Pharmacologically pertinent period of effect (PPPE).

BACKGROUND: The period of time during which a patient is exposed to a drug does not necessarily correspond to the period during which the drug produces the adverse effect under consideration. We propose the term Pharmacologically pertinent period of effect (PPPE) to address this time window. We explored the PPPE in light of the rofecoxib saga. METHODS: We identified the observational database studies of rofecoxib at doses 25 and 50 mg daily and thromboembolic events. We also obtained the Kaplan-Meier curves of Vioxx Gastrointestinal Outcomes Research trial (VIGOR) and Adenomatous Polyp Prevention on Vioxx (APPROVE) trials. RESULTS: We found seven observational studies with nine analyses. All the studies only looked at current exposure. At the dose of 25 mg, only three of nine analyses were barely statistically significant. At the dose of 50 mg, the risk ratios were much higher. The visual inspection of the Kaplan-Meier curves shows that in the APPROVE trial (25 mg), the placebo and rofecoxib curves start separating to become statistically significantly different only after 36 months. In contrast the VIGOR (50 mg), curves start separating very early and the divergence increases after 8 months. DISCUSSION: The 50 mg observational studies, looking at current exposure, correctively identified the almost immediate increase in risk evident in the VIGOR Kaplan-Meier curves. The absence of an immediate increase in risk shown by the APPROVE trial was also correctively identified by most observational 25 mg studies. To our knowledge no observational study was done on the long-term cardiac toxicity of the 25-mg dose. It would thus appear that the two doses of rofecoxib have different PPPEs.

Cost-Effectiveness Analysis of Fosfomycin for Treatment of Uncomplicated Urinary Tract Infections in Ontario.

Background and Objective. Bacterial resistance to antibiotics traditionally used to treat uncomplicated urinary tract infections (uUTIs) is rising in Canada. We compared the cost-per-patient in Ontario of including fosfomycin (an antibiotic with a low resistance profile) as an option for first-line empirical treatment of uUTIs with current cost of treatment with sulfonamides, fluoroquinolones, and nitrofurantoin. Methods. A decision-tree model was used to perform a cost-minimization analysis. All possible outcomes of a uUTI caused by bacterial species treated with either sulfonamides, fluoroquinolones, nitrofurantoin, or fosfomycin were included. Results. In the base case analysis, the cost-per-patient for treating uUTI with fosfomycin was $105.12. This is similar to the cost-per-patient for each of the other currently reimbursed antibiotics (e.g., $96.19 for sulfonamides, $98.85 for fluoroquinolones, and $99.09 for nitrofurantoins). The weighted average cost-per-patient for treating uUTI was not substantially elevated with the inclusion of fosfomycin in the treatment landscape ($98.41 versus $98.29 with and without fosfomycin, resp.). The sensitivity analyses revealed that most (88.34%) of the potential variation in cost was associated with the probability of progressing to pyelonephritis and hospitalization for pyelonephritis. Conclusion. Fosfomycin in addition to being a safe and effective agent to treat uUTI has a low resistance profile, offers a single-dose treatment administration, and is similar in cost to other reimbursed antibiotics.

The missing cause approach to unmeasured confounding in pharmacoepidemiology.

Unmeasured confounding is a major threat to the validity of pharmacoepidemiological studies of medication safety and effectiveness. We propose a new method for detecting and reducing the impact of unobserved confounding in large observational database studies. The method uses assumptions similar to the prescribing preference-based instrumental variable (IV) approach. Our method relies on the new 'missing cause' principle, according to which the impact of unmeasured confounding by (contra-)indication may be detected by assessing discrepancies between the following: (i) treatment actually received by individual patients and (ii) treatment that they would be expected to receive based on the observed data. Specifically, we use the treatment-by-discrepancy interaction to test for the presence of unmeasured confounding and correct the treatment effect estimate for the resulting bias. Under standard IV assumptions, we first proved that unmeasured confounding induces a spurious treatment-by-discrepancy interaction in risk difference models for binary outcomes and then simulated large pharmacoepidemiological studies with unmeasured confounding. In simulations, our estimates had four to six times smaller bias than conventional treatment effect estimates, adjusted only for measured confounders, and much smaller variance inflation than unbiased but very unstable IV estimates, resulting in uniformly lowest root mean square errors. The much lower variance of our estimates, relative to IV estimates, was also observed in an application comparing gastrointestinal safety of two classes of anti-inflammatory drugs. In conclusion, our missing cause-based method may complement other methods and enhance accuracy of analyses of large pharmacoepidemiological studies.

Head to head comparison of the propensity score and the high-dimensional propensity score matching methods.

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.

Performance of the high-dimensional propensity score in adjusting for unmeasured confounders.

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 <0.1) on all 18 characteristics. CONCLUSION: Our results indicate that the hdPS method was able to adjust for hidden confounders supporting the claim that the hdPS method can adjust for at least some unmeasured confounders.

Diagnostic accuracy of algorithms to identify hepatitis C status, AIDS status, alcohol consumption and illicit drug use among patients living with HIV in an administrative healthcare database.

PURPOSE: 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)). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cost effectiveness of 'on demand' HIV pre-exposure prophylaxis for non-injection drug-using men who have sex with men in Canada.

BACKGROUND: Recent trials report the efficacy of continuous tenofovir-based pre-exposure prophylaxis (PrEP) for prevention of HIV infection. The cost effectiveness of 'on demand' PrEP for non-injection drug-using men who have sex with men at high risk of HIV acquisition has not been evaluated. OBJECTIVE: To conduct an economic evaluation of the societal costs of HIV in Canada and evaluate the potential benefits of this PrEP strategy. METHODS: Direct HIV costs comprised outpatient, inpatient and emergency department costs, psychosocial costs and antiretroviral costs. Resource consumption estimates were derived from the Centre Hospitalier de l'Université de Montréal HIV cohort. Estimates of indirect costs included employment rate and work absenteeism. Costs for 'on demand' PrEP were modelled after an ongoing clinical trial. Cost-effectiveness analysis compared costs of 'on demand' PrEP to prevent one infection with lifetime costs of one HIV infection. Benefits were presented in terms of life-years and quality-adjusted life-years. RESULTS: The average annual direct cost of one HIV infection was $16,109 in the least expensive antiretroviral regimen scenario and $24,056 in the most expensive scenario. The total indirect cost was $11,550 per year. Total costs for the first year of HIV infection ranged from $27,410 to $35,358. Undiscounted lifetime costs ranged from $1,439,984 ($662,295 discounted at 3% and $448,901 at 5%) to $1,482,502 ($690,075 at 3% and $485,806 at 5%). The annual cost of PrEP was $12,001 per participant, and $621,390 per infection prevented. The PrEP strategy was cost-saving in all scenarios for undiscounted and 3% discounting rates. At 5% discounting rates, the strategy is largely cost-effective: according to least and most expensive scenarios, incremental cost-effectiveness ratios ranged from $60,311 to $47,407 per quality-adjusted life-year. CONCLUSION: This 'on demand' PrEP strategy ranges from cost-saving to largely cost-effective. The authors believe it represents an important public health strategy for the prevention of HIV transmission.

HISTORIQUE: De récents essais rendent compte de l'efficacité d'une prophylaxie préexposition continue à base de ténofovir (PrEP) pour prévenir l'infection par le VIH. La rentabilité de la PrEP sur demande n'a pas été évaluée chez les hommes qui ne consomment pas de drogues injectables, mais qui ont des relations sexuelles avec d'autres hommes très susceptibles de contracter le VIH. OBJECTIF: Réaliser une évaluation économique des coûts du VIH pour la société au Canada et évaluer les avantages potentiels de cette stratégie de PrEP. MÉTHODOLOGIE: Les coûts directs du VIH incluaient les coûts des rendez-vous ambulatoires, des séjours hospitaliers et des visites à l'urgence, les coûts psychosociaux et les coûts des antirétroviraux. L'évaluation de la consommation des ressources était dérivée de la cohorte de VIH du Centre hospitalier de l'Université de Montréal. Les évaluations des coûts indirects incluaient le taux d'emploi et l'absentéisme au travail. Les coûts de la PrEP sur demande reprenaient le modèle d'un essai clinique en cours. L'analyse de rentabilité reposait sur une comparaison des coûts de la PrEP sur demande pour prévenir une infection avec les coûts de traitement à vie d'une infection par le VIH. Les avantages étaient présentés d'après les années de vie et les années de vie pondérées par la qualité. RÉSULTATS: Le coût direct annuel moyen d'une infection par le VIH s'élevait à 16 109 $ d'après le scénario de posologie antirétrovirale le moins coûteux, et à 24 056 $ d'après le scénario le plus coûteux. Le coût indirect total s'élevait à 11 550 $ par année. Les coûts totaux pour la première année d'infection par le VIH oscillaient entre 27 410 $ et 35 358 $. Les coûts de traitement à vie non actualisés variaient entre 1 439 984 $ (662 295 $ actualisés à 3 % et 448 901 $, à 5 %) et 1 482 502 $ (690 075 $ à 3 % et 485 806 $ à 5 %). Le coût annuel de la PrEP était de 12 001 $ par participant, et de 621 390 $ par infection prévenue. La stratégie de PrEP était économique dans tous les scénarios non actualisés et actualisés à 3 %. Dans les scénarios actualisés à 5 %, la stratégie était largement rentable. En effet, selon les scénarios le moins et le plus coûteux, le rapport coût-efficacité différentiel se situait entre 60 311 $ et 47 407 $ par année de vie pondérée par la qualité. CONCLUSION: Cette stratégie de PrEP sur demande se situe quelque part entre la production d'économies et une rentabilité substantielle. Les auteurs sont d'avis qu'elle représente une importante stratégie de santé publique pour prévenir la transmission du VIH.

Risk of spontaneous intracranial hemorrhage in HIV-infected individuals: a population-based cohort study.

BACKGROUND: We studied the association between HIV infection, antiretroviral medications, and the risk of spontaneous intracranial hemorrhage. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A Cost-Effectiveness Analysis of Biomarkers for Risk Prediction in Atrial Fibrillation.

RATIONALE: Atrial fibrillation (AF) is associated with an increased risk of thromboembolism. This risk is currently assessed with scoring systems based on clinical characteristics. However, these tools have limited prognostic performance. Circulating biomarkers are proposed for improved prediction of major clinical events and individualization of treatments in patients with AF. OBJECTIVE: The aim was to assess the cost-effectiveness of precision medicine (PM), i.e., the use of combined biomarkers and clinical variables, in comparison to standard of care (SOC) for risk stratification in a hypothetical cohort of AF patients at risk of stroke. METHODS: A Markov cohort model was developed to evaluate the costs and quality-adjusted life-years (QALYs) of PM compared to SOC, over 20 years using a Canadian healthcare system perspective. RESULTS: PM decreased the mean per-patient overall costs by 7% ($94,932 vs $102,057 [Canadian dollars], respectively) and increased the QALYs by 12% (8.77 vs 7.68 QALYs, respectively). The calculated incremental cost-effectiveness ratio was negative, indicating that PM is an economically dominant strategy. These results were robust to one-way and probabilistic sensitivity analyses. CONCLUSION: PM compared to SOC is economically dominant and is projected to generate cost savings.

Sex Differences in the Patterns of Systemic Agent use Among Patients With Psoriasis: A Retrospective Cohort Study in Quebec, Canada.

Background: Sex differences exist in psoriasis manifestation and expectations from treatment with systemic agents, including, conventional systemic agents (CSA) and tumor necrosis factor inhibitors or ustekinumab (TNFi/UST). However, sex differences in patterns of systemic agent use, such as CSA discontinuation and switch from CSA to TNFi/UST have not been examined. Objectives: To assess sex differences in patterns of CSA use and identify factors associated with switch to (or add) a TNFi/UST and those associated with CSA discontinuation. Methods: We conducted a retrospective cohort study using the Quebec health administrative databases. We included patients with psoriasis initiating a CSA in 2002-2015. We excluded patients with a psoriasis diagnosis in the 3 years prior to the first diagnosis date between 2002 and 2015, and those with a systemic agent dispensation in the year prior to that date. We used Cox regression models with the Least Absolute Shrinkage and Selection Operator method to identify factors associated with Switch/add TNFi/UST, and those associated with CSA discontinuation. Separate analyses were performed for male and female patients. Results: We included 1,644 patients (55.7% females, mean age 60.3 years), among whom 60.4% discontinued their CSA and 7.4%, switched/added TNFi/UST (3.4% switched and 4.0% added) within a median of 0.78 years of follow-up. Among male and female patients, rates of Switch/add TNFi/UST per 1,000 person-year were 49.1 and 41.0 and rates of CSA discontinuation were 381.2 and 352.8. Clinical obesity in male patients (HR 3.53, 95% CI 1.20-10.35), and adjustment/somatoform/dissociative disorders (HR 3.17, 95% CI 1.28-7.85) and use of nonsteroidal anti-inflammatory drugs (HR 2.70, 95% CI 1.56-4.70) in female patients were associated with Switch/add TNFi/UST. Male patients followed by a rheumatologist (HR 0.66, 95% CI 0.46-0.94) and those with a prior hospitalization (HR 0.70, 95% CI 0.57-0.87) were at lower risk of CSA discontinuation, while those initiated on acitretin (vs methotrexate) were at higher risk to discontinue their CSA (HR 1.61, 95% CI 1.30-2.01). Female patients with rheumatoid arthritis comorbidity (HR 0.69, 95% CI 0.51-0.93), those with a dispensed lipid-lowering agent (HR 0.72, 95% CI 0.59-0.88) and hypoglycemic agent (HR 0.75, 95% CI 0.57-0.98) and those initiated on methotrexate (vs all other CSAs) were less likely to discontinue their CSA. Male and female patients entering the cohort between 2011 and 2015 were at reduced risk of CSA discontinuation compared to those entering the cohort before 2011. Conclusion: Most male and female patients discontinued their CSA within 1 year of follow-up. Our study highlighted sex differences in patients' characteristics associated with switch/add a TNFi/UST and CSA discontinuation; treatment switch and discontinuation may be indications of treatment failure in most patients.

Trajectories of systemic agent use and associated depression- and anxiety-related health care costs among patients with psoriasis.

Background: Systemic treatment patterns and related mental health disorders and economic burden among patients with psoriasis are largely unknown. Objective: To assess systemic treatment patterns and associated depression and anxiety-related health care costs among patients with psoriasis initiating a conventional systemic treatment (CST). Methods: Using a retrospective cohort design with sequence and cluster analyses, we assessed systemic treatment trajectories (CST and tumor necrosis factor inhibitors or ustekinumab, [TNFi/UST]) over a 2-year period following CST initiation. We compared health care costs between trajectories using 2-part models. Results: We included 781 patients and identified 8 trajectories: persistent methotrexate users, persistent acitretin users, early CST discontinuation, late methotrexate discontinuation, switch to TNFi/UST, adding TNFi/UST, discontinuation then restart on methotrexate, and discontinuation then restart on acitretin or multiple CST switches. Overall, 165 (21%) patients incurred depression- and anxiety-related health care costs (median annual cost, CAN$56; quartiles, $14-$127). Compared with persistent methotrexate users, adding a TNFi/UST (cost ratio, 3.63; 95% CI, 1.47-5.97) and discontinuation then restart on acitretin or multiple switches between systemic agents (cost ratio, 13.3; 95% CI 5.76-22.47) had higher costs. Limitations: Trajectory misclassification may have occured. These date represent an association, and causality cannot be inferred, particularly given the risk of confounding. Conclusion: Depression- and anxiety-related health care costs were high among patients adding TNFi/UST and those discontinuing then restarting on acitretin or experiencing multiple switches between systemic agents.

Domperidone increases harmful cardiac events in Parkinson's disease: A Bayesian re-analysis of an observational study.

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.

Cost-effectiveness of low-dose colchicine after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

AIMS: In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy. METHODS AND RESULTS: A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy. CONCLUSION: Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.

Vascular access-related bloodstream infections in First Nations, community and teaching Canadian dialysis units, and other centre-level predictors.

BACKGROUND/AIMS: Vascular access-related bloodstream infection (BSI) is frequent among patients undergoing hemodialysis increasing their morbidity and mortality, but its occurrence across various dialysis centre types is not known. The aims of this study were to describe the incidence rates and assess the variability in BSI risk between dialysis centre types and other centre-level variables. METHODS: We conducted a retrospective cohort study of 621 patients initiating hemodialysis in 7 Canadian dialysis centres. Cox regression models, where access type was continuously updated, were used to identify predictors of BSI occurrence. RESULTS: During follow-up of the cohort (median age 68.1 years, 41.7% female, and 76.7% initiating with a central venous catheter, CVC), 73 patients had a BSI (rate: 0.21/1000 person-days). The BSI risk was not different in First Nation units (adjusted relative risk: 0.47, 95% confidence interval: 0.06-3.72) and teaching hospitals (1.33, 0.70-2.54) compared to community hospitals. No other centre-related variables were associated with the risk of BSI. CONCLUSION: We did not find differences in the BSI risk among dialysis unit types, or any other centre-related variables. The rates of BSI in our population were lower than those observed in other settings, but the high proportion of patients using CVCs is concerning.

The challenge of conducting pharmacoeconomic evaluations in oncology using crossover trials: the example of sunitinib for gastrointestinal stromal tumour.

This paper examines the challenge of conducting economic evaluations to support patient access to cancer therapies when the cost-effectiveness estimation is hampered by crossover trial design. To demonstrate these limitations, we present the submission to the Canadian Drug Review (CDR) of a cost-effectiveness evaluation of sunitinib versus best supportive care (BSC) for the treatment of gastrointestinal stromal tumour in patients intolerant or resistant to imatinib. The economic model generated an incremental cost-effectiveness ratio for sunitinib versus BSC of dollars 79,884/quality-adjusted life-year gained. Eight months after initial submission, CDR granted a final recommendation to fund sunitinib following the manufacturer's appeal against their first recommendation. Although cost-effectiveness is an important consideration in reimbursement decisions, there is a need for improved decision-making processes for cancer drugs, as well as a better understanding of the limitations of clinical trial design.

Vascular access-related infections: definitions, incidence rates, and risk factors.

Hemodialysis is associated with a high risk of morbidity and mortality, often caused by infections. Infections account for approximately 15% of all deaths in this patient population (the second leading cause after cardiovascular events) and for about one-fifth of admissions. Approximately one-fourth of infection-related admissions are caused by dialysis-associated peritonitis or vascular access infection that may lead to such significant complications as endocarditis or death. Published studies that assessed the determinants of hemodialysis-related vascular infections reported inconsistent findings. Variations in the definitions of infection among these studies despite the existence of standard guidelines proposed by at least 3 major work groups may explain, at least in part, these inconsistencies. A comprehensive in-depth review of those studies is needed to examine the inconsistencies in the published results. We first revised the existing vascular access-related infection definitions, then conducted a narrative review of the published literature that examined predictors of vascular access-related infections, highlighting the heterogeneity in methods and findings. Better understanding of the risk factors for vascular access-related infections may inform efficacious prevention strategies and lead to early detection of infections and improved patient care.

Association between use of acid-suppressive drugs and risk of gastric cancer. A nested case-control study.

BACKGROUND: The risk of gastric cancer could be influenced by acid-related diseases or by the use of acid-suppressive drugs, such as histamine H(2) 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 H(2) 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 H(2) receptor antagonists and risk of gastric cancer). CONCLUSIONS: A minor increase in the risk of gastric cancer was observed if exposure to either H(2) 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.