Effectiveness and safety of anticoagulants among patients with venous thromboembolism and active cancer who also had prior bleed or prior renal disease.

OBJECTIVE: Patients with active cancer and venous thromboembolism (VTE) have elevated risk of recurrent VTE (rVTE) and major bleeding (MB). The risk is even higher within those with a prior bleeding event or renal disease. There is a need to understand the risk of rVTE and MB of commonly used anticoagulants among these high-risk patients. METHODS: VTE patients with active cancer and treated with apixaban, warfarin, or low molecular weight heparin (LMWH) within 30 days of VTE were identified from five claims databases in the United States. Inverse probability of treatment weighting (IPTW) was used to balance patient characteristics. The post-IPTW population was stratified by prior bleed or renal disease status. Cox proportional hazards models were used to evaluate interactions between treatment and prior bleed or renal disease on risk of rVTE and MB, with p value <.1 considered significant. RESULTS: Study criteria were met by 30,586 VTE cancer patients: 35.0% had prior bleed and 29.0% had renal disease. For apixaban, LMWH, and warfarin cohorts, the incidence (events per 100 person-years) of MB was higher in patients with prior bleed (17.48 vs 7.58, 25.61 vs 13.11, and 20.38 vs 8.97) or renal disease (15.79 vs 8.71, 22.11 vs 15.90, and 18.49 vs 10.39) vs those without the conditions. Generally, there were no significant interactions between anticoagulant use and prior bleed or renal disease on rVTE and MB (p for interaction >.1). CONCLUSION: The incidence of MB was higher among those with prior bleed or renal disease. Effects of apixaban, warfarin, or LMWH were generally consistent regardless of prior bleed or renal disease status.

Effectiveness and safety of anticoagulants among patients with venous thromboembolism and common cancers or cancers with high venous thromboembolism risk.

Aim: Treatment effects among anticoagulant-treated patients with venous thromboembolism (VTE) and cancer across tumor types were evaluated. Methods: Patients initiating an anticoagulant within 30 days after VTE were identified. After inverse probability treatment weighting, patients were stratified by tumor type. Interactions between treatment and tumor type on recurrent VTE, major bleeding and clinically relevant non-major bleeding were assessed using Cox proportional hazard models. Results: Treatment effects were generally not significantly different among patients with or without the following cancer types: prostate, breast, lung, pancreatic or multiple myeloma. Few significant interactions were observed for lung and pancreatic cancer. Conclusion: Anticoagulant treatment effects were generally consistent across tumor types. The significant interactions may indicate tumor-specific effects of anticoagulants, but further research is needed.

Estimating the Population Newly Eligible for the Pneumococcal Conjugate Vaccine.

INTRODUCTION: Recommendations for adult pneumococcal vaccination in the U.S. were revised in 2022 after the introduction of 15- and 20-valent pneumococcal conjugate vaccines (PCV15 and PCV20) to call for routine PCV use among immunocompetent adults with risk conditions aged 19-64 years. The present study estimated the size of this newly recommended population. METHODS: A retrospective cohort study was conducted using the Optum de-identified electronic health record (EHR) dataset. Patients who were active in the EHR between January 2016 and June 2021 and had ≥1 condition included in the current pneumococcal recommendation without an immunocompromising condition were included. Data were weighted to account for potential differences between the EHR and U.S. POPULATION: Data analyses were conducted in 2022. RESULTS: Of 45.6 million adults aged 19-64 years in the database, 12.5 million met inclusion criteria and had ≥1 qualifying condition, primarily smoking, with chronic lung disease/asthma and/or diabetes also common. After weighting, the U.S. population aged 19-64 years newly eligible for PCVs was approximately 56 million. CONCLUSIONS: Approximately one in four U.S. adults aged <65 years is now recommended to receive PCV15 or PCV20, which highlights the need for providers to assess vaccination status, administer the vaccine, or refer patients as appropriate, as well as the need for tools to facilitate patient identification and vaccination.

Effectiveness and safety of anticoagulants among venous thromboembolism cancer patients with and without brain cancer.

INTRODUCTION: Patients with brain cancer are at a high risk of developing venous thromboembolism (VTE) and are underrepresented in clinical trials. This study compared the risk of recurrent VTE (rVTE), major bleeding (MB), and clinically relevant non-major bleeding (CRNMB) among VTE cancer patients initiating apixaban, low molecular weight heparin (LMWH), or warfarin stratified by patients with brain vs other cancer types. MATERIALS AND METHODS: Active cancer patients initiating apixaban, LMWH, or warfarin within 30 days after VTE diagnosis were identified from 4 US commercial and the Medicare databases. Inverse probability of treatment weights (IPTW) was used to balance patient characteristics. Cox proportional hazards models were used to evaluate the interaction between brain cancer status and treatment on outcomes (rVTE, MB, and CRNMB), with a p-value <0.1 indicating a significant interaction. RESULTS: Of 30,586 patients with active cancer (5 % had brain cancer), apixaban (vs. LMWH and warfarin) was associated with lower risk of rVTE, MB, and CRNMB. Generally, no significant interactions (P > 0.1) were found between brain cancer status and anticoagulant treatment across outcomes. The exception was MB for apixaban [vs LMWH (p-value for interaction = 0.091)] with a higher reduction among those with brain cancer (HR = 0.32) than those with (HR = 0.72) other cancer. CONCLUSIONS: Among VTE patients with all types of cancer, apixaban (vs LMWH and warfarin) was associated with a lower risk of rVTE, MB, and CRNMB. In general, anticoagulant treatment effects were not significantly different between VTE patients with brain cancer and those with other cancer.

Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network.

This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.6% of patients had de novo A/MBC at initial breast cancer diagnosis, 50.8% had bone-only disease, and 32.2% had visceral disease. Median follow-up was 22.4 months. Disease progression (26.4%) and intolerance/toxicity (14.9%) were the main reasons for treatment discontinuation. The median (95% CI) real-world progression-free survival was 31.7 (27.9-not estimable (NE)) months and 2-year estimated overall survival (OS) rate was 78.0%. In total, 25.6% of patients died; however, OS data are limited by the small population size and insufficient follow-up time. These real-world effectiveness outcomes complement findings from other real-world studies and randomized controlled trials and support palbociclib plus an aromatase inhibitor as first-line therapy for HR+/HER2- A/MBC.

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits.

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

Absence of association of a single-nucleotide polymorphism in the TERT-CLPTM1L locus with age-related phenotypes in a large multicohort study: the HALCyon programme.

Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other aging traits such as physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from nine UK cohorts were genotyped for the single-nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses. No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score = 0.02, 95% CI: -0.01 to 0.04, P-value = 0.12, n = 18,737), physical performance tests (e.g. pooled beta for grip strength = -0.02, 95% CI: -0.045 to 0.006, P-value = 0.14, n = 11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment. The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multicohort study suggests that while this SNP may be associated with cancer, it is not an important contributor to other markers of aging.