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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Duration of Dual Antiplatelet TherapyAfter Coronary Stenting
A Review of the Evidence
Gilles Montalescot, MD, PHD,* David Brieger, MBBS, MMED, PHD,y Anthony J. Dalby, MB, CHB,zSeung-Jung Park, MD, PHD,x Roxana Mehran, MDk

ABSTRACT

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The duration of dual antiplatelet therapy (DAPT) after coronary stenting has been evaluated in randomized studies with

apparently conflicting results. Although longer exposure associates with more bleeding complications, late stent

thrombosis (ST) and myocardial infarction are reduced. In addition, as new drug-eluting stents carry a lower risk of

ST compared with the first-generation drug-eluting stents and possibly even bare-metal stents, a shift toward better

protection from ST may have an effect on the duration and intensity of DAPT. Whether the duration of DAPT should be

shorter or longer than the currently recommended 6 to 12 months is analyzed in this review, drawing on lessons from the

most recent studies. (J Am Coll Cardiol 2015;66:832–47) © 2015 by the American College of Cardiology Foundation.

C urrently, dual antiplatelet therapy (DAPT)refers to the addition of a P2Y12 platelet re-ceptor inhibitor (either a thienopyridine

[clopidogrel or prasugrel] or the cyclopentyl-triazolopyrimidine, ticagrelor) to aspirin, aiming toreduce stent thrombosis (ST) after coronary stent im-plantation and prevent coronary atherothromboticevents at sites outside of the stented segment.Although these treatment strategies have been

m the *ACTION Study Group, Institut de Cardiologie (AP-HP), Centre Hos

epartment of Cardiology, Concord Hospital, University of Sydney, Sydney

rica; xDivision of Cardiology, Asan Medical Center, University of Ulsan Col

ool of Medicine at Mount Sinai, Cardiovascular Research Foundation, N

nsulting fees from Acuitude, Amgen, AstraZeneca, Bayer, Berlin Chimi

igham Women’s Hospital, Cardiovascular Research Foundation, CME re

idera, GLG, Hopitaux Universitaires Genève, Lead-Up, McKinsey & Compan

zer, Sanofi, Stentys, The Medicines Company, TIMI Study Group, Unive

dical; and grant support from ADIR, Amgen, AstraZeneca, Bristol-Myers S

nçaise de Cardiologie, Gilead, ICAN, Janssen-Cilag, Pfizer, Recor, Sanofi, a

d honoraria for speaking engagements from AstraZeneca, Sanofi, Eli Lilly,

eived research grants and consulting fees from Abbott, Cordis, Boston Scie

Cardiovascular Research Foundation. Dr. Mehran has served as an adviso

yer, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Jo

mpany, Osprey Medical Inc., Watermark Research Partners, and Sanofi;

traZeneca, Bristol-Myers Squibb, CardioKinetix Inc., Daiichi-Sankyo, Eli L

s reported that he has no relationships relevant to the contents of this pa

ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Vale

nuscript received May 26, 2015; accepted May 26, 2015.

successful, prolonged DAPT is accompanied by anincrease in bleeding (1). This complex interactionbetween the efficacy and safety of DAPT has prompt-ed a series of investigations to determine which dura-tion of DAPT optimizes the risk-benefit equation. Allstudies thus far have used DAPT initially, althoughfor variable periods, followed by randomly assignedtreatment with DAPT versus single-antiplatelettherapy (SAPT). All trials to date have used aspirin

pitalier Universitaire Pitié-Salpêtri _ere, Paris, France;

, Australia; zMilpark Hospital, Johannesburg, South

lege of Medicine, Seoul, South Korea; and the kIcahnew York, New York. Dr. Montalescot has received

e AG, Boehringer Ingelheim, Bristol-Myers Squibb,

sources, Conway, Daiichi-Sankyo, Eli Lilly, Europa,

y, Medcon International, Menarini, Medtronic, MSD,

rsitat Basel, WebMD, Williams & Connolly, and Zoll

quibb, Celladon, Daiichi-Sankyo, Eli Lilly, Fédération

nd Stentys. Dr. Brieger has received research support

Boehringer Ingelheim, and BMS/Pfizer. Dr. Park has

ntific, and Medtronic; and has ownership interest in

r or consultant for Abbott Laboratories, AstraZeneca,

hnson & Johnson, Merck & Co., Inc., The Medicines

and has received grants for clinical research from

illy, Sanofi, and The Medicines Company. Dr. Dalby

per to disclose.

ntin Fuster.

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http://dx.doi.org/10.1016/j.jacc.2015.05.053

AB BR EV I A T I O N S

AND ACRONYM S

ACS = acute coronary

syndrome(s)

BMS = bare-metal stent(s)

CAD = coronary artery disease

DAPT = dual antiplatelet

therapy

DES = drug-eluting stent(s)

L-DAPT = long duration of

dual antiplatelet therapy

(12 months)

MI = myocardial infarction

S-DAPT = short duration of

dual antiplatelet therapy

(£6 months)

ST = stent thrombosis

VL-DAPT = very long duration

of dual antiplatelet therapy

(>12 months)

J A C C V O L . 6 6 , N O . 7 , 2 0 1 5 Montalescot et al.A U G U S T 1 8 , 2 0 1 5 : 8 3 2 – 4 7 Duration of DAPT After Coronary Stenting

833

as SAPT; continuation of P2Y12 inhibition as mono-therapy is yet to be studied.

ISSUES WITH DAPT FOR

CORONARY STENTING

HISTORICAL CONSIDERATIONS ON DAPT. Clopidogrelwas first shown to be more effective than aspirin inreducing ischemic stroke, myocardial infarction (MI),or vascular death in patients with a prior athero-thrombotic event (2). Then, in 2001, the CURE(Clopidogrel in Unstable Angina to Prevent RecurrentEvents) study investigators reported that the combi-nation of clopidogrel and aspirin resulted in a 2%absolute reduction in the risk of cardiovascular death,MI, and stroke in patients with an acute coronarysyndrome (ACS) at the expense of an absolute 1%increase in the risk of major bleeding versus aspirinalone (3,4). The percutaneous coronary intervention(PCI)-CURE substudy, in which 82% of patientsreceived a bare-metal stent (BMS), found that addingclopidogrel to aspirin reduced the composite of car-diovascular death, MI, and revascularization withinthe first 30 days after patients underwent PCI (5).After the CREDO (Clopidogrel for the Reduction ofEvents During Observation) study demonstrated that12 months of DAPT after elective PCI reduced theincidence of death, MI, and stroke by 27% whencompared with DAPT administered for 30 days fol-lowed by aspirin alone (6), DAPT became the standardof care for the first year after an ACS (7) on thegrounds that DAPT attenuated recurrent ischemicevents. At that time, the mandatory duration of DAPTfor ST prevention was only 1 month.

FIRST CONCERNS ABOUT THE EFFICACY OF SHORT-

DURATION DAPT. Drug-eluting stents (DES) wereapproved after the demonstration that the frequencyof in-stent restenosis was reduced compared withBMS. Some 3 years later, it was recognized thatalthough the restenosis benefit extended beyond12 months, patients with DES were at continuouslyhigher risk of MI and death after the conversion fromDAPT to SAPT, presumably due to late ST (8). Late STwas attributed to delayed stent endothelialization,and was encountered 2.75� more often with DES thanwith BMS. The U.S. Food and Drug Administration’s(FDA) 2006 advisory on DES recommended DAPT for12 months after implantation on the basis of broadexpert consensus (9).

Although reports vary, the frequency of ST afterDES implantation is probably around 0.5% to 2%per annum and is more prevalent after an ACS(8,10,11). Although a number of risk factors for SThave been identified (12,13), it is neither possible to

predict its occurrence accurately norpossible to prevent it entirely with DAPT(14). Despite the low frequency of late ST, itis associated with high rates of acute MIand death. This concern led the FDA toinitiate a trial on duration of DAPT afterstenting.

FIRST CONCERNS ABOUT THE SAFETY OF

PROLONGED DAPT. Safety concerns withprolonged DAPTwere raised in the CHARISMA(Clopidogrel for High Atherothrombotic Riskand Ischemic Stabilization, Management,and Avoidance) study (1). Although DAPTdid not provide significant protection againstischemic events in patients with stablevascular disease or at risk of atherothromboticevents, it was associated with a significant60% excess of moderate bleeding and a non-significant excess of severe or fatal bleedingcomplications (15). A meta-analysis also sug-
gested harm with prolonged DAPT (16).
Combined antiplatelet therapy was also tested withvorapaxar, an antagonist of protease-activated recep-tor type 1 receptors. The primary efficacy endpoint—acomposite of cardiovascular death, MI, or stroke—wassignificantly reduced with vorapaxar in addition toaspirin, dipyridamole, thienopyridine, or a combina-tion of these antiplatelet agents in patients with stableatherosclerosis, but it also increased the risk ofmoderate or severe bleeding, including intracranialhemorrhage (17). In both trials, the issue of safety wasless pronounced in patients with symptomatic ath-erothrombosis or MI.

The recent demonstration that the new second-generation DES reduces ST compared with first-generation paclitaxel-eluting stents (PES) suggestsbetter protection against ST in the future, in partic-ular with the newer cobalt-chromium everolimus-eluting stents (EES) (18,19). A series of randomizedstudies were then launched to test whether DAPTfor <12 months might improve the net clinical benefitafter DES implantation.

CURRENT INTERNATIONAL SOCIETY

GUIDELINES ON DAPT DURATION

U.S. GUIDELINES. On revascular i zat ion . In relationto the duration of antiplatelet therapy, the 2011 U.S.guidelines on PCI (Table 1) (20) assigned a Class Irecommendation to the following strategies:

� Aspirin should be continued indefinitely after PCI.� P2Y12 inhibition should be continued for at least

12 months after PCI for ACS.

TABLE 1 Guideline Recommendations on Duration of Dual Antiplatelet Therapy Post-Stenting

Patient Subpopulation U.S. GuidelinesEuropean Society ofCardiology Guidelines

U.K. National Institute forHealth and Care Excellence Australian Guidelines

Stent (BMS or DES) inpatients with ACS

At least 12 months (COR I, LOE: B). Longer durations maybe considered in patients with DES (COR IIb, LOE: C)

Up to 12 months (COR I,LOE: A)

Up to 12 months* 12 months (COR I, LOE: B)†

BMS in non-ACS At least 1 month (minimum 2 weeks if increased bleedingrisk, ideally up to 12 months) (COR I, LOE: B)

At least 1 month (COR I,LOE: A)

According to device-specificinstructions*

Endorses U.S. guideline*

DES in non-ACS At least 12 months (COR I, LOE: B) 6 months (COR I, LOE: B) At least 12 months* Endorses U.S. guideline*

Secondary prevention May be considered (COR IIb, LOE: B) Selected patients at highrisk of ischemic events*

Not recommended beyond12 months*

Consider in patients withrecurrent ischemicevents*

*No COR or LOE provided. †COR and LOE adapted from Australian National Health and Medical Research Council guidelines (87).

ACS ¼ acute coronary syndrome(s); BMS ¼ bare-metal stent(s); COR ¼ class of recommendation; DES ¼ drug-eluting stent(s); LOE ¼ Level of Evidence.

Montalescot et al. J A C C V O L . 6 6 , N O . 7 , 2 0 1 5

Duration of DAPT After Coronary Stenting A U G U S T 1 8 , 2 0 1 5 : 8 3 2 – 4 7

834

� If a DES is placed for a non-ACS indication, clopi-dogrel should be administered for at least 12months if patients are not at high risk of bleeding.

� In patients receiving a BMS for a non-ACS indica-tion, clopidogrel should be administered for at least1 month (a minimum of 2 weeks in patients atincreased bleeding risk) and ideally up to 12months.

These guidelines suggest that it is reasonable tostop P2Y12 inhibition earlier than 12 months if the riskof bleeding outweighs the anticipated benefit ofcontinuing the second antiplatelet agent. However,extending DAPT beyond 12 months may be consid-ered in patients at high risk of ST and/or low risk ofbleeding after DES implantation. This latter recom-mendation is endorsed in the more recent 2014 AHA/ACC Guideline for the Management of Patients WithNon–ST-Elevation Acute Coronary Syndromes (21–23).On secondary prevent ion . The 2011 U.S. secondaryprevention guidelines address the duration of anti-platelet therapy in patients with stable CAD (24).Using evidence from the CHARISMA trial, it lendssupport to combining aspirin and clopidogrel in thispopulation.

EUROPEAN GUIDELINES. On revascular izat ion . The2014 European guidelines on myocardial revasculari-zation, incorporating evidence from studies publishedbetween 2011 and 2013 that highlight bleeding hazardsassociated with DAPT (Table 1) (25), differ from theU.S. guidelines in recommending DAPT for amaximumof 12 months after ACS, for only 1 month after BMSimplantation for non-ACS indications, and for only6 months after DES for non-ACS indications.On secondary prevent ion . The 2013 recommenda-tions concerning DAPT in the management of stableCAD (26) cite post-hoc analyses from CHARISMA andTRA-2P TIMI-50 (Thrombin Receptor Antagonist inSecondary Prevention of Atherothrombotic IschemicEvents) (17), concluding that although DAPT may bebeneficial in selected patients at high risk of ischemic

events, it cannot be recommended systematically inpatients with stable CAD.

OTHER GUIDELINES. In the United Kingdom, guid-ance regarding stenting has not been updated since2008, and the recommendations broadly align withthose of the United States (27–29). DAPT is not rec-ommended for patients more than 12 months post-MI.Australian guidelines broadly reflect those of theUnited States (30,31), although they uniquely recom-mend long-term DAPT for secondary prevention inpatients with recurrent ischemic events (32).

STUDIES EVALUATING A

3- TO 6-MONTH DURATION OF DAPT

STUDIES. On the basis of the lower risk of ST withsecond-generation DES and the reduction of bleedingevents with a short duration (S)-DAPT strategy, thesestudies tested the hypothesis that combiningfrequent (if not exclusive) use of latest-generationDES with DAPT for <12 months (S-DAPT) wouldresult in an improved net clinical benefit for patients.Net clinical benefit, combining both ischemic andbleeding complications, was chosen as the primaryendpoint in 5 of the 7 studies.

The first study assessing S-DAPT was the EXCELLENT(Comparison of the Efficacy of Everolimus-ElutingVersus Sirolimus-Eluting Stent for Coronary Lesions)trial (Table 2) (33). A total of 50% of patients pre-sented with ACS. An EES was implanted in 75% ofpatients and a sirolimus-eluting stent (SES) in theremainder.

Subsequently, the PRODIGY (PROlonging DualAntiplatelet Treatment In Patients With CoronaryArtery Disease After Graded Stent-induced IntimalHyperplasia) and RESET (A New Strategy RegardingDiscontinuation of Dual Antiplatelet; Real Safety andEfficacy of a 3-month Dual Antiplatelet TherapyFollowing Zotarolimus-eluting Stents Implantation)studies were published (34,35). The PRODIGY trial

TABLE

2St

udiesEv

alua

ting

Abb

reviat

edDur

ationof

DAPT(#

6Mon

ths)

After

DES

Trial

(Ref

.#)

Yea

rStud

yPop

ulation(n

)Des

ign

Long

est

Follow

-Up

PrimaryEn

dpoint

Mea

nAge

DM

(%)

ACS

(%)

1st-Gen

eration

DES

(%)

2nd-Gen

eration

DES

(%)

Stud

yOut

come

ISAR-SAFE

(39)

2014

4,000

6mon

thsvs.

12mon

thsDAPT

12mon

ths

Compo

site

ofde

ath,

MI,stroke

,ST

,or

TIMIm

ajor

blee

ding

at15

mon

thsafterPC

I

67

2540

1072

6mon

thsNIto

12mon

ths

ITALIC

(38)

2014

1,822

6mon

thsvs.

12mon

thsDAPT

12mon

ths

Compo

site

ofde

ath,

MI,repe

atTV

R,

stroke

,or

TIMIm

ajor

blee

ding

at12

mon

thsafterPC

I

62

3724

—10

06mon

thsNIto

12mon

ths

SECU

RITY

(37)

2014

1,39

96mon

thsvs.

12mon

thsDAPT

24mon

ths

Compo

site

ofcardiacde

ath,

MI,stroke

,ST

,or

BARC3or

5blee

ding

at12

mon

thsafterPC

I

65

3138

—10

06mon

thsNIto

12mon

ths

OPT

IMIZE

(36)

2014

3,119

3mon

thsvs.

12mon

thsDAPT

12mon

ths

Compo

site

ofde

ath,

MI,stroke

,or

major

blee

ding

at12

mon

ths

afterPC

I

61

3532

—10

03mon

thsNIto

12mon

ths

PRODIGY

(34)

2012

1,970

6mon

thsvs.

24mon

thsDAPT

24mon

ths

Compo

site

ofde

ath,

MI,or

cerebrov

ascu

laraccide

nts

at24

mon

thsafterPC

I

68

2475

2550

6mon

thsNIto

24mon

ths

RES

ET (35)

2012

2,117

3mon

thsvs.

12mon

thsDAPT

12mon

ths

Compo

site

ofcardiacde

ath,

MI,ST

,isch

emia-driv

enTV

R,o

rblee

ding

at12

mon

thsafterPC

I

62

2955

2185

3mon

thsNIto

12mon

ths

EXCE

LLEN

T(33)

2011

1,44

36mon

thsvs.

12mon

thsDAPT

12mon

ths

Compo

site

ofcardiacde

ath,

MI,or

TVR

at12

mon

thsafterPC

I63

3851

2575

6mon

thsNIto

12mon

ths

BARC

¼Bleed

ingAcade

micResea

rchCo

nsortium

;DAPT

¼du

alan

tiplatelet

therap

y;DM

¼diab

etes

mellitus;E

XCE

LLEN

T¼

Efficacy

ofXienc

e/Prom

usVersusCy

pher

toRed

uceLa

teLo

ssAfter

Sten

ting

;ISA

R-SAFE

¼Ran

domized

,Dou

ble-Blind,

Placeb

o-co

ntrolle

dTrial

of6vs.12Mon

thsClop

idog

relT

herapy

After

Implan

tation

ofaDrug-ElutingSten

t;ITALIC¼

IsTh

ereALIfe

forDES

After

Disco

ntinua

tion

ofClop

idog

rel;MI¼

myo

cardialinfarction;

NI¼

noninferior;OPT

IMIZE¼

Optim

ized

Durationof

Clop

idog

relT

herapy

Follo

wing

Trea

tmen

tWiththeEn

deav

orZo

tarolim

us-Eluting

Sten

tin

theRea

lWorld

Clinical

Practice;P

CI¼

percutan

eous

corona

ryinterven

tion

;PRODIGY¼

PROlong

ingDua

lAntiplateletTrea

tmen

tIn

Patien

tsWithCo

rona

ryArteryDisea

seAfter

Grade

dSten

t-indu

cedIntimal

Hyp

erplasia;R

ESET

¼ANew

Strategy

Reg

arding

Disco

ntinua

tion

ofDua

lAntiplatelet;Rea

lSafetyan

dEfficacy

ofa3-mon

thDua

lAntiplateletTh

erap

yFo

llowingZo

tarolim

us-eluting

Sten

tsIm

plan

tation

;SEC

URITY

¼Se

cond

-Gen

erationDrug-ElutingSten

tIm

plan

tation

Follo

wed

by6-Versus12-M

onth

Dua

lAntiplateletTh

erap

y;ST

¼sten

tthrombo

sis;

TIMI¼

Thrombo

lysisIn

Myo

cardialInfarction

;TV

R¼

target

vessel

reva

scularization;

othe

rab

brev

iation

sas

inTa

ble1.


835

was a 4-by-2 randomized, open-label, multicentertrial that evaluated the efficacy and safety of 6 versus24 months of DAPT in an all-comer populationreceiving a balanced mixture of stents. Patientsundergoing PCI were 1:1:1:1 randomized to receive 1 of4 stent types, including BMS, EES, PES and theEndeavor zotarolimus-eluting stent (ZES) (Medtronic,Inc., Santa Rosa, California). More than 70% ofpatients presented with ACS. The RESET trial was thefirst study evaluating a mandatory DAPT duration of3 months with a second-generation DES (35). Patients,55% of whom had ACS, were randomized in a 1:1fashion to either an Endeavor ZES with DAPT for3 months or an EES, Resolute ZES (Medtronic), or SESwith DAPT for 12 months.

OPTIMIZE (Optimized Duration of ClopidogrelTherapy Following Treatment With the EndeavorZotarolimus-Eluting Stent in the Real World ClinicalPractice) was another study to evaluate 3 months ofmandatory DAPT (36). It was a multicenter, open-label, randomized trial evaluating 3 versus 12 monthsof DAPT in patients, of whom 32% had ACS, althoughnone had MI.

In 2014, the SECURITY (Second-Generation Drug-Eluting Stent Implantation Followed by 6- Versus12-Month Dual Antiplatelet Therapy), ITALIC (Is ThereA LIfe for DES After Discontinuation of Clopidogrel),and ISAR-SAFE (Randomized, Double-Blind, Placebo-controlled Trial of 6 vs. 12 Months Clopidogrel TherapyAfter Implantation of a Drug-Eluting Stent) trials(37–39) reported on evaluating S-DAPT for 6 monthsversus 12 months. SECURITY was a randomized, open-label multicenter study evaluating the safety andefficacy of 6 months versus 12 months of DAPT inpatients undergoing PCI with a second-generationDES. This study included the largest proportion ofbioresorbable polymer DES. The ITALIC study evalu-ated 6 months versus 24 months of DAPT after XienceEES (Abbott Vascular, Santa Clara, California) implan-tation. Randomization occurred at the time of the in-dex procedure, and results have so far been reportedonly up to 1-year follow-up. Interestingly, ITALICexcluded patients resistant to aspirin. The prevalenceof ACS at baseline was low (24%). Finally, ISAR-SAFEwas a multicenter, double-blind, placebo-controlled,randomized trial testing the efficacy and safety of6 months versus 12 months of DAPT. Only patients onDAPT who were event-free in the first 6 months afterDES implantation were randomized to either continuewith DAPT or be treated with aspirin and placebo. Atotal of 72% had received second-generation DES. Theprevalence of ACS at presentation before the indexprocedure was 40% (8% ST-segment elevation acutecoronary syndrome [STEMI] and 32% non-STEMI).

TABLE 3

Trial (Re

ISAR-SAFE

ITALIC (38

SECURITY

OPTIMIZE

PRODIGY

RESET (35

EXCELLEN

Total

Values are n

ARI ¼ abs



836

Noninferiority of the primary endpoint for S-DAPTversus long duration (L)-DAPT was demonstrated ineach of these studies irrespective of stent type, clin-ical indication, or DAPT duration. Moreover, no dif-ferences were observed in the components of theprimary endpoint, ST or bleeding, in most of thestudies. The PRODIGY trial was the only exception, inwhich 24 months of DAPT was associated with higherrates of major bleeding than 6-month DAPT. Mostprobably, the statistical significance for higher risk ofbleeding with L-DAPT in this study was related to thelonger exposure in the L-DAPT group compared withthe S-DAPT group, as neither group reflected standardpractice (i.e., 1-year DAPT) as defined by contempo-rary guidelines. Of note, prolonged DAPT providedischemic benefit in certain subgroups—for example,diabetic patients in the EXCELLENT trial and patientswith in-stent restenosis target lesions in the PRODIGYtrial (33,40).

Accepting differences in study design and baselineclinical risk profile, when pooling the events fromall 7 studies (Table 3), S-DAPT (3 or 6 months)was associated with an overall rate of ST of 0.5%compared with 0.4% with L-DAPT (absolute riskreduction with L-DAPT: 0.1%). The pooled rate of MIwas 1.7% with S-DAPT and 1.5% with L-DAPT (abso-lute risk reduction: 0.2%). The rate of major bleedingwas 0.4% with S-DAPT and 0.8% with L-DAPT (ab-solute risk increase with L-DAPT: 0.4%), whereas thedeath rate was 1.7% with S-DAPT and 1.9% withL-DAPT (absolute risk increase: 0.2%). These resultssuggest a risk/benefit ratio favoring an S-DAPTregimen (Figure 1). Recently published meta-analysesreport similar findings (41,42).CLINICAL INTERPRETATION. Several issues must beconsidered when interpreting results from thesetrials evaluating the safety and efficacy of S-DAPT(3 to 6 months). First, all were underpowered todetect differences in hard endpoints, including the

Endpoints in Studies Evaluating Abbreviated Duration of DAPT (#6 Mo

f. #)

Stent Thrombosis MI

S-DAPT L-DAPT ARR S-DAPT L-DAPT ARR

(39) 5 (0.3) 4 (0.2) 0.1 13 (0.7) 14 (0.7) 0

) 3 (0.3) 0 0.3 6 (0.7) 4 (0.4) 0.

(37) 2 (0.3) 3 (0.4) �0.1 16 (2.3) 15 (2.1) 0.

(36) 13 (0.8) 12 (0.8) 0 49 (3.2) 42 (2.7) 0.

(34) 15 (1.5) 13 (1.3) 0.2 41 (4.2) 39 (4) 0.

) 2 (0.2) 3 (0.3) �0.1 2 (0.2) 4 (0.4) �0.

T (33) 6 (0.9) 1 (0.1) 0.8 13 (1.8) 7 (1) 0.

46 (0.5) 36 (0.4) 0.1 140 (1.7) 125 (1.5) 0.

(%).

olute risk increase; ARR ¼ absolute risk reduction; L-DAPT ¼ long dual antiplatelet therapy

composite primary endpoints. The low statistical po-wer among studies was related to study design issues,slow enrollment, premature interruption of severalstudies, lower than expected event rates, andpossibly, under-reporting. Second, with 1 exception,all studies were open-label trials, introducing thepotential for observer bias. Third, treatment cross-over, selection bias, and regression to the meanpose problems, as a not insignificant proportion ofpatients who were randomized to the S-DAPT armwere still on DAPT at the end of the follow-up period(and vice-versa). Fourth, most of these trials had only1 year of follow-up, which is insufficient to evaluatevery late clinical outcomes. Fifth, the number of pa-tients lost to follow-up was not always reported and,when reported, was as high as 7%. Sixth, all of theprevious issues have a particularly deleterious effecton studies with a noninferiority design; the 7 studiesconsidered here had a noninferiority design withwide noninferiority margins. Seventh, except for thePRODIGY trial, results from these studies lackexternal validity (generalizability), as high-risk pa-tients were excluded from the majority. Finally, pri-mary endpoint definitions were heterogeneous; somestudies included target vessel revascularization, andothers did not include ST in the composite endpoint.

Considering these potential limitations, resultsfrom S-DAPT trials must be evaluated carefully. Aseach individual study is inconclusive for events likeMI or major bleeding, meta-analytic methods maymore reliably approximate the true risk/benefit bal-ance of S-DAPT (Figures 2 and 3). There was no excessrisk of MI with S-DAPT, but there was a significantreduction in major bleeding, confirmed recently inseveral pooled analyses of these studies (41,42). All ofthese meta-analyses have serious limitations relatedto heterogeneity in study designs, populations, defi-nitions of events, and lengths of follow-up, in addi-tion to the limitations of the individual studies

nths) After DES

Major Bleeding Death

S-DAPT L-DAPT ARI S-DAPT L-DAPT ARI

4 (0.2) 5 (0.3) 0.1 8 (0.4) 12 (0.6) 0.2

3 5 (0.5) 7 (0.7) 0.2 8 (0.9) 7 (0.8) 0.1

2 4 (0.6) 8 (1.1) 0.5 8 (1.2) 8 (1.2) 0

5 10 (0.6) 14 (0.9) 0.3 43 (2.8) 45 (2.9) �0.1

2 6 (0.6) 16 (1.6) 1 65 (6.6) 65 (6.6) 0

2 5 (0.5) 10 (1) 0.5 5 (0.5) 8 (1) 0.5

8 4 (0.6) 10 (1.4) 0.8 4 (0.6) 7 (1) 0.4

2 38 (0.4) 70 (0.8) 0.4 141 (1.7) 152 (1.9) 0.2

; S-DAPT ¼ short dual antiplatelet therapy; other abbreviations as in Tables 1 and 2.

FIGURE 1 Net Clinical Benefit of Longer DAPT in Studies Evaluating a Period of

DAPT #6 Months

Net Clinical Benefit for L-DAPT Versus S-DAPT in Short-Term Studies4.5

Harm

Neutrality

Benefit

43.5

32.5

21.5

10.5

0

NNT / NNHST / MB

4 2 2 1ST / Death MI / MB MI / Death

For each ST prevented with L-DAPT, 4 major bleeding events or 2 deaths would be caused.

DAPT ¼ dual antiplatelet therapy; L-DAPT ¼ long dual antiplatelet therapy; MB ¼ major

bleeding; MI ¼ myocardial infarction; NNH ¼ number needed to harm; NNT ¼ number

needed to treat; S-DAPT ¼ short dual antiplatelet therapy; ST ¼ stent thrombosis.


837

outlined earlier. However, they provide additionalinformation that no individual study on its own canprovide.

The benefits of prolonged DAPT may be moreevident in studies of first-generation DES, in whichincomplete strut coverage and delayed vascular heal-ing increase the risk of late ST (43), whereas significantimprovement in safety with second-generation DEShas been demonstrated (18,44). Moreover, DAPTduration and DES generation interact to attenuate lateST (45). Accordingly, a short mandatory period ofDAPT of 3 or 6 months may be considered safe andeffective in non-ACS patients undergoing PCI withlatest-generation DES, in particular in patients at riskof bleeding and/or at low risk of recurrent ischemia.This may find much wider application henceforthbecause first-generation DES are no longer routinelyimplanted.

STUDIES EVALUATING A DURATION

LONGER THAN 12 MONTHS

STUDIES. Characteristics and major findings ofthe trials evaluating DAPT durations longer than12 months (very long [VL]-DAPT) are summarized inTable 4. These studies evaluated patients who hadcompleted 1 year of DAPT without ischemic orbleeding complications, perhaps implying selectionof a lower-risk population.

The DES-LATE (Optimal Duration of ClopidogrelTherapy With DES to Reduce Late Coronary ArterialThrombotic Event) trial was a prospective, multi-center, open-label, randomized trial to determine thebenefits and risks of continuing DAPT beyond 1 yearafter DES insertion (n ¼ 5,045) (46). This trial was aseamless extension of the previously conductedREAL-LATE (Correlation of Clopidogrel TherapyDiscontinuation in Real-World Patients Treatedwith Drug-Eluting Stent Implantation and LateCoronary Arterial Thrombotic Events) and ZEST-LATE (Evaluation of the Long-Term Safety afterZotarolimus-Eluting Stent, Sirolimus-Eluting Stent,or Paclitaxel-Eluting Stent Implantation for CoronaryLesions—Late Coronary Arterial Thrombotic Events)studies. It concluded that, compared with aspirinalone, continuing DAPT beyond 1 year after DESimplantation was not beneficial (47). Both first- andsecond-generation DES were used. At 2 years afterrandomization, the rate of the primary endpoint(death, MI, or stroke) was similar between the aspirin-alone and DAPT groups (2.4% vs. 2.6%, respectively;p ¼ 0.75). The rate of Thrombolysis In MyocardialInfarction (TIMI) major bleeding was also similarbetween the aspirin-alone and DAPT groups (1.1% vs.

1.4%; p ¼ 0.20). These findings suggest that the 2antiplatelet strategies provide similar protectionagainst ischemic events with similar risk of bleedingevents.

ARCTIC (Assessment by a double Randomizationof a Conventional antiplatelet strategy versus amonitoring-guided strategy for drug-eluting stentimplantation and of Treatment Interruption versusContinuation 1 year after stenting)-Interruption was aprospective, multicenter, open-label randomizedstudy (48) that was a planned extension of theARCTIC-Monitoring trial, which had randomly allo-cated 2,440 patients to a strategy of platelet functiontesting with antiplatelet treatment adjustment or aconventional antiplatelet strategy without moni-toring after coronary stenting with DES (49). After1 year, 1,259 eligible patients were randomized in theARCTIC-Interruption trial. After a median follow-upof another 17 months, 78% of patients in the contin-uation group were still on thienopyridine, and therate of the primary endpoint (death, MI, ST, stroke, orurgent revascularization) was similar between theinterruption L-DAPT group and the continuationVL-DAPT group (4% vs. 4%; p ¼ 0.58). Major bleedingevents tended to occur more frequently withVL-DAPT than with L-DAPT (1% vs. <0.5%; p ¼ 0.073);major or minor bleeding events were significantlyincreased with VL-DAPT, suggesting possible harmwith no tangible benefit from a VL-DAPT strategy.

The DAPT trial, a large, international, multicenter,randomized, placebo-controlled trial, was designed todetermine the benefits and risks of continuingDAPT beyond 1 year after the placement of a coronary

FIGURE 2 MI in the Meta-Analysis of L-DAPT Versus S-DAPT for Studies With

S-DAPT for #6 Months

Oddsratio

All

EXCELLENT 1.870 0.742 4.715

1.773

2.728

2.191

1.655

1.986

5.333

1.446

0.1 1Favorsshort

Favorslong

10

p=0.30

0.768

0.091

0.622

0.676

0.436

0.422

0.891

1.167

0.499

1.167

1.058

0.931

1.500

1.135

OPTIMIZE

RESET

SECURITY

PRODIGY

ISAR-SAFE

ITALIC

Lowerlimit

Upperlimit

Reproduced with permission from Montalescot G. Risk and benefit of dual antiplatelet

therapy. Paper presented at: the American Heart Association, Late Breaking Clinical Trial

session; November 16, 2014. EXCELLENT ¼ Efficacy of Xience/Promus Versus Cypher to

Reduce Late Loss After Stenting; ISAR-SAFE ¼ Randomized, Double-Blind, Placebo-

controlled Trial of 6 vs. 12 Months Clopidogrel Therapy After Implantation of a Drug-

Eluting Stent; ITALIC ¼ Is There A LIfe for DES After Discontinuation of Clopidogrel;

OPTIMIZE ¼ Optimized Duration of Clopidogrel Therapy Following Treatment With the

Endeavor Zotarolimus-Eluting Stent in the Real World Clinical Practice; PRODIGY ¼PROlonging Dual Antiplatelet Treatment In Patients With Coronary Artery Disease After

Graded Stent-induced Intimal Hyperplasia; RESET ¼ A New Strategy Regarding Discon-

tinuation of Dual Antiplatelet; Real Safety and Efficacy of a 3-month Dual Antiplatelet

Therapy Following Zotarolimus-eluting Stents Implantation; SECURITY ¼ Second-

Generation Drug-Eluting Stent Implantation Followed by 6- Versus 12-Month Dual Anti-

platelet Therapy; other abbreviations as in Figure 1.



838

DES (50). At 12 months after DES implantation,9,961 patients who had not had a major ischemic orbleeding event and had been adherent to DAPT wereassigned to continue thienopyridine and aspirintreatment (VL-DAPT arm) or to receive placebo plusaspirin for the next 18 months (L-DAPT arm). Thecoprimary efficacy endpoints were ST and the com-posite of death, MI, or stroke during the period from12 to 30 months after DES implantation. The primarysafety endpoint was moderate or severe bleeding. Assecondary analyses, examination of the same end-points in all patients over the course of the 21-monthpost-randomization period was undertaken, duringthe last 3 months of which the patients were notreceiving randomized treatment (to assess potentialhazards before and after discontinuation of the studydrug for qualitative differences). As a primary result,continuing thienopyridine, as compared with pla-cebo, reduced the rates of both coprimary endpoints,ST (0.4% vs. 1.4%; p < 0.001) and death, MI, or stroke(4.3% vs. 5.9%; p < 0.001). Continued thienopyridine

increased the rate of moderate or severe bleeding(2.5% vs. 1.6%; p ¼ 0.001). An increased risk of STand MI was observed in both groups during the3 months after stopping thienopyridine. A borderlineincrease in all-cause mortality was observed withcontinued thienopyridine (2.0%) versus placebo (1.5%;p ¼ 0.052).

All 3 trials evidently studied patients who were atlower risk for late adverse events. The screeningperiod of the ARCTIC-Interruption trial correspondedwith the first phase of the trial. One year after stent-ing, 47% of the patients were excluded from thesecond randomization evaluating VL-DAPT. In theDAPT study, 22,866 patients were deemed eligible forthe study, but a year later, 56% were excluded at thetime of randomization for the evaluation of VL-DAPT.Although the 2 study designs differ, these 2 enroll-ment processes clearly indicate the difficulties inconducting such trials and the super-selection ofpatients who finally participated in the evaluation ofVL-DAPT.

When considering the 3 trials together, there wasa reduction of MI or ST with VL-DAPT, but anincrease of major bleeding and, possibly, of all-causedeath when compared with L-DAPT. Meta-analysis(Figure 4) indicates a trend toward higher risk of all-cause mortality associated with the use of VL-DAPT.This finding on mortality remains controversialbecause of the criteria used to select the studiesincorporated in different meta-analyses, some sug-gesting harm with prolonged DAPT after stenting,others not confirming the harm associated with pro-longed DAPT (41,52). The recent PEGASUS-TIMI 54(Prevention of Cardiovascular Events in Patients WithPrior Heart Attack Using Ticagrelor Compared to Pla-cebo on a Background of Aspirin-Thrombolysis InMyocardial Infarction 54) study is reassuring, withfavorable trends on mortality with prolonged DAPT inpost-MI patients (51).

CLINICAL INTERPRETATION. The DES-LATE trialincluded mostly first-generation DES, patients pre-senting with ACS, and a DAPT regimen using clopi-dogrel exclusively, which may have reduced the effectof prolonged DAPT in preventing ischemic eventswhen compared with the more potent P2Y12 inhibitorsnow available (i.e., prasugrel or ticagrelor). Whencompared with other studies performed in Westernpopulations, the event rates in the DES-LATE studywere lower and could be explained by the East Asianparadox (53): the fact that East Asian patients have asimilar or even lower rate of ischemic events afterstenting compared with Caucasians, despite greaterplatelet reactivity on DAPT treatment. VL-DAPT didnot provide incremental benefit to the subgroup

FIGURE 3 Major Bleeding in the Meta-Analysis of S-DAPT Versus L-DAPT for Studies

With S-DAPT for #6 Months

Oddsratio

All

EXCELLENT

OPTIMIZE

RESET

SECURITY

PRODIGY

ISAR-SAFE

ITALIC

Lowerlimit

Upperlimit

Favorsshort

p=0.01

Favorslong

0.498 0.091 2.727

2.406

1.647

2.011

0.956

2.991

2.754

0.8850.1 1 10

0.315

0.067

0.213

0.145

0.215

0.007

0.338

0.871

0.332

0.655

0.373

0.802

0.142

0.547



session; November 16, 2014. Abbreviations as in Figures 1 and 2.


839

of patients with clinical or angiographic high-risk fea-tures. High on-treatment platelet reactivity did nothelp identify optimal candidates for VL-DAPT.

The ARCTIC-Interruption trial was underpoweredand published simultaneously with a meta-analysisconfirming the main findings of the trial, in particularthe safety concern regarding VL-DAPT. Measurementof platelet reactivity was another unique aspect of theARCTIC-Interruption trial. Although high plateletreactivity was shown to be a marker for ischemicevents and was strongly associated with mortality,platelet reactivity did not differ between the continu-ation and interruption groups, and there was nointeraction between interruption and platelet reac-tivity on clinical outcomes. Once again, platelet reac-tivity did not assist in selecting patients for VL-DAPT.

The DAPT study is the largest and only double-blinded trial. DAPT is the only study adequatelypowered for its primary endpoints (ST and majoradverse cardiac and cerebrovascular events [MACCE])and also for major bleeding. Both first- and second-generation DES types were used, and clopidogreland prasugrel were both utilized. Continued thieno-pyridine attenuated ischemic events, including lateST; the demonstration of a “rebound” in ischemicevents after interruption more than 2 years afterstenting adds to the concept of ongoing protectionwith VL-DAPT. Moreover, the reduction of MIoriginated within the stented artery as frequentlyas within the nonstented arteries, suggesting thatthere is a secondary prevention effect of a VL-DAPTstrategy. The PEGASUS-TIMI 54 study, using tica-grelor in addition to aspirin in secondary preventionon average 4 years after an MI, lends additionalsupport to the hypothesis that VL-DAPT providesbetter global protection (51). Whether these findingssubstantiate “indefinite” DAPT treatment after DES inselected patients remains uncertain. The effects onST and MACCE were very consistent across the DAPTtrial subgroups, suggesting that the results may notbe confined to any specific patient profile. Unex-pectedly, VL-DAPT was not better in patients withrisk factors for ST and tended to be even less effectivein diabetic patients (p value for interaction ¼ 0.01).Similarly, the excess of GUSTO (Global Utilizationof Streptokinase and Tissue Plasminogen Activatorfor Occluded Coronary Arteries) moderate/severebleeding complications with VL-DAPT was consistentacross subgroups, not identifying profiles of patientsat particular excess bleeding risk with VL-DAPT.

In this regard, the remaining question is howrobust the finding of excess mortality with VL-DAPTis in this large trial. It should be recognized that thisis a weak signal derived from a small number of

events appearing late in follow-up. Fatal bleeding(Bleeding Academic Research Consortium 5) oc-curred in 0.15% versus 0.09% (p ¼ 0.38) for the30-month versus the 12-month period of DAPT. Theexcess of deaths from any cause with VL-DAPT wasdriven by an increase in noncardiovascular deaths.The reasons identified could be related to bleeding,trauma, or cancer, while accepting that some of thetrauma- or cancer-related deaths were also relatedto, revealed, or accentuated by bleeding. Therewas an asymmetrical split in fatal bleeding (21with VL-DAPT vs. 5 with L-DAPT) when all non-cardiovascular deaths were considered. There werealso more cancer-related deaths among patients onVL- than L-DAPT (31 vs. 14; p ¼ 0.02, including 3 vs.0 bleeding-related deaths) although the incidence ofcancer did not differ significantly at the time ofrandomization. The relationship between majorbleeding and death, which is widely documented inthe published data, appears to be present here again,although causality cannot be ascertained. The sametrend is present in the meta-analysis of the 3 studies,which examined VL-DAPT after DES (Figure 4).However, a large and more global meta-analysis of 14trials that randomly assigned 69,644 participants toextended-duration DAPT for various medical condi-tions showed that it was not associated with a dif-ference in the risk of all-cause, cardiovascular, ornoncardiovascular death compared with aspirinalone or short-duration DAPT (52). Although the

TABLE

4Ch

arac

teristicsof

theSt

udiesEv

alua

ting

Ver

yLo

ngDur

ationof

DAPT($

24Mon

ths)

After

DES

Stud

y(R

ef.#

)Date

Des

ign

Size

(First-

Gen

erat

ionDES

*)Dur

ation

(Mon

ths)

Acu

teCo

rona

rySy

ndro

me(%

)Ty

peof

Thieno

pyridine

PrimaryEn

dpoint

PrimaryOut

come

Major

Bleed

ingOut

come

DES

LATE

(47)

2014

RCT

,ope

nlabe

l5,045

(64%

)12

vs.2

461%

Clop

idog

relon

lyCo

mpo

site

ofCD

,MI,or

stroke

2.4%

vs.2

.6%;HR:0.94;

p¼

0.75

TIMI†

major;1.1%

vs.1

.4%;

HR:0.71;

p¼

0.20

ARCT

IC-

Interrup

tion

(48)

2014

RCT

,ope

nlabe

l1,25

9(41%

)12

vs.2

426

%Clop

idog

rel(91.5%

)Prasug

rel(8.5%)

Compo

site

ofde

ath,

MI,ST

,stroke

,or

urge

ntreva

scularization

4.0%

vs.4

.0%;HR:1.17;p¼

0.58

STEE

PLE‡

major;1.0%

vs.

<0.5%;HR:0.15;

p¼

0.073

DAPT

stud

y(50)

2014

RCT

,dou

ble

blind

9,961(38%)

12vs.3

043

%Clop

idog

rel(65.3%

)Prasug

rel(34.7%

)ST

andco

mpo

site

ofde

ath,

MI,or

stroke

0.4%

vs.1

.4%;HR:0.29;p<

0.001

and4.3%

vs.5

.9%;HR:0.71;

p<

0.001

GUST

O§seve

reor

mod

erate;

2.5%

vs.1.6%;HR:1.6;p¼

0.001

*Paclitaxel

andsirolim

usdrug

-eluting

sten

t.†TIMImajor

blee

ding

refers

totheTIMIc

riteria.‡ST

EEPL

Emajor

blee

ding

refers

totheST

EEPL

Ede

finition

.§GUST

Oseve

reor

mod

erateblee

ding

refers

totheGUST

Ocriteria.

ARCT

IC¼

Assessm

entby

ado

uble

Ran

domisationof

aCo

nven

tion

alan

tiplatelet

strategy

versus

amon

itoring-gu

ided

strategy

fordrug

-eluting

sten

tim

plan

tation

and,

ofTrea

tmen

tInterrup

tion

versus

Continua

tion

1ye

araftersten

ting

;CD

¼cardiacde

ath;

DES

-LATE

¼Optim

alDurationof

Clop

idog

relT

herapy

WithDES

toRed

uceLa

teCo

rona

ryArterialT

hrom

boticEv

ent;GUST

O¼

Globa

lUtilizationof

Streptok

inasean

dTissue

Plasminog

enActivator

forOcclude

dCo

rona

ryArteries;HR¼

hazard

ratio;

RCT

¼rand

omized

controlle

dtrial;ST

EEPL

E¼

Safety

andEfficacy

ofEn

oxap

arin

inPe

rcutan

eous

Corona

ryInterven

tion

(PCI)Pa

tien

ts,an

Internationa

lRan

domized

Evalua

tion

;othe

rab

brev

iation

sas

inTa

bles

1to

3.



840

question remains open, it is fair to state that nosurvival benefit may be expected from administeringVL-DAPT after DES.

Registry data also have shown conflicting resultson the optimal duration of DAPT (54,55). The largePARIS (Patterns of Non-Adherence to Anti-PlateletRegimens In Stented Patients) registry also assessedassociations between the different modes of DAPTcessation and cardiovascular risk over 2 years afterPCI. The overall incidence of any DAPT cessation was57.3%, and cardiac events differed according to themode of dual antiplatelet cessation and diminishedover time (56).

EVIDENCE AND EXTRAPOLATIONS

TYPE OF STENT. In the DAPT study, VL-DAPTreduced the risks of MACCE and ST across all DEStypes, with adjusted hazard ratios (HRs) for MACCEranging from 0.52 to 0.89 (50). The TAXUS LibertéPost Approval Study was embedded in the DAPTstudy as a surveillance of DES performance aftercommercial release to fulfill an FDA requirement (57).This exploratory analysis reported overall similarresults to the main findings of the DAPT trial, withoff-label use of prasugrel in patients who did notall have ACS. It demonstrated that besides patientcharacteristics and clinical setting (stable vs. un-stable presentation), the type of stent also affectedclinical outcome. Consistent with meta-analysesof first-generation versus second-generation stents(18,44,45), the safety of PES may be somewhatimproved by long-term use of prasugrel (58). Ratherthan promoting VL-DAPT, this study supports nolonger using first-generation DES, particularly pacli-taxel stents.

A cohort of patients with BMS were included inthe DAPT trial. Among 10,026 propensity-matchedsubjects, DES-treated subjects had a lower rate ofST through 33 months compared with BMS-treatedsubjects (1.70% vs. 2.61%; p ¼ 0.008) and a non-inferior rate of MACCE (11.37% vs. 13.24%; non-inferiority p < 0.001) (59). Results in BMS-treatedsubjects randomized to VL-DAPT are consistentwith DES results in relation to ST and bleeding.Interestingly, and in contrast to the DES-treatedpatients, the BMS-treated cohort did not demon-strate a difference in mortality between VL- and L-DAPT. This information, in addition to the recentlypublished PEGASUS-TIMI 54 trial and Elmariahmeta-analysis, is reassuring (51,52).TYPE OF P2Y12 ANTAGONIST. In the DAPT trial,comparisons between specific thienopyridines maybe confounded, as the patients’ therapy was not

FIGURE 4 All-Cause Death in the 3 Studies Evaluating Very Long Duration of

DAPT ($24 Months)

DAPT

All

0.8000.6961.3130.792

0.5990.4420.4860.625

1.0681.0973.5471.004

>12 monthsworse

>12 monthsbetter

p=0.054

DES-LATEARCTIC-interruption

Oddsratio

DeathStudy name Odds ratio and 95% CI

Lowerlimit

Upperlimit

0.1 1 10



session; November 16, 2014. ARCTIC ¼ Assessment by a double Randomization of a

Conventional antiplatelet strategy versus a monitoring-guided strategy for drug-eluting

stent implantation and of Treatment Interruption versus Continuation 1 year after stenting;

DAPT ¼ dual antiplatelet therapy; DES-LATE ¼ Optimal Duration of Clopidogrel Therapy

With DES to Reduce Late Coronary Arterial Thrombotic Event.


841

randomly assigned. Although protection againstMACCE was significant with clopidogrel (HR: 0.80), itwas more pronounced with prasugrel (HR: 0.52; p forinteraction ¼ 0.03). This data was confirmed in theTAXUS Libert�e Post Approval Study, in which off-label use of prasugrel was particularly effectivein reducing MI resulting from ST (0% vs. 2.6%;p < 0.001) and from sites remote from the stent (1.9%vs. 4.5%; p ¼ 0.007). Bleeding complications weremodestly and nonsignificantly increased with prasu-grel, with no effect on mortality. The extendedfollow-up 3 months after interruption of prasugrelshowed a particularly marked rebound of ischemicevents beyond 30 months, suggesting that prasugrelwas particularly effective in suppressing stent- andnonstent-related thrombotic complications.

In the CHARISMA trial, among patients with priorMI, ischemic stroke, or symptomatic peripheral arte-rial disease (n ¼ 9,478), there was a significantreduction of the risk of MI, stroke, or death associatedwith a combination of low-dose aspirin plus clopi-dogrel compared with aspirin alone at 30 months(60). The TRILOGY-ACS (The Targeted Platelet Inhi-bition to Clarify the Optimal Strategy to MedicallyManage Acute Coronary Syndromes) study alsoshowed that, among the patients with angiographicconfirmation of CAD after an ACS (n ¼ 3,085), treat-ment with prasugrel and aspirin significantly reduceddeath, MI, or stroke compared with clopidogrel andaspirin at 30 months (61). Similarly, in the TRA 2P-TIMI 50 trial, vorapaxar, a protease-activated recep-tor 1 inhibitor, reduced the composite risk of death,MI, or stroke in patients with prior MI (n ¼ 17,779)compared with the placebo group at 36 months (17).The largest study examining the role of VL-DAPT insecondary prevention is the PEGASUS-TIMI 54 trial(51). This randomized, double-blind trial evaluatedthe efficacy and safety of ticagrelor in addition tolow-dose aspirin for long-term treatment of 21,162patients in stable condition with a history of sponta-neous MI 1 to 3 years before randomization. ThePEGASUS-TIMI 54 trial evaluated 2 intensities of an-tiplatelet therapy using the 90-mg twice-daily dose ofticagrelor studied in PLATO (The Study of PlateletInhibition and Patient Outcomes) as well as a lowerdose: 60 mg twice daily. Both doses of ticagrelorreduced the risk of cardiovascular death, MI, or strokeby 15% and doubled the risk of TIMI major bleeding.The rates of fatal bleeding or nonfatal intracranialhemorrhage did not differ significantly between theticagrelor dose group and the placebo group. Therates of bleeding and other side effects such as dys-pnea were numerically lower with the 60-mg dose ofticagrelor than with the 90-mg dose, resulting in a

lower rate of discontinuation of the study drug and abetter safety profile with the 60-mg dose. There was atrend with ticagrelor 60 mg twice daily toward areduction in the rate of cardiovascular death anddeath from any cause, but this effect was not signif-icant. For every 10,000 patients treated with tica-grelor 60 mg twice daily, 42 ischemic events (death,MI or stroke) per year would be prevented at the costof 31 TIMI major bleeding. All of these studies supporta role for extended and more potent antiplatelettreatment for secondary prevention in patients withproven CAD and, in particular, with a prior history ofMI. Interestingly, the subgroup of patients presentingwith acute MI in the DAPT trial had a reduction inMACCE with continued thienopyridine that wasgreater (HR: 0.56) than in patients without MI (HR:0.83; interaction p ¼ 0.03). Bleeding, however, wassimilarly increased in both subgroups (62). Theconsistent excess of bleeding across studies withprolonged DAPT suggests that patients should beselected on the basis of the ischemic versus bleedingrisk.

ONGOING STUDIES. Alternative strategies with noveltherapies, as well as withdrawing some agents, repre-sent an area of investigation that will add to ourunderstanding of optimal antiplatelet management(63). A number of studies are examining the effec-tiveness of shorter-duration DAPT in patients aftercoronary stenting. The largest of these, GLOBALLEADERS (Comparative Effectiveness of 1 Month of Tica-grelor Plus Aspirin Followed by Ticagrelor MonotherapyVersus a Current-day Intensive Dual Antiplatelet Therapy

TABLE 5 Ongoing St

Study (Ref. #)

GLOBAL LEADERS(NCT01813435)

REDUCE(NCT02118870)

SMART-CHOICE(NCT02079194)

SMART-DATE(NCT01701453)

DAPT-STEMI(NCT01459627)

TWILIGHT(NCT02270242)

CVA ¼ cerebrovascular accMyocardial Infarction; GLOAll-comers Patients Undergin Patients With Acute CoroUndergOing ImplantationIntervention in Patients Wi



842

in All-comers Patients Undergoing Percutaneous Coro-nary Intervention With Bivalirudin and BioMatrixFamily Drug-eluting Stent Use; NCT01813435) willrandomize 16,000 patients receiving the BiomatrixDES (Biosensors Interventional Technologies, Singa-pore) to either 1 month of DAPT with aspirin and tica-grelor followed by 23 months of ticagrelor alone, or 12months of standard DAPT followed by aspirin mono-therapy. Other randomized studies are also exploringthe safety of shorter durations of DAPT with novelstent platforms, and some will focus on the ACS pop-ulation receiving newer-generation DES. The TWI-LIGHT (Ticagrelor With Aspirin or Alone in High-RiskPatients After Coronary Intervention) study [NCT02270242] takes a new approach to SAPT. The active armwill have interruption of aspirin at 3 months post-PCIcontinuing on ticagrelor alone. The comparator armwill have DAPT with aspirin and ticagrelor for 1 year(Table 5). Other smaller studies evaluating long-termDAPT in stented populations (NCT02079194) are stillongoing.

THE CLINICIAN’S CHOICE

Medicine is both art and science. The science relies ondata provided by randomized clinical trials andobservational studies elucidating incidence, risk fac-tors, effect on outcomes, and optimal treatment for amedical condition. The art relies on the ability of thephysician to synthesize medical knowledge andtranslate it into the optimal patient-specific manage-ment strategy. The decision to either continue or stopDAPT after a mandatory period after the implantation

udies Examining Abbreviated Duration of DAPT

Design SizeActive

(Months)Control(Months) Population

RCT(Biomatrix stent)

16,000 1 12 DES

RCT(COMBO dual

therapy stent)

1,500 3 12 ACS

RCT 5,100 3 12 DES

RCT 3,000 6 12 ACS

RCT 1,100 6 12 STEMI

RCT 8,000 3 12 complex PCIwith DES

ident; DAPT-STEMI ¼ Prospective, Randomized, Open Label Trial of 6 Months vs. 12 MonBAL LEADERS ¼ Comparative Effectiveness of 1 Month of Ticagrelor Plus Aspirin Followed boing Percutaneous Coronary InterventionWith Bivalirudin and BioMatrix Family Drug-elutingnary Syndrome Treated With the COMBO Dual-therapy stEnt; SMART-CHOICE ¼ Comparisoof Coronary Drug-Eluting Stents; SMART-DATE ¼ Smart Angioplasty Research Team: Safeth Acute Coronary Syndromes; TWILIGHT ¼ Ticagrelor With Aspirin or Alone in High-Risk Pat

of a DES perfectly reflects this concept (64). An initialmandatory period of DAPT after DES implantationis needed to prevent stent- and nonstent-relatedthrombotic complications. During this period, cessa-tion of DAPT is associated with an unacceptably highrate of thrombotic events (65–67). The duration ofmandatory DAPT,which can range from 3 to 12months,depends on the patient’s clinical presentation, overallrisk profile, lesion complexity, and the type of stentimplanted. Beyond the mandatory period, DAPT pro-longation has to be carefully considered (68). Exten-sion of DAPT confers protection against stent- andnonstent-related atherothrombotic events (50). How-ever, the antithrombotic benefit may be counter-balanced by an increased bleeding risk, which affectsmorbidity and mortality and cannot be disregarded.Therefore, a realistic estimation of the long-termischemic and bleeding risk in every patient undergo-ing PCI is of paramount importance to tailor theoptimal DAPT duration.

ISCHEMIC RISK EVALUATION. Coronary thromboticevents after PCI can be classified as stent- andnonstent-related (69). DAPT confers protection onboth types of thrombotic events through suppressionof platelet reactivity and aggregability (70).

The pathophysiology of ST includes patient-, stent-,and procedure-related factors (71). Patient-relatedfactors include presentation with ACS (in whichSTEMI carries the highest thrombotic risk), diabetesmellitus, chronic kidney disease, and clinical surro-gates such as multivessel CAD, previous MI, left ven-tricular dysfunction, and high on-treatment plateletreactivity (65–67,72,73). Procedural factors include

Primary EPExpected

Completion Date

Composite of all-cause mortality or nonfatal newQ-wave MI up to 2 yrs post-randomization

June 2016

Composite of all-cause mortality, MI, ST, stroke,or bleeding at 12 months

March 2017

Composite of death, MI, cerebrovascular events,or bleeding over 3–12 months after theindex procedure

February 2020

Composite of death, MI, CVA, ST, or major bleedingover 6–18 months post-hospitalization

August 2016

Composite of death, MI, revascularization, CVA,or bleeding at 18 months post-randomization

December 2017

Major bleeding at 15 months post-PCI March 2017

ths Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation In ST-elevationy Ticagrelor Monotherapy Versus a Current-day Intensive Dual Antiplatelet Therapy inStent Use; REDUCE¼ Randomized Evaluation of Short-termDUal Anti Platelet Therapyn Between P2Y12 Antagonist MonotHerapy and Dual Antiplatelet Therapy in Patientsty of 6-month Duration of Dual Antiplatelet Therapy After Percutaneous Coronaryients After Coronary Intervention; other abbreviations as in Tables 1 to 3.

https://clinicaltrials.gov/ct2/show/NCT01813435











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stent underexpansion or undersizing, incompletestent apposition, residual edge dissection, number ofstents implanted, final stent length, and lesioncomplexity. Finally, stent-related factors includepolymer hypersensitivity with incomplete endotheli-alization, stent design, and strut thrombogenicity.A substantial improvement in stent endothelializationand strut thrombogenicity has been achieved withsecond-generation DES, as compared with theirpredecessors (18). Moreover, bioresorbable polymerDES have the potential advantage of eliminatingpolymer-related triggers for late and very late ST afterthe elution of the antirestenotic drugs (44).

The PROSPECT (Providing Regional Observationsto Study Predictors of Events in the Coronary Tree)study demonstrated that adverse ischemic eventsoccurring at follow-up after PCI for ACS are almostequally distributed between thrombosis in culprit andnonculprit lesions (69). Neoatherosclerosis can occureither inside or outside of the stented vascularsegment (74). Evidence from intravascular imagingand histologic studies in DES demonstrate theoccurrence of continuous neointimal growth (75). In-stent neoatherosclerosis may be an important mech-anism of stent failure, accounting for both ST andrestenosis after either BMS or DES implantation (74).

Having considered these factors, the prolongationof DAPT after the mandatory period to prevent theoccurrence of future thrombotic events, both withinand beyond the target coronary lesion, may be anattractive and “desirable” strategy after meticulousindividualized evaluation of the hemorrhagic risk.

BLEEDING RISK EVALUATION. As opposed to STor recurrent MI, bleeding severity ranges fromevents that are clinically insignificant to those thatare life-threatening or fatal (76). Among existing,commonly-used definitions, Bleeding AcademicResearch Consortium type 3 or 5, TIMI major orminor, and GUSTO moderate or severe bleeding mayseriously affect morbidity and mortality and, there-fore, should be considered clinically relevant (77,78).

Several risk scores have been developed to predictlate and very late bleeding, most of which do notapply specifically to a PCI population (79). Forexample, the HAS-BLED (hypertension, abnormalrenal/liver function, stroke, bleeding history or pre-disposition, labile international normalized ratio,elderly, drugs/alcohol concomitantly) risk score wasdeveloped to predict bleeding in patients on chronicanticoagulation for atrial fibrillation and is not rele-vant to PCI patients (79). Other risk factors, such asmalignancy, thrombocytopenia, anemia, white bloodcell count, low platelet reactivity, excessive fall risk,

and genetic factors have been described (80–83).Considering the heterogeneity of risk factors andpotential sites for bleeding, the individual bleedingrisk should be carefully evaluated.

IMPORTANCE OF THE CLINICAL CHOICE. Clinicallysignificant bleeding events are numerically morefrequent than ST or MI, and their effect on late mor-tality has been extensively described (50,82). Inaddition, for some patients or clinicians, a moderatebleed may not carry the same weight as an ST orspontaneous MI. On the basis of data derived fromearly events after PCI, ST is associated with a higherfatality rate than major bleeding (84,85).

Pooling the available evidence, prolonging DAPTafter the mandatory period seems to be more appro-priate in patients at high risk for ischemic events andrelatively low bleeding risk. Conversely, consideringthe greater safety of newer-generation DES, the rela-tively high incidence of late bleeding events on DAPT,and their deleterious effect on survival, limitingDAPT to the 3- to 6-month mandatory period may bethe optimal strategy in patients at moderate or highrisk for bleeding. Similarly, the strategy of S-DAPTwould apply to patients who would require oralanticoagulation (e.g., for atrial fibrillation) or semi-urgent noncardiac surgery (e.g., for cancer) or inves-tigation (e.g., gastrointestinal endoscopy). Ideally,prescription of DAPT after PCI with DES has to be adynamic (i.e., potentially modifiable over time) re-commendation. After the procedure, patients shouldbe prescribed DAPT for the initial mandatory periodof 3 to 6 or 12 months according to clinical presenta-tion, ischemic risk, bleeding risk, and the type ofstent implanted. After this initial mandatory period,the physician may face 3 main scenarios regarding therisk/benefit ratio of a potentially “desirable” longerDAPT recommendation:

1. Patient had a recurrent ischemic event on DAPT;these patients will probably benefit from prolong-ing DAPT.

2. Patient had clinically significant bleeding; thesepatients should stop DAPT or at least complete theminimal mandatory period.

3. Patient is event-free; patients at low risk forbleeding and at high risk for ischemia may benefitfrom DAPT prolongation, considering the benefi-cial effect of DAPT in preventing stent- andnonstent-related thrombotic events. Conversely,patients at moderate or high risk for bleeding maybenefit from DAPT cessation. Finally, patients maypresent with both high bleeding risk and highischemic risk, and this is when the science ofmedicine becomes art (64).

CENTRAL ILLUSTRATION Decision-Making After the Mandatory DAPT Period

Drug-eluting coronary stent implantation

Mandatory period of DAPT

STOP DAPT AFTER MANDATORY PERIOD CONTINUE WITH DAPT

Comprehensive clinical evaluation

ISCHEMIC RISK OUTWEIGHS BLEEDING RISK

Patient presentation:• Recurrent ischemic

event on DAPT• Stent-related complications• Acute coronary syndrome• Male• Diabetes mellitus• Left ventricular

dysfunction• Chronic kidney disease• Peripheral vascular disease• Prior ischemic stroke

BLEEDING RISK OUTWEIGHS ISCHEMIC RISK

Patient presentation:• Clinically significant

bleeding on DAPT • Advanced age • Female• Liver disease• Peptic ulcer disease• Chronic oral nonsteroidal

anti-inflammatory drug (NSAID) therapy

• Anemia and/or thrombocytopenia

• Uncontrolled hypertension• Bleeding diathesis• Prior major bleeding/

prior hemorrhagic stroke• Atrial fibrillation/chronic

anticoagulation therapy• High bleeding risk score

UNFAVORABLE PROFILE

Clinical considerations:• Short life

expectancy• Poor socio-

economic status• Poor expected

DAPT adherence• Poor mental status• Malignancy• End stage

renal failure• Smoker

• Clopidogrel nonresponsiveness

• Prior myocardial infarction• Lesion complexity• Incomplete stent apposition• Stent undersizing/

underexpansion• Residual edge dissection• Stent deployment in

necrotic core• Stent overlap

Montalescot, G. et al. J Am Coll Cardiol. 2015; 66(7):832–47.

When a mandatory period of DAPT is completed, a careful evaluation of the patient’s ischemic risk and bleeding risk, and of the overall clinical profile should be

undertaken. DAPT ¼ dual antiplatelet therapy; NSAID ¼ nonsteroidal anti-inflammatory drug.



844

Any change in the patient’s clinical profile thatmay influence the benefit/risk ratio or tolerance of orcompliance with DAPT should be evaluated beforedeciding whether to prolong DAPT or not. A summaryof the factors to consider in deciding whether tocontinue or discontinue DAPT after a mandatoryperiod is depicted in the Central Illustration.

Finally, a very important and often underestimatedaspect of post-procedural PCI management is optimalmedical therapy (OMT). The control of multiple car-diovascular risk factors reduces the incidence of car-diovascular events (86). OMT is a broad term thatincorporates the control of lifestyle risk factors(weight loss, smoking cessation, dietary regimen,exercise, and life rhythms) and specific pharmaco-therapy to control arterial hypertension, hyperlipid-emia, and chronic hyperglycemia. As stated by theEuropean Society of Cardiology guidelines “OMTshould not be considered an alternative but a syner-gistic approach to revascularization” (26).

CONCLUSIONS

Considering the consistent results from the reportedstudies, safe interruption of DAPT 6 months after DESimplantation may be possible in selected patients.Two randomized studies and a few registries havesuggested that 3 months of DAPT was possible withthe latest DES generation.

Prolongation of DAPT beyond 1 year after DESimplantation is possible. This has been tested now inpatients selected after a year of follow-up. Thestrategy of using DAPT to reinforce secondary pre-vention is more sensible in patients at high ischemicrisk, although the benefit was observed acrossalmost all subgroups. Long-term DAPT reducesstent- and nonstent-related thrombotic events at thecost of more bleeding complications, translating intono survival advantage. Long-term DAPT may useclopidogrel or a new oral P2Y12 antagonist. In eithercase, removing the P2Y12 antagonist exposes patients


845

to a reactivation of the ischemic disease, even 2years after stenting. Removing the last antiplateletagent is not recommended in any coronary patient.

Finally, after a short mandatory period of 3 to6 months, DAPT should be tailored over time on thebasis of the clinical profile, the type of stent, and thepatient’s tolerance, comorbidities, and preference.At this stage, clinicians are advised to individualize

decisions regarding the type and duration of DAPT instented patients.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Gilles Montalescot, ACTION Study Group, Institut deCardiologie, Centre Hospitalier Universitaire Pitié-Salpêtri _ere, 47 Boulevard de l’Hôpital, 75013 Paris,France. E-mail: [email protected].

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KEY WORDS antiplatelet therapy, aspirin,coronary stent, drug-eluting stent,P2Y12 inhibitors

























































































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