Effect of an antimicrobial stewardship programme on antimicrobial utilisation and costs in patients with leukaemia: a retrospective controlled study.

OBJECTIVES: To examine the effectiveness of an antimicrobial stewardship programme on utilization and cost of antimicrobials in leukaemia patients in Canada. METHODS: We conducted a multisite retrospective observational time series study from 2005 to 2013. We implemented academic detailing as the intervention of an antimicrobial stewardship programme in leukaemia units at a hospital, piloted February-July 2010, then fully implemented December 2010-March 2013, with no intervention in August-November 2010. Internal control was the same hospital's allogeneic haematopoietic stem-cell transplantation unit. External control was the combined leukaemia-haematopoietic stem-cell transplantation unit at another hospital. Primary outcome was antimicrobial utilization (antibiotics and antifungals) in defined daily dose per 100 patient-days (PD). Secondary outcomes were antimicrobial cost (Canadian dollars per PD); cost and utilization by drug class; length of stay; 30-day inpatient mortality; and nosocomial Clostridium difficile infection. We used autoregressive integrated moving average models to evaluate the impact of the intervention on outcomes. RESULTS: The intervention group included 1006 patients before implementation and 335 during full implementation. Correspondingly, internal control had 723 and 264 patients, external control 1395 and 864 patients. Antimicrobial utilization decreased significantly in the intervention group (p <0.01, 278 vs. 247 defined daily dose per 100 PD), increased in external control (p = 0.02, 237.4 vs. 268.9 defined daily dose per 100 PD) and remained stable in internal control (p = 0.66). Antimicrobial cost decreased in the intervention group (p = 0.03; $154.59 per PD vs. $128.93 per PD), increased in external control (p = 0.01; $109.4 per PD vs. $135.97 per PD) but was stable in internal control (p = 0.27). Mortality, length of stay and nosocomial C. difficile rate in intervention group remained stable. CONCLUSIONS: The antimicrobial stewardship programme reduced antimicrobial use in leukaemia patients without affecting inpatient mortality and length of stay.

Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis.

UNLABELLED: We completed a network meta-analysis of published papers to compare bisphosphonate gastrointestinal safety. We found that zoledronic acid had the highest chance of causing gastrointestinal adverse events. Etidronate had the highest chance of discontinuation due to an adverse event. No difference was found for serious adverse events. INTRODUCTION: Bisphosphonates are first-line treatment for osteoporosis. Gastrointestinal (GI) adverse events (AE) are the primary reason for non-adherence. Little is known about the comparative GI safety of bisphosphonates. PURPOSE: Leverage published clinical trial data to examine the comparative GI safety of bisphosphonates. METHODS: We completed a systematic review of all English-language clinical trials that assessed bisphosphonate safety and/or efficacy in primary osteoporosis through to 2012. Randomized, blinded, and controlled studies were eligible. The primary outcome was any GI-related AE. Subanalyses were completed for upper GI symptoms, serious GI, nausea, esophageal-related events, and discontinuation due to AE. A Bayesian-based network meta-analysis was completed to allow for indirect comparisons. Results were reported as the probability that a specific drug had the highest number of events. RESULTS: We identified 50 studies: 32 alendronate, 12 risedronate, 5 etidronate, and 7 zoledronic acid. Zoledronic acid had the highest probability of having the highest number of any GI AE (91%) and nausea (70%). Etidronate (70%) and zoledronic acid (28%) had the highest probability of having the greatest attrition due to AE. Etidronate had the highest probability (56%) of having the greatest number of upper GI symptoms among oral bisphosphonates. CONCLUSION: Zoledronic acid had the highest probability of causing the greatest number of GI AE, possibly related to nausea. These results question the assumption that annual zoledronic acid will translate into better adherence. Little difference was found between alendronate and risedronate for serious AE. More research into real-world implications of the comparative safety of bisphosphonates is needed.

Trends in selection and timing of first-line pharmacotherapy in older patients with type 2 diabetes diagnosed between 1994 and 2006.

AIMS: To characterize temporal trends in the selection and timing of first-line pharmacotherapy among older patients with Type 2 diabetes. DESIGN AND METHODS: We studied five population-based cohorts every 3 years, from 1994 to 2006. In each of those years, we identified all subjects aged 66 years or older newly diagnosed with diabetes and determined the initial glucose-lowering drug and the time between diagnosis and drug initiation. We calculated the proportion of patients prescribed each agent and estimated time from diagnosis to initiation using Kaplan-Meier survival analysis. RESULTS: We identified a total of 64 368 eligible people who initiated drug therapy during the study period. From 1994 to 2006, first-line metformin use increased from 20.1 to 79.0%. Glyburide (glibenclamide) decreased from 71.1% of all first-line therapies in 1994 to 9.8% in 2006, while first-line use of insulin or combination therapy have changed little at approximately 5% each. No other medication exceeded 2% of first-line therapies. The median time from diagnosis to initiation of pharmacotherapy increased dramatically during the study period, from 1.8 years in 1994 to 4.6 years in 2006. CONCLUSIONS: Metformin has become the most commonly used initial medication for the treatment of diabetes. Although guidelines have evolved to recommend more aggressive initiation and intensification of pharmacotherapy, our results suggest that the time from diagnosis to initiation has increased substantially.

Progression through diabetes therapies among new elderly users of metformin: a population-based study.

AIMS: To examine temporal changes in progression to second-line therapies among older patients with diabetes newly treated with metformin. METHODS: We conducted a population-based study among residents of Ontario, Canada aged 66 years and older with diabetes newly treated with metformin monotherapy in 1997, 2000, 2003 or 2006. Each annual cohort was followed until progression to a second oral hypoglycaemic agent, insulin or until 31 December 2010. Time to progression to a second oral hypoglycaemic agent or insulin was compared across the cohorts. RESULTS: In the four annual cohorts, we identified a total of 46 104 people newly treated with metformin monotherapy. The median time to progression to any second diabetes therapy lengthened significantly over time, from 5.0 years in 1997 to 6.1 years in 2003 (P < 0.0001). Similarly, the time to progression to insulin lengthened over the study period (P = 0.03). Furthermore, the choice of second-line therapy changed over time. While 80.7% of new metformin users in 1997 progressed to glyburide therapy as second-line treatment, the corresponding figure by 2006 was only 45.1% as newer treatment options emerged. CONCLUSIONS: Although recent guidelines recommend aggressive intensification of oral therapy for patients with Type 2 diabetes, older Ontarians with diabetes who started metformin in 2006 remained on monotherapy for longer than those who started in 1997. Furthermore, although there is no consensus regarding a preferred second-line therapy, the introduction of new alternatives has led to greater variation in the selection of second-line therapies in this population.

A population-based assessment of the drug interaction between levothyroxine and warfarin.

Most drug interaction resources suggest that levothyroxine can dramatically potentiate the effect of warfarin. However, the mechanistic basis of the interaction is speculative, and little evidence supports a meaningful drug interaction. We conducted a population-based nested case-control study to examine the risk of hospitalization for hemorrhage following the initiation of levothyroxine in a cohort of 260,076 older patients receiving warfarin. In this group, we identified 10,532 case subjects hospitalized for hemorrhage and 40,595 controls. In the primary analysis, we found no association between hospitalization for hemorrhage during warfarin therapy and initiation of levothyroxine in the preceding 30 days (adjusted odds ratio 1.11, 95% confidence interval 0.67-1.86). Secondary analyses using more remote initiation of levothyroxine also found no association. These findings suggest that concerns about a clinically meaningful levothyroxine-warfarin drug interaction are not justified. Drug interaction resources that presently characterize this interaction as important should reevaluate this classification.

Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population.

AIMS: Sulphonylureas promote insulin release by inhibiting pancreatic potassium channels. Older sulphonylureas such as glyburide (glibenclamide), but not newer ones such as gliclazide, antagonize similar channels in myocardium, interfering with the protective effects of ischaemic preconditioning. Whether this imparts a higher risk of adverse cardiac events is unknown. METHODS: We conducted a population-based cohort study of patients aged 66 years and older who were hospitalized for acute myocardial infarction or who underwent percutaneous coronary intervention between 1 April 2007 and 31 March 2010 while receiving either glyburide or gliclazide. We used a high-dimensional propensity score matching process to ensure similarity of glyburide- and gliclazide-treated patients. The primary outcome was a composite of death or hospitalization for myocardial infarction or heart failure. RESULTS: During the 2-year study period, we matched 1690 patients treated with glyburide to 984 patients treated with gliclazide at the time of hospitalization for acute myocardial infarction or percutaneous coronary intervention. We found no difference in the risk of the composite outcome among patients receiving glyburide (adjusted hazard ratio 1.01; 95% CI 0.86-1.18). We found similar results in secondary analyses of each outcome individually, and in two supplementary analyses (haemorrhage and pneumonia) in which we anticipated no difference between the two patient groups. CONCLUSIONS: Among older patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, treatment with glyburide is not associated with an increased risk of future adverse cardiovascular events relative to gliclazide, suggesting that the effect of glyburide on ischaemic preconditioning is of little clinical relevance.

Macrolide-induced digoxin toxicity: a population-based study.

In this 15-year, population-based, nested case-control study, we investigated the association between hospitalization for digoxin toxicity and recent exposure to individual macrolide antibiotics. Clarithromycin was associated with the highest risk of digoxin toxicity (adjusted odds ratio (OR) 14.8; 95% confidence interval (CI) 7.9-27.9), whereas erythromycin and azithromycin were associated with much lower risk (adjusted OR 3.7; 95% CI 1.7-7.9; and adjusted OR 3.7; 95% CI 1.1-12.5, respectively). We found no increased risk with a neutral comparator, cefuroxime (adjusted OR 0.8; 95% CI 0.2-3.4).

New use of rosiglitazone decreased following publication of a meta-analysis suggesting harm.

AIMS: It is uncertain whether meta-analyses lead to changes in prescribing practices. We studied trends in the prescribing of glucose-lowering therapy before and after the publication of a meta-analysis suggesting harm from rosiglitazone. METHODS: We examined the prescription records of all residents of Ontario, Canada, aged > or = 66 years. For each week between January and December 2007, we identified new users of five categories of glucose-lowering medications: rosiglitazone, pioglitazone, metformin, glibenclamide (glyburide) and insulin. The effect of the meta-analysis was assessed using interventional autoregressive integrated moving-average models. RESULTS: Following the release of the meta-analysis, there was a sudden decline in new users of rosiglitazone (P = 0.01), mirrored by a nearly identical but transient increase in new users of pioglitazone (P < 0.001). There was also a net decline in new users of thiazolidinediones as a class (P < 0.001). The number of new users of other glucose-lowering medications did not change. CONCLUSIONS: A highly-publicized meta-analysis regarding rosiglitazone's potential harms led to an abrupt decline in new users of the drug, as well as a transient surge in new use of pioglitazone.

High rate of maternal vitamin B12 deficiency nearly a decade after Canadian folic acid flour fortification.

Vitamin B12 deficiency may be an independent risk factor for neural tube defects (NTD). We determined the prevalence of biochemical B12 deficiency (<125 pmol/l) among 10 622 Ontarian women aged 15-46 years who underwent concomitant testing of serum bhCG and B12 9 years after the implementation of Canadian folic acid flour fortification. The overall prevalence of biochemical B12 deficiency was 7.4%. Relative to non-pregnant women, the adjusted odds ratio (95% confidence interval) of biochemical B12 deficiency was 0.78 (0.60-1.0) among women pregnant 28 days gestation or less and was 1.4 (1.1-1.8) after 28 days gestation. About 1 in 20 women may be deficient in B12 in early pregnancy. The impact on maternal and fetal well-being, including preventable NTD, should be considered.

Giant cell arteritis and cardiovascular disease in older adults.

OBJECTIVE: To explore the association between giant cell arteritis (GCA) and subsequent cardiovascular disease in older adults. DESIGN: Population based retrospective cohort study. SETTING: The entire province of Ontario, Canada. PARTICIPANTS: Patients aged 66 years and older with newly diagnosed GCA (n = 1141), osteoarthritis (n = 172,953), or neither (n = 200,000). Patients with neither were randomly selected from the general population and formed the control group. MAIN OUTCOME MEASURES: The primary composite outcome was based on a subsequent diagnosis or surgical treatment for coronary artery disease, stroke, peripheral arterial disease, or aneurysm or dissection of the aorta. RESULTS: The composite end point was more common in seniors with GCA (12.1/1000 person-years) than in patients with osteoarthritis (7.3/1000 person-years) or neither condition (5.3/1000 person-years). The adjusted hazard ratio for cardiovascular disease was 1.6 (95% confidence interval (CI) 1.1 to 2.2) in patients with GCA versus patients with osteoarthritis, and 2.1 (95% CI 1.5 to 3.0) in patients with GCA versus unaffected controls. CONCLUSIONS: Older adults with GCA appear to be at increased risk for developing cardiovascular disease. Whether an aggressive approach to cardiovascular risk factor modification is particularly beneficial in these patients remains to be determined.

A population based time series analysis of asthma hospitalisations in Ontario, Canada: 1988 to 2000.

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.

Inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding in elderly patients: retrospective cohort study.

OBJECTIVES: To determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding. DESIGN: Retrospective cohort study from population based databases. SETTING: Ontario, Canada. PARTICIPANTS: 317 824 elderly people observed for more than 130 000 person years. The patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper gastrointestinal bleed, or died or the study ended. MAIN OUTCOME MEASURE: Admission to hospital for acute upper gastrointestinal bleeding. RESULTS: Overall, 974 bleeds were observed, with an overall bleeding rate of 7.3 per 1000 person years. After controlling for age or previous gastrointestinal bleeding, the risk of bleeding significantly increased by 10.7% and 9.8%, respectively, with increasing inhibition of serotonin reuptake. Absolute differences in bleeding between antidepressant groups were greatest for octogenarians (low inhibition of serotonin reuptake, 10.6 bleeds/1000 person years v high inhibition of serotonin reuptake, 14.7 bleeds/1000 person years; number needed to harm 244) and those with previous upper gastrointestinal bleeding (low, 28.6 bleeds/1000 person years v high, 40.3 bleeds/1000 person years; number needed to harm 85). CONCLUSIONS: After age or previous upper gastrointestinal bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper gastrointestinal bleeding. These increases are clinically important for elderly patients and those with previous gastrointestinal bleeding.

Proton pump inhibitors. Compliance with a mandated step-up program.

OBJECTIVE: To assess compliance with a step-up approach to proton pump inhibitor (PPI) therapy before implementation of a new provincial policy to promote histamine-type 2 receptor antagonist (H2RA) use before PPI therapy. DESIGN: Population-based, retrospective, open cohort study using prescribing and medical procedure data from January 1, 1995, to April 30, 1999. SETTING: Health administration databases for the universal health care system in Ontario. PARTICIPANTS: Approximately 1.4 million residents of Ontario older than 65 years. MAIN OUTCOME MEASURES: Proportion of patients who received a trial of H2RA therapy or gastrointestinal diagnostic testing 12 months before starting PPI therapy in 1996. RESULTS: Among the 25,870 patients who met study criteria in 1996, about 63% had received H2RAs 12 months before starting PPI therapy and 73% had had a trial of H2RAs or gastrointestinal diagnostic testing. Repeat analysis for January through April 1999, following the new policy implementation, showed that about 72% of patients had had a trial of H2RAs within 12 months of starting PPI therapy. CONCLUSION: A modest gain (9%) in compliance with using H2RA therapy within 12 months before starting PPI therapy was seen following introduction of the step-up intervention. In future, costs and benefits of potential interventions should be carefully considered before implementing new policies.

Progressive trends in the prevalence of benzodiazepine prescribing in older people in Ontario, Canada.

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 > or =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.

Are there seasonal patterns to ruptured aortic aneurysms and dissections of the aorta?

OBJECTIVE: to test the hypothesis that there are seasonal increases in aortic aneurysm ruptures and dissections. METHODS: a retrospective, population-based time series analysis of hospital admissions for dissection and rupture of the aortic aneurysm in the Province of Ontario from 1988-1997. Analyses were carried out on weekly and monthly aggregations of hospital admissions. RESULTS: there is weak statistical evidence of seasonality in the weekly time series (BKS=0.0987, p=0.03) and no evidence of seasonality in the monthly time series. There is no evident seasonality in the time plots. The incidence of dissections increased significantly over the study period while the incidence of ruptures decreased. CONCLUSIONS: this large population-based study, contrary to other published reports, fails to find convincing evidence of seasonality in rupture or dissection of aortic aneurysm though did demonstrate contrasting trends in incidence.

Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy.

BACKGROUND: 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.