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Studies in patients with brain lesions play a fundamental role in unraveling the brain's functional anatomy. Lesion‐symptom mapping (LSM) techniques can relate lesion location to cognitive performance. However, a limitation of current LSM approaches is that they can only evaluate one cognitive outcome at a time, without considering interdependencies between different cognitive tests. To overcome this challenge, we implemented canonical correlation analysis (CCA) as combined multivariable and multioutcome LSM approach. We performed a proof‐of‐concept study on 1075 patients with acute ischemic stroke to explore whether addition of CCA to a multivariable single‐outcome LSM approach (support vector regression) could identify infarct locations associated with deficits in three well‐defined verbal memory functions (encoding, consolidation, retrieval) based on four verbal memory subscores derived from the Seoul Verbal Learning Test (immediate recall, delayed recall, recognition, learning ability). We evaluated whether CCA could extract cognitive score patterns that matched prior knowledge of these verbal memory functions, and if these patterns could be linked to more specific infarct locations than through single‐outcome LSM alone. Two of the canonical modes identified with CCA showed distinct cognitive patterns that matched prior knowledge on encoding and consolidation. In addition, CCA revealed that each canonical mode was linked to a distinct infarct pattern, while with multivariable single‐outcome LSM individual verbal memory subscores were associated with largely overlapping patterns. In conclusion, our findings demonstrate that CCA can complement single‐outcome LSM techniques to help disentangle cognitive functions and their neuroanatomical correlates. [ABSTRACT FROM AUTHOR]

Although many studies have shown the performance of machine-learned tools to be at least comparable to the performance of expert physicians, this is not always the case,[24] which underscores the need to conduct clinical verification studies before moving forward with more resource-intensive forms of evaluation. See related articles at www.cmaj.ca/lookup/doi/10.1503/cmaj.202434 and www.cmaj.ca/lookup/doi/10.1503/cmaj.202066 KEY POINTS Evaluation of machine-learned systems is a multifaceted process that encompasses internal validation, clinical validation, clinical outcomes evaluation, implementation research and postimplementation evaluation. Conclusion Evaluation of machine-learned solutions is a multifaceted process that requires the expertise of data scientists, clinician experts and implementation scientists. [Extracted from the article]

An Intel survey of approximately 200 healthcare decision-makers in the United States indicated that more than half of respondents expect widespread AI adoption by 2023 and more than one-third are already using AI-based solutions in their settings [[4]]. Further, many hospitals do not have suitable data environments where very large volumes of data can be safely captured, stored, and processed rapidly for purposes of AI development. Data and infrastructure requirements to enable AI development in the ICU will be a key focus in our series on AI in intensive medicine. [Extracted from the article]

Background: Timely follow-up after hospital discharge may decrease readmission to hospital. Financial incentives to improve follow-up have been introduced in the United States and Canada, but it is unknown whether they are effective. Our objective was to evaluate the impact of an incentive program on timely physician follow-up after hospital discharge.Methods: We conducted an interventional time series analysis of all medical and surgical patients who were discharged home from hospital between Apr. 1, 2002, and Jan. 30, 2015, in Ontario, Canada. The intervention was a supplemental billing code for physician follow-up within 14 days of discharge from hospital, introduced in 2006. The primary outcome was an outpatient visit within 14 days of discharge. Secondary outcomes were 7-day follow-up and a composite of emergency department visits, nonelective hospital readmission and death within 14 days.Results: We included 8 008 934 patient discharge records. The incentive code was claimed in 31% of eligible visits by 51% of eligible physicians, and cost $17.5 million over the study period. There was no change in the average monthly rate of outcomes in the year before the incentive was introduced compared with the year following introduction: 14-day follow-up (66.5% v. 67.0%, overall p = 0.5), 7-day follow-up (44.9% v. 44.9%, overall p = 0.5) and composite outcome (16.7% v. 16.9%, overall p = 0.2).Interpretation: Despite uptake by physicians, a financial incentive did not alter follow-up after hospital discharge. This lack of effect may be explained by features of the incentive or by extra-physician barriers to follow-up. These barriers should be considered by policymakers before introducing similar initiatives. [ABSTRACT FROM AUTHOR]

Purpose: The positive predictive value (PPV) of carotid endarterectomy (CEA) and carotid artery stenting (CAS) procedure and post-operative complication coding were assessed in Ontario health administrative databases.Methods: Between 1 April 2002 and 31 March 2014, a random sample of 428 patients were identified using Canadian Classification of Health Intervention (CCI) procedure codes and Ontario Health Insurance Plan (OHIP) billing codes from administrative data. A blinded chart review was conducted at two high-volume vascular centers to assess the level of agreement between the administrative records and the corresponding patients' hospital charts. PPV was calculated with 95% confidence intervals (CIs) to estimate the validity of CEA and CAS coding, utilizing hospital charts as the gold standard. Sensitivity of CEA and CAS coding were also assessed by linking two independent databases of 540 CEA-treated patients (Ontario Stroke Registry) and 140 CAS-treated patients (single-center CAS database) to administrative records.Results: PPV for CEA ranged from 99% to 100% and sensitivity ranged from 81.5% to 89.6% using CCI and OHIP codes. A CCI code with a PPV of 87% (95% CI, 78.8-92.9) and sensitivity of 92.9% (95% CI, 87.4-96.1) in identifying CAS was also identified. PPV for post-admission complication diagnosis coding was 71.4% (95% CI, 53.7-85.4) for stroke/transient ischemic attack, and 82.4% (95% CI, 56.6-96.2) for myocardial infarction.Conclusions: Our analysis demonstrated that the codes used in administrative databases accurately identify CEA and CAS-treated patients. Researchers can confidently use administrative data to conduct population-based studies of CEA and CAS. [ABSTRACT FROM AUTHOR]

Background and Aims The burden of premature mortality due to opioid-related death has not been fully characterized. We calculated temporal trends in the proportion of deaths attributable to opioids and estimated years of potential life lost (YLL) due to opioid-related mortality in Ontario, Canada. Design Cross-sectional study. Setting Ontario, Canada. Participants Individuals who died of opioid-related causes between January 1991 and December 2010. Measurements We used the Registered Persons Database and data abstracted from the Office of the Chief Coroner to measure annual rates of opioid-related mortality. The proportion of all deaths related to opioids was determined by age group in each of 1992, 2001 and 2010. The YLL due to opioid-related mortality were estimated, applying the life expectancy estimates for the Ontario population. Findings We reviewed 5935 opioid-related deaths in Ontario between 1991 and 2010. The overall rate of opioid-related mortality increased by 242% between 1991 (12.2 per 1 000 000 Ontarians) and 2010 (41.6 per 1 000 000 Ontarians; P < 0.0001). Similarly, the annual YLL due to premature opioid-related death increased threefold, from 7006 years (1.3 years per 1000 population) in 1992 to 21 927 years (3.3 years per 1000 population) in 2010. The proportion of deaths attributable to opioids increased significantly over time within each age group (P < 0.05). By 2010, nearly one of every eight deaths (12.1%) among individuals aged 25–34 years was opioid-related. Conclusions Rates of opioid-related deaths are increasing rapidly in Ontario, Canada, and are concentrated among the young, leading to a substantial burden of disease. [ABSTRACT FROM AUTHOR]

Background: Despite a lack of data describing the long-term efficacy and safety of testosterone replacement therapy (TRT), prescribing of testosterone to older men has increased with the availability of topical formulations. The magnitude of this increase and the impact of formulary restrictions on testosterone prescribing are poorly characterized. Methods: We conducted a time series analysis using the linked health administrative records of men aged 66 years or older in Ontario, Canada between January 1, 1997 and March 31, 2012. We used interventional autoregressive integrated moving average models to examine the impact of a restrictive drug reimbursement policy on testosterone prescribing and examined the demographic profile of men initiating testosterone in the final 2 years of the study period. Results: A total of 28,477 men were dispensed testosterone over the study period. Overall testosterone prescribing declined 27.9% in the 6 months following the implementation of the restriction policy (9.5 to 6.9 men per 1000 eligible; p<0.01). However, the overall decrease was temporary and testosterone use exceeded pre-policy levels by the end of the study period (11.0 men per 1000 eligible), largely driven by prescriptions for topical testosterone (4.8 men per 1000 eligible). Only 6.3% of men who initiated testosterone had a documented diagnosis of hypogonadism, the main criteria for TRT reimbursement according to the new policy. Conclusion: Government-imposed restrictions did not influence long-term prescribing of testosterone to older men. By 2012, approximately 1 in every 90 men aged 66 or older was being treated with TRT, most with topical formulations. [ABSTRACT FROM AUTHOR]

Background: Although warfarin has been extensively studied in clinical trials, little is known about rates of hemorrhage attributable to its use in routine clinical practice. Our objective was to examine incident hemorrhagic events in a large population-based cohort of patients with atrial fibrillation who were starting treatment with warfarin. Methods: We conducted a population-based cohort study involving residents of Ontario (age = 66 yr) with atrial fibrillation who started taking warfarin between Apr. 1, 1997, and Mar. 31, 2008. We defined a major hemorrhage as any visit to hospital for hemorrage. We determined crude rates of hemorrhage during warfarin treatment, overall and stratified by CHADS2 score (congestive heart failure, hypertension, age = 75 yr, diabetes mellitus and prior stroke, transient ischemic attack or thromboembolism). Results: We included 125 195 patients with atrial fibrillation who started treatment with warfarin during the study period. Overall, the rate of hemorrhage was 3.8% (95% confidence interval [CI] 3.8%-3.9%) per person-year. The risk of major hemorrhage was highest during the first 30 days of treatment. During this period, rates of hemorrhage were 11.8% (95% CI 11.1%-12.5%) per person-year in all patients and 16.7% (95% CI 14.3%-19.4%) per personyear among patients with a CHADS2 scores of 4 or greater. Over the 5-year follow-up, 10 840 patients (8.7%) visited the hospital for hemorrhage; of these patients, 1963 (18.1%) died in hospital or within 7 days of being discharged. Interpretation: In this large cohort of older patients with atrial fibrillation, we found that rates of hemorrhage are highest within the first 30 days of warfarin therapy. These rates are considerably higher than the rates of 1%- 3% reported in randomized controlled trials of warfarin therapy. Our study provides timely estimates of warfarin-related adverse events that may be useful to clinicians, patients and policy-makers as new options for treatment become available. [ABSTRACT FROM AUTHOR]

The article discusses the findings of a study to investigate the association between antihypertensive drug treatment and hip fracture risk in elderly patients. It notes that the community-based research was conducted for 301,591 elderly patients in Ontario, Canada with hip fracture occurrences between April 1, 2000 to March 31, 2009. The study confirms a 43 percent increased risk for hip fractures among elderly patients in the first 45 days of receiving antihypertensive drugs.

Objective: Timely aftercare can be viewed as a patient safety imperative. In the context of decreasing inpatient length of stay (LOS) and known child psychiatry human resource challenges, we investigated time to aftercare for adolescents following psychiatric hospitalization. Method: We conducted a population-based cohort study of adolescents aged 15 to 19 years with psychiatric discharge between April 1, 2002, and March 1, 2004, in Ontario, using encrypted identifiers across health administrative databases to determine time to first psychiatric aftercare with a primary care physician (PCP) or a psychiatrist within 395 days of discharge. Results: Among the 7111 adolescents discharged in the study period, 24% had aftercare with a PCP or a psychiatrist within 7 days and 49% within 30 days. High socioeconomic status (adjusted hazard ratio [AHR] 1.31; 95% CI 1.21 to 1.43, ? ≼ 0.001) and psychotic disorders (AHR 1.24; 95% CI 1.12 to 1.36, P≼ 0.001) were associated with greater likelihood of aftercare. Youth in the northern part of the province (AHR 0.48; 95% CI 0.32 to 0.71, ? ≼ 0.001 ), rural areas (AHR 0.82; 95% CI 0.76 to 0.89, ? ≼ 0.001 ), and with selfharm or suicide attempts (AHR 0.58; 95% CI 0.53 to 0.64, ? ≼ 0.001) and substance use disorders (AHR 0.50; 95% CI 0.44 to 0.56, ? ≼ 0.001) were less likely to receive aftercare. Conclusions: Hospitalization is our most intensive, intrusive, and expensive psychiatric treatment setting, yet in our cohort of formerly hospitalized adolescents fewer than 50% received psychiatry-related aftercare in the month postdischarge. Innovations are necessary to address geographic inequities and improve timely access to mental health aftercare for all youth. INSETS: Clinical Implications;Limitations. [ABSTRACT FROM AUTHOR]

Background: Although fluoroquinolones are sometimes associated with mild, transient elevations in aminotransferase levels, serious acute liver injury is uncommon. Regulatory warnings have identified moxifloxacin as presenting a particular risk of hepatotoxicity. Thus, we examined the risk of idiosyncratic acute liver injury associated with the use of moxifloxacin relative to other selected antibiotic agents. Methods: We conducted a population-based, nested, case-control study using health care data from Ontario for the period April 2002 to March 2011. We identified cases as outpatients aged 66 years or older with no history of liver disease, and who were admitted to hospital for acute liver injury within 30 days of receiving a prescription for 1 of 5 broadspectrum antibiotic agents: moxifloxacin, levofloxacin, ciprofloxacin, cefuroxime axetil or clarithromycin. For each case, we selected up to 10 age- and sex-matched controls from among patients who had received a study antibiotic, but who were not admitted to hospital for acute liver injury. We calculated odds ratios (ORs) to determine the association between admission to hospital and previous exposure to an antibiotic agent, using clarithromycin as the reference. Results: A total of 144 patients were admitted to hospital for acute liver injury within 30 days of receiving a prescription for one of the identified drugs. Of these patients, 88 (61.1%) died while in hospital. After multivariable adjustment, use of either moxifloxacin (adjusted OR 2.20, 95% confidence interval [CI] 1.21--3.98) or levofloxacin (adjusted OR 1.85, 95% CI 1.01--3.39) was associated with an increase in risk of acute liver injury relative to the use of clarithromycin. We saw no such risk associated with the use of either ciprofloxacin or cefuroxime axetil. Interpretation: Among older outpatients with no evidence of liver disease, moxifloxacin and levofloxacin were associated with an increased risk of acute liver injury relative to clarithromycin. [ABSTRACT FROM AUTHOR]

The article presents a case study which researches how aftercare for children in the U.S. and Canada impacts emergency department (ED) visits and psychiatric hospitalization readmission by examining health administrative databases. Children in need of mental health services were assessed, and the results found that aftercare increases the possibility of readmission and continuity of care, but it did not increase the need for ED visits or emergency psychiatry.

The article discusses a study about the relationship between opioid dose and opioid-related mortality in patients with non-malignant pain in Ontario. The study involved patients ranging in age from 15 to 64 who were eligible for publicly funded prescription drug coverage and had received an opioid from August 1, 1997 to December 31, 2006. Results showed that the risk of opioid-related death was highest in patients who were treated with 200 milligrams or more of morphine daily.

The article focuses on a population-based, nested case-control study which determined whether prolonged bisphosphonate therapy is associated with an increased risk of subtrochanteric or femoral shaft fracture among women aged 68-years or older in Ontario. The researchers were able to identify 716 women who sustained a subtrochanteric or femoral shaft fracture following initiation of bisphosphonate therapy and 9723 women who sustained typical osteoporotic fracture of the intertrochanteric region or femoral neck. Results indicated high risk of subtrochanteric or femoral shaft fracture among women who are receiving the treatment for more than 5 years.

Introduction: Opioid-related mortality appears to be increasing in Canada. We examined the true extent of the problem and the impact of the introduction of long-acting oxycodone. Methods: We examined trends in the prescribing of opioid analgesics in the province of Ontario from 1991 to 2007. We reviewed all deaths related to opioid use between 1991 and 2004. We linked 3271 of these deaths to administrative data to examine the patients' use of health care services before death. Using time-series analysis, we determined whether the addition of long-acting oxycodone to the provincial drug formulary in January 2000 was associated with an increase in opioid-related mortality. Results: From 1991 to 2007, annual prescriptions for opioids in creased from 458 to 591 per 1000 individuals. Opioid-related deaths doubled, from 13.7 per million in 1991 to 27.2 per million in 2004. Prescriptions of oxycodone increased by 850% between 1991 and 2007. The addition of long-acting oxycodone to the drug formulary was associated with a 5-fold increase in oxycodone-related mortality (p < 0.01) and a 41% increase in overall opioid-related mortality (p = 0.02). The manner of death was deemed unintentional by the coroner in 54.2% and undetermined in 21.9% of cases. Use of health care services in the month before death was common: for example, of the 3066 patients for whom data on physician visits were available, 66.4% had visited a physician in the month before death; of the 1095 patients for whom individual-level prescribing data were available, 56.1% had filled a prescription for an opioid in the month before death. Interpretation: Opioid-related deaths in Ontario have in - creased markedly since 1991. A significant portion of the increase was associated with the addition of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional. The frequency of visits to a physician and prescriptions for opioids in the month before death suggests a missed opportunity for prevention. [ABSTRACT FROM AUTHOR]

Objectives: Health insurers, physicians, and patients worldwide need information on the comparative effectiveness and safety of prescription drugs in routine care. Nonrandomized studies of treatment effects using secondary databases may supplement the evidence based from randomized clinical trials and prospective observational studies. Recognizing the challenges to conducting valid retrospective epidemiologic and health services research studies, a Task Force was formed to develop a guidance document on state of the art approaches to frame research questions and report findings for these studies. Methods: The Task Force was commissioned and a Chair was selected by the International Society for Pharmacoeconomics and Outcomes Research Board of Directors in October 2007. This Report, the first of three reported in this issue of the journal, addressed issues of framing the research question and reporting and interpreting findings. Results: The Task Force Report proposes four primary characteristics—relevance, specificity, novelty, and feasibility while defining the research question. Recommendations included: the practice of a priori specification of the research question; transparency of prespecified analytical plans, provision of justifications for any subsequent changes in analytical plan, and reporting the results of prespecified plans as well as results from significant modifications, structured abstracts to report findings with scientific neutrality; and reasoned interpretations of findings to help inform policy decisions. Conclusions: Comparative effectiveness research in the form of nonrandomized studies using secondary databases can be designed with rigorous elements and conducted with sophisticated statistical methods to improve causal inference of treatment effects. Standardized reporting and careful interpretation of results can aid policy and decision-making. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia. Methods and Findings: We examined the health care records of more than 1.4 million older adults using a case-timecontrol design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3:1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29-3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16-4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy. Conclusions: Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians. [ABSTRACT FROM AUTHOR]

Abstract: Background: In light of growing concerns of bacterial resistance to fluoroquinolones, the province of Ontario instituted a fluoroquinolone restriction policy in March of 2001. The objective of this study was to examine the immediate impact of this policy on the rates of antibiotic prescription use and infectious disease-related hospitalizations among elderly individuals who are dispensed antibiotics. Methods: An interrupted time series analysis was conducted from January 1, 1994, to March 31, 2002, using administrative health care databases covering more than 1.4 million residents of Ontario, Canada, aged 65 years and older. Population rates of antibiotic use and infectious disease-related hospitalizations within 4 weeks after an antibiotic prescription were examined using interventional autoregressive integrated moving average models. Results: Immediately after the introduction of the fluoroquinolone policy, fluoroquinolone prescription rates decreased to approximately 70% of expected rates (P <.01). Approximately 30% higher than expected use of sulfonamide (P =.01) and urinary anti-infectives (primarily nitrofurantoin and trimethoprim; P <.01) were observed within 1 year after policy implementation. No significant changes in the use of any other groups of antibiotics were observed. Although no significant changes in the rates of overall infection-related hospital admissions among antibiotic users were observed, the rate of hospital admission for gastrointestinal infections was 32% lower than expected in the 1 year after the policy change (P <.01). The hospital admission rate for urinary tract infections was approximately 8% higher than expected (P <.01). Conclusions: These findings suggest that formulary restrictions to fluoroquinolones can be implemented effectively to decrease use among an elderly population without adverse impact on hospital admission rates. [Copyright &y& Elsevier]

Background: Population rates of upper gastrointestinal (GI) hemorrhage have been observed to increase with the introduction and rapid uptake of selective cyclooxygenase-2 (COX-2) inhibitors. Changes in COX-2 inhibitor use and upper GI bleeding rates in regions with relatively restrictive drug policies (e.g., British Columbia) have not been compared with changes in regions with relatively less restrictive drug policies (e.g., Ontario). Methods: We collected administrative data for about 1.4 million people aged 66 years and older in British Columbia and Ontario for the period January 1996 to November 2002. We examined temporal changes in the prevalence of NSAID use and admissions to hospital because of upper GI hemorrhage in both provinces using cross-sectional time series analysis. Results: During the period studied, the prevalence of NSAID use in British Columbia's population of older people increased by 25% (from 8.7% to 10.9%; p < 0.01), as compared with a 51% increase in Ontario (from 10.9% to 16.5%; p < 0.01). Hospital admissions because of upper GI hemorrhage increased significantly in Ontario by about 16% on average, or about 2 admissions per 10 000 elderly people, above expected values (p < 0.01). A similar increase was not observed in British Columbia. Interpretation: More restrictive drug coverage policies, although limiting access to drugs and their potential benefits, may protect the population from adverse drug effects. [ABSTRACT FROM AUTHOR]

Rationale Observational cohort studies are frequently used to measure the impact of therapies on the time to a particular outcome. Treatment often has a time-variant nature since it is frequently initiated at varying times during a patient’s follow-up. Studies in the medical literature frequently ignore the time-dependent nature of treatment exposure. Survivor treatment bias can arise when the time dependent nature of treatment exposure is ignored since patients who survived to receive treatment may be healthier than patients who died prior to receipt of treatment. Aims and objectives The objective of the current study was to explicitly quantify the magnitude of survivor-treatment bias. Methods Monte Carlo simulations using parameters obtained from an analysis of patients admitted to hospital with a diagnosis of acute myocardial infarction in Ontario, Canada. Results and conclusions When the true treatment was null (hazard ratio of 1), estimated treatment effects varied from a 4% reduction in mortality to a reduction in mortality of 27% when the time varying nature of the treatment was ignored. Furthermore, survivor-treatment bias increased as the time required foe exposed patients to receive treatment increased. Similarly, survivor treatment bias was amplified as exposure was defined to be exposure at any time prior to mortality compared to exposure within a fixed time interval starting at the time origin. Ignoring the time-dependent nature of treatment results in overly optimistic estimates of treatment effects. Depending on the period required for patients to initiate therapy, treatments with no effect on survival can appear to be strongly associated with improved survival. The current study is the first to explicitly quantify the magnitude of bias that results from ignoring the time-varying nature of treatment exposure in survival studies. [ABSTRACT FROM AUTHOR]

Background. Previous studies have examined the association between proton pump inhibitor (PPI) use and the risk of Clostridium difficile-associated disease (CDAD), with conflicting results. Whether outpatient PPI use influences the risk of hospital admission for CDAD among older patients who have recently been treated with antibiotics is unknown. Methods. We conducted a population-based, nested case-control study of linked health care databases in Ontario, Canada, from 1 April 2002 through 31 March 2005. We identified patients aged ≥66 years who were hospitalized for CDAD within 60 days of receiving outpatient antibiotic therapy. Each case patient with CDAD was matched with 10 control subjects on the basis of age, sex, and details of antibiotic use (antibiotic class, timing, and number of antibiotics used). PPI use by case patients and control subjects was categorized as current (within 90 days), recent (91-180 days), or remote (181-365 days). We used conditional logistic regression to estimate the odds ratio for the association between outpatient PPI use and risk of hospitalization for CDAD. Results. We identified 1389 case patients and 12,303 matched control subjects. Case patients were no more likely than control subjects to have received a PPI in the preceding 90 days (adjusted odds ratio, 0.9; 95% confidence interval, 0.8-1.1). Similarly, we found no association between hospitalization for CDAD and more remote use of PPIs. Conclusions. Among community-dwelling older patients, PPI use is not a risk factor for hospitalization with CDAD. [ABSTRACT FROM AUTHOR]

A research letter to the editor focusing on generic warfarin substitution is presented.

Abstract: Objectives: To illustrate how multiple hypotheses testing can produce associations with no clinical plausibility. Study Design and Setting: We conducted a study of all 10,674,945 residents of Ontario aged between 18 and 100 years in 2000. Residents were randomly assigned to equally sized derivation and validation cohorts and classified according to their astrological sign. Using the derivation cohort, we searched through 223 of the most common diagnoses for hospitalization until we identified two for which subjects born under one astrological sign had a significantly higher probability of hospitalization compared to subjects born under the remaining signs combined (P <0.05). Results: We tested these 24 associations in the independent validation cohort. Residents born under Leo had a higher probability of gastrointestinal hemorrhage (P =0.0447), while Sagittarians had a higher probability of humerus fracture (P =0.0123) compared to all other signs combined. After adjusting the significance level to account for multiple comparisons, none of the identified associations remained significant in either the derivation or validation cohort. Conclusions: Our analyses illustrate how the testing of multiple, non-prespecified hypotheses increases the likelihood of detecting implausible associations. Our findings have important implications for the analysis and interpretation of clinical studies. [Copyright &y& Elsevier]

Objectives: To examine temporal trends in electroconvulsive therapy (ECT) use among all 12 million Ontario residents between January 1992 and December 2004 and to examine the differential trends in older adults, compared with younger ones.Methods: We undertook a time-series analysis to examine annual trends in the use and prevalence of ECT, using linked provincial datasets. Descriptive data were presented for the population as a whole, and then trends were described separately by age groups (younger and older). As a comparator, we similarly examined antidepressant prevalence for older adults over the same time period.Results: Overall rates of ECT prevalence were stable. Annual population rates of individuals receiving ECT increased by about 27%, from 12.3 per 100 000 population in 1992 to 15.6 per 100 000 in 1997, and then decreased to 12.5 per 100 000 by 2004. The population rates of ECT were about threefold higher among older adults, relative to the younger population. Antidepressant prevalence increased by 90.1% among older adults over the same time period. The female-to-male ratio was relatively stable over time.Conclusions: The rate of ECT has been relatively stable since the early 1990s. Older adults were much more likely to be prescribed a course of ECT than younger adults. ECT remains a commonly prescribed treatment, particularly in old age. [ABSTRACT FROM AUTHOR]

Evidence that is both accurate (internally valid) and relevant (externally valid) is needed to decide which treatment is best for a particular patient. Evidence rankings facilitate the marshalling of evidence on clinical decisions in the common context of an overwhelming number of studies, some with conflicting results. Evidence from randomized control trials is typically ranked above evidence from non-experimental studies since rankings are based primarily, if not exclusively, on considerations of internal validity. We propose that evidence rankings should consider equally both internal and external validity. External validity includes how closely the study population, the institution types in the study, the types of physicians in the study, the role of clinician decision-making (e.g. dose adjustment) in the study, and the role of patient preferences in the study resemble those in actual practice. The example of spironolactone use in heart failure illustrates the danger in using evidence that is internally but not externally valid. Ideally, a treatment should only be used when both internally and externally valid evidence indicates that it will be useful for the particular patient. [ABSTRACT FROM AUTHOR]

There is an increasing interest in the use of propensity score methods to estimate causal effects in observational studies. However, recent systematic reviews have demonstrated that propensity score methods are inconsistently used and frequently poorly applied in the medical literature. In this study, we compared the following propensity score methods for estimating the reduction in all-cause mortality due to statin therapy for patients hospitalized with acute myocardial infarction: propensity-score matching, stratification using the propensity score, covariate adjustment using the propensity score, and weighting using the propensity score. We used propensity score methods to estimate both adjusted treated effects and the absolute and relative risk reduction in all-cause mortality. We also examined the use of statistical hypothesis testing, standardized differences, box plots, non-parametric density estimates, and quantile-quantile plots to assess residual confounding that remained after stratification or matching on the propensity score. Estimates of the absolute reduction in 3-year mortality ranged from 2.1 to 4.5 per cent, while estimates of the relative risk reduction ranged from 13.3 to 17.0 per cent. Adjusted estimates of the reduction in the odds of 3-year death varied from 15 to 24 per cent across the different propensity score methods. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: The authors explored the relationship between the initiation of therapy with selective serotonin reuptake inhibitor (SSRI) antidepressants and completed suicide in older patients. Method: The authors linked population-based coroner's records with patient-level prescription data, physician billing claims, and hospitalization data for more than 1.2 million Ontario residents 66 years of age and older from 1992 to 2000. For each suicide case, four closely matched comparison subjects were selected using propensity score methods. The authors determined the odds ratio for suicide with SSRIs versus other antidepressant treatment, calculated at discrete monthly intervals from the start of treatment. Results: Of 1,329 suicide cases, 1,138 (86%) were each fully matched to four comparison subjects using propensity scores. During the first month of therapy, SSRI antidepressants were associated with a nearly fivefold higher risk of completed suicide than other antidepressants (adjusted odds ratio: 48, 95% confidence interval=1.9-12.2). The risk was independent of a recent diagnosis of depression or the receipt of psychiatric care, and suicides of a violent nature were distinctly more common during SSRI therapy. Numerous sensitivity analyses revealed consistent results. No disproportionate suicide risk was seen during the second and subsequent months of treatment with SSRI antidepressants, and the absolute risk of suicide with all antidepressants was low. Conclusions: Initiation of SSRI therapy is associated with an increased risk of suicide during the first month of therapy compared with other antidepressants. The absolute risk is low, suggesting that an idiosyncratic response to these agents may provoke suicide in a vulnerable subgroup of patients. [ABSTRACT FROM AUTHOR]

Objective The goal of this study was to examine the association between antidepressant use and hospitalization rate for mania or bipolar depression in a large, community-based sample of elderly bipolar patients. Method Population-based retrospective cohort design. Administrative healthcare databases were linked for all individuals aged 66 years or older in the Province of Ontario, Canada. Bipolar subjects who received a prescription for an antidepressant medication (n = 1,072) between 1 April 1997 and 31 March 2001 comprised the antidepressant cohort. The control group (n = 3,000) consisted of randomly selected subjects from the eligible bipolar population who did not receive a prescription for an antidepressant medication during the same surveillance period. Primary outcomes were admission to hospital for a manic/mixed or depressive episode. Results During a total of 5135 person-years of follow up, 113 admissions for a manic/mixed episode and 28 admissions for a depressive episode were identified. Model based estimates adjusted for a number of covariates revealed that, as compared with the control group, the antidepressant cohort had significantly lower likelihood of admissions for manic/mixed (adjusted rate ratio [aRR] = 0.5, 95% CI = 0.3–0.8) but not depressive episodes (aRR = 0.7, 95% CI = 0.2–2.2). Conclusion Antidepressant use among elderly bipolar patients was associated with decreased rates of hospitalization for manic/mixed episodes. This finding requires confirmation with further data of antidepressant use among elderly bipolars. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary Background Atherosclerosis and sepsis share several pathophysiological similarities, including immune dysregulation, increased thrombogenesis, and systemic inflammation. The relation between statins and risk of sepsis in patients with atherosclerosis is unknown. Methods We did a population-based cohort analysis through linked administrative databases in Ontario, Canada, with accrual from 1997 to 2002. We identified 141 487 patients older than 65 years who had been hospitalised for an acute coronary syndrome, ischaemic stroke, or revascularisation, who survived for at least 3 months after discharge. 46 662 (33%) were prescribed a statin within 90 days of discharge, 94 825 (67%) were not. Propensity-based matching, which accounted for each individual's likelihood of receiving a statin, yielded a cohort of 69 168 patients, of whom half (34 584) received a statin and half (34 584) did not. Findings Incidence of sepsis was lower in patients receiving statins than in controls (71·2 vs 88·0 events per 10 000 person-years; hazard ratio [HR] 0·81; 95% CI 0·72-0·91). Adjustment for demographic characteristics, sepsis risk factors, comorbidities, and health-care use gave similar results (HR 0·81; 95% CI 0·72-0·90). The protective association between statins and sepsis persisted in high-risk subgroups, including patients with diabetes mellitus, chronic renal failure, or a history of infections. Significant reductions in severe sepsis (HR 0·83; 95% CI 0·70-0·97) and fatal sepsis (0·75; 0·61-0·93) were also observed. No benefit was noted with non-statin lipid-lowering agents (0·95; 0·75-1·22). Implications Use of statins in patients with atherosclerosis is associated with a reduced risk of subsequent sepsis. Randomised trials of statins for prevention of sepsis are warranted. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to assess trends in utilization and costs of antipsychotic drugs among a population of older adults over time, with respect to the prevalence of users, shifts in prescribing patterns, and related financial implications. Design Cross-sectional time series of quarterly and annual antipsychotic utilization and cost were obtained from administrative databases for calendar years 1993 through 2002. Setting and Participants A population-based study of more than 1.4 million residents of the province of Ontario aged 65 years or older. Measurements Data sources used included the Ontario Drug Benefits (ODB) database and Statistics Canada census data. Results The prevalence of antipsychotic users increased by 34.8% over the study period from 2.2% at the beginning of 1993 to 3.0% of the elderly at the end of 2002 (p < 0.01). This was associated with a 749% increase in total cost (from $3.7 million in 1993 to $31.4 million in 2002; p < 0.01). The atypical antipsychotics, which were not available in 1993, made up 82.5% of the antipsychotics dispensed and 95.2% of costs in 2002. Conclusions The modest increase in antipsychotic prevalence in the elderly over the last ten years has been associated with a substantial increase in cost, with a significant shift towards use of the atypical antipsychotics. As the atypical antipsychotics are increasingly used for patients with dementia, which is becoming more prevalent in the aging population, an understanding of the benefits of these medications must be balanced with a detailed understanding of the material and financial implications. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

There is an increasing interest in using administrative data to estimate the treatment effects of interventions. While administrative data are relatively inexpensive to obtain and provide population coverage, they are frequently characterized by lack of clinical detail, often leading to problematic confounding when they are used to conduct observational research. Propensity score methods are increasingly being used to address confounding in estimating the effects of interventions in such studies. Using data on patients discharged from hospital for whom both administrative data and detailed clinical data obtained from chart reviews were available, we examined the degree to which stratifying on the quintiles of propensity scores derived from administrative data was able to balance patient characteristics measured in clinical data. We also determined the extent to which measures of treatment effect obtained using propensity score methods were similar to those obtained using traditional regression methods. As a test case, we examined the treatment effects of ASA and beta-blockers following acute myocardial infarction. We demonstrated that propensity scores developed using administrative data do not necessarily balance patient characteristics contained in clinical data. Furthermore, measures of treatment effectiveness were attenuated when obtained using clinical data compared to when administrative data were used. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background The prescribing cascade model involves the misinterpretation of an adverse reaction to 1 drug and the subsequent, potentially inappropriate prescription of a second drug. We present a new example of the prescribing cascade involving cholinesterase inhibitors and anticholinergic drugs used to manage urinary incontinence. Methods A population-based retrospective cohort study was carried out in Ontario, Canada. Participants included 44 884 older adults with dementia (20 491 were dispensed a cholinesterase inhibitor and 24 393 were not), enrolled between June 1, 1999, and March 31, 2002. Subjects were observed until they received an anticholinergic drug, stopped the cholinesterase inhibitor treatment, died, or the study period ended (March 31, 2003). The main outcome measure was receipt of an anticholinergic drug to manage urinary incontinence. Results After adjusting for potential confounding factors, we observed that older adults with dementia who were dispensed cholinesterase inhibitors had an increased risk of subsequently receiving an anticholinergic drug (4.5% vs 3.1%; P<.001; adjusted hazard ratio, 1.55; 95% confidence interval, 1.39-1.72), relative to those not receiving cholinesterase inhibitors. This finding was consistent in a series of subgroup analyses. Conclusions Use of cholinesterase inhibitors is associated with an increased risk of receiving an anticholinergic drug to manage urinary incontinence. The use of an anticholinergic drug in this setting may represent a clinically important prescribing cascade. Clinicians should consider the possible contributing role of cholinesterase inhibitors in new-onset or worsening urinary incontinence and the potential risk of coprescribing cholinesterase inhibitors and anticholinergic drugs to patients with dementia. [ABSTRACT FROM AUTHOR]

The effectiveness of the different angiotensin-converting enzyme (ACE) inhibitors in the treatment of patients with congestive heart failure (CHF) was compared by performing a retrospective cohort study using linked administrative databases on elderly patients admitted to the hospital for the treatment of CHF. Relative to those initiated on enalapril, no significant differences in the combined end point of readmission to the hospital for CHF or mortality were observed among users of lisinopril, ramipril, or other ACE inhibitors. In terms of effectiveness for the treatment of patients with CHF, the findings of this study suggest a class effect among ACE inhibitors. [Copyright &y& Elsevier]

In vitroevidence suggests that some serotonin-specific reuptake inhibitors (SSRIs) inhibit P-glycoprotein, a multidrug efflux pump responsible for the elimination of several drugs including digoxin. We sought to determine if some SSRIs cause digoxin toxicity in the clinical setting.Population-based nested case–control study set in Ontario, Canada from 1994 to 2001. We studied all patients 66 years or older treated with digoxin. Prescription and hospital admission records were analysed to determine the relationship between the initiation of SSRI therapy and hospital admission for digoxin toxicity in the subsequent 30 days.Among 245 305 older patients treated with digoxin, we identified 3144 cases of digoxin toxicity. After adjusting for potential confounders, we observed an increased risk of digoxin toxicity following initiation of paroxetine[odds ratio (OR) 2.8; 95% confidence interval (CI) 1.6, 4.7], fluoxetine (OR 2.9; 95% CI 1.5, 5.4), sertraline (OR 3.0; 95% CI 1.9, 4.7), and fluvoxamine (OR 3.0; 95% CI 1.5, 5.7). However, an elevated risk was also seen with tricyclic antidepressants (OR 1.5; 95% CI 1.0, 2.4) and benzodiazepines (OR 2.1; 95% CI 1.7, 2.5), drugs classes having no known pharmacokinetic interaction with digoxin. There was no statistical difference in the risk of digoxin toxicity among any of the agents tested.We found no major discrepancy in the risk of digoxin toxicity after initiation of various SSRI antidepressants, suggesting that the inhibition of P-glycoprotein by sertraline and paroxetine observedin vitrois unlikely to be of major clinical significance. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The aim of this study was to determine whether the incidence of type 2 diabetes differed among elderly users of four major antihypertensive drug classes. RESEARCH DESIGN AND METHODS -- This was a retrospective, observational cohort study of previously untreated elderly patients (aged ≥66 years) identified as new users of an antihypertensive drug class between April 1995 and March 2000. Using a Cox proportional hazards model, the primary analysis compared diabetes incidence in users of ACE inhibitors, β-blockers, and calcium channel blockers (CCBs), with thiazide diuretics allowed as second-line therapy. In the secondary analysis, thiazide diuretics were added as a fourth study group. RESULTS -- In the multivariable-adjusted primary analysis (n = 76,176), neither ACE inhibitor use (hazard ratio 0.96 [95% CI 0.134-1.1]) nor β-blocker use (0.86 [0.74-1.0]) was associated with a statistically significant difference in type 2 diabetes incidence compared with the CCB control group. In the secondary analysis (n = 100,653), compared with CCB users, type 2 diabetes incidence was not significantly different between users of ACE inhibitors (0.97 [083-1.1]), β-blockers (0.84 [0.7-1.0]), or thiazide diuretics (1.0 [0.89-1.2]). CONCLUSIONS -- Type 2 diabetes incidence did not significantly differ among users of the major antihypertensive drug classes in this elderly, population-based administrative cohort. These results do not support the theory that different antihypertensive drug classes are relatively more or less likely to cause diabetes. [ABSTRACT FROM AUTHOR]

Patients are often treated in hospital by physicians other than their regular community doctor. After they are discharged, their care is often returned to their regular community doctor and patients may not see the hospital physician. Transfer of information between physicians can be poor. We determined whether early postdischarge outcomes changed when patients were seen after discharge by physicians who treated them in the hospital. This cohort study used population-based administrative databases to follow 938,833 adults from Ontario, Canada, after they were discharged alive from a nonelective medical or surgical hospitalization between April 1, 1995, and March 1, 2000. We determined when patients were seen after discharge by physicians who treated them in the hospital, physicians who treated them 3 months prior to admission (community physicians), and specialists. The outcome of interest was 30-day death or nonelective readmission to hospital. Of patients studied, 7.7% died or were readmitted. The adjusted relative risk of death or readmission decreased by 5% (95% confidence interval [CI], 4% to 5%) and 3% (95% CI, 2% to 3%) with each additional visit to a hospital physician rather than a community physician or specialist, respectively. The effect of hospital physician visits was cumulative, with the adjusted risk of 30-day death or nonelective readmission reduced to 7.3%, 7.0%, and 6.7% if patients had 1, 2, or 3 visits, respectively, with a hospital rather than a community physician. The effect was consistent across important subgroups. Patient outcomes could be improved if their early postdischarge visits were with physicians who treated them in hospital rather than with other physicians. Follow-up visits with a hospital physician, rather than another physician, could be a modifiable factor to improve patient outcomes following discharge from hospital. J GEN INTERN MED 2004;19:624–631. [ABSTRACT FROM AUTHOR]

Background Non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of congestive heart failure, but little is known about the cardiovascular effects of a newer group of NSAIDS called selective cyclo-oxygenase (COX)-2 inhibitors. We aimed to compare rates of admission for congestive heart failure in elderly patients who were newly dispensed COX-2 inhibitors or non-selective NSAIDs. Methods In this population-based retrospective cohort study we identified NSAID-naive individuals aged 66 years or older, who were started on rofecoxib (n=14,583), celecoxib n=18,908), and non-selective NSAIDs (n=5,391), and randomly selected non-NSAID users as controls (n=100,000). Findings Relative to non-NSAID users, patients on rofecoxib and non-selective NSAIDS had an increased risk of admission for congestive heart failure (adjusted rate ratio 1.8, 95% CI 1.5--2., and 1., 1.0-1., respectively), but not celecoxib (1.0 0.8-1.3). Compared with celecoxib users, admission was significantly more likely in users of nonselective NSAIDs (1.4, 1.0-1.9) and rofecoxib (1.8, 1.4-2.4). Risk of admission for rofecoxib users was higher than that for non-selective NSAID users (1.5, 1.1-2.1). Of patients with no admission in the past 3 years, only rofecoxib users were at increased risk of subsequent admission relative to controls (1.8, 1.4-2.3). Interpretation These findings suggest a higher risk of admission for congestive heart failure in users of rofecoxib and non-selective NSAIDs, but not celecoxib, relative to non- NSAID controls. [ABSTRACT FROM AUTHOR]

: PurposeTo review trends in drug therapy and concomitant outcomes of elderly heart failure patients in Ontario, Canada.: MethodsUtilization of drug therapies, mortality, and rehospitalization rates from April 1992 to March 2000 were determined in 77,421 elderly (aged ≥65 years), community-based heart failure patients using linked administrative databases. Treatment effects were identified from published meta-analyses and randomized trials. The effect of drug trends on mortality and morbidity were assessed based on their absolute treatment effects.: ResultsFrom 1992 to 2000, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use increased from 58% to 62% (P = 0.001) while beta-blocker use increased from 6% to 22% (P <0.001). There was a decrease in the use of treatments for which no survival advantage had been demonstrated in randomized trials, such as digitalis (49% to 35%, P <0.001), Vaughan-Williams class I antiarrhythmic agents (3.5% to 1.4%, P <0.001), and first-generation calcium antagonists (21.3% to 9.6%, P <0.001). The trends in drug therapy were associated with a 2.8% reduction in age-, sex-, and comorbidity-adjusted 1-year mortality and a 4.1% reduction in 1-year hospitalization rates. The observed trends in therapy over time explained 37% of the decrease in mortality and 30% of the decrease in rehospitalization rates. The treatment effect from beta-blockers was most pronounced, explaining 30% of the decrease in mortality and 10% of the decrease in rehospitalization rates.: ConclusionDuring 1992 to 2000, mortality and morbidity improved among elderly patients with heart failure, with increased utilization of beta-blockers contributing most to the beneficial trends in outcomes. [Copyright &y& Elsevier]

To study the association between hospital admission for lithium toxicity and the use of diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDs) in the elderly. Population-based nested case-control study. Ontario, Canada. Ontario residents aged 66 and older treated with lithium. Estimated relative risk of hospital admission for lithium toxicity. From January 1992 to December 2001, 10,615 elderly patients continuously receiving lithium were identified, of whom 413 (3.9%) were admitted to the hospital at least once for lithium toxicity. After adjustment for potential confounders, a dramatically increased risk of lithium toxicity was seen within a month of initiating treatment with a loop diuretic (relative risk (RR)=5.5, 95% confidence interval (CI)=1.9–16.1) or an ACE inhibitor (RR=7.6, 95% CI=2.6–22.0). Conversely, neither thiazide diuretics nor NSAIDs were independently associated with a significantly increased risk of hospitalization for lithium toxicity. The use of loop diuretics or ACE inhibitors significantly increases the risk of hospitalization for lithium toxicity, particularly in naïve recipients. [ABSTRACT FROM AUTHOR]

Context The benefits of cardiovascular therapies such as statins for secondary prevention have been well documented, although they may not be optimally used in patients most likely to benefit. Ideally, aggressiveness in the use of these beneficial therapies should correlate with baseline cardiovascular risk. Objective To examine the association between physicians' treatment aggressiveness and baseline cardiovascular risk. Design, Setting, and Patients Retrospective cohort study incorporating the use of multiple linked health care administrative databases covering more than 1.4 million elderly residents of Ontario. We included 396 077 patients aged 66 years or older who had a history of cardiovascular disease or diabetes while undergoing medical treatment and who were alive on April 1, 1998. Baseline cardiovascular risk was derived using a risk-adjustment index in which we modeled probability of death after 3 years of follow-up. Main Outcome Measure Likelihood of statin use, stratified by baseline cardiovascular risk, after adjusting for age, sex, socioeconomic status, and rural or urban residence. Results Only 75 617 patients (19.1%) in this secondary prevention cohort were prescribed statins. In patients 66 to 74 years old, the adjusted probabilities of statin prescription were 37.7%, 26.7%, and 23.4% in the categories of low, intermediate, and high baseline risk, respectively. The likelihood of statin prescription was 6.4% lower (adjusted odds ratio, 0.94; 95% confidence interval, 0.93-0.95) for each year of increase in age and each 1% increase in predicted 3-year mortality risk. The influence of age also interacted synergistically with baseline risk on the prescription of statins (P<.001). Conclusions We found that prescription of statins diminished progressively as baseline cardiovascular risk and future probability of death increased. Since the benefits of a therapy are dependent on the baseline risk, the maximum benefits of statins may not be fully realized... [ABSTRACT FROM AUTHOR]

Examines the epidemiology of acute appendicitis in Ontario. Age and sex of patients; Length of hospital stay; Incidence and seasonal variation of acute appendicitis.

Objective: To determine whether the climate of increased anxiety following the terrorist attacks of September 11, 2001, and the subsequent anthrax cases led to increased anxiety-related physician visits.Method: We undertook a retrospective, population-based study of all Ontario residents. We identified physician visits using Ontario's universal health care insurance program. Interventional autoregressive integrated moving average (ARIMA) time series models were used to examine the impact of the terrorist attacks and anthrax infections on the rate of anxiety-related physician visits.Results: Neither the terrorist attacks of September 11 (P > or = 0.40) nor the anthrax infections in October and November (P > or = 0.14) had a statistically significant impact on the rate of anxiety-related visits to physicians.Conclusions: The climate of heightened anxiety did not result in increased demand for mental health services. [ABSTRACT FROM AUTHOR]

Context: Drug-drug interactions are a preventable cause of morbidity and mortality, yet their consequences in the community are not well characterized. Objective: To determine whether elderly patients admitted to hospital with specific drug toxicities were likely to have been prescribed an interacting drug in the week prior to admission. Design: Three population-based, nested case-control studies. Setting: Ontario, Canada, from January 1, 1994, to December 31, 2000. Patients: All Ontario residents aged 66 years or older treated with glyburide, digoxin, or an angiotensin-converting enzyme (ACE) inhibitor. Case patients were those admitted to hospital for drug-related toxicity. Prescription records of cases were compared with those of controls (matched on age, sex, use of the same medication, and presence or absence of renal disease) for receipt of interacting medications (co-trimoxazole with glyburide, clarithromycin with digoxin, and potassium-sparing diuretics with ACE inhibitors). Main Outcome Measure: Odds ratio for association between hospital admission for drug toxicity (hypoglycemia, digoxin toxicity, or hyperkalemia, respectively) and use of an interacting medication in the preceding week, adjusted for diagnoses, receipt of other medications, the number of prescription drugs, and the number of hospital admissions in the year preceding the index date. Results: During the 7-year study period, 909 elderly patients receiving glyburide were admitted with a diagnosis of hypoglycemia. In the primary analysis, those patients admitted for hypoglycemia were more than 6 times as likely to have been treated with co-trimoxazole in the previous week (adjusted odds ratio, 6.6; 95% confidence interval, 4.5-9.7). Patients admitted with digoxin toxicity (n = 1051) were about 12 times more likely to have been treated with clarithromycin (adjusted odds ratio, 11.7; 95% confidence interval, 7.5-18.2) in the previous week, and patients treated with ACE inhibitors admitted... [ABSTRACT FROM AUTHOR]

Background: The Heart Outcomes Prevention Evaluation (HOPE), a Canadian-led, multicentre, randomized controlled trial, demonstrated the effectiveness of the ACE inhibitor ramipril in the secondary prevention of cardiovascular disease in patients who were at high risk for cardiovascular events but did not have left ventricular dysfunction or heart failure. We studied whether HOPE affected the prescribing of ACE inhibitors generally, and ramipril specifically, in Ontario, where the trial was coordinated. Methods: We used linked administrative databases to examine prescribing patterns for ACE inhibitors in the 1.29 million to 1.54 million elderly (aged 66 and over) residents of Ontario during the study period and specifically those with diabetes or congestive heart failure. For all new prescriptions for these drugs filled between Jan. 1, 1993, and Mar. 31, 2001, we conducted time-series analyses to measure any association with the release of the HOPE results. Results: The monthly number of new prescriptions for ramipril from the time it was introduced in 1995 until HOPE's early termination, in April 1999, peaked at 58 per 100 000 elderly Ontario residents. The rate increased to 92/100 000 in May, coincident with newspaper coverage of the trial's early termination, then fell back to 63/100 000 in August. After HOPE's results were formally released, starting Aug. 31, the rate increased significantly; it peaked at 304/100 000 in May 2000 (p < 0.01). The market share of ramipril among ACE inhibitors also increased significantly (p < 0.01), both overall and among patients with diabetes or congestive heart failure. Interpretation: HOPE led to a striking and unprecedented increase, over 400%, in ramipril prescribing to elderly Ontario residents, including those not eligible for the trial. Many physicians are now prescribing ramipril for patients with diabetes or congestive heart failure. [ABSTRACT FROM AUTHOR]

Background: Recent debate has emerged regarding the cardiovascular safety of selective cyclooxygenase 2 inhibitors and the possible cardioprotective effect of naproxen sodium. We compared the rates of acute myocardial infarction (AMI) among elderly patients dispensed selective cyclooxygenase 2 inhibitors, naproxen, and nonselective nonnaproxen nonsteroidal antiinflammatory drugs (NSAIDs). Methods: We conducted a population-based retrospective cohort study using administrative health care data from Ontario, Canada, from April 1, 1998, to March 31, 2001. We identified NSAID-naive cohorts of subjects aged 66 years and older in whom treatment was initiated with celecoxib (n = 15 271), rofecoxib (n = 12156), naproxen (n = 5669), and nonnaproxen nonselective NSAIDs (n = 33 868), along with a randomly selected control cohort not exposed to NSAIDs (n = 100 000). Multivariate Cox proportional hazards models were used to compare AMI rates between study drug groups while controlling for potential confounders. Results: Relative to control subjects, the multivariate model showed no significant differences in AMI risk for new users of celecoxib (adjusted rate ratio [aRR], 0.9; 95% confidence interval [CI], 0.7-1.2), rofecoxib (aRR, 1.0; 95% CI, 0.8-1.4), naproxen (aRR, 1.0; 95% CI, 0.61.7), or nonnaproxen nonselective NSAIDs (aRR, 1.2; 95% CI, 0.9-1.4). Conclusions: The findings of this observational study suggest no increase in the short-term risk of AMI among users of selective cyclooxygenase 2 inhibitors as commonly used in clinical practice. Furthermore, the findings do not support a short-term reduced risk of AMI with naproxen. [ABSTRACT FROM AUTHOR]

Objective To compare rates of upper gastrointestinal haemorrhage among elderly patients given selective cyclo-oxygenase-2 (COX 2) inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Design Observational cohort study. Setting Administrative data from Ontario, Canada, used from 17 April 2000 to 31 March 2001 to identify population based, NSAID-naive cohorts of patients. Patients Subjects aged > 66 years who started taking non-selective NSAIDs (n=5391), diclofenac plus misoprostol (n=5087), rofecoxib (n=14 583), or celecoxib (n=18 908) and a randomly selected control cohort not exposed to NSAIDs (n=100 000). Main outcome measures Rate ratios of hospital admission for upper gastrointestinal haemorrhage in each drug cohort with adjustment for potential confounders. Results Relative to controls, the multivariate model revealed an increased short term risk of upper gastrointestinal haemorrhage for users of non-selective NSAIDs (adjusted rate ratio 4.0 (95% confidence intervals 2.3 to 6.9)), diclofenac plus misoprostol (3.0 (1.7 to 5.6)), and rofecoxib (1.9 (1.3 to 2.8)) but not celecoxib (1.0 (0.7 to 1.6)). Relative to celecoxib, significantly higher risks of upper gastrointestinal haemorrhage were observed for non-selective NSAIDs (4.4 (2.3 to 8.5)), diclofenac plus misoprostol (3.2 (1.6 to 6.5)), and rofecoxib (1.9 (1.2 to 2.8)). Relative to rofecoxib, non-selective NSAID users were at significantly higher risk of upper gastrointestinal haemorrhage (1.9 (1.0 to 3.5)). Conclusions This population based observational study found a lower short term risk of upper gastrointestinal haemorrhage for selective COX-2 inhibitors compared with non-selective NSAIDs. [ABSTRACT FROM AUTHOR]

Context: Landmark clinical trials have demonstrated the survival benefits of statins, with benefits usually starting after 1 to 2 years of treatment. Research prior to these trials of older lipid-lowering agents demonstrated low levels of 1-year adherence. Objective: To compare 2-year adherence following statin initiation in 3 cohorts of patients: those with recent acute coronary syndrome (ACS), those with chronic coronary artery disease (CAD), and those without coronary disease (primary prevention). Design and Setting: Cohort study using linked population-based administrative data from Ontario. Patients: All patients aged 66 years or older who received at least 1 statin prescription between January 1994 and December 1998 and who did not have a statin prescription in the prior year were followed up for 2 years from their first statin prescription. There were 22 379 patients in the ACS, 36 106 in the chronic CAD, and 85 020 in the primary prevention cohorts. Main Outcome Measures: Adherence to statins, defined as a statin being dispensed at least every 120 days after the index prescription for 2 years. Results: Two-year adherence rates in the cohorts were only 40.1% for ACS, 36.1% for chronic CAD, and 25.4% for primary prevention. Relative to the ACS cohort, nonadherence was more likely among patients receiving statins in the chronic CAD (relative risk [RR], 1.14; 95% CI, 1.11-1.16) and primary prevention cohorts (RR, 1.92; 95% CI, 1.87-1.96). Conclusions: Elderly patients with and without recent ACS have low rates of adherence to statins. This suggests that many patients initiating statin therapy may receive no or limited benefit from statins because of premature discontinuation. [ABSTRACT FROM AUTHOR]

: PurposePrevious guidelines for the management of uncomplicated hypertension in elderly patients have recommended diuretic agents and then beta-blockers. We examined trends in the initial treatment choice for elderly people with hypertension and the effects of a government-sponsored program to publish and disseminate a simplified version of the national guidelines for the treatment of hypertension to all physicians in Ontario, Canada.: Subjects and methodsLinked administrative databases containing information on the more than 1.2 million elderly residents in Ontario were used. Time series analysis was performed to determine prescribing trends from 1993 to 1998 for patients who began antihypertensive medication for the treatment of hypertension and to examine the effects of the simplified guidelines that were distributed in July of 1995.: ResultsDiuretic agents were the most commonly prescribed medications, with annual rates from 35% to 38% (P = 0.59) throughout the study. Beta-blocker prescribing rose from 12% to 16% (P <0.01), whereas angiotensin-converting enzyme (ACE) inhibitor prescribing rose from 27% to 32% (P <0.01). Prescriptions for calcium channel blockers dropped significantly, from 23% to 14% (P <0.01). However, the publication and dissemination of the Ontario hypertension guidelines had no statistically significant effects on the proportion of patients who began treatment with a diuretic agent (P = 0.55), beta-blocker, (P = 0.32), ACE inhibitor (P = 0.09), or calcium channel blocker (P = 0.07).: ConclusionThe dissemination of simplified practice guidelines for hypertension did not have notable effects on prescribing patterns in Ontario. [Copyright &y& Elsevier]