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Patients with peripheral artery disease (PAD) experience major cardiovascular and limb events. Antithrombotic strategies including antiplatelets and anticoagulants remain a cornerstone of treatment and prevention. Recent trials have shown heterogeneity in the response to antithrombotic therapies in patients presenting primarily with PAD when compared to those presenting primarily with coronary artery disease. In addition, there is observed heterogeneity with regards to the effects of antiplatelets and anticoagulants with respect to different outcomes including cardiovascular and major adverse limb events. This, coupled with risks of bleeding, requires a patient-centered and holistic assessment of benefit-risk when selecting antithrombotic strategies for patients with PAD. A global multidisciplinary work group was convened to evaluate antithrombotic strategies in PAD and to summarize the current state of the art. Common clinical scenarios around antithrombotic decision making were provided. Finally, insights with regard to implementation future investigation were described., Competing Interests: Funding Support and Author Disclosures Drs Bonaca and Hess work with CPC, a nonprofit academic research organization affiliated with the University of Colorado that has received research grant/consulting funding from Abbott Laboratories, Agios Pharmaceuticals Inc, Alexion Pharma, Alnylam Pharmaceuticals Inc, Amgen Inc, Angionetics Inc, Anthos Therapeutics, 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, Boston Clinical Research Institute, Bristol Myers Squibb Company, Cambrian Biopharma Inc, Cardiol Therapeutics Inc, CellResearch Corp, Cleerly Inc, Cook Regentec LLC, 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, Janssen and Affiliates, Kowa Research Institute Inc, Kyushu University, Lexicon Pharmaceuticals Inc, Medimmune Ltd, Medpace, Merck & Affiliates, Nectero Medical Inc, Novartis Pharmaceuticals Corp, Novo Nordisk Inc, Osiris Therapeutics Inc, Pfizer Inc, PhaseBio Pharmaceuticals Inc, PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals Inc, Regio Biosciences Inc, Saint Luke’s Hospital of Kansas City, Sanifit Therapeutics SA, Sanofi Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stanford Center for Clinical Research, 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, Worldwide Clinical Trials Inc, WraSer LLC, and Yale Cardiovascular Research Group. Dr Bonaca has received support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project). Dr Barnes has received grants from Boston Scientific; has received consulting fees from Pfizer, and Bristol Myers Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Abbott Vascular, Boston Scientific; has been part of the Data and Safety Monitoring Board (DSMB) for Translational Sciences (Clinical Events Adjudication Committee); and has been a member of the Board of Directors - Anticoagulation Forum. Dr Bauersachs has received personal fees from Bayer, Bristol Myers Squibb, LEO-Pharma, Pfizer, VIATRIS; and has received research support from the Bavarian State Ministry of Health and FADOI (Federazione delle Associazioni dei Dirigenti Ospedalieri Internisti). Dr Conte has received grants from BioGenCell and Profusa; and has been a member of the DSMB for Abbott Vascular. Dr Mena-Hurtado has received consulting fees from Abbott, Cook, and Penumbra; and has received grants from the National Institutes of Health, Philip, Shockwave, and Abbott. Dr Weitz has received consulting fees from Alnylam, Anthos, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Ionis, JnJ, Merck, and Regeneron. Dr Beckman has received grants from Bristol Myers Squibb; and has received consulting fees from JanOne, Janssen, Novartis, MingSight, and Merck. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

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: Preventive therapy among patients with established atherosclerotic cardiovascular disease (ASCVD) is generally underused. Whether new guideline recommendations and a focus on implementation have improved the use of high-intensity statins is unknown., Objectives: This study sought to evaluate the patterns and predictors of statin use among patients with ASCVD., Methods: In this retrospective cohort study, pharmacy and medical claims data from a commercial health plan were queried for patients with established ASCVD between January 31, 2018, and January 31, 2019. Statin use on an index date of January 31, 2019, was evaluated, as was 12-month adherence and discontinuation. Multivariable logistic regression was used to determine independent associations with statin use of varying intensities., Results: Of the 601,934 patients with established ASCVD, 41.7% were female, and the mean age was 67.5 ± 13.3 years. Overall, 22.5% of the cohort were on a high-intensity statin, 27.6% were on a low- or moderate-intensity statin, and 49.9% were not on any statin. In multivariable analysis, younger patients, female patients, and those with higher Charlson comorbidity score were less likely to be prescribed any statin. Among statin users, female patients, older patients, and those with peripheral artery disease were less likely to be on a high-intensity formulation, whereas a cardiology encounter in the prior year increased the odds. The majority of high-intensity stain users achieved high levels of adherence., Conclusions: Substantial underuse of statins persists in a large, insured, and contemporary cohort of patients with ASCVD from the United States. In particular, concerning gaps in appropriate statin use remain among younger patients, women, and those with noncoronary ASCVD., Competing Interests: Funding Support and Author Disclosures Dr Nelson has received grants from Diabetes Australia and the Royal Australasian College of Physicians. Dr Haynes is an employee of HealthCore, a subsidiary of Anthem. Dr Shambhu is an employee of HealthCore, a subsidiary of Anthem. Dr Eapen is a previous employee of HealthCore. Dr Cziraky is an employee of HealthCore, a subsidiary of Anthem. Dr Nanna has received funding from the American College of Cardiology Foundation supported by the George F. and Ann Harris Bellows Foundation, and from the National Institute on Aging/National Institutes of Health from R03AG074067 (GEMSSTAR award). Dr Calvert is supported by U.S. Food and Drug Administration grant U18FD005292 and Clinical Trials Transformation Initiative membership fees. Dr Gallagher is an employee of HealthCore. Dr Pagidipati has received grants from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Regeneron, Sanofi, Verily Life Sciences; and has received consulting fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, and Novo Nordisk. Dr Granger has received research grants and consulting/speaker fees from Boehringer Ingelheim, Bristol Myers Squibb, Janssen Pharmaceutica Products, LP, and Pfizer; has received research grants from AKROS, Apple, AstraZeneca, Daichii-Sankyo, U.S. Food and Drug Administration, GlaxoSmithKline, Medtronic Foundation, and Novartis Pharmaceutical Company; and has received consulting/speaker fees from AbbVie, Bayer Corp US, Boston Scientific Corp, CeleCor Therapeutics, Correvio, Espero BioPharma, Medscape, Medtronic Inc, Merck, National Institutes of Health, Novo Nordisk, Rhoshan Pharmaceuticals, and Roche Diagnostics., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The combination of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily compared with 100 mg aspirin once daily reduces major adverse cardiovascular (CV) events in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD)., Objectives: The aim of this work was to report the effects of the combination on overall and cause-specific mortality., Methods: The COMPASS trial enrolled 27,395 patients of whom 18,278 were randomized to the combination (n = 9,152) or aspirin alone (n = 9,126). Deaths were adjudicated by a committee blinded to treatment allocation. Previously identified high-risk baseline features were polyvascular disease, chronic kidney disease, mild or moderate heart failure, and diabetes., Results: During a median of 23 months of follow-up (maximum 47 months), 313 patients (3.4%) allocated to the combination and 378 patients (4.1%) allocated to aspirin alone died (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.71-0.96; P = 0.01). Compared with aspirin, the combination reduced CV death (160 [1.7%] vs 203 [2.2%]; HR: 0.78; 95% CI: 0.64-0.96; P = 0.02) but not non-CV death. There were fewer deaths following MI, stroke, and CV procedures, as well as fewer sudden cardiac, other, and unknown causes of CV deaths and coronary heart disease deaths. Patients with 0, 1, 2, and 3 or 4 high-risk features at baseline had 4.2, 4.8, 25.0, and 53.9 fewer deaths, respectively, per 1000 patients treated for 30 months., Conclusions: The combination of rivaroxaban and aspirin compared with aspirin reduced overall and CV mortality with consistent reductions in cause specific CV mortality in patients with chronic CAD or PAD. The absolute mortality benefits are greater with increasing baseline risk. (Cardiovascular Outcomes for People Using Anticoagulant Strategies [COMPASS]; NCT01776424)., Competing Interests: Funding Support and Author Disclosures The COMPASS study was sponsored by Bayer. Dr. Eikelboom has received consulting fees and grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Eli-Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi, and Servier. Dr. Bhatt discloses the following relationships: Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, and Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committee: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), 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), and Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, and ACC.org; Vice-Chair, ACC Accreditation Committee), 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), 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, 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), and WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr. Fox has received grant support from Bayer and AstraZeneca; and has received consulting fees from Bayer/Janssen, Sanofi/Regeneron, and Verseon. Dr. Bosch has received fees for advisory board work for Bayer. Dr. Connolly has received lecture and consulting fees from BI, BMS, DSI, Medtronic, Pfizer, Portola, and Servier. Dr. Anand has received speaker fees and has provided consultation services for Bayer and Janssen. Dr. Avezum has received lecture fees from Bayer, Daiichi-Sankyo, Boehringer Ingelheim, Lilly, and NovoNordisk. Dr. Berkowitz is employed as a clinical research physician by Bayer US. Dr. Branch has received grant support from Bayer and Eli Lilly; and has provided consultation services for Janssen, Bayer, Sana, and Sanofi. Dr. Dagenais has received honoraria for lectures from Bayer and Eli Lilly. Dr. Guzik has received grants and speaking/consulting fees from Bayer during the conduct of the study. Dr. Hart participated in COMPASS and received research support and personal remuneration from Bayer. Dr. Maggioni has received personal fees for participation in committees of studies sponsored by Bayer, Fresenius, and Novartis outside the present work. Dr. Muehlhofer is employed as a global clinical lead by Bayer, Germany. Dr. Sharma has received grants and honoraria from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Daiichi. Dr. Yusuf has received grants and honoraria from Bayer, Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, and Cadila. 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.)

Background: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in peripheral artery disease (PAD). Lipid-lowering therapies (LLT) that reduce LDL-C decrease this risk., Objectives: The authors examined LLT use and actual achieved LDL-C in PAD., Methods: PAD patients in MarketScan from 2014 to 2018 were identified. Outcomes included LLT use, defined as high-intensity (HI) (high-intensity statin, statin plus ezetimibe, or PCSK9 inhibitor), low-intensity (any other lipid regimen), or no therapy, and follow-up LDL-C. Factors associated with LDL-C <70 mg/dl were identified with multivariable logistic regression., Results: Among 250,103 PAD patients, 20.5% and 39.5% were treated at baseline with HI and low-intensity LLT, respectively; 40.0% were on no LLT. Over a 15-month median follow-up period, HI LLT use increased by 1.5%. Among 18,747 patients with LDL-C data, at baseline, 25.1% were on HI LLT, median LDL-C was 91 mg/dl, and 24.5% had LDL-C <70 mg/dl. Within the HI LLT subgroup, median LDL-C was 81 mg/dl, and 64% had LDL-C ≥70 mg/dl. At follow-up, HI LLT use increased by 3.7%, median LDL-C decreased by 4.0 mg/dl, and an additional 4.1% of patients had LDL-C <70 mg/dl. HI LLT use was greater after follow-up MACE (55.0%) or MALE (41.0%) versus no ischemic event (26.1%). After MACE or MALE, LDL-C was <70 mg/dl in 41.5% and 36.1% of patients, respectively, versus 27.1% in those without an event. Factors associated with follow-up LDL-C <70 mg/dl included smoking, hypertension, diabetes, prior lower extremity revascularization, and prior myocardial infarction but not prior acute or critical limb ischemia., Conclusions: In PAD, LLT use is suboptimal, LDL-C remains elevated, and LLT intensity is a poor surrogate for achieved LDL-C. Less aggressive lipid management was observed in PAD versus cardiovascular disease, highlighting missed opportunities for implementation of proven therapies in PAD., Competing Interests: Funding Support and Author Disclosures This study was funded through a research grant from Amgen to CPC Clinical Research. Dr. Hess has received research funding to CPC Clinical Research from Merck, Bayer, Janssen, and Amgen. Dr. Cannon has received research grants from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, Merck, and Pfizer; and has received consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, Rhoshan, and Sanofi. Dr. Beckman has provided consulting for AstraZeneca, Amgen, Bayer, GlaxoSmithKline, Janssen, and Sanofi; has provided Data Safety and Monitoring Board service for Novartis; and has ownership in EMX and Janacare. Dr. Patel has received research grants from/served on the advisory board for Bayer, Janssen, Amgen, and Heartflow; and has received research grants from Novartis and the National Heart, Lung, and Blood Institute. Dr. Hiatt has received grant support to CPC Clinical Research from the National Institutes of Health, Bayer, Janssen, Amgen, and Pluristem. Drs. Mues and Orroth and Ms. Shannon are employees of Amgen, Inc. Dr. Bonaca has received research grants to CPC Clinical Research from Amgen, AstraZeneca, Bayer, NovoNordisk, Regeneron, and Sanofi. Dr. Goodney has reported that he has 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.)

Background: Chronic kidney disease is associated with an increased risk of both bleeding and ischemic cardiovascular events., Objective: The purpose of this study was to determine the balance of risks and benefits from the dual pathway antithrombotic regimen (rivaroxaban 2.5 mg twice daily [bd] plus aspirin, compared with aspirin) in vascular patients with or without moderate renal dysfunction., Methods: This was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial involving 27,395 patients with chronic coronary or peripheral artery disease., Results: In COMPASS, 21,111 patients had an estimated glomerular filtration rate (GFR) at baseline of ≥60 ml/min, 6,276 had a GRF of <60 ml/min. Both the primary efficacy outcome (cardiovascular death, myocardial infarction, or stroke) and major bleeding were more frequent in those with renal dysfunction, and the frequency of these outcome events was inversely related to GFR. However, the primary outcome was consistently reduced with rivaroxaban 2.5 mg bd plus aspirin, irrespective of GFR category (GFR ≥60 ml/min, 3.5% rivaroxaban plus aspirin, 4.5% aspirin alone, hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.64 to 0.90; GFR <60 ml/min, 6.4% rivaroxaban plus aspirin, 8.4% aspirin alone, HR: 0.75; 95% CI: 0.60 to 0.94). Major bleeding was more frequent with rivaroxaban 2.5 mg plus aspirin versus aspirin alone in those with GFR ≥60 ml/min (2.9% rivaroxaban plus aspirin, 1.6% aspirin alone, HR: 1.81; 95% CI: 1.44 to 2.28) and similarly in those with GFR <60 ml/min (3.9% rivaroxaban plus aspirin, 2.7% aspirin alone, HR: 1.47, 95% CI: 1.05 to 2.07)., Conclusions: The benefits of the dual pathway COMPASS regimen (rivaroxaban 2.5 mg bd plus aspirin), versus aspirin alone, are preserved in patients with moderate renal dysfunction without evidence of an excess hazard of bleeding., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Diabetes confers an increased risk for atherosclerotic cardiovascular disease, but less is known about the independent risk diabetes confers on major cardiovascular and limb events in patients with symptomatic peripheral artery disease (PAD) on contemporary management., Objectives: The authors sought to assess the risk of cardiovascular and limb events in patients with PAD and diabetes as compared with those with PAD alone., Methods: In the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial, 13,885 patients with symptomatic PAD were evaluated with a primary endpoint of an adjudicated composite of major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, ischemic stroke) followed over a median of ∼30 months. The diabetes subgroup was analyzed compared with the subgroup without diabetes, and further examined for diabetes-specific factors such as glycosylated hemoglobin (HbA 1c ) that might affect risk for major cardiovascular and limb outcomes., Results: A total of 5,345 patients (38.5%) had diabetes; the majority (n = 5,134 [96.1%]) had type 2 diabetes. The primary endpoint occurred in 15.9% of patients with PAD and diabetes as compared with 10.4% of those without diabetes (absolute risk difference 5.5%; adjusted hazard ratio: 1.56; 95% confidence interval [CI]: 1.41 to 1.72; p < 0.001). Every 1% increase in HbA 1c was associated with a 14.2% increased relative risk for MACE (95% CI: 1.09 to 1.20; p < 0.0001)., Conclusions: Patients with PAD and diabetes are at high risk for cardiovascular and limb ischemic events, even on contemporary therapies. Every 1% increase in HbA 1c was associated with a 14.2% increased relative risk for MACE (95% CI: 1.09 to 1.20; p < 0.0001). (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Peripheral artery disease (PAD) affects over 200 million people globally and is a cause of significant morbidity, mortality, and disability due to limb loss. Although secondary prevention with antithrombotic therapy is a mainstay of treatment to prevent adverse cardiovascular events, PAD patients are often undertreated with antithrombotic agents. Furthermore, there is a paucity of high-quality data from randomized controlled trials of PAD patients, leading to wide variations in clinical practice and guideline recommendations. Recently, there have been important advances that have further increased the number of antiplatelet and anticoagulant choices potentially available for patients with PAD. In this context, this paper aims to summarize the current available evidence for the safety and efficacy of various antithrombotic agents in PAD, and discuss how to integrate this emerging evidence into actual clinical practice. An evidenced-based approach to PAD patients is essential to achieve optimal outcomes, weighing cardiovascular and limb benefits against bleeding risks., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). There is limited information on the prognosis of patients who experience MALE., Objectives: Among participants with lower extremity PAD, this study investigated: 1) if hospitalizations, MACE, amputations, and deaths are higher after the first episode of MALE compared with patients with PAD who do not experience MALE; and 2) the impact of treatment with low-dose rivaroxaban and aspirin compared with aspirin alone on the incidence of MALE, peripheral vascular interventions, and all peripheral vascular outcomes over a median follow-up of 21 months., Methods: We analyzed outcomes in 6,391 patients with lower extremity PAD who were enrolled in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. COMPASS was a randomized, double-blind placebo-controlled study of low-dose rivaroxaban and aspirin combination or rivaroxaban alone compared with aspirin alone. MALE was defined as severe limb ischemia leading to an intervention or major vascular amputation., Results: A total of 128 patients experienced an incident of MALE. After MALE, the 1-year cumulative risk of a subsequent hospitalization was 61.5%; for vascular amputations, it was 20.5%; for death, it was 8.3%; and for MACE, it was 3.7%. The MALE index event significantly increased the risk of experiencing subsequent hospitalizations (hazard ratio [HR]: 7.21; p < 0.0001), subsequent amputations (HR: 197.5; p < 0.0001), and death (HR: 3.23; p < 0.001). Compared with aspirin alone, the combination of rivaroxaban 2.5 mg twice daily and aspirin lowered the incidence of MALE by 43% (p = 0.01), total vascular amputations by 58% (p = 0.01), peripheral vascular interventions by 24% (p = 0.03), and all peripheral vascular outcomes by 24% (p = 0.02)., Conclusions: Among individuals with lower extremity PAD, the development of MALE is associated with a poor prognosis, making prevention of this condition of utmost importance. The combination of rivaroxaban 2.5 mg twice daily and aspirin significantly lowered the incidence of MALE and the related complications, and this combination should be considered as an important therapy for patients with PAD. (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]; NCT01776424)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Atherosclerotic cardiovascular (CV) disease remains a major health concern affecting more than 200 million adults worldwide, and lower extremity peripheral artery disease (PAD) is associated with significant morbidity and mortality. Treatment strategies to reduce the burden of major adverse CV events and limb events have mainly involved the use of antiplatelet and statin medications. Unlike other types of atherosclerotic CV disease, the evidence base is not well developed for therapies in patients with PAD. Recently, studies from subgroups of patients with PAD and a large clinical trial of PAD patients have been published, signaling a burgeoning interest in studying this higher risk population. This review outlines the inherent CV risks of patients with PAD, risk reduction strategies, emerging clinical trial data, and opportunities for the CV community to generate evidence in real-world settings and translate evidence into practice as new therapies become available., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this paper was to examine disparities in the use of cardioprotective medications in the treatment of peripheral artery disease (PAD) by socioeconomic status (SES)., Background: PAD is associated with increased cardiovascular risk and is more prevalent among those of lower SES. However, the use of guideline-recommended secondary preventive measures for the treatment of PAD across diverse income subgroups and the influence of practice site on potential treatment disparities by SES are unknown., Methods: Within the National Cardiovascular Disease Registry (NCDR) PINNACLE Registry, 62,690 patients with PAD were categorized into quintiles of SES, as defined by the median income of each patient's zip code. The association between SES and secondary preventive treatment with antiplatelet and statin medications was evaluated using sequential hierarchical modified Poison models, adjusting first for practice site and then for clinical variables., Results: Compared with the highest SES quintile (median income: >$60,868), PAD patients in the lowest SES quintile (median income: <$34,486) were treated less often with statins (72.5% vs. 85.8%; RR: 0.84; 95% CI: 0.83 to 0.86; p < 0.001) and antiplatelet therapy (79.0% vs. 84.6%; RR: 0.93; 95% CI: 0.91 to 0.94; p < 0.001). These differences were markedly attenuated after controlling for practice site variation: statins (adjusted RR: 0.97; 95% CI: 0.95 to 0.99; p = 0.003) and antiplatelet therapy (adjusted RR: 0.98; 95% CI: 0.97 to 1.00; p = 0.012). Additional adjustment for patients' clinical characteristics had minimal impact, with slight further attenuation with statins (adjusted RR: 1.00: 95% CI: 0.99 to 1.01; p = 0.772) and antiplatelet therapy (adjusted RR: 1.00; 95% CI: 0.99 to 1.01; p = 0.878)., Conclusions: Among PAD patients, the practice site at which patients received care largely explained the observed SES differences in treatment with guideline-recommended secondary preventive medications. Future efforts to reduce treatment disparities in these vulnerable populations should target systems improvement at practices serving high proportions of patients with low SES., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We hypothesized that low-density lipoprotein (LDL) reduction regardless of mechanism would improve calf muscle perfusion, energetics, or walking performance in peripheral arterial disease (PAD) as measured by magnetic resonance imaging and magnetic resonance spectroscopy., Background: Statins improve cardiovascular outcome in PAD, and some studies suggest improved walking performance., Methods: Sixty-eight patients with mild to moderate symptomatic PAD (age 65 ± 11 years; ankle-brachial index [ABI] 0.69 ± 0.14) were studied at baseline and annually for 2 years after beginning simvastatin 40 mg (n = 20) or simvastatin 40 mg/ezetimibe 10 mg (n = 18) if statin naïve, or ezetimibe 10 mg (n = 30) if taking a statin. Phosphocreatine recovery time was measured by (31)P magnetic resonance spectroscopy immediately after symptom-limited calf exercise on a 1.5-T scanner. Calf perfusion was measured using first-pass contrast-enhanced magnetic resonance imaging with 0.1 mM/kg gadolinium at peak exercise. Gadolinium-enhanced magnetic resonance angiography was graded. A 6-min walk and a standardized graded Skinner-Gardner exercise treadmill test with peak Vo(2) were performed. A repeated-measures model compared changes over time., Results: LDL reduction from baseline to year 2 was greater in the simvastatin 40 mg/ezetimibe 10 mg group (116 ± 42 mg/dl to 56 ± 21 mg/dl) than in the simvastatin 40 mg group (129 ± 40 mg/dl to 90 ± 30 mg/dl, p < 0.01). LDL also decreased in the ezetimibe 10 mg group (102 ± 28 mg/dl to 79 ± 27 mg/dl, p < 0.01). Despite this, there was no difference in perfusion, metabolism, or exercise parameters between groups or over time. Resting ABI did improve over time in the ezetimibe 10 mg group and the entire study group of patients., Conclusions: Despite effective LDL reduction in PAD, neither tissue perfusion, metabolism, nor exercise parameters improved, although rest ABI did. Thus, LDL lowering does not improve calf muscle physiology or functional capacity in PAD. (Comprehensive Magnetic Resonance of Peripheral Arterial Disease; NCT00587678)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this analysis was to characterize the progression of coronary atherosclerosis in patients with concomitant peripheral arterial disease (PAD)., Background: Peripheral arterial disease is associated with adverse cardiovascular outcomes. The impact of concomitant PAD on coronary atherosclerosis progression in patients with coronary artery disease has not been well established., Methods: The burden and progression of coronary atherosclerosis was investigated in 3,479 patients with coronary artery disease with (n = 216) and without (n = 3,263) concomitant PAD who participated in 7 clinical trials that employed serial intravascular ultrasound imaging., Results: Patients with PAD had a greater percent atheroma volume (40.4 ± 9.2% vs. 38.5 ± 9.1%, p = 0.002) and percentage of images containing calcium (35.1 ± 26.2% vs. 29.6 ± 24.2%, p = 0.002), in association with smaller lumen volume (275.7 ± 101.6 mm(3) vs. 301.4 ± 110.3 mm(3), p < 0.001) and vessel wall volume (467.7 ± 166.8 mm(3) vs. 492.9 ± 169.8 mm(3), p = 0.01). On serial evaluation, patients with PAD demonstrated greater progression of percent atheroma volume (+0.58 ± 0.38 vs. +0.23 ± 0.3%, p = 0.009) and total atheroma volume (-0.17 ± 2.69 mm(3) vs. -2.05 ± 2.15 mm(3), p = 0.03) and experienced more cardiovascular events (26.3% vs. 19.8%, p = 0.03). In patients with PAD and without PAD, respectively, achieving levels of low-density lipoprotein cholesterol <70 mg/dl was associated with less progression of percent atheroma volume (+0.16 ± 0.27% vs. +0.76 ± 0.20%, p = 0.04; and +0.05 ± 0.14% vs. +0.29 ± 0.13%, p < 0.001) and total atheroma volume (-3.0 ± 1.9 mm(3) vs. +1.0 ± 1.4 mm(3), p = 0.04; and -3.3 ± 1.1 mm(3) vs. -1.6 ± 1.0 mm(3), p < 0.001)., Conclusions: Patients with concomitant PAD harbor more extensive and calcified coronary atherosclerosis, constrictive arterial remodeling, and greater disease progression. These changes are likely to contribute to adverse cardiovascular outcomes. The benefit for all patients achieving low levels of low-density lipoprotein cholesterol supports the need for intensive lipid lowering in patients with PAD., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)