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Case Presentation
Friday, February 19th 2016
VERY LATE STENT THROMBOSIS;
PATHOPHYSIOLOGY, MECHANISM AND
RISK FACTOR
Christina Chandra
Supervisor
dr. Sunarya Soerianata, SpJP(K)
dr Siska Suridanda Danny, SpJP(K)
Division of Invasive Diagnostic and Non Surgical Intervention
Department of Cardiology and Vascular Medicine
Faculty of Medicine - Universitas Indonesia
2016
ABSTRACT
Introduction Coronary artery stents, are used in the majority of patients who undergo percutaneous
coronary intervention (PCI) to improve symptoms in patients with obstructive coronary artery disease.
Even it was uncommon complication, stent thrombosis almost always presents as death or a large
non-fatal myocardial infarction (MI), usually with ST elevation. Most of the data for very late stent
thrombosis after DES comes from the earlier SES and PES. But event with newer generation of DES
risk for stent thrombosis still exist.
Case Illustration Two cases of stent thrombosis manifest as STEMI. The first patient was 78-year
old female with history of PPCI for extensive anterior STEMI 5 years before. Stent thrombosis
manifest as another inferoposterior and lateral STEMI. Thrombus was present extensively at the old
stent and another coronary artery. The second case was 44-year old male with history of PPCI for
inferior STEMI 22 months before the second admission. He suffered acute inferior STEMI once again
and thrombus was found along the previous stent and proximal to it. Eptifibatide and heparin were
given and defered PCI was done with good result.
Summary Stent thrombosis stil remains a concern despite the advanced development of PCI.
Multifactorial risk factors was proposed as predictors for very late stent thrombosis. Double
antiplatelet therapy discontinuation, history of stent implantation on necrotic core while performing
PPCI for acute coronary syndrome, adelayed neointimal healing, in stent restenosis and development
of neoatherosclerosis may responsible for stent thrombosis in these two cases.
Keywords: stent thrombosis, late stent thrombosis, very late stent thrombosis, drug eluting stents,
bare metal stents, neoatherosclerosis, anti platelet therapy
Bare Metal Stents versus Drug Eluting Stents
Bare metal stent (BMS) thrombosis usually occurs within the first 24 to 48 hours (acute) or much less
often within the first month (subacute) after stent placement(4). In a pooled analysis of data from stent
trials registries, stent thrombosis developed in 0.9 percent by 30 days and approximately 80 percent of
these occurred within the first two days(4). Thrombotic events with BMS are uncommon after 30 days
of treatment with dual antiplatelet therapy . This observation is consistent with angioscopic studies
that showed complete re-endothelialization by three to six months(5) . Very late stent thrombosis
(after one year) is uncommonly seen with BMS using protocol definitions; using the ARC definition,
it occurs most often after a repeat procedure has been performed in the stented segment. In a report
from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), the rate of definite
stent thrombosis at two years was 1.4 percent(6).
Both randomized trial and observational study data have demonstrated that the cumulative rate of
stent thrombosis is similar for bare metal and the first generation drug-eluting stents (SES and PES) at
up to five years (Mauri NEJM 2007). The overall risk of stent thrombosis at up to one year is low for
both BMS and DES as long as patients are continued on dual antiplatelet therapy with both aspirin
and platelet P2Y12 receptor blocker for the recommended duration. Studies comparing early
generation DES (SES or PES) to BMS suggested that the risk of stent thrombosis at up to one year
was comparable (Kastrati JAMA 2005;294:819)
INTRODUCTION
The introduction of percutaneous coronary intervention (PCI) revolutionized the treatment of
patients with obstructive CAD including those presenting with acute myocardial infarction.
Coronary stents are the mainstay of percutaneous coronary revascularization procedures
and have significantly decreased the rates of acute vessel closure and restenosis. The
evolution of stent technology has improved patient outcomes by decreasing the risk of late
thrombotic events while maintaining anti-restenotic efficacy. Nevertheless, late stent failure
remains a concern even with the use of newer generation of DES since clinical trials have
shown an increase in the cumulative incidence of target lesion revascularization with time in
all generations of DES(1). Stent thrombosis, one of the manifestations of late stent failure, is
often a catastrophic event. It is important to understand its incidence, predictors, and
pathologic mechanisms for its occurrence.
AIM OF PRESENTATION
The aim of this case presentation is to discuss two cases of very late stent
thrombosis along with its pathophysiology, mechanisms and predictors.
CASE ILLUSTRASTION
The first case was a 78-year old with chief complaint of sudden onset of severe
chest pain lasting for more than 20 minutes, accompanied by diaphoresis and
nausea started 2 hours before admission. Upon arrival to with typical characteristic
of myocardial infarction. The onset of pain was 2 hour with pain scale of 8/10. At
NCCHK ED, her chest pain scale was decreased to 3/10 but with overt nausea and
vomit. Upon arrival to NCCHK the pain scale sudsided a little not from 8/10 to 3/10.
This patient had history of anterior extensive myocardial infarction on April 2011 treated with
primary percutaneus coronary intervention (PPCI) when one Bare Metal Stent (Tsunami
Gold 3.0x25 mm) was implanted at her totally occluded left anterior descending (LAD)
coronary artery with good result. There was another angiographically significant stenosis at
the Left Circumflex (LCx) which was left unaddressed at that time. The Left Main (LM) and
Right Coronary Artery (RCA) were within normal limits. Afterward the patient continued Dual
Antiplatelet Regimen (DAPT) for 18 months. She was hospitalized for three times during
the period of 2011-2013 for acute decompensated heart failure after the intervention.
Her risk factors for CAD were uncontrolled diabetes and menopausal state. She had
poor compliance of her medication including aspirin and had not been come to
outpatient clinic for the last 2 years after the intervention.
At ED she was still compos mentis with BP 123/62 mmHg and HR 85 bpm RR 20
x/min and SatO2 100% room air. Physical examination of heart, lung, abdomen and
extremities were within normal limit. Her ECG recording showed sinus rhythm with
ST segment elevation at II, III, aVF, V5,V6, V7, V8, V9, V3R and V4R (fig 1).
Laboratory result showed CKMB 34 U/L, hs Trop T 23 ng/L, random blood glucose
(RBG) was 329 mg/dL, ureum 88.21, creatinine 1.28, eGFR 40.
Fig 1. ECG revelead acute inferoposterolateral STEMI
She was diagnosed with acute inferoposterolateral STEMI 2 hours onset Killip I TIMI
7/14, uncontrolled type 2 diabetes and hypertension. She was sent to catheterization
laboratory for PPCI. Prior to PPCI she had repeated episodes of cardiac arrest with the
monitor showing ventricular fibrillation. Resuscitation was promptly performed and return
of spontaneous circulation was achieved. Immediate coroangiography revealed normal
left main (LM) but 80% stenosis at proximal from the old stent, fresh thrombus at the old
stent and 70% stenosis at distal from the old stent at LAD. 70% stenosis was also found
at proximal obtuse marginal (OM) 1 and there was total occlusion at proximal and distal
right coronary artery (RCA), with mid part collateral from ipsi and contralateral (Fig 2).
Fig 2. Trombus was found at previous stent and also at distal part of RCA
RCA was successfully wired but before predilatation could be performed the patient
fell into cardiac arrest again and did not response to resuscitation efforts. Death was
declared after 30 minutes of maximal resuscitation.
The second case was a 44-year old male presented to ED with chief complaint of
heaviness chest pain started 7 hours before admission. There pain was felt with scale
pain 10/10, radiated to back and accompanied by diaphoresis. He had already gone to
Thamrin Cileungsi Hospital and given isosorbid dinitrate sublingual there, then he was
referred to NCCHK. At our ED his chest pain was reduced with scale 6/10.
His risk factor for CAD was history of smoking. His history of past illness was post
PPCI for acute STEMI inferior with 1 stent BMS Multi Link 3.5 x 18 mm at RCA in
CAD 1 VD in March 2014. He had already stopped all of his medication including
DAPT 2 months after stent implantation.
He was compos mentis at our ED with BP 112/73 mmHg and HR 53 bpm. His physical
examination were within normal limit. The ECG recording showed sinus rhythm with ST
elevation at III, aVF, V7-V9 (fig. 3). His laboratory result showed RBG of 146 mg/dL, hs
Trop T 73 ug/dL, CKMB 42, ureum 27.29 mg/dL, creatinine 0.87 mg/dL, eGFR 95.
Fig 3. ECG showed ST elevation at inferior lead.
He was diagnosed as acute inferoposterior STEMI with 7 hours onset Killip I TIMI
2/14. He was then transferred to catheterization laboratory to undergo PPCI. The
angiographic finding revealed normal LM, TIMI 2 flow at LAD. While LCx showed
hazziness at proximal until mid part of with thrombus, 40% stenosis at mid part and
TIMI 2 flow. There was a total occlusion at proximal with high thrombus
Fig 4. Total occlusion was found at proximal part of RCA (left); Thrombus was
found at previous stent (right)
burden at RCA(Fig 4). The thrombus was then aspirated and ballon angioplasty was
done from distal to proximal part of RCA. It was decided not to implant the stent
because of the high thrombus burden. He was given eptifibatide intracoronary then
continued with enoxaparine for 5 days.
The patient was stable and observed at intensive care. After 5 day of heparin, he was then send
back to cath lab to undergo defered PCI to reevaluate the coronary arteries. Coroangiography
revealed total occlusion at distal (old stent). Pre and post dilatation was done before
and after deployment of 1 BMS 4.0 x 24 mm at distal part of RCA. Post stenting,
thrombus was still seen with TIMI 3 flow. Heparin was continued for another 3 days.
Patient was stable and discharge from hospital without any major adverse event.
DISCUSSION
Coronary artery stents, are used in the majority of patients who undergo percutaneous
coronary intervention (PCI) to improve symptoms in patients with obstructive coronary artery
disease. They function both to prevent abrupt closure of the stented artery soon after the
procedure as well as to lower the need for repeat revascularization compared to balloon
angioplasty alone. Stent thrombosis is an uncommon but serious complication of PCI with
stenting. Its cause is total or subtotal thrombotic occlusion of a coronary artery by thrombus
that originates in or close to an intracoronary stent. This finding is seen at the time of
coronary angiography and it is necessary in most cases to secure the diagnosis.
By definition, stent thrombosis is an abrupt onset of cardiac symptoms (i.e., an acute coronary
syndrome) along with an elevation in levels of biomarkers or electro- cardiographic evidence of
myocardial injury after stent deployment(2). A definite or angiographic stent thrombosis is
accompanied by angiographic evidence of a flow-limiting thrombus near a previously placed
stent(3). In contrast to events that do not occur in the context of an acute coronary syndrome,
clinically silent vessel closures documented during follow-up angiography are usually not referred
to as stent thromboses. The most widely utilized definition and timing classification of stent
thrombosis was developed by the ARC (Table 1)(4).
In general, an early stent thrombosis is an event that occurs within 30 days of
implantation (events within 24 hours of implant are called acute thromboses, and
events occurring in 1 to 30 days are called subacute thromboses). Events that occur
more than 30 days after stent implantation are late thromboses, and those occurring
beyond 12 months are very late thrombosis(2)(3).
Table 1. Academic Research Consortium. Definitions of Stent Thrombosis(4)
Classification
Definite
An acute coronary syndrome with angiographic or autopsy evidence of
thrombus or occlusion within or adjacent to a stent
Unexplained death within 30 days after stent implantation or acute
Probable
myocardial infarction
involving the target-vessel territory without angiographic confirmation
Possible
Any unexplained death beyond 30 days after the procedure
Timing
Acute
Within 24 hours (excluded events within the catheterization
Subacute
laboratory) 1–30 days
Early
Within 30 days
Late
30 days–1 year
Very late
After 1 year
Both of our patients presented to ED with typical symptoms of acute myocardial
infarction. The ECG findings and elevated cardiac enzyme suggested both of the
patients diagnosed as an acute STEMI. And both patients had a history of past acute
STEMI. The first patient had been undergone PPCI 5 years earlier. The second
patient had been undergone PPCI 22 months earlier. By definition adopted from
ARC, both of our patient classified as very late stent thrombosis, proven by
angiographic findings while the patient send to catheterization laboratory.
LATE AND VERY LATE STENT THROMBOSIS
PREDICTORS AND MECHANISMS OF LATE THROMBOSIS
Based on earlier studies from the bare metal stent era, Honda and Fitzgerald(2) proposed a
multifactorial model for predicting early stent thrombosis (Fig. 5). During this early period, most
incidents of early stent thrombosis are caused by technical aspects of stent implantation
Fig 5. Multifactorial causes for early thrombosis(2)
and premature discontinuation of DAPT. However late and very late thrombosis is largely a
separate phenomenon due to a different set of mechanisms from those of early thrombosis.
There are multifactorial and include stent-related factors as well as patient and procedural factors
(Fig. 6)(2). Stent thrombosis occurs more frequently in complex patients and lesions(5),
especially in patients with acute coronary syndromes and thrombotic lesions (possibly due to
stent implantation within or adjacent to necrotic core, diabetes and renal insufficiency, and
diffuse disease, small vessels, and bifurcation lesions requiring multiple stents). Hypersensitivity
reactions to the DES polymer and vascular inflammation have been associated with stent
thrombosis, as have stent underexpansion and residual disease at the stent margins.
Vulnerable
plaque near
stent
Antiplatelet
therapy
Antiplatelet
therapy
Stent
penetration
of necrotic
core
BMS and DES
Localized
hypersensitivity
vasculitis
DES
DES and BMS
Delayed
neointimal
healing
Stent
malapposition
ACS?
Bifurcation
stenting
DES and Radiation
May be higher burden of
delayed healing with longer
total stent length
DES and BMS
May be acquired from delayed
neointimal healing and
residua from incomplete
expansion
Renal
failure
Antiplatelet
therapy
DES and BMS
Includes stenting
across or into the
bifurcation
In-stent
restenosis
Antiplatelet
therapy
DES and BMS
Relative
platelet
resistance?
BMS and DES
Long lesions
Fig 6. Multifactorial causes for late thrombosis. ACS, acute coronary syndrome;
BMS, bare metal stent; DES, drug-eluting stent(6).
The most commonly proposed explanation underlying the increased rate of very late primary
stent thrombosis with newer generation of DES is delayed or absent endothelialization of the
stent struts(7). Angioscopic evaluation has revealed incomplete neo intimal coverage and
mural thrombi (not detected on angiography) 3 to 6 months after implantation of sirolimus
stents(2). Only 13% of sirolimus eluting stents had complete neointimal coverage, in contrast
to bare metal stents, which all showed complete neointimal coverage with no angioscopic
thrombi(2). In the cases of delayed neointimal healing, associated risk factors for thrombosis
included stenting near a bifurcation lesion, prior radiation therapy, disruption of a vulnerable
plaque near the stent, and penetration of a stent strut deep into a necrotic core.
Also, it has been observed that some cases of very late stent thrombosis may be due to the
development of neoatherosclerosis within stents, along with new plaque rupture. Usually there is
no communication between the lesion within the neointima and the underlying native
atherosclerosis. The earliest feature of neoatherosclerosis is foamy macrophage clusters, which
is frequently seen either in the peri-strut area or close to the luminal surface.
Histologically, neoatherosclerosis is characterized by accumulation of lipid-laden
foamy macro- phages within the neointima with or without necrotic core formation
and/or calcification(1).
Fig 7. Histologic images showing progression of in stent neoatherosclerosis. Foamy
macrophage clusters in peri-strut region and close to the luminal surface(1)
The development of neoatherosclerosis may occur in months to years following stent
placement, whereas atherosclerosis in native coronary arteries develops over decades.
The mechanisms responsible for the accelerated atherosclerosis in stented segments,
particularly in DES, remain unknown to date; however, it is speculated that incompetent
and dysfunctional endothelial coverage of the stented segment contributes to this
process. Stent implantation causes vascular injury with endothelial denudation.
Incomplete maturation of the regenerated endothelium, which is characterized by poor
cell-to-cell junctions, reduced expression of anti-thrombotic molecules, and decreased
nitric oxide production, are more frequently observed in DES when compared with BMS;
this is likely associated with the anti-proliferative effects of the eluted drugs(1).
However on both of our patient, BMS not DES was implanted on the previous history of STEMI,
in which stents was implanted on the necrotic core of plaque rupture. According to Otsuka et al
(1) hypotheses, that stent implanted in unstable lesions may be prone to greater delay in
vascular healing when compared with those implanted in stable lesions. In unstable lesions,
stent struts are embedded in the necrotic core, which is an avascular structure, where the effect
of drug likely persists for a long period of time that potentially causes dysfunctional
and/or
incompetent
endothelium,
leading
to
the
development
of
neoatherosclerosis(8). Also, it is possible that endothelial recovery is delayed owing
to the absence of enough viable tissue required for arterial repair.
Antiplatelet therapy
Poor compliance with the recommendation for dual antiplatelet therapy (DAPT) may be the
primary and the most important cause of development of stent thrombosis(9). Premature
interruption of dual-antiplatelet therapy carries the greatest hazard for late stent thrombosis,
because several studies have reported this to increase the odds for thrombosis by as much
as 25 to 90-fold(2). For drug-eluting stents, premature interruption of antiplatelet therapy is
defined as cessation of one or both antiplatelet agents less than 6 months after implantation.
Some investigators further specify pre- mature interruption as less than 3 months for
sirolimus and less than 6 months for paclitaxel, although for uniformity, the former definition
is preferable. Complete termination of antiplatelet therapy is defined as interruption of
antiplatelet therapy more than 6 months after implantation(2). Complete termination of dualantiplatelet therapy may account for approximately one third of late events, which highlights
the importance of proper patient selection for long-term use of antiplatelet therapy and
effective communication with our surgical colleagues(2). Limited data are available on late
stent thrombosis that occurs on aspirin monotherapy. These events appear to be more
idiosyncratic in nature, because they have been described 1 to 92 weeks after termination of
clopidogrel. In the Thoraxcenter report, this accounted for most of the events. In this study,
two thirds of stent thromboses occurred on aspirin monotherapy, but in the Korean registry,
only one third of events occurred on aspirin monotherapy (2).
ADAPT-DES study(10), a large-scale, prospective, multicentre registry study, found that high
platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49
[95% CI 1·43–4·31], p=0·001) and myocardial infarction (adjusted HR 1·42 [1·09–1·86],
p=0·01), was inversely related to bleeding (adjusted HR 0·73 [0·61–0·89], p=0·002), but was
not related to mortality (adjusted HR 1·20 [0·85–1·70], p=0·30). High platelet reactivity on
aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 [0·58–3·64],
p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR
0·65 [0·43–0·99], p=0·04). Stone, Gregg W et al proposed a hypothesis that more potent
inhibition of ADP-induced platelet activation would prevent ischaemic complications of drug-
eluting stent implantation and therefore improve survival, absent adverse effects
from more potent platelet inhibition(10).
The first patient had consumed DAPT for 15 months after the acute event. There
was no documented history of bleeding with her prolong DAPT. The second patient
terminated his DAPT prematurely. After the acute event he only came once to
outpatient clinic and consumed DAPT just for another 2 months after his STEMI.
However his second acute event of STEMI occurred 22 months later, suggesting
other mechanisms may play roles causing stent thrombosis. Unfortunately,
assessing the platelet reactivity had not been routinely checked yet in our centre.
The metabolic risk profile from the first patient were not controlled adequately. A
history of HbA1c of 11 and uncontrolled hypertension was documented from her
medical records. No renal failure was detected on both of these patients.
OUTCOMES OF LATE THROMBOSIS
Late thrombosis is frequently a catastrophic event. ST-elevation MI (STEMI) is
characterized by intraluminal thrombus irrespective of whether the initial event is de
novo (in association with plaque rupture) or stent related. However, clinical outcomes
appear worse with the latter (11). In an attempt to understand this difference, clinical and
angiographic outcomes in patients with STEMI due to stent thrombosis (n = 92) and de
novo coronary thrombosis (n = 98) were compared in a retrospective study of patients
who underwent primary PCI for STEMI (8). The following findings were noted in patients
with stent thrombosis compared to those with de novo coronary thrombosis; In-hospital
major adverse cardiovascular and cerebrovascular events were significantly higher (22.6
versus 9.2 percent), including a significantly higher in-hospital death rate (17.4 versus
7.1 percent). However, there were no differences at six-month follow-up.
In these case presentation, the first patient was unstable and developed cardiac arrest
before the coronary intervention was completed. Resucitation could not sustain spontaneous
circulation and the patient was declared dead. The second patient was stable and PPCI had
done but due to the high thrombus burden, stent implantation was delayed. Intracoronary
eptifibatide followed by 5-day heparin was given and the patient was send back to undergo
PCI. His angiography revealed thrombus was still present at the previous stent despite the
eptifibatide and heparin had been given. PCI was done with 1 DES, patient was
discharge in good condition.
SUMMARY
Very late stent thrombosis is a rare but potentially fatal event following coronary stents
implantation. Known predisposing factors for the occurrence of neoatherosclerosis and
subsequent thrombosis are: discontinuation of double antiplatelet therapy, history of
stent implantation on necrotic core while performing PPCI for acute coronary syndrome,
delayed neointimal healing, in stent restenosis and development of neoatherosclerosis
may responsible for stent thrombosis in these two cases.
Two cases with very late stent thrombosis manifested as acute ST elevation myocardial
infarction were described. Both patients received bare metal stents during an acute phase of
a prior acute coronary syndrome episode, which could contribute to delayed vessel healing.
The first patient had a BMS implanted 5 years earlier and continued DAPT for 15 months but
had poor glycemic and hypertension control during the last 2 years. The second patient also
had a BMS implantation 22 months prior to the current admission but his poor compliance to
medications, especially the DAPT regimen, might be the major contributing factor for the
development of stent thrombosis. The high morbidity and mortality in this group of patients
warrant in-depth knowledge on the mechanisms, prevention and management of stent
thrombosis among cardiologists and other physicians alike.
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