating), and anxiety correlated significantly with total score and significantly indicated clinical severity. Addition of an "agitation" item improved the correlation. The diagnostic accuracy is greater than 95% if any two or more items are present. The number of positive items, of which tremor can be one, to grade clinical severity shows that a score of 2 indicates "very mild"; 3, "mild"; 4, "moderate"; and 5, "severe." We propose that an Alcohol Withdrawal Diagnostic Inventory and a DSM-III-R —compatible brief Clinical Institute Withdrawal Assessment for Alcohol are useful for clinical research, where graded symptom characterization is needed. Our data may be helpful in the development of criteria for DSM-IV .

The importance of nonpharmacologic and pharmacologic interventions in the treatment of alcohol withdrawal is not known. A randomized, double-blind, placebo-controlled trial was conducted with 41 patients in alcohol withdrawal in an emergency department. The patients received either supportive care (10 min of standardized assessments, reassurance, reality orientation, and nursing care an hour) with three doses of sublingual lorazepam 2 mg every 2 hr (21 patients, drug group) or supportive care with three doses of sublingual placebo every 2 hr (20 patients, no-drug group). Immediately before each drug dose, the clinical course of alcohol withdrawal was assessed hourly by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A). Interraters reliability in using CIWA-A was high. After each assessment, supportive care was given for 10 min before each dose. After completion of a 7-hr initial phase, patients were discharged and reassessed daily for 5 days. Thirty-seven patients (90.2%) improved in the initial phase. Treatment failures (CIWA-A greater than 10) were more common in the patients treated without drug (3/20, 15%) than in those treated with drug (1/21, 4.8%). Overall variations in intergroup CIWA-A scores during the initial phase were not significant. The rate of improvement of CIWA-A scores over the first 2 hr after drug was slightly faster in patients receiving lorazepam than in the control group. CIWA-A scores were the same during follow-up. These results indicate that most outpatients in mild to moderate alcohol withdrawal without medical complications improve without drug therapy in the emergency department setting.

No effective drug for decreasing ethanol intake is available for clinical use. Our previous studies showed that zimeldine decreased ethanol intake in rats and nondepressed alcohol abusers. However, zimeldine was withdrawn from the market because of serious toxicity. We tested citalopram, a selective serotonin uptake inhibitor, in 39 male nondepressed early-stage problem drinkers (aged 19 to 61 years). Subjects were randomly allocated to receive either citalopram, 20 (n = 20) or 40 (n = 19) mg/day orally, or placebo in a double-blind, crossover trial. Citalopram administration and ethanol intake were assessed by self-report and objectively. Citalopram, 20 mg/day, did not show an effect. However, citalopram, 40 mg/day, decreased the number of drinks consumed (F1,17 = 5.27; P < 0.05) and increased the number of abstinent days (F1,17 = 13.18; P < 0.005). The effect is probably through modulation of the neurobiologic mechanisms regulating ethanol intake. Our results suggest a new pharmacologic approach to decrease ethanol intake. Clinical Pharmacology and Therapeutics (1987) 41, 266–274; doi:10.1038/clpt.1987.27

A shortened 10-item scale for clinical quantitation of the severity of the alcohol withdrawal syndrome has been developed. This scale offers an increase in efficiency while at the same time retaining clinical usefulness, validity and reliability. It can be incorporated into the usual clinical care of patients undergoing alcohol withdrawal and into clinical drug trials of alcohol withdrawal.

Summary A randomized, double-blind, placebo-controlled single cross-over study of the alcohol sensitizing drug, calcium carbimide (CC), was conducted in 128 patients with alcohol dependence. Seventy-one (55%) completed the 4-month study. Patients reported drinking and pill-taking behaviour, and submitted urines (for analysis of alcohol and the tablet marker riboflavin) on 97%, and 91% of treatment days, respectively. All of the 69 analyzable computers were abstinent on at least 85% of days, and 58% (40) were alcohol-free during the study. Medications were taken on at least 85% of days. Symptoms and adverse clinical findings were not increased in frequency during CC, compared to placebo. Seventy-eight per cent of the patients believed they had received CC throughout the study, suggesting that CC exerts a strong psychological deterrent effect. Alcohol consumption was significantly reduced to the same extent with CC and placebo, compared to pre-treatment levels.

The effect of zimelidine, a specific serotonin-reuptake inhibitor, on alcohol intake was tested in 13 healthy male, nondepressed heavy drinkers who were randomly allocated to receive zimelidine or placebo in a double-blind, crossover experiment. There were five 2-wk experimental periods (baseline, placebo 1 and 2, and zimelidine 1 and 2). Treatment was discontinued in three subjects due to a suspected adverse reaction and three other subjects dropped out. Thus, 13 subjects participated in at least two experimental drug periods and only 10 participated in all the periods. In the 13 subjects zimelidine increased the days of abstinence and decreased the daily number of drinks consumed, whereas in the 10 subjects only the number of days of abstinence increased. Subjects did not report aversive alcohol-sensitizing reactions. Spielberger state-anxiety test scores and depression scores (Montgomery/Asberg and Hamilton) were low at the beginning and throughout the study. Our data suggest that zimelidine modifies alcohol intake by a different mechanism than previously tested drugs, possibly by modulating the central neural mechanism that controls drinking of alcohol.

Alcohol withdrawal therapy can be simplified with a loading dose of diazepam, taking advantage of the kinetic tapering afforded by the drug's long t 1/2s and its metabolites, and of the effectiveness of nonpharmacologic maneuvers. In a double-blind trial, 50 inpatients in moderate to severe alcohol withdrawal received 20 mg oral diazepam and supportive care (n = 25) or placebo and supportive care (n = 25) every 2 hr until they were asymptomatic. Fifty-six percent of patients responded to placebo within 5 +/- 2.9 hr (mean +/- SD), whereas 72% responded to initial diazepam within 6.3 +/- 3.9 hr. Patients treated with diazepam had more rapid and greater improvement than those treated with placebo. Patients who did not respond to six doses of diazepam received further (unblinded) diazepam, 20 mg, every 1 to 2 hr. All patients who did not initially respond (n = 18) improved after more diazepam. Thus all patients who received diazepam (n = 36), during the experimental phase or subsequently, were effectively treated. There were no adverse effects. The median number of 20-mg diazepam doses to treat alcohol withdrawal were three, given over a period of 7.6 hr (range = 1 to 12 and 0.33 to 45 hr). Complications occurred only in those who received placebo during the experimental phase, indicating that delay in therapy may be responsible for the appearance of complications in alcohol withdrawal.

Objective To compare the incidence of admissions to hospital for stroke among older adults with dementia receiving atypical or typical antipsychotics. Design Population based retrospective cohort study. Setting Ontario, Canada. Patients 32 710 older adults (≤ 65 years) with dementia (17 845 dispensed an atypical antipsychotic and 14 865 dispensed a typical antipsychotic). Main outcome measures Admission to hospital with the most responsible diagnosis (single most important condition responsible for the patient9s admission) of ischaemic stroke. Observation of patients until they were either admitted to hospital with ischaemic stroke, stopped taking antipsychotics, died, or the study ended. Results After adjustment for potential confounders, participants receiving atypical antipsychotics showed no significant increase in risk of ischaemic stroke compared with those receiving typical antipsychotics (adjusted hazard ratio 1.01, 95% confidence interval 0.81 to 1.26). This finding was consistent in a series of subgroup analyses, including ones of individual atypical antipsychotic drugs (risperidone, olanzapine, and quetiapine) and selected subpopulations of the main cohorts. Conclusion Older adults with dementia who take atypical antipsychotics have a similar risk of ischaemic stroke to those taking typical antipsychotics.

Antipsychotic drugs are widely used to manage behavioral and psychological symptoms in dementia despite concerns about their safety.To examine the association between treatment with antipsychotics (both conventional and atypical) and all-cause mortality.Population-based, retrospective cohort study.Ontario, Canada.Older adults with dementia who were followed between 1 April 1997 and 31 March 2003.The risk for death was determined at 30, 60, 120, and 180 days after the initial dispensing of antipsychotic medication. Two pairwise comparisons were made: atypical versus no antipsychotic use and conventional versus atypical antipsychotic use. Groups were stratified by place of residence (community or long-term care). Propensity score matching was used to adjust for differences in baseline health status.A total of 27,259 matched pairs were identified. New use of atypical antipsychotics was associated with a statistically significant increase in the risk for death at 30 days compared with nonuse in both the community-dwelling cohort (adjusted hazard ratio, 1.31 [95% CI, 1.02 to 1.70]; absolute risk difference, 0.2 percentage point) and the long-term care cohort (adjusted hazard ratio, 1.55 [CI, 1.15 to 2.07]; absolute risk difference, 1.2 percentage points). Excess risk seemed to persist to 180 days, but unequal rates of censoring over time may have affected these results. Relative to atypical antipsychotic use, conventional antipsychotic use was associated with a higher risk for death at all time points. Sensitivity analysis revealed that unmeasured confounders that increase the risk for death could diminish or eliminate the observed associations.Information on causes of death was not available. Many patients did not continue their initial treatments after 1 month of therapy. Unmeasured confounders could affect associations.Atypical antipsychotic use is associated with an increased risk for death compared with nonuse among older adults with dementia. The risk for death may be greater with conventional antipsychotics than with atypical antipsychotics.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

The objective, sensitive, and reliable quantitation of withdrawal symptoms is essential to assess physical dependence on drugs. Data collected from 23 patients abusing high doses of benzodiazepines (mean diazepam dose equivalents, 150 mg/day; range, 40-500) and from 40 long-term therapeutic users randomized to receive either placebo (N = 19) or diazepam (N = 21; mean diazepam dose equivalents, 15 mg/day; range, 5-40; mean duration of use, 72 months; range, 6-240) were analyzed. Information on the type and severity of symptoms was obtained from several assessment instruments. In the high-dose abuse group, plasma benzodiazepine concentrations were measured daily and the 3 consecutive days of greatest relative daily fall were considered the critical withdrawal period. Selection of the 22 items of the Clinical Institute Withdrawal Assessment-Benzodiazepines (CIWA-B) was based on statistically significant differences between baseline and critical withdrawal periods in high-dose subjects and between symptoms associated with placebo and diazepam in low-dose subjects, using contingency tables and logistic regression analysis. Of the 104 symptoms measured by the assessment instruments, 22 symptoms were found to distinguish withdrawal from prewithdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)