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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y VO L . 7 4 , N O . 1 , 2 0 1 9

ª 2 0 1 9 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Management of Antithrombotic Therapyin Atrial Fibrillation PatientsUndergoing PCIJACC State-of-the-Art Review

Davide Capodanno, MD, PHD,a Kurt Huber, MD,b Roxana Mehran, MD,c Gregory Y.H. Lip, MD,d,e David P. Faxon, MD,f

Christopher B. Granger, MD,g Pascal Vranckx, MD, PHD,h Renato D. Lopes, MD, PHD,g Gilles Montalescot, MD, PHD,i

Christopher P. Cannon, MD,f Jurien Ten Berg, MD,j Bernard J. Gersh, MD,k Deepak L. Bhatt, MD, MPH,f

Dominick J. Angiolillo, MD, PHDl

ABSTRACT

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Most patients with atrial fibrillation (AF) and risk factors for stroke require oral anticoagulation (OAC) to decrease the

risk of stroke or systemic embolism. This is now best achieved with direct oral anticoagulants that decrease the risk of

intracranial bleeding compared with vitamin K antagonists. Of note, approximately 5% to 10% of patients undergoing

percutaneous coronary intervention have AF, which complicates antithrombotic therapy in daily practice, because the

guidelines recommend that these patients also receive dual antiplatelet therapy (DAPT) to reduce the risk of ischemic

complications. However, combining OAC with DAPT, a strategy also known as triple antithrombotic therapy, is known to

increase the risk of bleeding compared with the use of OAC or DAPT alone. Studies of direct oral anticoagulants are now

emerging that show the favorable safety profile of double antithrombotic therapy with OAC and a P2Y12 inhibitor in

comparison with triple antithrombotic therapy including the use of vitamin K antagonists. The scope of this review is to

provide an update on this topic as well as to discuss future directions in the management of antithrombotic therapy after

percutaneous coronary intervention in AF patients requiring chronic OAC. (J Am Coll Cardiol 2019;74:83–99) © 2019 by

the American College of Cardiology Foundation.

m the aDivision of Cardiology, A.O.U. “Policlinico-Vittorio Emanuele,” University of Catania, Catania, Italy; b3rd Medical

partment, Cardiology and Intensive Care Medicine and Sigmund Freud University, Medical Faculty, Vienna, Austria;

rdiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; dLiverpool Centre for Cardiovascular

ence, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; eAalborg Thrombosis Research

it, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; fBrigham andWomen’s Hospital Heart and Vascular

nter, Harvard Medical School, Boston, Massachusetts; gDuke Clinical Research Institute, Duke University School of Medicine,

rham, North Carolina; hDepartment of Cardiology and Critical Care Medicine, Hartcentrum Hasselt, and faculty of Medicine and

e Sciences at the University of Hasselt, Hasselt, Belgium; iCardiology Department, Nîmes University Hospital, ACTION Study

oup, Montpellier University, Nîmes, France; jDepartment of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands;

ayo Clinic College of Medicine, Rochester, Minnesota; and the lDivision of Cardiology, University of Florida College of Medi-

e, Jacksonville, Florida. Dr. Capodanno has received speakers honoraria from Bayer, AstraZeneca, Daiichi-Sankyo, Pfizer, and

ehringer Ingelheim; and has received consulting fees from Abbott Vascular, Bayer, and Daiichi-Sankyo. Dr. Huber has received

ture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Portola, Sanofi,

d The Medicines Company. Dr. Mehran has received institutional research funding from AstraZeneca, Bayer, Beth Israel

aconess, Bristol-Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi-Sankyo, Medtronic, Novartis, and OrbusNeich; has served

a consultant to Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Regeneron Pharmaceuticals (no fees),

ivant Sciences, and Sanofi; has served as an institutional consultant (payment to institution) for Abbott Vascular and Spec-

netics/Phillips/Volcano Corporation; has served on the Executive Committee for Janssen Pharmaceuticals and Bristol-Myers

uibb; has received institutional (payment to institution) Advisory Board funding from Bristol-Myers Squibb and Novartis;

s received Data and Safety Monitoring Board membership funding to his institution from Watermark Research; and has <1%

uity with Claret Medical and Elixir Medical. Dr. Lip has served as a consultant for Bayer/Janssen, Bristol-Myers Squibb/Pfizer,

N 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.05.016

https://doi.org/10.1016/j.jacc.2019.05.016

http://JACC.org/

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2019.05.016&domain=pdf

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HIGHLIGHTS

� AF patients require OAC to prevent therisk of thromboembolic events, whereasantiplatelet therapy is required toprevent stent thrombosis in the settingof PCI.

� Several randomized trials have demon-strated that a regimen of DAT with DOACsprovides better safety compared with aregimen of TAT with VKA.

� The current paradigm is that TAT(the association of OAC with DAPT)should be as short as possible or evenavoided based on the individual’sischemic and bleeding risk profile.

ABBR EV I A T I ON S

AND ACRONYMS

AF = atrial fibrillation

CAD = coronary artery disease

DAPT = dual antiplatelet

therapy

DAT = double antithrombotic

therapy

DOAC = direct oral

anticoagulant

OAC = oral anticoagulation

PCI = percutaneous coronary

intervention

SAPT = single antiplatelet

therapy

TAT = triple antithrombotic

therapy

VKA = vitamin K antagonist

Capodanno et al. J A C C V O L . 7 4 , N O . 1 , 2 0 1 9

Antithrombotic Therapy in AF Patients Undergoing PCI J U L Y 9 , 2 0 1 9 : 8 3 – 9 9

84

A trial fibrillation (AF) is a highly prev-alent condition with increasing age.A 2018 statistical update from the

American Heart Association (AHA) reports es-timates of AF prevalence in 2010 rangingfrom z2.7 to 6.1 million in the United Statesand 8.8 million (95% confidence interval[CI]: 6.5 to 12.3 million) in Europe (1). Theseestimates are projected to rise to 12.1 millionin 2030 in the United States and 17.9 million(95% CI: 13.6 to 23.7 million) in 2060 inEurope (1). AF increases the risk of thrombo-embolic complications, including stroke andextracranial systemic embolic events, whichcall for therapeutic prophylaxis with oralanticoagulation (OAC) (2). It is estimatedthat about 20% to 40% of patients with AFalso present with coronary artery disease
� The results of the AUGUSTUS trial will
likely impact and provide moreconsistency among guidelinerecommendations.

(CAD), a sizeable proportion of whom requires revas-cularization using percutaneous coronary interven-tion (PCI) and stent implantation (3). Such patientsneed dual antiplatelet therapy (DAPT) to prevent therisk of stent thrombosis and additional thromboticischemic events (4). Overall, about 5% to 10% of pa-tients referred to coronary angiography with orwithout PCI present with AF or other indications forchronic OAC (3).

Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo;

ers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-

entific, Medtronic, and Baim. Dr. Granger has received personal f

ed research grant support from AstraZeneca, Bayer, Boehringer

Daiichi-Sankyo, Janssen Pharmaceuticals, Bayer, Pfizer, Novartis,

dministration, and the National Heart, Lung, and Blood Institute

Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Medtronic, M

ticals, Verseon, and Janssen Pharmaceuticals. Dr. Vranckx has rec

ehring, and Daiichi-Sankyo. Dr. Lopes has received consulting fee

ibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; and has rece

Kline, Medtronic, Pfizer, and Sanofi. Dr. Montalescot has receiv

s from Abbott, Amgen, Actelion, AstraZeneca, Bayer, Boehringer

Deaconess Medical, Brigham Women’s Hospital, Cardiovascular

sevier, Fédération Française de Cardiologie, ICAN, Medtronic, Jou

erck Sharp & Dohme, Novo Nordisk, Pfizer, Sanofi, Servier, The M

has received institutional grants and personal fees from Boehring

Daiichi-Sankyo and Janssen; and honoraria from Amgen, Am

Regeneron. Dr. Ten Berg has received grant support, Advisory

a; has received Advisory Board fees, consulting fees, and lecture

Accumetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfize

d AstraZeneca. Dr. Gersh has received research contracts with

Ingelheim, Daiichi-Sankyo, Janssen, Novartis, GlaxoSmithKline, M

tion, and the National Institutes of Health; and has a consulting r

ibb, Boehringer Ingelheim, Boston Scientific, Gilead, Pfizer, Daiich

Diagnostics. Dr. Bhatt has served on the Advisory Board of Car

, PhaseBio, and Regado Biosciences; has served on the Board of D

ular Patient Care, and TobeSoft; has served as Chair of the Ameri

ION Registry Steering Committee, and the VA CART Research a

Committees of Baim Institute for Clinical Research (formerly H

d by St. Jude Medical, now Abbott), Cleveland Clinic (including for

nstitute, Mayo Clinic, Mount Sinai School of Medicine (for the E

The optimal antithrombotic treatment regimen forpatients with AF undergoing PCI is a clinical conun-drum. The combination of OAC and DAPT, a regimenalso known as triple antithrombotic therapy (TAT), is

and has received speaker’s honoraria from Bayer,

Sankyo. Dr. Faxon has received personal fees from

ees from Janssen, Boston Scientific, and Medtronic;

Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline,

Population Health Research Institute, the U.S. Food

; and has received consulting fees from Boehringer

erck & Co., Novartis, Pfizer, Daiichi-Sankyo, Rho

eived personal fees from AstraZeneca, Bayer Health

s from Amgen, Bayer, Boehringer Ingelheim, Bristol-

ived institutional grants from Bristol-Myers Squibb,

ed research grants to the institution or consulting/

Ingelheim, Boston Scientific, Bristol-Myers Squibb,

Research Foundation, Daiichi-Sankyo, Idorsia, Lilly,

rnal of the American College of Cardiology, Lead-Up,

ount Sinai School, TIMI Study Group, and WebMD.

er Ingelheim and Bristol-Myers Squibb; institutional

arin, Merck, Alnylam, Kowa, Pfizer, Eisai Co., Ltd.,

Board fees, consulting fees, and lecture fees from

s fees from Eli Lilly, Daiichi-Sankyo, The Medicines

r, and Bayer; and has received grant support from

Apple, AstraZeneca, Bayer, Bristol-Myers Squibb,

edtronic Foundation, Pfizer, the U.S. Food and Drug

elationship with Abbvie, AstraZeneca, Bayer, Bristol-

i-Sankyo, Novartis, Medtronic, Merck, Novo Nordisk,

dax, Elsevier Practice Update Cardiology, Medscape

irectors of Boston VA Research Institute, Society of

can Heart Association Quality Oversight Committee,

nd Publications Committee; has served on the Data

arvard Clinical Research Institute, for the PORTICO

the ExCEED trial, funded by Edwards), Duke Clinical

NVISAGE trial, funded by Daiichi-Sankyo), and the

J A C C V O L . 7 4 , N O . 1 , 2 0 1 9 Capodanno et al.J U L Y 9 , 2 0 1 9 : 8 3 – 9 9 Antithrombotic Therapy in AF Patients Undergoing PCI

85

theoretically required to decrease both the risk ofthromboembolism due to AF and the risk of throm-botic events due to coronary stents in patients withunderlying CAD. However, TAT markedly increasesthe risk of major and fatal bleeding (5). Randomizedcontrolled trials are now available that compare TATwith alternative antithrombotic therapy regimens,such as double antithrombotic therapy (DAT),which combines OAC with single antiplatelet therapy(SAPT) (6–10).

In keeping with the rapid evolution of the field ofantithrombotic therapy for AF and PCI, guidelines,focused updates and consensus documents arefrequently issued to incorporate the new evidence inthe field and inform clinical practice. The Americanand European guidelines for AF, DAPT, and myocar-dial revascularization represent a general frameworkfor the management of patients with AF and thoseundergoing PCI, respectively. The intersection be-tween the 2 scenarios (e.g., patients with AF-PCI) iscovered in the United States by the 2019 focusedupdate of the 2014 AF guideline from the AmericanCollege of Cardiology (ACC), AHA, and Heart RhythmSociety (HRS) (11), and in Europe by the 2018 guide-lines on myocardial revascularization from the Euro-pean Society of Cardiology (ESC) (12), which confirmthe recommendations included in the ESC focusedupdate on DAPT published in 2017 (13). These docu-ments provide practical recommendations that areendorsed by international scientific societies. Withmore focus on the specific subject of AF-PCI, prag-matic approaches to the treatment of AF-PCI patientswere also provided in 2018 by an earlier practicalguide from the European Heart Rhythm Association(14) and 2 later consensus documents that represent

Population Health Research Institute; has received honoraria from Ameri

Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Commit

Harvard Clinical Research Institute; RE-DUAL PCI Clinical Trial Steering Co

Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research

Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the Ame

Editor), Medtelligence/ReachMD (CME steering committees), Population He

committee, publications committee, steering committee, and USA national c

Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular P

Steering Committees); has served as Deputy Editor of Clinical Cardiology; h

Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb,

Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche,

received royalties from Elsevier (Editor, Cardiovascular Intervention: A Com

site coinvestigator for Biotronik, Boston Scientific, St. Jude Medical (now

American College of Cardiology; and has performed unfunded research for

and Takeda. Dr. Angiolillo has received consulting fees or honoraria as an

Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sank

PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has participated in

and has received institutional grants from Amgen, AstraZeneca, Bayer, Biose

Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, N

Stefan Hohnloser, MD, served as Guest Associate Editor for this paper.

Manuscript received April 24, 2019; revised manuscript received May 10, 20

the perspectives of North American and Europeanexperts in antithrombotic pharmacotherapy (15,16).The scope of this review is to provide an update onthe current status, evidence, recommendations, andfuture directions regarding the management ofantithrombotic therapy after PCI in AF patients onOAC. When mentioning recommendations and expertadvice, this review will refer to the last publishedguidelines and documents, with guidelines providinga framework of reference for classes of recommen-dation and levels of evidence, and consensus docu-ments expanding on practical issues from the NorthAmerican and European perspectives (11,12,15,16).

DEFINING THE CONTEXT

ANTITHROMBOTIC THERAPY FOR PATIENTS WITH

NONVALVULAR AF. When it comes to stroke pre-vention for AF, OAC outperforms SAPT (aspirin) orDAPT (aspirin plus clopidogrel). The ACTIVE (Atrialfibrillation Clopidogrel Trial with Irbesartan for pre-vention of Vascular Events) W trial, comparing OACwith DAPT, was stopped early because of a clear evi-dence of superiority: OAC with a vitamin K antagonist(VKA) resulted in 31% fewer vascular events at 1 year(p ¼ 0.0003) (17). In AF patients who are deemedunsuitable for OAC with VKA, despite demonstrationfrom the ACTIVE A trial that DAPT reduced the risk ofmajor vascular events compared with aspirin mono-therapy (18), the direct oral anticoagulant (DOAC)apixaban was found to reduce the risk of stroke orsystemic embolism without increasing the risk ofmajor bleeding when compared with aspirin (19). Assuch, there is a limited (if any) role for antiplatelettherapy alone in AF for stroke prevention, where

can College of Cardiology (Senior Associate Editor,

tee), Baim Institute for Clinical Research (formerly

mmittee funded by Boehringer Ingelheim), Belvoir

Institute (clinical trial steering committees), HMP

rican College of Cardiology (Guest Editor; Associate

alth Research Institute (for the COMPASS operations

oleader, funded by Bayer), Slack Publications (Chief

atient Care (Secretary/Treasurer), and WebMD (CME

as received research funding from Abbott, Amarin,

Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia,

Sanofi, Synaptic, and The Medicines Company; has

panion to Braunwald’s Heart Disease); has served as

Abbott), and Svelte; has served as a Trustee of the

FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma,

individual from Amgen, Aralez, AstraZeneca, Bayer,

yo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio,

review activities for CeloNova and St. Jude Medical;

nsors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai,

ovartis, Osprey Medical, and Renal Guard Solutions.

19, accepted May 13, 2019.

http://ACC.org



86

thrombi develop mainly in the left atrial appendage, aregion of low shear stress where the platelet compo-nent is less prevalent and an advantage of OAC isexpected (20)

The 2019 ACC/AHA/HRS guidelines for AF recom-mend that the selection of antithrombotic therapyfor AF is based on the risk of thromboembolismassessed with the CHA2DS2-VASc (Congestive Heartfailure, hypertension, Age $75 years [doubled], Dia-betes, Stroke [doubled], Vascular disease, Age 65 to74 years, and Sex [female]) score (11). In patientswith AF and a CHA2DS2-VASc score $2 in men or $3in women, OAC is recommended with warfarin (Classof Recommendation [COR] I, Level of Evidence[LOE]: A) or a DOAC, including dabigatran, rivarox-aban, apixaban, or edoxaban (COR I, LOE B) (11).Notably, a DOAC is now preferred to warfarin in allDOAC-eligible candidates, unless they present withmoderate-to-severe mitral stenosis or a mechanicalheart valve (COR I, LOE A) (11). Male AF patients witha CHA2DS2-VASc score of 1 and female AF patientswith a CHA2DS2-VASc score of 2 may receive OAC(COR IIb, LOE C). Conversely, in male patients with aCHA2DS2-VASc score of 0 and female patients with aCHA2DS2-VASc score of 1 it is reasonable to omit OAC(COR IIa, LOE B), which is not the case for AF pa-tients with CAD undergoing PCI who are assigned bydefault a score of at least 1 (men) or 2 (women) (11).The 2016 ESC guidelines for AF also recommend riskstratification by the CHA2DS2-VASc score and iden-tify different cut-offs for OAC based on sex, withslightly different grades of recommendation forthe time being (21). In particular, similarly to the2019 AHA/ACC/HRS guideline, OAC is recommendedfor all male AF patients with a CHA2DS2-VAScscore of $2 and for all female AF patients with aCHA2DS2-VASc score of $3 (COR I, LOE A), but therecommendation for male AF patients with aCHA2DS2-VASc score of 1 and female AF patients witha CHA2DS2-VASc score of 2 is IIa, LOE B (rather thanIIb, LOE C) after considering individual characteris-tics and patient preferences. In addition, OAC is notrecommended, rather than simply discouraged, inmale patients with a CHA2DS2-VASc score of 0 andfemale patients with a CHA2DS2-VASc score of 1 (CORIII, LOE B). Also in the European guidelines, in theabsence of contraindications (e.g., mechanicalvalves, moderate-to-severe mitral stenosis), a DOACis recommended as a first choice in preference to aVKA in all eligible candidates (COR I, LOE A). Ac-cording to both the AHA/ACC/HRS and ESC guide-lines, left atrial appendage occlusion may beconsidered in AF patients with contraindications forlong-term OAC (COR IIb, LOE B) (11,21).

ANTITHROMBOTIC THERAPY FOR PATIENTS

UNDERGOING PCI. When it comes to thrombosisprevention for patients undergoing PCI, the benefit ofDAPT over OAC is unequivocal (4,22–25). DAPT is thepresent standard of care (COR I) after PCI both in theelective setting, with aspirin and clopidogrel, and inthe course of an acute coronary syndrome (ACS), withaspirin and, preferably, ticagrelor or prasugrel (4).Default DAPT durations in these settings are 6 and12 months, respectively, but these durations are flex-ible depending on the individual risk of ischemia andbleeding (4). Multiple investigations in PCI patientsare ongoing to define whether in the era of newer-generation drug-eluting stents (DES) and morepotent P2Y12 inhibitors than clopidogrel (e.g., tica-grelor, prasugrel), SAPT is equally, if not more,protective as DAPT (26). The GLOBAL-LEADERS(A Clinical Study Comparing Two Forms of Anti-platelet Therapy After Stent Implantation) trial, a firstlarge study addressing this question, recently failed tomeet its primary objective to demonstrate a reductionin ischemic events with ticagrelor monotherapy,although there were no safety concerns comparedwith standard DAPT followed by aspirin monotherapy(27). Subsequently, 2 currently unpublished trials(STOPDAPT-2 [ShorT and OPtimal Duration of DualAntiPlatelet Therapy-2 Study] and SMART-CHOICE[Comparison Between P2Y12 Antagonist Monotherapyand Dual Antiplatelet Therapy After DES]) were pre-sented at the 2019 scientific sessions of the ACC con-ference indicating that short-term DAPT followed byP2Y12-inhibitor monotherapy may provide a safetybenefit compared with standard DAPT amongselected PCI patients receiving current-generationDES. Other studies of aspirin-free antithromboticstrategies after PCI are ongoing, including the TWI-LIGHT (Ticagrelor With Aspirin or Alone in High-RiskPatients After Coronary Intervention) study, whichhas recently completed its enrollment (28).

BLEEDING WITH COMBINATION OF OAC AND

ANTIPLATELET THERAPY. Patients with AF on TATexperience high rates of major bleeding (e.g., bleedingrequiring hospitalization or fatal bleeding) comparedwith patients on DAT or SAPT (5). In an updatednationwide Danish cohort study of 272,315 patientswith AF patients aged 50 years or older, comparedwith VKA monotherapy over a total follow-up periodof 1,373,131 patient-years, adjusted hazard ratios ofmajor bleeding were 1.13 (95% CI: 1.06 to 1.19) forDAPT, 1.82 (95% CI: 1.76 to 1.89) for DAT with a VKAand SAPT, 1.28 (95% CI: 1.13 to 1.44) for DAT with aDOAC and SAPT, 3.73 (95% CI: 3.23 to 4.31) for TATwith VKA, and 2.28 (95% CI: 1.67 to 3.12) for TAT with

FIGURE 1 Study Design and Key Outcomes of Double Therapy in OAC Patients Undergoing PCI in the Era of Vitamin K Antagonists: WOEST and ISAR-TRIPLE

0 1

Treatment Treatment11.1%

19.4%

Control17.6%

0% 1% 2% 3% 4% 5% 6%

44.4%

P < 0.0001

Treatment4.0%

5.3%

Control4.3%

4.0%

WOEST573 patients onOAC undergoing PCI

ISAR-TRIPLE614 patients onOAC undergoing PCI

Control

Treatment

Control

VKAClopidogrel

VKAClopidogrel

Aspirin

VKAClopidogrel

Aspirin

VKAClopidogrel

Aspirin

3 6

Antithrombotic TherapyDuration (Months) Clinical Outcomes

12

BMSBMS

DESDES

BMS DES

0% 10% 20% 30% 40% 50%

Any TIMI Bleeding (Primary Endpoint) Death, MI, Stroke, TVR, ST

TIMI Major Bleeding Cardiac Death, MI, Stroke, ST

BMS ¼ bare-metal stent; DES ¼ drug-eluting stent; ISAR-TRIPLE ¼ Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation;

MI ¼ myocardial infarction; OAC ¼ oral anticoagulation; PCI ¼ percutaneous coronary intervention; ST ¼ stent thrombosis; TIMI ¼ Thrombolysis In Myocardial

Infarction; WOEST ¼ What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing.


87

DOAC (5). The highest absolute rates of major bleedingwere observed in patients treated with VKA-TAT whowere older than 90 years (annualized rate 22.8%), hada CHA2DS2-VASc score >6 (17.1%), or presented with ahistory or major bleeding (17.5%) (5). Due to con-founding by indication and because TAT with a VKA orDOAC was only prescribed in 1% and 0.3% of patients,respectively, this study was unable to look at the ef-ficacy and net benefit of combining 3 antithromboticagents in AF patients. It is noteworthy that, in thesetting of high-risk ACS without AF, full-dose TATprovided no benefit but increased severe bleeding inthe APPRAISE 2 (Apixaban for Prevention of AcuteIschemic Events 2) trial (29). The high bleeding rates ofthe Danish registry emphasize that treatment withTAT, if deemed necessary, should be as short aspossible and likely best avoided altogether.

DOUBLE VERSUS TRIPLE THERAPY IN

AF-PCI PATIENTS

TRIALS OF VKAs. A summary of the study design andkey results of the WOEST (What is the Optimal anti-platElet & Anticoagulant Therapy in Patients WithOral Anticoagulation and Coronary StenTing) and

ISAR-TRIPLE (Triple Therapy in Patients on OralAnticoagulation After Drug Eluting Stent Implanta-tion) trials is provided in Figure 1. In WOEST andISAR-TRIPLE, simplification of the reference TATstrategy was attempted by aspirin withdrawal orshortening DAPT duration, respectively (6,7). InWOEST, the rationale for withdrawing aspirin wasdue to the observation that the risk of bleeding ishighest in the first month after PCI, likely as theconsequence of the procedure itself and of stackingmultiple oral and parenteral antithrombotic medica-tions (30). WOEST randomized in an open-labelfashion 573 patients on OAC, of whom 69% pre-sented with AF and 28% presented with an ACS. Thetrial found a 64% relative decrease in bleeding epi-sodes with DAT, driven by a reduced rate of minorbleeding episodes (hazard ratio: 0.36; 95% CI: 0.26 to0.50; p < 0.0001). Although it was not powered forischemic events, the trial also showed a decrease inthrombotic events in the DAT group. Notably, in thecontrol group, TAT was prolonged up to 1 year in thetwo-thirds of patients who received DES. In light ofthe results of the WOEST trial, the 1-year duration ofTAT has been questioned, and the standard durationof TAT, when used, has become shorter. Thus, the

FIGURE 2 Study Design and Key Outcomes of Double Therapy in OAC Patients Undergoing PCI in the Era of DOACs: PIONEER AF, RE-DUAL PCI, and AUGUSTUS

Treatment#1

Treatment#1

Treatment#2

Control#1

Treatment#1

Treatment#2

Control#1

Control#2

Control#2

Treatment#2

Control

Treatment#1

Treatment#1

Treatment#1

Treatment#2

Treatment#2

Control#1

Control#2

Control#1

Control#2

Treatment#2

Control

0%0 1 3 6 12

10% 20% 30%

0% 10% 20% 30%

0% 10% 20% 30%

6.5%16.8%

15.2%15.4%

11.8%20.2%

13.4%26.9%

12.8%25.7%

23.5%10.5%

26.2%16.1%

27.4%14.7%

24.7%9.0%

5.6%18.0%

6.0%26.7%

PIONEER AF2,124 patients withNVAF undergoing PCI

RE-DUAL PCI2,725 patients withNVAF undergoing PCI

AUGUSTUS4,614 NVAF patientswith ACS or PCI

Antithrombotic TherapyDuration (Months) Clinical Outcomes

Clinically Significant Bleeding (Primary Endpoint) CV Death, MI, Stroke

Major or CRNM Bleeding (Primary Endpoint) Death, MI, Stroke, SE, UR

Major or CRNM Bleeding (Primary Endpoint) Death, Hospitalization

15 mg od at P2Y12 stop

Rivaroxaban 15P2Y12 inhibitor

Rivaroxaban 2.5P2Y12 inhibitor

Aspirin

VKAP2Y12 inhibitor

Dabigatran 110P2Y12 inhibitor

Dabigatran 150P2Y12 inhibitor

Aspirin

VKAP2Y12 inhibitor

Aspirin

VKA

P2Y12 inhibitorAspirin

Apixaban 5P2Y12 inhibitor

Aspirin or placebo

Apixaban or VKAP2Y12 inhibitor

Aspirin

Apixaban or VKAP2Y12 inhibitor

Placebo

VKAP2Y12 inhibitor

Aspirin or placebo

BMS DES

BMS DES

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P = 0.002

P < 0.001

Participants in PIONEER AF were randomly assigned to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1);

very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2); or standard therapy with a dose-adjusted vitamin K antagonist (once-daily)

plus DAPT for 1, 6, or 12 months (group 3). Participants in RE-DUAL PCI were randomly assigned to receive, in a 1:1:1 ratio, triple antithrombotic therapy with warfarin

plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group); or double antithrombotic therapy with dabigatran (110 or 150 mg

twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110- and 150-mg double-therapy groups). Outside of the United States, elderly patients

($80 years of age; $70 years of age in Japan) were randomly assigned to the 110-mg double-therapy group or the triple-therapy group. AUGUSTUS ¼ An Open-label,

2 � 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial

Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention; CRNM ¼ clinically relevant non-major; CV ¼ cardiovascular; DOACs ¼ direct oral

anticoagulants; MI ¼ myocardial infarction; NVAF ¼ nonvalvular atrial fibrillation; OAC ¼ oral anticoagulation; PCI ¼ percutaneous coronary intervention; PIONEER

AF-PCI ¼ Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist

Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention; RE-DUAL PCI ¼ Randomized Evaluation of Dual Antith-

rombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention;

SE ¼ systemic embolism; UR ¼ urgent revascularization.



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WOEST trial, despite the small sample size and open-label design, provided some randomized evidencethat the early discontinuation of aspirin reducesbleeding in comparison to TAT, without any apparentincrease in ischemic events, leading to the subse-quent initiation of multiple trials of aspirin-freestrategies in PCI even outside of the AF context (26).

ISAR-TRIPLE randomized 614 patients with anyindication to OAC (83% for AF or atrial flutter)treated with PCI and DES (one-third with an ACS) toeither 6 weeks or 6 months of DAPT (7). The primaryendpoint, comprising a combination of ischemic andbleeding events, did not differ at 9 months betweenthe 2 groups, and in a landmark analysis of eventsbetween 6 weeks and 6 months, the risk ofbleeding was higher in the group where clopidogrelwas used longer (for 6 months), supporting thesafety benefit of DAT versus TAT. Importantly, likeWOEST, ISAR-TRIPLE was relatively small andunderpowered to detect significant differences inischemic endpoints (31).TRIALS OF DOACs. Figure 2 is a summary of thestudy design and key results of 3 trials: PIONEER AF-PCI (Open-Label, Randomized, Controlled, Multi-center Study Exploring Two Treatment Strategies ofRivaroxaban and a Dose-Adjusted Oral Vitamin KAntagonist Treatment Strategy in Subjects with AtrialFibrillation who Undergo Percutaneous CoronaryIntervention), RE-DUAL PCI (Randomized Evaluationof Dual Antithrombotic Therapy with Dabigatranversus Triple Therapy with Warfarin in Patients withNonvalvular Atrial Fibrillation Undergoing Percuta-neous Coronary Intervention) and AUGUSTUS (AnOpen-label, 2 � 2 Factorial, Randomized Controlled,Clinical Trial to Evaluate the Safety of Apixaban vs.Vitamin K Antagonist and Aspirin vs. Aspirin Placeboin Patients With Atrial Fibrillation and Acute Coro-nary Syndrome and/or Percutaneous Coronary Inter-vention) (8,9).

PIONEER AF-PCI compared 3 treatment strategiesafter PCI in 2,124 patients with AF: a WOEST-likestrategy of low-dose rivaroxaban (15 mg once daily[od]) plus a single P2Y12 inhibitor (group 1); a TATregimen of very low-dose rivaroxaban (2.5 mg twicedaily [bid]) plus DAPT, followed by rivaroxaban 15 mgod at the time of P2Y12 inhibitor discontinuation(group 2); and control TAT with a VKA plus DAPT(group 3) (8). It is important to note that the dosingregimens of rivaroxaban used in the trial do notrepresent the approved doses for stroke prevention inAF, although they were selectively chosen based onprior dose-finding investigations (32). At variancewith WOEST, patients were stratified by the intendedduration of DAPT (1, 6, or 12 months), with only 22%

finally found to be on TAT at 1 year in the controlgroup. Compared with control subjects, the primaryendpoint of clinically significant bleeding at12 months was reduced by both rivaroxaban-basedstrategies (hazard ratio for group 1 vs. group 3: 0.59;95% CI: 0.47 to 0.76; p < 0.001; hazard ratio for group2 vs. group 3: 0.63; 95% CI: 0.50 to 0.80; p < 0.001),driven by lower rates of bleeding requiring medicalattention and not by TIMI (Thrombolysis In Myocar-dial Infarction) major or minor bleeding. Therivaroxaban-based regimen resulted in a reduced riskof total bleeding events and recurrent hospitalizationfor adverse events (33,34). Conversely, there were nodifferences in major adverse cardiovascular events,but the power was low for ischemic endpoints (8).

RE-DUAL PCI randomized 2,725 PCI patients withAF (one-half of them in the setting of an ACS) to 2regimens of DAT that included dabigatran 150 or110 mg bid and mostly clopidogrel (ticagrelor in 12%)versus a regimen of TAT with warfarin (9). In the TATgroup, aspirin was discontinued after 1 month in pa-tients who received a bare-metal stent (17%) and after3 months in patients who received a DES (83%). At amean of 14 months, the risk of major or clinicallyrelevant nonmajor bleeding in the 110 mgdabigatran DAT group was noninferior to the riskobserved in the control group, and superiority wasalso established (hazard ratio: 0.52; 95% CI:0.42 to 0.63; p for noninferiority <0.0001, p forsuperiority ¼ 0.0001). The 150-mg dabigatran DATgroup also met both the noninferiority and superior-ity objectives compared with the TAT group (hazardratio: 0.72; 95% CI: 0.58 to 0.88; p for noninferiority<0.0001, p for superiority ¼ 0.002). These resultswere consistent irrespective of clinical presentation(e.g., stable CAD or ACS) and irrespective of whetherclopidogrel or ticagrelor was used in the treatmentand control arms (35). The risk of thromboembolicevents was noninferior in the 2 DAT groups combinedas compared with the TAT group, although a numer-ical (nonsignificant) absolute risk increase was notedwith the lower 110-mg dabigatran dose (11%) adcompared with the higher 150-mg dabigatran dose(7.9%) (9). It is important to note that the 110-mgdabigatran dose is not approved for stroke preven-tion in the United States. Finally, due to the design ofboth PIONEER-AF PCI and RE-DUAL PCI, they couldnot distinguish whether the reduction in bleedingwas attributed to the use of a DOAC versus VKA, tothe avoidance of aspirin, or both.

In AUGUSTUS, 4,614 patients with ACS and or PCIwithin 14 days were randomized in a 2 � 2 factorialdesign to apixaban 5 mg bid versus VKAs (open label)and to aspirin versus placebo (blinded) for 6 months



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(10). All patients received a P2Y12 inhibitor (mostlyclopidogrel). About one-quarter of patients had ACSand no PCI. At 6months, the primary outcome of majoror clinically relevant nonmajor bleeding was signifi-cantly reduced by apixaban compared with VKAs(hazard ratio: 0.69; 95% CI: 0.58 to 0.81; p< 0.001) andincreased by aspirin compared with placebo (hazardratio: 1.89; 95% CI: 1.59 to 2.24; p < 0.001). Patients inthe apixaban group had a lower risk of death or hos-pitalization than those in the VKA group (hazard ratio:0.83; 95% CI: 0.74 to 0.93; p ¼ 0.002), whereas nosignificant differences on this endpoint were notedbetween patients in the aspirin and placebo groups. Bymeans of its factorial design and at variance withPIONEER-AF PCI and RE-DUAL PCI, AUGUSTUS helpsto disentangle the individual contribution of DOACsand aspirin withdrawal on the risk of bleeding,demonstrating that both aspects are beneficial. Thebenefit of using a DOAC versus VKA in the setting of AFand ACS with or without PCI corroborates the recom-mendation from current guidelines for AF (11,21).Importantly, compared with prior studies of DOACs,AUGUSTUS also included medically managed ACSpatients who did not receive stents, who are known tobe at high ischemic risk. Therefore, this data expandson current knowledge in the field. The issue of earlyaspirin withdrawal in AUGUSTUS should be inter-preted in view of some aspects related to the studydesign and results of the trial. First, patients wereenrolled at a median of 6 days from ACS and/or PCI,which suggests that most patients in the trial had atleast short-term aspirin use before randomization.Second, the follow-up time was shorter than inPIONEER-AF PCI and RE-DUAL PCI (6 months vs.12 months). Third, nonsignificant 0.5% and 0.4% ab-solute increases in myocardial infarction and stentthrombosis, respectively, were noted in patients onplacebo compared with those on aspirin. Indeed, abetter understanding of patient profiles and timing ofthese events with relationship to aspirin discontinu-ation will be informative for clinical practice.

DOUBLE VERSUS TRIPLE ANTITHROMBOTIC THERAPY

IN META-ANALYSES OF BLEEDING AND ISCHEMIC

EVENTS. The safety and efficacy of DAT versus TAT inAF patients undergoing PCI has been the objective ofseveral pooled analyses of WOEST, ISAR-TRIPLE,PIONEER AF-PCI, and RE-DUAL PCI. In the meta-analysis from Golwala et al. (36), encompassing a to-tal of 5,317 patients, compared with the TAT group,TIMI major or minor bleeding was reduced by 47% inthe DAT arm (hazard ratio: 0.53, 95% credible inter-val: 0.36 to 0.85; I2¼42.9%). There was no differencein trial-defined major adverse cardiac events (hazard

ratio 0.85; 95% credible interval: 0.48 to 1.29,I2¼ 58.4%), or in the individual outcomes of all-causemortality, cardiac death, myocardial infarction, stentthrombosis, or stroke between the DAT and TATgroups (36). Although the credible interval for theefficacy outcomes remains large in this meta-analysis,these findings suggest that DAT represents a saferoption than TAT in PCI patients with AF. It should benoted that AUGUSTUS, the largest study of a DOAC inpatients with indication for antiplatelet therapy dueto PCI and/or ACS, was not incorporated in this meta-analysis that encompasses approximately the samenumber of the total patients randomized in the trial.

PRACTICAL MANAGEMENT OF AF PATIENTS

UNDERGOING PCI

Multiple guidelines and consensus documents havebeen published over the past decade to inform clini-cians on the optimal antithrombotic strategy for AFpatients undergoing PCI. Initially, most recommen-dations were based on expert consensus in theabsence of an evidence basis from randomizedcontrolled trials. While the evidence consolidates,some recommendations are strengthened, othersabandoned. As noted in the previous text, for thepurpose of the following discussion, we refer to the2019 ACC/AHA/HRS guidelines for AF and the 2018ESC guidelines for myocardial revascularization whenciting recommendations, and to the latest iteration ofthe consensus documents issued in 2018 by expertson antithrombotic therapy at the 2 sides of theAtlantic for practical issues (11,12,15,16). A summaryof practical recommendations from the 2 NorthAmerican and European consensus documents isprovided in Table 1 to highlight current areas ofconsensus and discrepancy. Key aspects are dis-cussed in the following text, integrated by authors’consensus on aspects that eventually emerged afterthe publication of the AUGUSTUS trial.

PROCEDURAL CONSIDERATIONS. PCI has become asafer procedure over the years with better patientselection using heart team decisions, avoidance ofunnecessary procedures through intracoronaryphysiology measurements, increasing use of radialarteries for vascular access, and improvement ofavailable DES technologies (12,15). As part of a generalperiprocedural bleeding avoidance strategy, proced-ures should be carried out with radial access(4,12,15,16). Indeed, urgent or emergent procedurescan be performed without withholding OAC. In gen-eral, patients on a DOAC undergoing elective ornonemergent procedures should withhold therapy for24 h (or 48 h for patients with impaired renal function

TABLE 1 Summary of Practical Recommendation for OAC Patients Undergoing PCI

North American Perspective European Perspective

Pre-procedural considerations

Indication to PCI Consider appropriateness. —

Risk management Qualitative, based on factors defining the ischemic/thromboticand bleeding risk.

Quantitative and qualitative, based on scores and factors definingthe ischemic/thrombotic and bleeding risk.

Procedural considerations

Anticoagulation A period of washout is always preferable (unless emergency PCI)and bridging with heparin is unnecessary (unless ACS).

Do not interrupt VKA, interrupt DOACs unless emergency PCI.

Vascular access Prefer radial access. Prefer radial access.

Additional intraproceduralUFH

Administer. Administer (reduced dose if VKA, standard dose if DOACs).

Bivalirudin use May be considered in high bleeding risk patients, particularly ACSand if femoral approach is used.

May be considered.

Use of GPIs Limit use to selected cases at high-risk for thromboticcomplications or for bail-out situations.

Do not use, except for bailout.

Use of periprocedural aspirin Periprocedural and in-hospital. Consider pre-treatment in most cases.

Use of periproceduralclopidogrel

Recommended. Recommended. Pre-treatment if known coronary anatomy,emergency cases, or PCI is likely). Halved loading dose in caseof VKA.

Stent selection Prefer new-generation DES. Prefer new-generation DES.

Post-procedural considerations

Risk management Re-evaluate the risk profile. —

Other therapies Use PPI, avoid NSAIDs. Use PPI.

Post-PCI antithromboticmanagement

Choice of OAC Prefer DOACs. Prefer DOACs.

If DOAC is chosen Use at established stroke prevention doses. If a DOAC has notbeen specifically studied in this setting, the doses tested inthe pivotal AF trials leading to drug approval should be used.It is reasonable to prefer a dabigatran 150-mg bid dosingregimen in patients considered to be at higher thromboticrisk, whereas a 110-mg bid regimen may be preferred inpatients at higher bleeding risk. Rivaroxaban 15 mg od may beused instead of 20 mg od.*

If part of TAT, prefer dabigatran 110 mg bid, rivaroxaban 15 mgod (or 20 mg od), apixaban 5 mg bid, or edoxaban 60 mg od.If part of DAT, prefer dabigatran 150 mg bid, rivaroxaban15 mg od (or 20 mg od, especially if transition from TAT toDAT), apixaban 5 mg bid, edoxaban 60 mg od.*

If VKA is chosen INR 2.0–2.5. INR 2.0–2.5 with TAT, INR 2.0–3.0 with DAT.

Duration of OAC Lifelong. Lifelong.

Duration of TAT Peri-PCI only, or 1 month in patients at high thrombotic risk andlow bleeding risk.

1 to 3–6 months (in ACS, 3–6 months).

Aspirin Use low-dose. Periprocedural and in-hospital. Use low dose.

Choice of P2Y12 inhibitor Prefer clopidogrel, with ticagrelor as an alternative for selectedpatients. Avoid prasugrel.

Prefer clopidogrel.

DAT Preferred strategy, with OAC and a P2Y12 inhibitor, startingimmediately after discharge.

Alternative to TAT if concerns of high bleeding risk.

Clopidogrel rather thanaspirin in DAT

Preferable. Preferable.

Duration of SAPT Discontinue at 12 months in most patients. Earlier or nodiscontinuation depending on risk.

Discontinue at 12 months in most patients. Continue in selectedpatients depending on risk.

*Unless dose reduction criteria are present in accordance with package labels.

ACS ¼ acute coronary syndrome; AF ¼ atrial fibrillation; bid ¼ twice daily; DAT ¼ double antithrombotic therapy; DES ¼ drug-eluting stent; GPI ¼ glycoprotein IIb/IIIa inhibitor; INR ¼ internationalnormalized ratio; DOACs ¼ direct oral anticoagulants; NSAIDs ¼ nonsteroidal anti-inflammatory drugs; OAC ¼ oral anticoagulation; od ¼ once daily; PCI ¼ percutaneous coronary intervention; PPI ¼ protonpump inhibitors; SAPT ¼ single antiplatelet therapy; TAT ¼ triple antithrombotic therapy; UFH ¼ unfractionated heparin; VKA ¼ vitamin K antagonist.


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on dabigatran) (15). If the patient is on VKA, the NorthAmerican recommendation suggests a wash-outperiod with target INR based on the type of vascularaccess (#2 and #1.5 for radial and femoral access,respectively), whereas the European document sug-gests that a strategy of uninterrupted VKA should bepreferred over a strategy of interrupted VKA withheparin bridging (15,16,37). Both documents agreethat patients with stable CAD can forgo bridging with

parenteral anticoagulation, while—according to theNorth American document only—bridging should beconsidered for ACS patients as an integral part of theircare. Additional unfractionated heparin should beadministered as per usual practice to support PCI, atstandard dose (70 to 100 U/Kg) in case of DOACs andreduced dose (30 to 50 U/Kg) in case of ongoing VKA.Bivalirudin may also be considered, particularly inpatients at high bleeding risk, in those presenting

TABLE 2 Criteria of High-Risk Features Tipping the Balance Toward More or Less Intense

Antithrombotic Therapy for AF Patients Undergoing PCI

Criteria of High Stent-DrivenThrombotic Risk

Criteria of High Bleeding Risk That Make theCombination of OAC and Antiplatelet Therapy

Unfavorable

� Prior stent thrombosis on adequateantiplatelet therapy

� Stenting of the last remaining patentcoronary artery

� Diffuse multivessel disease especially indiabetic patients

� Chronic kidney disease (e.g., creatinineclearance <60 ml/min)

� At least 3 stents implanted� Bifurcation with 2 stents implanted� Total stent length >60 mm� Treatment of a chronic total occlusion

� Short life expectancy� Ongoing malignancy with high bleeding

potential� Poor expected adherence� Poor mental status� End stage renal failure� Advanced age� Prior major bleeding/prior hemorrhagic

stroke� Chronic alcohol abuse� Anemia� Clinically significant bleeding on DAT

Reproduced with permission from Valgimigli et al. (13).

Abbreviations as in Table 1.



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with ACS, and if a femoral approach is being used (15).More potent therapies, such as cangrelor or glyco-protein IIb/IIIa inhibitors, are generally only recom-mended for selected cases at high, life-threateningrisk for ischemic complications or for bail-out situa-tions, although cangrelor may be preferred of the 2approaches due to a shorter half-life (38–41). Pre-treatment with clopidogrel is indicated when PCI islikely or decided (4,12). Importantly, aspirin shouldbe prescribed periprocedurally in all cases to decreasethe risk of early stent-related thrombotic complica-tions (4,12).

RISK STRATIFICATION FOR THROMBOSIS AND

BLEEDING. After the indications for OAC and anti-platelet therapy are established, the North Americanand European consensus documents suggest thatdecisions should be guided by balancing the indi-vidual risk of atherothrombosis with the risk of majorbleeding (15,16). This is an aspect of paramountpractical importance, because such risk stratificationwill shift the pendulum toward, for example, TAT orDAT, or the selection of different P2Y12 inhibitors. TheNorth American document emphasizes that physi-cians should rely on qualitative factors to characterizethe individual risk of ischemia and bleeding, whereasthe approach of the European consensus document ismore quantitative and relies on risk scores for bothischemia and bleeding. Indeed, to characterize theatherothrombotic risk, the European consensusdocument suggests using the SYNTAX (Synergy Be-tween PCI With Taxus and Cardiac Surgery) score forelective PCI and the GRACE (Global Registry of AcuteCoronary Event) score (with a cutoff of 140) for PCI inthe context of an ACS (16). In addition, concernsabout thrombotic risk apply to anatomic and clinical

presentations, such as stenting of the left main,proximal left anterior descending, proximal bifurca-tion, recurrent myocardial infarctions, and stentthrombosis (16). Also according to the Europeandocument, bleeding risk can be estimated using theHAS-BLED (Hypertension, Abnormal Renal/LiverFunction, Stroke, Bleeding History or Predisposition,Labile International Normalized Ratio, Elderly,Drugs/Alcohol) score (e.g., $3) with the aim ofscreening candidates who require more regular re-view and earlier follow-up, and to identify and cor-rect modifiable bleeding risk factors. In RE-DUAL PCI,the benefit of DAT with dabigatran in reducingbleeding events compared with TAT with VKA wasirrespective of the baseline risk of bleeding defined bythe HAS-BLED score (42). It should be recognized thatthe predictive performance of bleeding risk scores isgenerally modest, and that patients on OAC representa high bleeding risk category per se where furtherdiscrimination is problematic (43,44). In a study of AFpatients comparing different risk stratification toolsfor bleeding, the HEMORR(2)HAGES (Hepatic or RenalDisease, Ethanol Abuse, Malignancy, Older Age,Reduced Platelet Count or Function, Re-Bleeding[doubled], Hypertension, Anemia, Genetic Factors,Excessive Fall Risk and Stroke), ATRIA (Anti-coagulation and Risk Factors in Atrial Fibrillation),and HAS-BLED scores showed only weak performancein predicting any clinically relevant bleeding,although the HAS-BLED score performed better thanthe HEMORR(2)HAGES and ATRIA scores (c-indexes:0.60 vs. 0.55 and 0.50 for HAS-BLED vs. HEMORR(2)AGES and ATRIA, respectively) (45). Similar findingswere reported for different bleeding risk tools inDOAC-treated patients (46). A recent independentsystematic review concluded that the HAS-BLEDscore provides the best prediction for bleeding risk(44). Adding biomarker information significantly butstill suboptimally improves the discrimination per-formance of bleeding risk assessment over HAS-BLED(c-indexes 0.69 to 0.71 vs. 0.62 for HAS-BLED inexternal validation cohorts) (47,48), and showed noadvantage in real-world clinical practice (49). In theabsence of accurate predictive tools for bleeding,defining which AF-PCI patients have more or less tobenefit from different antithrombotic strategies re-mains a case-by-case decision. A list of suggestedcriteria of high risk for ischemia/thrombosis andbleeding from the European focused update on DAPTis provided in Table 2 (13).

CHOICE AND DURATION OF ANTITHROMBOTIC

STRATEGIES AFTER PCI. In selecting the optimalantithrombotic regimen for an AF patient who

CENTRAL ILLUSTRATION Consensus Recommendations on the Practical Management of Oral Anticoagulation andAntiplatelet Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

Peri-Percutaneous Coronary Intervention

Default approach

High ischemic risk,low bleeding risk

2018 North AmericanPerspective

High bleeding risk,low ischemic risk

1 mo 3 mo 6 mo

Time from Percutaneous Coronary Intervention

12 mo

Clopidogrel

Clopidogrel or Ticagrelor



Clopidogrel

Clopidogrel (or Ticagrelor in Double Antithrombotic Therapy)




Clopidogrel

Clopidogrel

Bleeding risk >ischemic risk

Ischemic risk >bleeding risk

2018 EuropeanPerspective

Bleeding risk >>ischemic risk

Oral Anticoagulation P2Y12 inhibitor Aspirin

Capodanno, D. et al. J Am Coll Cardiol. 2019;74(1):83–99.


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received PCI, physicians have to consider somefundamental questions. As far as the type of OACdrug is concerned (first question), both the NorthAmerican and European consensus documents agreewith current ACC/AHA/HRS and ESC guidelines(11,12) that, in the absence of contraindications,DOACs should be preferred to VKAs due to thelower risk of bleeding previously demonstrated tobe a class effect (50). A bivariate analysis using ameasure of risk difference in the net clinical

outcome based on data from PIONEER-AF PCI andRE-DUAL PCI demonstrated that both the rivarox-aban- and dabigatran-based regimens are favorablecompared with VKA plus DAPT (51). Indeed, thealternative of maintaining VKA is practically moreproblematic, because the intensity of the INR needsmodulation (e.g., values between 2.0 and 2.5) dur-ing the TAT term (52). In the AUGUSTUS trial, themedian percentage of time when the INR was below2 was 23% (10). Also, in the same study, the safety



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benefit of being on a DOAC compared with VKA wasdemonstrated on top of considerations on aspirinversus no aspirin use (10). Thus, in patients alreadyon a VKA, switching to a DOAC is a reasonable op-tion to reduce the risk of bleeding. However, a VKAremains the only indicated treatment in patientswith moderate to severe mitral stenosis and me-chanical prosthetic heart valves, and is generally amore accepted approach in patients with end-stagerenal disease—although, in the latter, more recentdata show that DOACs may be superior towarfarin (53).

The second question deals with the duration ofTAT (Central Illustration). This spans from very short(e.g., until after successful PCI) to extended (e.g.,6 months) depending on various clinical scenarios.Notably, both the 2019 ACC/AHA/HRS guidelines forAF and the 2018 ESC guidelines for myocardialrevascularization, published before the AUGUSTUStrial, recommend DAT as an alternative to TAT toreduce bleeding with COR IIa, but in the Europeanguidelines this indication is currently restricted topatients at baseline high bleeding risk (11,12). Basedon the North American expert consensus document,the default approach is DAT, and thus to keep aspirinonly in the periprocedural period and during hospitalstay. The rationale for DAT as a default strategy isbased on results of the 3 trials available at the time ofpublication that showed a more favorable safetyprofile compared with TAT (6,8,9). It is important tonote that all trials testing the safety of droppingaspirin early (i.e., prior to hospital discharge) arebased on the observation that most bleeding eventsoccur within the first month, as noted in the previoustext, due to periprocedural issues and use of multipleantithrombotic medications. The high rate ofbleeding early after PCI was also confirmed in themore recent studies, particularly during the timeframe that patients were still on aspirin (6–10).However, the North American document does indi-cate that TAT for up to 1 month can be considered inpatients who have high thrombotic risk and lowbleeding risk. In contrast, the European consensusdocument follows this approach only for patients inwhom the bleeding risk exceeds the thrombotic risk,whereas all other patients should receive 1 month ofTAT as a default approach, or longer-term (3 to6 months) TAT if the thrombotic risk exceeds thebleeding risk (COR IIa in the European guidelines formyocardial revascularization [12]). These differencesbetween consensus documents possibly reflect thedifferent weights that the 2 panels of experts havegiven to the findings of the PIONEER-AF PCI and RE-DUAL PCI trials, with the North Americans relying

more on such clinical trial data to support their rec-ommendations compared with their European coun-terparts. The results of the AUGUSTUS trial, in thecontext of previous evidence from the other trials,will likely affect future recommendations andperhaps provide more consistency between NorthAmerican and European experts who mostly divergeon duration of TAT. Further analyses from theAUGUSTUS trial, which showed consistent benefit ofDAT irrespective of baseline risk (e.g., with no sig-nificant interaction observed for multiple subgroups)will also better inform practitioners as well as helpdevelop guideline recommendations (10). It should benoted that these recommendations refer essentiallyto AF patients on DOACs. Indeed, the effect of aspirinwithdrawal in VKA patients who are not eligible forDOACs is limited to the small WOEST trial.

The third question deals with the specific anti-platelet drug to be discontinued in the transition fromTAT to DAT. The consensus of the North Americanand European documents is that a P2Y12 inhibitorshould be used without aspirin. This recommenda-tion is based on the well-established notion that,post-PCI, the use of a P2Y12 inhibitor is pivotal for theprevention of thrombotic complications (22–25). Thisis suggested despite the notion that a proportion ofpatients exhibit substantial variability in the plateletresponse to clopidogrel (54). However, this pharma-codynamic characteristic was not shown to translateinto an increase in adverse outcomes with clopidogrelin a large direct comparison with aspirin, where clo-pidogrel was actually shown to be superior inreducing ischemic events and also had a more favor-able safety profile (i.e., less hospitalization forgastrointestinal bleeding) (55,56). It is, however,important to note that aspirin was used at a 325-mgdaily regimen in this trial. Indeed, the key role thatthe P2Y12 receptor-mediated signaling has on modu-lating thrombotic processes in stented patients sup-ports keeping an agent blocking this pathway (57). Itis also important to note that there is synergism onmodulating thrombus formation when a P2Y12 inhib-itor is coupled with an OAC (58).

The fourth question deals with the dosing regimenof a DOAC for combination therapy in TAT or DATregimens. In TAT regimens, both documents recom-mend using approved doses proven to be effective inregulatory trials of AF, with dose reductions as perthe respective package labels (i.e., due to reducedrenal elimination in patients with chronic kidneydisease). In the case of dabigatran, the North Amer-ican document suggests to use a higher 150-mg biddose for patients who are at higher thrombotic risk,which is consistent with the 2019 ACC/AHA/HRS

FIGURE 3 Study Design of the ENTRUST-AF PCI Trial

P2Y12 inhibitor for all patients for 12 monthsAspirin for 1 to 12 months in the control group only

• OAC indicated for ≥12 months• Successful PCI with stent placement

Included• Known bleeding diathesis• Other reasons for OAC (mechanical valves, mitral stenosis)

Excluded

ENTRUST-AF PCI

Primary outcome: ISTH major or CRNM bleeding at 12 monthsKey secondary outcome: CV death, MI, stroke, SE, ST

Edoxaban Vitamin Kantagonist

N = 1,500

CRNM ¼ clinically relevant non-major; CV ¼ cardiovascular; ENTRUST-AF PCI ¼ Edoxaban Treatment Versus Vitamin K Antagonist in Patients

With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention; ISTH ¼ International Society of Thrombosis and Haemostasis;

ST ¼ stent thrombosis; other abbreviations as in Figure 2.


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guidelines for AF, where dabigatran 150 mg has CORIIa, LOE B; the European consensus documents,consistent with the 2018 ESC guidelines on myocar-dial revascularization, suggest using the 110-mg biddose during TAT (COR IIa, LOE C) and the 150-mg biddose during DAT (COR IIb, LOE B), due to concerns ofhigher thrombotic risk with the lower dose. If rivar-oxaban is used, the 15-mg od dose (e.g., rather thanthe 20-mg od dose tested in the regulatory trial of AF)is considered a reasonable option by the 2018 ESCguidelines for myocardial revascularization accordingto the design of PIONEER-AF PCI (COR IIa, LOE B inthe 2019 ACC/AHA/HRS guidelines for AF; COR IIb,LOE B in the 2018 ESC guidelines for myocardialrevascularization) (12). After discontinuation of theP2Y12 inhibitor, OAC should be continued at fullstroke prevention doses. Therefore, if a reduced doseregimen of rivaroxaban (e.g., 15 mg od; 10 mg od inpatients with renal dysfunction) was being used, it isimportant to resume the full recommended dose(20 mg od; 15 mg od in patients with renal dysfunc-tion) after suspension of antiplatelet therapy (15,16).

The fifth question deals with the choice of P2Y12

inhibitor. In this category, clopidogrel should beregarded as the agent of choice. Prasugrel and tica-grelor are approved for patients with ACS, and thereis limited data for their use in combination with OAC(4). Data of prasugrel for TAT with VKA are disap-pointing due to an unacceptable high rate of bleeding(59), and the 2018 ESC guidelines on myocardialrevascularization formally contraindicate the use ofboth prasugrel and ticagrelor in combination withOAC (COR III, LOE C), whereas the 2019 ACC/AHA/HRS guidelines for AF recommend clopidogrel in TATcombinations with COR IIa, LOE B. Indeed, inPIONEER-AF PCI, the use of prasugrel and ticagrelorwas allowed, but the proportion of patients whoactually received them was very small (2% to 4%) (8).In RE-DUAL PCI, ticagrelor was used in 12% of pa-tients, which provides some insights to the treatmenteffects, although without statistical power. Inparticular, although no statistical interaction wasnoted between the treatment effect of the 2 testeddoses of dabigatran and the use of clopidogrel or



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ticagrelor for DAT, the absolute rates of bleeding werehigher when ticagrelor was used in TAT combinationsas compared with DAT (9,35). In light of these find-ings, in patients who are at low risk for bleeding(particularly younger patients) and at high risk forthrombotic events (e.g., ACS, diabetes, complex PCI),the use of ticagrelor combined with a DOAC repre-sents a potential option (15). In AUGUSTUS, the use ofprasugrel or ticagrelor was also low (10). Althoughthere are no randomized clinical trial data supportingescalation of P2Y12-inhibiting therapy among patientswith inadequate response to clopidogrel, and routineplatelet function or genetic testing to define responseto clopidogrel is not recommended, the use of tica-grelor may be considered in patients in whom poorresponse to clopidogrel is known or after a side effectto the drug (60).

Finally, a sixth question deals with the optimalmanagement at 12 months from PCI, when the patientis typically on DAT unless the P2Y12 inhibitor has beendiscontinued earlier as suggested in both the NorthAmerican and European consensus documents forpatients at very high risk of bleeding. Ideally, thepatients should continue on OAC alone, based onregistry and other observational data showing that inpatients with stable CAD (e.g., >1 year, with no acuteevents), the addition of antiplatelet therapy to OACincreases bleeding without adding ischemic protec-tion compared with OAC alone (61,62). This consid-eration is valid unless concerns of thrombotic riskprevail, suggesting the need for continued DAT on acase-by-case basis (Table 1). According to the NorthAmerican document, the choice of SAPT to use after 1year (aspirin or clopidogrel) is at the discretion of thetreating physician, although it appears to be reason-able to maintain the same antiplatelet drug that thepatient was already taking. After discontinuation ofSAPT, DOACs should be continued at full stroke-prevention doses as described in the previous text.Because renal function is a dynamic process, it isprudent to reassess renal function before changingthe dose or after discontinuation of SAPT. The OAC-ALONE (Optimizing Antithrombotic Care in PatientsWith AtriaL fibrillatiON and Coronary stEnt) study, atrial initially designed to enroll 2,000 patients in12 months but prematurely terminated after enrolling696 patients in 38 months, did not establish non-inferiority of OAC alone to combined OAC and SAPTin patients with AF and stable CAD beyond 1 yearafter PCI (63). However, because patient enrollmentwas prematurely terminated, this study should beconsidered inconclusive. On the same subject, theAFIRE (Atrial Fibrillation and Ischemic Events WithRivaroxaban in Patients With Stable Coronary Artery

Disease Study) study (N ¼ 2,200) is ongoing in Japanto evaluate the efficacy and safety of monotherapywith the DOAC rivaroxaban versus DOAC plus SAPT instable CAD patients 1 year or more after PCI(NCT02642419), while the French AQUATIC (Assess-ment of Quitting versus Using Aspirin Therapy Inpatients treated with oral anticoagulation for atrialfibrillation and with stabilized Coronary artery dis-ease) (currently unregistered on clinicaltrials.gov)trial will investigate, in high-risk stabilized PCI pa-tients requiring OAC for AF, the superiority of DATwith aspirin and full-dose OAC for 24 to 48 monthsversus placebo and full-dose OAC alone on a com-posite endpoint including cardiovascular mortality,myocardial infarction, stroke, coronary revasculari-zation, systemic embolism, and acute limb ischemia.

OTHER BLEEDING AVOIDANCE STRATEGIES. Boththe North American and European consensus docu-ments recommend using proton pump inhibitors inall situations where OAC is combined with antiplate-let therapy (64,65). In addition, concurrent therapywith nonsteroidal anti-inflammatory drugs, possiblypotentiating the effect of antithrombotic therapy,should be avoided.

ONGOING STUDIES OF ANTITHROMBOTIC

THERAPY IN AF PATIENTS UNDERGOING PCI

The ENTRUST-AF PCI (Edoxaban Treatment VersusVitamin K Antagonist in Patients With Atrial Fibril-lation Undergoing Percutaneous Coronary Interven-tion) will soon complete the landscape of DOACtrials in AF patients who need antiplatelet agents(Figure 3) (66). Edoxaban 60 mg od will be testedagainst TAT with VKA in about 1,500 patients on aprimary endpoint of International Society onThrombosis and Haemostasis–defined major or clin-ically relevant nonmajor bleeding. Another trial witha safety focus on bleeding named APPROACH-ACS-AF (APixaban vs. PhenpRocoumon in Patients WithACS and AF) (NCT02789917), comparing DAT withapixaban versus TAT with VKA, is also underway.Two more randomized trials are ongoing in China.The COACH-AF PCI trial (Dabigatran Versus WarfarinWith NVAF Who Undergo PCI) (NCT03536611) is anopen-label, randomized trial designed to comparethe safety and efficacy of 1-month TAT followed byDAT with dabigatran versus 1-month TAT followedby DAT with warfarin in Chinese patients with AFundergoing PCI. This study will address a questionremained unanswered by the RE-DUAL PCI trial:whether the superior benefit of the investigationalstrategies is ascribable to the use of dabigatranversus a VKA or DAT versus TAT. The primary

https://clinicaltrials.gov/ct2/show/NCT02642419




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endpoint will be time to the first occurrence ofBleeding Academic Research Consortium–defined(grade 2 to 5) clinically relevant bleeding. Anothermulticenter trial (NCT03234114) will enroll 800 ACSpatients undergoing PCI to receive 12-month DATwith dabigatran 100 mg bid plus ticagrelor or clopi-dogrel versus TAT with warfarin randomized for 1 or6 months, followed by DAT with warfarin and clo-pidogrel for up to 12 months. The primary compositeendpoint will be the composite of all-cause death,nonfatal myocardial infarction, unplanned revascu-larization, ischemic stroke, or major bleeding. TheJapanese SAFE-A (SAFety and Effectiveness trial ofApixaban use in association with dual antiplatelettherapy in patients with atrial fibrillation undergoingpercutaneous coronary intervention) study willcompare 1-month vs. 6-month DAPT in combinationwith apixaban in patients with AF who undergo DESimplantation (67). Finally, the ongoing MASTERDAPT (Management of High Bleeding Risk PatientsPost Bioresorbable Polymer Coated Stent Implanta-tion With an Abbreviated Versus Standard DAPTRegimen) trial, randomizing approximately 4,300high-bleeding-risk patients undergoing DES implan-tation to an abbreviated versus a standard durationof antiplatelet therapy, will include a substantialproportion of patients with concomitant indicationto OAC (68).

CONCLUSIONS

When performed in the setting of AF, where OAC isused to prevent the risk of thromboembolic events,PCI requires the use of antiplatelet therapy to pre-vent the risk of stent thrombosis. The currentparadigm is that the association of OAC with DAPT(typically clopidogrel and aspirin), a strategy knownas TAT, should be as short as possible or even

avoided (69). However, there are different perspec-tives on the 2 sides of the Atlantic on when and inwhich patients SAPT should be started. A NorthAmerican perspective suggests that TAT should beused in-hospital but soon deescalated to DAT withOAC and clopidogrel for 6 to 12 months dependingon the bleeding risk, followed by OAC alone in mostcases. The European perspective suggests that TATshould be stopped at discharge, 1 month, or 3 to6 months depending on considerations surroundingthe balance between the individual thrombotic andbleeding profile. Indeed, the results of the AUGUS-TUS and ENTRUST-AF PCI trials will likely affectfuture recommendations and perhaps foster moresynergism between North American and Europeanexperts who mostly diverge on duration of TAT. Anumber of bleeding-avoidance strategies are alsosuggested to decrease the risk of bleeding with bothTAT and DAT. Three trials of dabigatran, rivarox-aban, and apixaban have provided randomized evi-dence that a regimen of DAT with DOACs providesbetter safety compared with a regimen of TAT withVKA. Further evidence is expected soon for edox-aban. Although the DAT strategy has clearlydemonstrated a reduction in bleeding complicationswithout any apparent trade-off in efficacy, none ofthe trials were powered for ischemic events. Giventhe unlikelihood of further large-scale trials pow-ered for efficacy, patient-level meta-analyses of theavailable evidence would indeed be informative tothis extent.

ADDRESS FOR CORRESPONDENCE: Dr. Dominick J.Angiolillo, University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville,Florida, 32209. E-mail: [email protected]. Twitter: @UFMedicineJax, @DFCapodanno.

RE F E RENCE S

1. Benjamin EJ, Virani SS, Callaway CW, et al. Heartdisease and stroke statistics-2018 update: a reportfrom the American Heart Association. Circulation2018;137:e67–492.

2. Lip G, Freedman B, De Caterina R, Potpara TS.Stroke prevention in atrial fibrillation: past, pre-sent and future. Comparing the guidelines andpractical decision-making. Thromb Haemost 2017;117:1230–9.

3. Michniewicz E, Mlodawska E, Lopatowska P,Tomaszuk-Kazberuk A, Malyszko J. Patients withatrial fibrillation and coronary artery disease–double trouble. Adv Med Sci 2018;63:30–5.

4. Capodanno D, Alfonso F, Levine GN,Valgimigli M, Angiolillo DJ. Dual antiplatelettherapy: appraisal of the ACC/AHA and ESC

focused updates. J Am Coll Cardiol 2018;72:103–19.

5. van Rein N, Heide-Jørgensen U, Lijfering WM,Dekkers OM, Sørensen HT, Cannegieter SC. Majorbleeding rates in atrial fibrillation patients onsingle, dual, or triple antithrombotic therapy. Cir-culation 2019;139:775–86.

6. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use ofclopidogrel with or without aspirin in patients takingoral anticoagulant therapy and undergoing percuta-neous coronary intervention: an open-label, rando-mised, controlled trial. Lancet 2013;381:1107–15.

7. Fiedler KA, Maeng M, Mehilli J, et al. Durationof triple therapy in patients requiring oral anti-coagulation after drug-eluting stent implantation.J Am Coll Cardiol 2015;65:1619–29.

8. Gibson CM, Mehran R, Bode C, et al. Preventionof bleeding in patients with atrial fibrillation un-dergoing PCI. N Engl J Med 2016;375:2423–34.

9. Cannon CP, Bhatt DL, Oldgren J, et al. DualAntithrombotic therapy with dabigatran after PCIin atrial fibrillation. N Engl J Med 2017;377:1513–24.

10. Lopes RD, Heizer G, Aronson R, et al. Antith-rombotic therapy after acute coronary syndromeor PCI in atrial fibrillation. N Engl J Med 2019;380:1509–24.

11. January CT, Wann LS, Calkins H, et al. 2019AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS Guideline for the Management of Pa-tients With Atrial Fibrillation. J Am Coll Cardiol2019 Jan 21 [E-pub ahead of print].


mailto:[email protected]

mailto:[email protected]

https://twitter.com/UFMedicineJax

https://twitter.com/DFCapodanno

http://refhub.elsevier.com/S0735-1097(19)35208-8/sref1


















































98

12. Neumann F-J, Sousa-Uva M, Ahlsson A, et al.2018 ESC/EACTS guidelines on myocardial revas-cularization. Eur Heart J 2019;40:87–165.

13. Valgimigli M, Bueno H, Byrne RA, et al. 2017ESC focused update on dual antiplatelet therapy incoronary artery disease developed in collaborationwith EACTS. Eur Heart J 2018;39:213–60.

14. Steffel J, Verhamme P, Potpara TS, et al. The2018 European Heart Rhythm Association prac-tical guide on the use of non-vitamin K antagonistoral anticoagulants in patients with atrial fibrilla-tion. Eur Heart J 2018;39:1330–93.

15. Angiolillo DJ, Goodman SG, Bhatt DL, et al.Antithrombotic therapy in patients with atrialfibrillation treated with oral anticoagulation un-dergoing percutaneous coronary intervention: aNorth American perspective–2018 update. Circu-lation 2018;138:527–36.

16. Lip GYH, Collet J-P, Haude M, et al. 2018 jointEuropean consensus document on the manage-ment of antithrombotic therapy in atrial fibrillationpatients presenting with acute coronary syndromeand/or undergoing percutaneous cardiovascularinterventions: a joint consensus document of theEuropean Heart Rhythm Association (EHRA), Eu-ropean Society of Cardiology Working Group onThrombosis, European Association of Percuta-neous Cardiovascular Interventions (EAPCI), andEuropean Association of Acute Cardiac Care(ACCA) endorsed by the Heart Rhythm Society(HRS), Asia-Pacific Heart Rhythm Society (APHRS),Latin America Heart Rhythm Society (LAHRS), andCardiac Arrhythmia Society of Southern Africa(CASSA). Europace 2019;21:192–3.

17. Connolly S, Pogue J, Hart R, et al., for theACTIVE Writing Group of the ACTIVE Investigators.Clopidogrel plus aspirin versus oral anti-coagulation for atrial fibrillation in the Atrialfibrillation Clopidogrel Trial with Irbesartan forprevention of Vascular Events (ACTIVE W): arandomised controlled trial. Lancet 2006;367:1903–12.

18. Connolly SJ, Pogue J, Hart RG, et al., for theACTIVE Investigators. Effect of clopidogrel addedto aspirin in patients with atrial fibrillation. N EnglJ Med 2009;360:2066–78.

19. Connolly SJ, Eikelboom J, Joyner C, et al.Apixaban in patients with atrial fibrillation. N EnglJ Med 2011;364:806–17.

20. Simmers MB, Cole BK, Ogletree ML, et al.Hemodynamics associated with atrial fibrillationdirectly alters thrombotic potential of endothelialcells. Thromb Res 2016;143:34–9.

21. Kirchhof P, Benussi S, Kotecha D, et al. 2016ESC guidelines for the management of atrialfibrillation developed in collaboration with EACTS.Eur Heart J 2016;37:2893–962.

22. Schömig A, Neumann F-J, Kastrati A, et al.A randomized comparison of antiplatelet andanticoagulant therapy after the placement ofcoronary-artery stents. N Engl J Med 1996;334:1084–9.

23. Bertrand ME, Legrand V, Boland J, et al. Ran-domized multicenter comparison of conventionalanticoagulation versus antiplatelet therapy in un-planned and elective coronary stenting. The full

anticoagulation versus aspirin and ticlopidine(fantastic) study. Circulation 1998;98:1597–603.

24. Urban P, Macaya C, Rupprecht HJ, et al.Randomized evaluation of anticoagulation versusantiplatelet therapy after coronary stent implan-tation in high-risk patients: the multicenteraspirin and ticlopidine trial after intracoronarystenting (MATTIS). Circulation 1998;98:2126–32.

25. Leon MB, Baim DS, Popma JJ, et al. A clinicaltrial comparing three antithrombotic-drug regi-mens after coronary-artery stenting. N Engl J Med1998;339:1665–71.

26. Capodanno D, Mehran R, Valgimigli M, et al.Aspirin-free strategies in cardiovascular diseaseand cardioembolic stroke prevention. Nat RevCardiol 2018;15:480–96.

27. Vranckx P, Valgimigli M, Jüni P, et al. Tica-grelor plus aspirin for 1 month, followed by tica-grelor monotherapy for 23 months vs aspirin plusclopidogrel or ticagrelor for 12 months, followedby aspirin monotherapy for 12 months after im-plantation of a drug-eluting stent: a multicentre,open-label, randomised superiority trial. Lancet2018;392:940–9.

28. Baber U, Dangas G, Cohen DJ, et al. Ticagrelorwith aspirin or alone in high-risk patients aftercoronary intervention: rationale and design of theTWILIGHT study. Am Hear J 2016;182:125–34.

29. Alexander JH, Lopes RD, James S, et al.Apixaban with antiplatelet therapy after acutecoronary syndrome. N Engl J Med 2011;365:699–708.

30. Hansen ML, Sørensen R, Clausen MT, et al.Risk of bleeding with single, dual, or triple therapywith warfarin, aspirin, and clopidogrel in patientswith atrial fibrillation. Arch Intern Med 2010;170:1433–41.

31. Bhatt DL. When is a double better than aTRIPLE? Stenting in patients with atrial fibrillation.J Am Coll Cardiol 2015;65:1630–2.

32. Gibson CM, Mehran R, Bode C, et al. An open-label, randomized, controlled, multicenter studyexploring two treatment strategies of rivaroxabanand a dose-adjusted oral vitamin K antagonisttreatment strategy in subjects with atrial fibrilla-tion who undergo percutaneous coronary inter-vention. Am Heart J 2015;169:472–8.e5.

33. Chi G, Yee MK, Kalayci A, et al. Total bleedingwith rivaroxaban versus warfarin in patients withatrial fibrillation receiving antiplatelet therapyafter percutaneous coronary intervention.J Thromb Thrombolysis 2018;46:346–50.

34. Gibson CM, Pinto DS, Chi G, et al. Recurrenthospitalization among patients with atrial fibrilla-tion undergoing intracoronary stenting treatedwith 2 treatment strategies of rivaroxaban or adose-adjusted oral vitamin K antagonist treatmentstrategy clinical perspective. Circulation 2017;135:323–33.

35. Oldgren J, Steg PG, Hohnloser SH, et al.Dabigatran dual therapy with ticagrelor or clo-pidogrel after percutaneous coronary interven-tion in atrial fibrillation patients with or withoutacute coronary syndrome: a subgroup analysisfrom the RE-DUAL PCI trial. Eur Heart J 2019;40:1553–62.

36. Golwala HB, Cannon CP, Steg PG, et al. Safetyand efficacy of dual vs. triple antithrombotictherapy in patients with atrial fibrillation followingpercutaneous coronary intervention: a systematicreview and meta-analysis of randomized clinicaltrials. Eur Heart J 2018;39:1726–35a.

37. Angiolillo DJ, Goodman SG, Bhatt DL, et al.Antithrombotic therapy in patients with atrialfibrillation undergoing percutaneous coronaryintervention. Circ Cardiovasc Interv 2016;9:e004395.

38. Bhatt DL, Stone GW, Mahaffey KW, et al. Ef-fect of platelet inhibition with cangrelor duringPCI on ischemic events. N Engl J Med 2013;368:1303–13.

39. Franchi F, Rollini F, Rivas A, et al. Platelet in-hibition with cangrelor and crushed ticagrelor inpatients with ST-elevation myocardial infarctionundergoing primary percutaneous coronary inter-vention: results of the CANTIC Study. Circulation2019;139:1661–70.

40. Vaduganathan M, Harrington RA, Stone GW,et al. Cangrelor with and without glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneouscoronary intervention. J Am Coll Cardiol 2017;69:176–85.

41. Vaduganathan M, Harrington RA, Stone GW,et al. Evaluation of ischemic and bleeding risksassociated with 2 parenteral antiplatelet strate-gies comparing cangrelor with glycoproteinIIb/IIIa inhibitors: an exploratory analysis fromthe CHAMPION Trials. JAMA Cardiol 2017;2:127–35.

42. Lip GYH, Mauri L, Montalescot G, et al. Rela-tionship of stroke and bleeding risk profiles toefficacy and safety of dabigatran dual therapyversus warfarin triple therapy in atrial fibrillationafter percutaneous coronary intervention: anancillary analysis from the RE-DUAL PCI trial. AmHeart J 2019;212:13–22.

43. Capodanno D, Angiolillo DJ. Tailoring durationof DAPT with risk scores. Lancet 2017;389:987–9.

44. Borre ED, Goode A, Raitz G, et al. Predictingthromboembolic and bleeding event risk in pa-tients with non-valvular atrial fibrillation: a sys-tematic review. Thromb Haemost 2018;118:2171–87.

45. Apostolakis S, Lane DA, Guo Y, Buller H,Lip GYH. Performance of the HEMORR(2)HAGES,ATRIA, and HAS-BLED bleeding risk-predictionscores in patients with atrial fibrillation undergo-ing anticoagulation: the AMADEUS (evaluating theuse of SR34006 compared to warfarin or aceno-coumarol in patients with atria. J Am Coll Cardiol2012;60:861–7.

46. Yao X, Gersh BJ, Sangaralingham LR, et al.Comparison of the CHA2DS2-VASc, CHADS2, HAS-BLED, ORBIT, and ATRIA risk scores in predictingnon-vitamin K antagonist oral anticoagulants-associated bleeding in patients with atrial fibrilla-tion. Am J Cardiol 2017;120:1549–56.

47. Hijazi Z, Oldgren J, Lindbäck J, et al. The novelbiomarker-based ABC (age, biomarkers, clinicalhistory)-bleeding risk score for patients with atrialfibrillation: a derivation and validation study.Lancet 2016;387:2302–11.








































































































































































































99

48. Berg DD, Ruff CT, Jarolim P, et al. Perfor-mance of the ABC scores for assessing the risk ofstroke or systemic embolism and bleeding in pa-tients with atrial fibrillation in ENGAGE AF-TIMI48. Circulation 2019;139:760–71.

49. Asunción Esteve-Pastor M, Miguel Rivera-Caravaca J, Roldán V, et al. Long-term bleedingrisk prediction in ‘real world’ patients with atrialfibrillation: comparison of the HAS-BLED and ABC-Bleeding risk scores. Thromb Haemost 2017;117:1848–58.

50. Ruff CT, Giugliano RP, Braunwald E, et al.Comparison of the efficacy and safety of new oralanticoagulants with warfarin in patients with atrialfibrillation: a meta-analysis of randomised trials.Lancet 2014;383:955–62.

51. Chi G, Kerneis M, Kalayci A, et al. Safety andefficacy of non–vitamin K oral anticoagulant foratrial fibrillation patients after percutaneous cor-onary intervention: a bivariate analysis of thePIONEER AF-PCI and RE-DUAL PCI trial. Am HeartJ 2018;203:17–24.

52. Rossini R, Musumeci G, Lettieri C, et al. Long-term outcomes in patients undergoing coronarystenting on dual oral antiplatelet treatmentrequiring oral anticoagulant therapy. Am J Cardiol2008;102:1618–23.

53. Qamar A, Bhatt DL. Stroke prevention in atrialfibrillation in patients with chronic kidney disease.Circulation 2016;133:1512–5.

54. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E,et al. Variability in individual responsivenessto clopidogrel. J Am Coll Cardiol 2007;49:1505–16.

55. CAPRIE Steering Committee. A randomised,blinded, trial of clopidogrel versus aspirin in pa-tients at risk of ischaemic events (CAPRIE). Lancet1996;348:1329–39.

56. Bhatt DL, Hirsch AT, Ringleb PA, Hacke W,Topol EJ, for the CAPRIE Investigators.

Reduction in the need for hospitalization forrecurrent ischemic events and bleeding withclopidogrel instead of aspirin. Am Heart J 2000;140:67–73.

57. Storey RF. Biology and pharmacology of theplatelet P2Y12 receptor. Curr Pharm Des 2006;12:1255–9.

58. Perzborn E, Heitmeier S, Laux V. Effects ofrivaroxaban on platelet activation and platelet-coagulation pathway interaction: in vitro andin vivo studies. J Cardiovasc Pharmacol Ther 2015;20:554–62.

59. Sarafoff N, Martischnig A, Wealer J, et al.Triple therapy with aspirin, prasugrel, and vitaminK antagonists in patients with drug-eluting stentimplantation and an indication for oral anti-coagulation. J Am Coll Cardiol 2013;61:2060–6.

60. Angiolillo DJ, Rollini F, Storey RF, et al. In-ternational expert consensus on switching plateletP2Y12 receptor–inhibiting therapies. Circulation2017;136:1955–75.

61. Hamon M, Lemesle G, Tricot O, et al. Inci-dence, source, determinants, and prognosticimpact of major bleeding in outpatients with sta-ble coronary artery disease. J Am Coll Cardiol2014;64:1430–6.

62. Alexander JH, Lopes RD, Thomas L, et al.Apixaban vs. warfarin with concomitant aspirin inpatients with atrial fibrillation: insights from theARISTOTLE trial. Eur Heart J 2014;35:224–32.

63. Matsumura-Nakano Y, Shizuta S, Komasa A,et al. Open-label randomized trial comparing oralanticoagulation with and without single anti-platelet therapy in patients with atrial fibrillationand stable coronary artery disease beyond 1 yearafter coronary stent implantation. Circulation2019;139:604–16.

64. Abraham NS, Hlatky MA, Antman EM, et al.ACCF/ACG/AHA 2010 expert consensus documenton the concomitant use of proton pump inhibitors

and thienopyridines: a focused update of theACCF/ACG/AHA 2008 Expert Consensus Docu-ment on Reducing the Gastrointestinal Risks ofAntiplatelet Therapy and NSAID use: a report ofthe American College of Cardiology FoundationTask Force on Expert Consensus Documents. J AmColl Cardiol 2010;56:2051–66.

65. Bhatt DL, Cryer BL, Contant CF, et al.Clopidogrel with or without omeprazole incoronary artery disease. N Engl J Med 2010;363:1909–17.

66. Vranckx P, Lewalter T, Valgimigli M, et al.Evaluation of the safety and efficacy of anedoxaban-based antithrombotic regimen in pa-tients with atrial fibrillation following successfulpercutaneous coronary intervention (PCI) withstent placement: rationale and design of theENTRUST-AF PCI trial. Am Heart J 2018;196:105–12.

67. Hoshi T, Sato A, Nogami A, Gosho M,Aonuma K, for the SAFE-A Investigators.Rationale and design of the SAFE-A study:SAFety and Effectiveness trial of apixaban usein association with dual antiplatelet therapy inpatients with atrial fibrillation undergoingpercutaneous coronary intervention. J Cardiol2017;69:648–51.

68. Frigoli E, Smits P, Vranckx P, et al. Design andrationale of the Management of High BleedingRisk Patients Post Bioresorbable Polymer CoatedStent Implantation With an Abbreviated VersusStandard DAPT Regimen (MASTER DAPT) Study.Am Heart J 2019;209:97–105.

69. Capodanno D, Angiolillo DJ. Triple antith-rombotic therapy at the intercept between threatsand opportunities. J Am Coll Cardiol Intv 2017;10:1086–8.

KEY WORDS atrial fibrillation, coronarystenting, oral anticoagulant, oral antiplatelet




















































































































