Real-world utilization and outcomes of docetaxel among older men with metastatic prostate cancer: a retrospective population-based cohort study in Canada.

BACKGROUND: The adoption of docetaxel for systemic treatment of metastatic prostate cancer (PCa), in both castration-sensitive (mCSPC) and castration-resistant (mCRPC) settings, is poorly understood. This study examined the real-world utilization of docetaxel in these patients and their outcomes. METHODS: A retrospective population-based study used administrative data from Ontario, Canada, to identify men aged ≥66 years who were diagnosed with de novo mCSPC or mCRPC between 2014 and 2019 and received docetaxel. The study assessed treatment tolerability and toxicity, and survival in both cohorts. Descriptive and comparative statistical analysis were conducted. RESULTS: The study identified 11.2% (399/3556) and 13.2% (203/1534) patients diagnosed with de novo mCSPC and with mCRPC who received docetaxel respectively. The median age in both cohorts was 72 years (IQR: 68-76). Overall, 43.9% (n = 175) patients with de novo mCSPC and 52.1% (n = 85) with mCRPC completed ≥6 cycles of docetaxel. Over two-fifth also needed dose adjustments in both cohorts. Hospitalization or emergency department visit for febrile neutropenia were noted in 15.8% (n = 63) of de novo mCSPC patients and similarly in 19% (n = 31) of mCRPC cohort. The median survival of PCa patients who completed ≥6 cycles of docetaxel was significantly longer relative to those who completed <4 cycles: 32.7 vs. 23.5 months (p < 0.001) for mCSPC and 20.5 vs. 10.7 (p = 0.012) for mCRPC respectively. CONCLUSIONS: In this population-based study of elderly patients with metastatic PCa, treatment with docetaxel was associated with poor tolerability and higher toxicity compared with clinical trials. Receipt of limited cycles and reduced overall dose of docetaxel were associated with inferior overall survival.

Unmet Need in People with Psoriasis and Skin of Color in Canada and the United States.

The experience of dermatological conditions such as psoriasis is different for people with skin of color (SoC) than for white individuals. The objective of this literature review was to understand challenges and unmet needs associated with access to care, diagnosis, and treatment of psoriasis among people with SoC in Canada and the United States. The review focused on studies published in the last 5 years. After screening 919 unique records, 26 studies were included. Importantly, lack of culturally competent care was identified as a key unmet need for psoriasis among people with SoC. In addition, cost of care and cultural views of psoriasis may influence decisions to seek care among people with SoC. Baseline patient characteristics in psoriasis studies and the prevalence/incidence of psoriasis vary across racial/ethnic groups, which may reflect differences in the rate and/or timing of diagnosis. The presentation of psoriasis differs across racial/ethnic groups, which may contribute to challenges in proper and timely diagnosis. Compared with white patients with psoriasis, individuals with SoC may be less familiar with and have different rates of treatment with biologic therapies for psoriasis, are more likely to be hospitalized for psoriasis, and their access to physicians may differ. Further, people with SoC are underrepresented in clinical trials of psoriasis therapies. Overall, the results of this literature review suggest that people with psoriasis and SoC face unique challenges in their disease experience. It is essential that clinicians and other stakeholders recognize and address these disparities to ensure equitable care.

Skin conditions such as psoriasis are experienced differently by people with skin of color (SoC) compared with white individuals. Although it is known that psoriasis can vary in how it appears between these groups, other factors that affect care for patients with SoC are not well understood. For this review, we focused on challenges associated with accessing healthcare, receiving a diagnosis, and receiving treatment for psoriasis among people with SoC. A search of the academic literature identified several such challenges for people with SoC in Canada and the United States. A major challenge for people with psoriasis and SoC is having access to care that is compatible with their cultural values and practices. The cost of healthcare and cultural views of psoriasis may influence whether individuals with SoC decide to seek care. People with SoC are more likely to be hospitalized for psoriasis, and their access to physicians may differ compared with white individuals. In addition, differences in how psoriasis appears across racial/ethnic groups may hinder diagnosis. Psoriasis treatments that patients with SoC receive may differ from those that white individuals receive, and people with SoC may be less likely to be properly represented in clinical trials evaluating psoriasis therapies. Taken together, the findings of our review indicate that people with psoriasis and SoC face unique challenges in how they receive medical care for their condition. It is essential that clinicians and other stakeholders in the healthcare system recognize these challenges and work to address them.

Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada.

BACKGROUND: Management of advanced prostate cancer has evolved rapidly with the availability of multiple systemic treatments such as androgen-receptor axis-targeted therapies (ARATs), taxane-based chemotherapy, radium-223, and other approaches. However, limited data exists on real-world treatment selection and clinical outcomes. This study examines the utilization and survival impact of these therapies in men with metastatic castration-resistant prostate cancer (mCRPC) in the real-world setting of Ontario, Canada. METHODS: This study was a retrospective, longitudinal, population-based study of administrative claims data between January 2016 and April 2020. Men ≥ 66 years with mCRPC receiving advanced treatment were included. Patients were indexed on the day they initiated mCRPC treatment and followed up until death or end of study period to assess treatment and survival. Multinomial regression was used to model the association between baseline covariates, treatment and survival. RESULTS: Median age was 75 years among the 944 mCRPC patients who received life-prolonging therapies during this time period. Over 90% of patients used an ARAT as a first-line therapy, and 71.5% received only first-line therapy before death or censoring. Of patients that received two or more lines, over 80% received subsequent therapy with a different mechanism of action. Median overall survival was 18.9 months. CONCLUSIONS: ARATs have become the predominant first-line systemic treatment option for mCRPC patients in recent years. Notably, the majority of patients received only a single line of life-prolonging therapy after developing mCRPC. In keeping with the recognized efficacy-effectiveness gap, real-world outcomes in this cohort appear poorer than in clinical trials.

Prognostic Association between Common Laboratory Tests and Overall Survival in Elderly Men with De Novo Metastatic Castration Sensitive Prostate Cancer: A Population-Based Study in Canada.

De novo cases of metastatic prostate cancer (mCSPC) are associated with poorer prognosis. To assist in clinical decision-making, we aimed to determine the prognostic utility of commonly available laboratory-based markers with overall survival (OS). In a retrospective population-based study, a cohort of 3556 men aged ≥66 years diagnosed with de novo mCSPC between 2014 and 2019 was identified in Ontario (Canada) administrative database. OS was assessed by using the Kaplan-Meier method. Multivariate Cox regression analysis was performed to evaluate the association between laboratory markers and OS adjusting for patient and disease characteristics. Laboratory markers that were assessed include neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin, hemoglobin, serum testosterone and PSA kinetics. Among the 3556 older men with de novo mCSPC, their median age was 77 years (IQR: 71-83). The median survival was 18 months (IQR: 10-31). In multivariate analysis, a statistically significant association with OS was observed with all the markers (NLR, PLR, albumin, hemoglobin, PSA decrease, reaching PSA nadir and a 50% PSA decline), except for testosterone levels. Our findings support the use of markers of systemic inflammation (NLR, PLR and albumin), hemoglobin and PSA metrics as prognostic indicators for OS in de novo mCSPC.

Results from a Canadian consensus forum of key controversial areas in the management of advanced prostate cancer: Recommendations for Canadian healthcare providers.

INTRODUCTION: Rapid progress in diagnostics and therapeutics for the management of prostate cancer (PCa) has created areas where high-level evidence to guide practice is lacking. The Genitourinary Research Consortium (GURC) conducted its second Canadian consensus forum to address areas of controversy in the management of PCa and provide recommendations to guide treatment. METHODS: A panel of PCa specialists discussed topics related to the management of PCa. The core scientific committee finalized the design, questions, and analysis of the consensus results. Attendees then voted to indicate their management choice regarding each statement/topic. Questions for voting were adapted from the 2019 Advanced Prostate Cancer Consensus Conference. The thresholds for agreement were set at ≥75% for "consensus agreement," >50% for "near-consensus," and ≤50% for "no consensus." RESULTS: The panel was comprised of 29 PCa experts, including urologists (n=12), medical oncologists (n=12), and radiation oncologists (n=5). Voting took place for 65 predetermined questions and three ad hoc questions. Consensus was reached for 34 questions, spanning a variety of areas, including biochemical recurrence, treatment of metastatic castration-sensitive PCa, management of non-metastatic and metastatic castration-resistant PCa, bone health, and molecular profiling. CONCLUSIONS: The consensus forum identified areas of consensus or near-consensus in more than half of the questions discussed. Areas of consensus typically aligned with available evidence, and areas of variability may indicate a lack of high-quality evidence and point to future opportunities for further research and education.

Real-world management of advanced prostate cancer: A description of management practices of community-based physicians and prostate cancer specialists.

INTRODUCTION: The Canadian Genitourinary Research Consortium (GURC) conducted a consensus development conference leading to 31 recommendations. Using the GURC consensus development questionnaire, we conducted a survey to measure the corresponding community-based practices on the management of metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). METHODS: An 87-item online questionnaire was sent to 600 community urologists and oncologists involved in the treatment of prostate cancer. RESULTS: Seventy-two community physicians responded to the survey. Of note, 50% community physicians indicated they would treat nmCRPC with agents approved for this indication if advanced imaging showed metastases. Radiation to the prostate for low-volume mCSPC was identified as a treatment practice by 27% of community physicians, and 35% indicated docetaxel as the next line of treatment after use of apalutamide. Use of genetic testing was reported in 36% of community physicians for newly diagnosed metastatic prostate cancer. CONCLUSIONS: There are several areas of community-based management of advanced prostate cancer that could represent potential areas for education, practice tools, and future research.

Optimizing management of advanced urothelial carcinoma: A review of emerging therapies and biomarker-driven patient selection.

INTRODUCTION: Advanced urothelial carcinoma has been challenging to treat due to limited treatment options, poor response rates, and poor long-term survival. New treatment options hold the promise of improved outcomes for these patients. METHODS: A multidisciplinary working group drafted a management algorithm for advanced urothelial carcinoma using "consensus development conference" methodology. A targeted literature search identified new and emerging treatments for inclusion in the management algorithm. Published clinical data were considered during the algorithm development process, as well as the risks and benefits of the treatment options. Biomarkers to guide patient selection in clinical trials for new treatments were incorporated into the algorithm. RESULTS: The advanced urothelial carcinoma management algorithm includes newly approved first-line anti-programmed death receptor-1 (PD1)/ programmed death-ligand 1 (PD-L1) therapies, a newly approved anti-fibroblast growth factor receptors (FGFR) therapy, and an emerging anti-Nectin 4 therapy, which have had encouraging results in phase 2 trials for second-line and third-line therapy, respectively. This algorithm also incorporates suggestions for biomarker testing of PD-L1 expression and FGFR gene alterations. CONCLUSIONS: Newly approved and emerging therapies are starting to cover an unmet need for more treatment options, better response rates, and improved overall survival in advanced urothelial carcinoma. The management algorithm provides guidance on how to incorporate these new options, and their associated biomarkers, into clinical practice.

Management algorithms for metastatic prostate cancer.

INTRODUCTION: Prostate cancer poses a significant lifetime risk to Canadian men. Treatment for metastatic prostatic cancer (mPCa) is an area of ongoing research with a lack of up-to-date clinical guidance. The multidisciplinary Canadian Genitourinary Research Consortium (GURC) determined that additional guidance focusing on management of mPCa was warranted. METHODS: The most up-to-date guidelines, consensus statements, and emerging phase 3 trials were identified and used to inform development of algorithms by a multidisciplinary genitourinary oncology panel outlining recommendations for the management of mPCa. RESULTS: A single pan-Canadian guideline and five national and international guidelines or consensus statements published since 2015 were identified, along with two new phase 3 trials and one additional randomized comparison. Iterative GURC discussions led to the development of two mPCa algorithms: the first addressing management of newly diagnosed metastatic castration-sensitive prostate cancer (mCSPC) patients and the second addressing treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). For newly diagnosed mCSPC patients with high-volume/high-risk disease, either docetaxel or abiraterone acetate and prednisone (AAP) added to androgen-deprivation therapy (ADT) is recommended. The addition of radiotherapy to ADT is suggested for those with low-volume disease and/or AAP to ADT for low-volume or low-risk disease. For first-line mCRPC, androgen receptor-axis-targeted (ARAT) therapy is recommended for most patients, while sequencing with docetaxel, radium-223, ARAT therapy, and/or cabazitaxel is recommended for later lines of therapy. CONCLUSIONS: Two treatment algorithms were developed for the management of mPC and can be used by multidisciplinary specialist teams to guide treatment.

Controversial issues in the management of patients with advanced prostate cancer: Results from a Canadian consensus forum.

INTRODUCTION: The management of advanced prostate cancer (PCa) continues to evolve with the emergence of new diagnostic and therapeutic strategies. As a result, there are multiple areas in this landscape with a lack of high-level evidence to guide practice. Consensus initiatives are an approach to establishing practice guidance in areas where evidence is unclear. We conducted a Canadian-based consensus forum to address key controversial areas in the management of advanced PCa. METHODS: As part of a modified Delphi process, a core scientific group of PCa physicians (n=8) identified controversial areas for discussion and developed an initial set of questions, which were then reviewed and finalized with a larger group of 29 multidisciplinary PCa specialists. The main areas of focus were non-metastatic castration-resistant prostate cancer (nmCRPC), metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC), oligometastatic prostate cancer, genetic testing in prostate cancer, and imaging in advanced prostate cancer. The predetermined threshold for consensus was set at 74% (agreement from 20 of 27 participating physicians). RESULTS: Consensus participants included uro-oncologists (n=13), medical oncologists (n=10), and radiation oncologists (n=4). Of the 64 questions, consensus was reached in 30 questions (n=5 unanimously). Consensus was more common for questions related to biochemical recurrence, sequencing of therapies, and mCRPC. CONCLUSIONS: A Canadian consensus forum in PCa identified areas of agreement in nearly 50% of questions discussed. Areas of variability may represent opportunities for further research, education, and sharing of best practices. These findings reinforce the value of multidisciplinary consensus initiatives to optimize patient care.

Management algorithms for prostate-specific antigen progression in prostate cancer: Biochemical recurrence after definitive therapy and progression to non-metastatic castrate-resistant prostate cancer.

INTRODUCTION: Current prostate cancer (PCa) guidelines primarily focus on localized or metastatic PCa. A multidisciplinary genitourinary oncology panel determined that additional guidance focusing on monitoring and management of biochemical recurrence (BCR) following radical therapy and non-metastatic castration-resistant prostate cancer (nmCRPC) was warranted. METHODS: The most up-to-date national and international guidelines, consensus statements, and emerging phase 3 trials were identified and used to inform development of algorithms by a multidisciplinary genitourinary oncology panel outlining optimal monitoring and treatment for patients with non-metastatic PCa. RESULTS: A total of eight major national and international guidelines/consensus statements published since 2015 and three phase 3 trials were identified. Working group discussions among the multidisciplinary genitourinary oncology panel led to the development of two algorithms: the first addressing management of patients with BCR following radical therapy (post-BCR), and the second addressing management of nmCRPC. The post-BCR algorithm suggests consideration of early salvage treatment in select patients and provides guidance regarding observation vs. intermittent or continuous androgen-deprivation therapy (ADT). The nmCRPC algorithm suggests continued ADT and monitoring for all patients, with consideration of treatment with apalutamide or enzalutamide for patients with high-risk disease (prostate-specific antigen [PSA] doubling time of ≤ 10 months). CONCLUSIONS: Two treatment algorithms have been developed to guide the management of non-metastatic PCa and should be considered in the context of local guidelines and practice patterns.

Disparity in public funding of therapies for metastatic castrate-resistant prostate cancer across Canadian provinces.

INTRODUCTION: Treatment using abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, and radium-223 (Ra-223) improves overall survival (OS) and quality of life for patients with metastatic castrate-resistant prostate cancer (mCRPC). Despite their proven benefits, access to these therapies is not equal across Canada. METHODS: We describe provincial differences in access to approved mCRPC therapies. Data sources include the pan-Canadian Oncology Drug Review database, provincial cancer care resources, and correspondence with pharmaceutical companies. RESULTS: Both androgen receptor-axis-targeted therapies (ARATs), abiraterone acetate plus prednisone and enzalutamide, are funded by provinces in the pre-and post-chemotherapy setting, however, sequential ARAT use is not funded. "Sandwich" therapy, where one ARAT is used pre-chemotherapy and a second is used upon progression on chemotherapy, is funded in six provinces: Ontario (ON), Alberta, New Brunswick, Prince Edward Island (PEI), Nova Scotia (NS), and Newfoundland and Labrador. Ra-223 is funded in five provinces: ON, Quebec (QC), British Columbia (BC), Saskatchewan, and Manitoba to varying degrees; ON allows Ra-223 either pre- or post-chemo (not both); QC allows Ra-223 post-chemo unless chemo is not tolerated; BC allows Ra-223 if other life-prolonging mCRPC therapies have been received or ineligible. Cabazitaxel is funded in all provinces post-docetaxel, except QC and PEI. Cabazitaxel is not funded as fist-line treatment for mCPRC or in combination with other agents. In ON, BC, QC, and PEI, cabazitaxel is not funded after progression on an ARAT in the post-chemotherapy setting. CONCLUSIONS: While all provinces have access to docetaxel and ARATs, sandwiching sequential ARATs with docetaxel is funded only in select provinces. Ra-223 and cabazitaxel access is not ubiquitous across Canada. Such inequalities in access to life-prolonging therapies could lead to disparities in survival and quality of life among patients with mCRPC. Further research should quantify interprovincial variation in outcomes and cost that may result from variable access.

Differences in Adverse Event Reporting Rates of Therapeutic Failure Between Two Once-daily Extended-release Methylphenidate Medications in Canada: Analysis of Spontaneous Adverse Event Reporting Databases.

PURPOSE: Our study evaluated adverse events of therapeutic failure (and specifically reduced duration of action) with the use of a branded product, Osmotic Release Oral System (OROS) methylphenidate, which is approved for the treatment of attention deficit/hyperactivity disorder, and a generic product (methylphenidate, methylphenidate ER-C), which was approved for marketing in Canada based on bioequivalence to OROS methylphenidate. This study was initiated following reports that some US-marketed generic methylphenidate ER products had substantially higher reporting rates of therapeutic failure than did the referenced brands. METHODS: Through methodology similar to that used by the US Food and Drug Administration to investigate the issue with the US-marketed generic, reporting rates were calculated from cases of therapeutic failure identified in the Canadian Vigilance Adverse Reaction Online database for a 1-year period beginning 8 months after each product launch. Corresponding population exposure was estimated from the number of tablets dispensed. An in-depth analysis of narratives of individual case safety reports (ICSRs) with the use of the generic product was conducted in duplicate by 2 physicians to assess causality and to characterize the potential safety risk and clinical pattern of therapeutic failure. Similar secondary analyses were conducted on the US-marketed products. FINDINGS: Reporting rates of therapeutic failure with the use of methylphenidate ER-C (generic) and OROS methylphenidate (brand name) were 411.5 and 37.5 cases per 100,000 patient-years, respectively (reporting rate ratio, 10.99; 95% CI, 5.93-22.21). In-depth analysis of narratives of 230 ICSRs of therapeutic failure with the Canadian-marketed generic determined that all ICSRs were either probably (60 [26%]) or possibly (170 [74%]) causally related to methylphenidate ER-C. Clinical symptoms suggestive of overdose were present in 31 reports of loss of efficacy (13.5%) and occurred primarily in the morning, and premature loss of efficacy (shorter duration of action) was described in 98 cases (42.6%) and occurred primarily in the afternoon. Impacts on social functioning, such as disruption in work or school performance or adverse social behaviors, were found in 51 cases (22.2%). IMPLICATIONS: The ~10-fold higher reporting rate of therapeutic failure with the generic product relative to its reference product in the present Canadian study resembles findings with US-marketed generic products. While these results should be interpreted with caution due to the limitations of spontaneous adverse event reporting, which may confound comparisons across products, similar findings nonetheless led the US Food and Drug Administration to declare in 2014 that 2 methylphenidate ER generic products in the United States were neither bioequivalent nor interchangeable with OROS methylphenidate-their reference product. Our results indicate a potential safety issue with the Canadian-marketed generic and suggest a need for further investigation by Health Canada.

Medication Persistence, Duration of Treatment, and Treatment-switching Patterns Among Canadian Patients Taking Once-daily Extended-release Methylphenidate Medications for Attention-Deficit/Hyperactivity Disorder: A Population-based Retrospective Cohort Study.

PURPOSE: We conducted a retrospective cohort study to compare medication use patterns of a long-acting extended-release methylphenidate (Osmotic Release Oral System [OROS(®)] methylphenidate, CONCERTA(®)) and Teva-methylphenidate (methylphenidate ER-C), a generic drug determined by the Canadian regulatory authority, Health Canada, to be bioequivalent to OROS(®) methylphenidate. METHODS: We established an OROS(®) methylphenidate-experienced and new-user population cohort to compare medication use patterns, including medication persistence, duration of therapy, and treatment-switching patterns. Multivariable log-binomial regression was used to adjust for confounders of the associations with persistence. FINDINGS: In the OROS(®) methylphenidate-experienced cohort (n = 21,940), OROS(®) methylphenidate was associated with a 70% higher rate of medication persistence at 12 months relative to methylphenidate ER-C (adjusted relative risk = 1.70; 95% CI, 1.64-1.77). In the new-user cohort (n = 20,410), OROS(®) methylphenidate had a 58% higher rate of medication persistence relative to methylphenidate ER-C (adjusted relative risk = 1.58; 95% CI, 1.51-1.65). Median duration of therapy was significantly longer in patients taking OROS(®) methylphenidate compared with those taking methylphenidate ER-C, and treatment-switching occurred significantly more frequently in patients taking methylphenidate ER-C compared with those taking OROS(®) methylphenidate. IMPLICATIONS: Significant differences were observed in how the medications were used by patients in the real-world setting. Because the data sources were administrative databases, it was not possible to control for all potentially important confounding variables. Although differences in medication persistence may not directly reflect differences in treatment efficacy, the findings are important because these products are used interchangeably in a number of Canadian provinces.

Using fractional polynomials to model the effect of cumulative duration of exposure on outcomes: applications to cohort and nested case-control designs.

PURPOSE: Determining the nature of the relationship between cumulative duration of exposure to an agent and the hazard of an adverse outcome is an important issue in environmental and occupational epidemiology, public health and clinical medicine. The Cox proportional hazards regression model can incorporate time-dependent covariates. An important class of continuous time-dependent covariates is that denoting cumulative duration of exposure. METHODS: We used fractional polynomial methods to describe the association between cumulative duration of exposure and adverse outcomes. We applied these methods in a cohort study to examine the relationship between cumulative duration of use of the antiarrhythmic drug amiodarone and the risk of thyroid dysfunction. We also used these methods with a conditional logistic regression model in a nested case-control study to examine the relationship between cumulative duration of use of bisphosphonate medication and the risk of atypical femur fracture. RESULTS: Using a cohort design and a Cox proportional hazards model, we found a non-linear relationship between cumulative duration of use of the antiarrhythmic drug amiodarone and the risk of thyroid dysfunction. The risk initially increased rapidly with increasing cumulative use. However, as cumulative duration of use increased, the rate of increase in risk attenuated and eventually levelled off. Using a nested case-control design and a conditional logistic regression model, we found evidence of a linear relationship between duration of use of bisphosphonate medication and risk of atypical femur fractures. CONCLUSIONS: Fractional polynomials allow one to model the relationship between cumulative duration of medication use and adverse outcomes.

Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women.

CONTEXT: Osteoporosis is associated with significant morbidity and mortality. Oral bisphosphonates have become a mainstay of treatment, but concerns have emerged that long-term use of these drugs may suppress bone remodeling, leading to unusual fractures. OBJECTIVE: To determine whether prolonged bisphosphonate therapy is associated with an increased risk of subtrochanteric or femoral shaft fracture. DESIGN, SETTING, AND PATIENTS: A population-based, nested case-control study to explore the association between bisphosphonate use and fractures in a cohort of women aged 68 years or older from Ontario, Canada, who initiated therapy with an oral bisphosphonate between April 1, 2002, and March 31, 2008. Cases were those hospitalized with a subtrochanteric or femoral shaft fracture and were matched to up to 5 controls with no such fracture. Study participants were followed up until March 31, 2009. MAIN OUTCOME MEASURES: The primary analysis examined the association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure. To test the specificity of the findings, the association between bisphosphonate use and fractures of the femoral neck or intertrochanteric region, which are characteristic of osteoporotic fractures, was also examined. RESULTS: We identified 716 women who sustained a subtrochanteric or femoral shaft fracture following initiation of bisphosphonate therapy and 9723 women who sustained a typical osteoporotic fracture of the intertrochanteric region or femoral neck. Compared with transient bisphosphonate use, treatment for 5 years or longer was associated with an increased risk of subtrochanteric or femoral shaft fracture (adjusted odds ratio, 2.74; 95% confidence interval, 1.25-6.02). A reduced risk of typical osteoporotic fractures occurred among women with more than 5 years of bisphosphonate therapy (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.93). Among 52,595 women with at least 5 years of bisphosphonate therapy, a subtrochanteric or femoral shaft fracture occurred in 71 (0.13%) during the subsequent year and 117 (0.22%) within 2 years. CONCLUSION: Among older women, treatment with a bisphosphonate for more than 5 years was associated with an increased risk of subtrochanteric or femoral shaft fractures; however, the absolute risk of these fractures is low.

Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study.

BACKGROUND: Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia. METHODS AND FINDINGS: We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3:1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29-3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16-4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy. CONCLUSIONS: Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians.

The adherence support gap: the 'ideal' versus 'reality' of antiretroviral adherence support provided by HIV health providers in clinical practice.

BACKGROUND: Guidelines suggest that clinicians should provide their patients with antiretroviral adherence support, but there is uncertainty about the types of adherence support clinicians think are important, the methods they use to provide adherence support, and the barriers they face in providing such support in clinical practice. OBJECTIVE: To study clinician perspectives on the importance of different antiretroviral adherence support activities and compare these with clinicians' self-reported actual adherence support practices. METHODS: From March to August 2005, surveys were mailed to physicians, pharmacists, and nurses who provide care to HIV patients in Ontario, Canada. The 84-item survey asked providers to rate how necessary it was to provide 30 types of adherence support activities and how frequently they actually provided each of the types of adherence support. From this, we assessed healthcare provider perceptions of best or ideal practices in supporting medication adherence and actual or usual care in adherence support provision. We also examined whether an adherence support gap existed between the provision of best practice adherence support and actual adherence support in clinical practice. RESULTS: One hundred sixty-nine of 300 mailed surveys were returned, for a response rate of 56%. Respondents were highly specialized in HIV care and nearly all practiced in urban settings. Respondents indicated that most of the surveyed adherence support activities should be provided to all patients. However, most clinicians did not actually provide these adherence supports to their patients to the extent that they desired. We calculated an adherence support gap that ranged from 31% to 75% across the different types of adherence support activities. CONCLUSIONS: We observed important adherence support gaps between ideal best practices in the provision of adherence support and actual provision of adherence support in clinical practice.

The effect of publication on Internet-based solicitation of personal-injury litigants.

Serious adverse drug events can prompt personal-injury lawsuits. However, the extent to which biomedical publication regarding drug-induced harm can influence the legal process has not been well characterized. Using an advanced Google search strategy, we determined the number of Internet "hits" for websites soliciting plaintiffs for medicolegal action before and after publication of a study that highlighted the risk of dysglycemia among patients taking the antibiotic gatifloxacin. We found that early online release and print publication were associated with an immediate and sustained increase in the number of websites soliciting plaintiffs for legal action.

Outcomes of dosage adjustments used to manage antiretroviral drug interactions.

Dosage adjustments are often used to manage HIV drug interactions, but little is known about their clinical significance. We examined patients from the Ontario HIV Cohort Study to assess the effects of dosage adjustments on plasma viral load. A significant reduction (0.67 log10 copies/mL) in viral load was associated with adjustments to manage efavirenz-based interactions (95% confidence interval, -1.33 to -0.01) but was not observed after adjustments to manage rifabutin-based (difference in viral load, 0.03 log10 copies/mL; 95% confidence interval, -0.71 to 0.77) or nevirapine-based interactions (difference in viral load, 0.09 log10 copies/mL; 95% confidence interval, -0.83 to 1.01).