Fine-Gray Subdistribution Hazard Model Research Articles

Assessment of prognostic factors in patients with primary ocular adnexal lymphoma when considering competing risk elements.

Accurate prognostic factors for primary ocular adnexal lymphoma (POAL) are scarce. Survival models and prognostic factors derived without considering competing risk factors suffer from major statistical errors. This study aimed to accurately assess prognostic factors in POAL patients using competing risk models, and compare this to the traditional COX proportional hazards model. This retrospective study utilised data from the Surveillance, Epidemiology, and End Results (SEER) program 2010-2015 and included patients with B-cell POAL. The cumulative incidence function and Gray's test for cause-specific survival were calculated as univariate analysis. The competing risk models were a Fine-Gray subdistribution hazard model and a cause-specific model, and a traditional COX model was employed as a multivariate analysis. This study enrolled 846 eligible patients with POAL: 60 patients (7.09%) died from POAL and 123 patients (14.54%) died from other causes. Multivariate competing risk models indicated that age, laterality, histology subtype, the 7th edition of American Joint Committee on Cancer stage T, and radiotherapy were independent predictors for cause-specific survival of patients with POAL. There was high consistency between the two competing risk models. The COX model made several misestimations on the statistical significance and hazard ratios of prognostic factors. This study established competing risk models as a method to assess POAL prognostic factors, which was more accurate than traditional methods that do not consider competing risk elements.

The Effect of Temporal Persistence of Loneliness on Dementia: A Longitudinal Analysis From the Hunter Community Study.

Loneliness is common and becoming a public health concern. Although there is the clear evidence of the variable effect of temporal differences in loneliness (transient/situational and persistent/chronic) on health, their effect on dementia risk is unclear. This study aims to assess the effect of transient/situational and persistent/chronic loneliness on dementia risk. Participants aged 55years and older from the Hunter Community Study were recruited. Loneliness was measured using a single item measure. Dementia was defined as per International Classification of Disease-10 (ICD 10) codes. The Fine-Gray subdistribution hazard model was performed to calculate dementia risk. Of 1968 total participants with mean age of 66years, (3%) 57 developed dementia and (7%) 135 died over the mean follow up of 10years. Both persistent/chronic and transient/situational loneliness significantly increased the risk of all cause dementia in adjusted models (HR 2.74, 95% CI 1.11-6.88, p 0.03 and HR 2.35, 95% CI 1.21-4.55, p 0.01 respectively) with mean time to event of 9.7years. Feeling lonely below the age of 70years elevated the risk of dementia in later life (HR 4.01, 95% CI 1.40-11.50, p 0.01). Loneliness (both persistent/chronic and transient/situational) was associated with increased risk of all cause dementia, especially if loneliness was experienced before the age of 70years. These results suggest that promoting coping strategies for loneliness especially in persons 70years and younger may play a role in preventing dementia.

Scoring System to Predict Mid-term Adverse Events after Elective Thoracic Endovascular Aortic Repair

To develop and validate a scoring system to predict mid-term adverse events after elective thoracic endovascular aortic repair (TEVAR). A multi-center, retrospective, and observational cohort study. A total of 350 patients who underwent elective TEVAR for thoracic aortic disease between January 2008 and December 2021 were analyzed. The primary outcome was the first adverse event occurring within 5 years of the initial TEVAR, which included death during the initial hospitalization, perioperative neurological complication, stent graft-induced new entry, dissection, rupture, graft infection, and reintervention related to the initial TEVAR. The scoring system was developed using the regression coefficients of the Fine-Gray subdistribution hazard model. Its performance was evaluated using the area under the receiver operating characteristic curve (AUC) for competing risk analysis and internally validated by cross-validation. Eighty-two patients had at least one adverse event within 5 years of the initial TEVAR. The 5-year cumulative incidence of adverse events was 26% (95% confidence interval, 21-31). Female gender, comorbidity score, use of anticoagulants, preoperative aortic diameter at the diaphragm level, proximal oversizing ratio, aortic coverage length, and hybrid procedure were included in the scoring system. The AUC of the scoring system in the internal validation was 0.748 (standard error, 0.009). When the scoring system was validated in patients with intact thoracic aortic aneurysm only, the AUC was 0.780 (standard error, 0.012). Although external validation is mandatory, our scoring system may be useful for decision making, especially in patients with intact thoracic aortic aneurysm.

The effect of anxiety on all-cause dementia: A longitudinal analysis from the Hunter Community Study.

Anxiety is common, however, the effect of chronicity of anxiety on dementia has not been explored. This study aims to assess the longitudinal relationship between chronic versus resolved versus new onset anxiety, and all-cause dementia risk. A total of 2132 participants with mean age 76 years from the Hunter Community Study were recruited. Anxiety was measured using Kessler Psychological Distress Scale (K10). Dementia was defined as per International Classification of Disease-10 codes. The Fine-Gray subdistribution hazard model was computed to assess dementia risk, while adjusting for the competing risk of death. Chronic anxiety and new onset anxiety at follow-up were associated with all-cause dementia risk (HR 2.80, 95% CI 1.35-5.72 and HR 3.20, 95% CI 1.40-7.45 respectively) with an average time to dementia diagnosis of 10 years (SD = 1.7) whereas resolved anxiety was not. In subgroup analyses, these results were driven particularly by chronic and new anxiety among participants below the age of 70 years (HR 4.58, 95% CI 01.12-18.81 and HR 7.21, 95%CI 1.86-28.02 respectively). Sensitivity analyses imputing missing data and addressing reverse causation gave very similar results. Chronic and new anxiety were associated with increased risk of all-cause dementia, and this association was significant in those 70 years and younger. However, the resolved anxiety at follow-up reduced the risk, similar to that of the non-exposed group. These results suggest that timely management of anxiety may be a viable strategy in reducing the risk of dementia.

Cerebral Amyloid Angiopathy-Related Inflammation and Biopsy-Positive Primary Angiitis of the CNS: A Comparative Study.

Cerebral amyloid angiopathy-related inflammation (CAA-RI) and biopsy-positive primary angiitis of the CNS (BP-PACNS) have overlapping clinicoradiologic presentations. It is unknown whether clinical and radiologic features can differentiate CAA-RI from BP-PACNS and whether both diseases have different relapse rates. The objectives of this study were to compare clinicoradiologic presentations and relapse rates in patients with CAA-RI vs BP-PACNS. Patients with CAA-RI and BP-PACNS were enrolled from 2 retrospective multicenter cohorts. Patients with CAA-RI were biopsy-positive or met probable clinicoradiologic criteria. Patients with BP-PACNS had histopathologic confirmation of CNS angiitis, with no secondary etiology. A neuroradiologist read brain MRIs, blinded to the diagnosis of CAA-RI or BP-PACNS. Clinicoradiologic features were compared using univariable logistic regression models. Relapse rates were compared using a univariable Fine-Gray subdistribution hazard model, with death as a competing risk. This study enrolled 104 patients with CAA-RI (mean age 73 years, 48% female sex) and 52 patients with BP-PACNS (mean age 45 years, 48% female sex). Patients with CAA-RI more often had white matter hyperintense lesions meeting the probable CAA-RI criteria (93% vs 51%, p < 0.001), acute subarachnoid hemorrhage (15% vs 2%, p = 0.02), cortical superficial siderosis (27% vs 4%, p < 0.001), ≥1 lobar microbleed (94% vs 26%, p < 0.001), past intracerebral hemorrhage (17% vs 4%, p = 0.04), ≥21 visible centrum semiovale perivascular spaces (34% vs 4%, p < 0.01), and leptomeningeal enhancement (70% vs 27%, p < 0.001). Patients with BP-PACNS more often had headaches (56% vs 31%, p < 0.01), motor deficits (56% vs 36%, p = 0.02), and nonischemic parenchymal gadolinium enhancement (82% vs 16%, p < 0.001). The prevalence of acute ischemic lesions was 18% in CAA-RI and 22% in BP-PACNS (p = 0.57). The features with the highest specificity for CAA-RI were acute subarachnoid hemorrhage (98%), cortical superficial siderosis (96%), past intracerebral hemorrhage (96%), and ≥21 visible centrum semiovale perivascular spaces (96%). The probable CAA-RI criteria had a 71% sensitivity (95% CI 44%-90%) and 91% specificity (95% CI 79%-98%) in differentiating biopsy-positive CAA-RI from BP-PACNS. The rate of relapse in the first 2 years after remission was lower in CAA-RI than in BP-PACNS (hazard ratio 0.46, 95% CI 0.22-0.96, p = 0.04). Clinicoradiologic features differed between patients with CAA-RI and those with BP-PACNS. Specific markers for CAA-RI were hemorrhagic signs of subarachnoid involvement, past intracerebral hemorrhage, ≥21 visible centrum semiovale perivascular spaces, and the probable CAA-RI criteria. A biopsy remains necessary for diagnosis in some cases of CAA-RI. The rate of relapse in the first 2 years after disease remission was lower in CAA-RI than in BP-PACNS.

Impact of Hypertension Duration on the Cardiovascular Benefit of Intensive Blood Pressure Control.

The optimal timing for initiating intensive systolic blood pressure (SBP) treatment remains unclear. While longer hypertension duration is positively associated with increased cardiovascular disease risk, it is unknown whether patients with prolonged hypertension can derive similar benefits from intensive SBP treatment. From the STEP trial (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients), 8442 participants with complete hypertension duration data were categorized by hypertension duration ≤5 years, 5 to 10 years, 10 to 15 years, and >15 years. The primary outcome was a composite of cardiovascular events. Hazard ratios were calculated using the Fine-Gray subdistribution hazard model. The incidences of the primary outcome increased significantly in patients with hypertension over 15 years than those <5 years in the standard SBP treatment group (adjusted hazard ratios, 1.68 [95% CI, 1.11-2.56]) but not in the intensive treatment group. Each 1-year increase in hypertension duration continuously increased the adjusted risk of major cardiovascular events by 4% (95% CI, 1.01-1.08) up to 20 years, plateauing at an adjusted hazard ratio of 2.27 (95% CI, 1.28-4.04). After intensive SBP treatment, the incidences of major cardiovascular events were similar across different hypertension duration groups, which were 2.22%, 1.69%, 3.02%, and 2.52%, respectively (P>0.05). Subgroup analyses indicated a potential sex difference in this relationship between hypertension duration and the primary outcome in the standard SBP treatment group (Pinteraction=0.05). Initiating intensive SBP treatment at any stage of hypertension duration could reduce cardiovascular disease risk to a comparable level. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311.

Why you should avoid using multiple Fine–Gray models: insights from (attempts at) simulating proportional subdistribution hazards data

Abstract Studies considering competing risks will often aim to estimate the cumulative incidence functions conditional on an individual’s baseline characteristics. While the Fine–Gray subdistribution hazard model is tailor-made for analysing only one of the competing events, it may still be used in settings where multiple competing events are of scientific interest, where it is specified for each cause in turn. In this work, we provide an overview of data-generating mechanisms where proportional subdistribution hazards hold for at least one cause. We use these to motivate why the use of multiple Fine–Gray models should be avoided in favour of better alternatives such as cause-specific hazard models.

End-Stage Kidney Disease After Partial and Radical Nephrectomy Among Patients With Severe Chronic Kidney Disease.

AUA guidelines prioritize nephron sparing in patients with preexisting chronic kidney disease (CKD). However, few studies analyze long-term renal function in patients with preoperative severe CKD who undergo extirpative renal surgery. Herein, we compare the hazard of progression to end-stage kidney disease (ESKD) following partial nephrectomy (PN) and radical nephrectomy (RN) among patients with preoperative severe CKD. Patients with stage 4 CKD who underwent PN or RN from 1970 to 2018 were identified. A multivariable Fine-Gray subdistribution hazard model was employed to assess associations with progression to ESKD accounting for the competing risk of death. A total of 186 patients with stage 4 CKD underwent PN (n = 71; 38%) or RN (n = 115; 62%) for renal neoplasms with median follow-up of 6.9 years (interquartile range 3.8-14.1). On multivariable analyses adjusting for competing risk of death, the subdistribution hazard ratio (SHR) for older age at surgery (SHR for 5-year increase 0.81; 95% CI 0.73-0.91; P < .001) and higher preoperative estimated glomerular filtration rate (SHR for 5-unit increase 0.63; 95% CI 0.47-0.84; P = .002) was associated with lower hazard of progression to ESKD. There was no significant difference in hazard of ESKD between PN and RN (SHR 0.82; 95% CI 0.50-1.33; P = .4). Among patients with preoperative severe CKD, higher preoperative estimated glomerular filtration rate was associated with lower hazard of progression to ESKD after extirpative surgery for renal neoplasms. We did not observe a significant difference in overall hazard for developing ESKD between PN and RN.

Survival analysis for patients with metachronous contralateral breast cancer: Insights from a retrospective study.

Continued advances in the diagnosis and treatment of breast cancer (BC) have led to an increase in the number of long-term BC survivors and an increase in the incidence of metachronous BC in the contralateral breast. Therefore, it is important to understand the factors that influence the development of metachronous BC; however, the impact of the laterality of the initial ipsilateral (I)BC as a risk factor for the development of metachronous contralateral (MC)BC has not been extensively investigated. The present study included 17,082 female patients with stage 0-3 IBC from the prospectively maintained Korean Breast Cancer Registry from 1989-2013 and divided them into two groups: Patients with MCBC (n=88) and those without MCBC (n=16,994). Risk factors that present at the initial BC diagnosis that could significantly influence the development of MCBC were screened for and risks were evaluated using the Fine-Gray subdistribution hazard model. Significant differences in baseline characteristics between MCBC and non-MCBC groups were demonstrated. Patients aged <40 years, those with histological and nuclear grade 3 tumors, and those with the triple-negative BC subtype were significantly more prevalent in the MCBC group than in the non-MCBC group. Additionally, the cumulative incidence of MCBC increased over time, with a notable increase from 0.1% in year 1 to 1.6% in year 10. Survival analysis revealed no significant differences in overall or BC-specific survival between the two groups. Key predictive factors identified for MCBC included an age of <40 years at initial diagnosis, a negative progesterone receptor status, and a Ki-67 score of >14%. Overall, the present study revealed several factors associated with MCBC and emphasized the need for long-term monitoring of BC survivors, considering these newly identified risk factors.

Kidney transplantation in patients with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a disorder of the mammalian target of the rapamycin (mTOR) pathway associated with the development of multisystem tumors, including renal angiomyolipoma (AML). These renal tumors are benign by nature but locally invasive and carry a risk for the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). The frequency of subsequent renal transplantation in this population is largely uncharacterized, although single-center data suggests that 5%-15% of adult TSC patients are kidney transplant recipients. This retrospective cohort study utilized United Network for Organ Sharing (UNOS) data. We included candidates waitlisted between 1987 and 2020 for a first kidney transplant with TSC-associated kidney failure. We utilized descriptive statistics to characterize the frequency of first-time kidney transplant waitlisting and transplantation among persons with TSC and the Fine-Gray subdistribution hazard model to evaluate characteristics associated with progression from waitlist. We identified 200 TSC-associated kidney failure patients within the waitlist cohort. Of these, 12 were pediatric patients. Two-thirds (N = 134) of waitlisted persons were female. One hundred forty patients received a transplant with a median waitlist time of 2 years. Younger age at waitlisting was associated with a greater probability of progressing to transplant (HR 0.98 [95% CI: 0.96-0.99]). 91.8% of kidney transplant recipients survived 1-year post-transplant with a functioning allograft. The majority of patients with TSC who are waitlisted for a kidney transplant progress onto transplantation with excellent 1-year post transplant patient and allograft survival.

Development of a risk prediction model for subsequent infection after colonization with carbapenem-resistant Enterobacterales: a retrospective cohort study

BackgroundColonization of carbapenem-resistant Enterobacterale (CRE) is considered as one of vital preconditions for infection, with corresponding high morbidity and mortality. It is important to construct a reliable prediction model for those CRE carriers with high risk of infection.MethodsA retrospective cohort study was conducted in two Chinese tertiary hospitals for patients with CRE colonization from 2011 to 2021. Univariable analysis and the Fine-Gray sub-distribution hazard model were utilized to identify potential predictors for CRE-colonized infection, while death was the competing event. A nomogram was established to predict 30-day and 60-day risk of CRE-colonized infection.Results879 eligible patients were enrolled in our study and divided into training (n = 761) and validation (n = 118) group, respectively. There were 196 (25.8%) patients suffered from subsequent CRE infection. The median duration of subsequent infection after identification of CRE colonization was 20 (interquartile range [IQR], 14–32) days. Multisite colonization, polymicrobial colonization, catheterization and receiving albumin after colonization, concomitant respiratory diseases, receiving carbapenems and antimicrobial combination therapy before CRE colonization within 90 days were included in final model. Model discrimination and calibration were acceptable for predicting the probability of 60-day CRE-colonized infection in both training (area under the curve [AUC], 74.7) and validation dataset (AUC, 81.1). Decision-curve analysis revealed a significantly better net benefit in current model. Our prediction model is freely available online at https://ken-zheng.shinyapps.io/PredictingModelofCREcolonizedInfection/.ConclusionsOur nomogram has a good predictive performance and could contribute to early identification of CRE carriers with a high-risk of subsequent infection, although external validation would be required.

Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Risk of depression and anxiety in 7.302 patients with sarcoidosis: a nationwide cohort study.

The aim was to investigate the association between sarcoidosis and anxiety and/or depression (A/D) in patients with sarcoidosis and comparators matched on age, gender, residency, and cohabitation status. Patients with newly diagnosed sarcoidosis between 2001 and 2015 were identified in the Danish National Patient Register. Cases were matched 1:4 with non-sarcoidosis comparators. We estimated the cumulative incidence of A/D using the Cumulative Incidence Function and the subdistribution hazard ratio (sHR) for A/D using the Fine-Gray subdistribution hazard model. Estimates were adjusted for socio-economic status and Deyo-Charlson Comorbidity Index. We identified 7.302 cases and 26.145 matched comparators. The cumulative incidence of A/D after five years was 6.0% (95%CI 5.5-6.4) for cases and 4.2% (95%CI 4.0-4.4) for matched comparators. The cumulative incidence was higher among cases for both males and females and in all age-groups compared with the matched comparators. The adjusted-sHR for A/D was 1.38 (95%CI 1.24-1.53). The adjusted-sHR for A/D was 1.51 (95%CI 1.30-1.75) for male cases and 1.25 (95%CI 1.08-1.45) for female cases compared with the matched comparators. The adjusted-sHR for A/D was higher for cases in all age-groups compared with the matched comparators, although not statistically significant among cases aged 30-39 years (a-sHR 1.15; 95%CI 0.92-1.44). Sarcoidosis cases had a higher risk of A/D compared with matched comparators during 18 years of follow-up. The risk of developing A/D was greater for male and female cases and within all age-groups compared with the matched comparators.

Pretherapeutic factors predicting conversion surgery in unresectable pancreatic ductal adenocarcinoma: A retrospective study.

Recently, conversion surgery (CS) has been reported to improve the prognosis in patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC) with a favorable response to intense chemotherapy or chemoradiotherapy. However, few pretherapeutic parameters predict the attainability of CS in patients with UR-PDAC. The present study aimed to explore the pretherapeutic predictors for the attainability of CS in patients with UR-PDAC. The present study retrospectively evaluated 130 patients with UR-PDAC treated at Gifu University Hospital (Gifu, Japan) from January 2015 to December 2021. Survival analysis was performed using the Simon and Makuch-modified Kaplan-Meier method. The hazard ratio (HR) was estimated using a time-varying Cox regression model. The association between each predictor and CS was evaluated using the univariate analysis and age-adjusted Fine-Gray sub-distribution hazard model. The bootstrap bias-corrected area under the receiver operating characteristic curve analysis for predicting CS was used to assess the cut-off values for each predictor. The cumulative incidence rate was calculated with CS as the outcome when divided into two groups based on the cut-off value of each pretherapeutic predictor. Among the 130 patients included in the analysis, only 14 (11%) underwent CS. The median survival time was significantly longer in patients who underwent CS compared with patients without CS (56.3 vs. 14.1 months; P<0.001). The age-adjusted Fine-Gray sub-distribution hazard regression showed that the total protein (TP) [HR 2.81, 95% confidence interval (CI) 1.19-6.65; P=0.018], neutrophil-to-lymphocyte ratio (NLR) (HR 0.53, 95% CI 0.31-0.90; P=0.020), and lymphocyte-to-monocyte ratio (LMR) (HR 1.28, 95% CI 1.07-1.53; P=0.006) were significantly associated with CS. Moreover, TP ≥6.8, NLR <2.84 and LMR ≥3.87 were associated with a higher cumulative incidence of CS. In conclusion, pretherapeutic TP, NLR and LMR are clinically feasible biomarkers for predicting the attainability of CS in patients with UR-PDAC.

Risk Factors Associated with Major Adverse Cardiovascular Events after Ischemic Stroke: A Linked Registry Study

Introduction: Survivors of stroke are at risk of experiencing subsequent major adverse cardiovascular events (MACE). We aimed to determine the incidence of, and risk factors for, MACE after first-ever ischemic stroke, by age group (18–64 years vs. ≥65 years). Methods: Observational cohort study using patient-level data from the Australian Stroke Clinical Registry (2009–2013), linked with hospital administrative data. We included adults with first-ever ischemic stroke who had no previous acute cardiovascular admissions and followed these patients for 2 years post-discharge, or until the first post-stroke MACE event. A Fine-Gray sub-distribution hazard model, accounting for the competing risk of non-cardiovascular death, was used to determine factors for incident post-stroke MACE. Results: Among 5,994 patients with a first-ever ischemic stroke (median age 73 years, 45% female), 17% were admitted for MACE within 2 years (129 events per 1,000 person-years). The median time to first post-stroke MACE was 117 days (89 days if aged <65 years vs. 126 days if aged ≥65 years; p = 0.025). Among patients aged 18–64 years, receiving intravenous thrombolysis (sub-distribution hazard ratio [SHR] 0.51 [95% CI, 0.28–0.92]) or being discharged to inpatient rehabilitation (SHR 0.65 [95% CI, 0.46–0.92]) were associated with a reduced incidence of post-stroke MACE. In those aged ≥65 years, being unable to walk on admission (SHR 1.33 [95% CI 1.15–1.54]), and history of smoking (SHR 1.40 [95% CI 1.14–1.71]) or atrial fibrillation (SHR 1.31 [95% CI 1.14–1.51]) were associated with an increased incidence of post-stroke MACE. Acute management in a large hospital (>300 beds) for the initial stroke event was associated with reduced incidence of post-stroke MACE, irrespective of age group. Conclusions: MACE is common within 2 years of stroke, with most events occurring within the first year. We have identified important factors to consider when designing interventions to prevent MACE after stroke, particularly among those aged <65 years.

Racial Differences in the Association of Glucagon-like Peptide 1 Agonist Use and the Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma in US Veterans with Diabetes Mellitus

Background: Glucagon-like peptide 1 (GLP-1) agonists are antidiabetic medications that exert cardiac and renal benefits in addition to their well-established antihyperglycemic effects. A prior analysis has shown that GLP-1 agonist use is associated with a 65% reduction in the risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) in US Veterans with diabetes mellitus (DM). However, it is unknown whether there are racial differences to this effect of GLP-1 agonists. We aimed to assess the racial differences in the association between GLP-1 agonist use and the progression risk in diabetic patients with MGUS. Methods: Patients diagnosed with MGUS in the Veterans Health Administration (VHA) database from 10/1/99-12/31/21 were identified using ICD codes. A natural language processing algorithm was used to confirm MGUS diagnosis and progression to smoldering MM or MM. Patients diagnosed with MGUS before DM and those who experienced progression within 1 year of MGUS diagnosis or within 2 years of DM diagnosis were excluded. For each race, we performed 1:2 matching for patients with and without GLP-1 agonist use based on follow-up time. The outcome was progression to smoldering MM or MM. Cumulative incidence functions stratified by GLP-1 agonist use (ever vs. never use) were plotted and a Gray's test was performed to detect the difference between the functions. The association between time-varying GLP-1 agonist use and MGUS progression was estimated using a multivariable Fine-Gray subdistribution hazard model with death as a competing event. Results: Our NLP algorithm confirmed 20,832 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 9,294 white patients and 4,981 black patients, of which 909 and 403, respectively, were GLP-1 agonist users. After matching, our analytic cohort included 2,718 white patients (33.3% with GLP-1 agonist use) and 1,191 black patients (33.3% with GLP-1 agonist use). GLP-1 agonist use was associated with a dramatically significant reduction in progression rate in white patients (aHR 0.25; 95% CI 0.09-0.68), while the association was not shown in black patients (aHR 1.01; 95% CI 0.36-2.90). Conclusion: For patients with MGUS and DM, GLP-1 agonist use is associated with a 75% reduction in progression risk in white patients and no significant reduction in black patients. This highlights a racial disparity in the potential role of GLP-1 agonist for chemoprevention in the management of MGUS.

Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease.

Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL·min-1·1.73 m-2). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.

The association of major adverse limb events and combination stent and atherectomy in patients undergoing revascularization for lower extremity peripheral artery disease.

The effectiveness of combined atherectomy and stenting relative to use of each procedure alone for the treatment of lower extremity peripheral artery disease has not been evaluated. The objective of this study was to evaluate the short- and long-term major adverse limb event (MALE) following the receipt of stenting, atherectomy, and the combination of stent and atherectomy. A retrospective cohort of patients undergoing atherectomy, stent, and combination stent atherectomy for lower extremity peripheral artery disease was derived from the Vascular Quality Initiative (VQI) data set. The primary outcome was MALE and was assessed in the short-term and long-term. Short-term MALE was assessed immediately following the procedure to discharge and estimated using logistic regression. Long-term MALE was assessed after discharge to end of follow-up and estimated using the Fine-Gray subdistribution hazard model. Among the 46,108 included patients, 6896 (14.95%) underwent atherectomy alone, 35,774 (77.59%) received a stent, and 3438 (7.5%) underwent a combination of stenting and atherectomy. The adjusted model indicated a significantly higher odds of short-term MALE in the atherectomy group (OR = 1.35; 95% confidence interval [CI]:1.16-1.57), and not significantly different odds (OR = 0.93; 95%CI:0.77-1.13) in the combination stent and atherectomy group when compared to stenting alone. With regard to long-term MALE, the model indicated that the likelihood of experiencing the outcome was slightly lower (HR = 0.90;95%CI:0.82-0.98) in the atherectomy group, and not significantly different (HR = 0.92; 95%CI:0.82-1.04) in the combination stent and atherectomy group when compared to the stent group. Patients in the VQI data set who received combination stenting and atherectomy did not experience significantly different rates of MALE when compared with stenting alone. It is crucial to consider and further evaluate the influence of anatomical characteristics on treatment strategies and potential differential effects of comorbidities and other demographic factors on the short and long-term MALE risks.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6months (6M) after RAM initiation were compared between the two groups. We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28days, 28-55days, and > 55days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). Sequential FOLFIRI plus RAM after BEV failure, especially within 55days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Effect of Helicobacter pylori Eradication Therapy on the Incidence of Noncardia Gastric Adenocarcinoma in a Large Diverse Population in the United States

High-quality data regarding the effect of Helicobacter pylori eradication on the risk of noncardia gastric adenocarcinoma (NCGA) remain limited in the United States. We investigated the incidence of NCGA after H pylori eradication therapy in a large, community-based US population. We performed a retrospective cohort study of Kaiser Permanente Northern California members who underwent testing and/or treatment for H pylori between 1997 and 2015 and were followed through December 31, 2018. The risk of NCGA was evaluated using the Fine-Gray subdistribution hazard model and standardized incidence ratios. Among 716,567 individuals with a history of H pylori testing and/or treatment, the adjusted subdistribution hazard ratios and 95% confidence intervals of NCGA for H pylori-positive/untreated and H pylori-positive/treated individuals were 6.07 (4.20-8.76) and 2.68 (1.86-3.86), respectively, compared with H pylori-negative individuals. When compared directly with H pylori-positive/untreated individuals, subdistribution hazard ratios for NCGA in H pylori-positive/treated were 0.95 (0.47-1.92) at <8 years and 0.37 (0.14-0.97) ≥8 years of follow-up. Compared with the Kaiser Permanente Northern California general population, standardized incidence ratios (95% confidence interval) of NCGA steadily decreased after H pylori treatment: 2.00 (1.79-2.24) ≥1 year, 1.01 (0.85-1.19) ≥4 years, 0.68 (0.54-0.85) ≥7 years, and 0.51 (0.38-0.68) ≥10 years. In a large, diverse, community-based population, H pylori eradication therapy was associated with a significantly reduced incidence of NCGA after 8 years compared with no treatment. The risk among treated individuals became lower than the general population after 7 to 10 years of follow-up. The findings support the potential for substantial gastric cancer prevention in the United States through H pylori eradication.