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Purpose: We describe constructs designed to protect the integrity of the results from comparative analyses using real‐world data (RWD): staging and clean room. Methods: Staging involves performing sequential preliminary analyses and evaluating the population size available and potential bias before conducting comparative analyses. A clean room involves restricted access to data and preliminary results, policies governing exploratory analyses and protocol deviations, and audit trail. These constructs are intended to allow decisions about protocol deviations, such as changes to design or model specification, to be made without knowledge of how they might affect subsequent analyses. We describe an example for implementing staging with a clean room. Results: Stage 1 may involve selecting a data source, developing and registering a protocol, establishing a clean room, and applying inclusion/exclusion criteria. Stage 2 may involve attempting to achieve covariate balance, often through propensity score models. Stage 3 may involve evaluating the presence of residual confounding using negative control outcomes. After each stage, check points may be implemented when a team of statisticians, epidemiologists and clinicians masked to how their decisions may affect study outcomes, reviews the results. This review team may be tasked with making recommendations for protocol deviations to address study precision or bias. They may recommend proceeding to the next stage, conducting additional analyses to address bias, or terminating the study. Stage 4 may involve conducting the comparative analyses. Conclusions: The staging and clean room constructs are intended to protect the integrity and enhance confidence in the results of analyses of RWD. [ABSTRACT FROM AUTHOR]

Purpose: This narrative review describes the application of negative control outcome (NCO) methods to assess potential bias due to unmeasured or mismeasured confounders in non‐randomized comparisons of drug effectiveness and safety. An NCO is assumed to have no causal relationship with a treatment under study while subject to the same confounding structure as the treatment and outcome of interest; an association between treatment and NCO then reflects the potential for uncontrolled confounding between treatment and outcome. Methods: We focus on two recently completed NCO studies that assessed the comparability of outcome risk for patients initiating different osteoporosis medications and lipid‐lowering therapies, illustrating several ways in which confounding may result. In these studies, NCO methods were implemented in claims‐based data sources, with the results used to guide the decision to proceed with comparative effectiveness or safety analyses. Results: Based on this research, we provide recommendations for future NCO studies, including considerations for the identification of confounding mechanisms in the target patient population, the selection of NCOs expected to satisfy required assumptions, the interpretation of NCO effect estimates, and the mitigation of uncontrolled confounding detected in NCO analyses. We propose the use of NCO studies prior to initiating comparative effectiveness or safety research, providing information on the potential presence of uncontrolled confounding in those comparative analyses. Conclusions: Given the increasing use of non‐randomized designs for regulatory decision‐making, the application of NCO methods will strengthen study design, analysis, and interpretation of real‐world data and the credibility of the resulting real‐world evidence. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of cardiovascular events among cancer patients with bone metastases is poorly understood. We examined rates of cardiovascular events among cancer patients with bone metastases and mortality following such events. Methods: Using Danish health registries, we identified all Danish cancer patients diagnosed with bone metastases (1994–2013) and followed them from bone metastasis diagnosis. We computed incidence rates (IR) per 100 person‐years and cumulative incidence for first‐time inpatient hospitalization or outpatient clinic visit for cardiovascular events, defined as myocardial infarction, ischemic stroke, or venous thromboembolism (VTE). We also analyzed all‐cause mortality rates including cardiovascular events as time‐varying exposure with adjustment for age, sex, and Charlson Comorbidity Index score. All analyses were performed overall and stratified by cancer type (prostate, breast, lung, and other). Results: We included 23,113 cancer patients with bone metastases. The cumulative incidence of cardiovascular events was 1.3% at 30 days, 3.7% at 1 year, and 5.2% at 5 years of follow‐up. The highest IR was observed for VTE, followed by ischemic stroke and myocardial infarction, both overall and by cancer types. Lung cancer patients with bone metastases had the highest incidence of cardiovascular events followed by prostate and breast cancer. Occurrence of any cardiovascular event was a strong predictor of death (5 years following the event, the adjusted hazard ratio was 1.8 [95% confidence interval: 1.7–1.9]). Conclusion: Cancer patients with bone metastases had a substantial risk of developing cardiovascular events, and these events were associated with a subsequent increased mortality. Our findings underscore the importance of continuous optimized prevention of and care for cardiovascular disease among cancer patients with bone metastases. [ABSTRACT FROM AUTHOR]

Objective: To estimate the baseline rates of vascular events among people with migraine. Background: Several novel medications that target the calcitonin gene‐related peptide (CGRP) pathway are approved to treat people with migraine. Given that the CGRP pathway also plays a role in maintaining cardiovascular homeostasis, determining the baseline rates of vascular events among people with migraine will help inform the safety of these novel medications. Methods: In this retrospective cohort study, patients 18‐ to 64‐year‐old patients with migraine were identified from the MarketScan® database (January 2013‐December 2017) and were categorized into 4 vascular risk categories: migraine with aura; and high, medium, and low vascular risk. Event rates (per 1000 person‐years [PY]) for 19 vascular events were estimated overall, by risk category, and by baseline characteristics. Results: Among 1,195,696 patients with migraine, 4.8% (57,853/1,195,696) had migraine with aura, and 2.8% (33,949/1,195,696), 15.5% (184,782/1,195,696), and 77.9% (931,059/1,195,696) were at high, medium, and low risk of vascular events, respectively. Rates of ischemic stroke (per 1000 PY) were 5.1 (95% confidence interval [CI]: 5.0, 5.2) overall, 8.6 (95% CI: 8.1, 9.1) for patients with migraine aura, 47.2 (95% CI: 45.3, 49.0) in the high‐risk group, 9.4 (95% CI: 9.1, 9.7) in the medium‐risk group, and 2.9 (95% CI: 2.9, 3.0) in the low‐risk group. Rates of acute myocardial infarction (per 1000 PY) were 1.8 (95% CI: 1.8, 1.9) overall, 1.9 (95% CI: 1.7, 2.2) for patients with migraine aura, 14.0 (95% CI: 13.0, 14.9) in the high‐risk group, 3.9 (95% CI: 3.7, 4.1) in the medium‐risk group, and 1.1 (95% CI: 1.0, 1.1) in the low‐risk group. High‐risk patients had the highest rates of each of 19 evaluated vascular events, and rates were higher for men, older age groups, and those with higher comorbidity scores, medication usage, and medical utilization. Conclusion: Our findings provide recent rates of vascular disease in patients with migraine. In the future, this information will be useful to help inform clinical risk:benefit decision making when assessing the use of therapies such as CGRP antagonists for migraine. [ABSTRACT FROM AUTHOR]

Background: Prior to 2018, intravenous bisphosphonates (IV BPs) were the only therapies recommended to prevent skeletal‐related events for patients diagnosed with multiple myeloma (MM). We examined patterns of IV BP initiation and interruption among patients with newly diagnosed MM (NDMM) in the United States. Methods: Electronic health records linked to administrative health insurance claims were used to identify adults with NDMM between 1 January 2011 and 30 April 2016. Patients were excluded for recent IV BP use or concurrent cancer. The incidences of IV BP initiation and interruption were estimated using competing risk regression. A generalized linear model was used to estimate risk factors for treatment initiation and interruption. Results: Among the 547 patients with NDMM, 64% initiated MM therapy within 30 days of diagnosis. By one year, 65% (95% CI: 59, 70) of patients with appropriately timed anti‐MM therapy had initiated an IV BP. Zoledronic acid was the most commonly initiated IV BP. Patients with Stage III MM were more likely to initiate an IV BP (adjusted risk difference (RD): 6.3; 95% CI: 2.7, 10.1), while those with eGFR <30 mL/min were less likely to initiate (RD: −9.7; 95% CI: −13.8, −5.8). Of the 264 patients who initiated an IV BP, 77% (95% CI: 71, 82) experienced an interruption within one year. Patients on concurrent anti‐MM therapy were less likely to experience an interruption in IV BP therapy. Conclusions: Many patients with NDMM do not initiate IV BPs, particularly those with renal complications. Interruptions of IV BPs were common. Data from routine clinical practice suggests that about 35% of patients with actively managed, newly diagnosed multiple myeloma did not receive intravenous bisphosphonates during the first year, even though these therapies have been shown to be effective in preventing SREs. The majority of patients who do initiate therapy, experience a treatment interruption within the first year after starting treatment. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To examine the dynamics of treatment with 2 bone‐targeting agents (BTAs)—denosumab and zoledronic acid—among men with bone metastases from prostate cancer. Methods: Using electronic health record data from oncology practices across the US, we identified prostate cancer patients diagnosed with bone metastasis in 2012/2013 without evidence of BTA use within 6 months prior to diagnosis. We examined the risk and predictors of BTA initiation, interruption, and re‐initiation. Results: Among 897 men diagnosed with prostate cancer, the cumulative incidence of BTA initiation after bone metastasis diagnosis was 34% (95% confidence interval [CI], 31–37%) at 30 days, 64% (95% CI, 61–68%) at 180 days, and 88% (95% CI, 85–91%) at 2 years. Denosumab was initiated more frequently than zoledronic acid. Men with diabetes, more bone lesions, history of androgen deprivation therapy, or no hospice enrollment were more likely to initiate treatment. Following initiation, the cumulative incidence of treatment interruption was 17% (95% CI, 14–19%) at 60 days and 70% (95% CI, 66–74%) at 2 years, with interruption more likely among patients receiving emerging therapies for prostate cancer or enrolling in hospice. The cumulative incidence of re‐initiation following interruption was 36.3% (95% CI, 32.7–40.2%) at 15 days, 49.8% (95% CI, 45.9–54.1%) at 30 days, and 81.0% (95% CI, 77.5–84.7%) at 1 year. Conclusions: Bone‐targeting agent therapy is initiated by the majority of men living with bone metastases following a prostate cancer diagnosis; however, the timing of initiation is highly variable. Once on treatment, gaps or interruptions in therapy are common. [ABSTRACT FROM AUTHOR]

Renal impairment is a common complication of multiple myeloma and deterioration in renal function or renal failure may complicate clinical management. This retrospective study in patients with multiple myeloma using an electronic medical records database was designed to estimate the prevalence of renal impairment (single occurrence of estimated glomerular filtration rate [ eGFR] <60 mL/min per 1.73 m2 on or after multiple myeloma diagnosis) and chronic kidney disease (at least two eGFR values <60 mL/min per 1.73 m2 after multiple myeloma diagnosis that had been measured at least 90 days apart), and to describe the use of nephrotoxic agents. Eligible patients had a first diagnosis of multiple myeloma ( ICD-9 CM: 203.0x) between January 1, 2012 and March 31, 2015 with no prior diagnoses in the previous 6 months. Of 12,370 eligible patients, the prevalence of both renal impairment and chronic kidney disease during the follow-up period was high (61% and 50%, respectively), and developed rapidly following the diagnosis of multiple myeloma (6-month prevalence of 47% and 27%, respectively). Eighty percent of patients with renal impairment developed chronic kidney disease over the follow-up period, demonstrating a continuing course of declining kidney function after multiple myeloma diagnosis. Approximately 40% of patients with renal impairment or chronic kidney disease received nephrotoxic agents, the majority of which were bisphosphonates. As renal dysfunction may impact the clinical management of multiple myeloma and is associated with poor prognosis, the preservation of renal function is critical, warranting non-nephrotoxic alternatives where possible in managing this population. [ABSTRACT FROM AUTHOR]

The renal status of patients with bone metastases secondary to solid tumors and their treatment with nephrotoxic agents is not well characterized. This retrospective study analyzed electronic medical records data from US-based oncology clinics to identify adult (age ≥18) solid tumor patients with first bone metastasis diagnosis and ≥1 serum creatinine recorded between January 1, 2009 and December 31, 2013. Patients with multiple myeloma, multiple primary tumor types, acute renal failure, and/or end-stage renal disease were excluded. Using the Chronic Kidney Disease Epidemiology Collaboration formula, we determined the prevalence of renal impairment ( RI: single estimated glomerular filtration rate [ eGFR] value <60 mL/min per 1.73 m2) and chronic kidney disease ( CKD: ≥2 eGFR values <60, at least 90 days apart). We also examined the use of intravenous bisphosphonates ( IV BP) and other nephrotoxic agents. Approximately half of the 11,809 patients were female. Breast (34%) and lung (28%) tumors were the most common. At bone metastasis diagnosis, mean age was 67 years and 24% of patients exhibited RI. The 5-year prevalence was 43% for RI and 71% for CKD among RI patients. Nearly half (46%) of CKD patients received IV BP in the 12 months following their confirming eGFR and 13% of these patients received at least one other nephrotoxic agent during that period. This is the first US-based study to examine the prevalence of RI among patients with bone metastases from solid tumors. RI is common at bone metastases diagnosis, and a substantial proportion of patients develop RI or CKD as their disease progresses. Whenever possible, treatments that are potentially less damaging for the kidney should be considered for patients with or predisposed to RI. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To quantify the association between cholinesterase inhibitors (ChE-Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia. DESIGN: Cox proportional hazards with time-dependent exposures were used to evaluate the association and examine the dose effect for donepezil and bradycardia. SETTING: New England Veterans Affairs Healthcare System. PARTICIPANTS: Patients with dementia who received care between January 1999 and June 2007 (N=11,328). MEASUREMENTS: Bradycardia was defined using three methods using a combination of International Classification of Diseases, Ninth Revision, codes and recorded heart rates of less than 60 beats per minute. RESULTS: A greater risk for bradycardia was found in patients taking any ChE-Is than in the no-treatment group (adjusted hazard ratio (HR)=1.4, 95% confidence interval (CI)=1.1–1.6). A dose-response effect was observed for donepezil, with the highest-dose group at greatest risk (HR=2.1, 95% CI=1.5–2.9). Results were consistent regardless of bradycardia definition. Patients with bradycardia were more likely to fall, experience syncope, or need a pacemaker implantation than those without. CONCLUSION: Using a large cohort, a modestly greater risk of bradycardia was found in patients with dementia taking ChE-Is than in those not taking these drugs. In patients taking donepezil, the risk of bradycardia may increase with increasing doses. Because of the potential clinical consequences, monitoring for bradycardia may be warranted in patients with dementia treated with ChE-Is. [ABSTRACT FROM AUTHOR]

The article reports on the result of the study concerning the risk of deep venous thrombosis and pulmonary embolism (DVT/PE) for patients treated with tamoxifen therapy. The study includes women ages 45 to 69 years diagnosed with international Union Against Cancer (UICC) stage I or II estrogen receptor-positive breast cancer between 1990 to 2004. The study shows that the five year risk of DVT/PE for women receiving tamoxifen was 1.2 percent while 0.50 percent for women not receiving tamoxifen.