JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 11, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.01.024

EDITORIAL COMMENT

DAPT Duration After DES What Is the “Mandatory” Duration?* Roxana Mehran, MD, Gennaro Giustino, MD, Usman Baber, MD

T

he worldwide implantation of intracoronary

duration after PCI on the basis of multiple random-

drug-eluting stents (DES) continues to in-

ized comparisons. To date, 7 randomized controlled

crease, with more than 5 million such inter-

trials (RCTs) (Figure 1) have reported similar is-

ventions expected by 2018. Despite widespread use,

chemic outcomes with 3- or 6-month DAPT duration

the optimal duration of dual antiplatelet therapy

compared with longer DAPT regimens following DES

(DAPT), defined as the combination of a platelet

implantation. Conversely, with the exception of the

P2Y12 inhibitor and aspirin, remains unclear. The

DAPT study, 2 RCTs failed to demonstrate a reduction

need for antiplatelet therapy post-DES implantation

in ischemic events with DAPT prolongation beyond

is predicated on mitigating risk for thrombotic

12 months (4–17).

events, which is highest in the first weeks to months

SEE PAGE 1092

after percutaneous coronary intervention (PCI). Not surprisingly, early cessation of DAPT has emerged as

It is within this context that Palmerini et al. (18)

a strong, consistent, and independent risk factor for

report their findings from a patient-level pooled

stent thrombosis (ST) (1,2). The potential for a sys-

analysis of 4 randomized trials (n ¼ 8,180) comparing

temic benefit of DAPT that extends beyond the local

shorter (3- or 6-month) versus longer (12-month)

stented segment to the remaining coronary vascula-

DAPT durations after DES PCI in this issue of the

ture, coupled with concerns for late ST with early

Journal (18). Reflecting contemporary PCI practice

generation DES, provide a pathobiological rationale

patterns, the most prevalent DES platforms in

for longer (>1 year) DAPT durations. The unavoidable

the pooled cohort were everolimus-eluting and

corollary to extending the duration of antiplatelet

zotarolimus-eluting stents, respectively. The authors

therapy is increased bleeding, a complication that

found nonsignificant differences in major adverse

may have a more durable impact on long-term risk

cardiac events (MACE), defined as the composite of

than recurrent thrombosis (3). Indeed, bleeding con-

cardiac death, myocardial infarction, and definite/

cerns—in concert with the improved biocompatibility

probable ST, between groups at 12 months (hazard

and clinical safety of second-generation DES—have

ratio: 1.11; 95% confidence interval: 0.86 to 1.43;

led to clinical equipoise on the optimal DAPT

p ¼ 0.44). A shorter DAPT duration, however, yielded significant reductions in bleeding (hazard ratio: 0.66; 95% confidence interval: 0.46 to 0.94; p ¼ 0.03).

*Editorials published in the Journal of the American College of Cardiology

Findings were concordant in several clinically re-

reflect the views of the authors and do not necessarily represent the

levant subgroups (sex, age, diabetes, clinical pre-

views of JACC or the American College of Cardiology.

sentation, multivessel disease, and left anterior

From The Zena and Michael A. Wiener Cardiovascular Institute, Icahn

descending artery as a target vessel) without evi-

School of Medicine at Mount Sinai, New York, New York. Dr. Mehran is a

dence of statistical interaction for the primary MACE

consultant for AstraZeneca, Bayer, CSL Behring, Janssen Pharmaceuticals Inc., Merck & Co. Inc., Osprey Medical Inc., Regado Biosciences Inc., The

endpoint.

Medicines Company, Watermark Consulting; and is on the scientific

In addition to the primary patient-level analysis,

advisory board of Abbott Laboratories, AstraZeneca, Boston Scientific

in which point estimates were stratified by trial,

Corporation, Covidien, Janssen Pharmaceuticals Inc., Merck & Co. Inc., The Medicines Company, and Sanofi. Drs. Giustino and Baber have re-

the authors also performed indirect comparisons be-

ported that they have no relationships relevant to the contents of this

tween DAPT durations across trials using a network

paper to disclose.

approach. Findings from these analyses were largely

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Mehran et al.

JACC VOL. 65, NO. 11, 2015

What Is the “Mandatory” Duration?

MARCH 24, 2015:1103–6

F I G U R E 1 DAPT Duration in Trials

Meta–analysis / Pooled Analysis

Trial REAL-LATE/ ZEST–LATE [2011]4 12 Vs. 33 Months

Cassese et al13 Meta–analysis

Evidence • •

No differences in MACE between shorter (median 6.2 Months) and longer (median 16.8 months) DAPT Shorter DAPT associated with less bleeding

5

PRODIGY [2012] 6 Vs. 24 Months

Palmerini et al18 Pooled Analysis

EXCELLENT [2012]6 6 Vs. 12 Months RESET [2013]7 3 Vs. 12 Months 8

OPTIMIZE [2014] 3 Vs. 12 Months

ARCTIC-Interruption [2014]9 12 Vs. 18–30 Months

Stefanini et al14 Meta–analysis Pandit et al15 Meta–analysis

•

EI–Hayek et al16 Meta–analysis

• •

No differences in MACE between shorter (3 or 6 Months) and longer (≥ 12 Months) DAPT. Shorter DAPT associated with less bleeding No differences in MACE and bleeding between 3 or 6 months DAPT

Bulluck et al20 Network Meta–analysis

SECURITY [2014]10 6 Vs. 12 Months ITALIC [2014]11 6 Vs. 12 Months

•

No differences in MACE and major bleeding between 6 and 12 months of DAPT

ISAR–SAFE [2014]12 6 Vs. 12 Months DAPT [2014]17 12 Vs. 30 Months

• • •

Lower rates of MACE, ST and MI with longer DAPT Lower rates of major bleeding with shorter DAPT Higher all-cause mortality with longer DAPT?

Available evidence on DAPT duration is summarized from randomized controlled trials and meta-analyses. ARCTIC ¼ Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy; DAPT ¼ dual antiplatelet therapy; EXCELLENT ¼ Comparison of the Efficacy of EverolimusEluting Versus Sirolimus-Eluting Stent for Coronary Lesions; ISAR-SAFE ¼ Safety and Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC ¼ Is There A LIfe for DES After Discontinuation of Clopidogrel; MACE ¼ major adverse cardiac event(s); MI ¼ myocardial infarction; OPTIMIZE ¼ Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor ZotarolimusEluting Stent in the Real World Clinical Practice; PRODIGY ¼ PROlonging Dual Antiplatelet Treatment In Patients With Coronary Artery Disease After Graded Stent-induced Intimal Hyperplasia study; REAL-LATE ¼ Correlation of Clopidogrel Therapy Discontinuation in Real World Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events; RESET ¼ 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 Antiplatelet Therapy; ST ¼ stent thrombosis; ZEST-LATE ¼ Evaluation of the Long-Term Safety after Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions and Late Coronary Arterial Thrombotic Events.

concordant with the primary results, showing a safety

most participants in the pooled cohort were taking

advantage with shorter DAPT duration without any

DAPT for several months post-PCI irrespective of

incremental thrombotic risk due to earlier cessation.

randomized treatment assignment, the authors re-

The investigators concluded that in a contemporary

peated all analyses in a landmark interval bounded

practice with second-generation DES, a DAPT strategy

by time of DAPT discontinuation and 1 year. This

of 3 or 6 months is acceptable in selected patients

period, when groups are most different vis-à-vis

who are not at high risk for ischemic events.

DAPT status, allows for more valid attribution of

Among the present analysis’ strengths is the in-

events to the correct DAPT group and is of greatest

clusion of patient-level data, thereby allowing valid

clinical interest. Findings from this “as-treated”

inferences in key subgroups and multivariable ad-

analysis were consistent with the primary intention-

justment within a propensity framework. Second, as

to-treat approach. Third, most patients were treated

Mehran et al.

JACC VOL. 65, NO. 11, 2015

What Is the “Mandatory” Duration?

MARCH 24, 2015:1103–6

with second-generation DES, enhancing generaliz-

both first- and second-generation DES). The uniform

ability to current PCI practice. These strengths

bleeding risk across stent platforms and the higher

notwithstanding, the greatest limitation (readily

thrombotic risk with first-generation DES highlight

acknowledged by the authors) is the low rate of

the variability in risk/benefit assessment as a func-

ischemic adverse events accrued in each of the

tion of stent type.

respective randomized trials. As a result, and despite

Interestingly, an updated study-level direct and

pooling these data, power remained low to detect

adjusted indirect meta-analysis on DAPT duration

modest, albeit clinically meaningful, differences in

has been published (20), with very similar results to

these endpoints.

those of the present study. In the evidence hierarchy

These results must be interpreted within the

of scientific research, the study of Palmerini et al.

context of the recently completed, large DAPT trial

(18) gives us the opportunity to move from study-

(17). In contrast to the present analysis and earlier

level to patient-level data. Individual patient-level

studies, results from this trial demonstrated a sub-

meta-analysis overcomes the limitations of study-

stantial advantage with prolonged (30-month) versus

level meta-analysis, improving internal validity and

standard (12-month) DAPT duration in reducing

allowing for time-to-event, subgroup, and covariate-

thrombotic events. The apparent discrepancies in

adjusted analyses, or even generating risk score

findings from these trials may be attributable to

models. Therefore, the present patient-level analysis

several factors. First, the inclusion of more than

validates the results of previous meta-analyses, con-

9,000 patients in the DAPT trial provided sufficient

firming that short-term DAPT appears safe in terms

power to detect differences in low-frequency events,

of thrombotic events, whereas extended DAPT, even

including ST. Second, the assignment to a shorter- or

for a relatively brief period, is associated with an

longer-duration group has been inconsistent across

increased hazard of bleeding.

trials, rendering comparisons of different DAPT stra-

How, then, might clinicians assimilate the avail-

tegies across studies difficult. Indeed, the long-DAPT

able and somewhat contradictory evidence to date to

group in the present analysis was defined as 1 year;

inform routine decision making? Early after PCI, the

this was the DAPT trial’s control arm. It is plausible

salient question centers on the minimum duration of

that the benefits of continuing DAPT beyond the

DAPT required to prevent largely local (i.e., stent-

initial high-risk period, when the need for potent

related) complications. After this initial period, how-

platelet inhibition is greatest, are realized in a time-

ever, identifying those patients who might benefit

dependent fashion after sufficient exposure to such

most from DAPT extension to prevent increasingly

therapy. Analogously, the benefits of statins are ap-

systemic thrombotic events becomes the key. The

parent several weeks after exposure in high-risk ACS

existing evidence, including the present analysis,

patients, whereas up to 1 year or longer is required for

suggests that 3 to 6 months of DAPT post-PCI may

the benefits to be apparent in more stable patients

suffice for the former. Answering the latter, however,

with ischemic heart disease (19). Third, the benefits

requires a careful appraisal of a patient’s inherent

of extending DAPT may vary by important patient

risk for recurrent thrombosis and bleeding and the

and/or procedural parameters. In the DAPT trial,

relative weight of each event on subsequent mortal-

for example, absolute risk reductions in MACE with

ity. With respect to late ST, risk algorithms identify

prolonged DAPT were 3.5% and 0.5% in patients

various patient- and procedural-level parameters

treated with first- and second-generation stents, res-

that correlate with this complication. Analogous data

pectively, translating into a number needed to treat

to identify patients at greatest risk for late bleeding,

z29 and z200 for each respective stent platform. In

however, remain unclear. This issue is clinically

the current study, however, only z15% of patients

relevant, as late bleeding is strongly associated with

received first-generation stents versus z38% of DAPT

mortality post-PCI and, therefore, should not be

study participants. In contrast to the variable results

considered a nuisance complication of DAPT. Finally,

across studies with respect to thrombotic benefits, a

although both thrombotic and bleeding complications

consistent and reproducible finding has been the

increase risk after PCI, the relative magnitude of

higher risk in bleeding complications with DAPT

each event may vary by time after PCI. In the

prolongation. For example, the relative reduction

recently reported DESERT (Drug-Eluting Stent Event

in bleeding with short DAPT in the present analysis

Registry of Thrombosis) registry, for example, Waks-

was 0.66, comparable to those observed in the

man et al. (21) found that late definite ST was asso-

DAPT trial between groups. Moreover, in the DAPT

ciated with a 2.6% mortality rate at 1 year, which is

trial,

across

much lower than the risk estimates previously re-

stent generations (number needed to harm z111 with

ported for acute and subacute ST. The risk/benefit

the

bleeding

risk

was

uniform

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Mehran et al.

JACC VOL. 65, NO. 11, 2015

What Is the “Mandatory” Duration?

MARCH 24, 2015:1103–6

calculation for DAPT after PCI, therefore, must also

thrombotic events. Beyond this timeframe, the deci-

incorporate time after PCI as a parameter with prog-

sion to continue or discontinue DAPT will be on the

nostic relevance.

basis of evaluating the trade-off between ischemic

At this juncture, after multiple RCTs in more

and bleeding risk according to the patient’s clinical

than 30,000 patients examining different durations

profile. Hopefully, the growing body of evidence on

of DAPT, the optimal duration of DAPT after DES

this subject will refine our ability to accurately esti-

remains unclear. As more evidence accrues, the

mate the patient’s ongoing ischemic and bleeding risk

answer to this complex question will not be a “one-

and will influence clinical decision making in optimal

size-fits-all” approach. We return to our “gut” feeling

DAPT regimen selection.

and the art of medicine to make important decisions regarding this critical issue. In the absence of

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

a definitive answer, we lack a firm “mandatory”

Roxana Mehran, The Zena and Michael A. Wiener

duration of DAPT after new-generation DES. This

Cardiovascular Institute, Icahn School of Medicine at

“mandatory” period should be defined as the min-

Mount Sinai, One Gustave L. Levy Place, Box 1030,

imum time after PCI during which cessation of

New York, New York 10029. E-mail: Roxana.Mehran@

DAPT results in an unacceptably high risk for

mountsinai.org.

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KEY WORDS bleeding, major adverse cardiac event(s), stent thrombosis