Abdelhamid, Magdy

Albrecht, Gerhard

Blaha, Michael J.

Cobo, Augusto Lavalle

Li, Li

Santilli, Francesca

Sibbing, Dirk

English

ARUd’A (Università “G. d’Annunzio CHIETI -PESCARA)

J A C C : A D V A N C E S V O L . 4 , N O . 7 , 2 0 2 5ª 2 0 2 5 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A NC O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E RT H E C C B Y L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y / 4 . 0 / ) .VIEWPOINTAdvanced Subclinical Atherosclerosisand Low-Dose AspirinGuideline-Based Extension Into Asymptomatic ChronicCoronary SyndromesMichael J. Blaha, MD, MPH,a Francesca Santilli, MD,b Dirk Sibbing, MDFESC, MHBA,c,d Augusto Lavalle Cobo, MD,eMagdy Abdelhamid, MD,f Gerhard Albrecht, MD,g Li Li, MDhC hronic coronary syndromes (CCSs) aredefined as a range of clinical presentationsor syndromes that arise due to structuraland/or functional alterations related to chronic dis-eases of the coronary arteries and/or microcircula-tion.1 While chronic coronary diseases are oftenstable for long periods, they are progressive andmay suddenly develop into acute coronarysyndromes.The European Society of Cardiology (ESC) guide-lines for the management of CCS have been updatedbased on changing epidemiology, diagnostic and riskprediction strategies, risk classification, and new ev-idence in the field for CCS, as well as medical therapylandscapes. One of the notable updates to theguidelines concerns the recommendation for low-dose aspirin in patients without prior myocardialinfarction or revascularization but with evidence ofsignificant obstructive coronary artery disease (CAD).ISSN 2772-963XFrom the aJohns Hopkins Ciccarone Center for the Prevention of Car-diovascular Disease, Baltimore, Maryland, USA; bDepartment of Medicineand Aging and Center for Advanced Studies and Technology, Universityof Chieti, Chieti, Italy; cPrivatklinik Lauterbacher Mühle am Ostersee,Iffeldorf, Germany; dDepartment of Cardiology, Klinikum der UniversitätMünchen, Ludwig-Maximilians-University, Munich, Germany; eDepart-ment of Cardiology, Sanatorio Otamendi, Ciudad Autonoma de BuenosAires, Argentina; fDepartment of Cardiovascular Medicine, Faculty ofMedicine, Kasr Al Ainy, Cairo University, Giza, Egypt; gMedical & ClinicalAffairs Consumer Health, Bayer U.S. L.L.C., Whippany, New Jersey, USA;and the hMedical Affairs & Pharmacovigilance, Pharmaceuticals, BayerAG, Berlin, Germany.The authors attest they are in compliance with human studiescommittees and animal welfare regulations of the authors’ institutionsand Food and Drug Administration guidelines, including patientconsent where appropriate. For more information, visit the AuthorCenter.This recommendation has been upgraded from classIIb in 2019 to class Ib in 2024.1,2The key pathological mechanism underlying mostepicardial CAD is atherosclerosis, a complex processthat develops over many years and even decadesbefore stenosis. The degree of stenosis was tradi-tionally used to assess an individual’s cardiovascular(CV) risk and determine whether the patient requirespreventive therapy. Obstructive coronary stenoseshave typically been defined using visual thresholds ofeither 50% or 70% stenosis, and stenosis of $50% isusually an indication for secondary prevention leveltherapy.However, increasing evidence demonstrates thatboth nonobstructive and obstructive CAD, detectedby coronary computed tomography angiography,confer an increased long-term risk of major adverseCV events and mortality.3 In fact, atheroscleroticplaque burden, and not stenosis per se, appears to bethe main predictor of CV events over a mid-term timehorizon.4-6 Atherosclerotic plaque burden can bedetermined in a number of ways, including coronarycomputed tomography angiography, the coronaryartery calcium (CAC) score, and carotid ultrasound.Aspirin is of particular interest since in guidelines itgenerally remains in the “obstructive CAD” paradigmas opposed to the “plaque burden” paradigm. How-ever, we believe that the quantification of plaqueburden can help individualize the allocation ofaspirin.7,8A recent publication by our writing group high-lighted a novel category within the CV risk contin-uum—advanced subclinical atherosclerosis.9 Theseasymptomatic patients are at a high risk of CV eventsdue to the presence of substantial underlyinghttps://doi.org/10.1016/j.jacadv.2025.101855FIGURE 1 Correlation BetweeACS ¼ acute coronary syndromeartery disease; CCS ¼ chronic coCardiology; INOCA ¼ ischemia wABBR EV I A T I ON SAND ACRONYMSCAC = coronary artery calciumCAD = coronary artery diseaseCCS = chronic coronarysyndromeCV = cardiovascularESC = European Society ofCardiologyBlaha et al J A C C : A D V A N C E S , V O L . 4 , N O . 7 , 2 0 2 5Asymptomatic CCS and Advanced Subclinical Atherosclerosis J U L Y 2 0 2 5 : 1 0 1 8 5 52subclinical atherosclerosis as determinedexclusively by their plaque burden. As such,they are best thought of as distinct fromtraditional primary prevention (whereaspirin has a limited role) and secondaryprevention (where aspirin is categoricallyrecommended). For example, patients withCAC >300 have atherosclerotic cardiovascu-lar disease events equivalent to patientswith known obstructive CAD, even withoutexploration for degree of coronary stenosis.10If patients with asymptomatic coronary stenosis of50% are considered to have CCS and, therefore,benefit from low-dose aspirin, then should theserecommendations also apply to those with advancedn Asymptomatic Chronic Coronary Syndrome, Advanced Subclin; ANOCA ¼ angina with no obstructive CAD; CABG ¼ coronary arronary syndrome; CCTA ¼ coronary computed tomography angiogith no obstructive CAD; LV ¼ left ventricular; PCI ¼ percutaneousubclinical atherosclerosis who have been demon-strated to have similar event rates? We think theanswer is yes. We believe that the concepts ofadvanced subclinical atherosclerosis and asymptom-atic CCS overlap, and the recent guideline regardingthe management of asymptomatic CCS with low-doseaspirin can be reasonably extended to advancedsubclinical atherosclerosis when there are nobleeding risk factors (Figure 1).As it is almost never recommended to activelysearch for obstructive CAD in asymptomatic patients,we propose to consider patients with advanced sub-clinical atherosclerosis, determined by any provenmethod, as having CCS, even if the degree of coronarystenosis has not been evaluated. Moreover, since low-ical Atherosclerosis, and Low-Dose Aspirintery bypass graft; CAC ¼ coronary artery calcium; CAD ¼ coronaryraphy; CPS ¼ carotid plaque ultrasound; ESC ¼ European Society ofs coronary intervention.J A C C : A D V A N C E S , V O L . 4 , N O . 7 , 2 0 2 5 Blaha et alJ U L Y 2 0 2 5 : 1 0 1 8 5 5 Asymptomatic CCS and Advanced Subclinical Atherosclerosis3dose aspirin is associated with a risk of bleeding, werecommend weighing the benefits and risks of low-dose aspirin therapy and prescribing low-doseaspirin only for patients aged <70 years who are pro-jected to obtain a clear net clinical benefit from pre-ventive therapy. As such, patients with no detectableatherosclerosis should rarely if ever take aspirin.To some, our recommendations may not seem newor may seem obvious. But for too long, guidelineshave been arbitrarily placed into 2 distinct buckets—primary and secondary prevention. The CCS conceptis consistent with our approach to coronary risk as acontinuum, best expressed by the degree of athero-sclerotic plaque (Figure 1). The concept of advancedsubclinical atherosclerosis can remove some of theambiguity around the appropriate use of aspirin,which has both benefits and harms and is probablybest thought of as removed from the strict primary vssecondary prevention dichotomy.In conclusion, the modern understanding of coro-nary risk has led to the merging of the concepts ofadvanced subclinical atherosclerosis and asymptom-atic obstructive CAD. As such, we believe thatadvanced subclinical atherosclerosis is part of theasymptomatic CCS as described by the ESC guide-lines. Therefore, the new ESC recommendations forthe use of lifelong low-dose aspirin in patients withasymptomatic CCS but with evidence of CAD on im-aging should probably apply to many or even mostpatients with advanced subclinical atherosclerosis. Infact, modeling studies suggest that the tipping pointfor net aspirin benefit is CAC >100 or moderate pla-que on carotid ultrasound (carotid plaque score of 2 orgreater) in the absence of bleeding risk factors. Futureprevention and American College of Cardiology/American Heart Association CCS guidelines shouldconsider these criteria for more specific and individ-ualized aspirin use in practice.ACKNOWLEDGMENTS The authors would like tothank Kirandeep Ghatahora, at Highfield Communi-cation, for editorial and technical support in thepreparation of the manuscript, funded by Bayer.FUNDING SUPPORT AND AUTHOR DISCLOSURESDr Blaha is a member of advisory boards: Novo Nordisk, Novartis,Bayer, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Idorsia, Gen-entech, Agepha, Vectura, and New Amsterdam. Received grants fromNIH, FDA, AHA, Novo Nordisk, Bayer, Amgen. Dr Santilli is a memberof a Bayer AG global advisory board that convenes to discuss riskassessment and preventive pharmacotherapy in primary and sec-ondary prevention. Dr Sibbing receives speaker fees and fees fromadvisory board activities from Bayer, Sanofi, and Daiichi Sankyo. DrCobo is a member of a Bayer AG global advisory board that convenesto discuss risk assessment and preventive pharmacotherapy in pri-mary and secondary prevention. Received speaker honoraria fromNovartis, Novo Nordisk, AstraZeneca, and Servier. Dr Abdelhamid is amember of a Bayer AG global advisory board that convenes to discussrisk assessment and preventive pharmacotherapy in primary andsecondary prevention. Received speaker honoraria from Bayer,Novartis, AstraZeneca, and Pfizer. Dr Albrecht is an employee ofBayer. Dr Li is an employee of Bayer.ADDRESS FOR CORRESPONDENCE: Dr Michael J.Blaha, Johns Hopkins Ciccarone Center for thePrevention of Cardiovascular Disease, Green SpringStation, Lutherville, 10755 Falls Road, Pavilion, STE360, Lutherville, Maryland 21093, USA. E-mail:mblaha1@jhmi.edu.RE F E RENCE S1. Vrints C, Andreotti F, Koskinas KC, et al. 2024ESC Guidelines for the management of chroniccoronary syndromes. Eur Heart J. 2024;45(36):3415–3537.2. Knuuti J, Wijns W, Saraste A, et al. 2019 ESCGuidelines for the diagnosis and management ofchronic coronary syndromes. Eur Heart J.2020;41(3):407–477.3. Pontone G, Rossi A, Guglielmo M, et al. Clinicalapplications of cardiac computed tomography: aconsensus paper of the European Association ofCardiovascular Imaging-part I. Eur Heart J Car-diovasc Imaging. 2022;23(3):299–314.4. Dzaye O, Razavi AC, Blaha MJ, Mortensen MB.Evaluation of coronary stenosis versus plaqueburden for atherosclerotic cardiovascular diseaserisk assessment and management. Curr Opin Car-diol. 2021;36(6):769–775.5. Fuster V, García-Álvarez A, Devesa A, et al. In-fluence of subclinical atherosclerosis burden andprogression on mortality. J Am Coll Cardiol.2024;84(15):1391–1403.6. Mortensen MB, Dzaye O, Steffensen FH, et al.Impact of plaque burden versus stenosis onischemic events in patients with coronary athero-sclerosis. J Am Coll Cardiol. 2020;76(24):2803–2813.7. Dzaye O, Razavi AC, Dardari ZA, et al. Carotidultrasound-based plaque score for the allocationof aspirin for the primary prevention of cardio-vascular disease events: the Multi-Ethnic Study ofAtherosclerosis and the Atherosclerosis Risk inCommunities study. J Am Heart Assoc.2024;13(12):e034718.8. Cainzos-Achirica M, Miedema MD, McEvoy JW,et al. Coronary artery calcium for personalizedallocation of aspirin in primary prevention of car-diovascular disease in 2019: the MESA study(Multi-Ethnic Study of Atherosclerosis). Circula-tion. 2020;141(19):1541–1553.9. Blaha MJ, Abdelhamid M, Santilli F, Shi Z,Sibbing D. Advanced subclinical atherosclerosis: anovel category within the cardiovascular riskcontinuum with distinct treatment implications.Am J Prev Cardiol. 2022;13:100456.10. Budoff MJ, Kinninger A, Gransar H, et al. Whendoes a calcium score equate to secondary pre-vention?: Insights from the multinationalCONFIRM registry. JACC Cardiovasc Imaging.2023;16(9):1181–1189.KEY WORDS atherosclerosis, aspirin,asymptomatic chronic coronary syndrome,coronary artery disease

Advanced Subclinical Atherosclerosis and Low-Dose Aspirin

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Advanced Subclinical Atherosclerosis and Low-Dose Aspirin

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