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ImportancePrimary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation.ObjectiveTo determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population.Design, Setting, and ParticipantsThis was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023.ExposuresPRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status.Main Outcomes and MeasuresIncident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events.ResultsA total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, −0.07% to 3.30%).Conclusions and RelevanceStudy results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.

Key Points Question Are current risk prediction models accurate at estimating risk of initial atherosclerotic cardiovascular (ASCVD) events in veterans? Findings In this cohort study of 1 672 336 veterans with an outpatient visit between 2002 and 2007, the 2013 American College of Cardiology/American Heart Association model overestimated absolute risk of ASCVD during 5 years of follow-up. Statin use was associated with 7% lower relative risk of ASCVD and 25% lower relative risk of ASCVD mortality. Meaning The findings of this study suggest that reestimation and the inclusion of statin use in ASCVD prediction models might be needed for their appropriate use in a health care system., This cohort study examines the performance of the Pooled Cohort Equations (PCE) for 5-year atherosclerotic cardiovascular disease risk estimation in a contemporary cohort and tests the hypothesis that inclusion of statin therapy improves model performance., Importance Current guidelines recommend statin therapy for millions of US residents for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). It is unclear whether traditional prediction models that do not account for current widespread statin use are sufficient for risk assessment. Objectives To examine the performance of the Pooled Cohort Equations (PCE) for 5-year ASCVD risk estimation in a contemporary cohort and to test the hypothesis that inclusion of statin therapy improves model performance. Design, Setting, and Participants This cohort study included adult patients in the Veterans Affairs health care system without baseline ASCVD. Using national electronic health record data, 3 Cox proportional hazards models were developed to estimate 5-year ASCVD risk, as follows: the variables and published β coefficients from the PCE (model 1), the PCE variables with cohort-derived β coefficients (model 2), and model 2 plus baseline statin use (model 3). Data were collected from January 2002 to December 2012 and analyzed from June 2016 to March 2020. Exposures Traditional ASCVD risk factors from the PCE plus baseline statin use. Main Outcomes and Measures Incident ASCVD and ASCVD mortality. Results Of 1 672 336 patients in the cohort (mean [SD] baseline age 58.0 [13.8] years, 1 575 163 [94.2%] men, 1 383 993 [82.8%] white), 312 155 (18.7%) were receiving statin therapy at baseline. During 5 years of follow-up, 66 605 (4.0%) experienced an ASCVD event, and 31 878 (1.9%) experienced ASCVD death. Compared with the original PCE, the cohort-derived model did not improve model discrimination in any of the 4 age-sex strata but did improve model calibration. The PCE overestimated ASCVD risk compared with the cohort-derived model; 211 237 of 1 136 161 white men (18.6%), 29 634 of 218 463 black men (13.6%), 1741 of 44 399 white women (3.9%), and 836 of 16 034 black women (5.2%) would be potentially eligible for statin therapy under the PCE but not the cohort-derived model. When added to the cohort-derived model, baseline statin therapy was associated with a 7% (95% CI, 5%-9%) lower relative risk of ASCVD and a 25% (95% CI, 23%-28%) lower relative risk for ASCVD death. Conclusions and Relevance In this study, lower than expected rates of incident ASCVD events in a contemporary national cohort were observed. The PCE overestimated ASCVD risk, and more than 15% of patients would be potentially eligible for statin therapy based on the PCE but not on a cohort-derived model. In the statin era, health care professionals and systems should base ASCVD risk assessment on models calibrated to their patient populations.

Importance Traumatic intracranial bleeding, which is most commonly attributable to falls, is a common concern among health care professionals, who are hesitant to prescribe oral anticoagulants to older adults with atrial fibrillation. Objective To describe the incidence of and risk factors for traumatic intracranial bleeding in a large cohort of older adults who were newly prescribed warfarin sodium. Design, Setting, and Participants Retrospective cohort study at the US Department of Veterans Affairs (VA). Participants included 31 951 veterans with atrial fibrillation 75 years or older who were new referrals to VA anticoagulation clinics (for warfarin therapy) between January 1, 2002, and December 31, 2012. The dates of the core analysis were March 2014 through May 2015, and subsequent ad hoc analyses were performed through December 2015. Patients with comorbid conditions requiring warfarin were excluded. Main Outcomes and Measures The primary outcome was hospitalization for traumatic intracranial bleeding. Secondary outcomes included hospitalization for any intracranial bleeding or ischemic stroke. We used International Classification of Diseases , Ninth Revision , Clinical Modification codes to identify the incidence rates of these outcomes after warfarin initiation using VA administrative data (in-system hospitalizations) and Medicare fee-for-service claims data (out-of-system hospitalizations). Clinical characteristics, laboratory results, and pharmacy data were extracted from the VA electronic medical record. For traumatic intracranial bleeding, Cox proportional hazards regression was used to determine predictors of interest selected a priori based on prior known associations. Results The study population comprised 31 951 participants. The mean (SD) patient age was 81.1 (4.1) years, and 98.1% were male. Comorbidities were common, including hypertension (82.5%), coronary artery disease (42.6%), and diabetes mellitus (33.8%). During the study period, the incidence rate of hospitalization for traumatic intracranial bleeding was 4.80 per 1000 person-years. In unadjusted models, significant predictors of traumatic intracranial bleeding included dementia, fall within the past year, anemia, depression, abnormal renal or liver function, anticonvulsant use, labile international normalized ratio, and antihypertensive use. After adjusting for potential confounders, the remaining significant predictors for traumatic intracranial bleeding were dementia (hazard ratio [HR], 1.76; 95% CI, 1.26-2.46), anemia (HR, 1.23; 95% CI, 1.00-1.52), depression (HR, 1.30; 95% CI, 1.05-1.61), anticonvulsant use (HR, 1.35; 95% CI, 1.04-1.75), and labile international normalized ratio (HR, 1.33; 95% CI, 1.04-1.72). The incidence rates of hospitalization for any intracranial bleeding and ischemic stroke were 14.58 and 13.44, respectively, per 1000 person-years. Conclusions and Relevance Among patients 75 years or older with atrial fibrillation initiating warfarin therapy, the risk factors for traumatic intracranial bleeding are unique from those for ischemic stroke. The high overall rate of intracranial bleeding in our sample supports the need to more systematically evaluate the benefits and harms of warfarin therapy in older adults.

Background: Long-term management of chronic pain with opioids may be stable over time or may be complicated by problematic dose increases, drug dependencies, and toxic effects. To determine clinical contexts in which stability or problems may occur, we examined the pharmacologic and clinical correlates of long-term prescriptions of oxycodone/acetaminophen, a commonly prescribed short-acting opioid formulation. Methods: We analyzed linked, archival outpatient pharmacy and clinical databases from the New England Veterans Integrated Service Network between January 1, 1998, and June 30, 2001. Durations, doses, and dose changes of oxycodone/acetaminophen prescriptions and concurrent use of long-acting opioids, benzodiazepines, tricyclic antidepressants, and anticonvulsants were determined. Results: In aggregate, 2195 patients (31% with cancer diagnoses per theInternational Classification of Diseases, NinthRevision,ClinicalModification) received oxycodone/ acetaminophen for more than 9 months at a mean prescribed daily dose of 3.9 tablets per day (range, 0.5-13.0 tablets per day) with minimal changes in daily prescribed mean dose over time. Patients with cancer were more likely than other patients to receive concurrent longacting opioids. For patients without cancer, a higher mean daily dose was associated with duration, older age, human immunodeficiency virus (HIV) and/or AIDS, and with prescribed benzodiazepines and long-acting opioids; concurrent benzodiazepine prescriptions were associated with anticonvulsant prescriptions and with psychogenic pain and alcohol abuse and/or dependence diagnoses. Conclusions: In veteran patients who received longterm oxycodone/acetaminophen prescriptions, mean daily doses were typically modest and stable, likely reflecting a selection of patients with successful, long-term management. Among patients without cancer, however, associations of higher oxycodone/acetaminophen doses with benzodiazepine prescriptions, psychogenic pain, alcohol abuse, and HIV/AIDS may portend opioid prescription management problems. Arch Intern Med. 2004;164:2361-2366

In Reply. —We appreciate Dr Folts' letter highlighting another possible mechanism by which the intake of fruits and vegetables may protect against the development of stroke. If the chief protective mechanism of flavonoids involves platelet inhibition, the benefit of these compounds might apply principally to ischemic stroke, since a platelet-inhibiting factor would not be expected to reduce the risk of hemorrhagic stroke. In our data, the intake of fruits and vegetables appeared to reduce the risk of both types of stroke, although the number of hemorrhagic strokes was small. It would be helpful if Hertog et al 1,2 or others with information on flavonoid intake could address directly the issue of stroke risk. As the comments of Folts also underscore, we examined the effect of a class of foods on stroke risk without knowing the identity of all beneficial (or harmful) substances these foods contain. However, much of dietary counseling

Objective. —To examine the effect of fruit and vegetable intake on risk of stroke among middle-aged men over 20 years of follow-up. Design. —Cohort. Setting. —The Framingham Study, a population-based longitudinal study. Participants. —All 832 men, aged 45 through 65 years, who were free of cardiovascular disease at baseline (1966 through 1969). Measurements and Data Analysis. —The diet of each subject was assessed at baseline by a single 24-hour recall. The estimated total number of servings per day of fruits and vegetables was the exposure variable for this analysis. Using Kaplan-Meier survival analysis, we examined age-adjusted cumulative incidence of stroke by quintile of servings per day. To adjust for multiple covariates, we used proportional hazards regression to calculate the relative risk (RR) of stroke for each increment of three servings per day. Main Outcome Measure. —Incidence of completed strokes and transient ischemic attacks. Results. —At baseline, the mean (±SD) number of fruit and vegetable servings per day was 5.1 (±2.8). During follow-up there were 97 incident strokes, including 73 completed strokes and 24 transient ischemic attacks. Age-adjusted risk of stroke decreased across increasing quintile of servings per day (log rank P for trend,.01). Age-adjusted RR for all stroke, including transient ischemic attack, was 0.78 (95% confidence interval [CI], 0.62 to 0.98) for each increase of three servings per day. For completed stroke the RR was 0.74 (95% CI, 0.57 to 0.96); for completed stroke of ischemic origin the RR was 0.76 (95% CI, 0.57 to 1.02); and for completed stroke of hemorrhagic origin, 0.49 (95% CI, 0.25 to 0.95). Adjustment for body mass index, cigarette smoking, glucose intolerance, physical activity, blood pressure, serum cholesterol, and intake of energy, ethanol, and fat did not materially change the results. Conclusion. —Intake of fruits and vegetables may protect against development of stroke in men. ( JAMA . 1995;273:1113-1117)

Background: To examine the rationale for preventive nutrition intervention and the potential efficacy of nutrition-related risk factor modification on heart disease incidence, the cardiovascular disease risk and dietary profiles of Framingham (Mass) men and women, 30 to 79 years old (n=1798 and 1845, respectively), were compared with the Healthy People 2000: National Health Promotion and Disease Prevention Objectives for the Nation and used to project the 10-year incidence of coronary heart disease with and without lowering serum cholesterol levels. Methods: Data for this report are derived from the 1984 to 1988 cycle III examinations of the Framingham offspring-spouse cohort. Estimates of the reduction in coronary heart disease risk associated with modifications in serum cholesterol levels and other cardiovascular disease risk factors are projected using Framingham models. Results: About 40% met guidelines for desirable total cholesterol levels ( Conclusion: Risk factor lowering, emphasizing preventive nutrition measures, is an important element of health care reform, particularly strategies to reduce cardiovascular disease rates and to promote population health. (Arch Intern Med. 1993;153:1549-1556)