Hazard Ratio Estimates Research Articles

Communication-efficient federated learning of temporal effects on opioid use disorder with data from distributed research networks.

To develop a distributed algorithm to fit multi-center Cox regression models with time-varying coefficients to facilitate privacy-preserving data integration across multiple health systems. The Cox model with time-varying coefficients relaxes the proportional hazards assumption of the usual Cox model and is particularly useful to model time-to-event outcomes. We proposed a One-shot Distributed Algorithm to fit multi-center Cox regression models with Time varying coefficients (ODACT). This algorithm constructed a surrogate likelihood function to approximate the Cox partial likelihood function, using patient-level data from a lead site and aggregated data from other sites. The performance of ODACT was demonstrated by simulation and a real-world study of opioid use disorder (OUD) using decentralized data from a large clinical research network across 5 sites with 69163 subjects. The ODACT method precisely estimated the time-varying effects over time. In the simulation study, ODACT always achieved estimation close to that of the pooled analysis, while the meta-estimator showed considerable amount of bias. In the OUD study, the bias of the estimated hazard ratios by ODACT are smaller than those of the meta-estimator for all 7 risk factors at almost all of the time points from 0 to 2.5 years. The greatest bias of the meta-estimator was for the effects of age ≥65 years, and smoking. ODACT is a privacy-preserving and communication-efficient method for analyzing multi-center time-to-event data which allows the covariates' effects to be time-varying. ODACT provides estimates close to the pooled estimator and substantially outperforms the meta-analysis estimator. The proposed ODACT is a privacy-preserving distributed algorithm for fitting Cox models with time-varying coefficients. The limitations of ODACT include that privacy-preserving via aggregate data does rely on relatively large number of data at each individual site, and rigorous quantification of the risk of privacy leaks requires further investigation.

P0248 Insomnia as a determinant of poor IBD disease course

Abstract Background Insomnia is one of the most common sleep disorders, affecting up to 30% of the adult population worldwide. Sleep disorders can have a marked impact on immune functions and inflammation, including in patients with inflammatory bowel diseases (IBD) in both active and inactive disease states. Whether insomnia preceding IBD flares affects clinical outcomes is unknown. We examined the association between insomnia and IBD-related outcomes in adults diagnosed with of Crohn’s disease (CD) or ulcerative colitis (UC). Methods A retrospective, real-world, cohort study utilizing the Lynx MD’s electronic medical record dataset, provided by a US-based community gastroenterology practice. Deidentified patient charts were analyzed to identify patients with a confirmed diagnosis of IBD (either CD or UC). Eligibility criteria included: ≥3 diagnoses of IBD, ≥1 diagnoses of IBD and: histopathologic diagnosis of IBD; or IBD related surgery; or ≥ 3 months of treatment with standard accepted therapies for IBD; and ≥3 years of follow-up. IBD-related events of hospitalization and/or surgery were recorded. The cohort was classified into two groups based on insomnia diagnosis, prior to IBD related hospitalizations or surgeries. We implemented Cox Proportional Regression models to estimate Hazard Ratios for the IBD-related outcomes. Results Among 20,011 patients with IBD, 10,775 (54%) were women, at a mean age of 48.2 ± 18.2 years old, 11,842 (59%) were diagnosed with UC and 8,169 (41%) with CD. Over 3,100 patients (16%) were diagnosed with insomnia prior to the first IBD related hospitalization or surgery. In an unadjusted model, insomnia was significantly associated with IBD-related hospitalizations - hazard ratio (HR) of 1.43 (95% CI 1.28, 1.59) and IBD related surgeries - HR of 1.42 (95% CI 1.12, 1.81). After adjustment for age, sex, race, body mass index, anxiety and type of IBD (CD vs. UC), IBD-affected patients with insomnia had a higher HR of hospitalization and surgery: HR of 1.35 (95% CI 1.2,1.51) and 1.29 (95% CI 1.01,1.66), respectively, compared to those without insomnia. Conclusion In a large real-life dataset of patients with IBD, we found higher rates of IBD-related hospitalizations and surgeries among patients with comorbid insomnia, suggesting that insomnia may be associated with a more severe course of IBD.

P0982 Efficacy of upadacitinib in patients with Crohn’s disease and an ostomy: A matched retrospective real-world cohort analysis

Abstract Background Upadacitinib (UPA) is an oral selective Janus kinase inhibitor approved for the management of moderate-to-severe Crohn’s disease (CD). One in ten CD patients may need a permanent ostomy (colostomy or ileostomy) during their disease course, and this may impact the efficacy of UPA, given its extended-release formulation. However, there is no data available in this population since patients with an ostomy are excluded from registrational CD trials. This study addresses this gap by comparing the real-world clinical effectiveness of UPA in CD patients with and without ostomy. Methods This retrospective cohort study analyzed data from the TriNetX US Collaborative Network of sixty-eight tertiary institutions, to examine adult (≥18 years) CD patients treated with UPA from May 19th, 2023 (FDA approval date) to October 31st, 2024. Patients were categorized based on presence or absence of an ostomy during the previous 5 years, after exclusion of patients with rheumatologic disease indications for UPA usage. A 1:1 propensity score matching (PSM) was performed to balance cohorts on demographics, baseline comorbidities, and CD severity indicators (CD phenotype, extraintestinal manifestations, concurrent corticosteroid and other biologics usage, hemoglobin, and body weight). Cox proportional hazards model estimated hazard ratios (HRs) in matched cohorts for clinical effectiveness as a composite outcome (corticosteroid use, hospitalizations, emergency room visits) and secondary individual outcomes, at one year post-treatment, with a significance threshold set at p < 0.05. Results The study sample of CD patients on UPA included 170 with and 1,428 without a prior ostomy. There were 144 patients in each cohort after PSM. Baseline characteristics of the cohorts are shown in Figure 1. After PSM (Figure 2), there were no significant differences between patients with CD on UPA, with and without prior ostomy, for composite outcomes (HR 0.93, p = 0.64), corticosteroid use (HR 0.78, p = 0.18), hospitalizations (HR 1.13, p = 0.64), or emergency room visits (HR 0.99, p = 0.97). Additionally, no significant differences were observed in opioid use (HR 0.95, p = 0.76), switch to another advanced therapy (HR 1.62, p = 0.06), or elevated biomarkers, including CRP (>10 mg/L, HR 1.00, p = 0.99) and fecal calprotectin (>150 µg/g, HR 0.85, p = 0.63) at the 1-year follow-up. Conclusion In CD patients, UPA demonstrated similar effectiveness for clinical outcomes of corticosteroid use, hospitalizations, emergency room visits and other secondary outcomes, regardless of their ostomy status.

Moderate full-fat and low-fat yoghurt consumption correlates with reduced mortality risk: a large-scale prospective analysis.

Yoghurt is a commonly consumed fermented food recommended by many guidelines. Yoghurt consumption can contribute to the intake of multiple nutrients and reduce the risk of several diseases. However, prospective evidence is limited on the associations between full/low-fat yoghurt consumption and mortality risk. In this prospective cohort study, we aimed to assess the dose-dependent associations between full/low-fat yoghurt intake and all-cause or cause-specific mortality. We enrolled 186 168 participants from the UK Biobank who had joined the study between 2006 and 2010 and were followed up until 2022. We obtained data on self-reported intake of full/low-fat yoghurt and mortality from all causes and specific causes of death, including cancers and cardiovascular diseases (CVDs). We then used Cox proportional hazard models to calculate the hazard ratio (HR) and 95% confidence interval (CI) to evaluate the associations between full-fat and low-fat yoghurt intake and mortality. Lastly, we conducted subgroup and sensitivity analyses to examine the robustness of our findings. A total of 9402 deaths occurred during a mean follow-up of 13.4 years, including 1687 CVD-related and 5073 cancer-related deaths. Relative to non-consumers, the HRs (95% CIs) for all-cause mortality risk in participants consuming >0-50, 50-100, and >100 g of full-fat yoghurt a day were 0.82 (95% CI = 0.72, 0.93), 0.97 (95% CI = 0.86, 1.09), and 0.96 (95% CI = 0.84, 1.1) respectively. The corresponding HR estimates relative to non-consumers for participants consuming low-fat yoghurt were 0.88 (95% CI = 0.81, 0.95), 0.91 (95% CI = 0.85, 0.98), and 0.95 (95% CI = 0.89, 1.01), respectively. Subgroup analysis indicated women who had moderate consumption of full-fat yoghurt had lower all-cause mortality risk, while men consuming low-fat yoghurt had lower all-cause mortality risk. Moderate consumption of full-fat and low-fat yoghurt was correlated with decreased all-cause mortality. Future cohort studies are warranted to verify the potential of adopting yoghurt consumption as part of a healthy diet to reduce mortality.

Childhood vaccinations and the risk of leukemia: A nationwide cohort study.

A protective effect of childhood vaccinations on leukemia risk, particularly acute lymphoblastic leukemia (ALL), has been hypothesized, though findings are inconsistent. We used a nationwide cohort of Danish children born 1997-2018 (n = 1,360,230), to examine associations between childhood vaccinations and leukemia (<20 years) using registry data (follow-up: December 31, 2018). Cox proportional hazard models with age as the underlying time estimated hazard ratios (HRs) for leukemia (any, ALL, acute myeloid [AML], and other), comparing vaccinated with unvaccinated children. We also accessed the effect of each additional vaccine dose. During 14,536,819 person-years, 771 children were diagnosed with leukemia (74% ALL, 16% AML, and 10% other). Any vaccination was associated with an increased HR for ALL (HR: 2.76; 95% CI: 0.66-11.58), compared to unvaccinated children, with a change in HR of 1.01 (95% CI: 0.96-1.05) per dose. The corresponding HRs for any leukemia, AML, and other leukemia were 1.04 (95% CI: 0.50-2.17), 0.67 (95% CI: 0.18-2.59) and 0.29 (95% CI: 0.09-0.99), with a change in HR of 0.97 (95% CI: 0.94-1.02), 0.92 (95% CI: 0.84-1.00, p = .062) and 0.88 (95% CI: 0.78-1.00, p = .044) per dose. No significant associations were found for vaccination types, except for the pneumococcal vaccine which was associated with a decreased risk of other leukemia (HR: 0.32; 95% CI: 0.14-0.74). In six-months lag analyses, no significant associations were observed, and decreased risks were attenuated. The results provide no strong evidence that childhood vaccinations reduce leukemia risk. The limited number of unvaccinated cases and wide confidence intervals suggest cautious interpretation of some findings.

Types of dietary sugars and carbohydrates, cardiometabolic risk factors, and risk of diabetes: a cohort study from the general Danish population

BackgroundThe role of carbohydrates in diabetes risk is of particular interest due to conflicting results. This study aims to examine the prospective association between types of dietary carbohydrates (fiber, starch, total sugar, glucose, fructose, lactose, maltose, and added sugar) and the risk of diabetes. Further, this study examines the cross-sectional associations between these nutrients and cardiometabolic risk factors.MethodsDanish Health Examination Survey (2007–2008) investigated 76,484 Danes in a representative sample using online questionnaires. Dietary information using a food frequency questionnaire was obtained from 42,836 participants. Information on incident cases of diabetes was obtained from the Danish National Diabetes Register. Cox proportional hazard models were used to estimate Hazard Ratios (95% CI). Multiple linear regression analyses were used to assess the associations between carbohydrate types and cardiometabolic risk factors measured in a subsample of 12,977 participants.ResultsDuring a median follow-up of 4.9 years, 970 participants developed diabetes. A higher consumption of fructose, but a lower consumption of glucose was associated with a lower risk of diabetes. In subgroup analyses, these associations were only significant among individuals with other risk factors, such as older age, obesity, low fiber consumption, sedentary behavior, smoking status, and hypertension. Participants with a higher intake of fiber tend to have a lower risk of diabetes and healthier anthropometric parameters compared to those with a lower intake.ConclusionsOur findings suggest that a higher intake of dietary fiber and fructose is associated with a lower risk of diabetes and healthier metabolic status, while higher glucose intake is associated with a higher diabetes risk.Graphical

Predictive Factors and the Predictive Scoring System for Falls in Acute Care Inpatients: Retrospective Cohort Study.

Falls in hospitalized patients are a serious problem, resulting in physical injury, secondary complications, impaired activities of daily living, prolonged hospital stays, and increased medical costs. Establishing a fall prediction scoring system to identify patients most likely to fall can help prevent falls among hospitalized patients. This study aimed to identify predictive factors of falls in acute care hospital patients, develop a scoring system, and evaluate its validity. This single-center, retrospective cohort study involved patients aged 20 years or older admitted to Shizuoka General Hospital between April 2019 and September 2020. Demographic data, candidate predictors at admission, and fall occurrence reports were collected from medical records. The outcome was the time from admission to a fall requiring medical resources. Two-thirds of cases were randomly selected as the training set for analysis, and univariable and multivariable Cox regression analyses were used to identify factors affecting fall risk. We scored the fall risk based on the estimated hazard ratios (HRs) and constructed a fall prediction scoring system. The remaining one-third of cases was used as the test set to evaluate the predictive performance of the new scoring system. A total of 13,725 individuals were included. During the study period, 2.4% (326/13,725) of patients experienced a fall. In the training dataset (n=9150), Cox regression analysis identified sex (male: HR 1.60, 95% CI 1.21-2.13), age (65 to <80 years: HR 2.26, 95% CI 1.48-3.44; ≥80 years: HR 2.50, 95% CI 1.60-3.92 vs 20-<65 years), BMI (18.5 to <25 kg/m²: HR 1.36, 95% CI 0.94-1.97; <18.5 kg/m²: HR 1.57, 95% CI 1.01-2.44 vs ≥25 kg/m²), independence degree of daily living for older adults with disabilities (bedriddenness rank A: HR 1.81, 95% CI 1.26-2.60; rank B: HR 2.03, 95% CI 1.31-3.14; rank C: HR 1.23, 95% CI 0.83-1.83 vs rank J), department (internal medicine: HR 1.23, 95% CI 0.92-1.64; emergency department: HR 1.81, 95% CI 1.26-2.60 vs department of surgery), and history of falls within 1 year (yes: HR 1.66, 95% CI 1.21-2.27) as predictors of falls. Using these factors, we developed a fall prediction scoring system categorizing patients into 3 risk groups: low risk (0-4 points), intermediate risk (5-9 points), and high risk (10-15 points). The c-index indicating predictive performance in the test set (n=4575) was 0.733 (95% CI 0.684-0.782). We developed a new fall prediction scoring system for patients admitted to acute care hospitals by identifying predictors of falls in Japan. This system may be useful for preventive interventions in patient populations with a high likelihood of falling in acute care settings.

Risk of Atherosclerotic Cardiovascular Disease After Chronic Obstructive Pulmonary Disease Hospitalization among Primary and Secondary Prevention Older Adults.

Meta-analyses have suggested that the risk of cardiovascular disease events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation, but the populations at highest risk have not been well characterized to date. The authors analyzed the risk of atherosclerotic cardiovascular disease (ASCVD) hospitalizations after COPD hospitalization compared with before COPD hospitalization and patient factors associated with ASCVD hospitalizations after COPD hospitalization among 2 high-risk patient cohorts. The primary outcome was risk of an ASCVD hospitalization composite outcome (myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, stroke, transient ischemic accident) after COPD hospitalization relative to before COPD hospitalization. Additional analyses evaluated for risk factors associated with the composite ASCVD hospitalization outcome. In the high-risk primary prevention cohort, the hazard ratio (HR) estimate following adjustment for the composite ASCVD hospitalization outcome after COPD hospitalization versus before COPD hospitalization for 30 days was 0.74 (95% CI, 0.66-0.82; P≤0.0001); for 90 days, 0.69 (95% CI, 0.64-0.75; P≤0.0001); and for 1 year, 0.78 (95% CI, 0.73-0.82; P≤0.0001). In the secondary prevention cohort, the HR for 30-day hospitalization was 1.15 (95% CI, 1.05-1.26; P=0.0036); 90-day hospitalization, 1.08 (95% CI, 1.01-1.15; P=0.0178); and 1-year hospitalization, 1.07 (95% CI, 1.02-1.11; P=0.0026). Among the 19 characteristics evaluated, hyperlipidemia and history of acute ASCVD event were associated with the highest risk of ASCVD events 1 year after COPD hospitalization in the high-risk primary and secondary prevention cohorts. The risk of ASCVD hospitalization was higher in patients with established ASCVD and lower among high-risk patients without established ASCVD after-COPD hospitalization relative to before hospitalization. We identified multiple risk factors for ASCVD hospitalization after COPD hospitalization.

The impact of specialist cardiology inpatient care on the long-term outcomes of non-ST-segment elevation myocardial infarction (NSTEMI): A nationwide cohort study.

Specialist cardiac care has been shown to reduce inpatient mortality following non-ST segment myocardial infarction (NSTEMI), but whether this benefit extends beyond index admission is unclear. Using the linked Myocardial Ischaemia National Audit Project (MINAP) registry, and Office for National Statistics mortality recording, we included 425,205 NSTEMI patients admitted to UK hospitals, between January 2005 and March 2019 that survived to discharge. 217,964 (52 %) were admitted to a specialty cardiac ward. Multivariable Cox-regression models were applied to imputed data to estimate Hazard Ratios for mortality over our study period. Patients admitted to specialty cardiology wards were younger (70 years vs. 75), less often female (32 % vs. 40 %) but more often received statins (86 % vs. 84 %) or beta-blockers (83 % vs. 77 %) (all P < 0.001). One-year (aHR:0.84, 95 % CI 0.83-0.86), and ten-year mortality (aHR: 0.88, 95 % CI 0.87-0.89) were lower in patients admitted to specialty cardiac wards, compared to admitted elsewhere (all P < 0.001). There was significant geographic variation in the proportion admitted to speciality cardiac wards (London 59 % vs. East of England 43 %), with over 1700 deaths potentially avoided if the MINAP target of 80 % was reached. Patients admitted to a cardiac ward had significantly lower mortality compared to alternate wards persisting up to ten-years. There is wide regional variation in the proportion of patients who received specialist cardiology care during their admission and an opportunity exists for lives saved if the proportion of NSTEMI patients admitted to a cardiac ward were to reach the MINAP target of 80 %.

Riluzole is associated with reduced risk of heart failure.

Reduction of intracellular Na+ accumulation through late Na+ current inhibition has been recognized as a target for cardiac Ca2+ handling which underlies myocardial contractility and relaxation in heart failure (HF). Riluzole, an Na+ channel blocker with enhancement of Ca2+-activated K+ channel function, used for management of amyotrophic lateral sclerosis (ALS), is effective in suppressing Ca2+ leak and therefore may improve cardiac function. The study aim was to investigate whether riluzole lowers HF incidence. Rates of HF incident were compared using a commercial insurance and Medicare supplement claims databases. Patients with a filled riluzole prescription (treatment) between 06/2009 and 12/2019 were compared to those with no-riluzole (control). We excluded HF patients during the 180-day baseline period. Study endpoint was the first HF diagnosis from the index riluzole prescription or ALS diagnosis. HF onset was compared between the propensity score matched treatment and control cohorts. The matched cohort consisted of 4060 pairs of riluzole/control patients. The 24-month cumulative incidence of HF onset for riluzole versus control patients was 4.96% versus 7.27%, calculating hazard ratio (HR) [95% CI, p-value] of 0.55 [0.40-0.76, p < 0.01]. The HR estimates favoring riluzole over the ALS control were consistent across the 3 months to 2-year follow-up. The clinically and statistically significant effect on HF onset was driven by the lower rate of HFrEF with the 2-year HR [95% CI] of 0.46 [0.21-0.99]. Riluzole is associated with a lower rate of HF onset, suggesting a potential prevention strategy for early management.

Long-Term Real-World Survival of Immunotherapy Compared to Chemotherapy for Metastatic Nonsmall Cell Lung Cancer: A Propensity Score-Matched Analysis.

The long-term real-world effect of immunotherapy (IO) is uncertain in metastatic nonsmall cell lung cancer (mNSCLC). This retrospective observational study aimed to describe treatment patterns following the introduction of IO, estimate real-world treatment effects of IO compared to standard of care, and evaluate the impact of introduction of IO on a real-world population, based on a large dataset of over 10 000 patients with several years of follow-up. Data from routine care of lung cancer patients were extracted from Flatiron Health including those who received either IO or platinum-based doublet chemotherapy (PBDC) in the first line (1L), or either IO or chemotherapy (CT) in the second line (2L). Real-world overall survival (rwOS) and real-world time to next therapy (rwTTNT) were estimated using Cox regression. Flexible parametric models, relaxing proportional hazard assumptions, were used to evaluate long-term IO effects. After 1:1 nearest neighbor matching among 16 754 1L and 6548 2L patients, the hazard ratio (HR) was 0.942 (95% CI, 0.902-0.984) in 1L and 0.853 (95% CI, 0.795-0.915) in 2L. Adjusting for crossover effects, HR was 0.887 in 1L and 0.775 in 2L. Over the 7-year follow-up, the mean rwOS benefit was 3.2 months for 1L and 2.7 months for 2L. IO significantly delayed rwTTNT in both 1L and 2L. The IO effects increased and persisted over time, with uncertainty in the time-varying HR estimate. IO improves survival in patients with mNSCLC, though the effect size is smaller than in trials and long-term survival estimates are uncertain.

A simplified scoring system for predicting treatment response in limited-stage small-cell lung cancer (EAST score).

This study aimed at developing a scoring system (EAST score) to predict recurrence after chemoradiotherapy in limited-stage small-cell lung cancer (LS-SCLC). Treatment-naïve LS-SCLC patients receiving concurrent chemoradiotherapy (CCRT) (N = 234) or sequential chemoradiotherapy (N = 53) were retrospectively reviewed. Using data from CCRT population, clinical and radiological variables associated with disease progression were identified. Selected variables were assigned numerical scores based on their estimated hazard ratios (HRs), and the EAST score was established. EAST score incorporated N3 disease and serum biomarkers (lactate dehydrogenase, pro-gastrin-releasing peptide, and cytokeratin-19 fragment). In the CCRT population, progression-free survival (PFS) was significantly shorter in the high-risk group (EAST score ≥ 2) than the low-risk group (EAST score ≤ 1) (median, 9.4 months vs. 20.6 months; HR [95% confidence interval (CI)], 2.09 [1.50-2.91]). As for the model performance, the 1- and 2-year area under the curve values for PFS were 0.68 and 0.65, respectively. Overall survival was also shorter in the high-risk group (HR [95% CI], 1.49 [1.02-2.16]). Similar trends were observed in the sequential chemoradiotherapy population (HR for PFS [95% CI], 2.43 [1.07-5.53]). EAST score effectively predicts recurrence risk in LS-SCLC, demonstrating the necessity for developing new treatment strategies for high-risk patients.

Built-in selection or confounder bias? Dynamic Landmarking in matched propensity score analyses

BackgroundPropensity score matching has become a popular method for estimating causal treatment effects in non-randomized studies. However, for time-to-event outcomes, the estimation of hazard ratios based on propensity scores can be challenging if omitted or unobserved covariates are present. Not accounting for such covariates could lead to treatment estimates, differing from the estimate of interest. However, researchers often do not know whether (and, if so, which) covariates will cause this divergence.MethodsTo address this issue, we extended a previously described method, Dynamic Landmarking, which was originally developed for randomized trials. The method is based on successively deletion of sorted observations and gradually fitting univariable Cox models. In addition, the balance of observed, but omitted covariates can be measured by the sum of squared z-differences.ResultsBy simulation we show, that Dynamic Landmarking provides a good visual tool for detecting and distinguishing treatment effect estimates underlying built-in selection or confounding bias. We illustrate the approach with a data set from cardiac surgery and provide some recommendations on how to use and interpret Dynamic Landmarking in propensity score matched studies.ConclusionDynamic Landmarking is a useful post-hoc diagnosis tool for visualizing whether an estimated hazard ratio could be distorted by confounding or built-in selection bias.

Cediranib and Olaparib Combination Compared With Cediranib or Olaparib Alone, or Chemotherapy in Platinum-Resistant or Primary Platinum-Refractory Ovarian Cancer: NRG-GY005.

We assessed the efficacy of cediranib, olaparib, and cediranib/olaparib compared with standard-of-care chemotherapy (SOC) in platinum-resistant or platinum-refractory epithelial ovarian cancer (PROC). NRG-GY005 is an open-label, four-arm, phase II/III superiority trial enrolling patients with high-grade serous/endometrioid PROC and one to three previous therapies. Key exclusion criteria included previous receipt of poly(ADP-ribose) polymerase inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Treatment arms (SOC [once weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin], cediranib, olaparib, or cediranib/olaparib) were equally randomized. A preplanned interim futility analysis on the basis of progression-free survival (PFS) selected treatment arms to advance to phase III. PFS and overall survival (OS) were phase III coprimary end points, with hierarchical testing of PFS followed by OS to preserve type 1 error control, designed to have 90% power for a 0.625 PFS hazard ratio (HR). OS was tested after PFS in the multiple hierarchical testing procedure. Secondary end points included objective response rate (ORR) and patient-reported outcomes. Five hundred sixty-two eligible patients were enrolled for phase II/III. Three arms met PFS criteria to carry forward to phase III (SOC, cediranib/olaparib, and cediranib). Median PFS was 3.4, 5.2, and 4 months with SOC, cediranib/olaparib, and cediranib, respectively, with a median follow-up duration of 42.2 months. PFS HR estimates for cediranib/olaparib and cediranib (v SOC) were 0.796 (98.3% CI, 0.597 to 1.060) and 0.972 (98.3% CI, 0.726 to 1.300), respectively. Median OS was 13.6, 12.8, and 10.5 months, and of 443 patients with measurable disease, ORR was 8.6%, 24.7%, and 13.1% for SOC, cediranib/olaparib, and cediranib, respectively. No new safety signals were identified. In patients receiving cediranib/olaparib, no statistically significant difference was observed on the NFOSI-DRS-P subscale compared with SOC (98.3% CI, -1.3 to 1.5, P = .8725). The cediranib-containing arms demonstrated clinical activity on the basis of PFS but were not superior compared with SOC.

An Indirect Treatment Comparison of Lenvatinib for the First-Line Treatment of Patients with Unresectable Hepatocellular Carcinoma.

This study compared the relative efficacy of first-line lenvatinib, a standard-of-care treatment for unresectable hepatocellular carcinoma (uHCC), vs licensed/license in-progress comparators. Using inverse probability of treatment weighting (IPTW) and network meta-analysis (NMA), updated evidence for lenvatinib monotherapy from LEAP-002, in addition to evidence from REFLECT, was included in the analyses. Randomized controlled trials (RCTs) were identified via systematic review. REFLECT and LEAP-002 investigated lenvatinib in uHCC, with patient-level data available for each; however, only REFLECT included a comparator arm of interest (sorafenib). The lenvatinib arm from LEAP-002 was adjusted to match aggregate data for confounding factors from REFLECT using IPTW. Weighted Cox regressions, including matching variables as covariates, were used to derive hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). These HR estimates were included in Bayesian NMAs to compare lenvatinib with comparators; survival was significantly improved if the 95% credible interval for the HR did not include 1.0. Scenario analyses explored alternative choices for IPTW estimators. Eight RCTs (including REFLECT) and the single-arm adjusted lenvatinib data from LEAP-002 were included in the NMA base case. Lenvatinib demonstrated significant improvement in OS compared with sorafenib 400 mg twice daily (BID) and significant improvement in PFS compared with sorafenib 400 mg BID, tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks (Q4W), and durvalumab 1500 mg Q4W. These results suggest that patients with uHCC treated with lenvatinib have similar or significantly improved OS and PFS compared with licensed/license in-progress therapies.

Pretreatment plasma vitamin D and response to neoadjuvant chemotherapy in breast cancer: evidence from pooled analysis of cohort studies.

Biological evidence has revealed antitumor effect of vitamin D, but whether it could predict the response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients remains inconclusive. The aim was to investigate the association between pretreatment vitamin D level and response to NAC and subsequent survival outcomes in BC patients. The authors systematically searched the Medline, Embase, Cochrane Library, and Web of Science databases and clinical trial registries to identify relevant articles from inception to 8 October 2024. Eligible studies investigating the associations between pretreatment plasma vitamin D and response to NAC in BC patients were selected according to the predefined criteria, with the study characteristics extracted by two reviewers. The primary outcome was pathological complete response (pCR), while overall pathological response and event-free survival (EFS) were adopted as secondary outcomes. Summary effect estimates of odds ratios (ORs) or hazard ratios (HRs) with 95% CIs were pooled using a random-effects model. Subgroup and sensitivity analyses were performed based on study characteristics and methodological quality. Six retrospective cohort studies involving 1291 BC patients were included. The authors observed a significant association between pretreatment vitamin D deficiency and 50% increased odds of non-pCR after NAC (OR=1.50, 95% CI: 1.11-2.03, P=0.008) with no heterogeneity (I2=0%). The authors also identified a significant association of vitamin D with the overall pathological response (OR=1.33, 95% CI: 1.01-1.75, P=0.046). A similar association with EFS (HR=1.27, 95% CI: 0.92-1.75, P=0.139) was also noted although the effect estimate was not statistically significant. Sensitivity analyses based on methodological quality showed consistent findings. Pretreatment vitamin D deficiency is associated with an inferior response to NAC in BC patients. Our meta-analysis advocates further prospective studies with large sample sizes before vitamin D supplementation could be administered to improve NAC response and subsequent prognosis of BC patients.

Association of Naples Prognostic Score with cardiovascular disease risk and its longitudinal prognostic impact on mortality in cardiovascular disease patients: Evidence from NHANES.

The Naples Prognostic Score (NPS) predicts outcomes in various diseases, but its impact on cardiovascular disease (CVD) is understudied. This study investigates the association between NPS and CVD prevalence and mortality among US adults. This study utilized data from the Continuous National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2016, with mortality follow-up data available through December 31, 2019. NPS was calculated using serum albumin, total cholesterol, neutrophil to lymphocyte ratio, and lymphocyte to monocyte ratio. Participants were stratified into low, moderate, and high NPS groups. Multiple logistic regression estimated odds ratios (OR) for CVD prevalence, while Cox proportional regression estimated hazard ratios (HR) for mortality. Of 39,572 participants, 20.24% were in the low group, 69.79% in the moderate group, and 9.96% in the high group. After adjusting for confounders, the CVD prevalence ORs for moderate and high groups were 1.19 (95% CI: 1.05, 1.34) and 1.78 (95% CI: 1.53, 2.07), respectively (P for trend <0.001). Compared to the low group, the high group had adjusted HRs of 1.92 (95% CI: 1.54, 2.41) for all-cause mortality, 1.61 (95% CI: 1.12, 2.34) for cardiovascular mortality, and 1.83 (95% CI: 1.11, 3.02) for cancer-related mortality (all P for trend <0.01). These associations remained significant across all subgroups. NPS is an independent risk factor for CVD and is positively associated with all-cause and cardiovascular mortality in individuals with CVD.

Abdominal Compared With Coronary Artery Calcification and Incident Cardiovascular Events and Mortality in Black Adults.

Black adults show heightened cardiovascular risk compared with other groups despite comparable or lower coronary artery calcium (CAC) scores, indicating potential cardiovascular risk underestimation by CAC. Abdominal aortic calcification (AAC), preceding CAC, may predict cardiovascular events better in Black adults who are prone to early atherosclerotic cardiovascular disease and excess events at low CAC scores. We included 2551 participants from the JHS (Jackson Heart Study) visit 2 examination (2005-2008) without cardiovascular disease, followed through 2016. Cox regression estimated hazard ratios for incident cardiovascular events defined as a composite of myocardial infarction, stroke, heart failure, and all-cause mortality. The predictive value of CAC and AAC, when added to the American College of Cardiology/American Heart Association cardiovascular risk algorithm (pool cohort equation), was assessed. Mean age was 57±10 years; 66% were women. Over a follow-up period of 12.6 years, 287 (11.3%) cardiovascular events and 360 (14.1%) mortality cases were observed. Adjusting for demographic and clinical variables, each 2-fold increase in CAC and AAC was associated with cardiovascular events (CAC: hazard ratio, 1.10 [95% CI, 1.06-1.13]; AAC: hazard ratio, 1.10 [95% CI, 1.06-1.13]) and all-cause mortality CAC: hazard ratio, 1.04 [95% CI, 1.01-1.08]; AAC: hazard ratio, 1.05 [95% CI, 1.01-1.08]). The incremental value of CAC (0.17 [95% CI, 0.08-0.23]) and AAC (0.15 [95% CI, 0.07-0.29]) to the pool cohort equation by net reclassification index was comparable. Notably, 45% of participants with 0 CAC showed some degree of AAC. Each 2-fold increase in AAC was associated with an increased risk of cardiovascular events (hazard ratio, 1.07 [95% CI, 1.01-1.19]) but not all-cause mortality among participants with 0 CAC. AAC is comparable to CAC in predicting cardiovascular events and all-cause mortality among Black adults, potentially valuable when CAC is absent.

Non-collapsibility and built-in selection bias of period-specific and conventional hazard ratio in randomized controlled trials

BackgroundThe hazard ratio of the Cox proportional hazards model is widely used in randomized controlled trials to assess treatment effects. However, two properties of the hazard ratio including the non-collapsibility and built-in selection bias need to be further investigated.MethodsWe conduct simulations to differentiate the non-collapsibility effect and built-in selection bias from the difference between the marginal and the conditional hazard ratio. Meanwhile, we explore the performance of the Cox model with inverse probability of treatment weighting for covariate adjustment when estimating the marginal hazard ratio. The built-in selection bias is further assessed in the period-specific hazard ratio.ResultsThe conditional hazard ratio is a biased estimate of the marginal effect due to the non-collapsibility property. In contrast, the hazard ratio estimated from the inverse probability of treatment weighting Cox model provides an unbiased estimate of the true marginal hazard ratio. The built-in selection bias only manifests in the period-specific hazard ratios even when the proportional hazards assumption is satisfied. The Cox model with inverse probability of treatment weighting can be used to account for confounding bias and provide an unbiased effect under the randomized controlled trials setting when the parameter of interest is the marginal effect.ConclusionsWe propose that the period-specific hazard ratios should always be avoided due to the profound effects of built-in selection bias.

Post-Marketing Safety of Ustekinumab Based on 14-Year Follow-Up in Danish National Patient Data.

Psoriasis (PsO), a chronic inflammatory skin disorder affecting a substantial proportion of populations globally, often necessitates systemic treatment including biologics. This 14-year cohort study, based on Danish national register data, aimed to investigate the enduring safety profile of ustekinumab compared to other systemic psoriasis treatments. Using comprehensive Danish national register data, this study scrutinized patients diagnosed with psoriasis or psoriatic arthritis (PsA) who received ustekinumab. The treatment group comparators were non-biological systemic treatment (non-biologic), tumor necrosis factor α inhibitor medicine groups (TNF-α), interleukin (IL)-17 inhibitors (IL-17), and IL-23 inhibitors (IL-23). The study periods for comparisons were 2009-2022 for non-biologic and TNF-α, 2015-2022 for IL-17, and 2018-2022 for IL-23. Outcomes were malignancies, cardiovascular events, serious infections, and serious hypersensitivity reactions. Cox proportional hazards regression models were employed to analyze two estimands: a standard intention-to-treat (ITT) estimand and a continuous-index-treatment (CIT) estimand, which considered switch and re-initiation of treatments within individuals. Users of ustekinumab were found to be younger on average, with an average age of 45.1 years compared to 51.6, 47.2, 49.0, and 48.4 years in the non-biologic, TNF-α, IL-17, and IL-23 groups, respectively. Also, 57.3% of the ustekinumab users were male, compared to 46.7%, 48.9%, 50.9%, and 58.3% for the non-biologic, TNF-α, IL-17, and IL-23 groups, respectively. Although the hazard ratio estimates varied across comparators, ustekinumab was found to be safe: regardless of PsA status, no discernible safety signals in terms of malignancy, MACE, severe infections, or severe hypersensitivity reactions were observed for ustekinumab when compared to the treatment comparators. The present study corroborated the enduring safety of ustekinumab in the context of PsO treatment.