Abstract:Background:Differences in Multiple sclerosis (MS) disease-modifying therapy (DMT) prescribing patterns between different groups of neurologists have not been explored.Objective:To examine concentrations of prescribing patterns and to assess if MS-specialists use a broader range of DMTs relative to general neurologists.Methods:We conducted a cross-sectional study using administrative claims databases in Ontario, Canada to link neurologists to 2009 DMT prescription data. MS specialization was defined using both practice location and prescription patterns. Lorenz curves and Gini coefficients were constructed to examine prescribing patterns, separating neurologist characteristics dichotomously and separating Avonex from the other standard DMTs (Betaseron, Rebif and Copaxone). Gini coefficient 95% confidence intervals (CIs) were derived using jack-knife statistical techniques.Results:Prescriptions were highly concentrated with 12% of Ontario neurologists prescribing 80% of DMTs. There was a trend towards Avonex being more commonly prescribed relative to the other DMTs. When MS specialization was defined by DMT prescribing, high-volume prescribing neurologists showed a broader range of DMT prescribing (Gini 0.38-0.44) in comparison to low-volume prescribers (Gini 0.57-0.66).Conclusions:The majority of DMTs are prescribed by a small subset of neurologists. High-volume prescribing MS-specialists show more variability in DMT use while low-volume prescribers tend to individually focus on a narrower range of DMTs.

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Objective To examine the effects of an intensive 2-day course on physicians' prescribing of opioids.Design Population-based retrospective observational study.Setting College of Physicians and Surgeons of Ontario (CPSO) in Toronto.Participants Ontario physicians who took the course between April 1, 2000, and May 30, 2008.Intervention A 2-day opioid-prescribing course with a maximum of 12 physician participants. Educational methods included didactic presentations, case discussions, and standardized patients. A detailed syllabus and office materials were provided.Main outcome measures Participants were matched with control physicians using specific variables. The primary outcome was the rate of opioid prescribing, expressed as milligrams of morphine equivalent per quarter.Results One hundred thirty-eight course participants (120 family physicians, 15 specialists, and 3 physicians whose status was uncertain) were eligible for analysis. Of these, 68.1% were self-referred and 31.9% were referred by the CPSO. Overall, among physicians referred by the CPSO, the rate of opioid prescribing decreased dramatically in the year before course participation compared with matched control physicians. The course had no added effect on the rate of physicians' opioid prescribing in the subsequent 2 years. There was no statistically significant effect on the rate of opioid prescribing observed among the self-referred physicians. Among 15 of the self-referred physicians who, owing to the high quantities of opioids they prescribed, were not matched with control physicians, the rate of opioid prescribing decreased by 43.9% in the year following course completion.Conclusion Physicians markedly reduced the quantities of opioids they prescribed after medical regulators referred them to an opioid-prescribing course. The course itself did not lead to significant additional reductions; however, a subgroup of physicians who prescribed high quantities of opioids might have responded to what was taught in the course.

BACKGROUND:Beta-blockers may be cardioprotective in patients receiving chronic dialysis. We examined cardiovascular outcomes among incident dialysis patients receiving beta-blocker therapy.METHODS:We conducted a retrospective cohort study employing linked healthcare databases in Ontario, Canada. We studied all consecutive chronic dialysis patients aged≥66 years who initiated dialysis between 1 July 1991 and 31 July 2007. Patients were divided into three groups according to new medication use after the initiation of chronic dialysis. The three groups were patients initiated on beta-blockers, calcium channel blockers and statins only. Patients in the beta-blocker and calcium channel blocker groups could also be concurrently receiving a statin. The primary outcome was time to a composite endpoint of death, myocardial infarction, stroke or coronary revascularization.RESULTS:There were a total of 1836 patients (504 beta-blocker, 570 calcium channel blocker and 762 statin-only users). Compared to statin-only use, beta-blocker use was not associated with improved cardiovascular outcomes [adjusted hazard ratio (aHR) 1.07, 95% confidence interval (CI) 0.92-1.23]. As expected, calcium channel blocker use was also not associated with improved cardiovascular outcomes (aHR 0.91, 95% CI 0.79-1.06). Among all subgroup analyses by beta-blocker attributes, only high-dose beta-blocker therapy was associated with better cardiovascular outcomes as compared to low-dose beta-blockers (aHR 0.50, 95% CI 0.29-0.88).CONCLUSIONS:We observed no beneficial effect of beta-blocker use among patients receiving chronic dialysis relative to our comparator groups. Given current uncertainty around the cardioprotective benefits of beta-blockers in patients receiving dialysis, a large randomized clinical trial is warranted.

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 broad-spectrum 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 levo floxacin (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.

Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials.To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription.Population-based cohort study.Ontario, Canada.Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008.Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate.Compared with ezetimibe users (n = 61,831), fibrate users (n = 19,072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease.Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times.New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear.Ontario Ministry of Health and Long-Term Care Drug Innovation Fund.

Comment. To my knowledge this is the first study to report that smokers of mentholated cigarettes, and in particular women and non–African Americans, have significantly increased odds of stroke compared with nonmentholated cigarette smokers. Although potential causal links cannot be established and further research is required to confirm the findings, the association between mentholated cigarette smoking and stroke is noteworthy, given that the results are based on large population-level data, with data spanning nearly a decade, and given that the relationship is independent of multiple sociodemographic, smoking behavior, and health status confounders. The mentholated cigarette–stroke association may even be underestimated because this analysis included only current smokers and not former smokers. Increased cigarette particulate matter entering the lungs because of facilitation of reflex breath-holding through menthol-induced upper airway cold receptor stimulation serves as a potential mechanism for how mentholated cigarettes might potentially cause increased stroke over nonmentholated cigarettes. It is curious why smoking mentholated cigarettes would not result in an increase in forms of cardiovascular disease, other than stroke, like myocardial infarction and hypertension. A possible explanation is that mentholated cigarettes exert some selective effects on the cerebrovascular system. Potentially in support of this theory, smoking mentholated cigarettes has been found to result in increased carotid artery stiffness compared with smoking nonmentholated cigarettes, whereas equal decreases in coronary artery reserve flow were observed between the 2 cigarettes types. Other potential explanations for the mentholated cigarette–stroke relationship deserve mention. First, smokers with stroke may have a greater predisposition for smoking mentholated cigarettes than regular cigarettes (ie, reverse causality). Second, confounders not included in the analysis may potentially explain the association (eg, the presence or not of medical therapy). Third, the mentholated cigarette–stroke relationship may be erroneous, as a result of several sources of potential bias associated with the analysis (eg, recall bias, prevalence bias). Finally, there is less than 5% probability that the association found between mentholated cigarette smoking and stroke is one of chance. The fact that multiple disease outcomes were examined increases to some degree the finding of a “chance” association. These results highlight the need for further review of the last legally allowed tobacco additive in North America, given that mentholated cigarettes may be placing individuals at even greater risk of potentially devastating cerebrovascular disease than regular cigarettes.

Case reports and pharmacologic theory suggest that some antidepressants can interfere with the hepatic metabolism of metoprolol by cytochrome P450 2D6 (CYP2D6), potentially increasing the risk of bradycardia. The objective of this study was to characterize the clinical consequences of this potential drug interaction at the population level. We conducted a population-based, nested case-control study of Ontario residents 66 years of age or older receiving metoprolol. Cases hospitalized for bradycardia were compared with matched controls (4:1) to explore the odds ratio for initiation of antidepressants that inhibit CYP2D6 (fluoxetine and paroxetine) and those that do not inhibit CYP2D6 (fluvoxamine, citalopram, venlafaxine, and sertraline) 30 days before hospitalization. From April 1997 to March 2009, we identified 332,254 older patients continuously receiving metoprolol, of whom 8232 (2.5%) were treated in hospital for bradycardia. The adjusted odds ratio for exposure to fluoxetine or paroxetine compared with other antidepressants 30 days prior to hospitalization for bradycardia was 0.76 (95% confidence interval 0.42-1.37). Among older patients receiving metoprolol, the initiation of antidepressants that inhibit CYP2D6 was not associated with a significant increase in the risk of bradycardia compared with antidepressants that do not inhibit CYP2D6.

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BACKGROUND/OBJECTIVE:Differences in patient adherence to various disease-modifying drugs (DMDs) in the treatment of multiple sclerosis (MS) are not well understood. The goal of this study was to evaluate adherence of adult MS patients in Ontario with public drug plan coverage to various DMDs: intramuscular interferon beta-1a (i.m. IFNβ-1a, Avonex), subcutaneous interferon beta-1a (s.c. IFNβ-1a, Rebif), subcutaneous interferon beta-1b (IFNβ-1b, Betaseron) or glatiramer acetate (Copaxone).METHODS:In this retrospective cohort study, Ontario Public Drug Plan beneficiaries aged 15 or older who were newly treated with i.m. IFNβ-1a, s.c. IFNβ-1a, IFNβ-1b or glatiramer acetate between April 2006 and March 2008 were followed forward until treatment discontinuation, switch to another DMD or a maximum two year follow-up period. Cumulative persistence rates were analyzed by the Kaplan-Meier method. The proportion of patients reaching the study endpoints after the two year follow-up period was also calculated.RESULTS:Cumulative persistence rates for all four DMDs were similar over time (p=0.80), ranging from 73.6-79.1% at six months, 59.1-63.1% at one year and 41.5-47.4% at two years. After two years, the proportion of patients who had discontinued treatment, switched to another DMD or died was similar among DMDs (p=0.79, Fisher's exact test). Switching between DMD types was low and occurred in 3.4-6.5% of new DMD users.CONCLUSIONS:Adherence to DMDs in adult MS patients in Ontario is poor, which is consistent with previously reported adherence rates to MS DMDs in other regions. No significant differences in adherence exist between the DMDs evaluated in this study.