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BACKGROUND: Little is known about the comparative effect of weight-loss diets on metabolic profiles during dieting. OBJECTIVE: The purpose of this study was to compare the effect of a low-carbohydrate diet (< or =20 g/d) with a high-carbohydrate diet (55% of total energy intake) on fasting and hourly metabolic variables during active weight loss. DESIGN: Healthy, obese adults (n = 32; 22 women, 10 men) were randomly assigned to receive either a carbohydrate-restricted diet [High Fat; mean +/- SD body mass index (BMI; in kg/m(2)): 35.8 +/- 2.9] or a calorie-restricted, low-fat diet (High Carb; BMI: 36.7 +/- 4.6) for 6 wk. A 24-h in-patient feeding study was performed at baseline and after 6 wk. Glucose, insulin, free fatty acids (FFAs), and triglycerides were measured hourly during meals, at regimented times. Remnant lipoprotein cholesterol was measured every 4 h. RESULTS: Patients lost a similar amount of weight in both groups (P = 0.57). There was an absence of any diet treatment effect between groups on fasting triglycerides or on remnant lipoprotein cholesterol, which was the main outcome. Fasting insulin decreased (P = 0.03), and both fasting (P = 0.040) and 24-h FFAs (P < 0.0001) increased within the High Fat group. Twenty-four-hour insulin decreased (P < 0.05 for both groups). Fasting LDL cholesterol decreased in the High Carb group only (P = 0.003). In both groups, the differences in fasting and 24-h FFAs at 6 wk were significantly correlated with the change in LDL cholesterol (fasting FFA: r = 0.41, P = 0.02; 24-h FFA: r = 0.52, P = 0.002). CONCLUSIONS: Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrations. This effect was related to the lack of suppression of both fasting and 24-h FFAs. © 2010 American Society for Nutrition. [ABSTRACT FROM AUTHOR]

Background: Rivaroxaban 2.5 mg plus aspirin reduced limb and cardiovascular events and increased bleeding in patients with symptomatic peripheral artery disease (PAD) after lower extremity revascularization in the VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) study. Fragile patients are at heightened risk for ischemic and bleeding events., Objectives: The purpose of this study was to investigate the safety and efficacy of rivaroxaban 2.5 mg in fragile patients from VOYAGER PAD., Methods: Patients were categorized as fragile based on prespecified criteria (age >75 years, weight ≤50 kg, or baseline estimated glomerular filtration rate <50 mL/min/1.73 m 2 ). The primary efficacy outcome was the composite of acute limb ischemia, major amputation of a vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was TIMI major bleeding., Results: Of 6,564 randomized patients, a total of 1,674 subjects were categorized as fragile at baseline. In the placebo arm, fragile patients were at higher risk of the primary outcome (HR: 1.34; 95% CI: 1.12-1.61) and TIMI major bleeding (HR: 1.57; 95% CI: 0.83-2.96), compared with nonfragile patients. The effect of rivaroxaban on the primary endpoint was not modified by frailty status (fragile HR: 0.93; 95% CI: 0.75-1.15; nonfragile HR: 0.83; 95% CI: 0.72-0.97; P interaction = 0.37). Rivaroxaban increased TIMI major bleeding in fragile (HR: 1.54; 95% CI: 0.82-2.91) and nonfragile patients (HR: 1.37; 95% CI: 0.84-2.23; P interaction = 0.65)., Conclusions: Patients with PAD after lower extremity revascularization meeting fragile criteria are at higher risk of ischemic complications and bleeding. Rivaroxaban reduces ischemic risk and increases bleeding regardless of frailty status. These data may assist in personalization of antithrombotic therapy in fragile population., Competing Interests: Funding Support and Author Disclosures VOYAGER PAD was funded by Bayer and Janssen Pharmaceuticals. The Colorado Prevention Center Clinical Research held the database and performed all analyses, and the decision to submit this manuscript for publication was made by the VOYAGER PAD Publications Committee. Drs Canonico, Low Wang, Hsia, Nehler, Capell, Berkowitz, and Bonaca receive salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between July 2021 and July 2023 from the following organizations: Abbott Laboratories, Agios Pharmaceuticals, Inc, Alexion Pharma Godo Kaisha, Amgen Inc, Anthos Therapeutics, Inc, ARCA biopharma, Inc, AstraZeneca Pharma India, AstraZeneca Pharmaceuticals LP, AstraZeneca UK Ltd, AstraZeneca Produtos Farmaceuticos, Lda, Atentiv, LLC, Bayer, Bayer (Proprietary) Limited, Bayer Aktiengesellschaft, Bayer Pharma AG, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, LLC, Bristol Myers Squibb, CellResearch Corporation Pte Ltd, Cleerly, Inc, Colorado Department of Public Health and Environment, Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc, EPG Communication Holdings Ltd, Esperion Therapeutics, Inc, Faraday Pharmaceuticals, Inc, HeartFlow Inc, Insmed, Ionis Pharmaceuticals, IQVIA Inc, Janssen Pharmaceuticals, Inc, Janssen Research and Development, LLC, Janssen Scientific Affairs LLC, Lexicon Pharmaceuticals, Inc, LSG Corporation, MedImmune Limited, Medpace, Inc, Medscape, Merck Sharp and Dohme Corp, Nectero Medical Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Osiris Therapeutics, Inc, Pfizer, PPD Development, LP, Prothena Biosciences Limited, Regeneron, Regents of the University of Colorado (aka UCD), Sanifit Therapeutics SA, Sanofi, Silence Therapeutics PLC, Stanford University, Stealth BioTherapeutics Inc, The Brigham and Women's Hospital, Inc, Thrombosis Research Institute, University of Colorado Denver, University of Pittsburgh, VarmX, and WraSer, LLC. Dr Hsia owns stock in AstraZeneca. Dr Debus has received grant support from Cook and Terumo Aortic. Dr Patel has received grant support, advisory board fees, and consulting fees from AstraZeneca, Bayer, and Janssen; has received grant support from Medtronic and Philips Healthcare; and has received grant support and advisory board fees from Heartflow. Dr Anand has received lecture fees from Bayer and Janssen. Dr Muehlhofer was employed by Bayer. Dr Haskell was employed by Janssen Pharmaceuticals; and has owned stock in Johnson and Johnson. Dr Berkowitz was employed by Bayer during the operationalization of the VOYAGER PAD study. Dr Bauersachs has received consulting fees and lecture fees from Bayer, Bristol Myers Squibb, and Pfizer. Dr Bonaca has received support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project); and has stock in Medtronic and Pfizer. Dr Ycas has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis., Objectives: This study sought to determine the effect of ticagrelor on limb events., Methods: Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline., Results: Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; P interaction  = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (P interaction  = 0.40) or TIMI major bleeding (P interaction  = 0.3239)., Conclusions: Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus [THEMIS]: NCT01991795)., Competing Interests: Funding Support and Author Disclosures THEMIS was funded and sponsored by AstraZeneca Research & Development. Dr Bonaca is the Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, Anthos, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol Myers Squibb, Cardiol Therapeutics, CellResearch, Cleerly, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, Novo Nordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group; has stock in Medtronic and Pfizer; and has received consulting fees from Audentes. Dr Bhatt serves as the co-chair of THEMIS and THEMIS-PCI with research funding from AstraZeneca paid to Brigham and Women’s Hospital. He discloses the following relationships: Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, Svelte, and Vascular Solutions; Trustee: American College of Cardiology; and Unfunded Research: FlowCo, Takeda. Dr Leiter has received research funding from, has provided CME on behalf of, and/or has received research funding from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, HLS, Kowa, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Servier. Dr Himmelmann is an employee of AstraZeneca. Drs Ridderstråle, Andersson, and Chen are employees of AstraZeneca. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on the advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has stock options in Artera Health and Saghmos Therapeutics. Dr McGuire has received honoraria for trial leadership from Boehringer Ingelheim, Sanofi, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring; and has received consulting fees from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, CSL Behring, Bayer, Altimmune, Intercept, and Pfizer. Dr Steg has received grants and nonfinancial support (cochair of the ODYSSEY OUTCOMES trial [Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab]; as such, he has received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi; has received research grants and personal fees from Bayer (Steering Committee MARINER [A Study of Rivaroxaban (JNJ-39039039) on the Venous Thromboembolic Risk of Post-Hospital Discharge Patients], grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (cochair of the ODYSSEY OUTCOMES trial; cochair of the SCORED trial (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk); has received consulting and speaker fees from Servier (Chair of the CLARIFY registry [Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease]; grant for epidemiological research), and Amarin (executive steering committee for the REDUCE-IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial]; consulting); has received personal fees from Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca; and has a European application number/patent number, issued on October 26, 2016 (No. 15712241.7), for a method for reducing cardiovascular risk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown., Methods: ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days., Results: Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was -16.8% (interquartile range, -45.7 to 36.8; P =0.41) with rNAPc2 treatment and -11.2% (-36.0 to 34.4; P =0.91) with heparin ( P intergroup =0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% [-14.9 to 145.2]; P =0.02) than the rNAPc2 group (median, 25.9% [-49.1 to 136.4]; P =0.14; P intergroup =0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, -32.7% [-44.7 to 4.3]; P =0.007 and heparin median, -16.8% [-36.0 to 0.5]; P =0.008, P intergroup =0.34)., Conclusions: rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04655586., Competing Interests: Disclosures I.A. Carroll, D. Marshall, C.A. Graybill, and S.P. Huebler report employment with ARCA biopharma during the conduct of ASPEN; T. Keuer reports that he is an employee and officer of ARCA biopharma; W. Ruf reports speaker’s income from NovoNordisk, research support from ICONIC Therapeutic, consultant, research support, intellectual property, and royalty income from ARCA biopharma, and ownership in MeruVasImmune; D.A. Morrow is a member of the TIMI Study group, which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott Laboratories, Amgen, Anthos Therapeutics, ARCA biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Janssen, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron, Roche, Siemens, and Zora Biosciences. D.A. Morrow has also received consulting fees from ARCA biopharma, InCarda, Inflammatrix, Merck, Novartis, and Roche Diagnostics; JCN reports grant support from Amgen, AstraZeneca, Bayer, Esperion, CLS Behring, Dalcor, Daiichi Sankyo, Janssen, Novartis, NovoNordisk, Sanofi, and Vifor and is recipient of a scholarship from the National Council for Scientific and Technological development (CNPq No. 301242/2017/8); O. Berwanger reports research grants (paid to his institution) from AstraZeneca, Bayer, Amgen, Novartis, Servier, Boehringer-Ingelheim, and BMS; M. Szarek reports grant support from Sanofi, Regeneron, Esperion, CiVi, Lexicon, and Bayer and consulting fees from Resverlogix; F. Franchi has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer and Sanofi; and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation; M.R. Bristow reports he is an employee, officer, and director of ARCA biopharma; C.N. Hess, W.H. Capell, M. Szarek, J. Hsia, and M.P. Bonaca receive salary support from CPC, a non-profit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding from the following organizations: Abbott Laboratories, Adamis Pharmaceuticals Corporation, Agios Pharmaceuticals, Inc, Alexion Pharma, Alnylam Pharmaceuticals, Inc, Amgen Inc, Angionetics, Inc, ARCA biopharma, Inc, Array BioPharma, Inc, AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc, Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc, BIDMC, Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Inc, Cardiol Therapeutics Inc, CellResearch Corp, Cook Medical Incorporated, Covance, CSL Behring LLC, Eidos Therapeutics, Inc, EP Trading Co Ltd, EPG Communication Holdings Ltd, Epizon Pharma, Inc, Esperion Therapeutics, Inc, Everly Well, Inc, Exicon Consulting Pvt Ltd, Faraday Pharmaceuticals, Inc, Foresee Pharmaceuticals Co Ltd, Fortress Biotech, Inc, HDL Therapeutics Inc, HeartFlow Inc, Hummingbird Bioscience, Insmed Inc, Ionis Pharmaceuticals, IQVIA Inc, JanOne Biotech Holdings Inc, Janssen and Affiliates, Kaneka, Kowa Research Institute, Inc, Kyushu University, Lexicon Pharmaceuticals, Inc, LSG Kyushu University, Medimmune Ltd, Medpace, Merck & Affiliates, Novartis Pharmaceuticals Corp, Novate Medical, Ltd, Novo Nordisk, Inc, Pan Industry Group, Pfizer Inc, PhaseBio Pharmaceuticals, Inc, PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Inc, Rexgenero, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stealth BioTherapeutics Inc, State of Colorado CCPD Grant, The Brigham & Women's Hospital, Inc, The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, WCT Atlas, Worldwide Clinical Trials Inc, WraSer, LLC, and Yale Cardiovascular Research Group. J. Hsia also reports owning AstraZeneca stock; M.P. Bonaca receives support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project) and reports stock in Medtronic and Pfizer. The other authors report no conflicts.

Background: Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described., Methods: In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline., Results: Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (P interaction  = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance., Conclusions: Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain., (Copyright © 2022 Society for Vascular Surgery. All rights reserved.)

Importance: Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER)., Objective: To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER., Design, Setting, and Participants: This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021., Exposure: Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician., Main Outcomes and Measures: Symptomatic VTE was a prespecified secondary outcome and prospectively collected., Results: Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67)., Conclusions and Relevance: In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.

Background: Vascular disease burden after lower extremity revascularization (LER) comprises more than the first event, more vascular beds than the local arteries, and more than one clinical event type., Objectives: Assess total arterial and venous thrombotic burden after LER for symptomatic peripheral artery disease (PAD) and effect of low-dose anticoagulation added to low-dose antiplatelet therapy., Patients/methods: VOYAGER PAD randomized 6564 symptomatic PAD patients undergoing LER to rivaroxaban 2.5 mg twice-daily or placebo on aspirin background. Marginal proportional-hazards models used to generate treatment hazard ratios and associated 95% CIs for first and total events; non-thrombotic deaths treated as competing terminal events. Incidence rates calculated as number of events per 100 patient-years follow-up., Results: Over 2.5 years (median), first and total thrombotic event rates: 7.1 and 10.3 events/100 patient-years, respectively, in placebo group. Two-thirds (925/1372) of total thrombotic events (arterial 95%, venous 5%) were nonfatal first events. Nearly one-third of patients with first event had a second arterial or venous thrombotic event. Rivaroxaban plus aspirin reduced first and total arterial and venous thrombotic events to 5.4 and 7.9 events/100 patient-years, respectively, a reduction in total thrombotic events over aspirin of 23% (HR: 0.77, 95%CI: 0.67-0.89, p = .0005), preventing 6.1 total arterial and venous thrombotic events at 3 years., Conclusions: Assessing total arterial and venous thrombotic events, not just first events, provides more complete information about disease burden and absolute on-treatment impact. Following LER, judicious modulation of more than one coagulation pathway can provide broader benefit than intensifying inhibition of one hemostatic system component., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: The interaction between thrombosis and inflammation appears central to COVID-19-associated coagulopathy and likely contributes to poor outcomes. Tissue factor is a driver of disordered coagulation and inflammatory signaling in viral infections and is important for viral replication; therefore, tissue factor may be an important therapeutic target in COVID-19., Study Design: ASPEN-COVID-19 (NCT04655586) is a randomized, prospective open-label blinded endpoint (PROBE), active comparator Phase 2b trial to evaluate the safety and efficacy of recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent tissue factor inhibitor, in patients hospitalized with COVID-19 with elevated D-dimer levels. This report describes the design of the Phase 2b dose ranging and proof of concept study. Participants are randomly assigned, in a 1:1:2 ratio, to lower or higher dose rNAPc2 by subcutaneous injection on days 1, 3, and 5 or to heparin according to local standard of care; randomization is stratified by baseline D-dimer level (at 2X upper limit of normal). The primary efficacy endpoint for Phase 2b is proportional change in D-dimer concentration from baseline to Day 8 or day of discharge, whichever is earlier. The primary safety endpoint is major or non-major clinically relevant bleeding through Day 8. Phase 2b enrollment began in December 2020 and is projected to complete ∼160 participants by Q4 2021., Conclusions: ASPEN-COVID-19 will provide important data on a novel therapeutic approach that may improve outcomes in hospitalized COVID-19 patients beyond available anticoagulants by targeting tissue factor, with potential effects on not only thrombosis but also inflammation and viral propagation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Previous lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking., Methods: The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; rNCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan-Meier estimates, and Cox proportional hazards models were used to generate hazard ratios and associated CIs. Analyses were performed as intention-to-treat., Results: Among 6564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, previous LER, baseline ankle-brachial index <0.50, surgical LER, and longer target lesion length were associated with increased risk of ALI. Incident ALI was associated with subsequent all-cause mortality (hazard ratio [HR], 2.59 [95% CI, 1.98-3.39]) and major amputation (HR, 24.87 [95% CI, 18.68-33.12]). Rivaroxaban reduced ALI relative to placebo by 33% (absolute risk reduction, 2.6% at 3 years; HR, 0.67 [95% CI, 0.55-0.82]; P =0.0001), with benefit starting early (HR, 0.45 [95% CI, 0.24-0.85]; P =0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and intensive care unit stay, HR, 0.58 [95% CI, 0.40-0.83]; P =0.003) and regardless of LER type (surgical versus endovascular revascularization, P interaction=0.42) or clopidogrel use ( P interaction=0.59)., Conclusions: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.

Background: Paclitaxel drug-coated devices (DCDs) were developed to improve lower extremity revascularization (LER) patency in peripheral artery disease (PAD) but have been associated with long-term mortality., Objectives: This study assessed DCD safety and effectiveness in LER for PAD., Methods: VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) randomized patients with PAD who underwent LER to rivaroxaban or placebo. The primary VOYAGER PAD study efficacy and safety outcomes were composite cardiovascular and limb events and Thrombolysis In Myocardial Infarction major bleeding. For prespecified DCD analyses, primary safety and effectiveness outcomes were mortality and unplanned index limb revascularization (UILR). Major adverse limb events (MALE) were a secondary outcome. Inverse probability treatment weighting was used to account for each subject's propensity for DCD treatment. Effects of rivaroxaban were assessed with Cox proportional hazards models., Results: Among 4,316 patients who underwent LER, 3,478 (80.6%) were treated for claudication, and 1,342 (31.1%) received DCDs. Median follow-up was 31 months, vital status was ascertained in 99.6% of patients, and there were 394 deaths. After weighting, DCDs were not associated with mortality (HR: 0.95; 95% CI: 0.83-1.09) or MALE (HR: 1.08; 95% CI: 0.90-1.30) but were associated with reduced UILR (3-year Kaplan-Meier: 21.5% vs 24.6%; HR: 0.84; 95% CI: 0.76-0.92). Irrespective of DCD use, consistent benefit of rivaroxaban for composite cardiovascular and limb events (P interaction  = 0.88) and safety of rivaroxaban with respect to bleeding (P interaction  = 0.57) were observed., Conclusions: In >4,000 patients with PAD who underwent LER, DCDs were not associated with mortality or MALE but were associated with persistent reduction in UILR. These findings provide insight into the safety and effectiveness of DCDs in PAD. (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [VOYAGER PAD]; NCT02504216)., Competing Interests: Funding Support and Author Disclosures VOYAGER PAD was funded by Bayer and Janssen Pharmaceuticals. A Pan-Industry Consortium (Medtronic, Boston Scientific, Cook, Philips, Bard, Surmodics, TriReme) provided funding through a grant to CPC Clinical Research to support statistical analyses performed at CPC Clinical Research. Dr Bonaca was supported by the American Heart Association Strategically Focused Research Network in Vascular Disease under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). Dr Hess has received grants to CPC Clinical Research from Bayer, Janssen, and Amgen during the conduct of the study; and has received grants from Merck and Amgen outside the submitted work. Dr Patel has received grants and personal fees from Bayer and from Janssen during the conduct of the study; has received grants and personal fees from AstraZeneca and Heartflow, outside the submitted work; and has received grants from the National Heart, Lung, and Blood Institute, Medtronic, and Phillips Healthcare. Dr Bauersachs has received personal fees from Bayer during the conduct of the study; and has received personal fees from Bristol Myers Squibb, Daiichi-Sankyo, and Pfizer, outside the submitted work. Dr Anand has received personal fees from Bayer AG and Janssen during the conduct of the study; and has received personal fees from Bayer AG and Janssen outside the submitted work. Dr Debus has received grants and personal fees from Bayer AG; and has received grants from Cook LTD and Terumo Aortic during the conduct of the study. Dr Nehler has received grants from Bayer and Janssen; and has received salary support from CPC Clinical Research during the conduct of the study. Dr Yeh has been a consultant and has received grants from Abbott Vascular, Boston Science, and Medtronic; and has received grants from BD Bard, Cook Medical, and Philips Medical. Dr Secemsky has received research grants to BIDMC from the NIH/NHLBI K23HjL150290, Harvard Medical School’s Shore Faculty Development Award, AstraZeneca, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic, and Philips; and has received consulting/speaking fees from Abbott, Bayer, BD, Boston Scientific, Cook, CSI, Inari, Janssen, Medtronic, Philips, and Venture Medical. Dr Beckman has been a consultant for Janssen and Bayer during the conduct of the study. Dr. Capell has received grants from Bayer and Janssen to CPC Clinical Research during the conduct of the study. Dr Berkowitz has received personal fees from Bayer U.S., LLC during the conduct of the study and outside of the submitted work from employment as a Clinical Research Physician. Dr Haskell was employed by Janssen Pharmaceuticals LLC during the conduct of the study; and holds stock in Johnson & Johnson. Dr Hiatt has received grants to CPC Clinical Research from Bayer and Janssen during the conduct of this study. Dr Bonaca has received grants to CPC Clinical Research from Bayer AG and Janssen Pharmaceuticals during the conduct of the study; and has received grants from Amgen, AstraZeneca, Merck, NovoNordisk, Pfizer, and Sanofi outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk-benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described., Methods and Results: The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan-Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding)., Conclusion: Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER., Methods: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee., Results: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method ( P -interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P =0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding ( P -interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding ( P -interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P =0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage ( P =0.95) and postprocedural bleeding requiring intervention ( P =0.93) was not significantly increased., Conclusions: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

Background: Patients with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER) are at high risk of major adverse limb and cardiovascular events. The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial demonstrated that rivaroxaban 2.5 mg twice daily reduced first events by 15%. The benefit of rivaroxaban on total (first and subsequent) events in this population is unknown., Objectives: This study sought to evaluate the total burden of vascular events in patients with PAD after LER and the efficacy of low-dose rivaroxaban on total events., Methods: VOYAGER PAD randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily plus aspirin or aspirin alone. The primary endpoint was time to first event of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The current analysis considered all events (first and subsequent) for components of the primary endpoint as well as additional vascular events including peripheral revascularizations and venous thromboembolism. HRs were estimated by marginal proportional hazards models., Results: Among 6,564 randomized events, there were 4,714 total first and subsequent vascular events including 1,614 primary endpoint events and 3,100 other vascular events. Rivaroxaban reduced total primary endpoint events (HR: 0.86; 95% CI: 0.75-0.98; P = 0.02) and total vascular events (HR: 0.86; 95% CI: 0.79-0.95; P = 0.003). An estimated 4.4 primary and 12.5 vascular events per 100 participants were avoided with rivaroxaban over 3 years., Conclusions: Patients with symptomatic PAD who are undergoing LER have a high total event burden that is significantly reduced with rivaroxaban. Total event reduction may be a useful metric to quantify the efficacy of rivaroxaban in this setting. (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities [VOYAGER PAD]; NCT02504216)., Competing Interests: Funding Support and Author Disclosures The VOYAGER PAD trial was funded through a grant to CPC Clinical Research from Bayer and Janssen. Dr Bauersachs has received grant support from Aspen Pharma; and has received personal fees from Bayer, Bristol Myers Squibb, Daichii-Sankyo, and Pfizer. Dr Szarek has received fees for performing analyses, steering committee fees, and travel support from Sanofi and Regeneron; has received fees for performing analyses from Lexicon; has received consulting fees from CiVi and Esperion; and has received Data Safety and Monitoring Board membership fees from Resverlogix and Janssen. Dr Broadman has received grant support from Bayer. Dr Gudz has received grant support from Bayer AG. Dr Debus has received grants and personal fees from Bayer AG; and has received grants from Cook Ltd and Terumo Aortic, during the conduct of the study. Dr Nehler has received grant support to Brigham and Women’s Hospital from AstraZeneca and Merck; and grant support to CPC from Amgen, Anthos, AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi, and WraSer. Dr Anand has received grant support from Bayer and Janssen. Dr Patel has received grant support from Bayer and Janssen. Dr Hess has received grant support to CPC from Amgen, Anthos, AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi, and WraSer. Dr Capell has received grant support to CPC from Amgen, Anthos, AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi, and WraSer. Dr Rogers has served as an adjudication committee member for VOYAGER; has received a small educational grant from Philipps; and has served as site co-principal investigator for trial sponsored by Abbott. Dr Muehlhofer has been employed by Bayer AG. Dr Haskell has been employed by Janssen. Dr Berkowitz was employed by Bayer as a clinical research physician at the time of this writing. Dr Hiatt has received grant support to CPC from Amgen, Anthos, AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi, and WraSer. Dr Bonaca was supported by the American Heart Association Strategically Focused Research Network in Vascular Disease under awards 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (Brigham and Women’s Hospital-Dartmouth Hitchcock Clinical Project); has received grant support to BWH from AstraZeneca and Merck; and has received grant support to CPC from Amgen, Anthos, AstraZeneca, Bayer, Janssen, Novo Nordisk, Sanofi, and WraSer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association., (Copyright © 2021. Published by Elsevier Inc.)

Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established., Study Design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events., Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Exercise therapy and lower extremity revascularization both improve walking performance in symptomatic patients with peripheral artery disease. The combination of therapies provides greater benefit than either alone and may reduce the need for subsequent revascularization procedures, but further trials with longer follow-up are needed for the outcome of subsequent revascularization., Competing Interests: Dr. Capell has received grants to CPC Clinical Research from Bayer AG and Janssen Pharmaceuticals. Dr. McDermott has received research funding from Regeneron and other research support (consisting of study interventions or provision of outcome measurements) from Helixmith, ArtAssist, Chromadex, ReserveAge, Mars, and Hershey. Dr. Jacobs has received CPC payments from Phillips; consulting contracts through the University of Colorado with Abbott and Terumo; and clinical research support from Mercator and Terumo. Dr. Beckman has served as a consultant for Amgen, Bayer, GlaxoSmithKline, Janssen, Sanofi, and Novartis. Dr. Bonaca has received grants to CPC Clinical Research from Bayer AG, Janssen Pharmaceuticals, Amgen, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Hiatt has received grants to CPC Clinical Research from Bayer AG, Janssen Pharmaceuticals, and Amgen. Dr. Biswas has reported that she has no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

A research participant's right to withdraw from all research procedures is widely accepted, but there can be justifiable limits to a participant's exercise of autonomy to withdraw from some procedures. Clinical outcomes trials depend on complete subject follow-up for accurate assessment of the safety and efficacy of investigational therapies. Subjects' refusal to complete follow-up, even through passive medical record review, can cause failure to detect safety signals, inaccurate estimation of efficacy, or lack of acceptance of trial results, which alters the study's benefit-risk ratio. Allowing participant refusal of follow-up data collection therefore creates tension between respect for persons and beneficence. With minimal risk study procedures that can help preserve trial benefit, such as passive data collection, we argue that the importance of upholding the principle of beneficence outweighs individual autonomy concerns. Furthermore, a consent process that prospectively informs participants of mandatory passive follow-up is ethically justified and optimizes the balance between autonomy and beneficence., (© 2021 by The Hastings Center. All rights reserved.)

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described., Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization., Results: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity ( P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel ( P for trend=0.06)., Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.

Background: Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain., Methods: In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome., Results: A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007)., Conclusions: In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Patients with peripheral artery disease (PAD) undergoing a lower-extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower-extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial., Study Design: VOYAGER PAD is an international randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low-dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y 12 inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event-driven trial is expected to observe outcomes over a mean patient follow-up of 30 months., Conclusions: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high-risk population of PAD patients undergoing peripheral revascularization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation., (© 2017 American Heart Association, Inc.)

Background/aims: Conducting clinical trials in skilled nursing facilities is particularly challenging. This manuscript describes facility and patient recruitment challenges and solutions for clinical research in skilled nursing facilities., Methods: Lessons learned from the SNF Connect Trial, a randomized trial of a heart failure disease management versus usual care for patients with heart failure receiving post-acute care in skilled nursing facilities, are discussed. Description of the trial design and barriers to facility and patient recruitment along with regulatory issues are presented., Results: The recruitment of Denver-metro skilled nursing facilities was facilitated by key stakeholders of the skilled nursing facilities community. However, there were still a number of barriers to facility recruitment including leadership turnover, varying policies regarding research, fear of litigation and of an increased workload. Engagement of facilities was facilitated by their strong interest in reducing hospital readmissions, marketing potential to hospitals, and heart failure management education for their staff. Recruitment of patients proved difficult and there were few facilitators. Identified patient recruitment challenges included patients being unaware of their heart failure diagnosis, patients overwhelmed with their illness and care, and frequently there was no available proxy for cognitively impaired patients. Flexibility in changing the recruitment approach and targeting skilled nursing facilities with higher rates of admissions helped to overcome some barriers., Conclusion: Recruitment of skilled nursing facilities and patients in skilled nursing facilities for clinical trials is challenging. Strategies to attract both facilities and patients are warranted. These include aligning study goals with facility incentives and flexible recruitment protocols to work with patients in "transition crisis."

Palliative care has faced moral and ethical challenges when conducting research involving human subjects. There are currently no resources to guide institutional review boards (IRBs) in applying standard ethical principles and terms-in a specific way-to palliative care research. Using as a case study a recently completed multisite palliative care clinical trial, this article provides guidance and recommendations for both IRBs and palliative care investigators to facilitate communication and attain the goal of conducting ethical palliative care research and protecting study participants while advancing the science. Beyond identifying current challenges faced by palliative care researchers and IRBs reviewing palliative care research, this article suggests steps that the palliative care research community can take to establish a scientifically sound, stable, productive, and well-functioning relationship between palliative care investigators and the ethical bodies that oversee their work., (Copyright © 2014 American Academy of Hospice and Palliative Medicine. All rights reserved.)

Cellular effects of FFA might differ from those of lipoprotein triglyceride (TG)-derived fatty acids (TGFA). The aim of the current study was to examine the relationship between lipoprotein lipase (LPL) expression, TGFA, or FFA availability and glucose metabolism in the absence of insulin in C2C12 myoblasts. Control myoblasts or myoblasts stably transfected with human lipoprotein lipase (C2/LPL; 15-fold greater LPL activity) were incubated for 12 h in fetal bovine serum-free medium in the absence or presence of Intralipid-20. Intracellular retention of labeled medium glucose was assessed in a subset of experiments. In the presence of Intralipid, medium glucose disappearance was increased in C2/LPL cells but not in control cells. In both cell types, glucose label retention in cellular TG was increased in the presence of Intralipid; incubation with albumin-bound oleate produced similar results. In the presence of Intralipid, the LPL hydrolytic inhibitor tetrahydrolipstatin blocked excess glucose retention in cellular TG but did not significantly decrease glucose disappearance in C2/LPL cells. Changes in glucose transport or hexokinase II did not explain the altered glucose disappearance in C2/LPL cells. Our results suggest that LPL overexpression in these cells leads to chronic metabolic adaptations that alter glucose uptake and retention.

Background: The purpose of this study was to evaluate the effects on LDL-cholesterol (LDL-C) from addition of plant sterol treatment to patients with dyslipidemia already taking a statin and colesevelam hydrochloride (HCl). Current cholesterol treatment guidelines recommend use of plant stanols/sterols to help reach LDL-C goals in patients taking other lipid-lowering therapies. Previous data demonstrate LDL-C lowering by adding stanols/sterols to statins. However, data are conflicting regarding the benefit from combination stanols/sterols with bile acid sequestrants., Methods: Fifty-five subjects on a stable dose of statin completed a 10-week, double-blind, randomized study of colesevelam HCl 3.75 g/day alone for 4 weeks, then 6 weeks of additional 2 g/day plant sterol-fortified orange juice (S-OJ) or placebo orange juice (P-OJ). Serum total cholesterol (TC), LDL-C, HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline, 4 weeks, and 10 weeks., Results: Baseline LDL-C measurements (mean ± SD) were similar between S-OJ and P-OJ groups (122 ± 20 vs 126 ± 24 mg/dL, respectively). Four weeks of colesevelam HCl in combination with a statin significantly reduced TC, LDL-C, and ApoB (9.6%, P < 0.001; 21.9%, P < 0.001; and 8.5%, P = 0.001, respectively), and significantly increased HDL-C (6.2%, P = 0.002) and TG (18.8%, P = 0.002). However, compared to P-OJ, 10 weeks of S-OJ produced no effect on any outcome parameter beyond that of colesevelam HCl., Conclusion: Plant S-OJ appears to be ineffective at further reducing LDL-C when added to statin and colesevelam HCl combination therapy in patients with dyslipidemia.

The aim of this study was to investigate the time course of C-reactive protein (CRP) reduction with simvastatin in patients with type 2 diabetes mellitus. Thirty-five subjects (mean +/- SEM body mass index 32.8 +/- 1 kg/m(2), mean +/- SEM glycated hemoglobin 7.3 +/- 0.2%) were studied using a randomized, crossover, double-blind design. Patients were treated with simvastatin 40 mg or placebo for 28 days, with a minimum 28-day intervening washout. On entry, all subjects had low-density lipoprotein cholesterol >100 mg/dl and/or non-high-density lipoprotein cholesterol >130 mg/dl. High-sensitivity CRP (hs-CRP) was measured on days 0, 1, 3, 7, 14, 21, and 28 of each phase; fasting lipids were measured weekly. The mean hs-CRP level was 4.2 +/- 0.6 mg/L at baseline (>3.0 mg/L represents high risk). After simvastatin administration, there was a significant reduction in levels of log(hs-CRP) (p = 0.001). This effect of simvastatin was seen by day 7 (p = 0.008), with maximal reduction seen at day 14 (p = 0.004; hs-CRP in original units 3.1 +/- 0.5 mg/L with simvastatin and 4.1 +/- 0.6 mg/L with placebo). As expected, the change in hs-CRP was not related to low-density lipoprotein cholesterol reduction. By day 28 with simvastatin, hs-CRP had returned to near baseline levels. In conclusion, in patients with type 2 diabetes mellitus, simvastatin reduced hs-CRP within 7 days. However, this potentially beneficial effect was lost within 28 days.

Hypertriglyceridemia is a disorder commonly encountered in clinical practice. Treatment of this condition aims to prevent the major complications of hypertriglyceridemia, which differ depending on whether triglyceride elevations are moderate or severe. This review discusses the pathophysiology and clinical consequences of hypertriglyceridemia and outlines treatment approaches based on the degree of triglyceride elevation. Special consideration is given to clinical trials using medications that primarily target triglycerides.

Background A 53-year-old man with a history of hypertension and gout was referred to our clinic for severe hypertriglyceridemia, diagnosed 3 years previously. He was asymptomatic and had no history of abdominal pain, pancreatitis or diabetes, but consumed six cans of beer per night. Over the previous 2 years, he had been treated unsuccessfully with multiple medications; during this period his fasting triglycerides ranged from 5.41 mM to 55.04 mM (479 to 4,871 mg/dl). Investigations Physical examination including fundoscopy, medication review, and laboratory tests.Diagnosis Severe hypertriglyceridemia due to a genetic combined hyperlipidemia, exacerbated by persistent excessive alcohol intake and metabolic syndrome. Management Cessation of alcohol intake, initiation of a fat-restricted diet, and fibrate therapy, with close follow-up. Once serum triglycerides were controlled, attention was turned to lowering LDL-cholesterol concentration according to The National Cholesterol Education Program, Adult Treatment Panel III guidelines.

Fatty acids inhibit insulin-mediated glucose metabolism in skeletal muscle, an effect largely attributed to defects in insulin-mediated glucose transport. Insulin-resistant mice transgenic for the overexpression of lipoprotein lipase (LPL) in skeletal muscle were used to examine the molecular mechanism(s) in more detail. Using DNA gene chip array technology, and confirmation by RT-PCR and Western analysis, increases in the yeast Sec1p homolog Munc18c mRNA and protein were found in the gastrocnemius muscle of transgenic mice, but not other tissues. Munc18c has been previously demonstrated to impair insulin-mediated glucose transport in mammalian cells in vitro. Of interest, stably transfected C2C12 cells overexpressing LPL not only demonstrated increases in Munc18c mRNA and protein but also in transcription rates of the Munc18c gene. To confirm the relevance of fatty acid metabolism and insulin resistance to the expression of Munc18c in vivo, a 2-fold increase in Munc18c protein was demonstrated in mice fed a high-fat diet for 4 weeks. Together, these data are the first to implicate in vivo increases in Munc18c as a potential contributing mechanism to fatty acid-induced insulin resistance.

Objective: The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction., Methods and Results: Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P<0.001), total cholesterol (P<0.01), and apolipoprotein B (P<0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P<0.0001), nitroprusside (P<0.001), and verapamil (P<0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P<0.0001) and post-heparin (P<0.001) TG and tended to lower 24-hour (P=0.054) and post-heparin (P=0.028) FFA., Conclusions: Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.

A predominance of small LDL particles (subclass phenotype B), as determined by gradient-gel electrophoresis is found among patients with myocardial infarction. Despite physical differences in phenotype A and B particles, differences in lipid composition of particles in these phenotypes have yet to be reported in an unselected population of males and females. The present study used lipid/apoB ratios to analyze the amount of lipid per LDL particle, isolated by density-gradient ultracentrifugation, in 70 healthy subjects. Relative to apoB, the LDL particles from phenotype B subjects were found to contain less free cholesterol (0.391 +/- 0.05 versus 0.465 +/- 0.05; mean +/- SD; P < .001), phospholipid (1.26 +/- 0.2 versus 1.43 +/- 0.2; P < .001), and cholesteryl ester (1.97 +/- 0.1 versus 2.11 +/- 0.2; P < .001) than particles from phenotype A subjects. The amount of triglyceride per LDL particle did not differ between the two phenotypes (0.410 +/- 0.1 versus 0.406 +/- 0.1; P = NS) despite higher plasma triglyceride levels in the phenotype B subjects. LDL size and buoyancy were positively correlated with particle free cholesterol, phospholipid, and cholesteryl ester but not with particle triglyceride. These data suggest that the physical properties of LDL from subjects with phenotype A and B reflect their lipid composition. The compositional differences between LDL particles of the two phenotypes may provide new insight into the increased risk of myocardial infarction in subjects with small, dense LDL.