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1.  Combination and Switching of Stimulants in Children and Adolescents with Attention Deficit/Hyperactivity Disorder in Quebec 
To assess the one-year period prevalence of stimulant combination therapy and switching in children/ adolescents with attention deficit/hyperactivity disorder (ADHD) in Quebec, Canada.
Patients aged 6–17 years, with at least two ADHD diagnosis codes documented in different visits and at least 30 days’ supply of a stimulant during their most recent one-year observation period were selected from the Regie de l’assurance maladie du Quebec database (03/2007–02/2012). Combination therapy was defined as at least 30 consecutive days of concomitant use of multiple stimulants with different active moieties, or use of a stimulant and another psychotropic medication. Therapy switching was defined as a prescription claim for a new psychotropic medication less than 30 days before or after the end of supply of a stimulant. The one-year period prevalence of therapy combination and switching was calculated.
The one-year period prevalence of combination therapy and switching among 9,431 children and adolescents with ADHD treated with stimulants was 19.8% and 18.7%, respectively. The most frequent combination categories were atypical antipsychotics (AAP: 10.8%), atomoxetine (ATX: 5.5%) and clonidine (5.3%). The most frequent switched-to categories were other stimulants (7.9%), AAP (5.5%) and ATX (4.7%).
Approximately one in five children/adolescents with ADHD on a stimulant experienced combination therapy or therapy switching; however, the majority of the medications used in combination or switching were not label-indicated for the treatment of ADHD in Canada. These results highlight the need for further research to evaluate the risk-benefit of stimulant combination and switching in children and adolescents with ADHD.
PMCID: PMC4197516  PMID: 25320609
combination therapy; ADHD; RAMQ; switching; stimulants; traitement par combinaison; TDAH; RAMQ; changement; stimulants
2.  Progression-free survival as a potential surrogate for overall survival in metastatic breast cancer 
OncoTargets and therapy  2014;7:1101-1110.
Progression-free survival (PFS) and time to progression (TTP) are frequently used to establish the clinical efficacy of anti-cancer drugs. However, the surrogacy of PFS/TTP for overall survival (OS) remains a matter of uncertainty in metastatic breast cancer (mBC). This study assessed the relationship between PFS/TTP and OS in mBC using a trial-based approach.
We conducted a systematic literature review according to the PICO method: ‘Population’ consisted of women with mBC; ‘Interventions’ and ‘Comparators’ were standard treatments for mBC or best supportive care; ‘Outcomes’ of interest were median PFS/TTP and OS. We first performed a correlation analysis between median PFS/TTP and OS, and then conducted subgroup analyses to explore possible reasons for heterogeneity. Then, we assessed the relationship between the treatment effect on PFS/TTP and OS. The treatment effect on PFS/TTP and OS was quantified by the absolute difference of median values. We also conducted linear regression analysis to predict the effects of a new anti-cancer drug on OS on the basis of its effects on PFS/TTP.
A total of 5,041 studies were identified, and 144 fulfilled the eligibility criteria. There was a statistically significant relationship between median PFS/TTP and OS across included trials (r=0.428; P<0.01). Correlation coefficient for the treatment effect on PFS/TTP and OS was estimated at 0.427 (P<0.01). The obtained linear regression equation was ΔOS =−0.088 (95% confidence interval [CI] −1.347–1.172) + 1.753 (95% CI 1.307–2.198) × ΔPFS (R2=0.86).
Results of this study indicate a significant association between PFS/TTP and OS in mBC, which may justify the use of PFS/TTP in the approval for commercialization and reimbursement of new anti-cancer drugs in this cancer setting.
PMCID: PMC4069144  PMID: 24971020
progression-free survival; time to progression; surrogate endpoint; metastatic breast cancer
3.  Cost-effectiveness of asenapine in the treatment of bipolar disorder in Canada 
BMC Psychiatry  2014;14:16.
Bipolar disorder (BPD) is prevalent and is associated with a significant economic burden. Asenapine, the first tetracyclic antipsychotic approved in Canada for the treatment of BPD, has shown a comparable efficacy profile to other atypical antipsychotics. In addition, it is associated with a favourable metabolic profile and minimal weight gain potential. This study aimed to assess the economic impact of asenapine compared to olanzapine in the treatment of BPD in Canada.
A decision tree combined with a Markov model was constructed to assess the cost-utility of asenapine compared with olanzapine. The decision tree takes into account the occurrence of extrapyramidal symptoms (EPS), the probability of switching to a different antipsychotic, and the probability of gaining weight. The Markov model takes into account long-term metabolic complications including diabetes, hypertension, coronary heart diseases (CHDs), and stroke. Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a five-year time horizon with yearly cycles.
In the treatment of BPD, asenapine is a dominant strategy over olanzapine from both a MoH and a societal perspective. In fact, asenapine is associated with lower costs and more quality-adjusted life years (QALYs). Results of the probabilistic sensitivity analysis indicated that asenapine remains a dominant strategy in 99.2% of the simulations, in both a MoH and a societal perspective, and this result is robust to the many deterministic sensitivity analyses performed.
This economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine in the treatment of BPD in Canada.
PMCID: PMC3905654  PMID: 24450548
Asenapine; Bipolar disorder; Antipsychotic; Canada; Cost-utility; Cost-effectiveness; Olanzapine
4.  The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer’s disease to nursing homes: cost-effectiveness analysis in France 
The costs associated with the care of Alzheimer’s disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were €98,609 for ChEIs alone and €90,268 for combination therapy, representing cost savings of €8,341. From a societal perspective, overall costs were €122,039 and €118,721, respectively, representing cost savings of €3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective.
PMCID: PMC4201748  PMID: 23928827
Alzheimer’s disease; Cholinesterase inhibitors; Memantine; Cost-effectiveness; Nursing home admission; D61; I10; I12; I18
5.  Medication adherence and persistence in the treatment of Canadian ulcerative colitis patients: analyses with the RAMQ database 
BMC Gastroenterology  2013;13:23.
Although high non-adherence to medication has been noticed for ulcerative colitis (UC), little is known about adherence to mesalamine treatments and determinants that can predict adherence. The objective of this study was to assess adherence and persistence to mesalamine treatments and their potential determinants in mild to moderate UC patients in a real-life setting in Quebec, Canada.
A retrospective prescription and medical claims analysis was conducted using a random sample of mesalamine users with UC. For inclusion, patients were required to initiate an oral mesalamine treatment between January 2005 and December 2009. Patients with a diagnosis of Crohn’s disease were excluded. Treatment adherence (medication possession ratio [MPR]) and persistence were evaluated over a 1-year period after the index prescription using the Kaplan-Meier method with log-rank test and stepwise regression to identify potential determinants.
A sample of 1,681 of the new oral mesalamine users (mean age = 55.3) patients was obtained. Overall, the percentage of patients with a MPR of 80% or greater at 12 months was 27.7%, while persistence was 45.5%. Among patients treated with mesalamine delayed/extended-release tablets (Mezavant®), adherence and persistence were 40.9% and 71.9%, respectively. Predictors of high adherence included, male gender (OR=1.3; 95% confidence interval [CI]=1.1–1.6), older age (>60 years; OR=1.6; 95% CI=1.3–2.0) and current use of corticosteroids (OR=1.4; 95% CI=1.1–1.8). Predictors of high persistence included male sex (OR=1.4; 95% CI=1.1–1.7), current use of corticosteroids (OR=1.4; 95% CI=1.1–1.7) and presence of hypertension or respiratory diseases (OR=1.2; 95% CI=1.01–1.55).
The majority of patients with UC exhibited low adherence and persistence to mesalamine treatments. Various determinants of improved adherence and persistence were identified.
PMCID: PMC3570329  PMID: 23363459
Ulcerative colitis; Anti-inflammatory drugs; Adherence; Persistence
6.  Economic Evaluation of Dexmedetomidine Relative to Midazolam for Sedation in the Intensive Care Unit 
Dexmedetomidine is an α2-receptor agonist administered by continuous infusion in the intensive care unit (ICU) for sedation of critically ill patients who are undergoing mechanical ventilation following intubation. Relative to ICU patients receiving midazolam (a γ-aminobutyric acid agonist) for sedation, those receiving dexmedetomidine spent less time on ventilation, had fewer episodes of delirium, and had a lower incidence of tachycardia and hypertension.
To assess the economic impact, in a Canadian context, of dexmedetomidine, relative to midazolam, for sedation in the ICU.
This economic evaluation was based on a cost–consequences analysis, from the perspective of the Canadian health care system. The selected time horizon was an ICU stay (maximum 30 days). Clinical data were obtained from a previously published prospective, randomized, double-blind trial comparing dexmedetomidine and midazolam. This evaluation considered the costs of the medications, mechanical ventilation, and delirium episodes, as well as costs associated with adverse events requiring an intervention. All costs were adjusted to 2010 and are reported in Canadian dollars.
The average cost of the medication was higher for dexmedetomidine than midazolam ($1929.57 versus $180.10 per patient), but the average costs associated with mechanical ventilation and management of delirium were lower with dexmedetomidine than with midazolam ($2939 versus $4448 for ventilation; $2127 versus $3012 for delirium). The overall cost per patient was lower with dexmedetomidine than with midazolam ($7022 versus $7680). Deterministic sensitivity analysis confirmed the robustness of the difference.
The use of dexmedetomidine was, in most contexts, a more favourable strategy than the use of midazolam, in terms of clinical consequences and economic impact. Dexmedetomidine was less expensive than midazolam and was associated with lower occurrence of delirium and shorter duration of mechanical ventilation.
PMCID: PMC3329902  PMID: 22529402
dexmedetomidine; sedation; intensive care unit; economic evaluation; dexmédétomidine; sédation; unité de soins intensifs; évaluation économique
7.  A one-year economic evaluation of six alternative strategies for the management of uninvestigated upper gastrointestinal symptoms in Canadian primary care 
The cost-effectiveness of initial strategies in managing Canadian patients with uninvestigated upper gastrointestinal symptoms remains controversial.
To assess the cost-effectiveness of six management approaches to uninvestigated upper gastrointestinal symptoms in the Canadian setting.
The present study analyzed data from four randomized trials assessing homogeneous and complementary populations of Canadian patients with uninvestigated upper gastrointestinal symptoms with comparable outcomes. Symptom-free months, quality-adjusted life-years (QALYs) and direct costs in Canadian dollars of two management approaches based on the Canadian Dyspepsia Working Group (CanDys) Clinical Management Tool, and four additional strategies (two empirical antisecretory agents, and two prompt endoscopy) were examined and compared. Prevalence data, probabilities, utilities and costs were included in a Markov model, while sensitivity analysis used Monte Carlo simulations. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were determined.
Empirical omeprazole cost $226 per QALY ($49 per symptom-free month) per patient. CanDys omeprazole and endoscopy approaches were more effective than empirical omeprazole, but more costly. Alternatives using H2-receptor antagonists were less effective than those using a proton pump inhibitor. No significant differences were found for most incremental cost-effectiveness ratios. As willingness to pay (WTP) thresholds rose from $226 to $24,000 per QALY, empirical antisecretory approaches were less likely to be the most cost-effective choice, with CanDys omeprazole progressively becoming a more likely option. For WTP values ranging from $24,000 to $70,000 per QALY, the most clinically relevant range, CanDys omeprazole was the most cost-effective strategy (32% to 46% of the time), with prompt endoscopy-proton pump inhibitor favoured at higher WTP values.
Although no strategy was the indisputable cost-effective option, CanDys omeprazole may be the strategy of choice over a clinically relevant range of WTP assumptions in the initial management of Canadian patients with uninvestigated dyspepsia.
PMCID: PMC2947002  PMID: 20711528
Antisecretory therapy; Cost-effectiveness; Dyspepsia; Economic modelling; Endoscopy; Helicobacter pylori
8.  Use, tolerability and compliance of spironolactone in the treatment of heart failure 
Risk of morbidity and mortality in patients with severe heart failure (HF) is reduced by blockade of aldosterone receptors with spironolactone. However, benefits of spironolactone are potentially limited by treatment compliance and adverse events profile. The aim of this study was to estimate use of spironolactone by patients with HF, incidence of key adverse events, and patient compliance.
This study was performed using data from the Quebec provincial medical and drug plans (Régie de l'Assurance Maladie du Québec, RAMQ) for patients who had a diagnosis of HF. Relative incidence of gynecomastia and hyperkalemia was estimated for users and non-users of spironolactone. Treatment adherence was estimated for users of spironolactone and compared to adherence with angiotensin converting enzyme (ACE) inhibitors, beta-blockers (β-blockers), and angiotensin receptor blockers (ARBs).
RAMQ data were obtained for a total of 82,018 patients with a diagnosis of HF. Of these patients, 59.9% used an ACE inhibitor, 59.5% used a beta-blocker, 28.4% used an ARB, and 15.1% (n = 12,344) used spironolactone. Despite underestimation due to limitation of the database, the documented incidence of hyperkalemia (3.3% versus 1.4%) and gynecomastia (1.8% versus 0.7%) was significantly higher in spironolactone users than non-users (p < 0.001). Treatment compliance was significantly lower with spironolactone compared to ACE inhibitors, β-blockers, and ARBs (45.6% versus 56.1%, 59.7%, and 57.0%, respectively; p < 0.001). Persistence to treatment over a one-year period was also lower with spironolactone compared to ACE inhibitors, β-blockers, and ARBs (50.7% versus 64.5%, 70.4%, and 66.3%, respectively; p < 0.001).
Use of spironolactone is associated with an incidence of adverse events, which may have an impact on treatment compliance.
PMCID: PMC3121672  PMID: 21599961
9.  Study protocol of the YOU CALL - WE CALL TRIAL: impact of a multimodal support intervention after a "mild" stroke 
BMC Neurology  2010;10:3.
More than 60% of new strokes each year are "mild" in severity and this proportion is expected to rise in the years to come. Within our current health care system those with "mild" stroke are typically discharged home within days, without further referral to health or rehabilitation services other than advice to see their family physician. Those with mild stroke often have limited access to support from health professionals with stroke-specific knowledge who would typically provide critical information on topics such as secondary stroke prevention, community reintegration, medication counselling and problem solving with regard to specific concerns that arise. Isolation and lack of knowledge may lead to a worsening of health problems including stroke recurrence and unnecessary and costly health care utilization.
The purpose of this study is to assess the effectiveness, for individuals who experience a first "mild" stroke, of a sustainable, low cost, multimodal support intervention (comprising information, education and telephone support) - "WE CALL" compared to a passive intervention (providing the name and phone number of a resource person available if they feel the need to) - "YOU CALL", on two primary outcomes: unplanned-use of health services for negative events and quality of life.
We will recruit 384 adults who meet inclusion criteria for a first mild stroke across six Canadian sites. Baseline measures will be taken within the first month after stroke onset. Participants will be stratified according to comorbidity level and randomised to one of two groups: YOU CALL or WE CALL. Both interventions will be offered over a six months period. Primary outcomes include unplanned use of heath services for negative event (frequency calendar) and quality of life (EQ-5D and Quality of Life Index). Secondary outcomes include participation level (LIFE-H), depression (Beck Depression Inventory II) and use of health services for health promotion or prevention (frequency calendar). Blind assessors will gather data at mid-intervention, end of intervention and one year follow up.
If effective, this multimodal intervention could be delivered in both urban and rural environments. For example, existing infrastructure such as regional stroke centers and existing secondary stroke prevention clinics, make this intervention, if effective, deliverable and sustainable.
Trial Registration
PMCID: PMC2818655  PMID: 20053273
10.  Choices, persistence and adherence to antihypertensive agents: Evidence from RAMQ data 
Most treatment recommendations for hypertension are based on criteria that consider efficacy, safety and cost. Given the need for long-term use of antihypertensive agents, treatment compliance should also be taken into consideration in the selection process.
The purpose of the present study was to estimate persistence and adherence to antihypertensive agents in a real-life setting.
Persistence and adherence to treatment were estimated using data from the Regie de l’assurance maladie du Quebec.
Data from a random sample of 4561 subjects with a diagnosis of hypertension covered by the Regie de l’assurance maladie du Quebec drug plan and using one of the antihypertensive agents reimbursed by the drug plan for the first time between January 2000 and December 2001 were analyzed. The persistence rate observed after a two-year period with diuretics was significantly lower (52.8%) than with any other classes of antihyperten-sive agent (P<0.01). Persistence rates for beta-blockers, calcium channel blockers, angiotensin-II receptor blockers and angiotensin-I converting enzyme inhibitors were 69.3%, 64.3%, 60.9% and 58.9%, respectively. After two years, the proportion of patients who were 80% adherent to their treatment was 64.9% for angiotensin-I converting enzyme inhibitors, 65.0% for angiotensin-II receptor blockers, 64.2% for calcium channel blockers, 60.3% for beta-blockers and 50.9% for diuretics. The proportion of patients who were 80% adherent to their treatment was significantly lower for diuretics than with any other antihypertensive agents (P<0.01).
Persistence and adherence to treatment are essential to treatment success. Results of the present study indicate that, in a real-life setting, patients are significantly less compliant to diuretics than to any other antihypertensive agents.
PMCID: PMC2644030  PMID: 18401466
Compliance; Hypertension; Population health

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