Association of Sex With Stroke and Bleeding Risk of Apixaban and Rivaroxaban in Elderly Atrial Fibrillation Patients Using Propensity Score Weights.

BACKGROUND: Evidence from clinical trials suggests a differential effect of sex on the effectiveness and safety of direct oral anticoagulants (DOACs) for stroke prophylaxis in atrial fibrillation (AF). METHODS: This population-based cohort study examined the independent effect of sex on hemorrhage and ischemic stroke in 23,884 patients (55% females; age ≥ 66 years) with AF starting apixaban or rivaroxaban treatment in Ontario, Canada. Patients were followed for 90 days after their DOAC prescription. Using female sex as the exposure of interest, differences in baseline characteristics were balanced between sexes using inverse probability weights based on propensity scores. Applying weighted modified Poisson regression, risk ratios (RRs) were estimated for major hemorrhage, ischemic stroke/systemic embolism/transient ischemic attack (hereafter stroke), myocardial infarction, and all-cause mortality, with males as a reference. RESULTS: Females were older, had higher predicted stroke risk (based on CHADS2 score), and had fewer comorbidities than did males. Males had a higher prevalence of coronary artery disease, diabetes, and cancer, and similar predicted bleeding risk (based on HAS-BLED score). After weighting, baseline characteristics were well balanced. The 90-day risks for hemorrhage (RR 0.96; 95% confidence interval [CI] 0.80-1.15; P = 0.69) and stroke (RR 1.01; 95% CI 0.86-1.19; P = 0.94) were similar between sexes, which remained true when assessing each DOAC separately by dosing regimen. Compared to males, females had a lower risk for myocardial infarction (RR 0.66; 95% CI 0.52-0.84; P = 0.0008), and for all-cause mortality (RR 0.76; 95% CI 0.67-0.87; P < 0.0001). CONCLUSIONS: Our findings do not suggest an association of sex with the 90-day risk of hemorrhage or ischemic stroke in older AF patients prescribed apixaban or rivaroxaban.

CONTEXTE: Les données probantes issues des essais cliniques donnent à penser que l'efficacité et l'innocuité des anticoagulants oraux directs (AOD) utilisés pour la prophylaxie des accidents vasculaires cérébraux (AVC) dans un contexte de fibrillation auriculaire (FA) varient selon le sexe du patient. MÉTHODOLOGIE: Cette étude de cohorte populationnelle a examiné l'effet indépendant du sexe sur l'hémorragie et l'AVC ischémique chez 23 884 patients (55 % de femmes; âge ≥ 66 ans) atteints de FA ayant amorcé un traitement par l'apixaban ou le rivaroxaban en Ontario (Canada). Les patients ont été suivis pendant 90 jours après avoir reçu une ordonnance d'AOD. Le sexe féminin constituant l'exposition d'intérêt, les différences quant aux caractéristiques initiales ont été réparties de façon équilibrée entre les sexes au moyen d'une pondération par probabilité inverse reposant sur le score de propension. La régression de Poisson modifiée avec pondération a servi à estimer les rapports de risques (RR) d'hémorragie majeure, d'AVC ischémique/d'embolie systémique/d'accident ischémique transitoire (ci-après AVC), d'infarctus du myocarde et de mortalité toutes causes confondues, les hommes formant la population de référence. RÉSULTATS: Les femmes étaient plus âgées, présentaient un risque prévu d'AVC plus élevé (d'après le score CHADS2) et présentaient moins de maladies concomitantes que les hommes. Les hommes présentaient une prévalence plus élevée de coronaropathie, de diabète et de cancer, et un risque prévu d'hémorragie similaire (compte tenu du score HAS-BLED). Après la pondération, la répartition des caractéristiques initiales des patients était bien équilibrée. Le risque d'hémorragie (RR : 0,96; intervalle de confiance [IC] à 95 % : 0,80-1,15; P = 0,69) et d'AVC (RR : 1,01; IC à 95 % : 0,86-1,19; P = 0,94) sur 90 jours était similaire pour les deux sexes, et il en était de même lorsque chaque AOD a été évalué séparément en fonction du schéma posologique. Par rapport aux hommes, les femmes présentaient un risque plus faible d'infarctus du myocarde (RR : 0,66; IC à 95 % : 0,52-0,84; P = 0,0008) et de mortalité toutes causes confondues (RR : 0,76; IC à 95 % : 0,67-0,87; P < 0,0001). CONCLUSIONS: Nos résultats ne laissent présumer aucune association entre le sexe et le risque d'hémorragie ou d'AVC ischémique sur une période de 90 jours chez les patients âgés atteints de FA à qui l'apixaban ou le rivaroxaban sont prescrits.

The Risk of Acute Kidney Injury with Oral Anticoagulants in Elderly Adults with Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Anticoagulation with either a vitamin K antagonist or a direct oral anticoagulant may be associated with AKI. Our objective was to assess the risk of AKI among elderly individuals with atrial fibrillation newly prescribed a direct oral anticoagulant (dabigatran, rivaroxaban, or apixaban) versus warfarin. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our population-based cohort study included 20,683 outpatients in Ontario, Canada, ≥66 years with atrial fibrillation who were prescribed warfarin, dabigatran, rivaroxaban, or apixaban between 2009 and 2017. Inverse probability of treatment weighting on the basis of derived propensity scores for the treatment with each direct oral anticoagulant was used to balance baseline characteristics among patients receiving each of the three direct oral anticoagulants compared with warfarin. Cox proportional hazards regression was performed in the weighted population to compare the association between the prescribed anticoagulant and the outcomes of interest. The exposure was an outpatient prescription of warfarin or one of the direct oral anticoagulants. The primary outcome was a hospital encounter with AKI, defined using Kidney Disease Improving Global Outcomes thresholds. Prespecified subgroup analyses were conducted by eGFR category and by the percentage of international normalized ratio measurements in range, a validated marker of anticoagulation control. RESULTS: Each direct oral anticoagulant was associated with a significantly lower risk of AKI compared with warfarin (weighted hazard ratio, 0.65; 95% confidence interval, 0.53 to 0.80 for dabigatran; weighted hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98 for rivaroxaban; and weighted hazard ratio, 0.81; 95% confidence interval, 0.72 to 0.93 for apixaban). In the subgroup analysis, the lower risk of AKI associated with each direct oral anticoagulant was consistent across each eGFR strata. The risk of AKI was significantly lower among users of each of the direct oral anticoagulants compared with warfarin users who had a percentage of international normalized ratio measurements ≤56%. CONCLUSIONS: Direct oral anticoagulants were associated with a lower risk of AKI compared with warfarin.

Efficacy and Safety of Surgical Kidney Stone Interventions in Autosomal Dominant Polycystic Kidney Disease: A Systematic Review.

BACKGROUND: Reduced kidney function and distorted kidney anatomy in patients with autosomal dominant polycystic kidney disease (ADPKD) may complicate stone interventions more compared with the general population. OBJECTIVES: To review studies describing the safety and efficacy of the 3 main stone interventions in adults with ADPKD: shock wave lithotripsy (SWL), ureteroscopy, and percutaneous nephrolithotomy (PCNL). DESIGN: Systematic review. SETTING: Any country of origin. PATIENTS: Adults with ADPKD who underwent SWL, ureteroscopy, or PCNL. MEASUREMENTS: Being stone free after the intervention and postoperative complications as reported by each study, which included pain, bleeding, and fever. METHODS: Relevant studies published until February 2019 were identified through a comprehensive search of MEDLINE, EMBASE, Web of Science, BIOSIS PREVIEW, and CINAHL. Studies were eligible for review if they reported at least one outcome following SWL, ureteroscopy, and/or PCNL in adults with ADPKD. We then abstracted information on study characteristics, patient characteristics, intervention details, and postintervention outcomes and assessed the methodological quality of each study using a modified Downs and Black checklist. RESULTS: We screened 221 citations from which we identified 24 studies that met our review criteria. We identified an additional article when manually reviewing the reference list of an included article, yielding a total of 25 studies describing 311 patients (32 SWL, 42 ureteroscopy, and 237 PCNL). The percentage of patients who were stone free after 1 session ranged from 0% to 69% after SWL, 73% to 100% after ureteroscopy, and 45% to 100% after PCNL. The percentage of patients with ADPKD that experienced at least one postoperative complication ranged from 0% to 33% for SWL, 0% to 27% for ureteroscopy, and 0% to 100% for PCNL. LIMITATIONS: The number and quality of studies published to date are limited. CONCLUSIONS: The efficacy and safety of stone interventions in patients with ADPKD remains uncertain, with wide-ranging estimates reported in the literature. TRIAL REGISTRATION: We did not register the protocol of this systematic review.

CONTEXTE: Les interventions visant à traiter les calculs rénaux sont plus compliquées chez les patients atteints de polykystose rénale autosomique dominante (ADPKD) que dans la population générale en raison de la fonction rénale réduite et des distorsions anatomiques des reins présentes chez ces patients. OBJECTIF: Passer en revue les études portant sur l'innocuité et l'efficacité des trois principales interventions pour traiter les calculs rénaux chez des adultes atteints d'ADPKD: la lithotripsie par ondes de choc (LOC), l'urétéroscopie et la néphrolithotomie percutanée (NLPC). TYPE D'ÉTUDE: Revue systématique. CADRE: Les pays d'origine des études. SUJETS: Des adultes atteints d'ADPKD ayant subi une LOC, une urétéroscopie ou une NLPC. MESURES: Une intervention réussie (absence de calculs rénaux) et les complications postopératoires rapportées (douleur, hémorragie et fièvre). MÉTHODOLOGIE: Une recherche exhaustive sur MEDLINE, EMBASE, Web of Science, BIOSIS PREVIEW et CINAHL a permis de répertorier toutes les études pertinentes publiées jusqu'en février 2019. Les études devaient rapporter minimalement une des mesures d'intérêt à la suite d'une LOC, d'une urétéroscopie ou d'une NLPC chez des adultes atteints d'ADPKD. Les caractéristiques des études, les caractéristiques des patients, les détails de l'intervention et les résultats postopératoires ont été extraits des études retenues. La qualité méthodologique de chaque étude a été mesurée selon la grille d'évaluation de Downs et Black. RÉSULTATS: Des 221 citations répertoriées par la revue de la littérature, 24 études satisfaisaient nos critères d'inclusion. Une 25e étude s'est ajoutée en passant en revue manuellement les références d'un des essais déjà inclus. Notre revue systématique porte donc sur un total de 311 patients (32 LOC, 42 urétéroscopie et 237 NLPC). Le pourcentage de patients sans calculs rénaux après une seule intervention variait de 0 à 69 % après une LOC, de 73 à 100 % après une urétéroscopie et de 45 à 100 % après une NLPC. Le pourcentage de patients ayant souffert d'au moins une complication postopératoire variait de 0 à 33 % après une LOC, de 0 à 27 % pour une urétéroscopie et de 0 à 100 % pour une NLPC. LIMITES: Le nombre et la qualité des études publiées sur le sujet sont limités. CONCLUSION: L'efficacité et l'innocuité des interventions visant le retrait de calculs rénaux chez des patients atteints d'ADPKD demeurent incertaines; les estimations rapportées dans la littérature présentent une grande variété. ENREGISTREMENT DE L'ESSAI: Le protocole de cette revue systématique n'a pas été enregistré.

Hydromorphone and the risk of infective endocarditis among people who inject drugs: a population-based, retrospective cohort study.

BACKGROUND: The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs. METHODS: We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids. RESULTS: Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p<0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p<0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p<0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072. INTERPRETATION: Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation. FUNDING: Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute.

The risk of infective endocarditis among people who inject drugs: a retrospective, population-based time series analysis.

BACKGROUND: Infective endocarditis is an increasingly common complication among people who inject drugs. We conducted this study to determine whether the removal of traditional controlled-release oxycodone from the Canadian market would be associated with an increase in the use of hydromorphone and an increased risk of infective endocarditis. METHODS: We conducted a retrospective, population-based time series analysis using the linked health administrative databases of Ontario, Canada. We measured the quarterly risk of admissions for infective endocarditis related to injection drug use and changes in opioid prescription rates from 2006 to 2015. We set the intervention point at the fourth quarter of 2011, when traditional controlled-release oxycodone was removed from the Canadian market. RESULTS: We observed an increase in the risk of admissions for infective endocarditis related to injection drug use during the study period. Before the intervention point, we observed a mean of 13.4 admissions per quarter, and after the intervention, we observed a mean of 35.1 admissions per quarter. However, no significant change in this risk occurred at the intervention point. Rather, the risk of infectious endocarditis appeared to have increased earlier and in parallel with the rise in hydromorphone prescriptions. Hydromorphone represented 16% of all opioid prescriptions at the start of the observation period and 53% by the end. INTERPRETATION: The risk of infective endocarditis related to injection drug use is increasing and is temporally associated with increasing prescriptions for hydromorphone. This relation warrants further exploration.

Clinical Outcomes of Failing to Dose-Reduce Cephalosporin Antibiotics in Older Adults with CKD.

BACKGROUND AND OBJECTIVES: Current dosing recommendations for cephalosporin antibiotics are on the basis of pharmacokinetic studies and are frequently ignored in practice. This study was undertaken to investigate the clinical outcomes of failing to dose-reduce cephalosporin antibiotics in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective cohort study conducted in Ontario, Canada using linked population-based health care databases. Nine thousand three hundred forty-seven outpatients (median age 83; interquartile range, 77-88 years; 57% women) with an eGFR<30 ml/min per 1.73 m2 and no prior history of dialysis were dispensed oral cephalexin, cefuroxime, or cefprozil between April of 2007 and March of 2016. Two thirds of the patients (6253 of 9347) received a higher than recommended daily dose of cephalexin (>1000 mg), cefuroxime (>500 mg), or cefprozil (>500 mg). The primary outcome was a hospital encounter (emergency room visit or hospital admission) with a condition listed as a possible side-effect of cephalosporins. Secondary outcomes were antibiotic treatment failure and all-cause mortality. All measures were assessed in the 30 days after cephalosporin initiation. RESULTS: Patients who received a higher than recommended dose of a cephalosporin antibiotic were similar in multiple indicators of baseline health to patients who received a reduced dose. Overall, 6% of patients presented to hospital with a possible cephalosporin side-effect, 13% failed antibiotic treatment, and 3% died. Compared with a reduced dose, receiving a higher dose of antibiotic was not associated with a different rate of side-effects (adjusted odds ratio, 1.00; 95% confidence interval, 0.84 to 1.20), treatment failure (1.01; 0.88 to 1.15), or death (0.99; 0.76 to 1.29). CONCLUSIONS: In this study we failed to demonstrate any association between the dose of cephalosporin antibiotic administered to elderly patients with CKD and the risk of side-effects leading to hospitalization, treatment failure, or mortality.

Population-Based Study of Risk of AKI with Levetiracetam.

BACKGROUND AND OBJECTIVES: Regulatory agencies warn about the risk of AKI with levetiracetam use on the basis of information from case reports. We conducted this study to determine whether new levetiracetam use versus nonuse is associated with a higher risk of AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a population-based retrospective cohort study of adults with epilepsy in Ontario, Canada. Patients who received a new outpatient prescription for levetiracetam between January 1, 2004 and March 1, 2017 were matched to two nonusers on stage of CKD, recorded seizure in the prior 90 days, and logit of a propensity score for levetiracetam use. The primary outcome was a hospital encounter (emergency department visit or hospitalization) with AKI within 30 days of cohort entry. Secondary outcomes were AKI within 180 days and change in the concentration of serum creatinine. We assessed the primary outcome using health care diagnosis codes. We evaluated the change in the concentration of serum creatinine in a subpopulation with laboratory measurements. RESULTS: We matched 3980 levetiracetam users to 7960 nonusers (mean age 55 years, 51% women). Levetiracetam use was not significantly associated with a higher risk of AKI within 30 days (13 [0.33%] events in levetiracetam users and 21 [0.26%] events in nonusers [odds ratio, 1.24; 95% confidence interval, 0.62 to 2.47]). Similarly, there was no significant association with AKI within 180 days (odds ratio, 0.70; 95% confidence interval, 0.43 to 1.13). The change in the concentration of serum creatinine did not significantly differ between levetiracetam users and nonusers. CONCLUSIONS: In this population-based study levetiracetam use was not associated with a higher risk of AKI. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_12_11_Yau_Podcast.mp3.

Blood Lithium Monitoring Practices in a Population-Based Sample of Older Adults.

OBJECTIVE: Lithium is an effective treatment for mood disorders, but lithium level and renal monitoring every 3 months is recommended in older patients treated with lithium to prevent serious adverse events. This study examined lithium monitoring practices in a large geriatric cohort. METHODS: This population-based cohort study (N = 11,006) used linked health care administrative databases. Older lithium users (n = 5,503; mean age = 70.6 years) in Ontario, Canada, enrolled between April 1, 2002, and March 31, 2014, were propensity score matched 1:1 to valproate users (n = 5,503). The frequency with which serum lithium levels were monitored and renal and endocrine laboratory testing was done during a 1-year follow-up period was examined. RESULTS: The baseline characteristics of the 2 groups were similar. At least 1 serum lithium concentration recorded within 90, 180, and 365 days of follow-up was present in 24.1%, 42.4%, and 66.8% of lithium users, respectively. Corresponding numbers for serum creatinine were 29.6%, 50.4%, and 75.4%, respectively. While serum creatinine monitoring (hazard ratio [HR] = 1.19; 95% CI, 1.12-1.27; P < .001), thyroid-stimulating hormone monitoring (HR = 1.47; 95% CI, 1.37-1.58; P < .001), and calcium testing (HR = 1.15; 95% CI, 1.02-1.29; P = .018) were statistically higher in lithium compared to valproate users, absolute differences between groups were not clinically meaningful. CONCLUSIONS: In a geriatric Canadian community sample, lithium monitoring was infrequent and inconsistent with international standards that call for screening of lithium levels and renal function every 3 months.

Thiazide Diuretic Dose and Risk of Kidney Stones in Older Adults: A Retrospective Cohort Study.

BACKGROUND: Thiazide diuretics are commonly prescribed to prevent kidney stones. However, it is unclear whether higher doses confer greater benefit. OBJECTIVE: To determine whether lower doses of thiazide diuretics confer a similar protective effect against kidney stone events as higher doses. DESIGN: Population-based cohort study. SETTING: Linked health administrative databases in Ontario, Canada. PATIENTS: Older adults newly prescribed a thiazide diuretic between 2003 and 2014 were separated into 2 groups based on daily dose: low dose (⩽12.5 mg hydrochlorothiazide/chlorthalidone, or ⩽1.25 mg indapamide) or high dose. MEASUREMENTS: The primary outcome was time to a kidney stone event, using diagnosis and procedure codes. A secondary outcome was kidney stone surgery. METHODS: An association between thiazide diuretic dose and a kidney stone event was estimated using Cox proportional hazards regression. RESULTS: A total of 536 of 105 239 patients (0.51%) experienced a kidney stone event. We did not detect a difference in kidney stone risk in the high-dose relative to the low-dose group (adjusted hazard ratio, 1.10; 95% confidence interval, 0.93-1.31). Results were similar when analysis was restricted to the more specific outcome of kidney stone surgery. Neither a history of prior kidney stones nor the type of thiazide diuretic modified the effect of diuretic dose on outcome. LIMITATIONS: Patients were >65 years old and we were unable to adjust for some potential confounders such as dietary factors. CONCLUSIONS: Lower dose thiazide diuretics appear to confer a similar protective effect as higher dose thiazides against the development of kidney stones.

CONTEXTE: Les diurétiques thiazidiques sont couramment prescrits pour prévenir la formation de calculs rénaux. On ignore toutefois si l'administration de doses plus élevées confère de plus grands avantages. OBJECTIF DE L'ÉTUDE: Déterminer si de faibles doses de diurétiques thiazidiques confèrent un effet protecteur contre la formation de calculs rénaux similaire à celui des doses plus élevées. TYPE D'ÉTUDE: Une étude de cohorte représentative de la population. CADRE: Les bases de données administratives interreliées du système de santé de la province de l'Ontario au Canada. PATIENTS: L'étude porte sur des patients âgés auxquels un diurétique thiazidique avait été nouvellement prescrit entre 2003 et 2014. Les sujets ont été séparés en deux groupes, selon la dose quotidienne prescrite : un premier groupe traité à faible dose d'hydrochlorothiazide ou de chlorthalidone (12,5 mg ou moins) ou d'indapamide (1,25 mg ou moins) et un deuxième groupe traité à des doses plus élevées. MESURES: Le principal critère d'intérêt était le laps de temps écoulé avant la survenue de calculs rénaux, établi d'après les codes de procédures et de diagnostic. Le critère secondaire consistait en une intervention chirurgicale visant l'extraction de calculs rénaux. MÉTHODOLOGIE: L'association entre la dose de diurétique thiazidique et la survenue de calculs rénaux a été estimée par la méthode de régression à risques proportionnels de Cox. RÉSULTATS: Des 105 239 patients retenus pour l'étude, 536 (0,51 %) ont vécu un épisode de calculs rénaux. Aucun écart significatif dans le risque de développer des calculs rénaux n'a pu être décelé entre les deux groupes et donc, selon la dose prescrite (rapport de risque ajusté : 1,10; I.C. à 95 % : 0,93 ­ 1,31). Des résultats similaires ont été obtenus lorsque l'analyse se limitait spécifiquement aux interventions visant l'extraction de calculs rénaux. De plus, il a été observé que ni les antécédents de calculs rénaux ni le type de diurétique thiazidique prescrit n'avaient modulé l'effet de la dose sur le résultat. LIMITES DE L'ÉTUDE: Les patients retenus pour l'étude étaient âgés de 65 ans et plus, et nous n'avons pas été en mesure de tenir compte de potentielles variables confusionnelles telles que les habitudes alimentaires. CONCLUSION: L'administration d'une faible dose de diurétique thiazidique semble conférer un effet protecteur contre la formation de calculs rénaux similaire à celui offert par une dose plus élevée.

A Province-wide, Cross-sectional Study of Demographics and Medication Use of Patients in Hemodialysis Units Across Ontario.

BACKGROUND: Hemodialysis patients are at an increased risk of polypharmacy as they have the highest pill burden of all chronically ill patient populations, with an estimated average of 12 medications per day. OBJECTIVES: The aim of this study was to evaluate prescribing patterns of outpatient medications in patients receiving in-center hemodialysis. This was done to identify potential candidate medications for future quality improvement initiations to optimize prescribing. DESIGN: We conducted a descriptive retrospective cross-sectional study in the province of Ontario, Canada, using several linked health care databases housed at the Institute for Clinical Evaluative Sciences (ICES). SETTING: We considered outpatient medications dispensed to patients eligible for the Ontario Drug Benefit program. PATIENTS: Patients were receiving chronic in-center hemodialysis at one of the 69 facilities in the province of Ontario, Canada as of October 1, 2013. MEASUREMENTS: We assessed whether any of our 28 study medications of interest were recently dispensed (within the prior 120 days), the type of prescribing physician, and the associated medication costs. The 28 included medications of interest (ie, proton pump inhibitors, benzodiazepines) were selected because they may not have a true indication for dialysis patients and/or there are safety concerns with their use in this population. Results are presented as median (25th, 75th percentile). METHODS: We conducted this study at ICES according to a prespecified protocol approved by the Research Ethics Board at Sunnybrook Health Sciences Centre (Toronto, Ontario). RESULTS: A total of 3094 patients on chronic in-center hemodialysis received a study drug of interest (age: 76.5 years [SD: 7.3]), 44% women). Patients were dispensed 11 (8, 14) unique medication products with more than two-thirds of patients dispensed 9 or more different medications. The median number of annual health care visits was 7 (3-15) with more than half the cohort receiving prescriptions from 3 or more specialists. The 10 most commonly dispensed study medications cost more than 3 million dollars in direct costs in 1 year. LIMITATIONS: Our study was also subjected to some limitations of health care databases. CONCLUSIONS: Polypharmacy is frequent in in-center hemodialysis patients. To decrease polypharmacy and its associated negative outcomes, health care providers need to implement tools to optimize medication use and deprescribe medications that lack evidence for efficacy and safety in hemodialysis patients. Therefore, strategies to improve prescribing and discontinue ineffective medications warrant testing for better patient outcomes and reduced health care costs.

CONTEXTE: Parmi la population atteinte d'une maladie chronique, le patient hémodialysé présente la charge médicamenteuse la plus lourde, soit une prise moyenne estimée à 12 médicaments distincts chaque jour. OBJECTIF: Nous avons analysé les habitudes de prescription externe de médicaments chez les patients hémodialysés en centre hospitalier afin de cibler des médicaments qui pourraient représenter des cibles d'amélioration pour une prescription médicamenteuse optimisée. TYPE D'ÉTUDEL: Il s'agit d'une étude transversale, descriptive et rétrospective menée en Ontario, au Canada. L'étude tire ses données de plusieurs bases interreliées, hébergées à l'Institut de recherche en services de santé (IRSS). CADRE DE L'ÉTUDE: Notre analyse s'est concentrée sur les médicaments prescrits aux patients ambulatoires admissibles au Programme de médicaments de l'Ontario. PARTICIPANTS: Étaient considérés dans l'étude tous les patients hémodialysés à long terme à l'un des 69 établissements prodiguant l'hémodialyse en Ontario depuis le 1er octobre 2013. MESURES: Nous avons vérifié si l'un des 28 médicaments d'intérêt avait été administré (au cours des 120 jours précédents), et nous avons noté la spécialité du médecin prescripteur et les coûts associés au traitement. Les 28 médicaments considérés (p. ex. inhibiteurs de la pompe à protons, benzodiazépines) ont été sélectionnés pour au moins l'une des deux raisons suivantes : i) il n'existe pas de réelle indication pour le traitement de patients hémodialysés; ii) l'innocuité du médicament n'est pas claire pour la population étudiée. Les résultats sont présentés sous forme de médiane et de percentile (du 25e au 75e centile). MÉTHODOLOGIE: L'étude a été menée à l'IRSS conformément au protocole préalablement approuvé par le comité d'éthique en recherche du Centre des sciences de la santé Sunnybrook (à Toronto). RÉSULTATS: Un total de 3 094 patients hémodialysés prenaient au moins un médicament d'intérêt; 44 % étaient de sexe féminin, et l'âge moyen était de 76,5 ans (ÉT : 7,3). Les patients prenaient 11 (8 à 14) médicaments distincts, et plus des deux tiers d'entre eux en prenaient au moins neuf. Le nombre de visites médicales annuelles médian était de 7 (3 à 15). Plus de la moitié de la population à l'étude recevait des prescriptions médicamenteuses de trois prescripteurs ou plus. Les 10 médicaments les plus communément prescrits représentaient des coûts directs annuels de plus de 3 millions de dollars. LIMITES: Les bases de données en santé utilisées comportaient certaines contraintes pour notre étude. CONCLUSION: La polypharmacie est fréquente chez les patients hémodialysés en centre. Pour endiguer le phénomène et ses répercussions, les fournisseurs de soins de santé doivent implanter des outils d'optimisation de la médication chez les patients hémodialysés et cesser tout médicament dont l'innocuité ou l'efficacité n'ont pas été suffisamment démontrées chez ces patients. On devra donc tester des stratégies d'amélioration des habitudes de prescription pour atteindre de meilleurs résultats sur les plans de la santé du patient et des coûts de soins de santé.

Antihypertensive medications and the risk of kidney stones in older adults: a retrospective cohort study.

Antihypertensives are widely prescribed and could influence kidney stone risk by altering urinary calcium excretion. However, the impact of different classes of antihypertensives on kidney stone risk is unknown. To assess this impact, we conducted a retrospective, population-based cohort study using linked health administrative databases. Individuals aged >65 years who initiated one of the four antihypertensive classes (that is, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers or thiazide diuretics) were included. The participants were followed for the occurrence of a kidney stone event while maintaining continuous usage on their drug class. The association between antihypertensive class and outcome was estimated by Cox regression. Of the 542 581 people included, we observed 4533 kidney stone events (0.83%) over a median follow-up of 368 days (365-729). Compared with beta-blockers, thiazides were associated with a lower risk of kidney stones (hazard ratio (HR) 0.76; 95% confidence interval (CI) 0.68-0.84), ACEis/ARBs with a borderline decreased risk (HR 0.90; 95% CI 0.83-0.98) and calcium channel blockers with a comparable risk (HR 1.02; 95% CI 0.92-1.13). When the risk of requiring an intervention for a kidney stone was examined, the results were consistent with the primary analysis; however, the protective effect of ACEis/ARBs was eliminated (HR 0.96; 95% CI 0.87-1.06). In conclusion, relative to beta-blockers, thiazide diuretics were associated with a decreased risk of kidney stone formation in adults aged >65 years, whereas ACEis/ARBs and calcium channel blockers had a comparable risk of presenting with a kidney stone.

Risk of Ventricular Arrhythmia with Citalopram and Escitalopram: A Population-Based Study.

BACKGROUND: The risk of ventricular arrhythmia with citalopram and escitalopram is controversial. In this study we investigated the association between these two drugs and the risk of ventricular arrhythmia. METHODS: We conducted a population-based retrospective cohort study of older adults (mean age 76 years) from 2002 to 2012 in Ontario, Canada, newly prescribed citalopram (n = 137 701) or escitalopram (n = 38 436), compared to those prescribed referent antidepressants sertraline or paroxetine (n = 96 620). After inverse probability of treatment weighting using a propensity score, the baseline characteristics of the comparison groups were similar. The primary outcome was a hospital encounter with ventricular arrhythmia within 90 days of a new prescription, assessed using hospital diagnostic codes. The secondary outcome was all-cause mortality within 90 days. RESULTS: Citalopram was associated with a higher risk of a hospital encounter with ventricular arrhythmia compared with referent antidepressants (0.06% vs. 0.04%, relative risk [RR] 1.53, 95% confidence intervals [CI]1.03 to 2.29), and a higher risk of mortality (3.49% vs. 3.12%, RR 1.12, 95% CI 1.06 to 1.18). Escitalopram was not associated with a higher risk of ventricular arrhythmia compared with the referent antidepressants (0.03% vs. 0.04%, RR 0.84, 95% CI 0.42 to 1.68), but was associated with a higher risk of mortality (2.86% vs. 2.63%, RR 1.09, 95% CI 1.01 to 1.18). CONCLUSION: Among older adults, initiation of citalopram compared to two referent antidepressants was associated with a small but statistically significant increase in the 90-day risk of a hospital encounter for ventricular arrhythmia.

Urban-rural differences in the uptake of new oral bisphosphonate formulations.

UNLABELLED: We identified significantly slower uptake, and consistently lower proportions of new oral bisphosphonate formulations dispensed in rural regions compared to urban regions of Ontario. Further research examining regional differences in outcomes may provide insight as to whether urban-rural differences in prescribing translate into health disparities between regions. PURPOSE: The aim of this study was to examine urban-rural differences in the uptake of new oral bisphosphonate formulations available on the Ontario drug formulary: alendronate + vitamin D3 (January 2007), monthly risedronate (June 2009), and risedronate delayed-release (February 2012). METHODS: We plotted the monthly proportion of new formulation claims of all claims with the same drug molecule, from their formulary listing date until March 2014. Results were stratified by major urban, nonmajor urban, and rural regions as defined by the Rurality Index of Ontario. We compared the rate of uptake over the first year of formulary availability using linear regression, and compared proportions dispensed between regions using chi-squared tests. RESULTS: We identified a regional gradient in uptake for alendronate + vitamin D3 and monthly risedronate; major urban regions had the fastest uptake, followed by nonmajor urban regions, and rural regions had the slowest uptake. Rural regions also had the slowest uptake of risedronate delayed-release; however, uptake in major urban and nonmajor urban regions were similar. Rural regions dispensed the lowest proportions for all new formulations 1 year after formulary availability: alendronate + vitamin D3 (32% major urban, 23% nonmajor urban, 12% rural), monthly risedronate (26% major urban, 21% nonmajor urban, 16% rural), and risedronate delayed-release (21% major urban, 22 % nonmajor urban, 13% rural). This pattern persisted throughout our study. CONCLUSION: We identified significantly slower uptake and lower proportions of new formulations dispensed in rural regions compared to urban regions. Further research examining regional differences in outcomes may demonstrate whether urban-rural differences in prescribing translate into health disparities between regions.

Macrolide antibiotics and the risk of ventricular arrhythmia in older adults.

BACKGROUND: Many respiratory tract infections are treated with macrolide antibiotics. Regulatory agencies warn that these antibiotics increase the risk of ventricular arrhythmia. We examined the 30-day risk of ventricular arrhythmia and all-cause mortality associated with macrolide antibiotics relative to nonmacrolide antibiotics. METHODS: We conducted a population-based retrospective cohort study involving older adults (age > 65 yr) with a new prescription for an oral macrolide antibiotic (azithromycin, clarithromycin or erythromycin) in Ontario from 2002 to 2013. Our primary outcome was a hospital encounter with ventricular arrhythmia within 30 days after a new prescription. Our secondary outcome was 30-day all-cause mortality. We matched patients 1:1 using propensity scores to patients prescribed nonmacrolide antibiotics (amoxicillin, cefuroxime or levofloxacin). We used conditional logistic regression to measure the association between macrolide exposure and outcomes, and repeated the analysis in 4 subgroups defined by the presence or absence of chronic kidney disease, congestive heart failure, coronary artery disease and concurrent use of a drug known to prolong the QT interval. RESULTS: Compared with nonmacrolide antibiotics, macrolide antibiotics were not associated with a higher risk of ventricular arrhythmia (0.03% v. 0.03%; relative risk [RR] 1.06, 95% confidence interval [CI] 0.83-1.36) and were associated with a lower risk of all-cause mortality (0.62% v. 0.76%; RR 0.82, 95% CI 0.78-0.86). These associations were similar in all subgroups. INTERPRETATION: Among older adults, macrolide antibiotics were not associated with a higher 30-day risk of ventricular arrhythmia than nonmacrolide antibiotics. These findings suggest that current warnings from the US Food and Drug Administration may be overstated.

Osteoporosis management and fractures in the Métis of Ontario, Canada.

UNLABELLED: Half of Métis citizens, compared to less than 10 % of the general population of Ontario, reside in northern regions, with little access to bone mineral density (BMD) testing. Métis citizens had lower sex-specific and age-standardized rates of BMD testing, yet similar rates of fracture (both sexes) and pharmacotherapy (women only). PURPOSE: To examine osteoporosis management and common osteoporosis-related fractures among Métis citizens compared to the general population of older adults residing in Ontario. METHODS: We linked healthcare (medical and pharmacy) utilization and administrative (demographic) databases with the Métis Nation of Ontario citizenship registry to estimate osteoporosis management (bone mineral density [BMD] testing, pharmacotherapy) and fractures (hip, humerus, radius/ulna) among adults aged ≥50 years, from April 1, 2006 to March 31, 2011. Pharmacotherapy data were limited to residents aged ≥65 years. Sex-specific and age-standardized rates were compared between the Métis and the general population. Multivariable logistic regression was used to compare rates of BMD testing after controlling for differences in age and region of residence between the Métis and the general population. RESULTS: We studied 4219 Métis citizens (55 % men), and 140 (3 %) experienced a fracture. Half of Métis citizens, compared to less than 10 % of the general population of Ontario, resided in northern regions. We identified significantly lower sex-specific and age-standardized rates of BMD testing among Métis compared to the general population, yet found little difference in fracture rates (both sexes) or pharmacotherapy (women only). Differences in BMD testing disappeared after adjusting for region of residence among women yet remained significant among men. CONCLUSIONS: Despite finding significantly lower rates of osteoporosis management among men, Métis men and women were found to have similar age-standardized fracture rates to the general population.

Interrupted time series analysis in drug utilization research is increasing: systematic review and recommendations.

OBJECTIVES: To describe the use and reporting of interrupted time series methods in drug utilization research. STUDY DESIGN AND SETTING: We completed a systematic search of MEDLINE, Web of Science, and reference lists to identify English language articles through to December 2013 that used interrupted time series methods in drug utilization research. We tabulated the number of studies by publication year and summarized methodological detail. RESULTS: We identified 220 eligible empirical applications since 1984. Only 17 (8%) were published before 2000, and 90 (41%) were published since 2010. Segmented regression was the most commonly applied interrupted time series method (67%). Most studies assessed drug policy changes (51%, n = 112); 22% (n = 48) examined the impact of new evidence, 18% (n = 39) examined safety advisories, and 16% (n = 35) examined quality improvement interventions. Autocorrelation was considered in 66% of studies, 31% reported adjusting for seasonality, and 15% accounted for nonstationarity. CONCLUSION: Use of interrupted time series methods in drug utilization research has increased, particularly in recent years. Despite methodological recommendations, there is large variation in reporting of analytic methods. Developing methodological and reporting standards for interrupted time series analysis is important to improve its application in drug utilization research, and we provide recommendations for consideration.

In vitro inhibition of cytochrome P450-mediated reactions by gemfibrozil, erythromycin, ciprofloxacin and fluoxetine in fish liver microsomes.

Inhibition of mammalian cytochrome P450 enzymes (CYPs) is well characterized; major hepatic CYPs can be inhibited by drugs and other environmental contaminants. CYP function and inhibition has not yet been well established in fish yet these studies are important for several reasons. First, such studies will provide functional information for non-mammalian CYPs. Second, specific inhibitors can be used as a diagnostic tool for studying CYP-mediated reactions. Lastly, pharmaceutical mixtures are found in the aquatic environment and adverse effects associated with drug-drug interactions, including CYP inhibition by pharmaceuticals may be of concern. Using liver microsomes from untreated and ß-naphthoflavone (BNF)-treated rainbow trout, eight fluorescent CYP-mediated catalytic assays were used to assess in vitro CYP inhibition by four pharmaceuticals: fluoxetine, ciprofloxacin, gemfibrozil and erythromycin. Expressed zebrafish CYP1 proteins (CYP1A, CYP1B1, CYP1C1 and CYP1C2) were assessed for inhibition with selected substrates. All pharmaceuticals decreased the metabolism of a number of substrates. Fluoxetine was the strongest and most broad inhibitor of CYP-mediated reactions in liver microsomes. Zebrafish CYP1s were strongly inhibited by erythromycin and fluoxetine. Although the pharmaceuticals are selective CYP inhibitors in mammals, inhibition across a number of substrates suggests they are broad inhibitors in fish. These data demonstrate that in vitro hepatic CYP inhibition by pharmaceuticals is possible in fish and the patterns seen here are different than what would be expected based on CYP inhibition in mammals.