Controversies in
Cardiovascular Medicine
Are at Least 12 Months of Dual
Antiplatelet Therapy Needed for All
Patients With Drug-Eluting Stents?
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All Patients With Drug-Eluting Stents Need at Least 12 Months
of Dual Antiplatelet Therapy
Sorin J. Brener, MD
C
oronary artery disease (CAD) remains a principal source
of morbidity and mortality among adults in both the
developed world and the developing world.1 Despite important advances in medical therapy for CAD, revascularization
is frequently necessary. Currently, nearly 2 million percutaneous coronary interventions (PCIs) are performed in the United
States and Europe, and >90% of them entail the deployment of
at least 1 coronary stent.2 The introduction of metallic coronary
stents (bare metal stents [BMS]) 2 decades ago resulted in a
significant reduction in the immediate and long-term complications of PCI, particularly dissections, abrupt vessel closure,
and need for repeat target lesion or target vessel revascularization. Abrupt vessel closure was essentially eliminated by
stents.3 The incidence of target lesion and target vessel revascularization was halved from ≈20% to 25% at 1 year to 10% to
15%. Stents became further refined a decade ago by the addition of eluting antiproliferative agents embedded in durable or
resorbable biopolymers (drug-eluting stents [DES]).4–6 This
innovation further reduced the need for target vessel or target
lesion revascularization to the single-digit range.
because of their inherent delayed endothelialization.7 Intensive
research into the causes and predictors of this phenomenon
resulted in the current recommendations of the various professional societies to treat patients after DES implantation with
6 to 12 months of dual antiplatelet therapy (DAPT) consisting
of aspirin and an ADP (P2Y12) receptor antagonist.
This article reviews the evidence supporting the continuation of DAPT for ≥12 months and direct our attention to 2
important concepts:
1.Is DAPT meant to prevent device-oriented cardiac events
or patient-oriented events? The latter refers to the classic
end points of clinical trials such as any death, any myocardial infarction (MI), stroke, or any revascularization,
whereas the former addresses stent-specific events such
as ST, target vessel MI, or target lesion revascularization,
with some obvious overlap between them.
2.Can prolonged DAPT prevent the formation of new or
the progression of existing atherosclerotic lesions in segments remote from the target lesion?
Moreover, we need to address the dilemma facing the
clinician with respect to whether all patients are treated in a
similar fashion or whether tailoring of therapy is indicated
according to existing comorbidity (diabetes mellitus, chronic
kidney disease, etc), the burden of coronary disease, and the
circumstances leading to PCI (elective setting versus acute
coronary syndrome [ACS]).
Response by Becker and Helmy on p 2009
The persisting weaknesses of coronary stents, the propensity to provoke stent thrombosis (ST) and late neoatherosclerosis, were not modified by the introduction of DES. In fact, a
sentinel report in 2004 indicated that first-generation DES are
prone to late (1–12 months) and very late (>12 months) ST
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From New York Methodist Hospital, Brooklyn, NY.
This article is Part I of a 2-part article. Part II appears on p 2010.
Correspondence to Sorin J. Brener, MD, New York Methodist Hospital, 506 6th St, KP-2, Brooklyn, NY 11215. E-mail [email protected]
(Circulation. 2015;131:2001-2009. DOI: 10.1161/CIRCULATIONAHA.114.013279.)
© 2015 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.114.013279
2001
2002 Circulation June 2, 2015
However, before we explore the data pertinent to this
topic, it may be appropriate to review the current professional
guidelines for DAPT after PCI with stenting.
Recommendations for DAPT
After PCI With DES
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The American professional societies (American College of
Cardiology, American Heart Association, and Society for
Coronary Angiography and Intervention) guidelines for PCI8
recommend DAPT for at least 12 months after PCI for ACS but
allow a shorter duration if ACS is not present (Class I; Level
of Evidence B) or the risk of bleeding is high regardless of
context of PCI (Class IIa; Level of Evidence C). Continuation
of DAPT beyond 12 months may be considered (Class IIb;
Level of Evidence C).
The European Society of Cardiology, in its most recent
guidelines for the management of and revascularization in
patients with stable CAD,2,9 recommends DAPT for 6 months
after PCI (Class I; Level of Evidence B) and allows even
shorter duration if the risk of bleeding is high (Class IIb; Level
of Evidence A) or a longer duration if the bleeding risk is low
and ischemic risk is high (Class IIb; Level of Evidence C).
In contrast, for patients with ACS10 or ST-segment–elevation
MI,11 the European Society of Cardiology recommends 12
months of DAPT, regardless of revascularization status or
stent used (Class I; Level of Evidence A).
In summary, American and European professional societies agree on the recommendation of (at least) 1 year of DAPT
after PCI for ACS but differ on the recommendation for duration of DAPT after elective PCI. Remarkably, the initial trials with DES recommended DAPT for 2 to 3 months with
sirolimus-eluting stents (eg, RAVEL)12 and 6 months with
paclitaxel-eluting stents (eg, TAXUS II).13
Experimental Evidence Supporting
Antiatherosclerotic Effect of DAPT
Just as aspirin alone has been shown to reduce the rate of
clinical events in patients with vascular disease of various
presentations and after different interventions,14 the addition
of platelet P2Y12 ADP receptor antagonists was expected to
contribute to further improvement in outcomes via important
anti-inflammatory and antiatherosclerotic effects, beyond the
inhibition of platelet function.
Azar et al15 randomized 73 patients with stable CAD to
clopidogrel or placebo in addition to background aspirin
therapy. Serum CD40 ligand decreased significantly at 8
weeks (P=0.03) in the clopidogrel group only. Serum CD40
ligand, an important mediator of inflammation, facilitates
the deposition of atheroma in injured vascular endothelium
(Figure 1).16,17 A few experimental studies in animals with
induced atherosclerosis support this concept. Compared with
placebo, clopidogrel reduced plaque size and increased its
stability via a larger fibrous component, which is not prone
to rupture. Clopidogrel also increased the number of atheroprotective regulatory CD4+CD25+ T cells.18 Similar reductions
Figure 1. Role of platelet-derived CD40 ligand in atherosclerosis
and atherothrombosis. Adapted from Libby16 and André et al.17
in neointima formation were observed in rabbits exposed to
an atherosclerotic diet and treated with clopidogrel or placebo.19 Une et al20 reported that DAPT for 1 year after surgical
revascularization reduced the progression of existing lesions
compared with aspirin alone (P=0.01) and decreased the proportion of new occlusions (P=0.02).
The relationship between platelet inhibition and inflammation is complex, particularly because the connection between
higher levels of inflammatory markers and atherosclerotic
events may not be necessarily causative. DAPT inhibits the
immediate inflammatory response after PCI, as shown in a large
cohort of patients undergoing PCI. Clopidogrel pretreatment
decreased the C-reactive protein surge after stenting by 65%
and was an independent predictor of C-reactive protein level
after adjustment for confounders.21 Lowering C-reactive protein
levels may confer a long-term advantage, as evidenced by lower
rates of events in patients with less vascular inflammation.22
Observational Data for Shorter Versus
Longer Duration of DAPT After DES
As is frequently the case, observations from registries hinted
at a possible benefit of prolonged DAPT and spurred the execution of randomized, clinical trials.
Eisenstein et al23 evaluated the outcomes of 4666 patients
stented with BMS (n=3165) or first-generation DES (n=1501)
between 2000 and 2005. Among patients with DES who were
free of events at 6 months, continued DAPT was a significant independent predictor of lower death (2.0% versus 5.3%;
P=0.03) and lower death or MI (3.1% versus 7.2%; P=0.02)
rates at 24 months compared with those on aspirin alone.
In an analysis from the Veterans Administration registry,
among 1445 patients treated with PCI (34% DES) in 2003 to
2004 and followed up for 2 years, those on continued DAPT
had significantly lower mortality than those off DAPT.24
Overall, in patients free of events at 6 months, cessation of
DAPT was associated with a higher adjusted risk of death
after DES (hazard ratio [HR]=3.57; 95% confidence interval
[CI], 1.13–11.3; P=0.01).
Preliminary data from the Convergent Registry of Catholic
and Chonnam University for Acute MI (COREA-AMI)
Brener DAPT After DES 2003
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registry suggested that, after PCI for ST-segment–elevation
MI in 2293 patients free of major adverse cardiac events
or bleeding at 1 year, longer DAPT was associated with a
lower rate of major adverse cardiac events (18.0% for 12–18
months, 10.2% for 18–24 months, and 8.9% for >24 months;
P<0.001).
Brar et al25 identified 749 patients with diabetes mellitus who underwent PCI with DES (n=491) or BMS (n=251)
between 2002 and 2004. Among the 671 patients free of events
after 6 months of DAPT, the incidence of death or MI was
3.2%, 9.4%, and 16.5% among those treated with DAPT for
>9, 6 to 9, and <6 months, respectively (P<0.001). Continued
DAPT was an independent predictor of lower rates of death
or MI for both DES (HR=0.22; 95% CI, 0.08–0.62; P=0.005)
and BMS (HR=0.25; 95% CI, 0.08–0.81; P=0.02).
The Bern-Rotterdam registry of patients treated with DES
analyzed the use of DAPT among patients with very late ST.
Among 69 patients with this event between 1 and 4 years
after PCI, only 20% were on DAPT, whereas 80% were not
Table. Randomized Trials of Longer Versus Shorter Duration
of DAPT After Coronary Stenting
Year
Published
n
Stable Angina/
Silent
Ischemia, %
EXCELLENT
2012
1443
48.4
6 vs 12
1
RESET
2012
2117
45.4
3 vs 12
1
PRODIGY
2012
1970
25.5
6 vs 24
2
OPTIMIZE
2013
3119
68.0
3 vs 12
1
SECURITY
2014
1399
61.6
6 vs 12
1
ISAR SAFE
2014
4005
59.8
6 vs 12
2
ITALIC
2014
1850
61.5
6 vs 24
2
REAL/ZEST
LATE
2010
2701
37.6
12 vs 24
2
DAPT Study
2014
9961
73.9
12 vs 30
2
Trial
DAPT
Protocol
Duration, mo Type*
DAPT indicates Dual Anti Platelet Therapy; EXCELLENT, Efficacy of Xience/
Promus Versus Cypher to Reduce Late Loss in Stent; ISAR SAFE, Safety and
Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting;
ITALIC, Is There a Life for DES After Discontinuation of Clopidogrel; OPTIMIZE,
Optimized Duration of Clopidogrel Therapy Following Treatment With the
Endeavor Zotarolimus-Eluting Stent in the Real World Clinical Practice;
PRODIGY, Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced
Intimal Hyperplasia; REAL, Correlation of Clopidogrel Therapy Discontinuation
in Real-World Patients Treated With Drug-Eluting Stent Implantation; RESET,
Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following
Endeavor Zotarolimus-Eluting Stent Implantation; SECURITY, Second Generation
Drug-Eluting Stents Implantation Followed by Six Versus Twelve-Month Dual
Antiplatelet Therapy; and ZEST LATE, Evaluation of the Long-Term Safety After
Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent
Implantation for Coronary Lesions–Late Coronary Arterial Thrombotic Events.
The first 7 trials compared <12 months of DAPT with at least 12 months of
DAPT. The last 2 trials compared 12 months of DAPT with longer durations (in
order of publication). EDUCATE data were already included in DAPT.
*1 indicates trials with enrollment after percutaneous coronary intervention;
and, 2, trials with enrollment after patients had been free of events for a
prespecified period of DAPT.
(P<0.05).26 This observation is particularly important because
it appears that implantation of a first-generation DES was
associated with a constantly accumulating annual rate of definite ST of 0.4% to 0.6%.
The largest observational report comes from the Swedish
Heart Registry (SWEDEHEART).27 Patients with ACS were
categorized according to duration of DAPT, and only those free
of events at 3 months were included. Among 28 680 patients,
15 009 received DAPT for >3 months, and 6640 were treated
for >6 months. One third of the patients were not revascularized at all. The rate of death, re-MI, or stroke was 65.2 per 1000
person-years for ≤3 months or DAPT, 29.4 per 1000 personyears for 6 months of DAPT, and 20.4 per 1000 person-years
for >6 months (P<0.0001). This reduction in ischemic events
was accompanied, as expected, by a higher rate of bleeding
(adjusted HR=1.45; 95% CI, 1.14–1.86; P=0.003).
The data mentioned above need to be interpreted with
caution. Besides the fact that they do not reflect randomization to longer or shorter DAPT, it is very difficult to tease the
reasons for continued DAPT in registries beyond a certain
period. Common causes are recurrent events during the initial
DAPT period necessitating its continuation or the desire to
suppress atherosclerosis progression. In contrast, reasons for
discontinuation may be financial difficulties, bleeding, or lack
of evidence that more prolonged therapy affects outcomes
favorably.
Randomized Comparison of Shorter Versus
Longer Duration of DAPT After DES
Nine randomized, clinical trials evaluated at least 12 months
versus a shorter duration of DAPT in patients undergoing
PCI with DES. The majority compared exactly 12 months of
DAPT with a shorter duration of therapy (Table and Figure 2).
The Efficacy of Xience/Promus Versus Cypher to Reduce
Late Loss in Stent (EXCELLENT) trial randomized patients
to 1 of the 2 stents (3:1) and to short- or long-duration DAPT
(1:1). For the DAPT analysis, the primary end point of target
vessel failure at 1 year (a composite of cardiac death, MI, or
ischemia-driven target vessel revascularization) occurred in
4.8% and 4.3%, respectively (P=0.60). It is notable that ST
occurred in 0.9% and 0.1%, respectively (P=0.10). In the prespecified high-risk group of diabetic patients, target vessel
failure was significantly more common in the short-duration
DAPT group (HR=3.16; P=0.005).28
The Real Safety and Efficacy of 3-Month Dual Antiplatelet
Therapy Following Endeavor Zotarolimus-Eluting Stent
Implantation (RESET) trial tested very short-duration DAPT
duration versus the conventional 12 months of DAPT after
PCI with DES.29 There was no significant difference in the
composite end point of cardiovascular death, MI, ST (definite
or probable),30 ischemia-driven target vessel revascularization,
or bleeding (Thrombolysis in Myocardial Infarction major or
minor)31 at 1 year between the short- and long-duration DAPT
regimens (4.7% versus 4.7%; P=0.84). There was no ST in the
short-duration DAPT group after 3 months.
2004 Circulation June 2, 2015
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Figure 2. Representative clinical end points (see text for details) in 9 trials comparing shorter with longer duration of dual antiplatelet
therapy. DAPT indicates Dual Anti Platelet Therapy Study; EXCELLENT, Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss
in Stent; ISAR SAFE, Safety and Efficacy of Six Months Dual Antiplatelet Therapy After Drug-Eluting Stenting; ITALIC, Is There a Life for
DES After Discontinuation of Clopidogrel; OPTIMIZE, Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor
Zotarolimus-Eluting Stent in the Real World Clinical Practice; PRODIGY, Prolonging Dual Antiplatelet Treatment After Grading StentInduced Intimal Hyperplasia; REAL, Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated With Drug-Eluting
Stent Implantation and Late Coronary Arterial Thrombotic Events; RESET, Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy
Following Endeavor Zotarolimus-Eluting Stent Implantation; SECURITY, Second Generation Drug-Eluting Stents Implantation Followed
by Six Versus Twelve-Month Dual Antiplatelet Therapy; and ZEST, Evaluation of the Long-Term Safety After Zotarolimus-Eluting Stent,
Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions–Late Coronary Arterial Thrombotic Events.
The Prolonging Dual Antiplatelet Treatment After Grading
Stent-Induced Intimal Hyperplasia Study (PRODIGY) compared 6 months of DAPT with 24 months of DAPT in patients
receiving BMS or DES (first and second generations) who
were free of adverse cardiac events at 30 days after the procedure.32 There was no difference in the primary end point
of cardiovascular death, MI, or stroke at 2 years (10.0% versus 10.1%, respectively; P=0.91). There was more bleeding
(Bleeding Academic Research Consortium types II, III, and
V)33 in the prolonged DAPT group (7.4% versus 3.5%, respectively; P=0.0002). In a separate landmark analysis from this
trial, patients assigned to first-generation DES (paclitaxel-eluting stents) had significantly higher rates of definite or probable
ST when receiving only 6 months of DAPT.34 The inhibition of
neointimal formation did not differ between the DAPT duration groups. In a subsequent analysis, patients undergoing
treatment for in-stent restenosis (n=224) benefited from longer
DAPT. The primary end point occurred in 16.7% of the shortduration DAPT group and 7.3% of the long-duration DAPT
group (P=0.034), related predominantly to a higher rate of
death or MI (15.5% versus 6.5%, respectively; P=0.03).35
The Optimized Duration of Clopidogrel Therapy
Following Treatment With the Endeavor Zotarolimus-Eluting
Stent in the Real World Clinical Practice (OPTIMIZE) tested
the safety of short-duration DAPT versus conventional DAPT
after PCI with the zotarolimus-eluting Endeavor stent in
patients with stable CAD or low-risk ACS.36 There was no difference in the primary end point of death, MI, stroke, or major
bleeding between the 2 groups at 1 year (6.0% versus 5.8%,
respectively; P=0.84). ST occurred in 0.6% versus 0.7% in the
first 3 months when both groups were on DAPT and in 0.3%
versus 0.1%, respectively, thereafter. Cardiovascular death or
MI occurred in 4.5% versus 4.0%, respectively (P=0.49).
The Second Generation Drug-Eluting Stents Implantation
Followed by Six Versus Twelve-Month Dual Antiplatelet
Therapy (SECURITY) trial randomized patients stented with
second-generation DES to short- or long-duration DAPT.37
At 1 year, a third of the patients in the 6-month DAPT group
were still on DAPT. The primary end point of cardiac death,
MI, stroke, definite or probable ST, and Bleeding Academic
Research Consortium bleeding types III or V at 12 months
occurred in 4.5% versus 3.7%, respectively (P=0.47), confirming noninferiority of the 2 regimens (P<0.05). Prolonged
DAPT beyond 6 months was not an independent predictor
of the primary end point at 12 months (HR=1.27; 95% CI,
0.75–2.15; P=0.37).
The Safety and Efficacy of Six Months Dual Antiplatelet
Therapy After Drug-Eluting Stenting (ISAR-SAFE), presented at the 2014 American Heart Association Annual
Scientific Meeting, also tested short- versus long-duration
DAPT in patients who were free of events at 6 months after
PCI.38 The trial was discontinued prematurely as a result of
low enrollment and lower-than-expected event rates. The
composite end point of death, MI, stroke, or ST was not different between the 2 groups at 9 months after randomization
(1.3% versus 1.5%; P=0.59).
The Is There a Life for DES After Discontinuation of
Clopidogrel (ITALIC) study compared short- and long-duration DAPT in patients not resistant to aspirin receiving the
everolimus-eluting second-generation DES and reported the
Brener DAPT After DES 2005
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on-therapy results at 1 year after randomization.39 The trial
was discontinued prematurely because of low enrollment and
lower-than-expected event rates. The primary end point (cardiovascular death, MI, stroke, emergency revascularization, or
Thrombolysis in Myocardial Infarction major bleeding) was
not different between the groups (1.5% versus 1.6%, respectively; P=0.85).
A combination of 2 randomized, clinical trials, the
Correlation of Clopidogrel Therapy Discontinuation in
Real-World Patients Treated With Drug-Eluting Stent
Implantation and Late Coronary Arterial Thrombotic Events
(REAL-LATE) and the Evaluation of the Long-Term Safety
After Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or
Paclitaxel-Eluting Stent Implantation for Coronary Lesions–
Late Coronary Arterial Thrombotic Events (ZEST-LATE),
which had similar study designs, evaluated patients free of
major adverse cardiac events after 12 months of DAPT after
DES implantation who were assigned to monotherapy or
to DAPT for another 12 months.40 The 2 trials could not be
completed because of low enrollment and were not reported
separately. There were no significant differences in the rates of
cardiac death or MI (1.2% versus 1.8%, respectively; P=0.17)
or of ST (0.4% in both groups; P=0.76) between the groups.
The incidence of death, MI, or stroke, however, was higher in
the extended DAPT group compared with the aspirin alone
group (3.2% versus 1.8%; P=0.05). Bleeding rates were very
low and comparable in the 2 groups.
The DAPT Study comparing 12 and 30 months of DAPT
(65% clopidogrel, 35% prasugrel) in nearly 10 000 patients
without clinical events 1 year after PCI showed a significant
reduction in the composite of death, MI, or stroke among the
longer-duration DAPT group (4.3% versus 5.9%; HR=0.71;
95% CI, 0.59–0.85; P<0.001), driven predominantly by
a reduction in MI. There also was a robust reduction in the
incidence of definite or probable ST (0.4% versus 1.4%,
respectively; P<0.001) and, importantly, a reduction in non–
stent-related MI (1.8% versus 2.9%, respectively; P<0.001;
Figure 3).41 In contrast the incidence of moderate or severe
bleeding (Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries
[GUSTO] scale) was higher in the extended DAPT group
(2.5% versus 1.6%; P=0.001), negating much of the reduction
in ischemic events. It is notable that overall death rates were
higher in the prolonged DAPT group at 33 months (2.3% versus 1.8%; HR=1.36; 95% CI, 1.02–1.82; P=0.04). This excess
was exclusively the result of a higher rate of noncardiovascular death (1.0% versus 0.5%; P=0.002), presumably related
to a higher rate of pre-existing cancer in the prolonged DAPT
group. Nevertheless, more noncardiovascular death related
to bleeding occurred in the extended DAPT group. The US
Federal Drug Administration is currently reviewing the individual patient data for more details. The benefit of extended
DAPT was more pronounced in men and in nondiabetics.
It is important to realize that the designs of these 9 trials differ significantly in the fact that some included patients
only after having been free of events at the end of a period of
DAPT (PRODIGY, REAL, ISAR SAFE, ITALIC, and DAPT),
whereas others (EXCELENT, OPTIMIZE, RESET, and
SECURITY) randomized patients immediately after PCI, thus
having potentially a higher rate of events. Most of them (DAPT
is the notable exception) were designed as noninferiority trials,
thus not excluding the possibility that a small benefit may exist
for longer DAPT, particularly for very rare events such as ST.
The follow-up period was also quite short in the trials with
a noninferiority design, precluding the opportunity to observe
reduction in events not related to stents, essentially secondary
prevention of CAD progression. EXCELLENT, REAL, and
DAPT did not include bleeding in their primary end point.
The most innovative approach is tested currently in the
GLOBAL LEADERS: A Clinical Study Comparing Two
Figure 3. Incidence of non–stent-related myocardial infarction (MI) in the Dual Antiplatelet Therapy trial. HR indicates hazard ratio.
Adapted from Mauri et al41 with permission from the publisher. Copyright © 2014 Massachusetts Medical Society. Authorization for this
adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation
or adaptation.
2006 Circulation June 2, 2015
Forms of Anti-platelet Therapy After Stent Implantation
(http://www.clinicaltrials.gov; NCT01813435), in which
≈20 000 patients were randomized to 12-month DAPT after
PCI for ACS or to 1 month of aspirin and ticagrelor followed
by 23 months of ticagrelor monotherapy. Results are expected
by 2016.
Separating Device-Oriented Events
From Patient-Oriented Events
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Many of the guideline recommendations mentioned above
either were based on consensus of opinion among experts or
were shaped by the design of the existing randomized, clinical
trials. For example, patients with ACS were treated for 9 to 15
months in 3 large trials of DAPT in ACS because these studies were event driven and it took this long to accumulate the
number of events projected for sufficient statistical power.42–44
Shorter durations of therapy were not considered, and longer
durations were not evaluated. It is evident from the rate of
accumulation of events in these 3 trials that at least one quarter
of all events occurred beyond the first 6 months, supporting
the recommendations for prolonged DAPT in patients with
ACS. Indeed, the only published randomized, clinical trials
to date evaluating the benefit of prolonged DAPT (albeit compared with monotherapy, not compared with shorter DAPT
duration) in patients with vascular disease also lend credence
to this concept.45 The Clopidogrel for High Atherothrombotic
Risk and Ischemic Stabilization, Management and Avoidance
(CHARISMA) study enrolled 15 603 patients either with
documented vascular disease (prior MI, prior stroke, multivessel revascularization, or symptomatic peripheral arterial
disease) or at high risk for developing it. The entire cohort
had a reduction with DAPT in the key secondary end point
of cardiovascular death, MI, stroke, or rehospitalization for
ACS, revascularization, or transient ischemic attack from
17.9% to 16.7% (P=0.04). Among the ≈80% of the patients
enrolled for secondary prevention, DAPT for 30 months
significantly reduced the rate of recurrent events compared
with aspirin monotherapy (6.9% versus 7.9%, respectively;
P=0.046; Figure 4). These results are somewhat echoed by the
Clopidogrel for the Reduction of Events During Observation
(CREDO) trial in which DAPT for 1 year was better at preventing death, MI, or stroke than aspirin alone after BMS
(8.5% versus 11.7%, respectively; P=0.02).46
Importantly, accruing evidence appears to suggest that
second-generation DES, particularly the cobalt-chromium
everolimus-eluting stent, have nearly eliminated the continuing risk of very late ST observed with first-generation DES.
In a network meta-analysis of 49 trials and 50 844 patients
comparing various types of stents, the everolimus-eluting
stent was associated with lower rates of definite ST compared
with BMS (odds ratio, 0.35; 95% CI, 0.17–0.69; P<0.05) or
paclitaxel-eluting stents (odds ratio, 0.34; 95% CI, 0.19–0.62;
P<0.05) at 2 years.47,48 These data may imply that, because the
rate of very late ST is reduced by the newer stents, the need
for prolonged DAPT may also be lower, at least with respect
Figure 4. Incidence of death, myocardial infarction, or stroke
in patients treated with dual vs single antiplatelet therapy. ASA
indicates acetylsalicylic acid; CAD, coronary artery disease; CVD,
cerebrovascular disease; PAD, peripheral arterial disease; and
RRR, relative risk reduction. Adapted from Bhatt et al.45 Copyright
© 2006 Massachusetts Medical Society. Authorization for this
adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the
translation or adaptation.
to stent-oriented clinical events. Nevertheless, a prespecified
analysis by stent type in the DAPT trial indicates that the benefit of longer DAPT is independent of stent type (first- versus
second-generation DES; PINT=0.76).
Summary and Personal Interpretation
The current professional guideline recommendations for
DAPT after PCI with DES are based on important data accrued
from randomized, clinical trials that were not specifically
designed to address the question of its duration. Observational
data sets and experimental models indicate that longer and
more effective DAPT may reduce ischemic events in patients
treated with DES, particularly when high-risk characteristics
such as large burden of atherosclerosis, recent ACS, diabetes
mellitus, or restenosis are present. Almost invariably, longer
exposure to DAPT leads to more bleeding, and the precise
risk-to-benefit ratio for each patient can hardly be codified in
an all-encompassing recommendation.
From my perspective, prolonged DAPT has a role in
reducing patient-oriented adverse events (secondary prevention) and very late ST and its consequences after stent
implantation, particularly in patients at high risk for recurrent
ischemic events. I recommend it for as long as it is well tolerated and does not interfere with the application of other medical therapies.
Disclosures
Dr Brener serves as a consultant and speaker for AstraZeneca LTD.
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Response to Brener
Richard C. Becker, MD; Tarek Helmy, MD
Dr Brener presents a thoughtful perspective that at least 12 months of dual antiplatelet therapy is needed for all patients with
drug-eluting stents. This overall premise considers: 1) the device, second generation drug-eluting stents with more favorable
stent design, local drug concentration, transport kinetics, tissue binding properties in the vessel wall, and less flow separation,
and 2) the patient, acknowledging that a 6-month treatment duration may be acceptable in (a) the absence of acute coronary
syndrome as the indication for drug-eluting stents implantation and (b) high bleeding risk. The ability of dual antiplatelet
therapy to impact the natural history of coronary arterial atherosclerosis is less compelling; yet, if the primary foundation for the hypothesis is based on platelet, vascular smooth muscle, and leukocyte and macrophage P2Y12 receptors, then
monotherapy with a potent P2Y12 receptor antagonist, as supported in the Clopidogrel for the Reduction of Events During
Observation (CREDO)-Kyoto Registry should become the next frontier of investigation. If the goal is to reduce the burden
of atherosclerosis and its phenotypic expressions of disease, including myocardial infarction, ischemic stroke and cardiovascular death, then optimal medical therapy in patients with known coronary artery disease must surpass the 40% mark
recently documented in the SYNTAX study. In the end, less may be more, and more may be gained by following the current
guidelines masterfully crafted by the American College of Cardiology, American Heart Association, and European Society
of Cardiology than by prescribing dual antiplatelet therapy indefinitely among patients undergoing stent implantation.
Are at Least 12 Months of Dual Antiplatelet Therapy Needed for All Patients With
Drug-Eluting Stents? : All Patients With Drug-Eluting Stents Need at Least 12 Months of
Dual Antiplatelet Therapy
Sorin J. Brener
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Circulation. 2015;131:2001-2009
doi: 10.1161/CIRCULATIONAHA.114.013279
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