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Background: Little is known about those vaccinated against influenza after pharmacists were added to the Ontario Universal Influenza Immunization Program, in 2012. Our aim was to identify characteristics of patients vaccinated against influenza and predictors of vaccination at a physician's office versus a community pharmacy. Methods: We conducted a cross-sectional study of Ontario residents who had a record of receipt of an influenza vaccine between October and March in the 2013/14 and 2015/16 influenza seasons in Ontario using health administrative databases. We used Poisson regression models to estimate associations between baseline characteristics and the receipt of influenza vaccination in a community pharmacy. All analyses were stratified by age group (≤ 65 yr or ≥ 66 yr). Results: Overall, we found a 7.9% decrease in vaccinations administered in 2015/16 (2 454 178) compared to 2013/14 (2 677 278). The number of patients vaccinated in community pharmacies increased between the 2 periods (757 729 [28.3%] in 2013/14 v. 859 794 [35.0%] in 2015/16). Living in nonurban areas or higher-income neighbourhoods, not identifying as an immigrant, not having a diagnosis of diabetes or hypertension, and receiving a pharmacist service on the same day as the vaccination were predictors of being vaccinated in a pharmacy, regardless of age group. Among patients aged 66 or more, those who had a hospital admission in the previous year were more likely to be vaccinated in a pharmacy than in a physician's office (adjusted incidence rate ratio [IRR] 1.08, 95% confidence interval [CI] 1.06–1.09), whereas those with higher annual medication costs were more likely to be vaccinated in a physician's office. The location of the previous season's vaccination predicted the current season's place of vaccination (age ≥ 66 yr: physician's office: adjusted IRR 0.56 [95% CI 0.56–0.57], pharmacy: adjusted IRR 2.37 [95% CI 2.35–2.39]; age ≤ 65 yr: physician's office: adjusted IRR 0.57 [95% CI 0.57–0.57], pharmacy: adjusted IRR 2.19 [95% CI 2.18–2.20]). Interpretation: For the 2013/14 and 2015/16 influenza seasons, the influenza vaccine was administered more frequently in physician offices than in community pharmacies, but the proportion of patients vaccinated in community pharmacies increased between the 2 periods. Physicians and pharmacists can encourage patients to take advantage of the availability of influenza vaccines across various settings. [ABSTRACT FROM AUTHOR]

Background: Denosumab inhibits the receptor activator of nuclear factor κB (RANK) pathway and is used to treat osteoporosis. Emerging evidence suggests RANK-blockade may play a role in mammary tumourigenesis. Thus, we undertook a population-based study of denosumab use and breast cancer risk in a large cohort of postmenopausal women.Methods: We included women 67+ years with prior bisphosphonate use who filled a first prescription for denosumab. They were matched on age, date, cumulative prior use of and time since last use of a bisphosphonate to women with no history of denosumab. Cox proportional hazards was used to estimate the hazard ratio (HR) of breast cancer with denosumab use.Results: A total of 100,368 women were included in the analysis with 1271 incident breast cancer events. Denosumab use was associated with a 13% decreased breast cancer risk (HR = 0.87; 95% CI 0.76-1.00). There was no relationship between increasing number of denosumab doses and breast cancer risk (P-trend = 0.15).Conclusion: These findings suggest a potential protective effect of ever denosumab use on breast cancer risk in a cohort of older women previously treated with bisphosphonates. [ABSTRACT FROM AUTHOR]

Background: The ability to locate those sampled has important implications for response rates and thus the success of survey research. The purpose of this study was to examine predictors of locating women requiring tracing using publicly available methods (primarily Internet searches), and to determine the additional benefit of vital statistics linkages. Methods: Random samples of women aged 65-89 years residing in two regions of Ontario, Canada were selected from a list of those who completed a questionnaire between 1995 and 1997 (n = 1,500). A random sample of 507 of these women had been searched on the Internet as part of a feasibility pilot in 2001. All 1,500 women sampled were mailed a newsletter and information letter prior to recruitment by telephone in 2003 and 2004. Those with returned mail or incorrect telephone number(s) required tracing. Predictors of locating women were examined using logistic regression. Results: Tracing was required for 372 (25%) of the women sampled, and of these, 181 (49%) were located. Predictors of locating women were: younger age, residing in less densely populated areas, having had a web-search completed in 2001, and listed name identified on the Internet prior to recruitment in 2003. Although vital statistics linkages to death records subsequently identified 41 subjects, these data were incomplete. Conclusion: Prospective studies may benefit from using Internet resources at recruitment to determine the listed names for telephone numbers thereby facilitating follow-up tracing and improving response rates. Although vital statistics linkages may help to identify deceased individuals, these may be best suited for post hoc response rate adjustment. [ABSTRACT FROM AUTHOR]

For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996–2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator. [ABSTRACT FROM AUTHOR]

Bisphosphonates are first-line therapy for osteoporosis, with alendronate, risedronate, and zoledronate as the main treatments used globally. After one year of therapy, bisphosphonates are retained in bone for extended periods with extended anti-fracture effects after discontinuation. Due to this continued fracture protection and the potential for rare adverse events associated with long-term use (atypical femoral fractures and osteonecrosis of the jaw), a drug holiday of two to three years is recommended for most patients after long-term bisphosphonate therapy. The recommendation for a drug holiday up to three years is derived primarily from extensions of pivotal trials with alendronate and zoledronate and select surrogate marker studies. However, certain factors may modify the duration of bisphosphonate effects on a drug holiday and warrant consideration when determining an appropriate time off-therapy. In this narrative review, we recall what is currently known about drug holidays and discuss what we believe to be the primary considerations and areas for future research regarding drug holiday duration: total bisphosphonate exposure, type of bisphosphonate used, bone mineral density and falls risk, and patient sex and body weight. [ABSTRACT FROM AUTHOR]

Background: Several clinical prediction rules (CPRs) for complications and mortality of Clostridioides difficile infection (CDI) have been developed but only a few have gone through external validation, and none is widely recommended in clinical practice. Methods: CPRs were identified through a systematic review. We included studies that predicted severe or complicated CDI (cCDI) and mortality, reported at least an internal validation step, and for which data were available with minimal modifications. Data from a multicenter prospective cohort of 1380 adults with confirmed CDI were used for external validation. In this cohort, cCDI occurred in 8% of the patients and 30-day all-cause mortality occurred in 12%. The performance of each tool was assessed using individual outcomes, with the same cut-offs and standard parameters. Results: Seven CPRs were assessed. Three predictive scores for cCDI showed low sensitivity (25–61%) and positive predictive value (PPV; 9–31%), but moderate specificity (54–90%) and negative predictive value (NPV; 82–95%). One model [using age, white blood cell count (WBC), narcotic use, antacids use, and creatinine ratio > 1.5× the normal level as covariates] showed a probability of 25% of cCDI at the optimal cut-off point with 36% sensitivity and 84% specificity. Two scores for mortality had low sensitivity (4–55%) and PPV (25–31%), and moderate specificity (71–78%) and NPV (87–92%). One predictive model for 30-day all-cause mortality [Charlson comorbidity index, WBC, blood urea nitrogen (BUN), diagnosis in ICU, and delirium] showed an AUC-ROC of 0.74. All other CPRs showed lower AUC values (0.63–0.69). Errors in calibration ranged from 12%- 27%. Conclusions: Included CPRs showed moderate performance for clinical use in a large validation cohort with a majority of patients infected with ribotype 027 strains and a low rate of cCDI and mortality. These data show that better CPRs need to be developed and validated. [ABSTRACT FROM AUTHOR]

Aims: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all‐cause mortality associated with domperidone exposure in PD. Methods: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987–2011). The first recorded PD diagnosis defined index date. Time‐dependent Cox proportional hazards models estimated hazard ratios (HRs) of all‐cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti‐Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non‐PD patients. Results: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two‐fold increase in all‐cause mortality (HRadj = 2.00, 95% confidence interval [CI]: 1.64–2.45), as compared to patients never exposed to domperidone. All‐cause mortality risk was highest in those starting domperidone in the previous month [HRadj = 2.97, 95% CI: 2.06–4.27]. When compared to matched non‐PD patients, PD was associated with a 43% increased risk of all‐cause mortality, yet this increased to a 2.4‐fold increased risk among PD patients currently using domperidone. Conclusion: Current use of domperidone was associated with a two‐fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone. [ABSTRACT FROM AUTHOR]

The article provides an overview of the STRengthening Analytical Thinking for Observational Studies (STRATOS) initiative as an international collaboration which was formed to offer guidance to help bridge the gap between methodological application and innovation. STRATOS is focused on distinguishing issues and promising approaches for analysing and planning observational studies.

Few studies have evaluated the mortality or quantified the economic burden of community-onset Clostridium difficile infection (CDI). We estimated the attributable mortality and costs of community-onset CDI. We conducted a population-based matched cohort study. We identified incident subjects with community-onset CDI using health administrative data (emergency department visits and hospital admissions) in Ontario, Canada between January 1, 2003 and December 31, 2010. We propensity-score matched each infected subject to one uninfected subject and followed subjects in the cohort until December 31, 2011. We evaluated all-cause mortality and costs (unadjusted and adjusted for survival) from the healthcare payer perspective (2014 Canadian dollars). During our study period, we identified 7,950 infected subjects. The mean age was 63.5 years (standard deviation = 22.0), 62.7% were female, and 45.0% were very high users of the healthcare system. The relative risk for 30-day, 180-day, and 1-year mortality were 7.32 (95% confidence interval [CI], 5.94–9.02), 3.55 (95%CI, 3.17–3.97), and 2.59 (95%CI, 2.37–2.83), respectively. Mean attributable cumulative 30-day, 180-day, and 1-year costs (unadjusted for survival) were $7,434 (95%CI, $7,122-$7,762), $12,517 (95%CI, $11,687-$13,366), and $13,217 (95%CI, $12,062-$14,388). Mean attributable cumulative 1-, 2-, and 3-year costs (adjusted for survival) were $10,700 (95%CI, $9,811-$11,645), $13,312 (95%CI, $12,024-$14,682), and $15,812 (95%CI, $14,159-$17,571). Infected subjects had considerably higher risk of all-cause mortality and costs compared with uninfected subjects. This study provides insight on an understudied patient group. Our study findings will facilitate assessment of interventions to prevent community-onset CDI. [ABSTRACT FROM AUTHOR]

Background: Medication reviews have become part of pharmacy practice across developed countries. This study aimed to identify factors affecting the likelihood of eligible Ontario seniors receiving a pharmacy-led medication review called MedsCheck annual (MCA). Methods: We designed a cohort study using a random sample of pharmacy claims for MCA-eligible Ontario seniors using linked administrative data from April 2012 to March 2013. Guided by a conceptual framework, we constructed a generalized-estimating-equations model to estimate the effect of patient, pharmacy and community factors on the likelihood of receiving MCA. Results: Of the 2,878,958 eligible claim-dates, 65,605 included an MCA. Compared to eligible individuals who did not receive an MCA, recipients were more likely to have a prior MCA (OR = 3.03), receive a new medication on the claim-date (OR = 1.78), be hypertensive (OR = 1.18) or have a recent hospitalization (OR = 1.07). MCA recipients had fewer medications (e.g., OR = 0.44 for ≥12 medications versus 0-4 medications), and were less likely to receive an MCA in a rural (OR = 0.74) or high-volume pharmacy (OR = 0.65). Conclusions: The most important determinant of receiving an MCA was having had a prior MCA. Overall, MCA recipients were healthier, younger, urban-dwelling, and taking fewer medications than non-recipients. Policies regarding current and future medication review programs may need to evolve to ensure that those at greatest need receive timely and comprehensive medication reviews. [ABSTRACT FROM AUTHOR]

Background: Bisphosphonates are the first-line therapy for the treatment of osteoporosis. In the province of Ontario, the Ontario Drug Benefit Program funds medications for patients aged 65 years and older. The Ontario Drug Benefit Program has a generic substitution policy that requires lower-cost generic drugs to be dispensed when they are available. However, there is controversy surrounding the efficacy and tolerability of generic bisphosphonates. The objective of this study was to describe patterns in the use of brand-name versus generic formulations when dispensing oral bisphosphonate over a 13-year period. Methods: We identified all osteoporotic preparations for alendronate and risedronate that were dispensed through the Ontario Drug Benefit Program from 2001 to 2014. We stratified our sample into community-dwelling residents and residents in long-term care facilities. The number of prescriptions dispensed per month were plotted to illustrate trends over time. Results: We found a rapid switch from brand-name to generic bisphosphonate equivalents immediately after the generic became available on the Ontario Drug Benefit formulary, with generics accounting for > 88% of dispensed drug within 2 months. We also observed a reduction in the number of generic drugs dispensed each time a new brand-name alternative (e.g., monthly risedronate, weekly alendronate plus vitamin D) was introduced to the formulary. The dispensing trends were similar in the community and long-term care settings. Interpretation: The Ontario Drug Benefit Program generic substitution policy resulted in rapid uptake of generic oral bisphosphonates among seniors in Ontario. However, there was a switch away from generic medications to new brand-name alternatives whenever they were introduced to the formulary. Therefore, some patients continued to use brand-name bisphosphonate despite the availability of generic options. [ABSTRACT FROM AUTHOR]

Knowing a person's fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m2), gender, and age (40-65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials. [ABSTRACT FROM AUTHOR]

Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60 ml/min per 1.73 m2). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To explore the “healthy user” and “healthy adherer” effects—hypothetical sources of bias thought to arise when patients who initiate and adhere to preventive therapies are more likely to engage in healthy behaviors than are other subjects. Methods: The authors examined the association between statin initiation and adherence, and the subsequent use of preventive health services and incidence of clinical outcomes unlikely to be associated with the need for, or use of, a statin among older enrollees in two state-sponsored drug benefit programs. Results: After adjustment for demographic and clinical covariates, patients who initiated statin use were more likely to receive recommended preventive services than noninitiators matched on age, sex, and state (hazard ratio [HR]: 1.10, 1.06–1.14 for males, HR: 1.09, 1.07–1.11 for females) and appeared to have a lower risk of a range of adverse outcomes (HR: 0.87, 0.85–0.89) thought to be unrelated to statin use. Adherence to a statin regimen was also associated with increased rates of preventive service use and a decreased rate of adverse clinical outcomes (HR: 0.93, 0.88–0.99). Conclusions: These results suggest that patients initiating and adhering to chronic preventive drug therapies are more likely to engage in other health-promoting behaviors. Failure to account for this relationship may introduce bias in any epidemiologic study evaluating the effect of a preventive therapy on clinical outcomes. [Copyright &y& Elsevier]

Background: Undertreatment of osteoporosis after hip or wrist fracture has been well documented, but the reasons for current patterns of care are poorly understood.Objective: We tested the role of physician and patient characteristics in predicting undertreatment when osteoporosis management was clearly indicated after a hip or wrist fracture in women over age 65.Methods: We assembled a cohort of 9,698 female Medicare beneficiaries aged > or = 65 years who experienced hip or wrist fracture between 2000 and 2004 and their prescribing physicians.Measurements: The dominant prescriber was identified as the physician prescribing at least 50% of patient prescriptions in the year after the fracture. Multivariate logistic regression estimated the role of physician and patient characteristics on osteoporosis management after hip or wrist fracture.Results: Patients older than 90 and black patients were less likely to be treated for osteoporosis relative to patients aged 65-69 and white patients. Female providers were more likely to manage osteoporosis. Models including patient characteristics discriminated well between managed and unmanaged patients (C statistic 0.81), while adding physician predictors to the model provided no additional discriminatory ability (C statistic 0.81).Conclusions: Our findings highlight that osteoporosis management rates are similar across providers, but vary considerably by patient types. [ABSTRACT FROM AUTHOR]