Individual Participant-level Data Research Articles

Effects of Sacubitril/Valsartan on all-cause hospitalizations in heart failure: participant-level pooled analysis of PARADIGM-HF and PARAGON-HF

Abstract Background Sacubitril/valsartan is indicated to reduce the risk of cardiovascular (CV) death and heart failure (HF) hospitalizations in patients with chronic HF. However, many of these patients are older and have multiple comorbidities that increase the risk of hospitalizations other than HF, yet the effects of sacubitril/valsartan on hospitalizations of any cause have not been well described. Methods PARADIGM-HF and PARAGON-HF were phase-3, global multicenter randomized clinical trials that evaluated sacubitril/valsartan versus enalapril (in PARADIGM-HF) or valsartan (in PARAGON-HF) across the spectrum of left ventricular ejection fraction (LVEF; ≤40% in PARADIGM-HF and ≥45% in PARAGON-HF). We pooled individual participant-level data from these 2 trials to examine the effects of sacubitril/valsartan on time-to-first investigator-reported all-cause and cause-specific hospitalization using Cox proportional hazards models, stratified by geographic region and trial. We additionally examined heterogeneity in treatment response by LVEF. Results Over 2.8 years median follow-up, among 13,194 participants in the pooled PARADIGM-HF/PARAGON-HF, sacubitril/valsartan significantly reduced the risk of all-cause hospitalizations compared with renin-angiotensin system inhibitor (HR 0.92; 95% CI 0.88-0.97; P=0.002); Figure 1 Panel A. The absolute risk reduction (ARR) was 2.1 per 100 patient-years corresponding to a number-needed-to-treat (NNT) of 48 patient-years of treatment exposure to prevent 1 all-cause hospitalization. Reductions in overall hospitalizations among patients with identifiable causes (N=5,783) seemed to be primarily driven by lower rates of cardiac and pulmonary hospitalizations associated with sacubitril/valsartan. Patients treated with sacubitril/valsartan did not have a higher rate of composite non-cardiac hospitalizations (Figure 1 Panel B). Similarly, sacubitril/valsartan reduced the risk of the composite of all-cause hospitalization or all-cause mortality (HR 0.92; 95% CI 0.87-0.96; P<0.001), with an ARR of 2.5 per 100 patients-years and an NNT of 40 patient-years. For all-cause hospitalization, we observed significant heterogeneity by LVEF as a continuous measure (Pinteraction=0.027); treatment effects were most apparent in those with an LVEF below 60% (HR 0.91 95% CI 0.86-0.96; Figure 2). Conclusions In a pooled analysis of >13,000 patients with chronic HF, sacubitril/valsartan reduced hospitalization for any reason with benefits most apparent among those with an LVEF below normal.

Diagnostic Prediction Model for Tuberculous Meningitis: An Individual Participant Data Meta-Analysis.

No accurate and rapid diagnostic test exists for tuberculous meningitis (TBM), leading to delayed diagnosis. We leveraged data from multiple studies to improve the predictive performance of diagnostic models across different populations, settings, and subgroups to develop a new predictive tool for TBM diagnosis. We conducted a systematic review to analyze eligible datasets with individual-level participant data (IPD). We imputed missing data and explored three approaches: stepwise logistic regression, classification and regression tree (CART), and random forest regression. We evaluated performance using calibration plots and C-statistics via internal-external cross-validation. We included 3,761 individual participants from 14 studies and nine countries. A total of 1,240 (33%) participants had "definite" (30%) or "probable" (3%) TBM by case definition. Important predictive variables included cerebrospinal fluid (CSF) glucose, blood glucose, CSF white cell count, CSF differential, cryptococcal antigen, HIV status, and fever presence. Internal validation showed that performance varied considerably between IPD datasets with C-statistic values between 0.60 and 0.89. In external validation, CART performed the worst (C = 0.82), and logistic regression and random forest had the same accuracy (C = 0.91). We developed a mobile app for TBM clinical prediction that accounted for heterogeneity and improved diagnostic performance (https://tbmcalc.github.io/tbmcalc). Further external validation is needed.

Tuberculosis-Associated Respiratory Disability in Children, Adolescents, and Adults: Protocol for a Systematic Review and Individual Participant Data Meta-Analysis.

Approximately 2% of the global population has survived tuberculosis (TB). Increasing evidence indicates that a significant proportion of pulmonary TB survivors develop TB-associated respiratory disability, commonly referred to as post-TB lung disease (PLTD) and marked by impaired respiratory function, persistent symptoms, and activity limitations. However, the prevalence, risk factors, and progression of TB-associated respiratory disability throughout the life course are not well understood. To address these gaps, we will undertake a systematic review and individual participant-level data meta-analysis (IPD-MA) focusing on TB-associated respiratory disability in children, adolescents, and adults successfully treated for pulmonary TB. We will systematically search MEDLINE, Embase, CENTRAL, Global Index Medicus, and medRxiv for original studies investigating TB-associated respiratory disability in people of all ages who have completed treatment for microbiologically confirmed or clinically diagnosed pulmonary TB. Authors of eligible studies will be invited to contribute de-identified data and form a collaborative group. Primary outcomes will be (1) abnormal lung function based on spirometry parameters and (2) chronic respiratory symptoms. We will estimate the overall and subgroup-specific prevalence of each outcome through IPD meta-analysis. Next, we will develop clinical prediction tools assessing the risk of future TB-associated respiratory disability at (i) the start of TB treatment and (ii) end of TB treatment for those without existing signs of disability. Finally, we will use stepwise hierarchical modelling to identify epidemiological determinants of respiratory disability. This study has been approved by the ethics review boards at the Rhode Island Hospital (2138217-2) and the Research Institute of the McGill University Health Centre (2024-10345). Individual study authors will be required to obtain institutional approval prior to sharing data. Results will be disseminated through open-access, peer-reviewed publications and conference presentations. CRD42024529906.

Nutritional Optimization for Brain Health in Contact Sports: A Systematic Review and Meta-Analysis on Long-Chain ω-3 Fatty Acids and Neurofilament Light

Accumulating evidence has highlighted the acute and chronic impact of repetitive subconcussive head impacts (rSHIs) in contact sports. Neurofilament-light (Nf-L), a brain-derived biomarker of neuroaxonal injury, elevates in concert with rSHI. Recently, long-chain ω-3 polyunsaturated fatty acids (LC ω-3 PUFAs) supplementation has been suggested to mitigate brain injury from rSHI as reflected by attenuation of Nf-L concentrations within contact sport athletes. Using a systematic review with a meta-analysis, we aimed to determine the effect of LC ω-3 PUFA supplementation on Nf-L concentrations in athletes routinely exposed to rSHI. Electronic databases (PubMed and CINAHL) were searched from inception through January 2024. One-stage meta-analysis of individual participant-level data was used to detect changes in Nf-L concentrations between LC ω-3 PUFA and control/placebo (PL) groups from baseline to midseason (MS) and postseason (PS). Least square means (±SE) for Nf-L change from baseline were compared by treatment group for MS/PS using contrast t tests. Significance was set a priori at adjusted P ≤ 0.05. Of 460 records identified, 3 studies in collegiate American football players (n = 179; LC ω-3 PUFA = 105, PL = 71) were included in the meta-analysis. Compared with PL, the change in Nf-L concentrations was statistically similar at MS [mean difference (MD) = –1.66 ± 0.82 pg·mL–1, adjusted P = 0.09] and significantly lower at PS (MD = –2.23 ± 0.83 pg·mL–1, adjusted P = 0.02) in athletes following LC ω-3 PUFA supplementation. Our findings demonstrate preliminary support for the prophylactic administration of LC ω-3 PUFA in contact sport athletes exposed to rSHI; however, further research is required to determine the effective dosage required.This trial was registered at OSF (DOI: https://doi.org/10.17605/OSF.IO/EY5QW).

Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials.

Background: Kidney outcomes have been variably defined using non-standardized composite endpoints in key heart failure (HF) trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in 6 contemporary HF trials. Methods: Individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER) were included. The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%, end-stage kidney disease, or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Results: Among 28,690 participants across the 6 trials (median age 69 years [IQR, 62-76]; 9,656 [33.7% ] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2-inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. Conclusions: When applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2-inhibitors have either neutral or beneficial effects on kidney outcomes in HF. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.

The Impact of Sparse Datasets When Harmonizing Data from Studies with Different Measures of the Same Construct.

Prevention science has increasingly turned to integrative data analysis (IDA) to combine individual participant-level data from multiple studies of the same topic, allowing us to evaluate overall effect size, test and model heterogeneity, and examine mediation. Studies included in IDA often use different measures for the same construct, leading to sparse datasets. We introduce a graph theory method for summarizing patterns of sparseness and use simulations to explore the impact of different patterns on measurement bias within three different measurement models: a single common factor, a hierarchical model, and a bifactor model. We simulated 1000 datasets with varying levels of sparseness and used Bayesian methods to estimate model parameters and evaluate bias. Results clarified that bias due to sparseness will depend on the strength of the general factor, the measurement model employed, and the level of indirect linkage among measures. We provide an example using a synthesis dataset that combined data on youth depression from 4146 youth who participated in 16 randomized field trials of prevention programs. Given that different synthesis datasets will embody different patterns of sparseness, we conclude by recommending that investigators use simulation methods to explore the potential for bias given the sparseness patterns they encounter.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). Individual participant-level data for hyperkalemia or acute kidney injury were not available. Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. National Institutes of Health. (PROSPERO: CRD42022307589).

Effects of the incredible years parenting program on children's interpersonal conflict: An integrative data analysis.

Behavioral parenting programs, such as Incredible Years (IY), reduce conduct problems in children. However, conduct problems encompass many different behaviors, and little is known about the effects of parenting programs on specific aspects of children's conduct problems, such as children's relationships with others. The aim of this study was to examine, for the first time, the effects of the IY parenting program on children's levels of conflict with their parents, siblings, and peers. We used individual participant-level data pooled across 12 randomized trials in Europe, comprising a total of 1,409 families: child aged 1-11 years (M = 5.53 years, SD = 1.56) and 61% male, 60% low-income families, and 30% from an ethnic minority. Multilevel models were used to explore the effects of IY on children's conflict with parents, siblings, and peers. The IY program reduced children's conflict with their parents (β = -.21), but there were no main effects of the program on conflict with siblings or peers. Moderation analyses showed that IY reduced conflict in sibling relationships for the 22% of families with the most severe sibling conflict at baseline. This suggests that high-quality behavioral parenting programs, such as IY, can effectively reduce children's conflict within the home (i.e., with parents and siblings), especially when initial levels of sibling conflict are high, but do not have broader benefits on children's interpersonal conflict outside of the home (i.e., with peers). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials.

Empagliflozin is a sodium-glucose co-transporter-2 inhibitor used to treat type 2 diabetes (T2D) to improve glycemic control, reduce risk of cardiovascular death in patients with T2D, and treat patients with symptomatic chronic heart failure (HF) and chronic kidney disease (CKD). The safety profile of empagliflozin is well documented, although adverse events (AEs) remain of interest to clinicians. This study provides an up-to-date safety evaluation of empagliflozin. Data were pooled from four long-term trials which included: patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME), patients with HF, with/without diabetes (EMPEROR-Reduced and EMPEROR-Preserved), and patients with CKD, with/without diabetes (EMPA-KIDNEY). Since three of the four trials evaluated empagliflozin 10mg, the meta-analysis was restricted to this dose. Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression. This meta-analysis of long-term safety data extends current knowledge and confirms the safety and tolerability of empagliflozin.

Economic Evaluation of an Integrated Care Program Compared to Conventional Care for Patients With Chronic Kidney Disease in Rural Communities of Thailand

IntroductionAn integrated care program for chronic kidney disease in Thailand has shown its effectiveness in delaying the decline in kidney function, as evidenced by the ESCORT-1 randomized control trial and the ESCORT-2 prospective cohort study. Designed for sustainability within the primary healthcare system, the program optimizes the use of the existing workforce by fostering collaboration among local multidisciplinary care teams and community care networks. MethodsA Markov model with a lifetime horizon was used to conduct a cost-utility analysis from a societal perspective. Individual participant level data from ESCORT studies, national registries, and relevant literature were used to estimate model parameters. A budget impact analysis from the payer’s perspective was also assessed over a five-year period. ResultsThe integrated care program yielded a dominant result with 1.84 QALYs gained with “less” lifetime cost, resulting in a negative incremental cost-effectiveness ratio. Probabilistic analysis showed that the intervention being cost-effective almost 100% of the time at the local willingness-to-pay threshold. The intervention maximized cost-effectiveness when delivered as early as possible, both in terms of age and stage. The budget impact analysis estimated that the introduction of the intervention could save about 7% of the Thai government's total health expenditure or 205 billion Thai-Baht ($5.9 billion) over five years with cost savings beginning from the third year onwards. ConclusionThe integrated care program for CKD offers potential benefits and cost savings for patients, caregivers, and payers. Future efforts should focus on the screening and implementation processes across various regions and healthcare settings.

Participant characteristics and exclusion from phase 3/4 industry funded trials of chronic medical conditions: meta-analysis of individual participant level data

ObjectivesTo assess whether age, sex, comorbidity count, and race and ethnic group are associated with the likelihood of trial participants not being enrolled in a trial for any reason (ie,...

Association Between Serum Magnesium Levels and Outcomes of Atezolizumab in Patients With Metastatic Urothelial Carcinoma.

Evidence suggests that serum magnesium levels are associated with outcomes of immune checkpoint inhibitors (ICIs). However, this association remains under-explored in patients with metastatic urothelial carcinoma (UC) treated with ICIs. This prognostic study used individual participant-level data from 1,281 patients with locally advanced or metastatic UC treated with atezolizumab (N=855) or chemotherapy (N=426) who participated in the IMvigor210 and the IMvigor211 trials. Multivariable Cox proportional hazards regression and Fine-Gray subdistribution hazards regression models were used to examine the association of baseline serum magnesium levels with overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). No evidence of an association was found between baseline serum magnesium levels and PFS or OS in patients treated with atezolizumab [PFS, hazard ratio (HR)=1.03, 95% confidence interval (CI)=0.78-1.35; OS, HR=1.13, 95%CI=0.84-1.51] or chemotherapy (PFS, HR=0.93, 95%CI=0.62-1.40; OS, HR=0.91, 95%CI=0.59-1.40). We also found no evidence of association with irAEs (subdistribution HR=1.29, 95%CI=0.81-2.07) in patients receiving atezolizumab. This study found no evidence of an association between baseline serum magnesium levels and treatment outcomes or irAEs in patients with metastatic UC receiving atezolizumab. Contrary to previous research suggesting a role for magnesium in cancer therapy, these results indicate that serum magnesium levels may not serve as a biomarker to predict outcomes in these patients.

Post-kala-azar dermal leishmaniasis (PKDL) drug efficacy study landscape: A systematic scoping review of clinical trials and observational studies to assess the feasibility of establishing an individual participant-level data (IPD) platform.

Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis which can occur after successful treatment of visceral leishmaniasis (VL) and is a public health problem in VL endemic areas. We conducted a systematic scoping review to assess the characteristics of published PKDL clinical studies, understand the scope of research and explore the feasibility and value of developing a PKDL individual patient data (IPD) platform. A systematic review of published literature was conducted to identify PKDL clinical studies by searching the following databases: PubMed, Scopus, Ovid Embase, Web of Science Core Collection, WHO Global Index Medicus, PASCAL, Clinicaltrials.gov, Ovid Global Health, Cochrane Database and CENTRAL, and the WHO International Clinical Trials Registry Platform. Only prospective studies in humans with PKDL diagnosis, treatment, and follow-up measurements between January 1973 and March 2023 were included. Extracted data includes variables on patient characteristics, treatment regimens, diagnostic methods, geographical locations, efficacy endpoints, adverse events and statistical methodology. A total of 3,418 records were screened, of which 56 unique studies (n = 2,486 patients) were included in this review. Out of the 56 studies, 36 (64.3%) were from India (1983-2022), 12 (21.4%) from Sudan (1992-2021), 6 (10.7%) were from Bangladesh (1991-2019), and 2 (3.6%) from Nepal (2001-2007). Five (8.9%) studies were published between 1981-1990 (n = 193 patients), 10 (17.9%) between 1991-2000 (n = 230 patients), 10 (17.9%) between 2001-2010 (n = 198 patients), and 31 (55.4%) from 2011 onwards (n = 1,865 patients). Eight (14.3%) were randomised clinical trials, and 48 (85.7%) were non-randomised studies. The median post-treatment follow-up duration was 365 days (range: 90-540 days) in 8 RCTs and 360 days (range: 28-2,373 days) in 48 non-randomised studies. Disease diagnosis was based on clinical criterion in 3 (5.4%) studies, a mixture of clinical and parasitological methods in 47 (83.9%) and was unclear in 6 (10.7%) studies. Major drugs used for treatment were miltefosine (n = 636 patients), liposomal amphotericin B (L-AmB) (n = 508 patients), and antinomy regimens (n = 454 patients). Ten other drug regimens were tested in 270 patients with less than 60 patients per regimen. Our review identified studies with very limited sample size for the three major drugs (miltefosine, L-AmB, and pentavalent antimony), while the number of patients combined across studies suggest that the IPD platform would be valuable. With the support of relevant stakeholders, the global PKDL community and sufficient financing, a PKDL IPD platform can be realised. This will allow for exploration of different aspects of treatment safety and efficacy, which can potentially guide future healthcare decisions and clinical practices.

Radiographic Progression Without Corresponding Prostate-specific Antigen Progression in Patients with Metastatic Castration-sensitive Prostate Cancer Receiving Apalutamide: Secondary Analysis of the TITAN Trial

Background and objectiveIn prostate cancer treated with androgen deprivation therapy (ADT), the initial sign of treatment resistance is often prostate-specific antigen (PSA) progression, followed by radiographic progression. However, the association between these two forms of progression remains unclear, especially in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with androgen receptor pathway inhibitors. We sought to evaluate the association between radiographic progression, PSA progression, and outcomes of apalutamide therapy in mCSPC. MethodsWe analyzed individual participant-level data for patients randomized within the TITAN trial who experienced radiographic progression during follow-up (N = 326). This study investigated radiographic progression without simultaneous or preceding PSA progression, as defined by the Prostate Cancer Working Group 2 (discordant progression), and explored the association of such progression with radiographic progression-free survival. Key findings and limitationsAmong the patients who developed radiographic progression, 115 (35.3%) had been treated with apalutamide plus ADT (the apalutamide group) and 211 (64.7%) with placebo plus ADT (the placebo group). Discordant progression occurred in 52.2% of patients (60 of 115) in the apalutamide group and 27.5% (58 of 211) in the placebo group (p < 0.001). A multivariable logistic regression analysis showed that discordant progression was associated with apalutamide treatment. We found evidence of an association between discordant progression and shorter radiographic progression-free survival. Conclusions and clinical implicationsThis study found that nearly half of the patients with mCSPC treated with apalutamide who experienced radiographic progression developed it without corresponding PSA progression, suggesting that heavy reliance on PSA monitoring may be inadequate for assessing disease activity in this context. Patient summaryIn patients who have metastatic castration-sensitive prostate cancer (mCSPC) and are being treated with apalutamide, radiographic images may show cancer progression even if prostate-specific antigen tests indicate no change. This highlights the importance of regular imaging when using apalutamide to manage mCSPC.

Antithrombotic utilization, adverse events, and associations with treatment outcomes in multiple myeloma: pooled analysis of three clinical trials.

Patients with multiple myeloma (MM) are at risk of venous thromboembolism (VTE), worsened by immunomodulatory drugs. Although antithrombotics are recommended for prophylaxis, existing guidelines are suboptimal and treatment outcomes remain unclear. This study aimed to investigate adverse events, antithrombotic utilization, and their associations with survival outcomes in patients with MM initiating multi-drug immunomodulatory combinations. A posthoc analysis of individual-participant level data (IPD). IPD from three daratumumab clinical trials (MAIA, POLLUX, and CASTOR) were pooled. Adverse events incidence and antithrombotic utilization were assessed. Logistic and Cox regression were utilized to examine associations between antithrombotics use with adverse events and survival outcomes at the baseline and 6-month landmark. Among 1804 patients, VTE occurred in 10%, bleeding in 14%, ischemic heart disease in 4%, and stroke in 2%. Patients with these adverse events demonstrated elevated rates of any grade ⩾3 events. Antiplatelet (primarily aspirin) and anticoagulant (primarily LMWH and direct oral anticoagulants) prescriptions have seen an increase from baseline (25% and 14%, respectively) to 6 months (35% and 31%). The primary indication for their use was prophylaxis. Anticoagulant use within 6 months was associated with reduced VTE (OR (95% CI) = 0.45 (0.26-0.77), p = 0.004), while antiplatelet use showed no associations with any evaluated adverse events. Antithrombotics and survival outcomes had no significant associations. This study underscores the complexities of antithrombotic therapy and adverse events in MM and highlights the need for vigilant and proactive management due to increased grade ⩾3 adverse events. While anticoagulant use was associated with reduced VTE risk, further research is needed to optimize thromboprophylaxis guidelines and explore antithrombotic efficacy and safety in patients with MM. MAIA (NCT02252172), POLLUX (NCT02076009), CASTOR (NCT02136134).

Is Kidney Function Associated with Age-Related Macular Degeneration?: Findings from the Asian Eye Epidemiology Consortium

PurposeChronic kidney disease (CKD) may elevate susceptibility to age-related macular degeneration (AMD) due to shared risk factors, pathogenic mechanisms, and genetic polymorphisms. Given the inconclusive findings in prior studies, we investigated this association using extensive datasets in the Asian Eye Epidemiology Consortium. DesignCross-sectional study. Participants51,253 participants from 10 distinct population-based Asian studies. MethodsAMD was defined using the Wisconsin Age-Related Maculopathy Grading System, the international Age-related Maculopathy epidemiological study group classification, or the Beckman clinical classification. CKD was defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m2. A pooled analysis using individual-level participant data was performed to examine the associations between CKD and eGFR with AMD (early and late), adjusting for age, sex, hypertension, diabetes, body mass index, smoking status, total cholesterol and study groups. Main Outcome Measuresodds ratio (OR) of early and late AMD. ResultsAmong 51,253 participants (mean age: 54.1±14.5 years), 5,079 had CKD (9.9%). The prevalence of early AMD was 9.0%, and late AMD was 0.71%. After adjusting for confounders, individuals with CKD were associated with higher odds of late AMD (OR, 1.46; 95% CI, 1.11-1.93; P=0.008). Similarly, poorer kidney function (per 10-unit eGFR decrease) was associated with late AMD (OR, 1.12; 95% CI, 1.05-1.19; P=0.001). Nevertheless, CKD and eGFR were not significantly associated with early AMD (all P ≥0.149). ConclusionsPooled analysis from 10 distinct Asian population-based studies revealed that CKD and compromised kidney function are significantly associated late AMD. This finding further underscores the importance of ocular examinations in CKD patients.

Social connections and risk of incident mild cognitive impairment, dementia, and mortality in 13 longitudinal cohort studies of ageing

Background:Good social connections are proposed to positively influence the course of cognitive decline by stimulating cognitive reserve and buffering harmful stress-related health effects. Prior meta-analytic research has uncovered links between social connections and the risk of poor health outcomes such as mild cognitive impairment, dementia, and mortality. These studies have primarily used aggregate data from North America and Europe with limited markers of social connections. Further research is required to explore these associations longitudinally across a wider range of social connection markers in a global setting.Research Objective:We examined the associations between social connection structure, function, and quality and the risk of our primary outcomes (mild cognitive impairment, dementia, and mortality).Method:Individual participant-level data were obtained from 13 longitudinal studies of ageing from across the globe. We conducted survival analysis using Cox regression models and combined estimates from each study using two-stage meta-analysis. We examined three social constructs: connection structure (living situation, relationship status, interactions with friends/family, community group engagement), function (social support, having a confidante) and quality (relationship satisfaction, loneliness) in relation to the risks of three primary outcomes (mild cognitive impairment, dementia, and mortality). In our partially adjusted models, we included age, sex, and education and in fully adjusted models used these variables as well as diabetes, hypertension, smoking, cardiovascular risk, and depression.Preliminary results of the ongoing study:In our fully adjusted models we observed: a lower risk of mild cognitive impairment was associated with being married/in a relationship (vs. being single), weekly community group engagement (vs. no engagement), weekly family/friend interactions (vs. not interacting), and never feeling lonely (vs. often feeling lonely); a lower risk of dementia was associated with monthly/weekly family/friend interactions and having a confidante (vs. no confidante); a lower risk of mortality was associated with living with others (vs. living alone), yearly/monthly/weekly community group engagement, and having a confidante.Conclusion:Good social connection structure, function, and quality are associated with reduced risk of incident MCI, dementia, and mortality. Our results provide actionable evidence that social connections are required for healthy ageing.

Development and Validation of the American Heart Association's PREVENT Equations.

Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Methods for Integrating Trials and Non-experimental Data to Examine Treatment Effect Heterogeneity.

Estimating treatment effects conditional on observed covariates can improve the ability to tailor treatments to particular individuals. Doing so effectively requires dealing with potential confounding, and also enough data to adequately estimate effect moderation. A recent influx of work has looked into estimating treatment effect heterogeneity using data from multiple randomized controlled trials and/or observational datasets. With many new methods available for assessing treatment effect heterogeneity using multiple studies, it is important to understand which methods are best used in which setting, how the methods compare to one another, and what needs to be done to continue progress in this field. This paper reviews these methods broken down by data setting: aggregate-level data, federated learning, and individual participant-level data. We define the conditional average treatment effect and discuss differences between parametric and nonparametric estimators, and we list key assumptions, both those that are required within a single study and those that are necessary for data combination. After describing existing approaches, we compare and contrast them and reveal open areas for future research. This review demonstrates that there are many possible approaches for estimating treatment effect heterogeneity through the combination of datasets, but that there is substantial work to be done to compare these methods through case studies and simulations, extend them to different settings, and refine them to account for various challenges present in real data.

A - 10 Comorbid Traumatic Brain Injury and Posttraumatic Stress Disorder: Evidence from the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System.

Although posttraumatic stress disorder (PTSD) is common following traumatic brain injury (TBI; Greer et al., 2020), the complex association between these conditions requires further explication. Data repositories, such as FITBIR, which is the product of a national effort to compile individual participant-level TBI data from multiple studies into a unified database, provide a useful avenue for exploring the PTSD-TBI relationship. The present project is a proof-of-concept study demonstrating the ability to harmonize data from numerous shared studies to better understand comorbid PTSD following TBI. We searched for, merged, and harmonized data from studies with TBI and PTSD variables to analyze rates of probable PTSD across TBI severity categories. The methods and code used to extract, clean, standardize, and harmonize the data have been publicly shared and as additional studies are contributed to FITBIR, they will be added to these meta-datasets. After harmonizing key variables across FITBIR datasets, the final sample consisted of 1633 participants. Approximately 79% of participants across studies had a history of mild TBI (mTBI) and 32-37% screened positive for PTSD. Those with mTBI had 2.8 greater odds of screening positive for PTSD compared to those with no TBI (95% CI: 1.90, 3.90). Study findings show that unifying patient-level data is possible and can contribute to knowledge of complex medical and psychiatric comorbidity. These methods allow for nuanced analyses addressing diversity, equity, and inclusion issues often left out of single studies due to small sample sizes of minoritized groups within individual studies.