Management of Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 74, NO. 1, 2019

ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE JACC STATE-OF-THE-ART REVIEW

Management of Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI JACC 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 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.

From the aDivision of Cardiology, A.O.U. “Policlinico-Vittorio Emanuele,” University of Catania, Catania, Italy; b3rd Medical Department, Cardiology and Intensive Care Medicine and Sigmund Freud University, Medical Faculty, Vienna, Austria; c

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

Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; eAalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; fBrigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts; gDuke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; hDepartment of Cardiology and Critical Care Medicine, Hartcentrum Hasselt, and faculty of Medicine and Life Sciences at the University of Hasselt, Hasselt, Belgium; iCardiology Department, Nîmes University Hospital, ACTION Study Group, Montpellier University, Nîmes, France; jDepartment of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands; k

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

cine, Jacksonville, Florida. Dr. Capodanno has received speakers honoraria from Bayer, AstraZeneca, Daiichi-Sankyo, Pfizer, and Listen to this manuscript’s

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

audio summary by

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

Editor-in-Chief

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

Dr. Valentin Fuster on

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

JACC.org.

as a consultant to Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Regeneron Pharmaceuticals (no fees), Roivant Sciences, and Sanofi; has served as an institutional consultant (payment to institution) for Abbott Vascular and Spectranetics/Phillips/Volcano Corporation; has served on the Executive Committee for Janssen Pharmaceuticals and Bristol-Myers Squibb; has received institutional (payment to institution) Advisory Board funding from Bristol-Myers Squibb and Novartis; has received Data and Safety Monitoring Board membership funding to his institution from Watermark Research; and has <1% equity with Claret Medical and Elixir Medical. Dr. Lip has served as a consultant for Bayer/Janssen, Bristol-Myers Squibb/Pfizer,

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

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Antithrombotic Therapy in AF Patients Undergoing PCI

ABBREVIATIONS AND ACRONYMS AF = atrial fibrillation

A

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

American Heart Association (AHA) reports es-

CAD = coronary artery disease DAPT = dual antiplatelet

timates of AF prevalence in 2010 ranging from z2.7 to 6.1 million in the United States

therapy

DAT = double antithrombotic therapy

and 8.8 million (95% confidence interval [CI]: 6.5 to 12.3 million) in Europe (1). These estimates are projected to rise to 12.1 million

DOAC = direct oral anticoagulant

in 2030 in the United States and 17.9 million

OAC = oral anticoagulation

(95% CI: 13.6 to 23.7 million) in 2060 in

PCI = percutaneous coronary

Europe (1). AF increases the risk of thrombo-

intervention

embolic complications, including stroke and

SAPT = single antiplatelet

extracranial systemic embolic events, which

therapy

call for therapeutic prophylaxis with oral

TAT = triple antithrombotic

anticoagulation (OAC) (2). It is estimated

therapy

that about 20% to 40% of patients with AF

VKA = vitamin K antagonist

also present with coronary artery disease

(CAD), a sizeable proportion of whom requires revascularization using percutaneous coronary intervention (PCI) and stent implantation (3). Such patients need dual antiplatelet therapy (DAPT) to prevent the risk of stent thrombosis and additional thrombotic ischemic events (4). Overall, about 5% to 10% of patients referred to coronary angiography with or without PCI present with AF or other indications for chronic OAC (3).

HIGHLIGHTS
AF patients require OAC to prevent the risk of thromboembolic events, whereas antiplatelet therapy is required to prevent stent thrombosis in the setting of PCI.
Several randomized trials have demonstrated that a regimen of DAT with DOACs provides better safety compared with a regimen of TAT with VKA.
The current paradigm is that TAT (the association of OAC with DAPT) should be as short as possible or even avoided based on the individual’s ischemic and bleeding risk profile.
The results of the AUGUSTUS trial will likely impact and provide more consistency among guideline recommendations. The optimal antithrombotic treatment regimen for patients with AF undergoing PCI is a clinical conundrum. The combination of OAC and DAPT, a regimen also known as triple antithrombotic therapy (TAT), is

Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo; and has received speaker’s honoraria from Bayer, Bristol-Myers Squibb/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. Dr. Faxon has received personal fees from Boston Scientific, Medtronic, and Baim. Dr. Granger has received personal fees from Janssen, Boston Scientific, and Medtronic; has received research grant support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Daiichi-Sankyo, Janssen Pharmaceuticals, Bayer, Pfizer, Novartis, Population Health Research Institute, the U.S. Food and Drug Administration, and the National Heart, Lung, and Blood Institute; and has received consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Medtronic, Merck & Co., Novartis, Pfizer, Daiichi-Sankyo, Rho Pharmaceuticals, Verseon, and Janssen Pharmaceuticals. Dr. Vranckx has received personal fees from AstraZeneca, Bayer Health Care, CLS Behring, and Daiichi-Sankyo. Dr. Lopes has received consulting fees from Amgen, Bayer, Boehringer Ingelheim, BristolMyers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; and has received institutional grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Montalescot has received research grants to the institution or consulting/ lecture fees from Abbott, Amgen, Actelion, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Cardiovascular Research Foundation, Daiichi-Sankyo, Idorsia, Lilly, Europa, Elsevier, Fédération Française de Cardiologie, ICAN, Medtronic, Journal of the American College of Cardiology, Lead-Up, Menarini, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Sanofi, Servier, The Mount Sinai School, TIMI Study Group, and WebMD. Dr. Cannon has received institutional grants and personal fees from Boehringer Ingelheim and Bristol-Myers Squibb; institutional grants from Daiichi-Sankyo and Janssen; and honoraria from Amgen, Amarin, Merck, Alnylam, Kowa, Pfizer, Eisai Co., Ltd., Sanofi, and Regeneron. Dr. Ten Berg has received grant support, Advisory Board fees, consulting fees, and lecture fees from AstraZeneca; has received Advisory Board fees, consulting fees, and lectures fees from Eli Lilly, Daiichi-Sankyo, The Medicines Company, Accumetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Bayer; and has received grant support from ZonMw and AstraZeneca. Dr. Gersh has received research contracts with Apple, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Janssen, Novartis, GlaxoSmithKline, Medtronic Foundation, Pfizer, the U.S. Food and Drug Administration, and the National Institutes of Health; and has a consulting relationship with Abbvie, AstraZeneca, Bayer, BristolMyers Squibb, Boehringer Ingelheim, Boston Scientific, Gilead, Pfizer, Daiichi-Sankyo, Novartis, Medtronic, Merck, Novo Nordisk, and Roche Diagnostics. Dr. Bhatt has served on the Advisory Board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and the VA CART Research and Publications Committee; has served on the Data Monitoring Committees of Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), and the

Capodanno et al.

JACC VOL. 74, NO. 1, 2019 JULY 9, 2019:83–99

Antithrombotic Therapy in AF Patients Undergoing PCI

theoretically required to decrease both the risk of

the perspectives of North American and European

thromboembolism due to AF and the risk of throm-

experts in antithrombotic pharmacotherapy (15,16).

botic events due to coronary stents in patients with

The scope of this review is to provide an update on

underlying CAD. However, TAT markedly increases

the current status, evidence, recommendations, and

the risk of major and fatal bleeding (5). Randomized

future directions regarding the management of

controlled trials are now available that compare TAT

antithrombotic therapy after PCI in AF patients on

with alternative antithrombotic therapy regimens,

OAC. When mentioning recommendations and expert

such

(DAT),

advice, this review will refer to the last published

which combines OAC with single antiplatelet therapy

guidelines and documents, with guidelines providing

(SAPT) (6–10).

a framework of reference for classes of recommen-

as

double

antithrombotic

therapy

In keeping with the rapid evolution of the field of

dation and levels of evidence, and consensus docu-

antithrombotic therapy for AF and PCI, guidelines,

ments expanding on practical issues from the North

focused updates and consensus documents are

American and European perspectives (11,12,15,16).

frequently issued to incorporate the new evidence in the field and inform clinical practice. The American

DEFINING THE CONTEXT

and European guidelines for AF, DAPT, and myocardial revascularization represent a general framework

ANTITHROMBOTIC THERAPY FOR PATIENTS WITH

for the management of patients with AF and those

NONVALVULAR AF. When it comes to stroke pre-

undergoing PCI, respectively. The intersection be-

vention for AF, OAC outperforms SAPT (aspirin) or

tween the 2 scenarios (e.g., patients with AF-PCI) is

DAPT (aspirin plus clopidogrel). The ACTIVE (Atrial

covered in the United States by the 2019 focused

fibrillation Clopidogrel Trial with Irbesartan for pre-

update of the 2014 AF guideline from the American

vention of Vascular Events) W trial, comparing OAC

College of Cardiology (ACC), AHA, and Heart Rhythm

with DAPT, was stopped early because of a clear evi-

Society (HRS) (11), and in Europe by the 2018 guide-

dence of superiority: OAC with a vitamin K antagonist

lines on myocardial revascularization from the Euro-

(VKA) resulted in 31% fewer vascular events at 1 year

pean Society of Cardiology (ESC) (12), which confirm

(p ¼ 0.0003) (17). In AF patients who are deemed

the recommendations included in the ESC focused

unsuitable for OAC with VKA, despite demonstration

update on DAPT published in 2017 (13). These docu-

from the ACTIVE A trial that DAPT reduced the risk of

ments provide practical recommendations that are

major vascular events compared with aspirin mono-

endorsed by international scientific societies. With

therapy (18), the direct oral anticoagulant (DOAC)

more focus on the specific subject of AF-PCI, prag-

apixaban was found to reduce the risk of stroke or

matic approaches to the treatment of AF-PCI patients

systemic embolism without increasing the risk of

were also provided in 2018 by an earlier practical

major bleeding when compared with aspirin (19). As

guide from the European Heart Rhythm Association

such, there is a limited (if any) role for antiplatelet

(14) and 2 later consensus documents that represent

therapy alone in AF for stroke prevention, where

Population Health Research Institute; has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI Clinical Trial Steering Committee funded by Boehringer Ingelheim), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME Steering Committees); has served as Deputy Editor of Clinical Cardiology; has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site coinvestigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has served as a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda. Dr. Angiolillo has received consulting fees or honoraria as an individual from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has participated in review activities for CeloNova and St. Jude Medical; and has received institutional grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. Stefan Hohnloser, MD, served as Guest Associate Editor for this paper. Manuscript received April 24, 2019; revised manuscript received May 10, 2019, accepted May 13, 2019.

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Antithrombotic Therapy in AF Patients Undergoing PCI

thrombi develop mainly in the left atrial appendage, a

ANTITHROMBOTIC

region of low shear stress where the platelet compo-

UNDERGOING PCI. When it comes to thrombosis

THERAPY

FOR

PATIENTS

nent is less prevalent and an advantage of OAC is

prevention for patients undergoing PCI, the benefit of

expected (20)

DAPT over OAC is unequivocal (4,22–25). DAPT is the

The 2019 ACC/AHA/HRS guidelines for AF recom-

present standard of care (COR I) after PCI both in the

mend that the selection of antithrombotic therapy

elective setting, with aspirin and clopidogrel, and in

for AF is based on the risk of thromboembolism

the course of an acute coronary syndrome (ACS), with

assessed with the CHA 2DS2-VASc (Congestive Heart

aspirin and, preferably, ticagrelor or prasugrel (4).

failure, hypertension, Age $75 years [doubled], Dia-

Default DAPT durations in these settings are 6 and

betes, Stroke [doubled], Vascular disease, Age 65 to

12 months, respectively, but these durations are flex-

74 years, and Sex [female]) score (11). In patients

ible depending on the individual risk of ischemia and

with AF and a CHA 2DS 2-VASc score $2 in men or $3

bleeding (4). Multiple investigations in PCI patients

in women, OAC is recommended with warfarin (Class

are ongoing to define whether in the era of newer-

of Recommendation [COR] I, Level of Evidence

generation drug-eluting stents (DES) and more

[LOE]: A) or a DOAC, including dabigatran, rivarox-

potent P2Y 12 inhibitors than clopidogrel (e.g., tica-

aban, apixaban, or edoxaban (COR I, LOE B) (11).

grelor, prasugrel), SAPT is equally, if not more,

Notably, a DOAC is now preferred to warfarin in all

protective as DAPT (26). The GLOBAL-LEADERS

DOAC-eligible candidates, unless they present with

(A Clinical Study Comparing Two Forms of Anti-

moderate-to-severe mitral stenosis or a mechanical

platelet Therapy After Stent Implantation) trial, a first

heart valve (COR I, LOE A) (11). Male AF patients with

large study addressing this question, recently failed to

a CHA 2 DS2-VASc score of 1 and female AF patients

meet its primary objective to demonstrate a reduction

with a CHA 2DS2-VASc score of 2 may receive OAC

in ischemic events with ticagrelor monotherapy,

(COR IIb, LOE C). Conversely, in male patients with a

although there were no safety concerns compared

CHA2DS 2-VASc score of 0 and female patients with a

with standard DAPT followed by aspirin monotherapy

CHA2DS 2-VASc score of 1 it is reasonable to omit OAC

(27). Subsequently, 2 currently unpublished trials

(COR IIa, LOE B), which is not the case for AF pa-

(STOPDAPT-2 [ShorT and OPtimal Duration of Dual

tients with CAD undergoing PCI who are assigned by

AntiPlatelet Therapy-2 Study] and SMART-CHOICE

default a score of at least 1 (men) or 2 (women) (11).

[Comparison Between P2Y12 Antagonist Monotherapy

The 2016 ESC guidelines for AF also recommend risk

and Dual Antiplatelet Therapy After DES]) were pre-

stratification by the CHA 2DS 2-VASc score and iden-

sented at the 2019 scientific sessions of the ACC con-

tify different cut-offs for OAC based on sex, with

ference indicating that short-term DAPT followed by

slightly different grades of recommendation for

P2Y 12 -inhibitor monotherapy may provide a safety

the time being (21). In particular, similarly to the

benefit

2019 AHA/ACC/HRS guideline, OAC is recommended

selected PCI patients receiving current-generation

compared

with

standard

DAPT

among

for all male AF patients with a CHA 2DS 2-VASc

DES. Other studies of aspirin-free antithrombotic

score of $2 and for all female AF patients with a

strategies after PCI are ongoing, including the TWI-

CHA2DS 2-VASc score of $3 (COR I, LOE A), but the

LIGHT (Ticagrelor With Aspirin or Alone in High-Risk

recommendation

Patients After Coronary Intervention) study, which

for

male

AF

patients

with

a

CHA2DS 2-VASc score of 1 and female AF patients with

has recently completed its enrollment (28).

a CHA2DS 2-VASc score of 2 is IIa, LOE B (rather than IIb, LOE C) after considering individual characteris-

BLEEDING

tics and patient preferences. In addition, OAC is not

ANTIPLATELET THERAPY. Patients with AF on TAT

WITH

COMBINATION

OF

OAC

AND

recommended, rather than simply discouraged, in

experience high rates of major bleeding (e.g., bleeding

male patients with a CHA 2DS2-VASc score of 0 and

requiring hospitalization or fatal bleeding) compared

female patients with a CHA 2DS2-VASc score of 1 (COR

with patients on DAT or SAPT (5). In an updated

III, LOE B). Also in the European guidelines, in the

nationwide Danish cohort study of 272,315 patients

absence

mechanical

with AF patients aged 50 years or older, compared

valves, moderate-to-severe mitral stenosis), a DOAC

with VKA monotherapy over a total follow-up period

is recommended as a first choice in preference to a

of 1,373,131 patient-years, adjusted hazard ratios of

VKA in all eligible candidates (COR I, LOE A). Ac-

major bleeding were 1.13 (95% CI: 1.06 to 1.19) for

cording to both the AHA/ACC/HRS and ESC guide-

DAPT, 1.82 (95% CI: 1.76 to 1.89) for DAT with a VKA

lines,

be

and SAPT, 1.28 (95% CI: 1.13 to 1.44) for DAT with a

considered in AF patients with contraindications for

DOAC and SAPT, 3.73 (95% CI: 3.23 to 4.31) for TAT

long-term OAC (COR IIb, LOE B) (11,21).

with VKA, and 2.28 (95% CI: 1.67 to 3.12) for TAT with

of

left

contraindications

atrial

appendage

(e.g.,

occlusion

may

Capodanno et al.

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Antithrombotic Therapy in AF Patients Undergoing PCI

F I G U R E 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

Antithrombotic Therapy Duration (Months)

Clinical Outcomes 0%

0 Treatment

1

3

VKA Clopidogrel

BMS

DES

6

10%

20%

30%

40%

50%

12 19.4%

Treatment

11.1% P < 0.0001

WOEST 573 patients on OAC undergoing PCI

VKA Control

Clopidogrel

BMS

DES

Aspirin

BMS

DES

44.4%

Control

17.6% Any TIMI Bleeding (Primary Endpoint) 0%

1%

2%

Death, MI, Stroke, TVR, ST

3%

4%

VKA Treatment

Clopidogrel

614 patients on OAC undergoing PCI

4.0%

VKA Control

Clopidogrel

6%

5.3%

Treatment

Aspirin

ISAR-TRIPLE

5%

4.0%

Control

4.3%

Aspirin 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.

DOAC (5). The highest absolute rates of major bleeding

ISAR-TRIPLE (Triple Therapy in Patients on Oral

were observed in patients treated with VKA-TAT who

Anticoagulation After Drug Eluting Stent Implanta-

were older than 90 years (annualized rate 22.8%), had

tion) trials is provided in Figure 1. In WOEST and

a CHA2DS2-VASc score >6 (17.1%), or presented with a

ISAR-TRIPLE, simplification of the reference TAT

history or major bleeding (17.5%) (5). Due to con-

strategy was attempted by aspirin withdrawal or

founding by indication and because TAT with a VKA or

shortening DAPT duration, respectively (6,7). In

DOAC was only prescribed in 1% and 0.3% of patients,

WOEST, the rationale for withdrawing aspirin was

respectively, this study was unable to look at the ef-

due to the observation that the risk of bleeding is

ficacy and net benefit of combining 3 antithrombotic

highest in the first month after PCI, likely as the

agents in AF patients. It is noteworthy that, in the

consequence of the procedure itself and of stacking

setting of high-risk ACS without AF, full-dose TAT

multiple oral and parenteral antithrombotic medica-

provided no benefit but increased severe bleeding in

tions (30). WOEST randomized in an open-label

the APPRAISE 2 (Apixaban for Prevention of Acute

fashion 573 patients on OAC, of whom 69% pre-

Ischemic Events 2) trial (29). The high bleeding rates of

sented with AF and 28% presented with an ACS. The

the Danish registry emphasize that treatment with

trial found a 64% relative decrease in bleeding epi-

TAT, if deemed necessary, should be as short as

sodes with DAT, driven by a reduced rate of minor

possible and likely best avoided altogether.

bleeding episodes (hazard ratio: 0.36; 95% CI: 0.26 to 0.50; p < 0.0001). Although it was not powered for

DOUBLE VERSUS TRIPLE THERAPY IN

ischemic events, the trial also showed a decrease in

AF-PCI PATIENTS

thrombotic events in the DAT group. Notably, in the control group, TAT was prolonged up to 1 year in the

TRIALS OF VKAs. A summary of the study design and

two-thirds of patients who received DES. In light of

key results of the WOEST (What is the Optimal anti-

the results of the WOEST trial, the 1-year duration of

platElet & Anticoagulant Therapy in Patients With

TAT has been questioned, and the standard duration

Oral Anticoagulation and Coronary StenTing) and

of TAT, when used, has become shorter. Thus, the

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Antithrombotic Therapy in AF Patients Undergoing PCI

F I G U R E 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

Antithrombotic Therapy Duration (Months)

0 Treatment #1

PIONEER AF 2,124 patients with NVAF undergoing PCI

Treatment #2

1

3

Rivaroxaban 15

6

Clinical Outcomes 0%

12

20%

6.5%

Rivaroxaban 2.5 15 mg od at P2Y12 stop

18.0%

Treatment #2

P2Y12 inhibitor Aspirin

30%

16.8%

Treatment #1

P2Y12 inhibitor

10%

P < 0.001

5.6% P < 0.001

VKA

Control

P2Y12 inhibitor

26.7%

Control

6.0%

Aspirin

Clinically Significant Bleeding (Primary Endpoint) 0% Treatment #1

Dabigatran 110

Treatment #2

Dabigatran 150

10%

20%

15.2%

P < 0.001

20.2%

Treatment #2

P2Y12 inhibitor

30%

15.4%

Treatment #1

P2Y12 inhibitor

CV Death, MI, Stroke

11.8%

RE-DUAL PCI 2,725 patients with NVAF undergoing PCI

VKA

Control #1

P2Y12 inhibitor

Control #2

P2Y12 inhibitor

Aspirin BMS

DES

26.9%

Control #1

VKA

Aspirin BMS

DES

25.7%

Control #2

12.8%

Major or CRNM Bleeding (Primary Endpoint) 0%

Treatment #1

Treatment #2 AUGUSTUS 4,614 NVAF patients with ACS or PCI

Control #1

Control #2

Apixaban 5 P2Y12 inhibitor

Treatment #1

10%

Death, MI, Stroke, SE, UR 20%

P2Y12 inhibitor

23.5%

VKA

26.2%

P2Y12 inhibitor

Control #2

P = 0.002

P < 0.001

14.7%

Control #1

27.4%

Aspirin or placebo

Apixaban or VKA

P < 0.001

16.1%

Treatment #2

Aspirin

P2Y12 inhibitor

30%

10.5%

Aspirin or placebo

Apixaban or VKA

P < 0.001

13.4%

9.0% 24.7%

Placebo

Major or CRNM Bleeding (Primary Endpoint)

Death, Hospitalization

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 Antithrombotic 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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Antithrombotic Therapy in AF Patients Undergoing PCI

WOEST trial, despite the small sample size and open-

finally found to be on TAT at 1 year in the control

label design, provided some randomized evidence

group. Compared with control subjects, the primary

that the early discontinuation of aspirin reduces

endpoint

bleeding in comparison to TAT, without any apparent

12 months was reduced by both rivaroxaban-based

increase in ischemic events, leading to the subse-

strategies (hazard ratio for group 1 vs. group 3: 0.59;

quent initiation of multiple trials of aspirin-free

95% CI: 0.47 to 0.76; p < 0.001; hazard ratio for group

strategies in PCI even outside of the AF context (26).

2 vs. group 3: 0.63; 95% CI: 0.50 to 0.80; p < 0.001),

ISAR-TRIPLE randomized 614 patients with any

driven by lower rates of bleeding requiring medical

indication to OAC (83% for AF or atrial flutter)

attention and not by TIMI (Thrombolysis In Myocar-

treated with PCI and DES (one-third with an ACS) to

dial

either 6 weeks or 6 months of DAPT (7). The primary

rivaroxaban-based regimen resulted in a reduced risk

endpoint, comprising a combination of ischemic and

of total bleeding events and recurrent hospitalization

of

clinically

Infarction)

major

significant

or

minor

bleeding

bleeding.

at

The

bleeding events, did not differ at 9 months between

for adverse events (33,34). Conversely, there were no

the 2 groups, and in a landmark analysis of events

differences in major adverse cardiovascular events,

between 6 weeks and 6 months, the risk of

but the power was low for ischemic endpoints (8).

bleeding was higher in the group where clopidogrel

RE-DUAL PCI randomized 2,725 PCI patients with

was used longer (for 6 months), supporting the

AF (one-half of them in the setting of an ACS) to 2

safety benefit of DAT versus TAT. Importantly, like

regimens of DAT that included dabigatran 150 or

WOEST,

and

110 mg bid and mostly clopidogrel (ticagrelor in 12%)

underpowered to detect significant differences in

versus a regimen of TAT with warfarin (9). In the TAT

ischemic endpoints (31).

group, aspirin was discontinued after 1 month in pa-

TRIALS OF DOACs. Figure 2 is a summary of the

tients who received a bare-metal stent (17%) and after

study design and key results of 3 trials: PIONEER AF-

3 months in patients who received a DES (83%). At a

PCI (Open-Label, Randomized, Controlled, Multi-

mean of 14 months, the risk of major or clinically

center Study Exploring Two Treatment Strategies of

relevant

Rivaroxaban and a Dose-Adjusted Oral Vitamin K

dabigatran DAT group was noninferior to the risk

Antagonist Treatment Strategy in Subjects with Atrial

observed in the control group, and superiority was

Fibrillation who Undergo Percutaneous Coronary

also

Intervention), RE-DUAL PCI (Randomized Evaluation

0.42 to 0.63; p for noninferiority <0.0001, p for

of Dual Antithrombotic Therapy with Dabigatran

superiority ¼ 0.0001). The 150-mg dabigatran DAT

versus Triple Therapy with Warfarin in Patients with

group also met both the noninferiority and superior-

Nonvalvular Atrial Fibrillation Undergoing Percuta-

ity objectives compared with the TAT group (hazard

neous Coronary Intervention) and AUGUSTUS (An

ratio: 0.72; 95% CI: 0.58 to 0.88; p for noninferiority

Open-label, 2  2 Factorial, Randomized Controlled,

<0.0001, p for superiority ¼ 0.002). These results

Clinical Trial to Evaluate the Safety of Apixaban vs.

were consistent irrespective of clinical presentation

Vitamin K Antagonist and Aspirin vs. Aspirin Placebo

(e.g., stable CAD or ACS) and irrespective of whether

in Patients With Atrial Fibrillation and Acute Coro-

clopidogrel or ticagrelor was used in the treatment

nary Syndrome and/or Percutaneous Coronary Inter-

and control arms (35). The risk of thromboembolic

vention) (8,9).

events was noninferior in the 2 DAT groups combined

ISAR-TRIPLE

was

relatively

small

PIONEER AF-PCI compared 3 treatment strategies

nonmajor

established

bleeding

(hazard

in

ratio:

the

0.52;

110

95%

mg

CI:

as compared with the TAT group, although a numer-

after PCI in 2,124 patients with AF: a WOEST-like

ical (nonsignificant) absolute risk increase was noted

strategy of low-dose rivaroxaban (15 mg once daily

with the lower 110-mg dabigatran dose (11%) ad

[od]) plus a single P2Y12 inhibitor (group 1); a TAT

compared with the higher 150-mg dabigatran dose

regimen of very low-dose rivaroxaban (2.5 mg twice

(7.9%) (9). It is important to note that the 110-mg

daily [bid]) plus DAPT, followed by rivaroxaban 15 mg

dabigatran dose is not approved for stroke preven-

od at the time of P2Y12 inhibitor discontinuation

tion in the United States. Finally, due to the design of

(group 2); and control TAT with a VKA plus DAPT

both PIONEER-AF PCI and RE-DUAL PCI, they could

(group 3) (8). It is important to note that the dosing

not distinguish whether the reduction in bleeding

regimens of rivaroxaban used in the trial do not

was attributed to the use of a DOAC versus VKA, to

represent the approved doses for stroke prevention in

the avoidance of aspirin, or both.

AF, although they were selectively chosen based on

In AUGUSTUS, 4,614 patients with ACS and or PCI

prior dose-finding investigations (32). At variance

within 14 days were randomized in a 2  2 factorial

with WOEST, patients were stratified by the intended

design to apixaban 5 mg bid versus VKAs (open label)

duration of DAPT (1, 6, or 12 months), with only 22%

and to aspirin versus placebo (blinded) for 6 months

89

90

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Antithrombotic Therapy in AF Patients Undergoing PCI

(10). All patients received a P2Y 12 inhibitor (mostly

ratio 0.85; 95% credible interval: 0.48 to 1.29,

clopidogrel). About one-quarter of patients had ACS

I 2 ¼ 58.4%), or in the individual outcomes of all-cause

and no PCI. At 6 months, the primary outcome of major

mortality, cardiac death, myocardial infarction, stent

or clinically relevant nonmajor bleeding was signifi-

thrombosis, or stroke between the DAT and TAT

cantly reduced by apixaban compared with VKAs

groups (36). Although the credible interval for the

(hazard ratio: 0.69; 95% CI: 0.58 to 0.81; p < 0.001) and

efficacy outcomes remains large in this meta-analysis,

increased by aspirin compared with placebo (hazard

these findings suggest that DAT represents a safer

ratio: 1.89; 95% CI: 1.59 to 2.24; p < 0.001). Patients in

option than TAT in PCI patients with AF. It should be

the apixaban group had a lower risk of death or hos-

noted that AUGUSTUS, the largest study of a DOAC in

pitalization than those in the VKA group (hazard ratio:

patients with indication for antiplatelet therapy due

0.83; 95% CI: 0.74 to 0.93; p ¼ 0.002), whereas no

to PCI and/or ACS, was not incorporated in this meta-

significant differences on this endpoint were noted

analysis that encompasses approximately the same

between patients in the aspirin and placebo groups. By

number of the total patients randomized in the trial.

means of its factorial design and at variance with PIONEER-AF PCI and RE-DUAL PCI, AUGUSTUS helps to disentangle the individual contribution of DOACs and aspirin withdrawal on the risk of bleeding, demonstrating that both aspects are beneficial. The benefit of using a DOAC versus VKA in the setting of AF and ACS with or without PCI corroborates the recommendation from current guidelines for AF (11,21). Importantly, compared with prior studies of DOACs, AUGUSTUS also included medically managed ACS patients who did not receive stents, who are known to be at high ischemic risk. Therefore, this data expands on current knowledge in the field. The issue of early aspirin withdrawal in AUGUSTUS should be interpreted in view of some aspects related to the study design and results of the trial. First, patients were enrolled at a median of 6 days from ACS and/or PCI, which suggests that most patients in the trial had at least short-term aspirin use before randomization. Second, the follow-up time was shorter than in PIONEER-AF PCI and RE-DUAL PCI (6 months vs. 12 months). Third, nonsignificant 0.5% and 0.4% absolute increases in myocardial infarction and stent thrombosis, respectively, were noted in patients on placebo compared with those on aspirin. Indeed, a better understanding of patient profiles and timing of these events with relationship to aspirin discontinuation will be informative for clinical practice.

PRACTICAL MANAGEMENT OF AF PATIENTS UNDERGOING PCI Multiple guidelines and consensus documents have been published over the past decade to inform clinicians on the optimal antithrombotic strategy for AF patients undergoing PCI. Initially, most recommendations were based on expert consensus in the absence of an evidence basis from randomized controlled trials. While the evidence consolidates, some recommendations are strengthened, others abandoned. As noted in the previous text, for the purpose of the following discussion, we refer to the 2019 ACC/AHA/HRS guidelines for AF and the 2018 ESC guidelines for myocardial revascularization when citing recommendations, and to the latest iteration of the consensus documents issued in 2018 by experts on antithrombotic therapy at the 2 sides of the Atlantic for practical issues (11,12,15,16). A summary of practical recommendations from the 2 North American and European consensus documents is provided in Table 1 to highlight current areas of consensus and discrepancy. Key aspects are discussed in the following text, integrated by authors’ consensus on aspects that eventually emerged after the publication of the AUGUSTUS trial. PROCEDURAL CONSIDERATIONS. PCI has become a

safer procedure over the years with better patient DOUBLE VERSUS TRIPLE ANTITHROMBOTIC THERAPY

selection using heart team decisions, avoidance of

IN META-ANALYSES OF BLEEDING AND

unnecessary

ISCHEMIC

procedures

through

intracoronary

EVENTS. The safety and efficacy of DAT versus TAT in

physiology measurements, increasing use of radial

AF patients undergoing PCI has been the objective of

arteries for vascular access, and improvement of

several pooled analyses of WOEST, ISAR-TRIPLE,

available DES technologies (12,15). As part of a general

PIONEER AF-PCI, and RE-DUAL PCI. In the meta-

periprocedural bleeding avoidance strategy, proced-

analysis from Golwala et al. (36), encompassing a to-

ures should be carried out with radial access

tal of 5,317 patients, compared with the TAT group,

(4,12,15,16). Indeed, urgent or emergent procedures

TIMI major or minor bleeding was reduced by 47% in

can be performed without withholding OAC. In gen-

the DAT arm (hazard ratio: 0.53, 95% credible inter-

eral, patients on a DOAC undergoing elective or

val: 0.36 to 0.85; I 2 ¼ 42.9%). There was no difference

nonemergent procedures should withhold therapy for

in trial-defined major adverse cardiac events (hazard

24 h (or 48 h for patients with impaired renal function

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91

Antithrombotic Therapy in AF Patients Undergoing PCI

T A B L E 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/thrombotic and bleeding risk.

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

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.

Procedural considerations Anticoagulation Vascular access

Prefer radial access.

Prefer radial access.

Additional intraprocedural UFH

Administer.

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

Bivalirudin use

May be considered in high bleeding risk patients, particularly ACS and if femoral approach is used.

May be considered.

Use of GPIs

Limit use to selected cases at high-risk for thrombotic complications 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 periprocedural clopidogrel

Recommended.

Recommended. Pre-treatment if known coronary anatomy, emergency cases, or PCI is likely). Halved loading dose in case of 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 antithrombotic management Choice of OAC

Prefer DOACs.

Prefer DOACs.

If DOAC is chosen

Use at established stroke prevention doses. If a DOAC has not been specifically studied in this setting, the doses tested in the pivotal AF trials leading to drug approval should be used. It is reasonable to prefer a dabigatran 150-mg bid dosing regimen in patients considered to be at higher thrombotic risk, whereas a 110-mg bid regimen may be preferred in patients at higher bleeding risk. Rivaroxaban 15 mg od may be used instead of 20 mg od.*

If part of TAT, prefer dabigatran 110 mg bid, rivaroxaban 15 mg od (or 20 mg od), apixaban 5 mg bid, or edoxaban 60 mg od. If part of DAT, prefer dabigatran 150 mg bid, rivaroxaban 15 mg od (or 20 mg od, especially if transition from TAT to DAT), 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 and low 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 selected patients. Avoid prasugrel.

Prefer clopidogrel.

DAT

Preferred strategy, with OAC and a P2Y12 inhibitor, starting immediately after discharge.

Alternative to TAT if concerns of high bleeding risk.

Clopidogrel rather than aspirin in DAT

Preferable.

Preferable.

Duration of SAPT

Discontinue at 12 months in most patients. Earlier or no discontinuation depending on risk.

Discontinue at 12 months in most patients. Continue in selected patients 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 international normalized 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 proton pump inhibitors; SAPT ¼ single antiplatelet therapy; TAT ¼ triple antithrombotic therapy; UFH ¼ unfractionated heparin; VKA ¼ vitamin K antagonist.

on dabigatran) (15). If the patient is on VKA, the North

parenteral anticoagulation, while—according to the

American

wash-out

North American document only—bridging should be

period with target INR based on the type of vascular

considered for ACS patients as an integral part of their

access (#2 and #1.5 for radial and femoral access,

care. Additional unfractionated heparin should be

respectively), whereas the European document sug-

administered as per usual practice to support PCI, at

gests that a strategy of uninterrupted VKA should be

standard dose (70 to 100 U/Kg) in case of DOACs and

preferred over a strategy of interrupted VKA with

reduced dose (30 to 50 U/Kg) in case of ongoing VKA.

heparin bridging (15,16,37). Both documents agree

Bivalirudin may also be considered, particularly in

that patients with stable CAD can forgo bridging with

patients at high bleeding risk, in those presenting

recommendation

suggests

a

92

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Antithrombotic Therapy in AF Patients Undergoing PCI

T A B L E 2 Criteria of High-Risk Features Tipping the Balance Toward More or Less Intense

Antithrombotic Therapy for AF Patients Undergoing PCI

presentations, such as stenting of the left main, proximal left anterior descending, proximal bifurcation, recurrent myocardial infarctions, and stent

Criteria of High Stent-Driven Thrombotic Risk

Criteria of High Bleeding Risk That Make the Combination of OAC and Antiplatelet Therapy Unfavorable


Prior stent thrombosis on adequate antiplatelet therapy
Stenting of the last remaining patent coronary artery
Diffuse multivessel disease especially in diabetic patients
Chronic kidney disease (e.g., creatinine clearance <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

thrombosis (16). Also according to the European document, bleeding risk can be estimated using the HAS-BLED

(Hypertension,

Abnormal

Renal/Liver

Function, Stroke, Bleeding History or Predisposition, Labile

International

Normalized

Ratio,

Elderly,

Drugs/Alcohol) score (e.g., $3) with the aim of screening candidates who require more regular review and earlier follow-up, and to identify and correct modifiable bleeding risk factors. In RE-DUAL PCI, the benefit of DAT with dabigatran in reducing bleeding events compared with TAT with VKA was

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

irrespective of the baseline risk of bleeding defined by

Abbreviations as in Table 1.

the HAS-BLED score (42). It should be recognized that the predictive performance of bleeding risk scores is generally modest, and that patients on OAC represent

with ACS, and if a femoral approach is being used (15). More potent therapies, such as cangrelor or glycoprotein IIb/IIIa inhibitors, are generally only recommended for selected cases at high, life-threatening risk for ischemic complications or for bail-out situations, although cangrelor may be preferred of the 2 approaches due to a shorter half-life (38–41). Pretreatment with clopidogrel is indicated when PCI is likely or decided (4,12). Importantly, aspirin should be prescribed periprocedurally in all cases to decrease the risk of early stent-related thrombotic complicaSTRATIFICATION

FOR

THROMBOSIS

AND

BLEEDING. After the indications for OAC and anti-

platelet therapy are established, the North American and European consensus documents suggest that decisions should be guided by balancing the individual risk of atherothrombosis with the risk of major bleeding (15,16). This is an aspect of paramount practical importance, because such risk stratification will shift the pendulum toward, for example, TAT or DAT, or the selection of different P2Y 12 inhibitors. The North American document emphasizes that physicians should rely on qualitative factors to characterize the individual risk of ischemia and bleeding, whereas the approach of the European consensus document is more quantitative and relies on risk scores for both ischemia and bleeding. Indeed, to characterize the atherothrombotic

discrimination is problematic (43,44). In a study of AF patients comparing different risk stratification tools for bleeding, the HEMORR(2)HAGES (Hepatic or Renal Disease, 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 performance in

predicting

any

clinically

relevant

bleeding,

although the HAS-BLED score performed better than

tions (4,12). RISK

a high bleeding risk category per se where further

risk,

the

European

consensus

document suggests using the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score for elective PCI and the GRACE (Global Registry of Acute

the 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 findings were reported for different bleeding risk tools in DOAC-treated patients (46). A recent independent systematic review concluded that the HAS-BLED score provides the best prediction for bleeding risk (44). Adding biomarker information significantly but still suboptimally improves the discrimination performance of bleeding risk assessment over HAS-BLED (c-indexes 0.69 to 0.71 vs. 0.62 for HAS-BLED in external validation cohorts) (47,48), and showed no advantage in real-world clinical practice (49). In the absence of accurate predictive tools for bleeding, defining which AF-PCI patients have more or less to benefit from different antithrombotic strategies remains a case-by-case decision. A list of suggested criteria of high risk for ischemia/thrombosis and bleeding from the European focused update on DAPT is provided in Table 2 (13).

Coronary Event) score (with a cutoff of 140) for PCI in

CHOICE

the context of an ACS (16). In addition, concerns

STRATEGIES AFTER PCI. In selecting the optimal

AND

DURATION

OF

ANTITHROMBOTIC

about thrombotic risk apply to anatomic and clinical

antithrombotic regimen for an AF patient who

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Antithrombotic Therapy in AF Patients Undergoing PCI

C E N T R A L IL LU ST R A T I O N Consensus Recommendations on the Practical Management of Oral Anticoagulation and Antiplatelet Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

Time from Percutaneous Coronary Intervention Peri-Percutaneous Coronary Intervention

1 mo

3 mo

6 mo

12 mo

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

Default approach

Clopidogrel

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

2018 North American Perspective

High ischemic risk, low bleeding risk

Clopidogrel or Ticagrelor

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

High bleeding risk, low ischemic risk

Clopidogrel

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

Ischemic risk > bleeding risk

Clopidogrel (or Ticagrelor in Double Antithrombotic Therapy)

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

2018 European Perspective

Bleeding risk > ischemic risk

Clopidogrel

Prefer Direct Oral Anticoagulant over Vitamin K Antagonist

Bleeding risk >> ischemic risk

Clopidogrel

Oral Anticoagulation

P2Y12 inhibitor

Aspirin

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

received PCI, physicians have to consider some

outcome based on data from PIONEER-AF PCI and

fundamental questions. As far as the type of OAC

RE-DUAL PCI demonstrated that both the rivarox-

drug is concerned (first question), both the North

aban- and dabigatran-based regimens are favorable

American and European consensus documents agree

compared with VKA plus DAPT (51). Indeed, the

with current ACC/AHA/HRS and ESC guidelines

alternative of maintaining VKA is practically more

(11,12) that, in the absence of contraindications,

problematic, because the intensity of the INR needs

DOACs should be preferred to VKAs due to the

modulation (e.g., values between 2.0 and 2.5) dur-

lower risk of bleeding previously demonstrated to

ing the TAT term (52). In the AUGUSTUS trial, the

be a class effect (50). A bivariate analysis using a

median percentage of time when the INR was below

measure of risk difference in the net clinical

2 was 23% (10). Also, in the same study, the safety

93

94

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Antithrombotic Therapy in AF Patients Undergoing PCI

benefit of being on a DOAC compared with VKA was

more on such clinical trial data to support their rec-

demonstrated on top of considerations on aspirin

ommendations compared with their European coun-

versus no aspirin use (10). Thus, in patients already

terparts. The results of the AUGUSTUS trial, in the

on a VKA, switching to a DOAC is a reasonable op-

context of previous evidence from the other trials,

tion to reduce the risk of bleeding. However, a VKA

will

remains the only indicated treatment in patients

perhaps provide more consistency between North

with moderate to severe mitral stenosis and me-

American and European experts who mostly diverge

chanical prosthetic heart valves, and is generally a

on duration of TAT. Further analyses from the

likely

affect

future

recommendations

and

more accepted approach in patients with end-stage

AUGUSTUS trial, which showed consistent benefit of

renal disease—although, in the latter, more recent

DAT irrespective of baseline risk (e.g., with no sig-

data

nificant interaction observed for multiple subgroups)

show

that

DOACs

may

be

superior

to

warfarin (53).

will also better inform practitioners as well as help

The second question deals with the duration of

develop guideline recommendations (10). It should be

TAT (Central Illustration). This spans from very short

noted that these recommendations refer essentially

(e.g., until after successful PCI) to extended (e.g.,

to AF patients on DOACs. Indeed, the effect of aspirin

6 months) depending on various clinical scenarios.

withdrawal in VKA patients who are not eligible for

Notably, both the 2019 ACC/AHA/HRS guidelines for

DOACs is limited to the small WOEST trial.

AF and the 2018 ESC guidelines for myocardial

The third question deals with the specific anti-

revascularization, published before the AUGUSTUS

platelet drug to be discontinued in the transition from

trial, recommend DAT as an alternative to TAT to

TAT to DAT. The consensus of the North American

reduce bleeding with COR IIa, but in the European

and European documents is that a P2Y12 inhibitor

guidelines this indication is currently restricted to

should be used without aspirin. This recommenda-

patients at baseline high bleeding risk (11,12). Based

tion is based on the well-established notion that,

on the North American expert consensus document,

post-PCI, the use of a P2Y12 inhibitor is pivotal for the

the default approach is DAT, and thus to keep aspirin

prevention of thrombotic complications (22–25). This

only in the periprocedural period and during hospital

is suggested despite the notion that a proportion of

stay. The rationale for DAT as a default strategy is

patients exhibit substantial variability in the platelet

based on results of the 3 trials available at the time of

response to clopidogrel (54). However, this pharma-

publication that showed a more favorable safety

codynamic characteristic was not shown to translate

profile compared with TAT (6,8,9). It is important to

into an increase in adverse outcomes with clopidogrel

note that all trials testing the safety of dropping

in a large direct comparison with aspirin, where clo-

aspirin early (i.e., prior to hospital discharge) are

pidogrel was actually shown to be superior in

based on the observation that most bleeding events

reducing ischemic events and also had a more favor-

occur within the first month, as noted in the previous

able safety profile (i.e., less hospitalization for

text, due to periprocedural issues and use of multiple

gastrointestinal bleeding) (55,56). It is, however,

antithrombotic

of

important to note that aspirin was used at a 325-mg

bleeding early after PCI was also confirmed in the

medications.

The

high

rate

daily regimen in this trial. Indeed, the key role that

more recent studies, particularly during the time

the P2Y12 receptor-mediated signaling has on modu-

frame that patients were still on aspirin (6–10).

lating thrombotic processes in stented patients sup-

However, the North American document does indi-

ports keeping an agent blocking this pathway (57). It

cate that TAT for up to 1 month can be considered in

is also important to note that there is synergism on

patients who have high thrombotic risk and low

modulating thrombus formation when a P2Y 12 inhib-

bleeding risk. In contrast, the European consensus

itor is coupled with an OAC (58).

document follows this approach only for patients in

The fourth question deals with the dosing regimen

whom the bleeding risk exceeds the thrombotic risk,

of a DOAC for combination therapy in TAT or DAT

whereas all other patients should receive 1 month of

regimens. In TAT regimens, both documents recom-

TAT as a default approach, or longer-term (3 to

mend using approved doses proven to be effective in

6 months) TAT if the thrombotic risk exceeds the

regulatory trials of AF, with dose reductions as per

bleeding risk (COR IIa in the European guidelines for

the respective package labels (i.e., due to reduced

myocardial revascularization [12]). These differences

renal elimination in patients with chronic kidney

between consensus documents possibly reflect the

disease). In the case of dabigatran, the North Amer-

different weights that the 2 panels of experts have

ican document suggests to use a higher 150-mg bid

given to the findings of the PIONEER-AF PCI and RE-

dose for patients who are at higher thrombotic risk,

DUAL PCI trials, with the North Americans relying

which is consistent with the 2019 ACC/AHA/HRS

Capodanno et al.

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Antithrombotic Therapy in AF Patients Undergoing PCI

F I G U R E 3 Study Design of the ENTRUST-AF PCI Trial

ENTRUST-AF PCI N = 1,500 Included • OAC indicated for ≥12 months • Successful PCI with stent placement

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

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

Vitamin K antagonist

Edoxaban

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

guidelines for AF, where dabigatran 150 mg has COR

The fifth question deals with the choice of P2Y12

IIa, LOE B; the European consensus documents,

inhibitor. In this category, clopidogrel should be

consistent with the 2018 ESC guidelines on myocar-

regarded as the agent of choice. Prasugrel and tica-

dial revascularization, suggest using the 110-mg bid

grelor are approved for patients with ACS, and there

dose during TAT (COR IIa, LOE C) and the 150-mg bid

is limited data for their use in combination with OAC

dose during DAT (COR IIb, LOE B), due to concerns of

(4). Data of prasugrel for TAT with VKA are disap-

higher thrombotic risk with the lower dose. If rivar-

pointing due to an unacceptable high rate of bleeding

oxaban is used, the 15-mg od dose (e.g., rather than

(59), and the 2018 ESC guidelines on myocardial

the 20-mg od dose tested in the regulatory trial of AF)

revascularization formally contraindicate the use of

is considered a reasonable option by the 2018 ESC

both prasugrel and ticagrelor in combination with

guidelines for myocardial revascularization according

OAC (COR III, LOE C), whereas the 2019 ACC/AHA/

to the design of PIONEER-AF PCI (COR IIa, LOE B in

HRS guidelines for AF recommend clopidogrel in TAT

the 2019 ACC/AHA/HRS guidelines for AF; COR IIb,

combinations with COR IIa, LOE B. Indeed, in

LOE B in the 2018 ESC guidelines for myocardial

PIONEER-AF PCI, the use of prasugrel and ticagrelor

revascularization) (12). After discontinuation of the

was allowed, but the proportion of patients who

P2Y12 inhibitor, OAC should be continued at full

actually received them was very small (2% to 4%) (8).

stroke prevention doses. Therefore, if a reduced dose

In RE-DUAL PCI, ticagrelor was used in 12% of pa-

regimen of rivaroxaban (e.g., 15 mg od; 10 mg od in

tients, which provides some insights to the treatment

patients with renal dysfunction) was being used, it is

effects,

important to resume the full recommended dose

particular, although no statistical interaction was

(20 mg od; 15 mg od in patients with renal dysfunc-

noted between the treatment effect of the 2 tested

tion) after suspension of antiplatelet therapy (15,16).

doses of dabigatran and the use of clopidogrel or

although

without

statistical

power.

In

95

96

Capodanno et al.

JACC VOL. 74, NO. 1, 2019 JULY 9, 2019:83–99

Antithrombotic Therapy in AF Patients Undergoing PCI

ticagrelor for DAT, the absolute rates of bleeding were

Disease Study) study (N ¼ 2,200) is ongoing in Japan

higher when ticagrelor was used in TAT combinations

to evaluate the efficacy and safety of monotherapy

as compared with DAT (9,35). In light of these find-

with the DOAC rivaroxaban versus DOAC plus SAPT in

ings, in patients who are at low risk for bleeding

stable CAD patients 1 year or more after PCI

(particularly younger patients) and at high risk for

(NCT02642419), while the French AQUATIC (Assess-

thrombotic events (e.g., ACS, diabetes, complex PCI),

ment of Quitting versus Using Aspirin Therapy In

the use of ticagrelor combined with a DOAC repre-

patients treated with oral anticoagulation for atrial

sents a potential option (15). In AUGUSTUS, the use of

fibrillation and with stabilized Coronary artery dis-

prasugrel or ticagrelor was also low (10). Although

ease) (currently unregistered on clinicaltrials.gov)

there are no randomized clinical trial data supporting

trial will investigate, in high-risk stabilized PCI pa-

escalation of P2Y12-inhibiting therapy among patients

tients requiring OAC for AF, the superiority of DAT

with inadequate response to clopidogrel, and routine

with aspirin and full-dose OAC for 24 to 48 months

platelet function or genetic testing to define response

versus placebo and full-dose OAC alone on a com-

to clopidogrel is not recommended, the use of tica-

posite endpoint including cardiovascular mortality,

grelor may be considered in patients in whom poor

myocardial infarction, stroke, coronary revasculari-

response to clopidogrel is known or after a side effect

zation, systemic embolism, and acute limb ischemia.

to the drug (60).

OTHER BLEEDING AVOIDANCE STRATEGIES. Both

Finally, a sixth question deals with the optimal

the North American and European consensus docu-

management at 12 months from PCI, when the patient

ments recommend using proton pump inhibitors in

is typically on DAT unless the P2Y 12 inhibitor has been

all situations where OAC is combined with antiplate-

discontinued earlier as suggested in both the North

let therapy (64,65). In addition, concurrent therapy

American and European consensus documents for

with nonsteroidal anti-inflammatory drugs, possibly

patients at very high risk of bleeding. Ideally, the

potentiating the effect of antithrombotic therapy,

patients should continue on OAC alone, based on

should be avoided.

registry and other observational data showing that in patients with stable CAD (e.g., >1 year, with no acute

ONGOING STUDIES OF ANTITHROMBOTIC

events), the addition of antiplatelet therapy to OAC

THERAPY IN AF PATIENTS UNDERGOING PCI

increases bleeding without adding ischemic protection compared with OAC alone (61,62). This consid-

The ENTRUST-AF PCI (Edoxaban Treatment Versus

eration is valid unless concerns of thrombotic risk

Vitamin K Antagonist in Patients With Atrial Fibril-

prevail, suggesting the need for continued DAT on a

lation Undergoing Percutaneous Coronary Interven-

case-by-case basis (Table 1). According to the North

tion) will soon complete the landscape of DOAC

American document, the choice of SAPT to use after 1

trials in AF patients who need antiplatelet agents

year (aspirin or clopidogrel) is at the discretion of the

(Figure 3) (66). Edoxaban 60 mg od will be tested

treating physician, although it appears to be reason-

against TAT with VKA in about 1,500 patients on a

able to maintain the same antiplatelet drug that the

primary

patient was already taking. After discontinuation of

Thrombosis and Haemostasis–defined major or clin-

SAPT, DOACs should be continued at full stroke-

ically relevant nonmajor bleeding. Another trial with

prevention doses as described in the previous text.

a safety focus on bleeding named APPROACH-ACS-

Because renal function is a dynamic process, it is

AF (APixaban vs. PhenpRocoumon in Patients With

prudent to reassess renal function before changing

ACS and AF) (NCT02789917), comparing DAT with

the dose or after discontinuation of SAPT. The OAC-

apixaban versus TAT with VKA, is also underway.

ALONE (Optimizing Antithrombotic Care in Patients

Two more randomized trials are ongoing in China.

With AtriaL fibrillatiON and Coronary stEnt) study, a

The COACH-AF PCI trial (Dabigatran Versus Warfarin

endpoint

of

International

Society

on

trial initially designed to enroll 2,000 patients in

With NVAF Who Undergo PCI) (NCT03536611) is an

12 months but prematurely terminated after enrolling

open-label, randomized trial designed to compare

696 patients in 38 months, did not establish non-

the safety and efficacy of 1-month TAT followed by

inferiority of OAC alone to combined OAC and SAPT

DAT with dabigatran versus 1-month TAT followed

in patients with AF and stable CAD beyond 1 year

by DAT with warfarin in Chinese patients with AF

after PCI (63). However, because patient enrollment

undergoing PCI. This study will address a question

was prematurely terminated, this study should be

remained unanswered by the RE-DUAL PCI trial:

considered inconclusive. On the same subject, the

whether the superior benefit of the investigational

AFIRE (Atrial Fibrillation and Ischemic Events With

strategies is ascribable to the use of dabigatran

Rivaroxaban in Patients With Stable Coronary Artery

versus a VKA or DAT versus TAT. The primary

Capodanno et al.

JACC VOL. 74, NO. 1, 2019 JULY 9, 2019:83–99

Antithrombotic Therapy in AF Patients Undergoing PCI

endpoint will be time to the first occurrence of

avoided (69). However, there are different perspec-

Bleeding Academic Research Consortium–defined

tives on the 2 sides of the Atlantic on when and in

(grade 2 to 5) clinically relevant bleeding. Another

which patients SAPT should be started. A North

multicenter trial (NCT03234114) will enroll 800 ACS

American perspective suggests that TAT should be

patients undergoing PCI to receive 12-month DAT

used in-hospital but soon deescalated to DAT with

with dabigatran 100 mg bid plus ticagrelor or clopi-

OAC and clopidogrel for 6 to 12 months depending

dogrel versus TAT with warfarin randomized for 1 or

on the bleeding risk, followed by OAC alone in most

6 months, followed by DAT with warfarin and clo-

cases. The European perspective suggests that TAT

pidogrel for up to 12 months. The primary composite

should be stopped at discharge, 1 month, or 3 to

endpoint will be the composite of all-cause death,

6 months depending on considerations surrounding

nonfatal myocardial infarction, unplanned revascu-

the balance between the individual thrombotic and

larization, ischemic stroke, or major bleeding. The

bleeding profile. Indeed, the results of the AUGUS-

Japanese SAFE-A (SAFety and Effectiveness trial of

TUS and ENTRUST-AF PCI trials will likely affect

Apixaban use in association with dual antiplatelet

future recommendations and perhaps foster more

therapy in patients with atrial fibrillation undergoing

synergism between North American and European

percutaneous

will

experts who mostly diverge on duration of TAT. A

compare 1-month vs. 6-month DAPT in combination

number of bleeding-avoidance strategies are also

with apixaban in patients with AF who undergo DES

suggested to decrease the risk of bleeding with both

implantation (67). Finally, the ongoing MASTER

TAT and DAT. Three trials of dabigatran, rivarox-

DAPT (Management of High Bleeding Risk Patients

aban, and apixaban have provided randomized evi-

Post Bioresorbable Polymer Coated Stent Implanta-

dence that a regimen of DAT with DOACs provides

tion With an Abbreviated Versus Standard DAPT

better safety compared with a regimen of TAT with

Regimen) trial, randomizing approximately 4,300

VKA. Further evidence is expected soon for edox-

high-bleeding-risk patients undergoing DES implan-

aban.

tation to an abbreviated versus a standard duration

demonstrated a reduction in bleeding complications

of antiplatelet therapy, will include a substantial

without any apparent trade-off in efficacy, none of

proportion of patients with concomitant indication

the trials were powered for ischemic events. Given

to OAC (68).

the unlikelihood of further large-scale trials pow-

coronary

intervention)

study

Although

the

DAT

strategy

has

clearly

ered for efficacy, patient-level meta-analyses of the

CONCLUSIONS

available evidence would indeed be informative to

When performed in the setting of AF, where OAC is

this extent.

used to prevent the risk of thromboembolic events, PCI requires the use of antiplatelet therapy to pre-

ADDRESS FOR CORRESPONDENCE: Dr. Dominick J.

vent the risk of stent thrombosis. The current

Angiolillo, University of Florida College of Medicine-

paradigm is that the association of OAC with DAPT

Jacksonville, 655 West 8th Street, Jacksonville,

(typically clopidogrel and aspirin), a strategy known

Florida, 32209. E-mail: [email protected]fl.

as TAT, should be as short as possible or even

edu. Twitter: @UFMedicineJax, @DFCapodanno.

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KEY WORDS atrial fibrillation, coronary stenting, oral anticoagulant, oral antiplatelet

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