Editor's Choice – European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on Antithrombotic Therapy for Vascular Diseases

Abdominal Aortic Aneurysm Atrial Fibrillation Acute Limb Ischaemia Activated Partial Thromboplastin Time Arteriovenous Fistula Arteriovenous Graft Coronary artery (atherosclerotic) disease Carotid Artery Stenting Carotid Endarterectomy Confidence Interval Chronic Kidney Disease Chronic Limb Threatening Ischaemia Coronavirus Disease 2019 Cyclo-oxygenase Computed Tomography Dual Antiplatelet Therapy Direct Oral Anticoagulant Deep Vein Thrombosis Estimated Glomerular Filtration Rate European Society for Vascular Surgery Endovascular Abdominal Aortic Aneurysm Repair Grading of Recommendation Assessment, Development, and Evaluation system1Guyatt G.H. Oxman A.D. Kunz R. Atkins D. Brozek J. Vist G. et al.GRADE guidelines: 2. Framing the question and deciding on important outcomes.J Clin Epidemiol. 2011; 64: 395-400Abstract Full Text Full Text PDF PubMed Scopus (1185) Google Scholar Guideline Writing Committee Global Utilisation of Streptokinase and Tissue plasminogen activator for Occluded Arteries Heparin Induced Thrombocytopenia Human Immunodeficiency Virus Hazard Ratio International Normalised Ratio International Society on Thrombosis and Haemostasis International Units Lower Extremity Arterial Disease (atherosclerotic) Low Molecular Weight Heparin Major Adverse Cardiovascular Events Major Adverse Limb Events Myocardial Infarction Magnetic Resonance Imaging Odds Ratio Peripheral Artery Disease Proton Pump Inhibitor Pulmonary Embolism Randomised Controlled Trial Risk Ratio Standard Deviation Superficial Vein Thrombosis Transient Ischaemic Attack Thrombolysis In Myocardial Infarction Unfractionated Heparin Vitamin K Antagonist Venous Thromboembolism Working Group Aspirin and Carotid Endarterectomy2Taylor D.W. Barnett H.J. Haynes R.B. Ferguson G.G. Sackett D.L. Thorpe K.E. et al.Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators.Lancet. 1999; 353: 2179-2184Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar AMBulatory Dual AntiPlatelet3King A. Bath P.M. Markus H.S. Clopidogrel versus dipyridamole in addition to aspirin in reducing embolization detected with ambulatory transcranial Doppler: a randomized trial.Stroke. 2011; 42: 650-655Crossref PubMed Scopus (25) Google Scholar Oral Apixaban for the Treatment of Acute Venous Thromboembolism4Agnelli G. Buller H.R. Cohen A. Curto M. Gallus A.S. 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Brenner B. et al.Fondaparinux for the treatment of superficial-vein thrombosis in the legs.N Engl J Med. 2010; 363: 1222-1232Crossref PubMed Scopus (286) Google Scholar Cervical Artery Dissection In Stroke Study8Markus H.S. Levi C. King A. Madigan J. Norris J. Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results.JAMA Neurol. 2019; 76: 657-664Crossref PubMed Scopus (112) Google Scholar Clopidogrel versus vs.Aspirin in Patients at Risk of Ischaemic Events9CAPRIE Steering CommitteeA randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).Lancet. 1996; 348: 1329-1339Abstract Full Text Full Text PDF PubMed Scopus (6167) Google Scholar Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis10Markus H.S. Droste D.W. Kaps M. Larrue V. Lees K.R. Siebler M. et al.Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial.Circulation. 2005; 111: 2233-2240Crossref PubMed Scopus (657) Google Scholar Clopidogrel and AcetylSalicylic Acid in bypass Surgery for Peripheral ARterial Disease11Belch J.J. Dormandy J. Biasi G.M. Cairols M. Diehm C. Eikelboom B. et al.Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.J Vasc Surg. 2010; 52: 825-833Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar Clopidogrel in High risk patients with Acute Non-disabling Cerebrovascular Events12Wang Y. Wang Y. Zhao X. Liu L. Wang D. Wang C. et al.Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.N Engl J Med. 2013; 369: 11-19Crossref PubMed Scopus (1107) Google Scholar Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management, and Avoidance13Bhatt D.L. Fox K.A. Hacke W. Berger P.B. Black H.R. Boden W.E. et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354: 1706-1717Crossref PubMed Scopus (2462) Google Scholar Cardiovascular OutcoMes for People using Anticoagulation Strategies14Anand S.S. Bosch J. Eikelboom J.W. Connolly S.J. Diaz R. Widimsky P. et al.Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial.Lancet. 2018; 391: 219-229Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar Carotid Revascularisation Endarterectomy versus Stenting Trial15Mantese V.A. Timaran C.H. Chiu D. Begg R.J. Brott T.G. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): stenting versus carotid endarterectomy for carotid disease.Stroke. 2010; 41: S31-S34Crossref PubMed Scopus (293) Google Scholar European-Australasian Stroke Prevention in Reversible Ischaemia Trial16Halkes P.H. van Gijn J. Kappelle L.J. Koudstaal P.J. Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial.Lancet. 2006; 367: 1665-1673Abstract Full Text Full Text PDF PubMed Scopus (926) Google Scholar The European Stroke Prevention Study-217Diener H.C. Cunha L. Forbes C. Sivenius J. Smets P. Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke.J Neurol Sci. 1996; 143: 1-13Abstract Full Text Full Text PDF PubMed Scopus (1751) Google Scholar Fast Assessment of Stroke and Transient ischaemic attack to prevent Early Recurrence18Kennedy J. Hill M.D. Ryckborst K.J. Eliasziw M. Demchuk A.M. Buchan A.M. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial.Lancet Neurol. 2007; 6: 961-969Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar Management of perIpheral aRterial inteRventions with mono Or dual antiplatelet theRapy trial19Tepe G. Bantleon R. Brechtel K. Schmehl J. Zeller T. 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Bucherini E. et al.A randomized double-blind study of low-molecular-weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum).J Thromb Haemost. 2012; 10: 1026-1035Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Superficial Thrombophlebitis treated by ENOXaparin25Superficial Thrombophlebitis Treated By Enoxaparin Study GroupA pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis.Arch Intern Med. 2003; 163: 1657-1663Crossref PubMed Scopus (160) Google Scholar Superficial vein thrombosis treated for 45 days with rivaroxaban versus fondaparinux26Beyer-Westendorf J. Schellong S.M. Gerlach H. Rabe E. Weitz J.I. Jersemann K. et al.Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open-label, randomised, non-inferiority SURPRISE phase 3b trial.Lancet Haematol. 2017; 4: e105-e113Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Acute STroke or Transient IscHaemic Attack Treated With TicAgreLor and ASA for PrEvention of Stroke and Death27Johnston S.C. Amarenco P. Denison H. Evans S.R. Himmelmann A. James S. et al.Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.N Engl J Med. 2020; 383: 207-217Crossref PubMed Scopus (227) Google Scholar Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischaemic Events trial28Morrow D.A. Braunwald E. Bonaca M.P. Ameriso S.F. Dalby A.J. Fish M.P. et al.Vorapaxar in the secondary prevention of atherothrombotic events.N Engl J Med. 2012; 366: 1404-1413Crossref PubMed Scopus (770) Google Scholar Vascular Outcomes Study of ASA (acetylsalicylic acid) Along with Rivaroxaban in Endovascular or surgical limb Revascularisation for Peripheral Arterial Disease29Bonaca M.P. Bauersachs R.M. Anand S.S. Debus E.S. Nehler M.R. Patel M.R. et al.Rivaroxaban in Peripheral Artery Disease after Revascularization.N Engl J Med. 2020; 382: 1994-2004Crossref PubMed Scopus (393) Google Scholar Warfarin and Antiplatelet Vascular Evaluation30Anand S. Yusuf S. Xie C. Pogue J. Eikelboom J. Budaj A. et al.Oral anticoagulant and antiplatelet therapy and peripheral arterial disease.N Engl J Med. 2007; 357: 217-227Crossref PubMed Scopus (330) Google Scholar The European Society for Vascular Surgery (ESVS) has developed a series of clinical practice guidelines for clinicians caring for patients with vascular diseases. This is the first guideline specifically examining antithrombotic therapy. The aim of the guideline is to assist clinicians and patients in selecting an optimal antithrombotic strategy. The antithrombotic field has evolved rapidly over the last few years with the introduction of new classes of agents and a better understanding of the use of established agents. This guideline is all encompassing to cover as many arterial and venous conditions as possible for patients cared for by vascular departments across Europe and the rest of the world. Some arterial territories are beyond the scope of this guidance such as intracerebral and coronary, although occasionally data have been extrapolated from trials in these areas. The term “patient” as used in the guideline is all encompassing. Where age is important for a specific recommendation, it will be considered in the relevant section. Otherwise, these guidelines apply to adults over the age of 18. The clinician responsible for that person’s care will differ by condition and country. They will include angiologists, cardiologists, interventional radiologists, haematologists, neurologists, phlebologists, vascular physicians, and vascular surgeons. The guidelines were therefore developed by a multidisciplinary group of specialists in the field to promote a high standard of care based on the highest quality evidence available. As always, guidelines should not be viewed as a legal standard of care. The document provides guidance and support, and the choice of therapy will depend on the individual patient and treatment setting. This guidance and support is especially important in the context of antithrombotic therapy as some drugs will not be available in certain countries, or the cost of use may be prohibitive. There may also be more than one antithrombotic option available for a patient. This is where shared decision making is particularly important and will need to balance the risk of bleeding (section 1.3.1) with the reduction in risk of cardiovascular events. Cost is likely to be the greatest barrier to implementation of these guidelines, especially for newer drugs. These guidelines do not have the scope to go into detail on the health economics of antithrombotic drugs, as both cost and cost thresholds vary by country. Health economic analysis will need to be performed locally, when relevant, using standardised methodology.31Guillemin F. de Wit M. Fautrel B. Grimm S. Joore M. Boonen A. Steps in implementing a health economic evaluation.RMD Open. 2020; 6Crossref Scopus (0) Google Scholar Bleeding concerns are also likely to be a barrier to implementation. This has been considered in detail in the relevant chapters, as well as section 1.3. Vascular centres are encouraged to audit any implementations made as a result of this guideline. Audit cycles should be repeated regularly and changes implemented based on results. As well as use of appropriate antithrombotic assessments, major bleeding using a standard definition should also be monitored (see section 1.3). There are many ways to perform clinical audit, and most centres now require that any audit is registered with a local audit committee. Paid and not-for-profit tools are readily available online if necessary. To enhance the global reach and applicability of this guideline, external international reviewers have reviewed the document. All ESVS guidelines and the app can be downloaded free of charge from the ESVS website (https://www.esvs.org/journal/guidelines/). The abbreviation “peripheral artery disease” (PAD) is used in the guideline to encompass atherosclerotic lower extremity arterial disease (LEAD) from the aorta to the toes, atherosclerotic upper limb arterial disease, atherosclerotic visceral artery disease, and atherosclerotic cerebrovascular disease. There are many terms and definitions for “chronic” or “stable” atherosclerotic arterial disease. In the guideline the term “chronic” is used to cover all non-acute presentations. The AGREE reporting standards for clinical practice guidelines were used throughout the guideline process and the checklist is included as Appendix B.32Brouwers M.C. Kerkvliet K. Spithoff K. The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines.BMJ. 2016; 352: i1152Crossref PubMed Scopus (378) Google Scholar Members of the Guideline Writing Committee (GWC) were selected by the guideline chairs and ESVS Guideline Steering Committee to represent clinician groups involved in antithrombotic therapy decision making for patients with vascular disease. This included representation from the disciplines of angiology, phlebology, cardiology, clinical pharmacology, interventional radiology, vascular medicine, and vascular surgery (Appendix A). Members of the GWC have provided disclosure statements regarding relationships that might be perceived as conflicts of interest. These are available from ESVS headquarters ([email protected]). Members of the GWC received no financial support from any pharmaceutical, device, or industry body to develop these guidelines. Videoconference software support was funded by the ESVS. The ESVS Guideline Steering Committee was responsible for undertaking the review process and reviewed the document at each round. The final version was checked and approved by the GWC and ESVS Guideline Steering Committee. The GWC held an introductory meeting on 3 and 4 July 2020 by videoconference where the list of topics and author tasks were determined. The GWC met monthly by videoconference to discuss the writing process and ongoing issues. After the first draft was completed and internally reviewed, the GWC held a further videoconference on 15 and 16 April 2021 to review and approve the wording of each recommendation. Consensus recommendations were discussed and agreed during these meetings and had to have majority consensus from all members of the GWC to be included. A further videoconference was held on 10 January 2022 to review and approve the wording of each recommendation following changes made after peer review. Detailed search strategies for sections of the guideline are available in Appendix C. Members of the GWC performed literature searches in Medline (through PubMed), Embase, Clinical Trials databases, and the Cochrane Library from inception up to the date specified in the search for peer reviewed publications. Hand searching of included references was also performed. Literature searches were updated for guideline publication in October 2022. Selection of studies for inclusion was based on the titles and abstracts of retrieved studies. The selection process followed the pyramid of evidence with systematic review and meta-analysis of randomised controlled trials (RCT) at the top, followed by RCTs, meta-analysis of observational studies, and finally observational studies. Case reports, abstracts, and in vitro studies were excluded leaving expert opinion at the base of the pyramid. Expanded information from the studies used for each recommendation is shown in the tables of evidence (ToE, Appendix D). A fundamental part of this guideline is to guide clinicians in assessing the risk of bleeding when recommending antithrombotic therapy (see section 1.3). There was no well validated scoring system to assess the risk of bleeding for a patient with PAD, so a study was performed to create and internally validate a score by the GermanVasc group and members of the GWC.33Behrendt C.A. Kreutzburg T. Nordanstig J. Twine C.P. Marschall U. Kakkos S. et al.The OAC3-PAD risk score predicts major bleeding events at one year after hospitalisation for peripheral artery disease.Eur J Vasc Endovasc Surg. 2022; 63: 503-510Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This score (the OAC3 PAD score) used data from over 80 000 patients hospitalised with PAD in Germany to predict the risk of major bleeding at one year. There is more detail in section 1.3.1. Section 3.2.2 on antiplatelet function testing following arterial endovascular intervention had a large amount of low quality literature with no RCT to form recommendations. A systematic review and meta-analysis specifically on the impact of antiplatelet function testing to detect high on treatment platelet reactivity following endovascular intervention was therefore performed by members of the GWC.34Zlatanovic P. Wong K.H.F. Kakkos S.K. Twine C.P. A Systematic Review and Meta-Analysis on the Impact of High On-Treatment Platelet Reactivity on Clinical Outcomes for Patients Taking ADP Receptor Inhibitors Following Lower Limb Arterial Endovascular Intervention.Eur J Vasc Endovasc Surg. 2022; 63: 91-101Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This meta-analysis included eight prospective and two retrospective studies examining platelet resistance (high on treatment platelet reactivity) in 1 444 patients following endovascular intervention for LEAD. The meta-analysis findings were of such low certainty that evidence based recommendations based on them could not be made (see section 3.2.2). Section 4.8, antithrombotics for aneurysmal disease had no systematic review and meta-analysis available to combine the small number of heterogeneous RCTs and cohort studies available. This was therefore performed by members of the GWC to guide recommendations (sections 4.8.1 – 4.8.2, recommendations 46 – 48).35Wong K.H.F. Zlatanovic P. Bosanquet D.C. Saratzis A. Kakkos S. Aboyans V. et al.Antithrombotic therapy for aortic and peripheral artery aneurysms: a systematic review and meta-analysis.Eur J Vasc Endovasc Surg. 2022; 64: 544-556Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Finally, an update of the Cochrane review, Medical adjuvant treatment to increase patency of arteriovenous fistulae and grafts,36Mohamed I. Kamarizan M.F.A. Da Silva A. Medical adjuvant treatment to increase patency of arteriovenous fistulae and grafts.Cochrane Database Syst Rev. 2021; 7Cd002786PubMed Google Scholar was triggered by the process of writing this guideline to guide recommendations in section 4.10 Vascular access for haemodialysis (section 4.10). A modification of the European Society of Cardiology (ESC) system was used for grading the level of evidence and class of recommendations. For each recommendation made in the guideline, the level of evidence was graded from A to C (Table 1) with A being the highest. The strength (class) of each recommendation was graded from I to III, with I being the strongest (Table 2).Table 1Levels of evidence from the adapted European Society of Cardiology evidence grading systemLevel of Evidence AData derived from multiple randomised trials or meta-analyses of randomised trialsLevel of Evidence BData derived from a single randomised trial, large non-randomised studies or a meta-analysis of non-randomised studiesLevel of Evidence CConsensus opinion of experts and or small studies, retrospective studies, registries Open table in a new tab Table 2Class of recommendations from the European Society of Cardiology evidence grading systemClassDefinitionSuggested wordingIEvidence and or general agreement that a given treatment or procedure is beneficial, useful, effectiveis recommendedIIConflicting evidence and or divergence of opinion about the usefulness or efficacy about the given treatment or procedure.IIaWeight of evidence or opinion is in favour of usefulness or efficacyshould be consideredIIbUsefulness or efficacy is less well established by evidence or opinionmay be consideredIIIEvidence or general agreement that a given treatment or procedure is not useful or effective and in some cases may be harmfulis not recommended Open table in a new tab Almost every ESVS guideline has a section on antithrombotic therapy. The purpose of this guideline was to update and add significant detail over the basic recommendations made in pre-existing guidelines. This led to differences in recommendations which are explained in Tables 3 and 4. There are multiple other guidelines from other major bodies with antithrombotic recommendations. Major differences in recommendations are also explored in Table 3 and 4. This guideline often goes into more detail and has more recommendations on various antithrombotic therapies than other guidelines. Unless there is a clear clash these are not highlighted. This includes recommendations on aspirin and rivaroxaban which were not considered by other guidelines (other than the 2023 update to the ESVS carotid guideline37Naylor R. Rantner B. Ancetti S. de Borst G.J. De Carlo M. Halliday A. et al.European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on the Management of Atherosclerotic Carotid and Vertebral Artery Disease.Eur J Vasc Endovasc Surg. 2023; 65: 7-111Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar and the European Society for Cardiology focused update38Aboyans V. Bauersachs R. Mazzolai L. Brodmann M. Palomares J.F.R. Debus S. et al.Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy.Eur Heart J. 2021; 42: 4013-4024PubMed Google Scholar) as the seminal studies were not published.Table 3Differences between recommendations from other major guidelines and this guideline for Section 4. Antithrombotics for patients with arterial diseaseGuideline, publication yearRecommendationESVS antithrombotic guideline recommendationReasons for differencesAntithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy38Aboyans V. Bauersachs R. Mazzolai L. Brodmann M. Palomares J.F.R. Debus S. et al.Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy.Eur Heart J. 2021; 42: 4013-4024PubMed Google Scholar 2021Long term low dose rivaroxaban plus aspirin may be proposed for inpatients with asymptomatic carotid stenosis or in those with a history of carotid revascularisation, who are considered at very high risk because of associated comorbidities (especially polyvascular patients), provided bleeding risk is not highNo recommendation for aspirin and rivaroxaban for carotid diseaseThis GWC along with the ESVS carotid guideline GWC notes the major problem with forming recommendations for patients with carotid stenoses from COMPASS was that patients with pre-existing indications for DAPT and a non-aspirin antiplatelet were excluded, which would exclude many patients with asymptomatic carotid disease2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery39Aboyans V. Ricco J.B. Bartelink M.E.L. Björck M. Brodmann M. Cohnert T. et al.Editor's Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS).Eur J Vasc Endovasc Surg. 2018; 55: 305-368Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar 2017For patients requiring antiplatelet therapy, clopidogrel may be preferred over aspirin (Class IIb, level B)Patients with chronic symptomatic lower extremity arterial disease should be considered for clopidogrel (75 mg) as the first choice antiplatelet agent when single antiplatelet therapy is indicated for secondary cardiovascular prevention (Class IIa, level B)The recommendation for stable or chronic symptomatic patients with LEAD was re-considered in the light of the COMPASS trial. The decision for this to be IIa or IIb was debated extensively over the course of developing this guideline, but on balance it was changed to IIa in line with the new recommendation on aspirin plus low dose rivaroxabanDAPT with aspirin and clopidogrel for at least one month should be considered after infrainguinal stent implantation (Class I, level B)Patients undergoing endovascular intervention for lower extremity arterial disease who are not at high risk of bleeding may be considered for a short course (a minimum of one month to a maximum of six) dual antiplatelet therapy (aspirin 75 mg plus clopidogrel 75 mg) to reduce the risk of secondary cardiovascular and major adverse limb events (Class IIb, level C)As there is no powered RCT evidence to support DAPT, this was downgraded. The only RCT (leading to a level B in the ESC guidelines) is MIRROR, which is too underpowered to be considered level BCombination treatment with ASA and cilostazol may be considered to improve patency and reduce amputation rates following infra-inguinal endovascular treatmentNo recommendations on cilostazolThis GWC recognised that cilostazol was contentious. The randomised evidence is weak (underpowered) and confusion over the antiplatelet properties of cilostazol with subsequent reports of major bleeding has led to a notification from the European Medicines Agency. This led the GWC to not form any recommendations2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease40Gerhard-Herman M.D. Gornik H.L. Barrett C. Barshes N.R. Corriere M.A. Drachman D.E. et al.2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Am Coll Cardiol. 2