JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 8, NO. 6, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-8798/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jcin.2015.04.001

EDITOR’S PAGE

Should All Stent Patients Have Prolonged Dual Antiplatelet Therapy? Ajay J. Kirtane, MD, SM, FACC,* Spencer B. King III, MD, MACC, Editor-in-Chief, JACC: Cardiovascular Interventions

T

he current standard of dual antiplatelet ther-

pooled analyses of randomized trials demonstrating

apy (DAPT) consisting of oral aspirin plus an

no excess in ST compared with BMS comparators out

inhibitor of the P2Y12 receptor following cor-

to 5 years (5), both the U.S. Food and Drug Adminis-

onary stent implantation was established in several

tration as well as society guidelines recommended

landmark studies conducted in the 1990s (1,2). Clin-

extension of DAPT to at least 1 year following DES

ical trials conducted with bare-metal stents (BMS)

implantation in patients at low risk for bleeding (6).

demonstrated that DAPT was highly effective at pre-

This was in part due to observational data demon-

venting early stent thrombosis (ST), which was

strating lower rates of late ST with continuance of

alarmingly common in the early days of coronary

DAPT beyond the durations prescribed in approval

stenting. This DAPT regimen, in conjunction with

studies (7).

higher-pressure stent deployment, was critically

In light of concerns regarding the robustness of

important in supporting the more widespread use of

existing datasets when apprehensions of late ST with

coronary stents as a default therapy for percutaneous

DES reached their height in late 2006, the U.S. Food

coronary intervention, particularly given that ST

and Drug Administration mandated further study of

occurring within the first 30 days following stent

prolonged DAPT as a means of mitigating ST risk. In a

implantation was associated with myocardial infarc-

formidable achievement of trial design and execu-

tion (MI) in w75% of patients, resulting in death in

tion, the DAPT trial began: specifically powered to

w20% of patients (3).

examine the effect of extended duration DAPT

Although implementation of DAPT can, therefore,

(30 months vs. 12 months) upon the occurrence of

be considered “obligatory” to prevent ST immediately

very late ST. Beyond ST prevention, the DAPT

following stent implantation, the ideal duration of

trial also aimed to study whether prolonged DAPT

DAPT has been a moving target. With the introduc-

could possibly also lead to passivation of ischemic

tion of drug-eluting stents (DES) came the recognition

events relating to generalized atherothrombosis in

that ST was not confined to the first 30 days following

stented patients with coronary artery disease. Several

stent implantation. Indeed, even the notion that ST

prior studies in broader patient populations had

following BMS was confined to the early period was a

previously aimed to assess this potential benefit of

fallacy, with observational data demonstrating ST

DAPT, but had produced mixed results; although

events years after the initial implant (4). Despite

some anti-ischemic efficacy could be demonstrated

the fact that early DES devices were approved on

(particularly in higher-risk subgroups), bleeding was

durations of DAPT ranging from 3 to 6 months, with

increased (8). The DAPT trial ultimately demonstrated in 9,961 randomized patients that prolonged DAPT was associated with reductions in late ST, late MI, and also late

From the *Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center at Columbia University Medical Center/New York-

composite ischemic events (death, MI, or stroke), but

Presbyterian Hospital and the Cardiovascular Research Foundation,

with an increase in bleeding events (9). Notably,

New York, New York.

although MI related to ST was reduced by prolonged

874

Kirtane and King

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 8, NO. 6, 2015 MAY 2015:873–5

Editor’s Page

DAPT, more than one-half of the overall reduction

Despite the overall anti-ischemic benefits of pro-

in MI was independent of ST, supporting the notion

longed DAPT, overall mortality in the trial trended

that DAPT has generalized anti-ischemic benefits

higher among patients treated with prolonged DAPT

in stented patients. These findings are very consis-

(2.0% vs. 1.5%, p ¼ 0.052). Perhaps this was due to

tent with those of the recently reported PEGASUS-

play of chance, especially given that the study was

TIMI 54 (Prevention of Cardiovascular Events in Pa-

not powered to detect differences in overall mortal-

tients with Prior Heart Attack Using Ticagrelor

ity. Nonetheless, the finding of a trend toward

Compared to Placebo on a Background of Aspirin–

increased all-cause mortality—driven by an increase

Thrombolysis in Myocardial Infarction 54) trial, which

in noncardiovascular mortality—within the DAPT trial

demonstrated that prolonged DAPT with aspirin and

is directionally consistent with a that of a number of

ticagrelor reduced ischemic events in stabilized pa-

other prolonged DAPT studies in DES-treated patients

tients >1 year after an MI, but with a significant in-

(12). Even when expanded to a broader population

crease in Thrombolysis In Myocardial Infarction

and much larger sample of patients with coronary

major bleeding (10).

artery disease (almost 70,000 patients with 139,000

So, what is the clinician to make of these results? Is

patient-years of follow-up including both stent trials

prolonged DAPT the new gold standard? In our mind—

as well as secondary prevention trials), there is not a

and despite the several positive effects of prolonged

trend toward an overall mortality benefit with pro-

DAPT previously outlined—the simple answer re-

longed duration DAPT, with a summary estimate

mains, “Not for most patients.” Our rationale for this

firmly neutral (13). The absence of a beneficial all-

statement stems from further analyses of the absolute

cause mortality signal (a result that will not change

magnitude of ischemic reduction seen within the

with the inclusion of 21,162 additional patients from

specific patients enrolled in the DAPT trial as well as a

PEGASUS-TIMI 54) should give us pause before

recognition of the importance of bleeding complica-

advocating prolonged DAPT for all. If clinically

tions to patient satisfaction and outcomes.

important ischemic complications are markedly low-

The DAPT trial enrolled a selected group of patients

ered by prolonged DAPT, then why are we not seeing

who were event-free at 12 months (i.e., they had

even a hint of a benefit in terms of mortality with this

already successfully tolerated 12 months of DAPT

approach?

prior to enrollment without events). Moreover, of

Weighing strongly against the ischemic protection

these patients, only 47% of DES-treated patients

provided by prolonged DAPT is a continual exposure

received stents currently utilized in clinical practice

to bleeding risk, which itself is prognostically impor-

(newer-generation DES). It should be noted that the

tant and associated with increased mortality. In the

relative magnitude of the treatment effect of pro-

DAPT trial, moderate-severe bleeding was increased

longed DAPT (relating to both ST reduction and MI

with prolonged DAPT as measured by several vali-

reduction) was consistent, irrespective of stent type.

dated bleeding scales. This increase in bleeding has

However, because the overall incidence of ST is

been a consistent finding in other studies of prolonged

significantly lower with newer-generation stents, the

DAPT (12). Although the clinical events committee in

number of events prevented with prolonged DAPT in

the DAPT trial did not adjudicate a difference in fatal

newer-generation stent patients in the trial was far

bleeding (bleeding directly resulting in a death), in

less (only 10 ST events prevented vs. 35 among other

more detailed analyses of bleeding events, there were

stent types). Stated another way, although prolonged

strong trends toward an increase in both bleeding-

DAPT did reduce the incidence of ST from 0.7% to

related death (11 events vs. 3 events, p ¼ 0.057) and

0.3% even with newer-generation stents, one would

trauma-related death (9 events vs. 2 events, p ¼ 0.07)

have to treat 250 such patients with prolonged DAPT

with prolonged DAPT. Add to this the real perception

to prevent 1 ST event occurring a year after stent im-

by many patients of what clinical trials often dismis-

plantation. This finding is even more relevant given

sively term “nuisance bleeding” (such as frequent

the significantly better prognosis (nearly one-half the

bruises and persistent bleeding from nicks/cuts) (14),

mortality) of having a late ST event compared with an

combined with the potential effect of bleeding upon

early ST event (11). Even the overall reduction in MI

patient behavior (such as medication discontinua-

events within the DAPT trial is modest on an absolute

tion), and the bleeding-related side effects of pro-

scale, with 2 events prevented per 100 patients

longed DAPT are not to be trivialized. Another

treated with prolonged DAPT in the overall study

important facet of the bleeding-ischemia tradeoff

cohort (only 1.1 event prevented per 100 newer-

additionally relates to the perspective of the patient

generation stent patients treated with prolonged

and treating physician: ischemic events may be

DAPT).

perceived as part of the natural history of disease,

Kirtane and King

JACC: CARDIOVASCULAR INTERVENTIONS VOL. 8, NO. 6, 2015 MAY 2015:873–5

Editor’s Page

whereas bleeding events have been caused by pre-

after stent implantation. As such, the bleeding risks

scribed medications. Although some patients may be

of prolonged DAPT combined with the neutral-

willing to accept significant up-front bleeding risks

negative effect of prolonged DAPT on all-cause mor-

to avoid an MI, we need to be very clear and honest

tality should give us pause before widely advocating

about the types of MI prevented by prolonged DAPT

prolonged DAPT to all stent patients. Among certain

when speaking with our patients. For example, when

groups for whom the absolute risk of ischemic events

patients participating in shared decision-making

is greatest (e.g., those with recurrent ischemic events,

are asked about theoretically preventing a future MI,

those with true acute coronary syndromes, or those

are they visualizing the prevention of “massive” heart

with early-generation DES), we ought to strongly

attacks or troponin elevations instead?

consider extension of DAPT. But for the majority of

Ultimately, the decision of whether to prescribe

stent patients—particularly for unselected stable

prolonged duration DAPT hinges upon the overall

patients treated with current generation devices—to

projected risks of ischemia and bleeding within an

broadly

individual patient. Prolonged DAPT clearly reduces

limited overall utility.

recommend

prolonged

DAPT

seems

of

the risks of both late stent- and nonstent-related ischemic events, but the iatrogenic bleeding risk

ADDRESS CORRESPONDENCE TO: Dr. Ajay J. Kirtane,

incurred is real, and ought not to be minimized in our

Center for Interventional Vascular Therapy, Columbia

zeal to prevent cardiovascular events. Moreover, the

University Medical Center/New York-Presbyterian

relative significance of these very late ischemic

Hospital, 161 Fort Washington Avenue, 6th Floor,

events may be appreciably less than when the same

New York, New York 10032. E-mail: akirtane@

events (e.g., ST) occur within the first few months

columbia.edu.

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