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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: 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]

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 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]

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]

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]

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]

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]

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]

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]

: 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]

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]

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]

: 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]

OBJECTIVES:The extensive use of benzodiazepines has been a concern of healthcare providers and policy makers in Canada and around the world. The purpose of this study was to examine temporal trends in benzodiazepine prescriptions dispensed in older people from 1993–1998. DESIGN:Retrospective population-based cross-sectional study using administrative databases. SETTING:Ontario, Canada. PARTICIPANTS:The over 1 million residents of Ontario age 65 and older covered by the provincial universal drug benefit program. MEASUREMENTS:The main outcome measures were the prevalence, overall and with respect to age and gender, of benzodiazepine prescriptions dispensed and the ratio of the number of people to whom short- versus long-acting benzodiazepine prescriptions were dispensed in each study year. The annual rates of switching to other psychotropic agents were examined for those patients that discontinued filling benzodiazepine prescriptions. RESULTS:The annual prevalence of benzodiazepine prescriptions dispensed decreased consistently over time (25.1% in 1993 to 22.5% in 1998; P < .001). Benzodiazepine dispensing prevalence increased with increasing age (approximately 20% of those age 65 to 69 to approximately 30% of those age ≥85; P < .001) and more females than males received the medication (relative risk = 1.50, 95% confidence interval = 1.49–1.51). The ratio of short- to long-acting benzodiazepine prescriptions filled increased over time (3.6 in 1993 to 5.8 in 1998; P < .001), in line with guideline recommendations. Rates of switching to antidepressants increased over time (8.5% in 1993 to 10.2% in 1998; P < .001), whereas switching to barbiturates was consistently low (0.12%; P = .403). CONCLUSION:The prevalence of benzodiazepine therapy for older people in Ontario has steadily declined between 1993 and 1998. There is a trend of dispensing relatively more short-acting than long-acting benzodiazepines and of replacing benzodiazepines with antidepressants in older people without a remarkable increase in barbiturate consumption. These findings suggest that, without undue regulation, physicians are making progress in the prescribing of benzodiazepine therapy on the basis of current knowledge available. J Am Geriatr Soc 49:1341–1345, 2001. [ABSTRACT FROM AUTHOR]

AbstractBackground: Several studies have indicated that estrogen may prime inflammatory and nociceptive pathways, leading to symptoms that mimic cholecystitis. We set out to confirm the relation between recent estrogen use and cholecystectomy in postmenopausal women and to test the novel hypothesis that a similar relation exists for appendectomy.Methods: We developed a retrospective cohort using prescribing and surgical procedure information from health administrative databases for approximately 800,000 female residents of Ontario who were over 65 years of age between July 1, 1993, and Mar. 31, 1998. We compared the incidence of cholecystectomy and appendectomy among women recently prescribed estrogen replacement therapy, levothyroxine and dihydropyridine calcium-channel antagonists (DCCA) using age-adjusted Cox proportional hazards models. Patients were followed for a mean of 540 (standard deviation [SD] 449) days.Results: Compared with women taking DCCA, those who had recently begun taking estrogen were significantly more likely to undergo cholecystectomy (age-adjusted risk ratio [aRR] 1.9, 95% confidence interval [CI] 1.6-2.2) and appendectomy (aRR 1.8, 95% CI 1.1-3.0). No significant difference in either outcome measure was found between the levothyroxine users and the DCCA users.Interpretation: This study identifies an increased risk of cholecystectomy and appendectomy among postmenopausal women who have recently begun estrogen replacement therapy. [ABSTRACT FROM AUTHOR]

Studies whether there is an association between lipid-lowering drugs and cholecystectomy. Association between fibrate use and cholecystectomy compared with statins and a cardiovascular drug control group in older patients; Results.

Examines changes over time in antidepressant utilization among elderly subjects regarding the prevalence of antidepressant users, shifts in prescription patterns and related financial implications. Population and treatment prevalence; Change in prescription patterns over time; Drug use and expenditures; Driving factors for antidepressant drug expenditures; Market share.

The article looks at the role of warfarin therapy in enabling persistence of atrial fibrillation patients. The study was done on senior residents in Ontario aged 66 and older who were provided the warfarin treatment from April 1, 1997 and March 31, 2008, where the therapy was evaluated through Kaplan-Meier curves. Results showed that persistence with the therapy was lower than their younger counterparts.

A response by David N. Juurlink, Muhammad M. Mamdani, and Donald A. Redelmeier to a letter to the editor in response to their article about hyperkalemia is presented.

Background: Drugs are the fastest growing cost in the Canadian health care system, owing to the increasing number of high-cost drugs. The objective of this study was to examine the characteristics of high–drug-cost beneficiaries of public drug plans across Canada relative to other beneficiaries. Methods: We conducted a cross-sectional study among public drug plan beneficiaries residing in all provinces except Quebec. We used the Canadian Institute for Health Information's National Prescription Drug Utilization Information System to identify all drugs dispensed to beneficiaries of public drug programs in 2016/17. We stratified the cohort into 2 groups: high–drug-cost beneficiaries (top 5% of beneficiaries based on annual costs) and other beneficiaries (remaining 95%). For each group, we reported total drug costs, prevalence of high-cost claims (> $1000), median number of drugs, proportion of beneficiaries aged 65 or more, the 10 most costly reimbursed medications and the 10 medications most commonly reimbursed. We reported estimates overall and by province. Results: High–drug-cost beneficiaries accounted for nearly half (46.5%) of annual spending, with an average annual spend of $14 610 per beneficiary, compared to $1570 among other beneficiaries. The median number of drugs dispensed was higher among high–drug-cost beneficiaries than among other beneficiaries (13 [interquartile range (IQR) 7–19] v. 8 [IQR 4–13]), and a much larger proportion of high–drug-cost beneficiaries than other beneficiaries received at least 1 high-cost claim (40.9% v. 0.6%). Long-term medications were the most commonly used medications for both groups, whereas biologics and antivirals were the most costly medications for high–drug-cost beneficiaries. Interpretation: High–drug-cost beneficiaries were characterized by the use of expensive medications and polypharmacy relative to other beneficiaries. Interventions and policies to help reduce spending need to consider both of these factors. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the impact of computerized provider order entry subcutaneous insulin order sets on inpatient glycemic control and ordering behavior.Methods: This was an interrupted time series study of non-intensive care patients at an urban teaching hospital. The primary outcome was proportion of capillary blood glucose in optimal range (4.0-10.0 mmol/L [72-180 mg/dL]) during the 6 months before and after a change to a computerized provider order entry-integrated insulin order set. Secondary outcomes included other measures of glycemia (hyperglycemia [>13.9mmol/L (250 mg/dL)], hypoglycemia [<4.0 mmol/L (72 mg/dL)], severe hypoglycemia [<2.2 mmol/L (40 mg/dL)]) and ordering behavior (use of basal-bolus-correctional insulin regimens). Comparisons of sensitivity-based versus generic correctional scale were also conducted.Results: A total of 63,393 measurements were obtained from June 2011 to June 2012. Order set usage was limited (51.5%). The weekly proportion of capillary blood glucose within the optimal range was not significantly different after the switch to computerized provider order entry order sets (pre-period: 64.9% vs post-period: 65.3%, P = .996). There were no differences in the proportions of moderate or severe hyperglycemia (pre-period: 10.9% vs post-period: 12.0%, P = .061) and hypoglycemia (pre-period: 1.9% vs post-period: 1.6%, P = .144). However, an increased proportion within the optimal range was seen in those with an order set featuring a sensitivity-based correctional scale versus orders without (65.3% vs 55.0%, P <.001). Increased basal-bolus-correctional ordering was observed after protocol implementation (20.3% vs 23.6%, P <.0001).Conclusions: With low institutional uptake, computerized insulin order sets did not improve inpatient glycemic control. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article written by Laurence Katz and associates on the impact of Health Canada's warning on the rates of anti-depressant prescription that was published in the previous issue.

Presents a research letter on the changes in prescribing patterns following publication of the ALLHAT Trial which studied treatment for hypertension to prevent heart attacks. Study of various antihypertensive agents; Methods of the study; Results; Comments from the authors.

Presents a research letter which examines patterns of prescriptions for estrogen replacement therapy (ERT). Statistics on the percentage of women, in Ontario, using ERT.

Details an investigation of whether the release of three landmark randomized controlled trials of statins and the release of atorvastatin were associated with the market share of different statins in Canada. Examination of prescribing patterns for June 1993 to June 1999; Limitations of the study, including the lack of information about promotional expenditures and methods.

Background: While it is well known that patients receiving opioids should refrain from alcohol consumption, little is known about the involvement of alcohol in opioid-related deaths.Methods: We conducted a population-based analysis of opioid-related deaths in Ontario with and without alcohol involvement between 1993 and 2013, and reported rates overall and stratified by manner of death. We compared the characteristics of individuals who died of an opioid overdose based on the presence or absence of alcohol involvement.Results: The rate of opioid-related deaths increased 288% from 11.9 per million (95% confidence interval (CI) 9.8-13.9 per million) in 1993-46.2 per million (95% CI 42.6-49.8 per million) in 2013. The rate of opioid-related deaths without alcohol involvement increased 388% from 7.4 per million to 36.1 per million, while deaths involving alcohol increased by 125% from 4.5 per million to 10.1 per million. Therefore, although the annual number of opioid-related deaths involving alcohol rose, the proportion of opioid-related deaths involving alcohol declined from 37.8% in 1993-21.9% by 2013. Generally, opioid-related deaths involving alcohol were less likely to involve other central nervous system depressants, and more likely to occur among men and those with a history of alcohol use disorder.Conclusions: Although the relative contribution of alcohol in opioid-related deaths has declined, 1 in 5 fatal opioid overdoses still involved alcohol in 2013. Our findings highlight the ongoing need for targeted messaging around risks of opioids alone, and in combination with alcohol and other CNS depressants. [ABSTRACT FROM AUTHOR]

Objective To examine the 30-day risk of hospitalization with hyponatremia associated with carbamazepine, valproic acid (V), phenytoin (P), or topiramate (T) use compared to nonuse in the outpatient setting among older adults. Methods We conducted two population-based, retrospective cohort studies in Ontario, Canada, between 2003 and 2015 using administrative health care databases of older adults. The first study compared carbamazepine users to a propensity-score matched group of antiepileptic drug nonusers, whereas the second compared V-P-T users to a propensity-score matched group of antiepileptic nonusers. The primary outcome was hospitalization with hyponatremia within 30 days of an antiepileptic prescription. Results The baseline characteristics between matched groups were similar in both cohorts. Carbamazepine use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (82/21,191 [0.39%] versus 30/63,573 [0.05%]; relative risk [RR] 8.20, 95% confidence interval [CI] 5.40-12.46). Similarly, V-P-T use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (34/20,155 [0.17%] versus 26/40,310 [0.06%]; RR 2.62, 95% CI 1.57-4.36). Significance Older adults prescribed carbamazepine and V-P-T have a higher risk of being hospitalized with hyponatremia compared to other adults with similar indicators of baseline health who were not prescribed antiepileptic drugs. Physicians should be mindful of this risk; when a patient presents to a hospital with symptomatic hyponatremia these drugs should be considered as potential causes. [ABSTRACT FROM AUTHOR]

Introduction: The recent publication of a national guideline and quality standards in Canada have provided clinicians with new, evidence-based recommendations on safe, appropriate opioid use. We sought to characterize how well opioid initiation practices aligned with these recommendations before and following their release. Methods: We conducted a population-based study among people initiating opioids prior to the release of national guidelines (April 2015—March 2016; fiscal year [FY] 2015) and in the most recent year available (January—December 2019) in Ontario, Canada. We used linked administrative claims data to ascertain the apparent indication for opioid therapy, and characterized the initial daily dose (milligrams morphine or equivalent; MME) and prescription duration for each indication. Results: In FY2015, 653,885 individuals commenced opioids, compared to 571,652 in 2019. Over time, there were small overall reductions in the prevalence of initial daily doses exceeding 50MME (23.9% vs. 20.1%) and durations exceeding 7 days (17.4% vs. 14.8%); but the magnitude of the reductions varied widely by indication. The prevalence of high dose (>50MME) initial prescriptions reduced significantly across all indications, with the exception of dentist-prescribed opioids (13.6% vs. 12.1% above 50MME). In contrast, there was little change in initial durations exceeding 7 days across most indications, with the exception of some surgical indications (e.g. common excision; 9.3% vs. 6.2%) and among those in palliative care (35.2% vs. 29.2%). Conclusion: Despite some modest reductions in initiation of high dose and long duration prescription opioids between 2015 and 2019, clinical practice is highly variable, with opioid prescribing practices influenced by clinical indication. These findings may help identify medical specialties well-suited to targeted interventions to promote safer opioid prescribing. [ABSTRACT FROM AUTHOR]

Background: The Randomized Aldactone Evaluation Study (RALES) demonstrated that spironolactone significantly improves outcomes in patients with severe heart failure. Use of angiotensin-converting–enzyme (ACE) inhibitors is also indicated in these patients. However, life-threatening hyperkalemia can occur when these drugs are used together. Methods: We conducted a population-based time-series analysis to examine trends in the rate of spironolactone prescriptions and the rate of hospitalization for hyperkalemia in ambulatory patients before and after the publication of RALES. We linked prescription-claims data and hospital-admission records for more than 1.3 million adults 66 years of age or older in Ontario, Canada, for the period from 1994 through 2001. Results: Among patients treated with ACE inhibitors who had recently been hospitalized for heart failure, the spironolactone-prescription rate was 34 per 1000 patients in 1994, and it increased immediately after the publication of RALES, to 149 per 1000 patients by late 2001 (P<0.001). The rate of hospitalization for hyperkalemia rose from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 (P<0.001), and the associated mortality rose from 0.3 per 1000 to 2.0 per 1000 patients (P<0.001). As compared with expected numbers of events, there were 560 (95 percent confidence interval, 285 to 754) additional hyperkalemia-related hospitalizations and 73 (95 percent confidence interval, 27 to 120) additional hospital deaths during 2001 among older patients with heart failure who were treated with ACE inhibitors in Ontario. Publication of RALES was not associated with significant decreases in the rates of readmission for heart failure or death from all causes. Conclusions: The publication of RALES was associated with abrupt increases in the rate of prescriptions for spironolactone and in hyperkalemia-associated morbidity and mortality. Closer laboratory monitoring and more judicious use of spironolactone may reduce the occurrence of this complication. N Engl J Med 2004;351:543-51. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor commenting on an article about the association between statin use and the risk of idiopathic venous thromboembolism. Nondifferential misclassification of disease status; Hazard ratio; Rate of statin exposure.

Background: Asthma is a common yet incompletely understood health problem associated with a high morbidity burden. A wide variety of seasonally variable environmental stimuli such as viruses and air pollution are believed to influence asthma morbidity. This study set out to examine the seasonal patterns of asthma hospitalisations in relation to age and gender for the province of Ontario over a period of 12 years.Methods: A retrospective, population-based study design was used to assess temporal patterns in hospitalisations for asthma from April 1, 1988 to March 31, 2000. Approximately 14 million residents of Ontario eligible for universal healthcare coverage during this time were included for analysis. Time series analyses were conducted on monthly aggregations of hospitalisations.Results: There is strong evidence of an autumn peak and summer trough seasonal pattern occurring every year over the 12-year period (Fisher-Kappa (FK) = 23.93, p > 0.01; Bartlett Kolmogorov Smirnov (BKS) = 0.459, p < 0.01). This pattern was observed in both sexes. However, young males (0-4 years) were hospitalised at two to three times the rate of females of the same age. Rates were much lower in the older age groups. A downward trend in asthma hospitalisations was observed in the total population over the twelve-year period (beta = -0.980, p < 0.01).Conclusions: A clear and consistent seasonal pattern was observed in this study for asthma hospitalisations. These findings have important implications for the development of effective management and prevention strategies. [ABSTRACT FROM AUTHOR]

Abstract: Reports have emerged of abrupt tapering among recipients of long-term prescription opioids to conform new prescribing guidelines. We conducted a population-based, repeated cross-sectional time-series study among very high-dose (≥200 MME) opioid recipients in Ontario, Canada, to examine changes in the monthly prevalence of rapid tapering from 2014 to 2018, defined as recipients experiencing either a ≥50% reduction in daily doses or abrupt discontinuation sustained for 30 days. Interventional autoregressive integrated moving average models were used to test for significant changes following key guidelines and drug policies and programs. A sensitivity analysis examined rapid tapering sustained for 90 days. The monthly prevalence of rapid tapering events was stable from January 2014 to September 2016 (average monthly prevalence: 1.4%) but increased from 1.4% in October 2016 to 1.8% in April 2017 (P = 0.001), coincident with Ontario's Fentanyl Patch-for-Patch Return Program implementation. Transient spikes in the prevalence of rapid tapering also occurred 2 months after Ontario's delisting of publicly funded high-strength opioids and the release of updated Canadian Opioid Prescribing Guideline for Chronic Pain, reaching 2.3% in March 2017 and July 2017, respectively. However, this prevalence decreased to 1.2% in December 2018 (P < 0.0001). Although the prevalence of abrupt opioid discontinuation was lower, similar trends were observed. Our sensitivity analysis examining long-lasting rapid tapering found similar trends but lower prevalence, with no changes in complete discontinuation. These temporary increases in rapid tapering events highlight the need for improved communication and evidence-based resources for prescribers to minimize negative consequences of evolving policies and guidelines. [ABSTRACT FROM AUTHOR]

Introduction: Language proficiency may influence safe medicine use among new immigrants and contribute to adverse drug events and healthcare utilization. Methods: A retrospective cohort study was conducted to investigate the effects of immigration status and self-reported language proficiency on unplanned healthcare visits. Each new immigrant (language proficient [LP] and non-language proficient [non-LP] immigrants) was matched 1:2 with longstanding Canadian residents. Outcomes while receiving warfarin therapy included unplanned hospital visits for any cause and for bleeding within 180 days of cohort entry (first prescription for warfarin after age 66 years). Results: A total of 906 immigrants (446 LP, 460 non-LP) were matched to 1812 longstanding Canadian residents. Immigrants were less likely than longstanding Canadian residents to have unplanned hospital visits during warfarin therapy (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.63–0.88). Immigrants who were non-LP were less likely than LP immigrants to present to hospital for any cause (HR 0.77; 95% CI 0.60–0.99). No significant differences in hospital visits for bleeding events were found between groups. Discussion: Immigrants were less likely than longstanding Canadian residents to have unplanned hospital visits. Among immigrants, those who were non-LP were less likely than those who were LP to have unplanned healthcare visits. However, unplanned healthcare visits related to bleeding were similar between groups. Several sociocultural factors and differing structural barriers may help to explain the observed differences in hospital visit rates. Failure to identify differences in bleeding events may relate to factors that preserve adherence to warfarin despite limited language proficiency. [ABSTRACT FROM AUTHOR]

Limited evidence suggests that isotretinoin may be associated with inflammatory bowel disease (IBD). To explore this association, we conducted a retrospective population-based cohort study in British Columbia, Canada, among participants who were newly treated with isotretinoin or topical acne medications. The entire population of untreated provincial residents aged 12-29 years served as the reference group. During the 12-year study period, we identified 46,922 participants treated with isotretinoin, 184,824 treated with a topical acne medication, and 1,526,946 untreated individuals. Compared with untreated individuals, we observed no significant association between isotretinoin use and IBD (rate ratio (RR) 1.14; 95% confidence interval (CI) 0.92-1.41). As expected, we found no association with topical acne medications (RR 1.11; 95% CI 0.99-1.24). In prespecified secondary analyses, isotretinoin was associated with IBD among individuals aged 12-19 years (RR 1.39; 95% CI 1.03-1.87) and topical acne medications were associated with ulcerative colitis (RR 1.19; 95% CI 1.00-1.42). Our primary analyses found no association between isotretinoin and IBD. In prespecified secondary analyses, some evidence was found of associations with isotretinoin as well as topical acne medications, suggesting a possible association between IBD and acne itself. Additional research is needed to explore this possibility. [ABSTRACT FROM AUTHOR]

• Drug interactions are an important and avoidable, yet underappreciated cause of phenytoin toxicity. • Trimethoprim (TMP), a potent inhibitor of the CYP2C8 isoenzyme that is commonly administered with sulfamethoxazole (SMX) for the treatment of urinary tract infections, is known to reduce phenytoin clearance by 30%. Given the saturable nature of phenytoin metabolism, decreases in phenytoin clearance of this magnitude may be clinically significant. • Prescription of TMP/SMX was associated with a more than doubling of the risk of hospitalization for phenytoin toxicity [adjusted odds ratio 2.11, 95% confidence interval (CI) 1.24, 3.60]. • Co-prescription of TMP/SMX and phenytoin is common. In our study, approximately 20% of phenytoin users received at least one prescription for TMP/SMX, thereby being placed at excess risk of phenytoin toxicity. Pharmacokinetic studies suggest that trimethoprim (TMP) can inhibit the hepatic metabolism of phenytoin, but the clinical relevance of this is uncertain. We studied the risk of phenytoin toxicity following the prescription of trimethoprim/sulfamethoxazole (TMP/SMX), a commonly used antibiotic, among elderly patients receiving phenytoin. We conducted a population-based, nested case-control study of a cohort of Ontario residents aged 66 years of age or older treated with phenytoin over a 17-year period (April 1 1992 to March 31 2009). Within this group, case patients were those hospitalized with phenytoin toxicity. For each case, we identified up to four control patients from the same cohort, matched for age and sex, and determined the odds ratio (OR) for the association between phenytoin toxicity and receipt of TMP/SMX in the preceding 30 days. Among 58 429 elderly patients receiving phenytoin during the study period, we identified 796 case patients hospitalized for phenytoin toxicity and 3148 matched controls. Following multivariable adjustment for potential confounders, we observed a more than doubling of the risk of phenytoin toxicity following the receipt of TMP/SMX [adjusted OR 2.11, 95% confidence interval (CI) 1.24, 3.60]. In contrast, we observed no such risk with amoxicillin, an antibiotic with similar indications but not expected to interact with phenytoin (adjusted OR 1.12, 95% CI 0.64, 1.98). Among older patients receiving phenytoin, treatment with TMP/SMX is associated with a more than twofold increase in the risk of phenytoin toxicity. When clinically appropriate, alternate antibiotics should be considered for these patients. [ABSTRACT FROM AUTHOR]

Background: The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P450 isoenzyme 3A4. However, this potential drug interaction is widely underappreciated and its clinical consequences have not been well characterized. We explored the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics. Methods: We conducted a population-based, nested, case-crossover study involving people aged 66 years and older who had been prescribed a calcium-channel blocker between Apr. 1, 1994, and Mar. 31, 2009. Of these patients, we included those who had been admitted to hospital for the treatment of hypotension or shock. For each antibiotic, we estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach to contrast each patient's exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier. Results: Of the 7100 patients admitted to hospital because of hypotension while receiving a calcium-channel blocker, 176 had been prescribed a macrolide antibiotic during either the risk or control intervals. Erythromycin (the strongest inhibitor of cytochrome P450 3A4) was most strongly associated with hypotension (odds ratio [OR] 5.8, 95% confidence interval [CI] 2.3-15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3-6.1). Azithromycin, which does not inhibit cytochrome P450 3A4, was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). We found similar results in a stratified analysis of patients who received only dihydropyridine calcium-channel blockers. Interpretation: In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the effect of warfarin in combination with cotrimoxazole and other antibiotics in the risk of upper gastrointestinal (UGI) tract hemorrhage in older patients. It states that the study was conducted through the analysis of the health care database in Ontario between April 1, 1997 and March 31, 2007. It reveals that cotrimoxazole is associated to almost 3-fold risk in UGI tract hemorrhage. However, other antibiitics such as amoxicillin are not related.

Objectives. We studied whether 5 regulatory agency advisories concerning the possible increased risk of suicidal behavior during antidepressant therapy had an effect on antidepressant prescription trends in Ontario. Methods. We conducted a population-based, time-series analysis of new monthly antidepressant prescriptions dispensed by the Ontario Drug Benefits program in 3 age groups (younger than 20 years, 20-65 years old, and older than 65 years) over a 7-year period (April 1998 to March 2005). The impact of five advisories about the possible risk of suicide during antidepressant therapy was also analyzed. Results. The number of new prescriptions for selective serotonin reuptake inhibitors as a group did not change after any antidepressant warning in any age group. However, the rate of new paroxetine prescriptions in patients younger than 20 years declined by 54% immediately after the first warning for paroxetine was issued in the United Kingdom in June 2003. That same warning had no effect on new paroxetine prescriptions in the other age categories. Conclusion. The warning about paroxetine use in depressed patients younger than 18 years that was issued in the United Kingdom led to a significant decrease in new paroxetine prescriptions for young patients in this country. By contrast, warnings in North America did not influence new antidepressant prescription rates in any patient group. (Am J Public Health. 2007;97:750-754.) [ABSTRACT FROM AUTHOR]

Background: Several Canadian provinces have introduced reimbursement policies mandating substitution of innovator biologics with lower-cost biosimilars. We estimated the number of patients affected and cost implications if such policy changes were to be implemented in Ontario, Canada. Methods: We conducted a cross-sectional time series analysis of Ontarians dispensed publicly funded biologics indicated for inflammatory diseases (rheumatic conditions, inflammatory bowel disease: infliximab, etanercept, adalimumab) between January 2018 and December 2019, and forecasted trends to Dec. 31, 2020. The primary source of data was pharmacy claims data for all biologics reimbursed by the public drug program. We modelled the number of patients affected and government expenditures (in nominal Canadian dollars) of several biosimilar policy options, including mandatory nonmedical biosimilar substitution, substitution in new users, introduction of a biosimilar for adalimumab, and price negotiations. In a secondary analysis, we included insulin glargine. Results: In 2018, 14 089 individuals were prescribed a publicly funded biologic for inflammatory diseases. A mandatory nonmedical biosimilar substitution would potentially have affected 7209 patients and saved $238.6 million from 2018 to 2020. A new-user substitution would have affected 757 patients and saved $34.2 million. If an adalimumab biosimilar were to become available, 12 928 patients would be affected by a mandatory nonmedical substitution and the 3-year savings would increase to $645.9 million (all biosimilars priced at 25% of innovator biologics). Finally, an expanded nonmedical substitution policy including insulin glargine would affect 115 895 patients and save $288.7 million (not including adalimumab). Interpretation: Policies designed to curb rising costs of biologics can have substantially different effects on patients and government expenditures. Such analyses warrant careful consideration of the balance between cost savings and effects on patients. [ABSTRACT FROM AUTHOR]

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... [ABSTRACT FROM AUTHOR]