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Stent Thrombosis Chapter | 15 223
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Chapter 16
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Stent Thrombosis: Implic ations for New
Stent Designs and Dual Antiplatelet
Therapy Durat ion
Satya S. Shreenivas, Ian J. Sarembock and Dean J. Kereiakes
The Christ Hospital, Cincinnati, OH, United States
INTRODUCTION
Stent thrombosis (ST) is a medical emergency that may be associated with death, myocardial infarction (MI), or the
requirement for urgent repeat revascularization [1e4]. The clinical consequences of ST are dependent upon the volume and
viability of the myocardium at risk, the degree of collateral vessel recruitment, the time course of occurrence (early vs. late
vs. very late following stent deployment), and the timeliness of emergency reperfusion therapy. Through the evolution,
from bare metal stents (BMSs) to first-generation (1GDESs) and subsequently second-generation drug-eluting stents
(2GDESs), there has been a progressive reduction in the incidence of definite ST (Fig. 16.1) [5,6]. Although the advent of
thin-strut bio-resorbable polymer metallic stent platforms (BP-DES) may further reduce stent-related thrombotic events
[7,8], the recently approved Absorb bio-resorbable vascular scaffold (BVS), which has increased strut dimensions, appears
to be associated with a numerically increased risk of device thrombosis [9]. In the context of progressive stent design
iteration as well as continued debate regarding the optimal duration and intensity of platelet inhibition following coronary
stent deployment, it is appropriate at this time to review and summarize new data that are pertinent to these issues.
The development of standardized definitions for both the time course and the probabilistic likelihood of thrombosis
following stent deployment by the Academic Research Consortium (ARC) has facilitated comparative analyses across
clinical studies and other data sets (Table 16.1) [10]. Although the ARC definitions add uniformity, they are still an
imperfect balance of sensitivity and specificity. “Definite” ST is highly specific, but probably underestimates the true
frequency of ST, whereas “possible” ST is more sensitive, but lacks diagnostic certainty. Most contemporary analyses
combine the categories of “definite” and “probable” to provide a balance of specificity and sensitivity. The time course for
ST occurrence is categorized as “early” (either acute or subacute), if within 30 days of stent deployment, and either “late”
(>30 days to 1 year) or “very late” (>1 year).
Multiple risk factors that contribute to the development of ST have been identified (Fig. 16.2), and may vary in
importance as a function of time course following stent deployment [11,12]. Early events may be related to residual targetlesion thrombus or percentage of residual stenosis, intimal dissection, stent undersizing and/or underexpansion, as well as
dual antiplatelet therapy (DAPT) noncompliance or a combination of these factors [2,12e15]. Other factors incriminated in
the etiology of early and late (but not very late) ST include longer target-lesion and/or stent length, multiple stents, smaller
target-vessel diameter, depressed left-ventricular function, and the acuity of the clinical syndrome at presentation [12,15].
Importantly, the antiproliferative properties of DESs, which are responsible for reducing restenosis (compared with BMSs),
have also been incriminated in the occurrence of late and/or very late ST following DES, particularly in the absence of
prolonged (>1 year) DAPT. Although studies of both animal models and humans have demonstrated variable degrees of
delayed endothelial coverage and incomplete stent healing with consequent stent strut exposure following implantation of a
1GDES versus a BMS [16e18], more recent studies using serial optical coherence tomography (OCT) imaging over time
Cardiovascular Thrombus. https://doi.org/10.1016/B978-0-12-812615-8.00016-8
Copyright © 2018 Elsevier Inc. All rights reserved.
225
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BMS vs. 1
Definite Stent Thrombosis
st
GEN DES vs. 2
BMS
1G-DES
2G-DES
3.0
2.5
2.0
1.5
1.0
Stentthrombosis (%)
0.5
0.0
0123
nd
GEN DES:
Munich**SCAAR*
2G-DES
YEARSMONTHS
*94,384 Consecutive PCI 2006-2010
FIGURE 16.1 Decreasing incidence of definite stent thrombosis by stent type (BMS vs. 1GDES vs. 2GDES). 1GDES, first-generation drug-eluting
stent; 2GDES, second-generation drug-eluting stent; Adj HR, adjusted hazard ratio; BMS, bare metal stent; PCI, percutaneous coronary intervention;
SCAAR, Swedish Coronary Angiography and Angioplasty Registry; Munich, Munich Germany. Adopted from Sarno G, Lagerqvist B, Fröbert O, Nilsson
J, Olivecrona G, Omerovic E, Saleh N, Venetzanos D, James S. Lower risk of stent thrombosis and restenosis with unrestricted use of “new-generation
drug-eluting stents: a report from the Nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Eur Heart J 2012;33:606e13 and
Tada T, Byrne RA, Simunovic I, King LA, Cassese S, Joner M, Fusaro M, Schneider S, Schulz S, Ibrahim T, Ott I, Massberg S, Laugwitz KL, Kastrati A.
Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry
of 18,334 patients. JACC Cardiovasc Interv 2013;6:1267e74.
TABLE 16.1 Academic Research Consortium Definitions of Stent Thrombosis (ST) to Standardize ST and Ensure
Unified Assessment Across Trials
Term Definition
Definite ST The highest level of certainty
Probable ST Any unexpected death within 30 days of stent implantation, or any myocardial
Possible ST Any unexplained death beyond 30 days until the end of follow-up
Early ST Acute: 0e24 h
Late ST >30 dayse1 year
Very late ST (includes ST occurring
after target-segment revascularization)
Either angiographic or postmortem evidence of thrombotic stent occlusion
infarction in the territory of the implanted stent irrespective of time
Subacute: >24 he30 days
>1 year
**18,334 Patients; 28,739 Lesions
Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 227
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Stent–Related factors
• Material
• Designs (open vs. closed cell)
• DES vs. BMS
• Delayed / incomplete stent healing
• Surface coating-polymer hypersensitivity / stent type
• Neoatherosclerosis
• Adjunctive therapeutic agents (type and dose of durg
eluted)
• Vascular brachytherapy
• Late scaffold discontinuity– intraluminal scaffold
dismantling
• Early discontinuity due to scaffold fracture
Procedure-Related Factors
• Morphometric abnormalities
(underexpansion, undersizing)
• Morphologic abnormalities
(dissection, ISA, thrombus, plaque prolapse)
• Stent overlap / stent length / bifurcation stenting
• Periprocedural antithrombotic therapy
Patient / Lesion-Related Factors
• Vessel size, lesion length
• Acuity of clinical syndrome
• Plaque characteristics, necrotic lipid core
• Intrinsic platelet/coagulation activity
• Left ventricle ejection fraction/CHF
• Diabetes mellitus
• Chronic renal insufficiency
• Clopidogrel resistance/ early discontinuation/
noncompliance
FIGURE 16.2 Factors associated with the occurrence of stent thrombosis. BMS, bare metal stent; CHF, congestive heart failure; DES, drug-eluting stent;
ISA, incomplete stent strut apposition. Reproduced with permission of MedReviews, LLC. Kereiakes DJ. Safety of drug-eluting stents. Rev Cardiovasc
Med 2010;11:186e200.
following deployment of a 2GDES or BP-DES have demonstrated greater than 90% stent strut coverage within 3e
4 months. Serial angioscopic and OCT evaluations as well as autopsy studies have demonstrated a relationship between
uncovered DES struts and ST, although endoluminal mural thrombus may be present despite neointimal coverage, due to
inflammation related to the drug-delivery polymer [19e21]. Nonerodible polymers may precipitate mural thrombus formation by inciting localized inflammation/hypersensitivity reactions and apoptosis of vascular smooth muscle cells
[17,18,22]. Polymer-related inflammation may also contribute to vessel remodeling and the development of late-acquired
incomplete stent apposition (ISA). Late ISA observed by intravascular ultrasound (IVUS) may also be due to gradual
dissolution of the thrombus or positive vessel remodeling [14,23].
In contrast, very late ST may be a consequence of neoatherosclerosisdthe development of yellow plaque and plaque
rupturedwithin a previously deployed stent [24e27]. Interestingly, neoatherosclerosis appears to occur more frequently
and with an accelerated time course following DES compared with BMS. Clinical evidence supports a relationship
between the degree of underlying vascular inflammation as reflected in the acuity of the presenting clinical syndrome and
the subsequent propensity for risk of ST [28,29]. Patients who present with an acute coronary syndrome (ACS) and have
coronary stent deployment have increased risk for ST regardless of stent type (DES or BMS). However, risk may be
particularly evident following DES, as struts embedded in the necrotic lipid core of unstable plaque demonstrate
incomplete healing and often lack neointimal coverage compared with struts of the same DES embedded in adjacent
fibrocalcific plaque [27]. Conversely, the concept that the degree of neointimal thickness as reflected by in-stent late lumen
loss may be protective against ST has been questioned by data from randomized clinical trials and meta-analyses, which
demonstrate little or no relationship between angiographic late lumen loss and ST [22]. Indeed, some DES types with the
lowest late lumen loss were also associated with the lowest incidence of ST [30]. These observations suggest that the
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physical presence and degree of neointimal thickness may not confer functional integrity and that chronic endothelial
dysfunction and/or residual inflammatory changes may contribute to very late ST.
Finally, ST may be precipitated by BVS scaffold discontinuity occurring early (scaffold fracture during deployment) or
late (intraluminal scaffold dismantling) by scaffold components that remain uncovered and, thus, prolapse into the vessel
lumen during the process of resorption [31e33]. These pathophysiologic mechanisms of ST (early and very late scaffold
discontinuity) are specific to BVSs and whether they can be mitigated by fastidious adherence to deployment technique
and/or prolonged DAPT is a subject of debate and planned further investigation.
BARE METAL STENTS VERSUS DRUG-ELUTING STENTS
DESs (vs. BMSs) provide considerable benefit for reduction in target-lesion and/or vessel revascularization, particularly
when stents are placed for “off-label” indications [34e38]. Although randomized, controlled clinical trials (RCCTs)
demonstrate similar rates of death and MI for both stent types, observational (real-world) registry experiences demonstrate
an apparent reduction in mortality favoring DES [39]. The mortality reduction in these nonrandomized studies may reflect
the effects of confounding due to covariate imbalance (both measured and unmeasured) despite attempts at adjustment
[36e38]. Both RCCTs and meta-analyses of RCCTs have demonstrated lower rates of ST for 2GDES than for BMS
following either primary (ST-segment elevation MI [STEMI]) or elective percutaneous coronary intervention (PCI)
[4,34,35,39,40] (Fig. 16.1). The incidence of ST is increased following PCI for “off-label” indications or in patients with
diabetes mellitus regardless of stent type. Beyond 1-year follow-up, the risk for very late ST remains lower for 2GDES
compared with BMS [35,40]. In addition, BP-DES with ultrathi n struts and more rapid polymer resorption (3e4 months)
designed to expedite stent coverage/healing may further reduce rates of ST compared with permanent polymer secondgeneration everolimus-eluting stents (EESs) [7]. Stent design iterations possibly contributing to the progressive decline
in ST rates observed following metallic stent deployment are listed in Table 16.2.
In contrast, BVSs appear to have an increased hazard for very late (beyond 1 year) scaffold thrombosis compared with
second-generation EES [9] (Fig. 16.3).
DRUG-ELUTING STENTS VERSUS DRUG-ELUTING STENTS
Rates of ST differ among DES platforms. In a network meta-analysis, ST was more frequent following 1GDES (TAXUS
paclitaxel-eluting stent [PES] vs. CYPHER sirolimus-eluting stent [SES]) compared with 2GDES as well as both earlyand later-generation BP- DES [8,34,35]. In the SPIRIT IV and the COMPARE (comparison of the everolimus-eluting
XIENCE V [Abbott Vascular, Santa Clara, CA, USA] stent with the paclitaxel-eluting TAXUS Liberté [Boston Scientific Corp., Natick, MA, USA] stent in all-comers) trials, the XIENCE V EES was compared in a randomized fashion with
TABLE 16.2 Stent Design Iterations That Impact the Incidence of Stent Thrombosis
and Major Adverse Cardiovascular Events
I. Strut thickness (thinner)
l >Rapid/complete stent coverage/healing
l <Inflammation
l <Thrombogenicity (zones of low shear stress)
II. Polymer
l Composition (thromboresistantdXience/Promus PVDF)
l BP versus DP
l Distribution (abluminal only vs. conformal)
l Time course for BP resorption (<3e4 vs. 9e18 months vs. permanent)
III. Platform flexibility/conformability
l Geometric distortion
l Fracture resistance (thrombosis/restenosis)
BP, bio-resorbable polymer; DP, durableepermanent polymer; PVDF, polyvinylidene difluoride. >, more; <,
less. Thinner struts, BP with abluminal-only distribution, and shorter time course for resorption, as well as a
more flexible platform, are all associated with lesser propensity for adverse events.
Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 229
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Thrombosis Following BVS or Xience
Study ST Through 2- Year Follow-up
RCT
ABSORB II
ABSORB Japan
EVERBIO II
Subtotal (I-squared=0.0%,p=0.830)
Registry
ABSORB-EXTEND (comparison)
Prague 19
BVS-EXAMINATION
Subtotal (I-squared=43.8%,p=0.169)
Overall (I-squared=0.0%,p=0.531)
Note:Weights are from rand effects analysis
.1
.5 1 5 10 .1 .5 1 5 10
Favors BVS
Favors EES Favors BVS Favors EES
(95% Cl) Stufy VLST Between 1- and 2- YearOR(95% Cl)
5.54 (0.30, 100.82)
2.05 (0.43, 9.77)
3.12 (0.13, 77.66)
2.64 (0.74, 9.36)
0.41 (0.05, 3.68)
(0.68, 263.70)
2.04 (0.76, 5.52)
1.85 (0.42, 8.02)
2.08 (1.02, 4.26)
RCT
ABSORB II
ABSORB Japan
EVERBIO II
Subtotal (I-squared=0.0%,p=0.775)
Registry
ABSORB-EXTEND
(comparison)
13.42
BVS-EXAMINATION
Prague 19
Subtotal (I-squared=26.4%,p=0.244)
Overall (I-squared=0.0%,p=0.621)
Note:Weights are from rand effects analysis
2.50 (0.12, 52.29)
3.43 (0.42, 28.31)
0.33 (0.02, 6.84)
2.53 (0.49, 13.13)
1.37 (0.22, 8.68)
2.03 (0.62, 6.71)
4.61
(0.25, 86.29)
(Excluded)
(Excluded)
FIGURE 16.3 The Absorb bio-resorbable vascular scaffold (BVS) appears to have increased risk for thrombosis, including very late scaffold throm-
bosis, compared with second-generation EES. CI, confidence interval; EES, everolimus-eluting stent; OR, odds ratio; RCT, randomized control trial; ST,
stent thrombosis; VLST: very late stent thrombosis. Adapted from Toyota T, Morimoto T, Shiomi H, Yoshikawa Y, Yaku H, Yamashita Y, Kimura T. Very
late scaffold thrombosis of bioresorbable vascular scaffold. J Am Coll Cardiol Interv 2017;10:27e37.
OR
either the TAXUS Express (Boston Scientific Corp.) or the TAXUS Liberté PES, respectively [30,41]. In each of these
large-scale randomized trials, EES was associated with a significantly lower incidence of ST up to 3-year follow-up
compared with TAXUS PES. All components of ST (early, late, very late) using the ARC definitions were proportionally reduced by EES (vs. PES) [42]. Furthermore, the relative benefit of the XIENCE/PROMUS EES (vs. TAXUS PES) for
reduction in ST is supported by a pooled, patient-level analysis of the SPIRIT II, III, and IV and COMPARE RCCTs.
Multivariable regression analysis of the pooled 6789-patient cohort (EES, n ¼ 4247; PES, n ¼ 2542) demonstrates that
randomly assigned stent type (EES) is an independent predictor of freedom from ST (vs. PES) [43].
Finally, the TAXUS PES was identified as an independent predictor of ischemic events among four different DES types
evaluated in the DAPT trial [44], and the CYPHER SES demonstrated increased risk of very late ST in the LEADERS trial
(vs. the early-generation biomatrix BP-DES) [45]. In this context, 1GDESs are no longer clinically available.
More recent RCCTs and meta-analyses of RCCTs demonstrate lower and similar rates of ST following 2GDES
(XIENCE/PROMUS EES or Resolute Integrity zotarolimus-eluting stent [ZES]) and recent-generation BP-DES
(SYNERGY EES; Orsiro SES) [8,46]. Indeed a recent, large- sca le RCCT de mo nstra te d low and sim ila r rates of
definite/probable ST (ARC definition) to 1-year follow-up (SYNERGY 0.4%, ORSIRO 0.4%, RESOLUTE 0.5%)
[46]. Finally, rates of very late ST (beyond 1 year) are extremely low (<0.2%/year) with these new coronary stent
platforms [47].
Aggregate data from multiple sources suggest that BMSs have a continued low risk for very late ST of approximately
0.15%e0.2% per year [3,29], comparable to rates observed following 2GDES or BP-DES. The increased relative risk of
ST associated with BMS (vs. 2GDES) appears largely confined to the first year following deployment. The relative
thromboresistant effects of the XIENCE/PROMUS EES fluorocopolymer (polyvinylidene difluoride [PVDF]) were also
evident in the Evaluation of Xience-V Stent EXAMINATION trial (EES vs. BMS in STEMI), which compared EES with
the corresponding BMS platform (MULTILINK-VISION) during primary PCI for STEMI. Freedom from definite (99.5%
vs. 98.1%; P ¼ .01) and definite/probable ST (99.1% vs. 97.4%; P ¼ .01) was enhanced following XIENCE/PROMUS
EES (vs. BMS) [48]. Differences in ST persisted through 5-year follow-up, although comparison between stent types was
underpowered [49].
230 Cardiovascular Thrombus
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BIO-RESORBABLE VASCULAR SCAFFOLD THROMBOSIS
The rates of device thrombosis were numerically increased following the Absorb BVS compared with the Xience EES in
the pivotal RCCT for US FDA approval, as well as in a pooled, patient-level meta-analysis of four RCCTs involving 3389
total patients, and in a trial-level meta-analysis including two additional studies (EVERBIO and TROFI-II) for a total of six
RCCTs that compared the Absorb BVS to the Xience EES [50,51].
Throughout multiple analyses, the relative risk of thrombosis following Absorb BVS (vs. Xience EES) approximates
2.0 and appears to persist beyond 1-year follow-up [9,52e54] (Fig. 16.3). The pathogenic mechanisms responsible for
increased thrombosis risk are multifactorial and include increased strut volume (both thickness and width), scaffold
malapposition, early (due to fracture) or late (due to strut resorption and lack of coverage) scaffold discontinuity, as well as
DAPT discontinuation [55]. Thrombosis risk is particularly evident in small vessels (baseline reference vessel diameter
[RVD] by quantitative coronary angiography <2.25 mm, which corresponds to a visua l estimate of <2.5 mm), and is in
large part explained by both the relative thickness (157 mm vs. 81 mm) and the width (140 m m vs. 81 mm) of the struts of
the first-generation Absorb BVS (vs. Xience EES, respectively) [56]. Indeed, in vessels with a baseline RVD < 2.25 mm,
Absorb BVS strut volume exceeds 10% of vessel volume and the abluminal strut surface area coverage (device footprint)
exceeds 36% [57]. The rather abrupt increase in thrombotic risk for BVS in very small vessels appears to be confirmed by
real-world clinical experience [58]. The time-to-event curves for ST stratified by baseline RVD (<2.25 vs. 2.25 mm) and
device (Fig. 16.4) from the ABSORB III RCCT demonstrate that the absolute difference in thrombosis rates between
devices varies by a factor of 10-fold (3.1% vs. 0.3%, respectively) based on RVD. Baseline RVD affects not only the
frequency but also the time course of scaffold thrombosis, with a preponderance of early events (less than 30 days) in the
very small vessels (Fig. 16.5). The incidence of ST appears to be reduced by high pressure after dilatation of the scaffold
and by employing a BVS-specific deployment protocol [58]. A post hoc analysis of trial data stratified by use of a threecomponent deployment strategy (predilation, appropriate sizing of vessel, and scaffold postdilation at 16 atm) or not
demonstrated a graded relationship between the components, with the lowest thrombosis rate observed in patients having
all three components utilized [59] (Fig. 16.6). The optimal duration of DAPT following BVS implantation is unknown, but
with the device still physically present for w3 years, a duration of >1-year would appear prudent [56].
DUAL ANTIPLATELET THERAPY
Although the clinical value of long-term DAPT (up to 12 months) following PCI for ACS is well established regardless of
stent type (DES or BMS), the optimal duration of DAPT following elective PCI with DES in clinically stable patients is a
subject of controversy.
Any RVD <2.25 mm*
4.6% (Absorb) vs. 1.5% (Xience)
0.8% (Absorb) vs. 0.5% (Xience)
Diff [95%CI] = 3.1 [-0.3, 6.4]
10%
8%
Definite/
Probable
*corresponds to < 2.5 mm by visual estimate
FIGURE 16.4 Time-to-event curves for stent thrombosis (ST) stratified by baseline reference vessel diameter (RVD) as measured by quantitative
coronary angiography. CI, confidence interval.
ST
(%)
6%
4%
2%
0%
0 100 200 300 400
Absorb
Xience
Days Post Index Procedure
10%
8%
6%
4%
2%
0%
All RVD ≥2.25 mm
Diff [95%CI] = 0.3 [-0.5, 1.1]
P int diff=0.12
N=1623N=375
0 100 200 300 400
Days Post Index Procedure
Stent Thrombosis: Implications for New Stent Designs and Dual Antiplatelet Therapy Duration Chapter | 16 231
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FIGURE 16.5 Baseline reference vessel diameter (RVD) affects both the incidence and the timing of device thrombosis. Smaller RVD is associated with
an increased incidence of early (<30 days) thrombosis.
5%
4%
3%
2%
1%
Stent/Scaffold Thrombosis Rate (%)
0%
0
Days
Non-PSP
Proper Sizing
Proper post-dil
PSP
0–365 days population: A-EXTEND, A-II, A-Japan, A-China, A-II
366–730 days population: A-EXTEND, A-II, A-Japan, A-China
731–1095 days population: A-II
FIGURE 16.6 Components of an optimal scaffold deployment strategy (predilation, sizing, and postdilation [post-dil]; “PSP”) have an impact on the
incidences of both early and late scaffold thrombosis. Patients who had no components had the highest thrombosis rate, while those with all three
components had the lowest thrombosis rate. Patient populations were pooled from the ABSORB (A) EXTEND registry and ABSORB II, III, Japan, and
China randomized trials through maximum reported follow-up.
Non-PSP
Proper sizing
Proper post-dil
PSP
180 365 540
The Post Index Procedure (Days)
0
2549
2261
365
297
365
2483
2211
357
290
730 910 1095
730
1354
1247
227
192
Log-rank p = 0.13
(PSP vs Non-PSP)
3.4 %
3.3 %
0.8 %
0.7 %
1095
291
238
26
21
232 Cardiovascular Thrombus
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The most recent (2016) American College of Cardiology/American Heart Association (ACC/AHA) guideline focused
update on DAPT duration recommends [60]:
1. In patients with stable ischemic heart disease (SIHD) after BMS implantation, P2Y12 inhibition with clopidogrel
should be given for a minimum of 1 month.
2. In patients with SIHD after DES implantation, P2Y12 inhibition with clopidogrel should be given for at least 6 months.
3. In patients with dual therapy, the recommended daily dose of aspirin is 81 mg (range 75e100 mg).
4. In patients with SIHD after BMS or DES implantation who tolerate dual therapy without a bleeding complication and
are not a high bleeding risk, continuation of dual therapy with clopidogrel (plus aspirin) for longer than 1 month (BMS)
or longer than 6 months (DES) may be reasonable.
5. In patients with SIHD after DES implantation who develop a high risk of bleeding (e.g., treatment with oral anticoag-
ulant therapy), are at high risk of severe bleeding complication (e.g., intracranial surgery), or develop significant overt
bleeding, discontinuation of P2Y12 inhibitor after 3 months may be reasonable.
Of note, in patients with ACS after coronary stent implantation, the new guideline states:
1. It is reasonable to use ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy.
2. In patients who are not at high risk for bleeding complications and have no history of stroke or transient ischemic
attack, it is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 inhibitor therapy.
3. In patients who have tolerated DAPT without bleeding, and are not at high bleeding risk, continuation of DAPT for
longer than 12 months may be reasonable.
4. In patients with ACS after DES who develop a high risk of bleeding or are at high risk of severe bleeding complication
or develop significant overt bleeding, discontinuation of P2Y12 therapy after 6 months may be reasonable.
These recommendations are made in context that <1% of persons who discontinue DAPT incur ST, while ST occurs
commonly among individuals who are still receiving DAPT [60]. For example, using population attributable risk methodology, it has been estimated that 68%e85% of ST cannot be ascribed to clopidogrel noncompliance [61]. This observation suggests the relative importance of “other factors” such as aspirin and/or clopidogrel resistance, stent underexpansion
and/or malapposition, polymer hypersensitivity, and/or neoatherosclerosis [1]. Although nonrandomized registry experiences have suggested that discontinuation of clopidogrel within the first 6 months following stent deployment, but not
thereafter, is a strong predictor of ST [12,62], extended-duration DAPT may also influence non-target-site-related
(systemic) ischemic events [44]. Multiple randomized clinical trials and meta-analyses of clinical trials have evaluated
the effects of various durations of DAPT following coronary stenting on clinical outcomes.
As of this writing, the only trial adequately powered to assess coprimary clinical end points of ST and major adverse
cardiovascular or cerebrovascular events (MACCEs; composite of death, MI, and stroke) has been the DAPT trial [44].
The DAPT trial enrolled 25,682 patients >18 years of age who were candidates for 12 months of DAPT within 72 h of PCI
with either US FDA-approved DES (CYPHER SES, Endeavor ZES, TAXUS PES, or XIENCE EES; n ¼ 22,866) or BMS
(n ¼ 2816). All patients received either clopidogrel (75 mg daily) or prasugrel (10 mg daily) maintenance dose (ticagrelor
was not approved in the United States at the time of study initiation) in combination with aspirin (75e162 mg daily).
Aspirin and thienopyridine were prescribed by protocol for 12 months, at which time patients who had not experienced an
MACCE, repeat revascularization, or moderate/severe bleeding, and who were adherent to thienopyridine therapy (had
taken 80%e120% of prescribed drug without interruption for >14 days), were eligible for randomization. Eligible patients
continued aspirin therapy and were random ized 1:1 to continued thienopyridine or placebo treatment (blinded) for an
additional 18 months (months 12e30 after enrollment). Those patients who discontinued thienopyridine at 12 (randomized
to placebo) or 30 months (by protocol) were followed to assess clinical events for an additional 3 months (observation
periods). Randomization was stratified by stent type (DES [n ¼ 9961] vs. BMS [1687]), hospital site, type of thienopyridine (clopidogrel vs. prasugrel), and the presence (or absence) of at least one prespeci
factor for ST [44] (Table 16.3). The coprimary efficacy end points were the cumulative incidence of definite or probable ST
(ARC defined) and MACCE during the randomized treatment period (months 12e30), and the primary safety end point
was the incidence of moderate or severe bleeding (global use of strategies to open occluded arteries [GUSTO] criteria).
Although patients treated with DES differed demographically from those treated with BMS, randomized groups (continued
thienopyridine vs. placebo) were similar within stent types. Similarly, the incidences of study drug adherence and
discontinuation (both thienopyridine and placebo) at 30 months did not differ within stent groups. During randomized treatment
(primary analysis period 12e30 months), patients treated with DES who received continued thienopyridine (compared with
placebo) had a lower incidence of ST (0.4% vs. 1.4%; hazard ratio [HR] [95% confidence interval (CI)] ¼ 0.29 [0.17e0.48];
P < .001) and MACCE (4.3% vs. 5.9%, HR [95% CI] 0.71 [0.59e0.85]; P < .001) (Fig. 16.7). Continued thienopyridine
fied clinical or lesion-related risk
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