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Objectives To assess the risks of ventricular tachyarrhythmia/sudden cardiac death (VT/SCD) with domperidone use in Parkinson’s disease (PD). Study designs and Settings Using Bayesian methods, results from an observationalstudy were combined with prior beliefs to calculate posterior probabilities of increasedrelative risk (RR)) of VT/SCD with use of domperidone compared to non-use and ofharm, defined as risk exceeding 15%. The analyses were carried with normallydistributed priors (log (RR)): uninformative (N(0,10)) or informative (N(0.53,179)),derived from a meta-analysis (OR (95%CI):1.70 (1.47-1.97)). Sensitivity analyses used:different priors’ strengths, different priors, and Bayesian meta-analysis Results The uninformative prior yielded a RR: 1.23 (95% credible interval (CrI):0.94-1.62), like the published frequentist RR: 1.22 (95% CI:0.99-1.50), with 69% probabilityof harm. With an informative prior weighted at 100%, 50% and 10%, the RR were 1.63(1.41-1.88), 1.57 (1.31-1.91) and 1.39 (1.10-1.93), respectively. The correspondingprobabilities of harm were 100%, 99%, and 94%, respectively. Conclusion While both the frequentist and Bayesian approaches with anuninformative prior were unable to reach a definitive conclusion concerning thearrhythmic risk of domperidone in PD patients, the Bayesian analysis with informativepriors showed a high probability of increased risk that was robust to multiple priorsensitivity analyses.

OBJECTIVES: (1) To evaluate the association between acute kidney injury (AKI) in the PICU and long-term mortality and (2) to determine the extent to which adding the urine output (UO)–defined AKI alters the association. METHODS: A 2-center retrospective cohort study of children (≤18 years old) admitted to the PICU between 2003 and 2005 for noncardiac surgery, with follow-up until 2010. Patients with end stage renal disease, no provincial health insurance number, who died during hospitalization, or could not be linked to administrative data were excluded. One hospitalization per patient was included. AKI was defined by using serum creatinine criteria and/or UO criteria. Mortality was ascertained by using administrative data. Cox regression analysis was performed to evaluate the association between AKI and long-term mortality. RESULTS: The study population included 2041 patients (55.7% male, mean admission age 6.5 ± 5.8 years). Of 2041 hospital survivors, 9 (0.4%) died within 30 days, 51 (2.5%) died within 1 year, and 118 (5.8%) died within 5 to 7 years postdischarge. AKI was independently associated with 5- to 7-year mortality (adjusted hazard ratio [95% confidence interval]: 3.10 [1.46–6.57] and 3.38 [1.63–7.02], respectively). Including UO did not strengthen the association. CONCLUSIONS: AKI is associated with 5- to 7-year mortality. Because this is an observational study we cannot determine if AKI is causative of mortality or of the pathophysiology. However, patients with AKI represent a high-risk group. It is reasonable that these patients be considered for targeted follow-up until future researchers better elucidate these relationships

Purpose High-dimensional propensity scores (hdPS) can adjust for measured confounders, but it remains unclear how well it can adjust for unmeasured confounders. Our goal was to identify if the hdPS method could adjust for confounders which were hidden to the hdPS algorithm. Method The hdPS algorithm was used to estimate two hdPS; the first version (hdPS-1) was estimated using data provided by 6 data dimensions and the second version (hdPS-2) was estimated using data provided from only two of the 6 data dimensions. Two matched sub-cohorts were created by matching one patient initiated on a high-dose statin to one patient initiated on a low-dose statin based on either hdPS-1 (Matched hdPS Full Info Sub-Cohort) or hdPS-2 (Matched hdPS Hidden Info Sub-Cohort). Performances of both hdPS were compared by means of the absolute standardized differences (ASDD) regarding 18 characteristics (data on seven of the 18 characteristics were hidden to the hdPS algorithm when estimating the hdPS-2). Results Eight out of the 18 characteristics were shown to be unbalanced within the unmatched cohort. Matching on either hdPS achieved adequate balance (i.e., ASDD

Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown. We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters. Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations. We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range

Atrial fibrillation (AF) is common in patients with heart failure. Rhythm- and rate-control strategies are associated with similar efficacy outcomes. We compared the economic impact of the 2 treatment strategies in patients with AF and heart failure from the province of Québec, Canada.In a substudy of the Atrial Fibrillation and Congestive Heart Failure trial, health care expenditures of patients from Québec randomized to rhythm and rate-control treatment strategies were compared from a single-payer perspective using a cost-minimization approach. In-trial resource utilization and unit costs were estimated from Québec Health Insurance Board databases supplemented by disease-specific costs from the Ontario Case Costing Initiative.In all, 304 patients were included, aged 68 ± 9 years; 86% male; ejection fraction, 26% ± 6%. Baseline characteristics were similar in rhythm-control (n = 149) and rate-control (n = 155) groups. Arrhythmia-related costs accounted for 45% of total expenditures. Rate-control patients had fewer cardiac procedures (146 vs. 238, P0.001), driven by fewer cardioversions, and lower costs related to antiarrhythmic drugs (CAD $48 per patient [95% confidence interval {CI}, $21-$96] vs. $1319 per patient [95% CI, $1124-$1522]). However, these differences were offset by higher expenditures due to hospitalizations for noncardiovascular diagnoses, implantable cardiac arrhythmia devices, and noncardiovascular drugs in the rate-control group. The total cost per patient was not significantly different between rhythm-control ($72,764 [95% CI, $61,575-$85,145]) and rate-control ($78,767 [95% CI, $67,101-$92,139]) strategies.In the study population, the therapeutic strategy used to manage AF in patients with severe heart failure appears to have little influence on the overall financial burden, which remains substantial.

We studied the association between HIV infection, antiretroviral medications, and the risk of spontaneous intracranial hemorrhage.We performed a cohort and nested case control study in an administrative database. We selected all HIV-positive individuals presenting between 1985 and 2007. Each HIV-positive subject was matched with 4 HIV-negative individuals. We used a Poisson regression model to calculate rates of intracranial hemorrhage according to HIV status. We conducted a case -control study nested within the cohort of HIV-positive individuals to look at the effect of antiretroviral medications. Odds ratios for antiretroviral exposure were obtained using conditional logistic regression.There were 7,053 HIV-positive and 27,681 HIV-negative subjects, representing 138,704 person-years. There were 49 incident intracranial hemorrhages, 29 in HIV-positive and 20 in HIV-negative individuals. The adjusted hazard ratio for intracranial hemorrhage in HIV-positive compared to HIV-negative patients was 3.28 (95% confidence interval [CI] 1.75-6.12). The effect was reduced to 1.99 (95% CI 0.92-4.31) in the absence of AIDS-defining conditions, and increased to 7.64 (95% CI 3.78-15.43) in subjects with AIDS-defining conditions. Hepatitis C infection, illicit drug or alcohol abuse, intracranial lesions, and coagulopathy were all strongly associated with intracranial hemorrhage (all P.001). In the case control study, 29 cases of ICH in HIV-positive individuals were matched to 228 HIV-positive controls. None of the antiretroviral classes were associated with an increase in the odds ratio of intracranial hemorrhage.The risk of intracranial hemorrhage in HIV-positive individuals seems to be mostly associated with AIDS-defining conditions, other comorbidities, or lifestyle factors. No association was found between use of antiretroviral medications and intracranial hemorrhage.

Background Many observational studies have found an association between the exposure to statins and the increased risk of diabetes, mostly through the use of intent-to-treat (ITT) like exposure measure (EM). ITT like EM may not adequately reflect the mechanism of action by which statins could cause diabetes. Objectives To determine if continuous EMs can more accurately reflect the mechanism of action by which statins and incidence of diabetes would be associated than ITT like EM. Methods We obtained a cohort of 404,129 diabetes-free incident statin users from the Quebec public drug insurance plan. Patients dispensed with a drug used in the treatment of diabetes or diagnosed with diabetes within 2-years follow-up were defined as cases. Controls were randomly matched to each case on the index date. Three EMs were tested. EM 1: exposure to a high versus low dose statin at baseline (ITT like); EM 2: cumulative standardized statin dose (cSSD) at the index date; and EM 3: cSSD in the 180 days prior to the index date. The optimal EM was selected based upon each model's Akaike's information criterion (AIC). Conditional logistic regressions were used to calculate conditional OR and model AIC. Results All three EMs identified an increased risk of diabetes among patients exposed to higher statin doses. Model AIC identified EM 3 as the best EM for this association. Conclusions Our results indicate that higher statin doses increase the risk of diabetes but favour a cumulative reversible diabetogenic effect of statins.

The objective of this study was to estimate the maximal clinical benefit that could be reasonably expected from a cholesterol-lowering intervention.We used a hypothetical population at high risk of cardiovascular disease events from three risk assessment models including the Framingham risk function, the Score Canada and the Pooled Cohort Risk Assessment Equations. Our source population were all 55-year-old smoking men with diabetes, hypertension and low HDL. From this population, we identified two different subpopulations named "high" and "low", referring to their cholesterol levels which were set at 8.60 and 4.14 mmol/L respectively. Both subpopulations were identified for each risk assessment model in order to estimate the maximal impact of lowering cholesterol on cardiovascular disease events.Our extrapolations estimated that the maximal theoretical efficacy of a cholesterol-lowering intervention corresponds to a risk ratio ranging between 0.46 and 0.66 over a 10-year period. The number of events prevented during this period were between 21 and 29 per 100 patients which corresponds to a number needed to treat varying from 3.47 to 4.76.Our estimation showed the maximal clinical benefit that could be reasonably expected by an intervention that would lower total cholesterol in high-risk patients.

Background Comparative performance of the traditional propensity score (PS) and high-dimensional propensity score (hdPS) methods in the adjustment for confounding by indication remains unclear. We aimed to identify which method provided the best adjustment for confounding by indication within the context of the risk of diabetes among patients exposed to moderate versus high potency statins. Method A cohort of diabetes-free incident statins users was identified from the Quebec’s publicly funded medico-administrative database (Full Cohort). We created two matched sub-cohorts by matching one patient initiated on a lower potency to one patient initiated on a high potency either on patients’ PS or hdPS. Both methods’ performance were compared by means of the absolute standardized differences (ASDD) regarding relevant characteristics and by means of the obtained measures of association. Results Eight out of the 18 examined characteristics were shown to be unbalanced within the Full Cohort. Although matching on either method achieved balance within all examined characteristic, matching on patients’ hdPS created the most balanced sub-cohort. Measures of associations and confidence intervals obtained within the two matched sub-cohorts overlapped. Conclusion Although ASDD suggest better matching with hdPS than with PS, measures of association were almost identical when adjusted for either method. Use of the hdPS method in adjusting for confounding by indication within future studies should be recommended due to its ability to identify confounding variables which may be unknown to the investigators. Electronic supplementary material The online version of this article (doi:10.1186/s12874-016-0119-1) contains supplementary material, which is available to authorized users.

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and has been associated with heart failure, stroke, and mortality. The prevalence of AF is expected to rise with the aging population. Our objectives were to characterize the Quebec AF patient population at the time of diagnosis of AF, quantify medical resource use prior to and after the initial diagnosis of AF, and determine overall survival. Methods A retrospective cohort study was undertaken using the Regie de l'Assurance Maladie du Quebec databases to evaluate patients diagnosed with AF between January 1, 1998, and April 30, 2009. Results A total of 64,157 patients were included in our study population. At the time of diagnosis of AF, patients also suffered from several diseases, including heart failure (15.8%) and angina pectoris (15.1%). Compared with the year prior to AF diagnosis, in the year after AF diagnosis patients were more frequently hospitalized (1.5 vs 1.1 hospitalizations) and for longer periods (5.6 vs 3.3 days), and had more outpatient visits (12.9 vs 11.7). Survival rapidly decreased during the first 60 days (60-day mortality, 6.1%) and steadily declined thereafter, with mortality rates of 14.7% and 36.8% at 1 and 5 years, respectively. Conclusion At the time of diagnosis of AF, patients often suffer from several comorbidities. Diagnosis of AF is associated with an increase in medical resource use and higher mortality rates, particularly within the first 60 days.

Background: Morbidity associated with cardiovascular disease is increasing in the HIV-infected population. We aimed to study the impact of HIV and of antiretrovirals on acute myocardial infarction (AMI). Methods: We performed a cohort and a nested case-control study using the dataset of the Regie de l'Assurance Maladie du Quebec. HIV-positive patients were identified using ICD-9 diagnostic codes and matched to HIV-negative patients. Within the HIV-positive cohort, cases of AMI were identified and matched to HIV-positive patients without AMI. The coprimary outcomes were the risk of AMI associated with HIV exposure in the cohort study and that associated with exposure to antiretrovirals in the case-control study. Data were analysed using Poisson and conditional logistic regression. Results: About 7053 HIV-positive patients were matched to 27,681 HIV-negative patients. Incidence rates of AMI in the HIV+ cohort was 3.88 95% confidence interval (CI) (3.26 to 4.58) per 1000 patient-years, compared to 2.21 95% CI (1.93 to 2.52) per 1000 patient-years in the HIV cohort. The adjusted incidence ratio of AMI for HIV-infected patients was 2.11 95%CI (1.69 to 2.63). Among HIV+ patients, 125 AMI cases were matched with 1084 HIV+ patients. We found increased odds ratio (95% CI) of AMI associated with any exposure to abacavir 1.79 (1.16 to 2.76), P = 0.02, efavirenz 1.83 (1.21 to 2.76) P = 0.004, lopinavir 1.98 (1.24 to 3.16) P = 0.004, and ritonavir 2.29 (1.48 to 3.54) P < 0.001. Conclusions: HIV+ individuals were at higher risk of AMI than the general population, and several antiretrovirals were associated with an increased risk of AMI. Results should be interpreted with caution in absence of data on smoking and HIV clinical status.

Despite being effective in the primary and secondary prevention of sudden cardiac arrest, the cost-effectiveness of implantable cardioverter-defibrillator (ICD) therapy remains debated. We attempted to estimate the value ICD recipients place on their ICD device. We used the contingent valuation method to evaluate the willingness to pay (WTP) and the cost benefit of ICD therapy in an unselected population of 237 recipients. A hypothetical scenario was presented to patients in which at the end of their current ICD no public reimbursement for the replacement would occur. Patients were asked to indicate their out-of-pocket WTP for a replacement ICD using a close-ended question format. Seven different "take-it-or-leave-it" bids were randomly varied and assigned to patients. Median WTP was calculated with nonparametric methods, and multiple logistic regression models were generated to identify factors associated with WTP. Only cost of the device was considered. Median WTP was estimated at CAN $4,125, which corresponds to 21% of the cost of the device (CAN $20,000). In multiple logistic regression analysis, a higher bid (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.91 to 0.99, per CAN $1,000 increase) was associated with a lower WTP, whereas a higher gross family income (OR 2.3, 95% CI 0.9 to 9.0) and higher education (OR 2.2, 95% CI 0.9 to 5.1) were associated with a trend for higher WTP. In conclusion, ICD recipients would be willing to pay a substantial amount for a replacement ICD. Considering the expensive price of the device, ICD recipients value favorably the benefits provided by the ICD.

Background— Percutaneous coronary intervention (PCI) remains limited by the risk of restenosis. Patients' perceptions of the health benefits and value of avoiding restenosis are incompletely known. Methods and Results— We used a contingent valuation approach to assess the willingness to pay (WTP) for a hypothetical treatment that eliminates the risk of restenosis among 270 PCI patients. Patients were provided with a scenario describing a baseline 10% or 20% probability of restenosis in the year following the procedure, which could lead to repeat PCI or, more rarely, bypass surgery, without any increase in mortality. Six different “take it or leave it” bids ($500, $1000, $1500, $2000, $2500, and $3000) and both risk levels were randomly assigned. Multiple logistic regression was used to identify independent predictors of a positive response to the WTP question. Using nonparametric methods, the median WTP to eliminate the risk of restenosis was estimated at $2802. As expected, higher income was independently associated with a higher probability of a positive response to the WTP question (odds ratio, 2.81; 95% CI, 1.32 to 5.97). Bids also were independently associated with the probability of being willing to pay, and this association followed a quadratic effect. Below $1500, bid had little impact on patient answers. However, as prices increased, the probability of being willing to pay started to decrease sharply. Conclusion— The potential to eliminate the risk of restenosis, a benign complication, would have substantial value for patients undergoing PCI.

Dizziness is known to be associated with the risk of falls. However, there is not much evidence for the increase of fractures caused by dizziness.The aim of the study was to investigate whether the symptom of dizziness is associated with an increased fracture rate.We performed a retrospective cohort study using a population-based administrative database in the Province of Quebec, Canada. A cohort of n = 2442 patients with at least one diagnosis of dizziness was compared to n = 16,125 unexposed patients. The main outcome measure was any kind of first fracture after the index date of dizziness.Analysis revealed a moderate effect of dizziness as an independent contributing factor to fractures (adjusted hazard ratio (HR) 1.26, 95% confidence interval 1.03 to 1.55). A fracture in the year before the index date was highly associated with the incidence of a subsequent fracture (HR 2.69, 2.09 to 3.47), and fractures were less frequent in women (HR 0.70, 0.60-0.82). Analysis further revealed that dizziness (HR 1.31, 1.05-1.64) and prior fractures (HR 2.41, 1.81-3.22) were associated with non-osteoporotic fractures, which were also less frequent in women (HR 0.59, 0.50-0.71). The incidence of fractures in sites typical for osteoporosis correlated with a precedent fracture (HR 3.91, 2.31-6.63), but not with dizziness (HR 1.10, 0.69-1.75).Besides the 'typical' elderly female patient being at risk of osteoporotic fractures, male patients suffering from dizziness should be carefully evaluated, and prevention strategies should be considered to minimise their risk of suffering non-osteoporotic fractures.

OBJECTIVE: To determine whether isotretinoin increases the risk of depression in patients with acne vulgaris. METHOD: A case-crossover study was performed among subjects who received > or = 1 isotretinoin prescription from 1984 through 2003. Data were obtained from the Regie de l'Assurance Maladie du Quebec (RAMQ) and Quebec's hospital discharge (Med-Echo) administrative databases. Cases were defined as those with a first diagnosis or hospitalization for depression (ICD-9 codes: 296.2, 298.0, 300.4, 309.0, 309.1, and 311) during the study period (1984-2003) and those who filled a prescription for an antidepressant in the 30 days following their diagnosis or hospitalization. The index date was the calendar date of the diagnosis or hospitalization for depression. Cases were covered by the RAMQ drug plan and had > or = 1 acne diagnosis in the 12 months prior to the index date. Those who received an antidepressant in 12 months prior to the index date were excluded. Exposure to isotretinoin in a 5-month risk period immediately prior to the index date was compared to a 5-month control period. Relative risks along with 95% CIs were estimated using conditional logistic regression. RESULTS: Of the 30,496 subjects in the initial cohort, 126 (0.4%) cases met inclusion criteria. The crude relative risk for those exposed to isotretinoin was 2.00 (95% CI = 1.03 to 3.89). After adjusting for potential time-dependent confounders, the relative risk for those exposed to isotretinoin was 2.68 (95% CI = 1.10 to 6.48). CONCLUSION: This is the first controlled study to find a statistically significant association between isotretinoin and depression. Because depression could have serious consequences, close monitoring of isotretinoin users is indicated. Language: en

Background: In Canada, access to clopidogrel is restricted by most provincial drug insurance plans in order to contain costs. Until April 2007, the Regie de l9assurance maladie du Quebec (RAMQ) Prescription Drug Insurance Plan reviewed special access forms before approving reimbursement for clopidogrel prescriptions. We investigated the impact of this restrictive process on patient9s filling of prescriptions and on all-cause mortality following coronary stenting. Methods: We analyzed prescriptions filled and all-cause mortality in the year following a percutaneous coronary intervention among patients who underwent stent implantation between January 2000 and September 2004. We obtained administrative data from the RAMQ databases. We included patients who filled at least 1 prescription for a nonrestricted cardiovascular drug after hospital discharge. We used Cox proportional models to compare mortality rates as a function of delayed or absent outpatient clopidogrel therapy. Results: Of 13 663 patients, 1571 (11.5%) did not fill any clopidogrel prescription despite filling at least 1 nonrestricted cardiovascular drug prescription after a percutaneous coronary intervention, and 1174 (8.6%) patients filled their clopidogrel prescription with a delay of at least 1 day (median delay 5 days) after filling the nonrestricted cardiovascular drug prescription. After controlling for pertinent covariables, not filling a clopidogrel prescription (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.35–2.15) and filling with a delay (HR 1.34, 95% CI 1.01–1.80) were associated with a significant increase in all-cause mortality. Interpretation: Restricted access to clopidogrel was associated with about 20% of patients either not receiving clopidogrel or receiving therapy after a delay. Delay or absence of clopidogrel therapy increased the risk of all-cause mortality after percutaneous coronary intervention with stenting.

Background: The risk of gastric cancer could be influenced by acid-related diseases or by the use of acid-suppressive drugs, such as histamine H2 receptor antagonists and proton pump inhibitors (PPIs). Objective: To assess the association between exposure to acid-suppressive drugs and the risk of gastric cancer. Methods: A nested case-control study was conducted among people registered in the Quebec health insurance plan (Canada). Cases represented a random sample of subjects diagnosed with gastric cancer between 1995 and 2003 who were matched on age and sex to at least four controls (using incidence density sampling). The index date was the date of cancer diagnosis for the cases, which was the index date for the matched controls. The exposure definition in the 5 years preceding the index date was based on the defined daily doses of acid-suppressive drugs and categorized into quartiles. Results: The study included 1598 gastric cancer cases and 12 991 controls. The adjusted odds ratios for the association between exposure to acid-suppressive drugs and risk of gastric cancer were 1.47 (95% CI 1.23, 1.76), 1.32 (95% CI 1.10, 1.58), 1.48 (95% CI 1.24, 1.77) and 1.18 (95% CI 0.97, 1.44) for the first, second, third and fourth exposure quartiles, respectively. Similar results were obtained when use of H2 receptor antagonists and PPIs were assessed separately (odds ratios for the association between PPIs and the risk of gastric cancer were slightly higher compared with H2 receptor antagonists and risk of gastric cancer). Conclusions: A minor increase in the risk of gastric cancer was observed if exposure to either H2 receptor antagonists or PPIs occurred within the past 5 years. However, this association is probably not causal since it is most likely due to confounding by indication.

Summary Background Combination therapy should be prescribed to patients with moderate to severe asthma after daily long-term treatment with inhaled inhaled corticosteroids (ICS) has been tried without obtaining adequate control and it is not indicated to be used as first line treatment in asthma. Objectives To describe the use of combination therapy for the treatment of asthma and to evaluate to which extent it is prescribed as recommended. Methods A cohort of 14 559 new users of a combination therapy identified between January 1, 2000 and September 30, 2003 was selected from beneficiaries of the Regie de l’assurance maladie du Quebec. We evaluated whether the combination therapy was prescribed according to the Canadian Asthma Guidelines. A logistic regression analysis was also performed to identify patient's and physician's characteristics associated with the adherence to the recommendations of the Canadian Asthma Guidelines for the prescription of a combination therapy. Results Only 40% of users of combination therapy filled a prescription of ICS in the year preceding the initiation of the therapy and this proportion decreased by 21.8% from 2000 to 2003. Patients who received their first combination therapy in an emergency department were less likely to have used ICS previously, but patients treated by a respiratory physician and patients with co-morbidities, markers of asthma severity and markers of uncontrolled asthma were more likely to have used ICS previously. Conclusion Combination therapy has not been used according to the Canadian Asthma Guidelines in a large proportion of patients.

To assess the risk of fractures after a solid organ transplantation among diabetic versus nondiabetic patients, we conducted a nested case-control study. Pretransplant diabetes was associated with a 2-fold increase in post-transplant fractures. Introduction: Diabetes has been associated with osteoporosis in the general population. However, among patients receiving solid organ transplantation, the association between pretransplant diabetes and post-transplant fractures is not clear, although both diabetes and fractures are prevalent among this patient population. We aimed to determine whether pretransplant diabetes increases the risk of fractures among patients receiving solid organ transplantation. Materials and Methods: We conducted a nested case-control study in a cohort of subjects 18 years and older, enrolled in the Quebec Drug Insurance Plan, who received a first solid organ transplantation between January 1986 and December 2005. Cases had sustained a fracture between the date of discharge from the hospitalization for solid organ transplantation and the end of the study period. All remaining patients were eligible controls. The fracture date was the case index date. Cases were matched to up to four controls on the type of organ transplanted and the date of transplantation. The index date of a control patient was that of his/her matched case. Crude and adjusted ORs were obtained with univariate and multivariate conditional logistic regression models. Results: The study included 238 cases and 873 controls. Pretransplant diabetes was present in 30% of the cases and 22% of the controls (crude OR: 2.16; 95% CI: 1.7–2.8). After adjusting for age, sex, previous fractures, past hyperthyroidism, hospitalization duration, use of narcotics, benzodiazepines, antidepressants, loop diuretics, thiazide diuretics, glucocorticoids, immunosuppressants, estrogens, bisphosphonates, calcium, vitamin D, and calcitonin, pretransplantation diabetes remained a significant risk factor for fractures (adjusted OR: 1.94; 95% CI: 1.5–2.6). Use of narcotics (OR: 3.0; 95% CI: 2.0–4.4) and antidepressants (OR: 1.9; 95% CI: 1.2–3.1) in the month preceding the index date and use of loop diuretics in the year preceding the index date (OR: 1.4; 95% CI: 1.1–1.9) were also associated with increased risks of fractures. Conclusions: Pretransplant diabetes seemed to significantly increase post-transplant fractures among adults receiving solid organ transplantation. Pretransplant fracture prophylaxis should be considered in these patients.

Purpose To evaluate the association between rofecoxib, celecoxib, diclofenac, and ibuprofen and the risk of hospitalization for acute myocardial infarction (AMI) in an elderly population. Methods We conducted a retrospective cohort study, using data from the government of Quebec health insurance agency databases, among patients 65–80 years of age who filled a prescription for any of the study drugs during 1999–2002. Cox regression models with time-dependent exposure were used to compare the incidence rates of hospitalization for AMI adjusting for patients' baseline characteristics. Analyses stratified by dose and number of supplied days were also conducted. Results At the index date, a total of 91 062 patients were taking rofecoxib, 127 928 celecoxib, 49 193 diclofenac, and 15 601 ibuprofen. The adjusted hazard ratio (HR) (95%CI) of hospitalization for AMI were: celecoxib versus rofecoxib: 0.90 (0.79, 1.01); ibuprofen versus rofecoxib: 0.95 (0.65, 1.37); diclofenac versus rofecoxib: 1.01 (0.84, 1.22). In secondary analyses based on intended duration of use, neither COX-2 selective inhibitor was associated with a higher risk than ibuprofen or diclofenac. The unadjusted risk of AMI for all NSAIDs increased with dose. In the direct two way adjusted comparison of each NSAID stratified by dose, the only statistically significant difference was with rofecoxib >25 mg/day versus celecoxib >200 mg/day. Conclusion In this study there was no difference between AMI occurrence in elderly patients taking rofecoxib or celecoxib at recommended doses for chronic indications versus those taking ibuprofen/diclofenac. However, the risk of AMI was higher among patients using higher doses of rofecoxib (>25 mg/day) compared to patients using higher doses of celecoxib (>200 mg/day). Copyright © 2006 John Wiley & Sons, Ltd.

This study aims to develop and evaluate diagnostic algorithms for AIDS, hepatitis C status, alcohol abuse and illicit drug use in the administrative healthcare database of the Province of Quebec, Canada (Régie de l'assurance-maladie du Québec (RAMQ)).We selected HIV-positive patients contributing to both the RAMQ database and a local clinical database, which was used as gold standard. We developed algorithms to identify the diagnoses of interest in RAMQ using data from hospital discharge summaries and medical and pharmaceutical claims databases. We estimated and compared sensitivity, specificity, positive predictive and negative predictive values and area under receiver operating curve for each algorithm.Four hundred twenty patients contributed to both databases. Prevalence of conditions of interest in the clinical database was as follows: AIDS 233 (55%), hepatitis C infection 105 (25%), alcohol abuse 106 (25%), illicit drug use 144 (34%) and intravenous drug use 107 (25%). Sensitivity to detect AIDS, hepatitis C, alcohol abuse, illicit drug use and intravenous drug use was 46% [95%CI: 39-53], 26% [18-35], 50% [37-57], 64% [55-72] and 70% [61-79], respectively. Specificity to detect these conditions was 91% [86-95], 97% [94-98], 92% [88-95], 95% [92-97] and 90% [87-93], respectively. Positive predictive values were 87% [80-92], 71% [54-85], 68% [56-78], 87% [79-93] and 72% [62-80], respectively. Area under receiver operating curve varied from 0.62 [0.57-0.65] for hepatitis C to 0.80 [0.76-0.85] for intravenous drug use.Sensitivity was low to detect AIDS, alcohol abuse, illicit drug use and especially hepatitis C in RAMQ. Researchers must be aware of the potential for residual confounding and must consider additional methods to control for confounding.

Empirical studies of antidepressant cost-effectiveness suggest that the use of venlafaxine may be no more costly than selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. The objectives of this study were to identify patients' characteristics and factors associated with the choice of antidepressant and to assess differences in persistence, healthcare utilization and direct medical costs associated with venlafaxine and SSRIs pharmacotherapy.We examined demographic and clinical characteristics of patients (n = 17 144) who received both a diagnosis of depression and a prescription for venlafaxine or an SSRI between 1996 and 2004 using the Quebec health administrative databases. Logistic regression models were used to identify factors independently associated with the choice of antidepressant. Persistence to treatment and overall direct medical costs during 12 months after initiation of therapy were assessed using Cox proportional hazard and GLM models, respectively.Age, sex, provider specialty, and prior 12-month healthcare utilization significantly influenced initial antidepressant choice. Fewer venlafaxine-treated patients discontinued their initial therapy relative to SSRIs' (persistence to initial treatment: 38.4% vs. 29.4% and 24.4% vs. 15.8% at 6 and 12 months, respectively; p0.0001), and they were less likely to require treatment switching. Overall 12-month direct medical costs for SSRI- and venlafaxine-treated patients were Can$2759 and Can$2604, respectively. Patients treated with SSRIs had significantly higher expenditures in a univariate analysis (cost ratio: 1.06 [95% CI: 1.02, 1.10]). However, after controlling for potential confounding factors such as patients' characteristics, prior healthcare utilization, and comorbid conditions in multivariate analyses, the overall expenditures were similar in both groups (cost ratio: 1.03 [95% CI: 0.99, 1.07]).Direct medical costs were generally similar among patients with depression treated with venlafaxine and SSRIs. In a 'real world' setting, the higher acquisition cost of venlafaxine is offset by savings due to fewer hospitalizations and fewer outpatient medical visits. Differences in treatment persistence may also, in part, explain the observed differences in average direct medical costs between venlafaxine and SSRIs.

Purpose We examined whether a continuing medical education intervention increased general practitioners' ability to select the proper pharmacological treatment for patients with osteoarthritis. Subjects and methods Eight towns in Quebec, Canada were randomly allocated to one of four intervention options, workshop and decision tree, workshop, decision tree, or no intervention. All general practitioners practicing in each town were eligible to participate. We evaluated all dispensed prescriptions for either a cyclooxygenase (COX)-2 inhibitor, nonselective nonsteroidal anti-inflammatory drug or acetaminophen written by eligible general practitioners between May 2000 and June 2001 to elderly patients suffering from osteoarthritis. We used a multi-level Bayesian hierarchical model to assess the impact of the interventions on prescription adequacy. Results We analyzed 5318 dispensed prescriptions written by 249 general practitioners in the five-month preintervention period and 4610 dispensed prescriptions written by the same physicians in the five-month postintervention period. A score of zero or one was given to every prescription, with one indicating prescription adequacy according to guidelines provided during the interventions. Bayesian hierarchical models showed some improvement in scores in the post- versus preintervention periods in all four groups. The probability of an improvement in the towns allocated the workshop and decision tree over the control was 94%, compared with 74% in the workshop group and 55% in the decision tree group. Conclusion An interactive approach offered by peers and complemented by easy to use guidelines may enhance the general practitioner's ability to manage osteoarthritis patients.

PURPOSE To compare functional autonomy, quality of life (QOL), and pain control after endovascular and open repair (OR) of abdominal aortic aneurysms. MATERIALS AND METHODS Forty patients with a low surgical risk profile and anatomic compatibility for stent-graft therapy were randomized to receive OR or endovascular aneurysm repair (EVAR). Technical and clinical success as well as mortality were assessed in both groups and compared by Kaplan-Meier analysis. Functional autonomy and QOL were assessed by Karnofsky score and Short Form 36 (SF-36) questionnaire. Pain control was assessed by a numeric rating scale and Brief Pain Inventory questionnaire. QOL outcomes by means of the SF-36 and pain questionnaires were compared with use of mixed-effects models for repeated-measures analysis. RESULTS All procedures were technically successful in both groups. Three late clinical failures requiring surgical conversion or repeated intervention were observed in the EVAR group and one was observed in the OR group. There was no significant difference between groups in terms of functional autonomy or QOL. No difference in pain level was evident during the early postoperative period, whereas the pain level was lower in the OR group after 1 month. Opioid analgesic drug consumption was significantly greater in the OR group during the postoperative period. Mean hospitalization duration was shorter in the EVAR group than in the OR group (4.5 days ± 2.4 vs 11.5 days ± 8.1; P = .001). CONCLUSION EVAR has no advantage over OR in patients at low risk in terms of functional autonomy, QOL, and pain control. However, EVAR was associated with shorter hospitalization durations compared with OR.

METHODS:The determinants of a new treatment with inhaled corticosteroids and secular trends in patient persistence with treatment among chronic obstructive pulmonary disease (COPD) patients were investigated. A cohort of 3768 physician-diagnosed, elderly COPD patients was selected between 1990 and 1996 from the health care administrative database of the Régie de l'assurance maladie du Québec. A nested case-control design was used to identify patient and physician characteristics that were associated with a new treatment with inhaled corticosteroids. Treatment persistence with inhaled corticosteroids was also estimated using Kaplan-Meier analysis. In addition to that, changes in treatment persistence over time, from 1990 to 1995, were investigated by estimating the yearly proportion of patients persisting for less than one year.RESULTS:Within the cohort, the yearly percentage of patients filling at least one prescription for inhaled corticosteroids was 42.2% in 1990 and increased to 53.1% in 1995 (P=0.001). Using a conditional logistic regression model, it was found that the patients most likely to initiate a treatment with inhaled corticosteroids were those who had severe COPD (rate ratio [RR] 1.7; 95% CI 1.4 to 2.0), those who were hospitalized for COPD (RR 10.0; 95% CI 5.6 to 17.9), those who consulted a respirologist in the previous month (RR 2.3; 95% CI 1.6 to 3.3) or those who visited more than three different physicians in the previous three months (RR 1.6; 95% Cl 1.3 to 1.9). The proportion of patients persisting with inhaled corticosteroids for less than one year rose by 19.4%, from 47.6% in 1990 to 67.0% in 1995 (P=0.011; test for trend).CONCLUSIONS:The use of inhaled corticosteroids increased while patient persistence decreased between 1990 and 1995. Disease severity, as well as recent consultation to a respirologist and multiple visits to a physician, were associated with a strong likelihood of being prescribed inhaled corticosteroids. The cost of this practice is far from negligible, while their clinical impact is still uncertain.

Background: In Canada, public drug plans may restrict the use of newer topical antiglaucoma agents. The goals of this retrospective study were to estimate the proportion of patients who, at the initiation of topical glaucoma therapy, had contraindications to the use of topical s-blockers and to identify whether changes in formulary listing status (from restricted-drug list to generally available drug list) influenced the use of topical glaucoma agents in patients with contraindications to s-blockers. Methods: Claims databases administered by the Regie de l'assurance maladie du Quebec were used to identify incident users of s-blockers (betaxolol and timolol) and newer antiglaucoma agents (brimonidine, dorzolamide and latanoprost) among patients aged 35 years or older. Drug claims and physician diagnoses were used to determine the prevalence of the following contraindications to the use of s-blockers (including warnings and precautions): asthma or chronic bronchitis, diabetes, dysrhythmia and heart failure, all in the year preceding the initiation of therapy; or use of systemic s-blockers at the time glaucoma therapy was started. The observation period was divided into 2 phases: the time during which newer agents were on the restricted-drug list (first-line use being limited to patients with contraindications to the use of s-blockers; January 1997 to March 1999) and the time during which these agents were on the generally available drug list (that is, after reimbursement restrictions were relaxed; April 1999 to June 2000). Results: Of the 20 309 eligible patients, 59.8% were female, and the mean age was 72 years. Contraindications to topical s-blocker therapy were significantly more frequent among the patients using newer antiglaucoma agents than among those using s-blockers (71.5% vs. 55.5%, p < 0.0001). Asthma and chronic bronchitis were also more frequent among the patients using the newer agents than among those using s-blockers (43.1 % vs. 22.5%, p < 0.0001). Among the patients without contraindications to topical s-blocker therapy, the overall proportions started on therapy with a newer agent were 22.7% when there were reimbursement restrictions and 30.0% when the restrictions were relaxed (p < 0.000 1). Conclusions: Among patients with contraindications to the use of s-blockers, newer topical antiglaucoma agents were used more often than s-blockers. Among patients without such contraindications, the use of the newer agents increased modestly when reimbursement restrictions were relaxed.

ADHD medications increase clinical encounters for cardiovascular symptoms. Uncertain are the roles of differences in ADHD medications and restrictive practices by drug programs.We conducted two nested case-control studies. The first was nested within a cohort of children de novo users of methylphenidate, amphetamines or atomoxetine and the second case-control study was nested within a subcohort of de novo amphetamine or atomoxetine users with no cardiovascular events prior to the first dispensing of either drug. The outcome for both studies was the composite of physician visits, emergency room visits or hospitalizations for cardiovascular reasons. Cases were matched on sex, age and date of entry within the cohorts, with up to 10 controls. Patients with an active dispensation of ADHD medications at the index date (and up to 90 days previously) were considered exposed. Conditional logistic regression was used to calculate odd ratios (OR).The full cohort comprised 38,495 patients. Among these patients, 3595 (9.3%) had no prior cardiovascular events (the subcohort). In the full cohort, an association was demonstrated with exposure to amphetamine and atomoxetine (but not methylphenidate) and the cardiovascular encounter outcomes. When the sub-cohort was analyzed the associations with amphetamine or atomoxetine were no longer evident.Reimbursement policies need to be considered when conducting observational studies. Had the analysis been conducted without consideration of these policies the results would have incorrectly identified amphetamine and atomoxetine as important risk factors for cardiovascular encounters.

OBJECTIVES: In August 1996, the Regie de l'assurance-maladie du Quebec (RAMQ), the government body responsible for medical insurance in the Canadian province of Quebec, introduced a cost-sharing drug insurance plan. Before this plan, individuals age 65 years and older had to pay Canadian (CDN)$2 per prescription, with the remaining cost paid by the RAMQ. With the new plan, beneficiaries may have to pay an amount between CDN$200 and CDN$925 per year, depending on their income. Concerned that this financial constraint imposed on older people might have an impact on the use of medications, we investigated whether the consumption of four classes of medications, antihypertensive agents, anticoagulants, nitrates, and benzodiazepines, was affected by the drug plan implementation. DESIGN: Time series models with pre/post comparison group. SETTING: Administrative computerized databases of the RAMQ. PARTICIPANTS: Random sample of Quebec residents age 65 years and older registered in the provincial drug plan between August 1992 and June 1997: 54,771 users of nitrates, 133,146 users of antihypertensive agents, 45,534 users of anti-coagulants, and 26,165 users of benzodiazepines. MEASUREMENTS: We modeled the monthly consumption of the medications under study between August 1992 and June 1996. Monthly drug consumptions predicted from the models were compared with those observed for the 13 months (August 1996 to August 1997) following the implementation of the new drug plan using 95% confidence intervals. The number of prescriptions dispensed served as an indicator for drug consumption. RESULTS: During the study period we observed a nonstatistically significant decrease in number of prescriptions of 5.1% for nitrates, 1.1% for antihypertensive agents, and 0.8% for benzodiazepines, and a nonstatistically significant increase of 1.6% for anticoagulants. CONCLUSION: Residents of Quebec age 65 years and older were not found to have reduced significantly their consumption of nitrates, antihypertensive agents, anticoagulants, and benzodiazepines during the 13 months that followed the implementation of a cost-sharing drug insurance plan.

Objective Two identical 24-week, double-blind, placebo-controlled trials of tobramycin solution for inhalation (TOBI ® [PathoGenesis Corporation, Seattle, Washington]) in cystic fibrosis patients with chronic Pseudomonas aeruginosa infection were conducted in the United States. The aim of the present study was to extrapolate the US trial data to a Canadian setting, using Canadian costs to estimate the savings in direct medical costs that might result from use of a similar 24-week TOBI regimen versus usual care in 2 Canadian provinces. Background Cystic fibrosis is a genetic disease in which persistent respiratory infection, usually due to P aeruginosa infection, is the major cause of morbidity and mortality. Methods The US trials demonstrated that TOBI produced significant improvements in pulmonary function test results, reduced sputum levels of P aeruginosa , and resulted in a 26% reduction in the probability of hospitalization (95% CI, 2%–43% vs placebo in the clinical trials). Individual patient data from the US trials were used to calculate the mean number of days in hospital as well as the mean number of days of home intravenous or oral antibiotic therapy. To adjust for Canadian pricing, pertinent economic data were obtained from Statistics Canada and the Ontario and Quebec health ministries. Demographic and baseline data were obtained from health surveys conducted by the Canadian Cystic Fibrosis Foundation. Results Economic analysis showed that the use of TOBI for 24 weeks would result in estimated mean per-patient savings in direct medical costs (in Canadian dollars) of $4055 in Ontario and $4916 in Quebec, which would substantially offset the Canadian acquisition price of $8602 for the same 24-week period. Conclusions Assuming that the percentage of reduction in hospital days observed in the US trials would also occur in the Canadian clinical setting, use of TOBI would reduce the use of health care services, particularly hospital days, and lead to substantial savings in direct medical costs that would offset its acquisition price. Whether this reduction actually occurs after TOBI enters the Canadian market is a subject for future investigation.

In case-control studies conducted using computerized databases, controls are often selected as a random sample from the base population. This representative choice of controls is intended to guard against selection bias. We show, using data from a database case-control study, that such a definition of controls may also lead to selection bias under two conditions: (1) if the target disease has a prolonged asymptomatic clinical course with its detection depending on a specific physical examination and (2) if exposed patients have a higher likelihood of having the disease detected than unexposed patients. The extent of the bias that could result from the use of randomly selected controls was investigated in the context of a case-control study of the risk of ocular hypertension or glaucoma associated with the use of glucocorticoids, conducted using the Quebec universal health insurance computerized databases. This article also illustrates that a computerized database can be useful to empirically explore opportunities for bias.

Aims: To describe the safety of immediate retransfer to community hospitals following primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Methods and results: In a cohort of 246 consecutive patients transferred to a tertiary institution who all underwent primary or rescue PCl, 166 (67%) were immediately retransferred back. The retransfer occurred only if they were haemodynamically stable and had undergone an uncomplicated procedure. In- hospital adverse events were assessed in each referral hospital. Patients had a mean age of 59 years, presented an anterior Ml in 39%, and 91% were in Killip class 1. In this cohort, 75% of patients underwent primary PCI and 25% received rescue PCI. A transradial approach was used in 74% of patients. During ambulance transport back to the referral hospital, no adverse events occurred. In-hospital outcomes were favourable, with low death (2.4%), reinfarction (3.6%) and stroke (1.2%) rates. TIMI major bleeding occurred in 1.8% (catheter-related in 0.6%). Conclusions: In this carefully selected population of STEMI patients, immediate retransfer to the referral hospital following primary or rescue PCI is feasible in more than 2/3 of patients and associated with a low risk of major clinical adverse events.

Background— Hypertension is a leading mortality risk factor yet inadequately controlled in most affected subjects. Effective programs to address this problem are lacking. We hypothesized that an information technology–supported management program could help improve blood pressure (BP) control. Methods and Results— This randomized controlled trial included 223 primary care hypertensive subjects with mean 24-hour BP >130/80 and daytime BP >135/85 mm Hg measured with ambulatory monitoring (ABPM). Intervention subjects received a BP monitor and access to an information technology–supported adherence and BP monitoring system providing nurses, pharmacists, and physicians with monthly reports. Control subjects received usual care. The mean (�SD) follow-up was 348 (�78) and 349 (�84) days in the intervention and control group, respectively. The primary end point of the change in the mean 24-hour ambulatory BP was consistently greater in intervention subjects for both systolic (−11.9 versus −7.1 mm Hg; P P =0.007). The proportion of subjects that achieved Canadian Guideline target BP (46.0% versus 28.6%) was also greater in the intervention group ( P =0.006). We observed similar BP declines for ABPM and self-recorded home BP suggesting the latter could be an alternative for confirming BP control. The intervention was associated with more physician-driven antihypertensive dose adjustments or changes in agents ( P =0.03), more antihypertensive classes at study end ( P =0.007), and a trend toward improved adherence measured by prescription refills ( P =0.07). Conclusions— This multidisciplinary information technology–supported program that provided feedback to patients and healthcare providers significantly improved blood pressure levels in a primary care setting.

Background Randomized controlled trials have established the clinical superiority of primary percutaneous coronary intervention (PCI) over fibrinolysis for ST segment elevation myocardial infarction (STEMI) in selected populations. However, the clinical effectiveness of the primary PCI strategy with modern adjunctive antiplatelet therapy deserves further evaluation. Objective To validate results from randomized controlled trials in a nonselected Canadian population. Methods A retrospective study of 243 consecutive patients who presented with a STEMI at a single academic centre was performed. Baseline characteristics, treatment strategies and in-hospital outcomes of patients treated in 2004 to 2005 (n=129) were compared with those of patients treated in 1999 to 2000 (n=114). Logistic regression was used to adjust for imbalanced baseline characteristics. Results Patients in the 2004 to 2005 cohort versus those in the 1999 to 2000 cohort were older and more likely to be hypertensive and to present in Killip class 2 to 4. All of the patients treated in 2004 to 2005 underwent a primary PCI strategy compared with 32.5% in the 1999 to 2000 cohort. The in-hospital incidence of death, reinfarction or stroke was reduced from 21.9% in 1999 to 2000, to 15.5% in 2004 to 2005 (adjusted OR 0.462; P=0.055), largely due to a reduction in reinfarction (10.5% to 3.1%, adjusted OR 0.275; P=0.041). In-hospital mortality and stroke rates did not change significantly. The median length of stay was reduced from eight to six days in the recent cohort (P=0.002). Conclusions In the present nonselected population, the change in reperfusion strategy from fibrinolysis to primary PCI in the treatment of STEMI reduced the length of hospitalization by two days and was associated with an adjusted 54% relative reduction in adverse in-hospital events, which was largely due to a significant reduction in reinfarction

Objective: To investigate clinical and economic consequences following generic substitution of one vs multiple generics of topiramate (Topamax; Ortho-McNeil Neurologics, Titusville, NJ). Methods: Medical and pharmacy claims data of Regie de l9Assurance-Maladie du Quebec from January 2006 to October 2007 were used. Patients with epilepsy treated with topiramate were selected. An open-cohort design was used to classify the observation period into periods of brand, single-generic, and multiple-generic use. One-year generic-switch and switchback-to-brand rates were estimated using Kaplan-Meier methodology. Medical resource utilization and costs were compared among the three periods using multivariate regression analysis. Results: In total, 948 patients were observed during 1,105 person-years of brand use, 233 person-years of single-generic use, and 92 person-years of multiple-generic use. A total of 23% of generic users received at least two different generic versions. Compared to brand use, multiple-generic use was associated with higher utilization of other prescription drugs (incidence rate ratio [IRR] = 1.27, 95% confidence interval [CI] = 1.24–1.31), higher hospitalization rates (0.48 vs 0.83 visit/person-year, IRR = 1.65, 95% CI = 1.28–2.13), and longer hospital stays (2.6 vs 3.9 days/person-year, IRR = 1.43, 95% CI = 1.27–1.60), but the effect was less pronounced in single-generic use (hospitalization: IRR = 1.08, 95% CI = 0.88–1.34, length of stay: IRR = 1.12, 95% CI = 1.03–1.23). The risk of head injury or fracture was nearly three times higher (hazard ratio = 2.84, 95% CI = 1.24–6.48) following a generic-to-generic switch compared to brand use. The total annualized health care cost per patient was higher in the multiple-generic than brand periods by C$1,716 (cost ratio = 1.21, p = 0.0420). Conclusion: Multiple-generic substitution of topiramate was significantly associated with negative outcomes, such as hospitalizations and injuries, and increased health care costs.

Dementia may be caused by Alzheimer's disease (AD), cerebrovascular disease (CVD), or a combination of both. When CVD is associated with dementia, survival is thought to be reduced. It is unclear whether treatment with cholinesterase inhibitors (ChEIs), which has been found to slow disease progression in AD patients, has similar benefits in vascular forms of dementia.The present study was designed to determine whether co-existing CVD is associated with survival or time to nursing home placement (NHP) among AD patients treated with ChEIs. Findings of poorer outcomes in patients with versus without CVD might argue against the use of ChEIs for AD patients in whom CVD co-exists.A retrospective cohort study was undertaken using the Régie de l'Assurance Maladie du Québec (RAMQ) databases to examine the time to NHP or death for AD patients aged 66+, with or without CVD, treated with ChEIs between July 1, 2000, and June 30, 2003. Because ChEIs are approved only for AD in Canada, a ChEI prescription was used as a surrogate for an AD diagnosis. Separate analyses were performed for patients with persistent ChEI use and those who discontinued ChEI therapy.A total of 4428 patients met inclusion criteria for AD with CVD; 13 512 were classified as having AD alone. For the composite endpoint of NHP or death, 1000-day survival rates were lower among AD patients with versus without CVD (p0.01), but absolute differences were very small (84 vs. 86% with continuous ChEI use; 77 vs. 78% with discontinuous ChEI therapy). Of the secondary endpoints, time to death was shorter for patients with versus without CVD, but time to NHP did not differ between groups.Results may have been affected by selection (misclassification) bias and between-group differences in smoking, body mass index, and duration of ChEI therapy.Associations between co-existing CVD and time to NHP or death appeared to be of little clinical relevance among AD patients treated with ChEIs. The lack of difference between AD patients with and without CVD suggests that CVD should not be used as a reason to deny AD patients access to ChEI treatment.

To measure the proportions of patients switching from generic to branded drugs among users of antiepileptic drugs (AED) compared to other therapeutic areas and to investigate medical services utilization associated with generic switching of lamotrigine.Medical and pharmacy claims data from Régie de l'Assurance Maladie du Québec database from April 1998 to July 2006 were used. Patients with an epilepsy diagnosis (International Classification of Diseases-9 345) and treated with lamotrigine for60 of the 90 days before the entry date of generic lamotrigine in Quebec (February 1, 2003) were selected. The proportion of patients switching back to brand were calculated for lamotrigine, for other AEDs (clobazam, carbamazepine CR, gabapentin) and for non-AED chronic medications (carvedilol, fosinopril, simvastatin). Medical resource utilization was compared between periods of branded vs generic use of lamotrigine.Of 671 patients treated with branded lamotrigine, 187 patients (27.9%) switched to a generic, and 51 of these patients (27.5%) switched back to the branded medication. Rates of switchback were from 20.8% to 44.1% for various AEDs and from 7.7% to 9.1% for non-AEDs. Relative to the branded lamotrigine use period, generic lamotrigine use period was associated with a 5.1% increase in mean daily dose of lamotrigine (239.1 vs 251.4 mg; p = 0.0149), a higher number of dispensations for other AEDs (20.4 vs 23.9 dispensations per person-year; p0.001) as well as non-AED drugs (26.4 vs 32.8 dispensations per person-year; p0.0001), a higher utilization rate of medical services (8.7 vs 9.8 visits per person-year; p0.0001), and a longer hospital length of stay (3.29 days vs 4.86 days per person-year; p0.0001).A higher propensity to switch back to branded medications was observed among antiepileptic drug users compared to users of antihypertensives and antihyperlipidemics, similar to findings from Andermann et al. Switch to generic lamotrigine was significantly associated with increased physician visits and hospitalizations.

Generic substitution may not always save health care costs for antiepileptic drugs (AED).(1) To examine the economic impacts of generic substitution of lamotrigine in Canada; and (2) to convert observed Canadian costs to a United States (US) setting.Health claims from Québec's health plan (RAMQ) between 08/2002 and 07/2006 were analyzed. Patients withor = 1 epilepsy claim and treated with branded lamotrigine (Lamictal) before generic entry were selected. Health care costs ($/person-year) were compared during periods of branded and generic use of lamotrigine. Two cost-conversion methods were employed; one using purchasing power parities, US/Canada service use ratios, and exchange rate, and another employing Canadian health care utilization and US unit costs.671 patients were observed during 1650.9 and 291.2 person-years of branded and generic use of lamotrigine, respectively. The generic-use period was associated with an increase in overall costs (2006 constant Canadian dollars) relative to brand use (C$7902 vs. C$6419/person-year; cost ratio (CR) = 1.22; p = 0.05), despite the lower cost of generic lamotrigine. Non-lamotrigine costs were 33% higher in the generic period (p = 0.013). Both conversion methods yielded increases in total projected health care costs excluding lamotrigine (2006 constant US dollars) during the generic period (Method 1: cost difference: US$1758/person-year, CR = 1.33, p = 0.01); Method 2: cost difference: US$2516, CR = 1.39, p = 0.004).Study limitations pertain to treatment differences, indicators used for conversion and possible claim inaccuracies.Use of generic lamotrigine in Canada was significantly associated with increased overall medical costs compared to brand use. Projected overall US health care costs would likely increase as well.

In the province of Quebec, Canada, the reimbursement of thiazolidinediones (TZDs) is limited to patients who do not respond to doses of metformin and a sulfonylurea.The objective of this research project was to study, in a real-life setting, the ârisk factorsâ for receiving these restricted drugs among patients who meet the reimbursement criteria.Among patients eligible for drug coverage under the RAMQ between May 2000 and June 2005, we selected those who received six consecutive dispensations of high doses of both metformin and a sulfonylurea. The date of the sixth dispensation was set as the index date. The proportion of patients who received a TZD in the year following the index date was calculated and a logistic regression was used to estimate the impact of several factors on the probability of receiving a TZD.There were 4,836 patients in the cohort. A TZD was dispensed to 24.9% (95% CI: 23.7%;26.2%) of the patients. Compared to the oldest group of patients (65 years and more), the probability to receive a TZD was higher for patients aged 51 to 64 years (OR=1.33 95% CI: 1.11;1.59) and patients aged 19 to 50 years [OR=1.81 (95% CI: 1.40;2.33)]. Patients with the highest income were more likely to receive a TZD (OR=1.55 95% CI: 1.21;1.98) compared to patients with the lowest income.These findings suggest that the restricted access to TZDs probably results in social inequities, as individuals with lower incomes are less likely to receive these drugs. Key words: Restricted drugs, TZDs, diabetes.

Background: Lipid-lowering therapeutics, particularly HMG Co-A reductase inhibitors, can be beneficial in primary and secondary cardiovascular prevention. The Canadian population frequently uses these medications but the manner in which they are used in community-based practice is unknown. Objectives: To assess the patient characteristics associated with lipid lowering drug use in community-based clinical practice across four geographic regions in Canada. To assess amongst lipid-lowering drugs users the proportion of patients that would meet accepted dyslipidemia management guidelines. To assess the community-based effectiveness of anti-hyperlipidemic drugs. Methods: Patients filling a prescription for any anti-hyperlipidemia therapy in selected pharmacies in Ontario (ON), Quebec (PQ), British Columbia (BC) and Nova Scotia (NS). All eligible patients were interviewed over the telephone. Physicians who were providing healthcare to the participating patients were requested to provide information from the patient’s medical record. Results: The mean patient age was > 60 yr in all four provinces. There were some differences amongst the four provinces pertaining to patient characteristics, prescription patterns and therapeutic indicators, but not to outcomes. Anti-hyperlipidemia therapy was associated with a 1.81 mmol/L decrease in LDL-Cholesterol (P < 0.001); however only 73% of patients achieved target LDL-Cholesterol concentrations. A lag time of 1.96 yr (P < 0.0001) was observed from the diagnosis of dyslipidemia until the drug treatment was initiated. Patients had an average of 2.8 cardiovascular (CV) risk factors and 86% of patients had at two or more CV risk factors. Thirty-nine percent (95% CI, 36% - 42%) of the patients were being treated for secondary prevention. Thirteen percent (11% - 16%) of patients who were being treated for primary prevention had diabetes. Metabolic syndrome was observed in 32% (29% - 35%) of patients. Conclusion: Almost all patients fulfilled guideline requirements for the use of anti-hyperlipidemic therapy. Although the use of pharmacotherapy was associated with a lowering of LDL cholesterol more aggressive management is required to attain target LDL cholesterol concentrations.

Objective Celecoxib has a superior upper-gastrointestinal (GI) safety profile compared with nonselective nonsteroidal antiinflammatory drugs (NS-NSAIDs). It is unclear whether the utilization of a proton-pump inhibitor (PPI) with celecoxib confers additional protection in elderly patients. We assessed the association between GI hospitalizations and use of celecoxib with a PPI versus celecoxib alone, and NS-NSAIDs with a PPI or NS-NSAIDs alone in elderly patients. Methods We conducted a population-based retrospective cohort study using the government of Quebec health services administrative databases. Elderly patients were included at their first dispensing date for celecoxib or an NS-NSAID between April 1999 and December 2002. Prescriptions were separated into 4 groups: celecoxib, celecoxib plus PPI, NS-NSAIDs, and NS-NSAIDs plus PPI. Cox regression models with time-dependent exposure were used to compare the hazard rates of GI hospitalization between the 4 groups adjusting for patient characteristics at baseline. Results There were 1,161,508 prescriptions for celecoxib, 360,799 for celecoxib plus PPI, 715,176 for NS-NSAIDs, and 148,470 for NS-NSAIDs plus PPI. The adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) were 0.69 (0.52–0.93) for celecoxib plus PPI versus celecoxib, 0.98 (0.67–1.45) for NS-NSAIDs plus PPI versus celecoxib, and 2.18 (1.82–2.61) for NS-NSAIDs versus celecoxib. Subgroup analyses showed that use of a PPI with celecoxib may be beneficial in patients ages ≥75 years but was not better than celecoxib alone among those ages 66–74 years (HR 0.98, 95% CI 0.63–1.52). Conclusion Addition of a PPI to celecoxib conferred extra protection for patients ages ≥75 years. PPI did not seem necessary with celecoxib for patients ages 66–74 years.

The cost effectiveness of drug-eluting stents in Canada is debated and deserves further evaluation in high-risk patients.We performed an economic analysis from the third-party payer perspective based on the clinical results and resource-utilization data of the C-SIRIUS (The Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients with Long De Novo Lesions in Small Native Coronary Arteries) trial, which examined the safety and efficacy of sirolimus-eluting stents (SES) versus bare metal stents (BMS) in high-risk patients with single long de novo lesions in small coronary arteries. Only inpatient costs were considered, including physician fees. We postulated that the incremental cost required to avoid a repeat revascularization (RR) procedure with BMS versus simple balloon angioplasty (BA) could be considered the willingness to pay (WTP) to avoid restenosis in Canada. We assessed the incremental cost-effectiveness ratio (ICER) of SES compared with BMS in these high-risk patients compared with WTP. Results are expressed in 2003 Canadian dollars.With a 7% absolute reduction in the need for RR compared with BA, BMS are associated on average with an ICER of US dollars 12,551/RR avoided (RRA) in Canada. In C-SIRIUS, SES further reduced the need for RR at 1 year from 22% to 4% (p = 0.015) compared with BMS. With a 1.5 stent-to-lesion (STL) ratio and an SES retail price of US dollars 2,700 compared with US dollars 700 for BMS, the ICER of SES versus BMS was US dollars 11,275/RRA -- borderline cost effective compared with the implicit WTP of US dollars 12,551 for such health benefit in Canada. Using a lower STL ratio (1.2) would improve the ICER to US dollars 7941/RRA.Treatment of long lesions in small vessels with SES increases net healthcare costs. However, the ICER for SES compares favorably with the currently accepted comparator, i.e. BMS, to reduce coronary restenosis -- at least for higher risk patients undergoing single-vessel revascularization.

Objective: To assess parental willingness to pay (WTP) for a shorter course of antibacterial treatment versus conventional antibacterial therapy for acute otitis media (AOM). Methods: The study population consisted of 562 parents of children who had been seen and treated by a paediatrician for an episode of AOM between February and November 2002 in Montreal, Quebec, Canada. At the end of the AOM treatment, a questionnaire that included demographic information about the parents and child, details of the child’s AOM history, a global wellbeing (i.e. quality of life) assessment, an evaluation of treatment compliance and a scripted WTP question was administered over the telephone. Descriptive analyses were performed in addition to a multivariate analysis to estimate possible predictors of parental WTP. Results: The children with AOM were representative of the AOM patient population, with 46% being

Purpose In Quebec, MED-ECHO database can be used to estimate inhospital length of stay (LOS) and number of hospitalizations (NOH) both accurately and reliably. However, access to MED-ECHO database is time-consuming. Quebec medical claims database (RAMQ) can be used as an alternative source to estimate these measures. Considering MED-ECHO as the ‘gold standard,’ this study examined the validity of using RAMQ medical claims to estimate LOS and NOH. Methods We used a cohort of 3768 elderly patients with chronic obstructive pulmonary disease (COPD) between 1990 and 1996 and identified those with inhospital claims. Inhospital LOS was defined as the total number of days with inhospital claims. Various grace periods (1–15 days) between consecutive claims were considered for the estimation of LOS and NOH. RAMQ and MED-ECHO databases were linked using unique patient identifiers. Estimates obtained from RAMQ data were compared to those from MED-ECHO using various measures of central tendency and predictive error estimates. Results Overall, 32.7% of patients were hospitalized at least once during the study period based on RAMQ claims, as compared to 32.0% in MED-ECHO ( p-value = 0.51). The best estimates [mean (p-value)] were found to be those obtained when using a 7-day grace period. RAMQ versus MED-ECHO estimates were: 12.2 versus 13.5 days (

Purpose To better communicate the impact of poor persistence when preventive therapies are initiated, we propose a new measure that is intuitively understandable for clinicians. This measure is the percent wasted patients (PWP). Methods The PWP is the percentage of patients, out of the new users of a given preventive treatment, who have discontinued therapy before the time point at which clinical benefits become apparent on the cumulative incidence curves in randomized controlled trials (RCTs) comparing active treatment to placebo. To calculate the PWP, the RCTs that demonstrated the efficacy of the therapy under study must be identified from a MEDLINE search. The point at which the cumulative incidence curves for the main outcome in the experimental and placebo group start diverging is identified and is called the point of visual divergence (PVD). Then, using pharmaceutical claims databases, the percent persistence at the PVD in new users of the therapy is determined. The PWP is then calculated as 100% persistence at PVD. Results For primary prevention with statins, in the province of Quebec, the PWP is 44%. Of 100 patients starting statins for the primary prevention of coronary events, 44 will represent a waste in health resources because they will have discontinued therapy before any clinical benefit can be expected. Conclusions The PWP is a simple measure that can be used by clinicians to select the therapies that need the most reinforcement concerning the importance of persistence. Copyright © 2005 John Wiley & Sons, Ltd.

Leukotriene receptor antagonists (LTRAs) and inhaled corticosteroids (ICSs) must be taken continuously to control persistent asthma. We compared the use of LTRAs and ICSs in patients with similar level of asthma control at treatment initiation with particular attention to treatment persistence.Two cohorts of 15 to 45 year old patients with asthma were selected from the Quebec Health Insurance Plan Database between January 1, 1998, and December 31, 2000. We first identified new users of LTRAs and from the remaining patients, we selected new users of ICSs. The ICS patients were then one-to-one matched to LTRA patients on the use of short-acting beta2-agonists and oral corticosteroids in the year prior to the date of the first LTRA or ICS dispensation (index date). We compared compliance to initial therapies using Cox proportional hazards models.Each of the LTRA and ICS cohorts included 2200 patients. Multivariate model showed that compliance was significantly better for LTRAs than for ICSs [adjusted rate ratio of treatment discontinuation (aRR), 0.46; 95% confidence interval (CI), 0.42-0.49]. If in both groups all medications filled were taken at the prescribed dose, the annual percent of days on therapy for LTRA users would have been twice that for ICS users (38% vs. 19%; p0.0001).The findings of this observational study indicate a far from optimal persistence to LTRAs and ICSs in asthmatic patients. The superior persistence to LTRAs might result in better effectiveness.

The antibacterial activity, tolerability profile and duration of treatment associated with antibiotics are important therapy attributes when considering treating patients for lower respiratory tract infections (LRTIs), such as community acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB).To investigate the effectiveness and cost-effectiveness of oral antibiotics used in the treatment of LRTIs.A cohort of inhaled corticosteroids users who were diagnosed with a LRTI and dispensed a prescription for one of the antibiotics under study on the same day as the diagnosis was selected from the administrative health databases of the Régie de l'assurance maladie du Québec (RAMQ). The risks of treatment failure were estimated using a logistic regression analysis. Treatment failure was defined as another prescription for any antibiotic, an emergency room visit or hospitalization for LRTIs, or death, in the 20 days following the dispensation of the first antibiotic prescribed. A cost-minimization analysis was performed in which only the drug costs related to the first antibiotic filled were considered.A total of 3,610 episodes of LRTIs were studied. There were no significant differences between antibiotics in terms of their respective adjusted odds ratios for rates of failure. However, the lower cost associated with azithromycin was significantly different from the costs associated with any other antibiotic (p0.0001).Clinical effectiveness appears to be similar amongst second line antibiotics that are commonly used in the treatment of LRTIs in the community. Using a cost-minimization analysis, azithromycin appears to be the most cost-effective antibiotic treatment in this setting.

Population-based studies may give results different from randomized clinical trials assessing the efficacy of antibiotics. Objective To determine the effectiveness of amoxicillin, azithromycin, cefprozil and clarithromycin in the treatment of acute otitis media (AOM) in children. Methods Using Quebec Health Insurance databases (RAMQ), we selected a cohort of children aged ≤6 years, with a first episode of AOM between 1999 and 2002. The index AOM was defined as a medical service claim with a diagnosis of AOM and an antibiotic dispensation in the following 72 hours. Failures were defined as a new antibiotic dispensation, a hospitalization or outpatient visit for complications related to AOM in the 30 days after the index AOM. Data were analyzed using logistic regression. Results Overall, 12 693 failures occurred among 60 513 first episodes of AOM. Azithromycin was the only antibiotic that was associated with a decreased risk of failure overall, when compared to amoxicillin (OR 0.88, 95%CI: 0.82, 0.94). However in the first 3 days of treatment (n = 680), azithromycin was more associated with treatment failure (OR 1.6, 95%CI: 1.3, 2.0). Compared to amoxicillin, post-therapy failures (n = 9387) were more likely to occur with cefprozil (OR 1.2, 95%CI: 1.2, 1.3) but were less with azithromycin (OR 0.8 95%CI: 0.8, 0.9). Conclusions Azithromycin had the lowest risk of failure 30 days after the onset of treatment but an increased risk of failure during the first few days of treatment. Amoxicillin remains an effective first-line drug for treating first AOM episodes. Copyright © 2004 John Wiley & Sons, Ltd.