Gill, Thomas M.

Importance The APOE ε4 variant is causally linked to cerebral amyloid angiopathy and is a risk factor for intracranial hemorrhage (ICH) among warfarin-treated patients with atrial fibrillation. Nevertheless, its impact on those treated with apixaban remains unknown. Objective To test the hypothesis that APOE ε4 allele carriership is associated with an increased risk of ICH in patients with atrial fibrillation taking apixaban. Design, Setting, and Participants This cohort study involved data from the All of Us Research Program, a longitudinal, population-based study in the United States. Inclusion criteria were age older than 50 years, history of atrial fibrillation, and anticoagulation with apixaban. Participants with a history of ischemic stroke or ICH were excluded. Up to 3 years of follow-up data were available. Data were collected from 2017 to 2022 and analyzed from November 2023 to December 2024. Exposure APOE ε2, ε3, and ε4 were ascertained using variants rs429358 and rs7412. APOE ε4 was modeled dichotomously (noncarriers [no alleles] vs carriers [1 or 2 alleles]). Main Outcomes and Measures Incident ICH, including any new intraparenchymal, subdural, or subarachnoid hemorrhage after initiation of apixaban therapy. Results Of 413 477 All of Us participants, 2038 were eligible. Their mean (SD) age was 71 (9) years; 918 (45%) were female, 1120 (55%) were male, and 1710 (83%) had European ancestry. Among these participants, 483 (23.7%) were carriers of at least 1 APOE ε4 allele. After a median follow-up of 2.9 years, 26 participants sustained an ICH (cumulative incidence, 1.5%; 95% CI, 1.0%-2.2%), of whom 12 (cumulative incidence, 3.1%; 95% CI, 1.7%-5.3%) were carriers and 14 (cumulative incidence, 1%; 95% CI, 0.6%-1.7%) were noncarriers ( P = .007). Multivariable Cox proportional hazard models confirmed this association: compared with noncarriership, APOE ε4 carriership was associated with a 3-fold increase in the risk of ICH (hazard ratio, 3.07; 95% CI, 1.42-6.65). APOE information improved the discrimination of risk prediction scores (C statistic of 0.74 and 0.68 for models with and without APOE , respectively; P = .03). Conclusions and Relevance Further research is needed to evaluate whether cerebral amyloid angiopathy mediates the observed association and whether APOE e4 information improves clinical decision-making about anticoagulation therapy in patients with atrial fibrillation. The latter is important now that APOE information is used in clinical settings to guide antiamyloid treatment for Alzheimer disease and has been returned to millions of persons by direct-to-consumer genotyping companies.

Introduction: Coagulation factor XI (FXI) inhibitors have shown a better safety profile than other anticoagulants, offering similar reductions in ischemic stroke (IS) risk with a lower risk of intracerebral hemorrhage (ICH). The APOE ε4 genotype is associated with increased risks of both IS and ICH, likely due to its effects on lipid levels, intracranial atherosclerosis, and cerebral amyloid angiopathy. We hypothesized that APOE ε4 carriers would gain greater therapeutic benefit from genetically reduced FXI levels compared to non-carriers. Methods: We conducted a two-stage Mendelian randomization (MR) analysis using the random-effects, inverse-variance weighted method. First, we estimated the effect of genetically proxied FXI inhibition on IS and ICH risk in the general population using summary data from genome-wide association studies of FXI levels (16,169 participants), IS (1,503,898 controls and 110,182 cases), and ICH (3,745 controls and 3,226 cases). Second, we performed stratified analyses to estimate the effect of genetically determined FXI levels on IS (10,343 cases and 476,838 controls) and ICH (2,236 cases and 484,945 controls) risk across APOE ε4 carriership strata (0, 1, or 2 alleles) using UK Biobank data. Results: In the general population, random-effects, inverse-variance weighted MR analyses showed that every 1 unit decrease in natural log-transformed FXI levels was associated with a 37% reduction in IS risk (OR:0.63; 95%CI:0.52–0.77; p <0.001) without a significant increase in ICH risk (OR:0.86; 95%CI:0.37–2.00; p =0.73). Stratified MR analyses indicated that genetically determined reductions in FXI levels had varying protective effects on IS risk based on APOE ε4 status: 31% in non-carriers (OR:0.69, 95%CI:0.53–0.91; p =0.008), 43% in carriers of 1 allele (OR:0.57, 95%CI:0.36–0.91; p =0.02), and 75% in carriers of 2 alleles (OR:0.25, 95%CI:0.06–1.06; p =0.06). Similar MR analyses showed no significant increase in ICH risk with genetically determined reductions in FXI levels in any APOE ε4 strata (all p >0.38, Figure 1). Conclusion: This two-stage genetic study provides causal evidence that lower FXI levels reduce IS risk in the general population, with an even stronger effect among APOE ε4 carriers, while not increasing ICH risk. These results indicate that FXI inhibitors might be a safer and more effective alternative to other anticoagulants among APOE ε4 carriers, who are known to be at higher risk for both ischemic and hemorrhagic events.

Abstract Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double‐blind, placebo‐controlled randomized pragmatic clinical trial, will compare high‐intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community‐dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site‐reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co‐secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

ObjectiveObservational studies point to an inverse correlation between low‐density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.MethodsWe constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high‐density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.ResultsWe identified 410, 339, 393, and 317 lipid‐related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10‐100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively.InterpretationGenetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56–66

OBJECTIVE To determine whether burden of multiple chronic conditions (MCCs) influences the risk of receiving inappropriate vs appropriate device therapies. DESIGN Retrospective cohort study. SETTING Seven US healthcare delivery systems. PARTICIPANTS Adults with left ventricular systolic dysfunction receiving an implantable cardioverter‐defibrillator (ICD) for primary prevention. MEASUREMENTS Data on 24 comorbid conditions were captured from electronic health records and categorized into quartiles of comorbidity burden (0‐3, 4‐5, 6‐7 and 8‐16). Incidence of ICD therapies (shock and antitachycardia pacing [ATP] therapies), including appropriateness, was collected for 3 years after implantation. Outcomes included time to first ICD therapy, total ICD therapy burden, and risk of inappropriate vs appropriate ICD therapy. RESULTS Among 2235 patients (mean age = 69 ± 11 years, 75% men), the median number of comorbidities was 6 (interquartile range = 4‐8), with 98% having at least two comorbidities. During a mean 2.2 years of follow‐up, 18.3% of patients experienced at least one appropriate therapy and 9.9% experienced at least one inappropriate therapy. Higher comorbidity burden was associated with an increased risk of first inappropriate therapy (adjusted hazard ratio [HR] = 1.94 [95% confidence interval {CI} = 1.14‐3.31] for 4‐5 comorbidities; HR = 2.25 [95% CI = 1.25‐4.05] for 6‐7 comorbidities; and HR = 2.91 [95% CI = 1.54‐5.50] for 8‐16 comorbidities). Participants with 8‐16 comorbidities had a higher total burden of ICD therapy (adjusted relative risk [RR] = 2.12 [95% CI = 1.43‐3.16]), a higher burden of inappropriate therapy (RR = 3.39 [95% CI = 1.67‐6.86]), and a higher risk of receiving inappropriate vs appropriate therapy (RR = 1.74 [95% CI = 1.07‐2.82]). Comorbidity burden was not significantly associated with receipt of appropriate ICD therapies. Patterns were similar when separately examining shock or ATP therapies. CONCLUSIONS In primary prevention ICD recipients, MCC burden was independently associated with an increased risk of inappropriate but not appropriate device therapies. Comorbidity burden should be considered when engaging patients in shared decision making about ICD implantation.

OBJECTIVETo examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM).RESEARCH DESIGN AND METHODSUsing claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) &lt;6%, 6 to &lt;7%, 7 to &lt;8%, 8 to &lt;9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18–44, 45–64, 65–74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more).RESULTSFrom 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P &lt; 0.001). The proportion of patients with HbA1c &lt;7% declined (from 56.4 to 54.2%; P &lt; 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P &lt; 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P &lt; 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36).CONCLUSIONSDuring the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged.