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All the major lipid prevention guidelines agree that the 10-year risk of a cardiovascular event should be the primary method to select individuals for statin prevention of a cardiovascular event. They also all rely on LDL cholesterol (LDL-C) as the primary metric to monitor lipid lowering therapy. These two principles form the major instruments on which primary prevention of cardiovascular disease is based worldwide. Their application is based on decades of prospective observational studies and large numbers of randomized clinical trials. Their development and application are milestones in medical progress. But are there limits, which were unseen and unintended, that need to be identified and overcome so that cardiovascular prevention can improve? Based on new insights and old knowledge, this Viewpoint will apply Clinical Reasoning, the process by which we integrate all the relevant knowledge, including the knowledge we have gained from physiology, pathology, epidemiology, metabolism, experimental models of disease, and our clinical experience as well as the results of randomized clinical trials to the analysis of a single case to answer these questions. Moreover, this Viewpoint will challenge the universal practice of relating the clinical outcomes of the major successful lipid lowering trials to the decrease in LDL-C and argue that cardiovascular prevention should move from the Risk model to the Causal Benefit model. This Viewpoint will be framed around a single case because, as caregivers, we make decisions case by case and because, as caregivers, the individual is the true object of our concern.

Aims The aim of our study was to analyse the benefits of a 9 week hybrid comprehensive telerehabilitation (HCTR) programme in heart failure (HF) patients according to aetiology, as a subanalysis of the Telerehabilitation in Heart Failure Patients (TELEREH‐HF) trial. Methods and results Overall, 555 (65.3%) patients with ischaemic (IS) and 295 (34.7%) patients with non‐ischaemic (NIS) HF aetiology were randomized. There were no differences between the effect of HCTR and usual care (UC) on the primary outcome of number of days alive and out of the hospital in 26 months from the time of randomization in either aetiology (Wilcoxon–Mann–Whitney test), and no heterogeneity of effect between the aetiologies was noted (van Elteren test, P = 0.746). In Cox proportional hazards regression analysis, treatment was not independently associated with the secondary outcomes. For all‐cause mortality, the adjusted hazard ratio for HCTR vs. UC was 0.90 (95% confidence interval, 0.54–1.51) in IS and 1.42 (95% confidence interval, 0.69–2.94) in NIS (P interaction = 0.316). Differences between HCTR and UC in terms of change in the 6 min walk test distance and cardiopulmonary exercise test time after 9 weeks reached statistical significance in the IS arm (P = 0.015 and P

Introduction This study examines the dose–response relationship between moderate-to-vigorous physical activity and cardiometabolic measures in adolescents. Methods Cross-sectional spline analyses were performed using 2003–2016 National Health and Nutrition Examination Survey data among adolescents (aged 12–19 years, N=9,195) on objectively measured (2003–2006) and self-reported (2007–2016) weekly mean minutes of moderate-to-vigorous physical activity and cardiometabolic measures (systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein, BMI, and cardiorespiratory fitness). Inflection points were determined for nonlinear relationships. Results For objective moderate-to-vigorous physical activity, female adolescents had significant nonlinear associations with inflection points at 90 minutes/week for BMI percentile and systolic blood pressure. Male adolescents had inflection points at 150 weekly minutes of objective activity for BMI percentile and cardiorespiratory fitness. BMI percentile was about 7% lower for female and male adolescents at 150 weekly minutes of objectively measured moderate-to-vigorous physical activity than at 0 minutes. For self-reported moderate-to-vigorous physical activity, inflection points were at 375 minutes/week (diastolic blood pressure for female adolescents) and 500 minutes/week (systolic blood pressure for male adolescents). Conclusions Among several significant dose–response relationships between physical activity and cardiometabolic health in adolescents, consistent and often nonlinear relationships were identified for BMI, with inflection points at 90–150 minutes of objective moderate-to-vigorous physical activity. Notable differences in associations and linearity were identified by sex and physical activity measure (objective or self-reported). These results support calls for any increase in physical activity among adolescents and suggest that recommendations closer to the adult guidelines of 150 weekly minutes of physical activity may be health promoting and more attainable for youth than the current recommendation of 420 weekly minutes.

Background: Lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disease rely principally on estimated 10-year risk. We sought to determine the optimal time for initiation of lipid lowering in younger adults as a function of expected 30-year benefit. Methods: Data from 3148 National Health and Nutrition Examination Survey (2009–2016) participants, age 30 to 59 years, not eligible for lipid-lowering treatment recommendation under the most recent US guidelines, were analyzed. We estimated the absolute and relative impact of lipid lowering as a function of age, age at initiation, and non–high-density lipoprotein cholesterol (HDL-C) level on the expected rates of atherosclerotic cardiovascular disease over the succeeding 30 years. We modeled expected risk reductions based on shorter-term effects observed in statin trials (model A) and longer-term benefits based on Mendelian randomization studies (model B). Results: In both models, potential reductions in predicted 30-year atherosclerotic cardiovascular disease risk were greater with older age and higher non–HDL-C level. Immediate initiation of lipid lowering (ie, treatment for 30 years) in 40- to 49-year-old patients with non–HDL-C ≥160 mg/dL would be expected to reduce their average predicted 30-year risk of 17.1% to 11.6% (model A; absolute risk reduction [ARR], 5.5%) or 6.5% (model B; ARR 10.6%). Delaying lipid lowering by 10 years (treatment for 20 years) would result in residual 30-year risk of 12.7% (A; ARR 4.4) or 9.9% (B; ARR 7.2%) and delaying by 20 years (treatment for 10 years) would lead to expected mean residual risk of 14.6% (A; ARR 2.6%) or 13.9% (B; ARR 3.2%). The slope of the achieved ARR as a function of delay in treatment was also higher with older age and higher non–HDL-C level. Conclusions: Substantial reduction in expected atherosclerotic cardiovascular disease risk in the next 30 years is achievable by intensive lipid lowering in individuals in their 40s and 50s with non–HDL-C ≥160 mg/dL. For many, the question of when to start lipid lowering might be more relevant than whether to start lipid lowering.

Purpose Guidelines recommend 150 minutes of weekly moderate-to-vigorous physical activity (MVPA) for all adults, although physical activity level correlation with cardiometabolic health is not well characterized for young adults. We determined the dose–response relationship of MVPA on measures of cardiometabolic health in young adults. Methods We examined young adults (aged 20–29 years; N = 5,395, 47.9% female) in the 2003–2016 National Health and Nutrition Examination Survey. Exposures were objective (accelerometer based) and self-reported weekly mean minutes of MVPA. Cardiometabolic outcome measures were body mass index (BMI), high-density lipoprotein (HDL), total cholesterol, systolic blood pressure, and diastolic blood pressure. The dose–response relationships were assessed with unadjusted spline analyses. Sex-stratified outcomes were modeled using multivariable linear regression with mean estimated change presented for 150-minute dose increases of MVPA. Results Among females, associations between objective activity and cardiometabolic measures were all linear. Compared with no activity, 150 minutes of objective activity was associated with a lower BMI (−1.37 kg/m2) and total cholesterol (−4.89 mg/dL), whereas 150 minutes of self-reported activity was associated with a higher HDL (1 mg/dL) and lower diastolic blood pressure (−.42 mm Hg). Among males, an inflection point was identified in the dose–response curves for objective activity with BMI around 100 minutes. Compared with no activity, 150 self-reported minutes was associated with lower BMI (−.26 kg/m2), higher HDL (.52 mg/dL), and lower total cholesterol (−1.35 mg/dL). Conclusions The dose–response relationships between physical activity and cardiometabolic markers in young adults were predominantly linear, supporting public health calls for any increase in physical activity in this population.

Prediction Models Prediction models’ newfound importance and the emergence of model development based on machine learning raise questions about how to ensure their safety and efficacy, given their ...

Background Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. Methods We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. Results Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. Conclusions Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

Background There is a paucity of data on the distribution of cardiovascular risk factors in patients with familial hypercholesterolemia (FH) as compared to the general population. The aim of the study was to compare cardiovascular risk factors in a cohort of FH patients to the representative sample of adults in Poland who represent a high–cardiovascular risk European region. Methods We compared the distribution of risk factors in 1,382 individuals with FH phenotype referred for genetic testing between 2006 and 2014 to the National Centre of Familial Hypercholesterolemia in Gdansk, Poland. The cohort was comprised of 637 positive FH(+) and 745 negative FH(−) patients who were compared to a nationally representative sample of 2,413 adults age 18-79, standardized by age and sex, from the NATPOL 2011 study (NATPOL). We analyzed patients' distribution of history of atherosclerotic cardiovascular disease (ASCVD) and standard risk factors including total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure (SBP, DBP), body mass index, smoking, and diabetes. Results FH(+) patients (mean age 45.6 years) had the highest LDL-C of 241.7 mg/dL (95% CI 234.8-248.5) compared to 206.1 mg/dL (200.5-211.7) in FH(−) patients (mean age 48.2) and 126.2 mg/dL (124.8-127.6) in NATPOL. Mean SBP was the lowest in FH(+) patients at 128.7 mm Hg (126.7-130.7) compared to 133.4 mm Hg (132.6-134.3) in NATPOL and 134.4 mm Hg (132.3-136.5) in FH(−). No differences were found in the prevalence of diabetes and body mass index. Smoking was less common in FH(+) at 12.4% (9.4-15.4) compared to both FH(−) and NATPOL: 20.4% (16.6-24.1) and 28.4% (26.6-30.2), respectively. The prevalence of individuals with a history of ASCVD in both FH(+) and FH(−) was nearly 3-fold higher compared to NATPOL: 26% (21.8-30.1) and 26.6% (22.2-30.9) versus 9.5% (8.3-10.7), respectively. Conclusions The FH(+) patients had significantly higher mean LDL-C, but the levels of nonlipid factors were lower or similar compared to the other groups. Both FH(+) and FH(−) were characterized by a heavy burden of ASCVD. This suggests that cholesterol, and no other risk factors, is a key contributor to cardiovascular risk in patients with FH, especially those with genetic mutation.

Background Guidelines recommend exercise training as a component of heart failure (HF) management. There are large disparities in access to rehabilitation and introducing hybrid comprehensive telerehabilitation (TR) consisting of remote monitoring of training in patients' homes might be an optimal solution in Poland. Purpose The primary objective of the TELEREH-HF trial is to determine whether introducing TR will significantly increase days alive and out of hospital compared with usual care. The secondary objectives including assessment the effects of TR compared to usual care on all-cause and cardiovascular mortality and all-cause, cardiovascular and HF hospitalization. The tertiary analyses include: evaluation of the safety, effectiveness, quality of life, depression, anxiety, patients' acceptance of and adherence to TR. Methods The TELEREH-HF study is a randomized, multi-center, prospective, open-label, parallel group controlled trial in 850 HF patients after a hospitalization incident in NYHA I-III and LVEF≤40%. Patients were randomized to TR + usual care (TR group) or to usual care only (control group) and are followed for a maximum of 24 months. The TR group patients underwent a 9-week TR program consisting of an initial stage (1 week) conducted at hospital and a basic stage (8-week) home-based TR five times weekly. Results All patients were randomized and completed initial intervention in the TR group. The follow up of both groups is in progress. Conclusion The TELEREH-HF trial will provide novel data on the effects of telerhabilitation on hospitalization and mortality in HF patients, and on safety, qaulity of life, depression, anxiety and acceptance of and adherence to this intervention.

Background Exercise training in heart failure (HF) patients should be monitored to ensure patients’ safety. Electrocardiographic (ECG) telemonitoring was used to assess the safety of hybrid comprehensive telerehabilitation (HCTR). Objective Analysis of ECG recorded during HCTR in HF patients. Methods The TELEREH‐HF multicenter, randomized, controlled trial enrolled 850 HF patients with New York Heart Association class I‐III and left ventricular ejection fraction of ≤40%. This subanalysis focuses on 386 patients (aged 62 ± 11 years, LVEF 31 ± 7%) randomized to HCTR. HCTR was telemonitored with a device allowing to record 16‐s fragments of ECG and to transmit the data via mobile phone network to the monitoring center. ResultsIn 386 patients, 16,622 HCTR sessions were recorded and 66,488 ECGs fragments were evaluated. Sinus rhythm was present in 320 (83%) and permanent atrial fibrillation (AF) in 66 (17%) patients, respectively. The most common arrhythmias were ventricular and atrial premature beats, recorded in 76.4% and 27.7% of the patients, respectively. Non‐sustained ventricular tachycardia (21 episodes in 8 patients) and paroxysmal AF episodes (6 in 4 patients) were rare. None of the analyzed demographic and clinical characteristics was predictive for onset of the new arrhythmias on exercise. Conclusion Telerehabilitation in HF patients was safe without the evidence for symptomatic arrhythmias requiring discontinuation of telerehabilitation. Only one mildly symptomatic paroxysmal AF episode led to the short‐term suspension of the training program. The most common arrhythmias were atrial and ventricular premature beats. These arrhythmias did not result in any changes in rehabilitation and therapy regimens.

Introduction The novel hybrid comprehensive telerehabilitation (HCTR) consisting of telecare (with psychological telesupport), telerehabilitation and remote monitoring of cardiovascular implantable electronic devices might be an option to improve both physical capacity and depressive symptoms. Purpose The aim of the study was to investigate the influence of HCTR on depressive symptoms and physical capacity in heart failure (HF) patients in comparison with usual care (UC) alone. Methods The present analysis formed part of a multicenter, randomized trial that enrolled 850 HF patients (New York Heart Association class I–III, left ventricular ejection fraction ≤40%). Patients were randomized 1:1 to HCTR plus UC or UC only. Patients underwent either an HCTR program (1 week in hospital and 8 weeks at home; exercise training 5 times weekly) or UC with observation. The psychological intervention in the HCTR group included supportive psychological counseling via mobile phone. The Beck Depression Inventory II (BDI II) score (cut point for depression ≥14) was used to assess depression and the physical capacity was measured by peak oxygen consumption (peak VO2). Measurements were made before and after a 9-week intervention (HCTR group)/ observation (UC group). Results Both groups were comparable in terms of demographic, clinical characteristics and medical therapy. In HCTR group at entry 23% of the sample (n=88/382) obtaining BDI-II scores ≥14 vs 27.5% (n=107/389) in UC group. The BDI II score at study entry was 9.8±6.6 and after intervention was 9.2±6.6, p=0.016 (HCTR group) vs at entry 10.6±8.2 and after observation 10.0±8.3, p=0.022 (UC group). There were no significant differences between groups regarding ΔBDI II score p=0.992. There was a significant improvement in physical capacity assessed by peak VO2 only in the HCTR group, both in patients with (p=0.033) and without (p Conclusions In heart failure patients, HCTR provided similar reduction of depressive symptoms as UC. Hybrid comprehensive telerehabilitation resulted in a significant improvement in physical capacity both in patients with and without depression. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The National Centre for Research and Development, Warsaw, Poland.

IntroductionCardiac rehabilitation is a component of heart failure (HF) management, but its effect on ventricular arrhythmias is not well understood. We analyzed the antiarrhythmic effect of a 9-week hybrid comprehensive telerehabilitation (HCTR) program and its influence on long-term cardiovascular mortality in HF patients taken from the TELEREHabilitation in Heart Failure Patients (TELEREH-HF) trial.Material and methodsWe evaluated the presence of non-sustained ventricular tachycardia (nsVT) and frequent premature ventricular complexes ≥ 10 beats/hour (PVCs ≥ 10) in 24-hour ECG monitoring at baseline and after 9-week HCTR or usual care (UC) of 773 HF patients (NYHA I-III, LVEF ≤ 40%). Functional response for HCTR was assessed by changes – delta () – in peak oxygen consumption (pVO2) as a result of comparing pVO2 from the beginning and the end of the program.ResultsAmong 143 patients with nsVT, arrhythmia subsided in 30.8% after HCTR. Similarly, among 165 patients randomized to UC who had nsVT 34.5% did not show it after 9 weeks (p = 0.481). There was no significant difference in the decrease in PVC ≥ 10 over 9 weeks between randomization arms (14.9% vs. 17.8%, respectively p = 0.410). Functional response for HCTR in ΔpVO2 > 2.0 ml/kg/min did not affect occurrence of arrhythmias. Multivariable analysis did not identify HCTR as an independent factor determining improvement of nsVT or PVCs ≥ 10. However, only in the HCTR group, the achievement of the antiarrhythmic effect significantly reduced the cardiovascular mortality in 2-year follow-up (p < 0.001).ConclusionsSignificant improvement in physical capacity after 9 weeks of HCTR did not correlate with the antiarrhythmic effect in terms of incidence of nsVT or PVCs ≥ 10. An antiarrhythmic effect after the 9-week HCTR affected long-term cardiovascular mortality in HF patients.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Background Type 2 diabetes mellitus (DM) is one of the most common comorbidities among patients with heart failure (HF) with reduced ejection fraction (HFrEF). There are limited data regarding efficacy of hybrid comprehensive telerehabilitation (HCTR) on cardiopulmonary exercise capacity in patients with HFrEF with versus those without diabetes. Aim The aim of the present study was to analyze effects of 9-week HCTR in comparison to usual care on parameters of cardiopulmonary exercise capacity in HF patients according to history of DM. Methods Clinically stable HF patients with left ventricular ejection fraction [LVEF] Results CPET was performed in 385 patients assigned to HCTR group: 129 (33.5%) had DM (HCTR-DM group) and 256 patients (66.5%) did not have DM (HCTR-nonDM group). Among 397 patients assigned to UC group who had CPET: 137 (34.5%) had DM (UC-DM group) and 260 patients (65.5%) did not have DM (UC-nonDM group). Among DM patients, differences in cardiopulmonary parameters from baseline to 9 weeks remained similar among HCTR and UC patients. In contrast, among patients without DM, HCTR was associated with greater 9-week changes than UC in exercise time, which resulted in a statistically significant interaction between patients with and without DM: difference in changes in exercise time between HCTR versus UC was 12.0 s [95% CI − 15.1, 39.1 s] in DM and 43.1 s [95% CI 24.0, 63.0 s] in non-DM, interaction p-value = 0.016. Furthermore, statistically significant differences in the effect of HCTR versus UC between DM and non-DM were observed in ventilation at rest: − 0.34 l/min [95% CI − 1.60, 0.91 l/min] in DM and 0.83 l/min [95% CI − 0.06, 1.73 l/min] in non-DM, interaction p value = 0.0496 and in VE/VCO2 slope: 1.52 [95% CI − 1.55, 4.59] for DM vs. − 1.44 [95% CI − 3.64, 0.77] for non-DM, interaction p value = 0.044. Conclusions The benefits of hybrid comprehensive telerehabilitation versus usual care on the improvement of physical performance, ventilatory profile and gas exchange parameters were more pronounced in patients with HFrEF without DM as compared to patients with DM. Trial registration: ClinicalTrials.gov Identifier: NCT02523560. Registered 3rd August 2015. https://clinicaltrials.gov/ct2/show/NCT02523560?term=NCT02523560&draw=2&rank=1. Other Study ID Numbers: STRATEGME1/233547/13/NCBR/2015

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Centre for Research and Development, Warsaw, Poland. Background. Cardiac rehabilitation is a component of heart failure (HF) management but its effect on ventricular arrhythmias is not well recognized. Purpose. We analyzed the antiarrhythmic effect of a 9-week hybrid cardiac telerehabilitation (HCTR) and its influence on long term cardiovascular mortality in HF patients taken from the TELEREH-HF trial. Methods. We evaluated the presence of non-sustained ventricular tachycardia (nsVT) and frequent premature ventricular complexes ≥10 beats/hour (PVCs ≥10) with 24-hour ECG monitoring at the baseline and after 9-week HCTR or usual care (UC) of 773 HF patients (NYHA I-III, LVEF ≤ 40%). Results. Among 143 patients with nsVT, arrhythmia subsided in 30.8% after HCTR, similarly among 165 patients randomized to UC who had nsVT 34.5% did not show them after 9 weeks (p = 0.481). There was no significant difference in the decrease in PVC ≥10 over 9 weeks between randomization arms (14.9% vs. 17.8%, respectively p = 0.410). Functional response for HCTR (Δ peak oxygen consumption [pVO2] in cardiopulmonary exercise test >2.0 ml/kg/min) did not affect occurrence of arrhythmias. The multivariable analysis of the entire population did not identify HCTR as an independent factor determining improvement in terms of nsVT or PVCs >10. However, only in the HCTR group, the achievement of the antiarrhythmic effect significantly reduced the cardiovascular mortality in 2 years follow-up (Logrank p = 0.0009) (Figure). Conclusions. Significant improvement in physical capacity after 9 weeks of HCTR did not correlate with the antiarrhythmic effect in terms of incidence of nsVT or PVCs ≥10. An antiarrhythmic effect after the 9-week HCTR affected long term cardiovascular mortality in HF patients. Abstract Figure

Background Extended elevations of non–high-density lipoprotein cholesterol (non–HDL-C) across a lifespan are associated with increased risk of cardiovascular disease (CVD). However, optimal testing intervals to identify individuals with high lipid-related CVD risk are unknown. Objectives This study determined the extent to which lipid levels in young adulthood predict future lipid trajectories and associated long-term CVD risk. Methods A sample of 2,516 Framingham Offspring study participants 25 to 40 years of age free of CVD and diabetes had their non–HDL-C progression modeled over 8 study examinations (mean follow-up 32.6 years) using group-based methods. CVD risk based on 25 to 30 years of follow-up was evaluated using Kaplan-Meier analyses for those with mean non–HDL-C ≥160 mg/dl (“high”) and Results The trajectories of the lipid levels were generally stable over the 30-year life course; mean non–HDL-C measured in young adulthood were highly predictive of levels later in life. Individuals could be reliably assigned to high and low non–HDL-C groups based on 2 measurements collected between 25 to 40 years of age. Overall, 80% of those with non–HDL-C ≥160 mg/dl at the first 2 exams remained in the high group on subsequent 25-year testing, whereas 88% of those with non–HDL-C Conclusions Most adults with elevated non–HDL-C early in life continue to have high non–HDL-C over their life course, leading to significantly increased risk of CVD. The results demonstrate that early lipid monitoring before 40 years of age would identify a majority of those with a high likelihood for lifetime elevated lipid levels who also have a high long-term risk for CVD. This information could facilitate informed patient–provider discussion about the potential benefits of preventive lipid-lowering efforts during the early midlife period.

Supplemental Digital Content is available in the text., Background: To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors—specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking—with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. Methods: Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non–high-density lipoprotein cholesterol (non–HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. Results: Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non–HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non–HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to

The last two decades have witnessed an explosion in research focused on the development and assessment of novel biomarkers for improved prognosis of diseases. As a result, best practice standards guiding biomarker research have undergone extensive development. Currently, there is great interest in the promise of biomarkers to enhance research efforts and clinical practice in the setting of chronic kidney disease, acute kidney injury, and glomerular disease. However, some have questioned whether biomarkers currently add value to the clinical practice of nephrology. The current state of the art pertaining to statistical analyses regarding the use of such measures is critical. In December 2014, the National Institute of Diabetes and Digestive and Kidney Diseases convened a meeting, "Toward Building Better Biomarker Statistical Methodology," with the goals of summarizing the current best practice recommendations and articulating new directions for methodological research. This report summarizes its conclusions and describes areas that need attention. Suggestions are made regarding metrics that should be commonly reported. We outline the methodological issues related to traditional metrics and considerations in prognostic modeling, including discrimination and case mix, calibration, validation, and cost-benefit analysis. We highlight the approach to improved risk communication and the value of graphical displays. Finally, we address some "new frontiers" in prognostic biomarker research, including the competing risk framework, the use of longitudinal biomarkers, and analyses in distributed research networks.

Balanced representation learning methods have been applied successfully to counterfactual inference from observational data. However, approaches that account for survival outcomes are relatively limited. Survival data are frequently encountered across diverse medical applications, i.e., drug development, risk profiling, and clinical trials, and such data are also relevant in fields like manufacturing (e.g., for equipment monitoring). When the outcome of interest is a time-to-event, special precautions for handling censored events need to be taken, as ignoring censored outcomes may lead to biased estimates. We propose a theoretically grounded unified framework for counterfactual inference applicable to survival outcomes. Further, we formulate a nonparametric hazard ratio metric for evaluating average and individualized treatment effects. Experimental results on real-world and semi-synthetic datasets, the latter of which we introduce, demonstrate that the proposed approach significantly outperforms competitive alternatives in both survival-outcome prediction and treatment-effect estimation., Accepted at ACM Conference on Health, Inference, and Learning (ACM CHIL 2021). Code at https://github.com/paidamoyo/counterfactual_survival_analysis

IMPORTANCE: Accurate prediction of adverse outcomes after acute myocardial infarction (AMI) can guide the triage of care services and shared decision-making, and novel methods hold promise for using existing data to generate additional insights. OBJECTIVE: To evaluate whether contemporary machine learning methods can facilitate risk prediction by including a larger number of variables and identifying complex relationships between predictors and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used the American College of Cardiology Chest Pain-MI Registry to identify all AMI hospitalizations between January 1, 2011, and December 31, 2016. Data analysis was performed from February 1, 2018, to October 22, 2020. MAIN OUTCOMES AND MEASURES: Three machine learning models were developed and validated to predict in-hospital mortality based on patient comorbidities, medical history, presentation characteristics, and initial laboratory values. Models were developed based on extreme gradient descent boosting (XGBoost, an interpretable model), a neural network, and a meta-classifier model. Their accuracy was compared against the current standard developed using a logistic regression model in a validation sample. RESULTS: A total of 755 402 patients (mean [SD] age, 65 [13] years; 495 202 [65.5%] male) were identified during the study period. In independent validation, 2 machine learning models, gradient descent boosting and meta-classifier (combination including inputs from gradient descent boosting and a neural network), marginally improved discrimination compared with logistic regression (C statistic, 0.90 for best performing machine learning model vs 0.89 for logistic regression). Nearly perfect calibration in independent validation data was found in the XGBoost (slope of predicted to observed events, 1.01; 95% CI, 0.99-1.04) and the meta-classifier model (slope of predicted-to-observed events, 1.01; 95% CI, 0.99-1.02), with more precise classification across the risk spectrum. The XGBoost model reclassified 32 393 of 121 839 individuals (27%) and the meta-classifier model reclassified 30 836 of 121 839 individuals (25%) deemed at moderate to high risk for death in logistic regression as low risk, which were more consistent with the observed event rates. CONCLUSIONS AND RELEVANCE: In this cohort study using a large national registry, none of the tested machine learning models were associated with substantive improvement in the discrimination of in-hospital mortality after AMI, limiting their clinical utility. However, compared with logistic regression, XGBoost and meta-classifier models, but not the neural network, offered improved resolution of risk for high-risk individuals.

Background Heart failure (HF) is a clinical syndrome associated with physical capacity impairment and poor quality of life (QoL). The hybrid comprehensive telerehabilitation (HCTR) consisting of telecare, telerehabilitation and homemonitoring of implantable devices might be an option to improve QoL. Purpose to investigate the influence of HCTR on various facets of QoL in HF pts in comparison to usual care (UC). Methods The present analysis formed part of TELEREH-HF multicenter, randomized trial that enrolled 850 HF pts (NYHA I-III, LVEF≤40%). Patients were randomized 1:1 to HCTR plus UC or UC. Patients underwent either an HCTR (1 week in hospital and 8 weeks at home) or UC with observation. The psychology telecare had a form of supportive psychotherapy via phone. The Short Form 36 Questionnaire was used to assess QoL. Measurements were made before and after intervention/observation. Results HCTR group showed significant improvement in overall QoL, physical domain, and 4 areas of QoL (physical functioning [PF], role functioning related to physical state, general health, vitality). A significant positive change in QoL in UC group was observed in vitality and social functioning. There were significant differences in QoL after intervention/observation between groups. Results showed higher improvement in HCTR for overall QoL, physical domain and 3 areas of QoL (PF, role functioning related to physical state and bodily pain [BP]), Table 1. Conclusion In comparison to UC, HCTR resulted in significant improvement in overall QoL, physical domain and 3 specific areas of QoL: PF, role functioning related to physical state and BP. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Centre for Research and Development, Warsaw, Poland

Background Adherence to treatment guidelines in heart failure (HF) patients (pts) is of major prognostic importance, but thorough implementation of guidelines in routine care remains insufficient. Introducing hybrid comprehensive telerehabilitation (HCTR) consisting of telecare, telerehabilitation and remote monitoring of implantable devices might be an option to improve adherence to recommendation and can affect the prognosis. Purpose to investigate the association of adherence to HCTR with mortality and hospitalization. Methods The present analysis formed part of TELEREH-HF multicenter, randomized trial that enrolled 850 HF pts (NYHA I-III,LVEF≤40%). Patients were randomized 1:1 to HCTR plus usual care or usual care only and followed up for 14 to 26 months. During the first 9 weeks, pts underwent either an HCTR (1 week in hospital and 8 weeks at home) or usual care. This analysis focuses on pts randomized to HCTR. Adherent pts were those who adhered both to the number of training sessions prescribed and to the duration of the prescribed cycle by at least80%; non-adherent pts, were those who adhered Results There were 350 (88.4%) adherent pts, 39 (9.8%) partially adherent pts and 7 (1.8%) non-adherent pts. There were 54 deaths during follow-up in the HCTR arm. Non-adherence or partial adherence was associated with statistically significantly higher risk of cardiovascular (CV) mortality (hazard ratio (HR) = 2.62, p=0.021); all-cause mortality or HF hospitalization (HR=1.71, p=0.038); CV mortality or HF hospitalization (HR=1.89, p=0.014). Conclusion The adherence to HCTR was very high. Adherence to HCTR was associated with improved prognosis for CV mortality. Kaplan-Meier Probability of CV Mortality Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Centre for Research and Development, Warsaw, Poland

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneous treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made based only on an overall average treatment effect. We distinguished two categories of predictive HTE approaches (a “risk modeling” and an “effect modeling” approach) and developed four sets of guidance statements: 1) criteria to determine when risk modeling approaches are likely to identify clinically meaningful HTE; 2) methodological aspects of risk modeling methods; 3) considerations for translation to clinical practice; and 4) considerations and caveats in the use of effect modeling approaches. We also discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation; and discusses related analytic considerations, caveats, and reservations.

IMPORTANCE: The extent to which levels of high-sensitivity C-reactive protein (hs-CRP), a known marker of increased cardiovascular risk, are elevated and are associated with standard cardiovascular risk factors in patients with a history of myocardial infarction (MI) is unknown. OBJECTIVES: To determine the pattern and determinants of the distribution of hs-CRP in those with a prior MI in the United States using a nationally representative sample. DESIGN AND PARTICIPANTS: Adults with hs-CRP data in the National Health and Nutrition Examination Surveys from 1999–2010. RESULTS: Among 1296 individuals in our cohort, the median age was 65 years and the median hs-CRP level was 2.69 mg/L, measured an average of 7.1 years after the MI. Among these patients, 22% had hs-CRP levels of

Supplemental Digital Content is available in the text., Background: Total cholesterol and high-density lipoprotein cholesterol (HDL-C) measurements are central to cardiovascular disease (CVD) risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. Methods: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346 686), were included in the primary analysis. An incident fatal or nonfatal CVD event occurred in 6216 participants (1656 fatal) over a median of 8.9 years. Associations of nonfasting lipid measurements (total cholesterol, HDL-C, non–HDL-C, direct and calculated low-density lipoprotein cholesterol [LDL-C], and apolipoproteins [Apo] A1 and B) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index. Prediction was also tested in 68 649 participants taking a statin with or without baseline CVD (3515 CVD events). Results: ApoB, LDL-C, and non–HDL-C were highly correlated (r>0.90), while HDL-C was strongly correlated with ApoA1 (r=0.92). After adjustment for classical risk factors, 1 SD increase in ApoB, direct LDL-C, and non–HDL-C had similar associations with composite fatal/nonfatal CVD events (hazard ratio, 1.23, 1.20, 1.21, respectively). Associations for 1 SD increase in HDL-C and ApoA1 were also similar (hazard ratios, 0.81 [both]). Adding either total cholesterol and HDL-C, or ApoB and ApoA, to a CVD risk prediction model (C-index, 0.7378) yielded similar improvement in discrimination (C-index change, 0.0084; 95% CI, 0.0065, 0.0104, and 0.0089; 95% CI, 0.0069, 0.0109, respectively). Once total and HDL-C were in the model, no further substantive improvement was achieved with the addition of ApoB (C-index change, 0.0004; 95% CI, 0.0000, 0.0008) or any measure of LDL-C. Results for predictive utility were similar for a fatal CVD outcome, and in a discordance analysis. In participants taking a statin, classical risk factors (C-index, 0.7118) were improved by non–HDL-C (C-index change, 0.0030; 95% CI, 0.0012, 0.0048) or ApoB (C-index change, 0.0030; 95% CI, 0.0011, 0.0048). However, adding ApoB or LDL-C to a model already containing non–HDL-C did not further improve discrimination. Conclusions: Measurement of total cholesterol and HDL-C in the nonfasted state is sufficient to capture the lipid-associated risk in CVD prediction, with no meaningful improvement from addition of apolipoproteins, direct or calculated LDL-C.

In clinical trials, placebo response can affect the inference about efficacy of the studied treatment. It is important to have a robust way to classify trial subjects with respect to their response to placebo. Simple, criterion-based classification may lead to classification error and bias the inference. The uncertainty about placebo response characteristic has to be factored into the treatment effect estimation. We propose a novel approach that views the placebo response as a latent characteristic and the study sample as an unlabeled mixture of “placebo responders” and “placebo nonresponders.” The likelihood-based methodology is used to estimate the treatment effect corrected for placebo response as defined within sequential parallel comparison design.

IMPORTANCE: Guidelines recommend exercise training as a component of heart failure management. There are large disparities in access to rehabilitation, and introducing hybrid comprehensive telerehabilitation (HCTR) consisting of remote monitoring of training at patients’ homes might be an appealing alternative. OBJECTIVE: To assess whether potential improvements in quality-of-life outcomes after a 9-week HCTR intervention in patients with heart failure translate into improvement in clinical outcomes during extended 12 to 24 months of follow-up, compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: The Telerehabilitation in Heart Failure Patients (TELEREH-HF) trial is a multicenter, prospective, open-label, parallel-group randomized clinical trial that enrolled 850 patients with heart failure up to 6 months after a cardiovascular hospitalization with New York Heart Association levels I, II, or III and left ventricular ejection fraction of 40% or less. Patients from 5 centers in Poland were randomized 1:1 to HCTR plus usual care or usual care only and followed up for 14 to 26 months after randomization. INTERVENTIONS: During the first 9 weeks, patients underwent either an HCTR program (1 week in hospital and 8 weeks at home) or usual care with observation. The HCTR intervention encompassed telecare, telerehabilitation, and remote monitoring of implantable devices. No intervention occurred in the remaining study period. MAIN OUTCOMES AND MEASURES: The percentage of days alive and out of the hospital from randomization through the end of follow-up at 14 to 26 months. RESULTS: A total of 850 patients were enrolled, with 425 randomized to the HCTR group (377 male patients [88.7%]; mean [SD] age, 62.6 [10.8] years) and 425 randomized to usual care (376 male patients [88.5%]; mean [SD] age, 62.2 [10.2] years). The HCTR intervention did not extend the percentage of days alive and out of the hospital. The mean (SD) days were 91.9 (19.3) days in the HCTR group vs 92.8 (18.3) days in the usual-care group, with the probability that HCTR extends days alive and out of the hospital equal to 0.49 (95% CI, 0.46-0.53; P = .74) vs usual care. During follow-up, 54 patients died in the HCTR arm and 52 in the usual-care arm, with mortality rates at 26 months of 12.5% vs 12.4%, respectively (hazard ratio, 1.03 [95% CI, 0.70-1.51]). There were also no differences in hospitalization rates (hazard ratio, 0.94 [95% CI, 0.79-1.13]). The HCTR intervention was effective at 9 weeks, significantly improving peak oxygen consumption (0.95 [95% CI, 0.65-1.26] mL/kg/min vs 0.00 [95% CI, −0.31 to 0.30] mL/kg/min; P

Much of medical risk prediction involves externally derived prediction equations, nomograms, and point-based risk scores. These settings are vulnerable to misleading findings of incremental value based on versions of the net reclassification index (NRI) in common use. By applying non-nested models and point-based risk scores in the setting of stroke risk prediction in patients with atrial fibrillation (AF), we demonstrate current recommendations for presentation and interpretation of the NRI. We emphasize pitfalls that are likely to occur with point-based risk scores that are easy to neglect when statistical methodology is focused on continuous models. In order to make appropriate decisions about risk prediction and personalized medicine, physicians, researchers, and policy makers need to understand the strengths and limitations of the NRI.

BACKGROUND: Current cholesterol guidelines recommend using 10-year risk of atherosclerotic cardiovascular disease (ASCVD) to guide informed decisions regarding statin therapy, yet patients may have difficulty conceptualizing absolute risk estimates. Peer comparisons may provide an improved tool for patient risk comprehension. METHODS: Using data from the 2009–2014 National Health and Nutrition Examination Survey (NHANES), we estimated standardized cardiovascular risk percentiles for various age-, sex-, and race-specific subgroups based on their 10-year ASCVD risks using the Pooled Cohort Equations. RESULTS: We examined 9,160 adults in NHANES who were free of cardiovascular disease and had complete clinical data. Among specific age, sex, and race groups, we estimated the distribution of 10-year risk, calculating the 10-year risk corresponding to each percentile in order to generate standardized cardiovascular risk percentiles. Estimated 10-year ASCVD absolute risk varied markedly by age, sex, and race subgroups. A 10-year risk of 7.0% would put a 55 year-old black male in the 20(th) percentile relative to his peers (i.e., at lower risk than 80% of his peers), whereas a 10-year risk of 7.0% would put a 55 year-old white female in the 95(th) percentile (i.e., only 5% of her peers would have higher risk). Standardized cardiovascular risk percentiles by age, race, and sex are available online at populationrelativerisk.dcri.org. CONCLUSION: Cardiovascular risk varies substantially by age, sex, and race. These data allow for 10-year absolute risks of ASCVD to be translated into a standardized cardiovascular risk percentile, providing patients with information that is easy to understanding regarding how their personal risk of cardiovascular disease compares with their age-, sex-, and race-matched peers.

Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.

IMPORTANCE: There are limited clinical trial data and discrepant recommendations regarding use of anticoagulation therapy in patients with atrial fibrillation (AF) aged 65 to 74 years without other stroke risk factors. OBJECTIVES: To evaluate the risk of stroke without anticoagulation therapy in men and women with AF aged 66 to 74 years without other CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, female sex) risk factors and examine the association of stroke incidence with patient age. DESIGN, SETTING, AND PARTICIPANTS: A population-based retrospective cohort study was conducted using linked administrative databases. The population included 16 351 individuals aged 66 to 74 years who were newly diagnosed with AF in Ontario, Canada, between April 1, 2007, and March 31, 2017. Exclusion criteria included long-term care residence, prior anticoagulation therapy, valvular disease, heart failure, hypertension, diabetes, stroke, and vascular disease. The cumulative incidence function was used to estimate the 1-year incidence of stroke in patients who did not receive anticoagulation therapy. Fine-Gray regression was used to study the association of patient characteristics with stroke incidence and derive estimates of stroke risk at each age. Death was treated as a competing risk and patients were censored if they initiated anticoagulation therapy. Inverse probability of censoring weights was used to account for patient censoring. Data analysis was performed from May 26, 2019, to December 9, 2020. EXPOSURES: Atrial fibrillation and age. MAIN OUTCOMES AND MEASURES: Hospitalizations for stroke. RESULTS: Of the 16 351 individuals with AF (median [interquartile range] age, 70 [68-72] years), 8352 (51.1%) were men; 6314 individuals (38.6%) started anticoagulation therapy during follow-up. The overall 1-year stroke incidence among patients who did not receive anticoagulation therapy was 1.1% (95% CI, 1.0%-1.3%) and the incidence of death without stroke was 8.1% (95% CI, 7.7%-8.5%). The incidence of stroke was not significantly associated with sex. The estimated 1-year stroke risk increased with patient age from 66 years (0.7%; 95% CI, 0.5%-0.9%) to 74 years (1.7%; 95% CI, 1.3%-2.1%). CONCLUSIONS AND RELEVANCE: The risk of stroke more than doubled in this study as men and women with AF but no other CHA(2)DS(2)-VASc risk factors aged from 66 to 74 years. These data suggest that anticoagulation therapy is more likely to benefit older individuals within this group of patients, whereas younger individuals are less likely to gain net clinical benefit from anticoagulation therapy.

We conducted a meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs to synthesize evidence about the efficacy and safety of alternate-day vs daily dosing of statins.We searched selected databases through January 2, 2017 to identify relevant RCTs and quasi-RCTs. The primary outcome was change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), while secondary outcomes included adverse events and adherence.Twelve RCTs and 1 quasi-RCT (n = 1023 patients) were included in the analysis. Pooled analysis revealed no statistically significant difference between alternate-day and daily regimens of atorvastatin and rosuvastatin in terms of change in LDL-C (mean difference [MD] 6.79 mg/dL, 95% confidence interval [CI] -1.59, 15.17, p = 0.11, and 10.51 mg/dL, 95%CI -0.23, 21.26, p = 0.06, respectively) and TG (p 0.05). Daily regimens of atorvastatin and rosuvastatin were superior to alternate-day regimes in term of change in TC (MD 12.45 mg/L, 95%CI 8.14, 16.76, p 0.00001, and 15.80 mg/dL, 95%CI 5.66, 25.95, p = 0.002, respectively). For all outcomes, there was no statistically significant difference between alternate-day and daily regimens for both fluvastatin and pravastatin (p 0.05). Both regimens of statins were generally well tolerated with good adherence.Alternate-day dosing of individual statins (especially atorvastatin and rosuvastatin) is as efficacious as daily dosing on LDL-C and TG.

Background Randomized trials support the use of transcatheter aortic valve replacement (TAVR) for the treatment of aortic stenosis in high- and intermediate-risk patients, but the generalizability of those results in clinical practice has been challenged. Objectives The aim of this study was to determine the safety and effectiveness of TAVR versus surgical aortic valve replacement (SAVR), particularly in intermediate- and high-risk patients, in a nationally representative real-world cohort. Methods Using data from the Transcatheter Valve Therapy Registry and Society of Thoracic Surgeons National Database linked to Medicare administrative claims for follow-up, 9,464 propensity-matched intermediate- and high-risk (Society of Thoracic Surgeons Predicted Risk of Mortality score ≥3%) U.S. patients who underwent commercial TAVR or SAVR were examined. Death, stroke, and days alive and out of the hospital to 1 year were compared, as well as discharge home, with subgroup analyses by surgical risk, demographics, and comorbidities. Results In a propensity-matched cohort (median age 82 years, 48% women, median Society of Thoracic Surgeons Predicted Risk of Mortality score 5.6%), TAVR and SAVR patients experienced no difference in 1-year rates of death (17.3% vs. 17.9%; hazard ratio: 0.93; 95% confidence interval [CI]: 0.83 to 1.04) and stroke (4.2% vs. 3.3%; hazard ratio: 1.18; 95% CI: 0.95 to 1.47), and no difference was observed in the proportion of days alive and out of the hospital to 1 year (rate ratio: 1.00; 95% CI: 0.98 to 1.02). However, TAVR patients were more likely to be discharged home after treatment (69.9% vs. 41.2%; odds ratio: 3.19; 95% CI: 2.84 to 3.58). Results were consistent across most subgroups, including among intermediate- and high-risk patients. Conclusions Among unselected intermediate- and high-risk patients, TAVR and SAVR resulted in similar rates of death, stroke, and DAOH to 1 year, but TAVR patients were more likely to be discharged home.

Background: Optimal management of patients with stable chest pain relies on the prognostic information provided by noninvasive cardiovascular testing, but there are limited data from randomized trials comparing anatomic with functional testing. Methods: In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain and intermediate pretest probability for obstructive coronary artery disease (CAD) were randomly assigned to functional testing (exercise electrocardiography, nuclear stress, or stress echocardiography) or coronary computed tomography angiography (CTA). Site-based diagnostic test reports were classified as normal or mildly, moderately, or severely abnormal. The primary end point was death, myocardial infarction, or unstable angina hospitalizations over a median follow-up of 26.1 months. Results: Both the prevalence of normal test results and incidence rate of events in these patients were significantly lower among 4500 patients randomly assigned to CTA in comparison with 4602 patients randomly assigned to functional testing (33.4% versus 78.0%, and 0.9% versus 2.1%, respectively; both P P P =0.87], 2.65 [ P =0.001], 3.88 [ P P =0.04). If 2714 patients with at least an intermediate Framingham Risk Score (>10%) who had a normal functional test were reclassified as being mildly abnormal, the discriminatory capacity improved to 0.69 (95% CI, 0.64–0.74). Conclusions: Coronary CTA, by identifying patients at risk because of nonobstructive CAD, provides better prognostic information than functional testing in contemporary patients who have stable chest pain with a low burden of obstructive CAD, myocardial ischemia, and events. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01174550.

Background/aims Use of data monitoring committees to oversee clinical trials was first proposed nearly 50 years ago. Since then, data monitoring committee use in clinical trials has increased and evolved. Nonetheless, there are no well-defined criteria for determining the need for a data monitoring committee, and considerable variability exists in data monitoring committee composition and conduct. To understand and describe the role and function of data monitoring committees, and establish best practices for data monitoring committee trial oversight, the Clinical Trials Transformation Initiative—a public–private partnership to improve clinical trials—launched a multi-stakeholder project. Methods The data monitoring committee project team included 16 individuals charged with (1) clarifying the purpose of data monitoring committees, (2) identifying best practices for independent data monitoring committee conduct, (3) describing effective communication practices, and (4) developing strategies for training data monitoring committee members. Evidence gathering included a survey, a series of focus group discussions, and a 2-day expert meeting aimed at achieving consensus opinions that form the foundation of our data monitoring committee recommendations. Results We define the role of the data monitoring committee as an advisor to the research sponsor on whether to continue, modify, or terminate a trial based on periodic assessment of trial data. Data monitoring committees should remain independent from the sponsor and be composed of members with no relevant conflicts of interest. Representation on a data monitoring committee generally should include at least one clinician with expertise in the therapeutic area being studied, a biostatistician, and a designated chairperson who has experience with clinical trials and data monitoring. Data monitoring committee meetings are held periodically to evaluate the unmasked data from ongoing trials, but the content and conduct of meetings may vary depending on specific goals or topics for deliberation. To guide data monitoring committee conduct and communication plans, a charter consistent with the protocol’s research design and statistical analysis plan should be developed and agreed upon by the sponsor and the data monitoring committee prior to patient enrollment. We recommend concise and flexible charters that explain roles, responsibilities, operational issues, and how data monitoring committee recommendations are generated and communicated. The demand for data monitoring committee members appears to exceed the current pool of qualified individuals. To prepare a new generation of trained data monitoring committee members, we encourage a combination of didactic educational programs, practical experience, and skill development through apprenticeships and mentoring by experienced data monitoring committee members. Conclusion Our recommendations address data monitoring committee use, conduct, communication practices, and member preparation and training. Furthermore recommendations form the foundation for ongoing efforts to improve clinical trial oversight and enhance the safety and integrity of clinical research. These recommendations serve as a call to action for implementation of best practices that benefit study participants, study sponsors, and society.

An increasingly important data source for the development of clinical risk prediction models is electronic health records (EHRs). One of their key advantages is that they contain data on many individuals collected over time. This allows one to incorporate more clinical information into a risk model. However, traditional methods for developing risk models are not well suited to these irregularly collected clinical covariates. In this paper, we compare a range of approaches for using longitudinal predictors in a clinical risk model. Using data from an EHR for patients undergoing hemodialysis, we incorporate five different clinical predictors into a risk model for patient mortality. We consider different approaches for treating the repeated measurements including use of summary statistics, machine learning methods, functional data analysis, and joint models. We follow up our empirical findings with a simulation study. Overall, our results suggest that simple approaches perform just as well, if not better, than more complex analytic approaches. These results have important implication for development of risk prediction models with EHRs. Copyright © 2017 John Wiley & Sons, Ltd.

Drug-eluting stents (DES) reduce restenosis but require prolonged antiplatelet therapy, when compared with bare metal stents. Ideally, the patient should be involved in this risk:benefit assessment prior to selecting DES, to maximize the benefits and cost-effectiveness of care, and to improve medication adherence. However, accurate estimation of restenosis risk may require angiographic factors identified at cardiac catheterization.In a large PCI registry, we used logistic regression to identify clinical and angiographic predictors of clinically-driven target lesion revascularization (TLR) over the first year after stent placement. Discrimination c-statistic and integrated discrimination improvement (IDI) were used to calculate the incremental utility of angiographic variables when added to clinical predictors.Of 8501 PCI patients, TLR occurred in 4.5%. After adjusting for DES use, clinical TLR predictors were younger age, female sex, diabetes, prior PCI, and prior bypass surgery (model c-statistic 0.630). Angiographic predictors were vein graft PCI, in-stent restenosis lesion, longer stent length, and smaller stent diameter (c-statistic 0.650). After adding angiographic factors to the clinical model, c-statistic improved to 0.680 and the average separation in TLR risk among patients with and without TLR improved by 1% (IDI=0.010, 95% CI 0.009-0.014), primarily driven by those experiencing TLR (from 5.9% to 6.9% absolute risk).Among unselected PCI patients, the incidence of clinically-indicated TLR is5% at 1-year, and standard clinical variables only moderately discriminate who will and will not experience TLR. Angiographic variables significantly improve TLR risk assessment, suggesting that stent selection may be best performed after coronary anatomy has been delineated.Although several recent studies have challenged traditional expectations regarding the duration of dual antiplatelet therapy, current guidelines recommend at least 6 to 12months of treatment after implantation of a drug eluting stent, with a shorter course for bare metal stents. Stent selection ideally should involve input from the patient receiving these stents, but multiple studies have suggested that angiographic factors - obtained after the patient has received sedation during the diagnostic catheterization - are important predictors of repeat revascularization. In this analysis from a large registry of patients receiving coronary stents, angiographic characteristics were found to significantly improve risk assessment for target lesion revascularization, when added to clinical variables alone.

Polytomous discrimination index is a novel and important diagnostic accuracy measure for multi-category classification. After reconstructing its probabilistic definition, we propose a nonparametric approach to the estimation of polytomous discrimination index based on an empirical sample of biomarker values. In this paper, we provide the finite-sample and asymptotic properties of the proposed estimators and such analytic results may facilitate the statistical inference. Simulation studies are performed to examine the performance of the nonparametric estimators. Two real data examples are analysed to illustrate our methodology.

Background and Purpose: Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees’ independence and effectiveness. Methods: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. Results and Conclusions: Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee’s independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

Objectives This study sought to determine whether processes of care and long-term clinical outcomes for heart failure (HF) admissions across Get With The Guidelines-Heart Failure (GWTG-HF) program participating centers differ according to HF-specific risk-adjusted 30-day readmission rates (excess readmission ratio [ERR]) as determined by the Hospital Readmission Reduction Program (HRRP). Background HRRP penalizes hospitals with higher than expected risk-adjusted 30-day readmission rates (ERR >1) for common conditions including HF. However, it is unclear whether the differences in this metric of hospital performance used by HRRP and related penalties are associated with measured quality of care and long-term outcomes. Methods We analyzed data from the GWTG-HF registry linked to Medicare claims from July 2008 to June 2011. Using publically available data on HF-ERR in 2013, we stratified the participating centers into groups with low (HF-ERR ≤1) versus high (HF-ERR >1) risk-adjusted readmission rates. We compared the care quality, in-hospital, and 1-year clinical outcomes across the 2 groups in unadjusted and multivariable adjusted analysis. Results The analysis included 171 centers with 43,143 participants; 49% of centers had high risk-adjusted 30-day readmission rates (HF-ERR >1). There were no differences between the low and high risk-adjusted 30-day readmission groups in median adherence rate to all performance measures (95.7% vs. 96.5%; p = 0.37) or median percentage of defect-free care (90.0% vs. 91.1%; p = 0.47). The composite 1-year outcome of death or all-cause readmission rates was also not different between the 2 groups (median 62.9% vs. 65.3%; p = 0.10). The high HF-ERR group had higher 1-year all-cause readmission rates (median 59.1% vs. 54.7%; p = 0.01). However, the 1-year mortality rates were lower among high versus low HF-ERR group with a trend toward statistical significance (median 28.2% vs. 31.7%; p = 0.07). Conclusions Quality of care and clinical outcomes were comparable among hospitals with high versus low risk-adjusted 30-day HF readmission rates. These findings raise questions about the validity of the HRRP performance metric in identifying and penalizing low-performance centers.

Background Costs and uncertainty about the benefits of nonstatin therapies limit their use. Objectives The authors sought to identify patients who might benefit from the addition of a nonstatin to background statin therapy. Methods We performed systematic reviews of subgroup analyses from randomized trials and observational studies with statin-treated participants to determine estimated 10-year absolute risk of atherosclerotic cardiovascular disease (ASCVD) and to define high-risk and very high-risk patients. We used the relative risk reductions for the addition of a nonstatin to lower low-density lipoprotein (LDL-C) used to determine the number needed to treat (NNT) to prevent 1 ASCVD event over 5 years for each patient group and to allow comparisons with 5-year cost analyses. Results The 10-year ASCVD risk is at least 30% (very high risk) for statin-treated participants with clinical ASCVD and comorbidities, and 20% to 29% (high risk) for those with ASCVD without comorbidities or who have heterozygous familial hypercholesterolemia. Adding ezetimibe to reduce low-density LDL-C by 20% would provide a 5-year NNT ≤50 for very high-risk patients with LDL-C ≥130 mg/dl or for high-risk patients with LDL-C ≥190 mg/dl, and an NNT ≤30 for very high-risk patients with LDL-C ≥160 mg/dl. Adding a PCSK9 monoclonal antibody to lower LDL-C by at least 50% would provide an NNT ≤50 for very high-risk and high-risk patients with LDL-C ≥70 mg/dl, and an NNT ≤30 for very high-risk and high-risk patients with an LDL-C ≥130 mg/dl. Conclusions Adding ezetimibe or PCSK9 monoclonal antibodies to maximally tolerated statin therapy may be cost effective in very high-risk and high-risk patients, depending on baseline LDL-C levels.

BACKGROUND: Trapping of apoB lipoprotein particles within the arterial wall initiates and drives the atherosclerotic process from beginning to end. Very low-density lipoprotein particles (VLDL) contain most of the triglyceride in plasma whereas low-density lipoprotein particles (LDL) particles contain most of the cholesterol. Smaller numbers of chylomicron and Lp(a) particles are also present in plasma. All these particles have one molecule of apoB. Therefore, plasma apoB equals the total number of apoB particles. Because the lipid content of apoB particles is variable, plasma triglyceride and cholesterol are not always accurate-measures of the number of apoB particles. THE CHOLESTEROL MODEL OF ATHEROSCLEROSIS: The conventional model of atherosclerosis presumes that the mass of cholesterol within VLDL and LDL particles is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. But cholesterol can only enter the arterial wall within apoB particles and the mass of cholesterol that will be deposited is determined by the rate at which apoB particles are trapped within the arterial wall rather than passing harmless through. THE APOB PARTICLE MODEL OF ATHEROGENESIS: The number of apoB particles that enter and are trapped within the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. If so, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle. By contrast, more smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and Lp(a), all apoB particles are equally atherogenic. ApoB, therefore, unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins.

Background Statins are now widely used for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, existing risk prediction models were developed primarily on patients not on statins. We developed a novel model to estimate the risk of ASCVD among contemporary patients taking statins. Methods Using combined data from 3 large NIH-sponsored cohort studies: Atherosclerosis Risk in Communities, Framingham Offspring Study, and Multi-ethnic Study of Atherosclerosis we examined adults aged 40–79 years without prior ASCVD who were on statin therapy at the baseline exam. A Cox proportional hazards model was used to identify factors associated with a 10-year risk of CV death, MI, or stroke. Age, sex, and race were forced into the model while other potential candidate predictors were retained if statistically significant at the 0.05 level. Interaction terms with age, sex, and race were retained if significant at the 0.01 level. The model was assessed with c-statistic and calibration plots of observed events versus model-based risks after cross-validation and contrasted with the Pooled Cohorts Equations (PCE) recommended by the current U.S. guidelines. Results Among 2333 primary prevention patients on statins at baseline, a total of 220 events occurred over a median 8.8 years of follow-up. Most risk factors retained in our final model overlapped with those included in the PCE (age, sex, race, systolic blood pressure [sBP], diabetes, smoking, high-density lipoprotein cholesterol, total cholesterol). Our model also included creatinine clearance, aspirin use, and the interaction between age and sBP. Optimism-corrected discrimination of the new model was marginally higher than PCE: 0.69 (95% CI 0.66–0.72) versus 0.68 (95% CI 0.65–0.72). Cross-validated calibration was superior on our contemporary sample, especially at the higher levels of risk (Figure), where PCE over-estimated risk. Calibration plots Conclusion Accurate estimation of 10-year ASCVD risk among patients currently on statins necessitates recalibration of the current PCE model or application of our algorithm developed specifically for this cohort. This might help avoid over-estimation of risk and reduce the need for unnecessary additional lipid-lowering therapy. Acknowledgement/Funding Regeneron Pharmaceuticals

Background The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) guidelines for the management of arterial hypertension and the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the prevention, detection, evaluation, and management of high blood pressure in adults differ in approach to defining stages of hypertension and recommendations for treatment of high blood pressure. Purpose To contrast the implications of the ESC/ESH versus ACC/AHA hypertension guidelines among the general population in Poland – a country representing a high CVD risk region in Europe. Methods We used data from a representative random sample of 1439 Polish adults aged 40 to 79 from the research program NATPOL 2011. The analysis was weighted in order to reflect the structure of the population in Poland and was stratified by age and gender. We applied the ESC/ESH 10-year SCORE (Systematic COronary Risk Evaluation) and the ACC/AHA ASCVD (atherosclerotic CV disease) risk assessment tools and followed guideline-specific algorithms to detect hypertension and follow recommendations for treatment. Results The overall prevalence of hypertension among Polish adults according to the ACC/AHA guideline was 76.9% (95% CI, 74.7–79.0%) versus 51.8% (95% CI, 49.2–54.4%) according to the ESC/ESH guidelines. Application of the ACC/AHA guideline recommendations would result in antihypertensive drug treatment for 63.0% (95% CI, 60.5–65.5%) of Polish adults compared with 46.2% (95% CI, 43.6–48.7%) based on application of the ESC/ESH guidelines (difference 16.8% (95% CI, 14.9–18.8%), table 1). Table 1 2017 ACC/AHA guideline 2018 ESC/ESH guideline Δ (difference) Hypertension Recommended treatment Hypertension Recommended treatment Hypertension Recommended treatment % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) Age 40–49 (n=391) 63.2 (58.4–68.0) 37.3 (32.6–42.1) 32.0 (27.4–36.6) 21.2 (17.2–25.3) 31.2 (26.6–35.8) 16.1 (12.5–19.8) 50–59 (n=452) 77.7 (73.8–81.5) 61.7 (57.2–66.2) 49.1 (44.5–53.7) 40.0 (35.5–44.6) 28.5 (24.4–32.7) 21.7 (17.9–25.5) 60–69 (n=356) 82.3 (78.3–86.3) 75.3 (70.8–79.8) 62.4 (57.3–67.4) 61.5 (56.5–66.6) 19.9 (15.8–24.1) 13.8 (10.2–17.3) 70–79 (n=231) 90.0 (86.2–93.9) 90.0 (86.2–93.9) 74.5 (68.8–80.1) 76.6 (71.2–82.1) 15.6 (10.9–20.3) 13.4 (9.0–17.8) Gender Male (n=689) 80.4 (77.4–83.4) 67.5 (64.0–71.0) 52.5 (48.8–56.3) 47.2 (43.4–50.9) 27.9 (24.5–31.2) 20.3 (17.3–23.3) Female (n=741) 73.6 (70.4–76.7) 58.8 (55.3–62.4) 51.2 (47.6–54.8) 45.2 (41.6–48.8) 22.4 (19.4–25.4) 13.6 (11.2–16.1) Conclusions Application of the ACC/AHA guideline would result in a considerable increase in the prevalence and antihypertensive drug treatment of hypertension in Polish adults compared with application of the ESC/ESH guidelines.

IMPORTANCE: American College of Cardiology/American Heart Association cholesterol guidelines prioritize primary prevention statin therapy based on 10-year absolute risk (AR(10)) of atherosclerotic cardiovascular disease (ASCVD). However, given the same AR(10), patients with higher levels of low-density lipoprotein cholesterol (LDL-C) experience greater absolute risk reduction from statin therapy. OBJECTIVES: To estimate the cost-effectiveness of expanding preventive statin treatment eligibility from standard care to patients at borderline risk (AR(10), 5.0%-7.4%) for ASCVD and with high levels of LDL-C and to estimate cost-effectiveness of statin treatment across ranges of age, sex, AR(10), and LDL-C levels. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated 100 simulated cohorts, each including 1 million ASCVD-free survey respondents (50% men and 50% women) aged 40 years at baseline. Cohorts were created by probabilistic sampling of the 1999-2014 US National Health and Nutrition Examination Surveys from the perspective of the US health care sector. The CVD Policy Model microsimulation version projected lifetime health and cost outcomes. Probability of first-ever coronary heart disease or stroke event was estimated by analysis of 6 pooled US cohort studies and recalibrated to match contemporary event rates. Other model variables were derived from national surveys, meta-analyses, and published literature. Data were analyzed from May 15, 2018, through June 10, 2019. EXPOSURES: Four statin treatment strategies were compared: (1) treat all patients with AR(10) of at least 7.5%, diabetes, or LDL-C of at least 190 mg/dL (standard care); (2) add treatment for borderline risk and LDL-C levels of 160 to 189 mg/dL; (3) add treatment for borderline risk and LDL-C levels of 130 to 159 mg/dL; and (4) add treatment for remainder of patients with AR(10) of at least 5.0%. Statin treatment was also compared with no statin treatment in age, sex, AR(10), and LDL-C strata. MAIN OUTCOMES AND MEASURES: Lifetime quality-adjusted life-years (QALYs) and costs (2019 US dollars) were projected and discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. RESULTS: In these 100 simulated cohorts, each with 1 million patients aged 40 years at baseline (50% women and 50% men), adding preventive statins to individuals with borderline AR(10) and LDL-C levels of 160 to 189 mg/dL would be cost-saving; further treating borderline AR(10) and LDL-C levels of 130 to 159 mg/dL would also be cost-saving; and treating all individuals with AR(10) of at least 5.0% would be highly cost-effective ($33 558/QALY) and would prevent the most ASCVD events. Within age, AR(10), and sex categories, individuals with higher baseline LDL-C levels gained more QALYs from statin therapy. Cost-effectiveness increased with LDL-C level and AR(10). CONCLUSIONS AND RELEVANCE: In this study, lifetime statin treatment of patients in a hypothetical cohort with borderline ASCVD risk and LDL-C levels of 160 to 189 mg/dL was found to be cost-saving. Results suggest that treating all patients at borderline risk regardless of LDL-C level would likely be highly cost-effective.