Comparing the effects of various ß-blockers on cardiovascular mortality in breast cancer patients.

BACKGROUND: Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual ß-blockers have been investigated to manage CV complications, various ß-blockers have not been compared for their effects on CV death in this population. We aimed to compare CV mortality in older BC patients taking one of the commonly used ß-blockers. METHODS: This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) - Medicare data (2010-2015). Patients of age 66 years or older at BC diagnosis receiving metoprolol, atenolol, or carvedilol monotherapy were included. The competing risk regression model was used to determine the risk of CV mortality in the three ß-blocker groups. The multivariable model was adjusted for demographic and clinical covariates. The adjusted hazard ratio (HR) and 95% confidence intervals (CI) were reported for the risk of CV mortality. RESULTS: The study cohort included 6,540 patients of which 55% were metoprolol users, 30% were atenolol users, and 15% were carvedilol users. Metoprolol was associated with a 37% reduced risk of CV mortality (P = 0.03) compared to carvedilol after adjusting for the covariates (HR = 0.63; 95% CI 0.41-0.96). No significant difference in the risk of CV mortality between atenolol and carvedilol users was observed (HR = 0.74; 95% CI 0.44-1.22). CONCLUSIONS: Our findings suggest that metoprolol is associated with a reduced risk of CV mortality in BC patients. Future studies are needed to confirm these findings and understand the mechanism of action.

Limited Access to Aortic Valve Procedures in Socioeconomically Disadvantaged Areas.

BACKGROUND: To explore how differences in local socioeconomic deprivation impact access to aortic valve procedures and the treatment of aortic valve disease, in comparison to other open and minimally invasive surgical procedures. METHODS AND RESULTS: Procedure volume data were obtained from the Healthcare Cost and Utilization Project from 18 states from 2016 to 2019 and merged with area deprivation index data, an index of zip code-level socioeconomic distress. We estimate the relationship between local deprivation ranking and differences in volumes of aortic valve replacement, which include transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR), versus coronary artery bypass graft surgery and laparoscopic colectomy (LC). All regressions control for state and year fixed effects and an array of zip code-level characteristics. TAVR procedures have increased over time across all zip codes. The rate of increase is negatively correlated with deprivation ranking, regardless of the higher share of hospitalizations per population in high deprivation areas. Distributional analysis further supports these findings, showing that lower area deprivation index areas account for a disproportionately large share of SAVR, TAVR, and LC procedures in our sample relative to their share of all hospitalizations in our sample. By comparison, the cumulative distribution of coronary artery bypass graft procedures was nearly identical to that of total hospitalizations, suggesting that this procedure is equitably distributed. Regressions show high area deprivation index areas have lower prevalence of SAVR (ß=-15.1%, [95% CI, -26.8 to -3.5]), TAVR (ß=-9.1%, [95% CI, -18.0 to -0.2]), and LC (ß=-19.9%, [95% CI, -35.4 to -4.4]), with no statistical difference in the prevalence of coronary artery bypass graft (ß=-2.5%, [95% CI, -12.7 to 7.6]), a widespread and commonly performed procedure. In the population aged ≥80 years, results show high area deprivation index areas have a lower prevalence of TAVR (ß=-11.9%, [95% CI, -18.7 to -5.2]) but not SAVR (ß=-0.8%, [95% CI, 8.1 to 6.3]), LC (ß=-3.5%, [95% CI, -13.4 to -6.4]), or coronary artery bypass graft (ß=5.2%, [95% CI, -1.1 to 1.1]). CONCLUSIONS: People living in high deprivation areas have less access to life-saving technologies, such as SAVR, and even moreso to device-intensive minimally invasive procedures such as TAVR and LC.

Long-term risk of reintervention after transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has surpassed surgical aortic valve replacement (SAVR) as the predominant mode of valve replacement for the treatment of severe aortic stenosis (AS). However, the long-term need for valvular reintervention after TAVR remains unknown. METHODS: Using data from the Medicare Fee for Service 100% dataset, all patients receiving TAVR between July 2011 and December 2020 were identified. Patients were categorized as receiving a valve reintervention (either surgical or transcatheter) or not using the appropriate International Classification of Diseases 10th Revision Procedure Coding System (ICD-10-PCS). A competing risk regression model was used to estimate the cumulative probability of valve reintervention. RESULTS: Of 230,644 TAVR patients were identified, of whom 1,880 received a reintervention. Patients receiving a reintervention were younger and more likely to be male. At 10 years, the crude rate of reintervention was 0.59% within a surviving cohort of 341 patients. After adjusting for the competing risk of death and other covariates, the adjusted cumulative incidence of reintervention at 10 years after TAVR was 1.63%. When the rate of reinterventions was compared between early (2011-2016) and later (2017-2020) time periods, the risk-adjusted rate of reintervention at 4 years had decreased over time (0.85% vs 0.51%). CONCLUSION: The 10-year risk of valve reintervention after TAVR is low and appears to be decreasing over time. Further research is necessary to determine the driving factors contributing to valve reintervention in the current era.

Screening of GPCR drugs for repurposing in breast cancer.

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on ß-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of ß3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.

Dose-dependent relation between metformin and the risk of hormone receptor-positive, her2-negative breast cancer among postmenopausal women with type-2 diabetes.

PURPOSE: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM). METHODS: This nested case-control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008-2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0-30,000, (3)30,001-136,000, (4)136,001-293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1-500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use. RESULTS: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55-0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42-0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46-0.82,p < 0.01) compared to the 0 mg/day group. CONCLUSIONS: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect.

FACTORS ASSOCIATED WITH SWITCHING FROM INJECTABLE TO ORAL DISEASE MODIFYING AGENTS AMONG PATIENTS WITH MULTIPLE SCLEROSIS.

BACKGROUND: Since the introduction of oral disease-modifying agents (DMA) in 2010, the treatment options for multiple sclerosis (MS) have changed significantly. There is limited information regarding the factors associated with switching to oral DMA among prevalent injectable DMA users. OBJECTIVE: This study evaluated the factors associated with switching to oral DMAs among prevalent injectable DMA users with MS. METHODS: A retrospective observational cohort study using the TriNetX electronic medical records (EMR) data was conducted among patients with MS. The study included prevalent injectable DMA users with at least two injectable DMA (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, or glatiramer acetate) prescription records within 6 months between September 2010 and May 2018. The second injectable DMA prescription date was considered as the index date. Switching was defined as any oral DMA prescription record (fingolimod, dimethyl fumarate, or teriflunomide) within 12 months after the index date. Patients with any infusion DMA prescription after the first injectable DMA prescription, and those less than 18 years of age were excluded from the study. The Andersen Behavioral Model was used as the conceptual framework to identify predisposing, enabling, and need factors measured during the 1-year baseline period before the index date. A multivariable logistic regression model was used to examine the predisposing (age, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, MS-related medication, and healthcare utilization) associated with switching from injectable to oral DMAs. RESULTS: Among 2,943 prevalent injectable users included in this study, 8.09% (n=238) patients switched to oral DMAs. Patients who switched to oral DMAs were primarily younger adults aged 18-44 years (64.29%), females (82.77%), had sensory and visual symptoms, and had corticosteroid utilization during the one-year look-back period compared to non-switchers. Results from multivariable logistic regression model revealed that middle-aged adults (45-64 years, adjusted odds ratio [aOR]: 0.43, 95% Confidence Interval [CI]: 0.32-0.58), old adults (≥65 years, aOR: 0.30, 95% CI: 0.13-0.66) and men (aOR: 0.67, 95% CI: 0.47-0.96) were associated with decreased odds of switching to oral DMAs. Presence of MS-related sensory symptoms (aOR: 1.52, 95% CI: 1.07-2.16), visual symptoms (aOR: 1.59, 95% CI: 1.10-2.31), and corticosteroids usage (aOR: 1.44, 95% CI: 1.04-1.98) were associated with increased odds of switching to oral DMAs. CONCLUSION: The study found that about one in twelve prevalent injectable DMA users switched to oral DMA. Both demographic and clinical factors were associated with switching to oral DMAs. Further research is needed to evaluate the outcomes of switching to inform treatment decisions for MS management.

Outcomes of "Real-World" Insulin Strategies in the Management of Hospital Hyperglycemia.

CONTEXT: Guidelines recommend scheduled long-acting basal and short-acting bolus insulin several times daily to manage inpatient hyperglycemia. In the "real world," insulin therapy is complicated, with limited data on the comparative effectiveness of different insulin strategies. OBJECTIVE: This work aimed to evaluate the association of different insulin strategies with glucose control and hospital outcomes after adjustment for patient and physician factors that influence choice of therapy. METHODS: This retrospective, observational study took place at an academic hospital. Participants included noncritically ill hospitalized medical/surgical patients (n = 4558) receiving subcutaneous insulin for 75% or longer during admission. Insulin therapy was grouped into 3 strategies within the first 48 hours: basal bolus (BB: scheduled long and short/rapid n = 2358), sliding scale (SS: short/rapid acting n = 1855), or basal only (BO: long only: n = 345). Main outcome measures included glucose control: hypoglycemic days, hyperglycemic days, euglycemic days, mean glucose; and hospitalization: in-hospital mortality, length of stay (LOS), and readmissions. RESULTS: Initial therapy with BB was associated with more hypoglycemic (2.40; CI, 2.04 to 2.82) (P < .001) and fewer euglycemic days (0.90; CI, 0.85 to 0.97) (P = .003) than SS, whereas BO was associated with fewer hyperglycemic days (0.70; CI, 0.62 to 0.79) (P < .001), lower mean glucose (-18.03; CI, -22.46 to -12.61) (P < .001), and more euglycemic days (1.22; CI, 1.09 to 1.37) (P < .001) compared to SS. No difference in mortality, LOS, and readmissions was found. However, decreased LOS was observed in the BB subgroup with a medical diagnostic related group (0.93; CI, 0.89 to 0.97) (P < .001). CONCLUSION: BO had a more favorable hyperglycemia profile than SS. BB, on the other hand, showed worse glycemic control as compared to SS. In the real-world hospital, BO may be a simpler and more effective insulin strategy.

Incidence of chemotherapy-induced peripheral neuropathy within 12 weeks of starting neurotoxic chemotherapy for multiple myeloma or lymphoma: a prospective, single-center, observational study.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) may necessitate chemotherapy dose reduction, delay, or discontinuation. This pilot study tested feasibility of patient enrollment, CIPN screening, and data collection in cancer patients for a future clinical study that will assess the safety and efficacy of an intervention that may prevent CIPN. METHODS: This prospective, observational, single-center, pilot study included adults with newly diagnosed lymphoma or multiple myeloma receiving neurotoxic chemotherapy. Patients were enrolled between September 2016 and February 2017. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire was completed by patients at 3 time points: baseline, week 6, and week 12. The primary outcome was change in the neurotoxicity score between these time points. RESULTS: Of 33 patients approached for consent, 28 (85%) provided consent and were enrolled. The FACT/GOG-Ntx questionnaire was completed by 28 (100%) at baseline, 25 (89%) at week 6, and 24 (86%) at week 12. Average (standard deviation) neurotoxicity scores were 36.5 (6.6) at baseline, 34.0 (8.3) at week 6, and 30.6 (7.6) at week 12. Neurotoxicity scores changed from baseline by - 2.7 points (95% CI - 5.5 to 0.1; p = 0.061) at week 6 and - 6.0 points (95% CI - 5.6 to - 0.8; p = 0.012) at week 12. Clinically meaningful declines (decrease of > 10% from baseline) in neurotoxicity score were detected in 36% (9 of 25) at week 6 and in 67% (16 of 24) at week 12. CONCLUSION: Sixty-seven percent of patients experienced clinically significant CIPN within 12 weeks of starting chemotherapy. Feasibility metrics for enrollment, consent, CIPN assessment, and follow-up were met.

Clinical Outcomes Associated with Drug-Drug Interactions of Oral Chemotherapeutic Agents: A Comprehensive Evidence-Based Literature Review.

BACKGROUND: Oral chemotherapy use is increasing due to new drug approvals as well as the convenience of the administration of oral drugs. This increased use also raises concern regarding drug-drug interactions (DDIs) with concomitantly administered drugs, resulting in loss of therapeutic effect, decreased tolerability, and/or increased toxicity. OBJECTIVE: The objective of this study was to review existing evidence of the clinical impact of DDIs with oral chemotherapeutic agents. METHODS: A comprehensive search of literature using PubMed was conducted in April 2018 for studies of DDIs associated with oral chemotherapy. Included studies were in English. We included randomized clinical trials, observational studies, and case reports evaluating a DDI between any oral chemotherapy drug and any other drug. Included studies needed to have at least one outcome of clinical relevance potentially attributed to the DDI, for example, effects on survival or toxicity. The quality of the articles was determined using published metrics appropriate for the study design. RESULTS: There were 2626 studies identified in the initial search, of which 35 met all eligibility criteria. These included 15 retrospective cohort studies, 16 case reports or case series and four post hoc analyses of clinical trials. Among these, DDIs contributed to a statistically significant change in a clinical outcome in 12 studies. Eight of these studies evaluated overall survival and progression-free survival and found that the presence of the DDI was associated with reduced survival. CONCLUSION: Our findings suggest that more real-world studies evaluating the association between oral chemotherapy DDIs and clinical outcomes are needed. The adverse clinical outcomes due to DDIs may be a reason for treatment failures and therapy discontinuation.