A clinical evaluation comparing the efficacy of Absorb everolimus-eluting bioresorbable vascular scaffold vs. everolimus-eluting metallic stent in the management of acute coronary syndrome in young patients

(1)

1. ABSTRACT

AIMS: to evaluate the clinical outcomes after the use of the Absorb® bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, CA, USA) compared with Xience® and Promus® metal everolimus-‐eluting stent (EES) (Abbott Vascular, Santa Clara, CA, USA; Boston Scientific, Marlborough, MA, USA), in young patients (≤ 45 years old) with acute coronary syndrome (ACS).

METHODS: a total of 129 young (≤ 45 years old) patients with acute coronary syndrome, were collected for this study. Those patients were divided in two groups: a first group of 71 all consecutive patients treated with BVS between September 2012 and September 2015 (BVS group) was compared with a second group of 58 consecutive patients treated with a Xience or Promus metal everolimus-‐eluting stent, between January 2009 and October 2012 (EES group), when the BVS was not already available. The primary end point was device-‐oriented composite end point (DOCE) including cardiac death, device thrombosis and device restenosis at two years follow-‐ up.

RESULTS: baseline characteristics are similar between groups. Lesion characteristics were also similar between groups, except for the bifurcations lesions that were more frequent in EES group. Procedural success was obtained in all but three patients in the BVS group. At two years follow-‐up, no significant differences were observed in terms of DOCE (BVS 4.2% vs EES 5.2%, p > 0.05). Definite or probable in-‐ stent/scaffold thrombosis occurred in one patient in each group.

CONCLUSIONS: BVS implantation for young patients with ACS is safe, with outcomes comparable with those of drug-‐eluting metal stents.

(3)

2. CORONARY HEART DISEASE IN YOUNG PATIENTS

2.1. Epidemiology

Coronary heart disease (CHD) represents the leading cause of death in adults in the western worldcame1_{.
Although
CHD
primarily
occurs
in
patients
over
the
age
of}

45, younger men and women can be affected. To define ‘’young patients’’ with CHD, the age cut-‐off varies significantly from study to study, ranging from under 35 years of age to under 55 years of age. For the purposes of this study, we define “young” patients as under 46 years of age.

Studies indicate approximately 3% of all coronary artery disease cases occurring in patients younger than 40 years2_{.
The
prevalence
of
CHD
in
younger
subjects
is}

difficult to establish accurately since it is frequently a silent process. The frequency with which this occurs was examined in an autopsy study of 760 young (age 15 to 34 years) victims of accidents, suicides, or homicides3_{.
Advanced
coronary}

atherosclerotic lesions were identified in 20% of men and 8% of women aged 30 to 34 years, while a ≥40 % stenosis of the left anterior descending artery was identified in 19 and 8 %, respectively. In another study, intravascular ultrasound performed in young asymptomatic heart transplant recipients found atherosclerosis in 28% of the population under 30 years of age and 17% of the population under 20 years of age4_.

There are also limited data on the frequency of MI in younger subjects. In the Framingham Heart Study, the incidence of an MI over a 10-‐year follow-‐up was 12.9/1000 in men 30 to 34 years old and 5.2/1000 in women 35 to 44 years old5_{.
The}

incidence of MI was eight to nine times greater in men and women aged 55 to 64 years. In other studies, 4 to 10 % of patients with MI were ≤40 or 45 years of age 6-‐8_.

In two series of patients with CHD at ≤40 years of age, women comprised 5.6 and 11.4 % of patients6,9_.

Although CHD is an uncommon entity in young patients, it constitutes an important problem for the patient and the treating physician because of the devastating consequences on the more active lifestyle of young patients. In addition, these patients have different risk factor profiles, clinical presentations, and prognoses than older patients. All of these factors should be taken into consideration when treating young patients with CHD.

(4)

2.2. Risk factors and etiologies

The relative importance of risk factors for the development of CHD according to age was evaluated in a report in which 11,016 men aged 18 to 39 years were followed for 20 years10_{.
The
relative
risks
associated
with
the
traditional
risk
factors
were
of}

similar magnitude as in a group of 8955 men aged 40 to 59 years. These included: -‐ Age — relative risk 1.63 per six year increase

-‐ Serum cholesterol — relative risk 1.92 per 40 mg/dL [1.04 mmol/L] increase -‐ Systolic blood pressure — relative risk 1.32 per 20 mmHg increase

-‐ Cigarette smoking — relative risk 1.36 per 10 cigarette/day increase

Young patients with MI usually have multiple risk factors for CHD. In some studies, for example, as many as 90% to 97% had one or more traditional risk factors for atherosclerosis11-‐13_{.
In
a
prospective
study
of
over
7000
women
of
mean
age
27}

years at baseline followed for an average of 31 years, there were 47 CHD deaths14_.

The CHD mortality rates for those with no risk factors, only one risk factor, or two or more risk factors were 0.7, 2.4, and 5.4 per 1000 person-‐years, respectively. A comparable relationship was seen for cardiovascular disease mortality and for all-‐ cause mortality

2.2.1. Atherosclerotic coronary artery disease

Early atherosclerosis is a known risk factor for CHD in young adults, and coronary atherosclerosis is associated with 80% of AMIs in young people15_.

As seen in the previous paragraph, the risk factors associated with atherosclerosis in the population of young adults are similar to risk factors in older populations, and nearly all young patients with CHD have at least one conventional cardiovascular risk factor (table 1) 11-‐13_.

The most strongly associated risk factor for CHD in young adults is current tobacco use. It has been noted in 76% to 92% of young patients with MI, compared to 24 to 56 % of patients older than 45 years of age9,12,16-‐19_{.
This
risk
factor
is}

particularly strong in women: in one study of women admitted to the hospital with acute MI, 95% of women under 45 years of age were current smokers, compared with 45% of women of all ages20_{.
In
a
registry
study
that
enrolled
6892
patients
with
acute}

ST-‐elevation MI treated by primary percutaneous coronary intervention from 1998 to 2010, smoking rates were highest for those aged 18 to 34 years, at 78.02 %,

(5)

compared with a smoking rate of 23.72 % in that age stratum of the general population, with smoking rates notably decreasing with increasing age in the STEMI population21_.

The association between CHD in young adults and a family history for coronary disease is reported in several studies: 41 compared to 28 and 12 % in middle aged or elderly patients, respectively12_{;
and
57
versus
43
%
in
two
series}17_{.
A
higher}

incidence of a positive family history in young patients (64 %) was noted in the largest report of 823 patients9_{.
The
association
between
family
history
and}

premature CHD can be due to both genetic and environmental factors. This was addressed in a study of 398 families in which 62 vascular biology genes were evaluated22_{.
Missense
variants
of
several
thrombospondin
genes
were
significantly}

associated with MI and CHD.

Being male is also a particularly strong risk factor for heart disease in younger populations. In a recent study, 92.5% of young patients (≤45 years of age) admitted for AMI were male, compared with 76.0% of older patients23_{.
Overall,
research
has}

suggested that only 5% to 15% of young CHD patients are women, compared with 40% to 50% in older populations, although some have suggested that this proportion among the young may be growing7_.

Primary or secondary dyslipidaemia is another common risk factor for heart disease in young populations, with studies reporting a prevalence that varies from 12% to 89%20,24_{.
When
compared
to
older
patients
young
patients
have
lower
mean}

serum high density lipoprotein (HDL) concentrations (35 versus 43 mg/dL) and higher serum triglycerides (239 versus 186 mg/dL)19_{.
Hypertriglyceridemia
was,
in}

one series, the most common lipid abnormality in young patients with MI25_{.
It
may
be}

associated with glucose intolerance and a predominance of small atherogenic LDL particles, both of which predispose to atherosclerosis.

Diabetes appears to be less common in young patients with CHD than in older patients, present in only 3% to 5% of patients under 45 years of age with acute MI17,20_{.
Diabetes
is,
however,
a
strong
predictor
of
mortality
in
this
population,
with}

diabetes patients diagnosed with heart disease having a 15-‐year mortality rate of 65%, regardless of treatment type9_.

Being overweight and obese are significantly more common in younger CHD patients than in older patients. Obesity is thought to increase the risk of acute MI in

(6)

individuals under 45 years by two-‐ to threefold9_{.
This
statistic
is
of
particular}

concerning, as the prevalence of obesity is increasing rapidly in the young population. A report from the Framingham Heart Study suggested that obesity in middle-‐aged subjects could account for as much as 23 % of cases of CHD in men and 15 % in women 26_.

2.2.2. Non-‐atherosclerotic coronary artery disease

Approximately the 20% of CHD in young adults is not associated with coronary artery atherosclerosis9,15,20_{.
The
primary
causes
other
than
coronary
artery
stenosis}

are coronary artery embolism, thrombosis, anomaly, and vessel inflammation or spasm, caused by a variety of mechanisms (table 1).

Congenital coronary artery disease has been estimated to cause 5% to 35% of cases of sudden cardiac death in young people. Abnormal origin of the coronary arteries, present in a small number of patients, is one example of a congenital abnormality that can cause CHD27_{.
Patent
foramen
ovale
has
also
been
associated}

with rare cases of systemic paradoxical embolic events, including acute MI. It is believed that emboli that form in the veins of the legs or pelvis and reach the coronary arteries from right-‐to-‐left shunting through the patent foramen ovale. A recent study found that half of patients with acute MI due to paradoxical embolism had no cardiac risk factors28_{.
Myocardial
bridging
is
a
condition
in
which
the
coronary}

artery, usually the left anterior descending (LAD), is anatomically covered by the myocardium and compressed during systole, which can occasionally lead to CHD through two distinct mechanisms. Compression of the coronary artery during systole can result in delayed opening during diastole, reducing perfusion and causing ischemia. In addition, endothelial injury caused by abnormal hemodynamic during systolic compression may enhance coronary atherosclerosis29_.

Illicit drug use, cocaine abuse in particular, has been reported to be associated with acute MI for nearly 30 years30_{.
In
the
Third
National
Health
and
Nutrition}

Examination Survey, 10085 adults between the ages of 18 and 45 were enrolled; approximately the 25% of non-‐fatal MI was attributable to frequent cocaine use31_.

Cocaine use results in acute MI by various mechanisms including coronary vasospasm and hypercoagulability in the background of increased sympathetic activity32_{.
Long-‐}

(7)

barrier and increasing permeability to LDL33_{.
Serious
arrhythmias
including}

ventricular tachycardia can occur in cocaine users in the absence of MI34,35_.

Amphetamines can result in acute MI through mechanisms similar than cocaine, including coronary vasospasm and hypercoagulability coupled with increased sympathetic activity36_{.
Smoking
marijuana
may
be
a
rare
trigger
of
MI}37_.

Coagulation disorders are estimated to account for 5% of all AMIs in young patients20_{,
and
several
genetic
polymorphisms
that
disrupt
the
balance
between}

coagulation and fibrinolysis have been associated with CHD in young adults. Factor V Leiden mutations, associated with a procoagulant state, have been shown to cause CHD in young people38_{.
In
a
report
of
107
patients
with
premature
MI
but
no}

significant coronary artery stenosis (average age 44), the prevalence of carriers for factor V Leiden was significantly higher in these patients compared to 244 with an MI and significant stenosis and 400 healthy controls (12 versus 4.5 and 5 percent)39_.

Likewise, oral contraceptives, which can be pro-‐thrombotic, have been associated with increased incidence of acute MI, primarily when combined with heavy smoking, although the risks appear to be lower with newer agents40-‐42_.

Connective tissue disorders can be a cause of non-‐ atherosclerotic coronary artery disease. Takayasu’s disease and giant cell arteritis are types of granulomatous vasculitis that can affect the coronary arteries and result in myocardial infarction43_{.
In}

addition, Kawasaki disease, which typically affects children under 5 years of age, can cause coronary arteritis leading to coronary aneurysm and stenosis in children44_.

Kawasaki disease is relevant for young adults because post-‐ Kawasaki disease patients have an higher risk to develop early atherosclerosis45-‐47_.

Spontaneous coronary artery dissection (SCAD) is another rare cause of acute coronary syndromes in young adults. This condition is most common in women under 40 years of age and one third of all cases are associated with pregnancy48_{.
In}

this disease, a hematoma forms in the outer wall of the coronary artery (typically the LAD), creating a false lumen, which expands and ultimately compresses the real lumen, causing ischemia. It is thought that mild atherosclerosis may be an underlying cause, but SCAD can also be associated with connective tissue disorders such as Ehlers-‐Danlos syndrome and Marfan syndrome48_.

Autoimmune disorders are also associated with CHD. In particular, antiphospholipid syndrome (APLS), characterized by hypercoagulability due to the

(8)

presence of antiphospholipid antibodies, can cause a variety of cardiac symptoms49_.

The frequency of AMI was found to be 2.8% in a large study of APLS patients50_{.
This}

disorder can occur alone or in conjunction with other immune disorders, such as systemic lupus erythematosus (SLE)51_{.
SLE
patients
are
at
a
fivefold
increased
risk
for}

developing CHD, even without APLS, and their rates of acute MI are significantly higher than the general population. Patients with SLE often have early atherosclerosis due to increased inflammation and endothelial dysfunction52_{.
Even
in
patients}

without atherosclerotic disease, SLE can cause other coronary abnormalities that can lead to acute MI.

Table 1. Risk factors and etiologies of coronary heart disease in young patients

Atherosclerotic risk factors Non-‐Atherosclerotic risk factors

Smoking Congenital coronary artery disease Male gender Cocaine and other illicit drug use

Family history of CHD Coagulations disorders (eg, Factor V Leiden mutations) Lipid abnormalities Oral contraceptive use

Diabetes Connective tissue disorders (eg, Takayasu’s disease, giant cell arteritis, post-‐Kawasaki disease patients)

Overweight and obesity Spontaneous coronary artery dissection

Autoimmune disorders (eg, Antiphospholipid syndrome, Systemic lupus erythematosus)

2.3. Clinical presentation

The clinical presentation of CHD in younger patients differs from their older counterparts. A higher proportion of young patients do not experience angina and, in the majority of cases, an acute coronary syndrome that progresses rapidly to MI (most often an ST elevation MI) is the first manifestation of CHD6,19,53_{.
These}

relationships were illustrated in a series of 200 patients with CHD: Patients ≤45 years of age had a lower incidence of stable angina than patients ≥60 years of age (24% versus 51%) and a higher incidence of acute coronary syndromes (76% versus 49%)19_{.
Similar
findings
were
noted
in
another
report
of
85
patients
less
than
40}

years of age who were referred for cardiac catheterization and angiography53_{.
The}

first manifestation of CHD was angina in 14% and acute coronary syndrome in 69%, two-‐thirds of whom denied any chest pain before the infarct. Among those who have preceding chest pain, the first episodes often occur only in the week prior to MI6_.

(9)

These findings support the suggestion that the pathophysiology behind these clinical syndromes may differ; perhaps this may be related to a lower degree of collateral circulation development54_.

In every young patient presenting with ACS, use of recreational drugs in the recent times should be recorded. Family history of premature CHD, risk factor profile such as smoking, obesity, diabetes, and dyslipidaemia would give better clues as to the likelihood of athermanous coronary artery disease. History of recurrent venous and arterial thrombosis should also be reported. Initial clinical examination should concentrate on hemodynamic stability, evidence of sympathetic hyperactivity such as tachycardia and sweating, and evidence of previous injected drug misuse.

Establishing the diagnosis of an acute MI is based upon the typical rise and gradual fall (troponin) or more rapid rise and fall (CK-‐MB) in biochemical markers of myocardial necrosis with at least one of the following: ischemic symptoms; development of pathologic Q waves on the electrocardiogram (ECG); or ECG changes indicative of ischemia (ST segment elevation or depression)55_.

A potential diagnostic problem that is most common in younger subjects is that myocarditis can mimic an acute MI. This disorder should be particularly considered in young patients with a clinical presentation of an acute coronary syndrome who have a normal coronary angiogram56,57_{.
In
one
study
of
45
such
patients,
35
(78%)
had
a}

diffuse or focal myocarditis on myocardial imaging. Complete recovery of left ventricular function occurred at six months in 81%.

2.4. Angiographic findings

In the majority of patients younger than 45 years of age, angiographic studies were performed because of a history of MI. As expected, major differences were found when compared to older patients.

Younger patients have a higher incidence of normal coronary arteries, mild luminal irregularities, and single vessel coronary artery disease than do older patients17,19,58-‐60_.

One of the largest reports of angiographic findings in young patients with CHD comes from a sub-‐study of the Coronary artery surgery study (CASS), which compared the results of coronary angiography in 504 young men (≤35 years of age)

(10)

and women (≤45 years of age) with a history of an MI to those in over 8300 older patients17_{.
The
following
significant
differences
were
noted:}

-‐ Normal coronary arteries were more common in the young patients (18% versus 3%). Young women had a higher frequency of angiographically normal coronary arteries than young men, despite a 10-‐year age difference in the definition of "young."

-‐ Single vessel coronary disease was more common (38% versus 24%) and three vessel disease was less common (14% versus 39%) in the younger patients.

-‐ Although some series have shown a predilection for involvement of the left anterior descending artery in young patients59,60_{,
this
was
not
found
in
the
CASS}

sub-‐study.

In another large series of 823 young patients with CHD, single vessel disease was present in 55 to 60 percent9_.

2.5. Management of acute coronary syndromes

Most studies have suggested that treatment of acute coronary syndromes in young patients should be similar to treatment for older adults. Differences in etiology and prognosis for young individuals, however, elicit concerns that are unique to this population.

2.5.1. ST elevation MI

Young patients with an acute ST elevation MI should be treated with primary percutaneous coronary intervention (PCI) or, if not available, thrombolytic therapy. Prospective randomized trials assessing primary PCI and thrombolytic therapy for an acute ST elevation MI have observed that both young and old patients have a better outcome with PCI than thrombolysis. However, young patients do better than older patients regardless of the therapy received. In the GUSTO-‐IIb trial, for example, the outcome was improved with PCI compared with thrombolytic therapy for each 10-‐ year patient group. Irrespective of treatment, the risk increased with age; outcomes in young patients seem to be better than those in older patients regardless of whether PCI or thrombolytic therapy is used61-‐63_.

Although data are limited, young patients also appear to respond well to thrombolytic therapy11,64_{.
In
one
study,
for
example,
the
clinical
response
to}

(11)

streptokinase, as measured by TIMI II or III flow in the infarct-‐related artery, was similar in patients ≤35 and ≥55 years of age (74% versus 73%)11_.

2.5.2. Non-‐ST elevation ACS

For management of non-‐ST elevation MI or unstable angina, patients should first be stabilized using medical therapy, followed by revascularization if necessary. The efficacy of this early invasive strategy in patients under age 40 is uncertain since few patients were included in the large clinical trials. Multiple randomized trials have shown that coronary angiography produces better outcomes only in young patients with high-‐risk features such as recurrent ischemia or multiple risk factors. Many other lower-‐risk patients with an uncomplicated course can undergo exercise stress testing for risk stratification. An exercise stress test is a simpler and more cost-‐ effective modality to risk stratifies young patients with CHD and an MI59,65. Most of the younger patients who managed stage 3 of the Bruce protocol (nine minutes or more) were found to have normal coronary arteries9_.

2.6. Secondary prevention

In young patients, the natural progression of atherosclerosis is often accelerated due to the high prevalence of risk factors. Therefore, risk factor reduction is extremely important, and efforts should include diet, exercise and smoking cessation counselling, lipid-‐lowering therapy, and, if necessary, treatment of diabetes and hypertension.

Antiplatelet agents like aspirin, clopidogrel, ticagrelor and prasugrel should be used as per the guidelines for adults. Warfarin is necessary in patients in a hypercoagulable state and continued lifelong in patients with recurrent ischemic events66_.

Start of beta-‐blockers can be delayed for a few days as they might exacerbate coronary artery vasoconstriction67_{,
especially
in
cocaine-‐associated
acute
MIs.}

Statins are invariably prescribed in all patients with MI and their clinical effects extend beyond lipid lowering. Statins are said to stabilize plaques in patients with atheromatous CHD, thereby improving their outcome, and reducing recurrent events68_{.
In
young
patients,
this
lipid-‐lowering
therapy
may
be
initiated
early
in
life}

(12)

in children and adolescents with familial hypercholesterolemia for up to 2 years of follow-‐up69,70_{,
robust,
long-‐term
studies
on
the
safety
of
statins
do
not
exist.}

Other agents like niacin and omega 3 fatty acids should be considered in special situations like hypertriglyceridemia and low HDL concentrations71,72_{.
B-‐complex}

vitamins are useful in patients with hyperhomocysteinaemia73_.

Angiotensin converting enzyme inhibitors (ACE-‐I) should be offered to all patients with left ventricular dysfunction as substantial benefits were shown in using ACE-‐I in this group of patients74,75_.

Lifestyle changes play an important part in the management of these patients. Stopping smoking should be strongly advised. Extensive progression of CHD was noted in younger patients who continue to smoke after their bypass surgery. Good control of diabetes and correction of lipid abnormalities were shown to improve prognosis in patients less than 45 years64_{.
Risk
factors
modification
could
prove
to
be}

a challenging task in these people.

2.7. Prognosis after MI

Initial studies in the 1980s and 1990s suggested that outcomes are more favorable in young CHD patients (most studies of patients <45 years) than any group of older patients for up to 7 years following hospitalization17,19,53,64,76_{.
This
is}

consistent with other studies that have found younger age to be an independent prognostic factor of favorable clinical course following AMI in all age ranges, with younger patients having decreased recurrence of coronary events77_{.
Cole
et
al
have}

found that the mortality in young patients with MI was as high as 30% at 15 year follow up9_{.
Part
of
this
high
mortality
may
be
attributable
to
inclusion
of
a
significant}

number of patients with diabetes mellitus and ejection fraction less than 30%. Additional studies have also indicated that sudden death may be higher in the younger population61,77_{.
Future
studies
should
seek
to
determine
more
accurate
long-‐}

(13)

3. INTERVENTIONAL CARDIOLOGY: FROM THE CORONARY

ANGIOPLASTY TO THE EVEROLIMUS-‐ELUTING STENT

3.1. Historical background

Coronary angioplasty, conceptually described by Dotter and Judkins in 1964, was first performed by Andreas Gruntzig in 197778_{.
Coronary
stents
were
developed
in}

the mid-‐1980s and since then have seen major refinements in design and composition79_.

3.1.1. Plain old balloon angioplasty

The angioplasty procedures performed initially were without stent deployment, a technique that is now referred as plain old balloon angioplasty (POBA). POBA undoubtedly revolutionized the treatment of coronary artery disease. However, the outcomes were compromised by re-‐narrowing of coronary arteries due to acute vessel closure for dissection or elastic recoil, late vascular negative remodeling and neointimal hyperplasia80_{.
Elastic
recoil
usually
occurred
in
5–10%
patients}

immediately (minutes-‐hours) after the procedure leading to a rebound occlusion of the artery, which often led to severe complications, including acute myocardial infarction and the need for emergency coronary artery bypass grafting (CABG). Angioplasty-‐induced endothelial cells denudation and medial tearing also exposed circulating blood cells to the sub-‐endothelial matrix leading to platelet aggregation and thrombosis, and hence contributing to acute closure of the artery81_{.
Balloon}

injury also initially induced medial smooth muscle cell necrosis, followed by a phase of coordinated proliferation of medial smooth muscle cells and subsequent migration of these cells into the intima in response to the release of chemo-‐attractants such as the platelet-‐derived growth factor81,82_{About
80%
of
the
migrating
cells
are
reported}

to be in the G1 and S phases of the cell cycle resulting in further proliferation of these intimal smooth muscle cells83_{.
This
neointimal
proliferation
leads
to
post-‐angioplasty}

restenosis84_.

Coronary stents were, therefore, developed to overcome these issues, by scaffolding the balloon-‐dilated artery, sealing the dissection flaps and preventing late recoil. The vast majority of PCI procedures performed currently involve balloon angioplasty and stent deployment.

(14)

3.1.2. Development of coronary stents

WALLSTENT® (Schneider AG), a self-‐expanding, stainless steel wire-‐mesh structure, was the first coronary stent implanted in a human coronary artery by Sigwart et al. in 198685_{The
technical
challenges
in
using
the
stent
delivery
system
(an}

inner shaft and outer constraining sheath) limited its clinical utility and it was withdrawn from market in 1991. Schatz and co-‐workers developed the Palmaz-‐ Schatz® (Johnson & Johnson) stent in 1987, the first Food and Drug Administration-‐ approved stent in the USA79_{.
It
was
the
first
balloon-‐expandable,
stainless
steel,}

slotted tube device and remained one of the most studied and widely used stent in 1990s. Many other stents were subsequently developed in early 1990s and included: Flexstent® (Cook), Wiktor® (Medtronic), Micro® (Applied Vascular Engineering), Cordis® (Cordis) and Multi-‐link® (Advanced Cardiovascular Systems). The use of these stents, indeed, reduced early elastic recoil and restenosis seen with POBA86_.

However, this new technology was not without its drawbacks. These initial stents had high metallic density, resulting in a high incidence of sub-‐acute stent thrombosis (ST), and were bulky and technically challenging to use, resulting in frequent failure in deployment and embolization87_{.
Furthermore,
these
initial
coronary
stents,
although}

reduced the incidence of restenosis compared with POBA, were still at a significant risk of in-‐stent restenosis (ISR)87_{.
These
technical
challenges
and
potential}

complications kept the use of stents limited to the cases of acute or threatened closure or restenosis after POBA. In 1993, two landmark trials, the Belgium Netherlands Stent Arterial Revascularization Therapies Study (BENESTENT) and the North American Stent Restenosis Study (STRESS), demonstrated superiority of the bare metal stents (BMS) over POBA, thus establishing coronary stent implantation as an accepted standard of care for PCI88,89_{.
The
use
of
coronary
stents
increased}

exponentially over the next few years and by 1999, stents were used in nearly 85% of PCI procedures.

However, the medium and longer term follow-‐up of BMS revealed as high as 20– 30% incidence of ISR, due to in-‐stent neointimal hyperplasia90_{.
ISR
may
be
associated}

with significant morbidity and mortality and the drug-‐eluting stents (DES) were developed to specifically address the problems of ISR encountered with BMS91_.

(15)

3.1.3. Development of DES

Development of DES was another revolution in interventional cardiology. Various compounds targeting inflammation, platelet activation, thrombosis and vascular smooth muscle cells proliferation were tried. Coating BMS with gold (thought to be inert), carbon (like diamond), phosphorylcholine (PC) (mimicking the cell membrane) and heparin (to prevent thrombosis), amongst many others, did not confer any benefit. Activation or antagonism of various hormonal receptors, including estrogen, glucocorticoids and mineralocorticoids, had modest effects92-‐94_.

However, coating BMS with anti-‐proliferative drugs sirolimus or paclitaxel substantially reduced ISR compared with BMS95-‐97_{.
Sirolimus
(rapamycin;
an}

immunosuppressive compound derived from a fungus found on Easter Island, known as Rapa Nui) acts by receptor inhibition of the mammalian target of rapamycin (mTOR), resulting in the cessation of cell-‐cycle progression in the late G1 to S phases and, consequently, inhibits vascular smooth muscle cells proliferation98_{.
Paclitaxel
(a}

well-‐known anti-‐cancer drug derived from Taxus brevifolia, the Pacific Yew tree) inhibits cell proliferation and migration by disturbing cellular microtubule organization99_{.
These
drugs
were
incorporated
within
a
polymer
and
coated
on
the}

surface of BMS, and were released slowly over a few weeks after stent deployment. Eduardo Sousa implanted the first sirolimus-‐eluting stent in 1999 and it became available for clinical use as CYPHER® (Cordis) stent in 2002. CYPHER® has been tested in numerous randomized controlled trials (RCTs), showing a significant reduction in ISR and target vessel revascularization compared with BMS95,96,100_.

TAXUS® (Boston Scientific), a paclitaxel-‐eluting stent (PES), closely followed CYPHER® and again many randomized controlled trials (TAXUS 1-‐IV) confirmed its efficacy against BMS97,101_.

In 2006, a potential safety issue emerged with reports linking DES with the increased risk of ST. This issue might be due to delayed endothelialization by the anti-‐ restenotic drugs or delayed hypersensitivity reaction to the polymer in DES102-‐104_.

The concern of ST with the first generation of DES transiently reduced the use of DES and stimulated many studies furthering research into the mechanism of ST and development of novel anti-‐ platelet agents, better polymers and newer generation DES105-‐108_.

(16)

3.1.4. Development of adjunctive anti-‐platelet therapy

The presence of exposed metal struts in the coronary arteries acts as a nidus for platelet aggregation and thrombosis, and the early use of stents was associated with a high risk of ST. This potentially devastating complication is associated with a 50% incidence of acute MI and a 20% mortality rate109_{Initially,
it
was
tackled
by
the
use
of}

complex anticoagulation regimens using aspirin, heparin and warfarin, but this combination led to high rates of major bleeding, vascular complications and prolonged hospital stays.

The development of new antiplatelet agents led to a breakthrough in the use of coronary stents with the adoption of a dual anti-‐platelet treatment (DAPT), combining aspirin with a thienopyridine110_{.
Aspirin
and
ticlopidine
were
used}

initially; however, ticlopidine was soon replaced with clopidogrel, which is more effective and better tolerated. Clopidogrel is a pro-‐drug that after hepatic P450 metabolism to an active compound, irreversible inhibits the P2Y12 receptors on

platelets. PCI-‐CURE trial showed that in patients with acute coronary syndrome (ACS) receiving aspirin, a strategy of clopidogrel pre-‐treatment followed by long-‐term therapy is beneficial in reducing major adverse cardiac events (MACE), compared with placebo111_{.
Clopidogrel
is
a
pro-‐drug,
which
requires
hepatic
activation
by
P450}

system, and consequently numbers of patients are clopidogrel resistant or poor responders. Therefore, newer P2Y12 inhibitors, prasugrel and ticagrelor have been developed in recent years112_{.
Prasugrel
therapy
in
ACS
patients
undergoing
PCI
has}

significantly reduced rates of ischemic events, including ST, but with an increased risk of bleeding and no effect on mortality113_{.
Ticagrelor,
a
non-‐thienopyridine
derivative}

P2Y12 inhibitor, is an active drug, which following intestinal absorption can rapidly achieve adequate levels of platelet inhibition and has shown mortality benefit in patients with ACS, in comparison with clopidogrel.

3.2. Drug-‐Eluting stent design

Each DES has three components: platform, polymer and drug. Over the past decade, biomedical engineers periodically re-‐examined each component to improve on overall stent design and achieve the ideal characteristics of flexibility, trackability, radial strength, and biocompatibility.

(17)

3.2.1. Stent platform

Traditionally, relatively thicker stainless steel struts were the material used for most BMS and first generation DES scaffolds. Stents with thinner struts were found to be more deliverable and to have reduced arterial damage when deployed114,115_.

Moreover, they elicit less inflammation than a thick strut stent, further reducing the propensity for restenosis and ST114_{.
In
addition,
thinner
struts
create
fewer}

disturbances of blood flow patterns around a strut leading to less recirculation and stagnation of blood pool and have been shown to be less thrombogenic, thereby, reducing the risk of ST116_{.
Cobalt
chromium
and
platinum
chromium
alloy
scaffolds}

have been introduced into the design of most second generation DES providing thinner struts with better radial strength and deliverability with less inflammation and thrombogenecity, all of which have resulted in better safety and efficacy outcomes116_.

3.2.2. Polymer coating

The metallic strut of a stent is coated with polymer that serves to deposit and steadily release the antiproliferative drug.

To be successful, polymers required two characteristics: predictable drug release over a targeted period of time and minimization of local inflammation117,118_.

3.2.3. Antiproliferative drug

In search of the ideal antiproliferative drug, three characteristics needed to be met: (1) wide therapeutic window, (2) lipophilic properties, and (3) long enough tissue retention time such that the endothelium could regrow after PCI-‐induced injury without a neointimal hyperplasia pattern.

Over time, the dosage of the antiproliferative drug was reduced and more biocompatible agents were used in newer stent designs. First generation DES contained paclitaxel and sirolimus, whereas second generation DES contained everolimus and zotarolimus as the antiproliferative agent119,120_{.
Drugs
such
as}

everolimus have been shown to have antiplatelet properties, potentially contributing to cobalt chromium EES superb clinical performance.

(18)

3.3. Current generation of drug-‐eluting stents

As we exposed in the previous paragraph, the first two DES to be approved in the United States were the sirolimus-‐eluting stent (SES) in 2003 and paclitaxel-‐eluting stent (PES) in 2004. They are now often referred to as "first generation" DES. SES are no longer available in the United States and Europe and PES are infrequently used due to superiority of second generation stents.

In 2008, the zotarolimus-‐eluting stent (ZES) and the everolimus-‐eluting stent (EES) were approved for use and they are referred to as "second generation" DES. The newer DES have a stent platform of a cobalt-‐cromium or platinum-‐chromium alloy and are thinner and more deliverable than the first generation DES. In addition, second generation DES are more biocompatible than first generation DES: they may generate less inflammatory response and have more rapid vessel endothelialization or healing. This biocompatibility and associated reduced inflammatory response is likely due to improvements in polymer technology and may translate into lower rates of myocardial infarction and stent thrombosis121,122_{.
However,
despite
this
potential}

improvement in biocompatibility, the recommended duration of dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is 12 months, similar to the first

generation DES107_.

3.3.1. Everolimus-‐eluting stents

Two versions of the everolimus-‐eluting stents are available: one with cobalt-‐ chromium alloy, the Xience-‐V® (Abbott Vascular) and another with platinum-‐ chromium alloy, the Promus Element® (Boston Scientific). Relating the design and the pharmacology, the two stents only differs for the material composition. The main characteristics of those EES are summarized in table 2.

Everolimus is a semi-‐synthetic sirolimus derivative in which the hydroxyl group at position C40 of sirolimus has been alkylated with a 2-‐hydroxyethyl group and that was shown in early small studies to be effective at preventing restenosis123_{.
It
is}

slightly more lipophilic than sirolimus, and therefore it is more rapidly absorbed into the arterial wall. Everolimus is in use in durable polymer and bioabsorbable polymer devices.

Xience-‐V and Promus Element were found to have similar efficacy and safety in the PLATINUM trial, which randomly assigned 1530 patients with one or two de novo

(19)

native lesions to one stent design or the other124_{.
The
12-‐month
rates
of
target
lesion}

failure (a composite of target vessel-‐related cardiac death, target vessel-‐related myocardial infarction, or ischemia-‐driven target lesion revascularization) were 2.9% and 3.4%, respectively.

Table 2. Main characteristics of EES

Xience-‐V Promus Element

Manufacturer Abbott Vascular Boston scientific

Platform Vision Omega

Design

Material Cobalt-‐chromium Platinum-‐chromium

Thickness of struts (μm) 81 81

Polymer PBMA, PVDF-‐HFP PBMA, PVDF-‐HFP

Polymer thickness (μm) 7.6 6

Drug conc. (μg/cm2₎ ₁₀₀ ₁₀₀

Drug release in 4 weeks 80% 80%

The Clinical Evaluation of XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients with De Novo Coronary Artery Lesions III (SPIRIT III) trial randomized 1002 patients to EES-‐CoCr versus PES and demonstrated a significant 43 % relative reduction in composite MACE at 9 months with EES-‐CoCr, primarily due to fewer MIs and TLR procedures121_{.
These
outcomes
persisted
to
3
years,
suggesting}

improved long-‐term safety and efficacy125_{.
The
SPIRIT
IV
trial
demonstrated
similar}

results in more complex coronary lesions at 9-‐month and 2-‐year follow-‐up124,126

However, it remained unclear whether it was the rapamycin derivative, the CoCr platform with thinner struts, or some combination of both which had a beneficial effect on out-‐ comes. To further delineate the underlying mechanism of benefit with EES-‐CoCr, the Comparison of Everolimus Eluting XIENCE V Stent with Paclitaxel Eluting TAXUS LIBERTE Stent in All Comers (COMPARE) trial compared EES-‐CoCr with the newer Taxus Liberte PES, which remained on the original stainless steel platform but had strut thickness com-‐ parable to second-‐generation DES. This study demonstrated a reduced rate of the composite outcome of death, MI, and TVR with

(20)

EES-‐CoCr compared to Taxus Liberte PES (6 vs. 9 %, p=0.02) at 1-‐year follow-‐up127_.

The benefit with EES-‐CoCr was maintained at 2-‐year follow-‐up despite a significantly lower percentage of dual antiplatelet therapy use in the EES-‐ CoCr group and suggested, again, the superiority of rapamycin derivatives over paclitaxel128_.

The SORT OUT IV trial compared rapamycin derivatives on the second-‐generation CoCr versus first-‐generation stain-‐ less steel platforms, EES-‐CoCr versus SES. Although EES-‐ CoCr was non-‐inferior to SES on the primary composite end-‐ point of cardiac death, MI, definite ST, and TVR at both 9 months and 2 years, EES-‐CoCr was associated with a lower rate of definite ST at 2 years129_.

The Randomized evaluation of Sirolimus Eluting Versus Everolimus Eluting Stent (RESET) trial demonstrated similar non-‐inferiority of EES-‐ CoCr to SES on TLR at 1 year, while a propensity score-‐ matched analysis demonstrated significant reductions in MI, TVR, and definite ST with EES-‐CoCr compared to SES on median follow-‐up of 1.5 years130_{.
A
meta-‐analysis
of
trials
comparing
EES-‐CoCr
versus
SES,
however,}

showed no significant difference in MACE or composite of definite and probable ST on median follow-‐up of 13 months131_{.
Al-‐
though,
the
difference
between
EES-‐CoCr
and}

SES was not apparent on short-‐term follow-‐up, 3-‐year follow-‐up in the SORT OUT IV and the recently published Randomized Comparison of Everolimus Eluting Stents and Sirolimus Eluting Stent in Patients with ST Elevation MI (RACES-‐MI) trials demonstrated no significant difference in MACE but significant reductions in overall and very late definite ST132_.