Adherence, clinical benefits, and adverse effects of endocrine therapies among women with nonmetastatic breast cancer in developing countries: A systematic review and meta-analysis.

BACKGROUND: Despite significant advances in breast cancer control and survival with endocrine therapies (ETs), treatment utilization and outcomes in developing countries have not been adequately explored. This review evaluated ET adherence, potential benefits, and harms in populations across developing countries. METHODS: A literature search was conducted through August 2023 in five databases: PubMed, Cochrane Library, Web of Science, Global Health, and WHO Global Index Medicus. Retrieved records were screened to identify observational research presenting at least one outcome in women with nonmetastatic breast cancer in developing countries who received ET (tamoxifen or aromatase inhibitors). A random effects model was used to compute the rates of adherence, discontinuation, adverse events (AEs), disease progression, and death. RESULTS: A total of 104 studies met the inclusion criteria. Risk of bias was low in most studies, and a large portion of the patients involved Asians. The overall heterogeneity between studies was partially attributed to variations in study design or outcome measurement method. Results showed a pooled adherence rate of 75% (95% confidence interval [CI], 67%-81%) and a discontinuation rate of 16% (95% CI, 10%-25%). Treatment side effects and young age consistently emerged as significant predictors of nonadherence. A wide range of AEs was identified in our analysis. The estimated average rates of cancer recurrence and mortality at 5-years were 16% and 8%, respectively. CONCLUSIONS: The findings of this study underscore suboptimal ET use in developing countries and provide comprehensive insights into treatment experiences in the real-world setting. Targeted strategies are warranted to enhance adherence and subsequently optimize treatment benefits.

Bruton tyrosine kinase inhibitor monotherapy in B-cell lymphoma and risk of infection: A systematic review and meta-analysis of randomized controlled trials.

Bruton's tyrosine kinase (BTK) inhibitors are important therapeutic advances with promising efficacy outcomes in the treatment of patients with chronic lymphocytic leukemia and other B-cell lymphoma subtypes. However, the utility of BTK inhibitors can be limited by adverse events such as infections. In this systematic review and meta-analysis, we aim to determine the risk of various infections associated with BTK inhibitor monotherapy in B-cell lymphoma patients. A comprehensive search was conducted in MEDLINE/PubMed, Embase, and Web of Science databases from their inception until October 2023. ClinicalTrials.gov, bibliographies, and relevant conference abstracts were also searched for additional records. Randomized controlled trials that included any B-cell lymphoma patients treated with BTK inhibitor monotherapy and reported infection were included. Meta-analysis was performed to calculate risk ratio (RR) using a random-effects model in R Statistical Software, version 4.3.2. Of 3292 studies retrieved, we included 12 studies in this systematic review and meta-analysis. The median age of patients across the study arms ranged between 64 and 73 years. The overall pooled RR for any grade upper respiratory tract infections (URTI) associated with BTK inhibitor treatment was 1.55 (95% Confidence Interval (CI) 1.22-1.97). The RR of grade ≥3 URTI was reported in 14 out of 1046 patients, yielding an RR of 1.46 (95% CI 0.61-3.54), which was not statistically significant. The pooled RR of any grade pneumonia was 1.20 (95% CI 0.68-2.10) and grade ≥3 pneumonia was 1.12 (95% CI 0.67-1.85), both of which were not statistically significant. Patients with B-cell lymphoma who are undergoing BTK inhibitor monotherapy face an elevated risk of developing URTI. Clinicians prescribing BTK inhibitors should be aware of the potential infectious events that may occur. Close monitoring and the implementation of effective prophylactic measures are essential for managing these patients.

Efficacy and Effectiveness Outcomes of Treatments for Double-Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review.

BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax-treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double-exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double-exposed CLL patients. METHODS: PubMed, Embase, and Web of Science databases were searched until December 2023. RESULTS: We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T-cell therapy. CONCLUSION: This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.

Innovation, affordability, access: Alzheimer disease drugs and the Inflation Reduction Act.

OBJECTIVES: This analysis examines the implications of new Alzheimer disease drugs in the era of the Inflation Reduction Act (IRA). It focuses on balancing innovation in Alzheimer disease treatment with affordability and access, assessing the impact on Medicare's budget, patient cost, and health care system readiness. STUDY DESIGN: A comprehensive review was conducted, synthesizing information from recent FDA drug approvals, drug pricing models, Medicare coverage policies, and the updated regulations under the IRA. This analysis reflects on the broader clinical and economic consequences of introducing new Alzheimer disease treatments. METHODS: The study employs a qualitative review of existing literature, policy documents, and economic data. It explores the implications of Alzheimer disease drugs on health care policy, analyzing the economic and clinical impacts within the current health care landscape in the US. RESULTS: The study highlights the economic challenges posed by the high costs of new Alzheimer disease drugs, contrasting with their moderate clinical benefits and potential risks. It discusses the limitations of the IRA in regulating drug prices and the resulting implications for Medicare's budget. Additionally, it examines disparities in health care access and system preparedness for these new treatments. CONCLUSIONS: The study findings underscore the need for a comprehensive approach to ensure fair pricing and equitable access to Alzheimer disease treatments. It suggests the application of frameworks such as the ISPOR Value Flower, focusing on diversity, equity, and comprehensive economic evaluations, to navigate the evolving landscape of Alzheimer disease treatment in the context of the IRA.

Acute Adverse Effects of Therapeutic Doses of Psilocybin: A Systematic Review and Meta-Analysis.

Importance: Psilocybin has been studied in the treatment of depression and anxiety disorders. Clinical studies have mainly focused on efficacy, with systematic reviews showing favorable efficacy; however, none have primarily focused on psilocybin safety. Objective: To evaluate the acute adverse effects of psilocybin at therapeutic doses in the treatment of depression and anxiety. Data Sources: MEDLINE via PubMed, Web of Science, and ClinicalTrials.gov were searched for publications available between 1966 and November 30, 2023. Study Selection: Randomized, double-blind clinical trials that reported adverse effects of psilocybin in patients treated for depression and anxiety were screened. Data Extraction and Synthesis: Data were independently extracted by 2 authors and verified by 2 additional authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. The inverse variance method with the Hartung-Knapp adjustment for the random-effects model was used, with a continuity correction of 0.5 for studies with 0 cell frequencies. Sensitivity analysis was conducted by sequentially removing 1 study at a time to assess the robustness of the results. Main Outcomes and Measures: The primary outcome was considered as the adverse effects of psilocybin at high and moderate (ie, therapeutic) dose regimens and compared with placebo, low-dose psilocybin, or other comparator in the treatment of depression and/or anxiety. Results: Six studies met the inclusion criteria with a total sample of 528 participants (approximately 51% female; median age 39.8 years; IQR, 39.8-41.2). Seven adverse effects were reported in multiple studies and included in the analysis. Among these, headache (relative risk [RR], 1.99; 95% CI 1.06-3.74), nausea (RR, 8.85; 95% CI, 5.68-13.79), anxiety (RR, 2.27; 95% CI, 1.11-4.64), dizziness (RR, 5.81; 95% CI, 1.02-33.03), and elevated blood pressure (RR, 2.29; 95% CI, 1.15- 4.53) were statistically significant. Psilocybin use was not associated with risk of paranoia and transient thought disorder. Conclusions and Relevance: In this meta-analysis, the acute adverse effect profile of therapeutic single-dose psilocybin appeared to be tolerable and resolved within 48 hours. However, future studies need to more actively evaluate the appropriate management of adverse effects.

Exploring Safety in Gender-Affirming Hormonal Treatments: An Observational Study on Adverse Drug Events Using the Food and Drug Administration Adverse Event Reporting System Database.

BACKGROUND: People with gender dysphoria are treated with hormone therapy for gender reassignment. The indication of this therapy was initially for the opposite sex, and information on potential adverse drug reaction (ADR) is lacking. OBJECTIVE: To describe ADR associated with gender transition medication in transgender individuals reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: Data from the FAERS database up to June 2023 were examined, focusing on reports of gender transition medication use in the context of gender dysphoria. The ADRs were categorized using the Medical Dictionary for Regulatory Activities at both Preferred Term and System Organ Class (SOC) levels. Descriptive statistics summarized report counts, medication types, indications, and ADR severity. RESULTS: For individuals assigned female at birth undergoing gender transition to male (transgender men), 82 reports (230 ADRs) were analyzed, with an average age of 29.5 years. Transgender hormonal therapy was cited in 72% of reports, predominantly from the United States (67.1%). A striking 88% were categorized as serious ADRs, primarily SOC injury, poisoning, and procedural complications (26.5%), followed by psychiatric disorders (14.8%) and nervous system disorders (12.2%). Among those assigned sex male at birth transitioning to female (transgender women) (81 reports, 237 ADRs), mean age was 33.3 years, with 58% indicating use for gender dysphoria. A significant proportion (53.6%) were serious ADRs, primarily SOC: injury, poisoning, and procedural complications (26.6%). CONCLUSIONS AND RELEVANCE: The FAERS data reveal significant ADRs in transgender individuals using hormone therapy, sometimes unintended for their recipient gender. Population-level studies are crucial to enhance transgender health care. Spontaneous surveillance databases like FAERS illuminate off-label ADRs, urging health care providers to approach hormone therapies with informed caution.

Barriers to Adoption of Tailored Drug-Drug Interaction Clinical Decision Support.

OBJECTIVE: Despite the benefits of the tailored drug-drug interaction (DDI) alerts and the broad dissemination strategy, the uptake of our tailored DDI alert algorithms that are enhanced with patient-specific and context-specific factors has been limited. The goal of the study was to examine barriers and health care system dynamics related to implementing tailored DDI alerts and identify the factors that would drive optimization and improvement of DDI alerts. METHODS: We employed a qualitative research approach, conducting interviews with a participant interview guide framed based on Proctor's taxonomy of implementation outcomes and informed by the Theoretical Domains Framework. Participants included pharmacists with informatics roles within hospitals, chief medical informatics officers, and associate medical informatics directors/officers. Our data analysis was informed by the technique used in grounded theory analysis, and the reporting of open coding results was based on a modified version of the Safety-Related Electronic Health Record Research Reporting Framework. RESULTS: Our analysis generated 15 barriers, and we mapped the interconnections of these barriers, which clustered around three entities (i.e., users, organizations, and technical stakeholders). Our findings revealed that misaligned interests regarding DDI alert performance and misaligned expectations regarding DDI alert optimizations among these entities within health care organizations could result in system inertia in implementing tailored DDI alerts. CONCLUSION: Health care organizations primarily determine the implementation and optimization of DDI alerts, and it is essential to identify and demonstrate value metrics that health care organizations prioritize to enable tailored DDI alert implementation. This could be achieved via a multifaceted approach, such as partnering with health care organizations that have the capacity to adopt tailored DDI alerts and identifying specialists who know users' needs, liaise with organizations and vendors, and facilitate technical stakeholders' work. In the future, researchers can adopt the systematic approach to study tailored DDI implementation problems from other system perspectives (e.g., the vendors' system).

Chimeric antigen receptor T-cell immunotherapies adverse events reported to FAERS database: focus on cytopenias.

Chimeric antigen receptor (CAR) T-cell therapy presents a promising treatment for hematologic malignancies, displaying high efficacy but not being exempt from toxicity. In this observational study, we assessed adverse events (AEs) reported to the Food and Drug Adverse Event Reporting System (FAERS) including any of the six approved CAR T-cell therapies. A total of 5249 reports mentioning a CAR T-cell as a suspect product were retrieved from the FAERS database, containing a total of 24333 AEs, of which 3236 (13.3%) were cytopenias. The highest number of AEs mentioned by the report was observed for tisagenlecleucel (mean = 6.7), with the lowest for ciltacabtagene (mean = 1.3). Among all reports, hematopoietic leukopenia was the most frequently reported AEs (n = 1386, 5.7%), with hematopoietic erytropenia the least reported (n = 291, 1.2%). Tisagenlecleucel showed a high reporting odds ratio for hematopoietic erythropenia (27.28, 95%CI 14.04-53.00), leukopenia (4.04, 95%CI 3.52-4.64), and thrombocytopenia (4.01, 95%CI 3.19-5.03). Cytopenias represent one of the most frequently reported AEs in FAERS, a CAR T-cell therapy is indicated, with haematopoetic leukopenia being the most common. When comparing different CAR-T cell therapies, the cytopenias' reporting odds ratio was particularly high for tisagenlecleucel, especially in relation to hematopoietic erythropenia.

Cost-effectiveness analysis of nivolumab-chemotherapy as first-line therapy for locally advanced/metastatic gastric cancer: a United States payer perspective.

OBJECTIVES: Nivolumab, an immune checkpoint inhibitor, was approved by the United States (US) Food and Drug administration as a first-line systemic therapy for locally advanced/metastatic gastric cancer patients. The current study aimed to investigate the cost-effectiveness of nivolumab-chemotherapy combination versus chemotherapy alone as a first-line therapy from a US payer perspective. METHODS: An economic evaluation was conducted using a partitioned survival model in Microsoft Excel® using data from the CheckMate 649 trial. Three discrete mutually exclusive health states (progression-free, post-progression, and death) were included in the model. The health state occupancy was calculated using the overall survival and progression-free survival curves derived from the CheckMate 649 trial. Cost, resource use, and health utility estimates were estimated from a US payer perspective. Deterministic and probabilistic sensitivity analyses assessed the uncertainty of the model parameters. RESULTS: Nivolumab-chemotherapy provided additional 0.25 life years compared to chemotherapy alone and the quality-adjusted life years (QALYs) were 0.701 and 0.561, respectively, producing a gain of 0.140 QALYs and an incremental cost-effectiveness ratio of $574,072/QALY. CONCLUSION: From the US payer perspective, at a willingness to pay threshold of $US150,000/QALY, nivolumab-chemotherapy was not found to be cost-effective as a first-line therapy for locally advanced/metastatic gastric cancer.

Cost-effectiveness analysis of five anti-obesity medications from a US payer's perspective.

BACKGROUND AND AIMS: To determine the cost-effectiveness of anti-obesity medications (AOM): tirzepatide, semaglutide, liraglutide, phentermine plus topiramate (PpT), and naltrexone plus bupropion (NpB). METHODS AND RESULTS: From a U.S. perspective we developed a Markov model to simulate weight change over a 40-year time horizon using results from clinical studies. According to the body mass index (BMI), cardiovascular diseases, diabetes and mortality risk were the health states considered in the model, being mutually exclusive. Costs of AOM, adverse events, cardiovascular events, and diabetes were included. We applied a 3% per-year discount rate and calculated the incremental cost-effectiveness ratios (ICERs) of cost per quality-adjusted life-year (QALY) gained. Probabilistic sensitivity analyses incorporated uncertainty in input parameters. A deterministic analysis was conducted to determine the robustness of the model. The model included a cohort of 78.2% females with a mean age of 45 years and BMI of 37.1 (SD 4.9) for females and 36.8 (SD 4.9) for males. NpB and PpT were the least costly medications and, all medications differed no more than 0.5 QALYs. Tirzepatide ICER was $355,616 per QALY. Liraglutide and semaglutide options were dominated by PpT. CONCLUSION: Compared to other AOM, PpT was lowest cost treatment with nearly identical QALYs with other agents.

Drugs That Interact With Colchicine Via Inhibition of Cytochrome P450 3A4 and P-Glycoprotein: A Signal Detection Analysis Using a Database of Spontaneously Reported Adverse Events (FAERS).

BACKGROUND: Colchicine has a narrow therapeutic index. Its toxicity can be increased due to concomitant exposure to drugs inhibiting its metabolic pathway; these are cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). OBJECTIVE: To examine clinical outcomes associated with colchicine drug interactions using the spontaneous reports of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHODS: We conducted a disproportionality analysis using FAERS data from January 2004 through June 2020. The reporting odds ratio (ROR) and observed-to-expected ratio (O/E) with shrinkage for adverse events related to colchicine's toxicity (ie, rhabdomyolysis/myopathy, agranulocytosis, hemorrhage, acute renal failure, hepatic failure, arrhythmias, torsade de pointes/QT prolongation, and cardiac failure) were compared between FAERS reports. RESULTS: A total of 787 reports included the combined mention of colchicine, an inhibitor of both CYP3A4 and P-gp drug, and an adverse event of interest. Among reports that indicated the severity, 61% mentioned hospitalization and 24% death. A total of 37 ROR and 34 O/E safety signals involving colchicine and a CYP3A4/P-gp inhibitor were identified. The strongest ROR signal was for colchicine + atazanavir and rhabdomyolysis/myopathy (ROR = 35.4, 95% CI: 12.8-97.6), and the strongest O/E signal was for colchicine + atazanavir and agranulocytosis (O/E = 3.79, 95% credibility interval: 3.44-4.03). CONCLUSION AND RELEVANCE: This study identifies numerous safety signals for colchicine and CYP3A4/P-gp inhibitor drugs. Avoiding the interaction or monitoring for toxicity in patients when co-prescribing colchicine and these agents is highly recommended.

Colchicine Drug Interaction Errors and Misunderstandings: Recommendations for Improved Evidence-Based Management.

Colchicine is useful for the prevention and treatment of gout and a variety of other disorders. It is a substrate for CYP3A4 and P-glycoprotein (P-gp), and concomitant administration with CYP3A4/P-gp inhibitors can cause life-threatening drug-drug interactions (DDIs) such as pancytopenia, multiorgan failure, and cardiac arrhythmias. Colchicine can also cause myotoxicity, and coadministration with other myotoxic drugs may increase the risk of myopathy and rhabdomyolysis. Many sources of DDI information including journal publications, product labels, and online sources have errors or misleading statements regarding which drugs interact with colchicine, as well as suboptimal recommendations for managing the DDIs to minimize patient harm. Furthermore, assessment of the clinical importance of specific colchicine DDIs can vary dramatically from one source to another. In this paper we provide an evidence-based evaluation of which drugs can be expected to interact with colchicine, and which drugs have been stated to interact with colchicine but are unlikely to do so. Based on these evaluations we suggest management options for reducing the risk of potentially severe adverse outcomes from colchicine DDIs. The common recommendation to reduce the dose of colchicine when given with CYP3A4/P-gp inhibitors is likely to result in colchicine toxicity in some patients and therapeutic failure in others. A comprehensive evaluation of the almost 100 reported cases of colchicine DDIs is included in table form in the electronic supplementary material. Colchicine is a valuable drug, but improvements in the information about colchicine DDIs are needed in order to minimize the risk of serious adverse outcomes.

Drug-drug interaction between dexamethasone and direct-acting oral anticoagulants: a nested case-control study in the National COVID Cohort Collaborative (N3C).

OBJECTIVE: The goal of this work is to evaluate if there is an increase in the risk of thromboembolic events (TEEs) due to concomitant exposure to dexamethasone and apixaban or rivaroxaban. Direct oral anticoagulants (DOACs), as well as corticosteroid dexamethasone, are commonly used to treat individuals hospitalised with COVID-19. Dexamethasone induces cytochrome P450-3A4 enzyme that also metabolises DOACs apixaban and rivaroxaban. This raises a concern about possible interaction between dexamethasone and DOACs that may reduce the efficacy of the DOACs and result in an increased risk of TEE. DESIGN: We used nested case-control study design. SETTING: This study was conducted in the National COVID Cohort Collaborative (N3C), the largest electronic health records repository for COVID-19 in the USA. PARTICIPANTS: Study participants were adults over 18 years who were exposed to a DOAC for 10 or more consecutive days. Exposure to dexamethasone was at least 5 or more consecutive days. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary exposure variable was concomitant exposure to dexamethasone for 5 or more days after exposure to either rivaroxaban or apixaban for 5 or more consecutive days. We used McNemar's Χ2 test and adjusted logistic regression to evaluate association between concomitant use of dexamethasone with either apixaban or rivaroxaban. RESULTS: McNemar's Χ2 test did not find a discernible association of TEE in patients concomitantly exposed to dexamethasone and a DOAC (χ2=0.5, df=1, p=0.48). In addition, a conditional logistic regression model did not find an increase in the risk of TEE (adjusted OR 1.15, 95% CI 0.32 to 4.18). CONCLUSION: This nested case-control study did not find evidence of an association between concomitant exposure to dexamethasone and a DOAC with an increase in risk of TEE. Due to small sample size, an association cannot be completely ruled out.

Complications Associated with Foodborne Listeriosis: A Scoping Review.

Listeria monocytogenes is a relatively rare but highly pathogenic bacterium that can cause foodborne infections. In the United States there are ∼1600 cases per year, 94% of which result in hospitalizations and 20% in deaths. Per-case burden is high because the disease also causes serious complications, including sepsis, encephalitis, meningitis, miscarriage, and stillbirth. The disease burden of L. monocytogenes is underestimated because some of these acute complications can also result in long-term outcomes. In this article, we conducted a scoping review of L. monocytogenes complications and longer term outcomes from articles published between 2000 and 2018. Search terms were developed for four major databases (PubMed, Scopus, Web of Science, and Embase) as well as gray literature and hand searches of review articles. We follow standard scoping review methodology and assessment. Out of 10,618 unique articles originally identified, 115 articles were included, representing 49 unique outcomes. The majority of studies were cohort designs (n = 67) and conducted in the United States or Europe (n = 98). Four major outcome groupings were death, neurological disorders, sepsis, and congenital infection. This study identifies substantial research on the common acute complications of L. monocytogenes and few long-term consequences of L. monocytogenes. We identify the need for additional studies to determine the longer term impacts of these acute complications.

Colchicine and macrolides: a cohort study of the risk of adverse outcomes associated with concomitant exposure.

Colchicine is increasingly used as the number of potential indications expands. However, it also has a narrow therapeutic index that is associated with bothersome to severe side effects. When concomitantly use with medications inhibiting its metabolism, higher plasma levels will result and increase likelihood of colchicine toxicity. We conducted a cohort study using electronic health records comparing encounters with colchicine plus a macrolide and colchicine with an antibiotic non-macrolide. We assessed the relationship between the two groups using adjusted multivariate logistic regression models and the risk of rhabdomyolysis, pancytopenia, muscular weakness, heart failure, acute hepatic failure and death. 12670 patients on colchicine plus an antibiotic non-macrolide were compared to 2199 patients exposed to colchicine plus a macrolide. Patients exposed to colchicine and a macrolide were majority men (n = 1329, 60.4%) and white (n = 1485, 67.5%) in their late sixties (mean age in years 68.4, SD 15.6). Heart failure was more frequent in the colchicine plus a macrolide cohort (n = 402, 18.3%) vs the colchicine non-macrolide one (n = 1153, 9.1%) (p < 0.0001) and also had a higher mortality rate [(85 (3.87%) vs 289 (2.28%), p < 0.0001 macrolides vs non-macrolides cohorts, respectively]. When the sample was limited to individuals exposed to either clarithromycin or erythromycin and colchicine, the adjusted OR for acute hepatic failure was 2.47 (95% CI 1.04-5.91) and 2.06 for death (95% CI 1.07-3.97). There is a significant increase in the risk of hepatic failure and mortality when colchicine is concomitantly administered with a macrolide. Colchicine should not be used concomitantly with these antibiotics or should be temporarily discontinued to avoid toxic levels of colchicine.