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Antithrombotic Drug Therapy in Cardiovascular Disease
(PCI) have improved the ability to restore flow in an infarct related artery, the majority of benefits can
be attributed to enhanced adjunctive pharmacotherapies.
The inciting events of a non-ST-segment-elevation myocardial infarction (NSTEMI) are, most often,
erosion and rupture of atherosclerotic plaque(s) within the coronary tree
(1). With the rupture of the
atherosclerotic plaque, the sub-endothelial matrix and lipid core of the plaque are exposed to circulat-
ing pro-thrombotic factors including tissue factor and von Willebrand Factor (vWF). vWF, a key com-
ponent to the initiation of thrombosis, binds to the subendothelial collagen matrix and is then able to
bind platelets via the combination of shear stress and the glycoprotein (GP) 1b receptor (2,3). The bind-
ing of vWF to the GP 1b receptor has been shown to be important in platelet activation via the P2Y
12
ADP receptor
(4). Once the initial defect in the endothelium has been covered by platelets, the process
of further platelet recruitment, activation, and cross-linking with fibrinogen begins. This sequence of
events forms the basis for understanding the importance of antiplatelet and antithrombotic therapies in
NSTEMI.
In the minority of cases, NSTEMI is caused by a fixed stenosis leading to a secondary reduction in
epicardial coronary blood flow such that the oxygen supply cannot meet an increased demand (i.e.,
tachycardia, sepsis, etc). This chapter will expound upon the importance of platelet biology and will
discuss the present and future of antiplatelet pharmacotherapy for NSTEMI.
PLATELETS: CONNECTING INFLAMMATION AND THROMBOSIS
Despite their size, platelets are complex and display a wide functionality. In the setting of plaque
rupture, after initial platelet response, activated platelets are then able to attract other platelets to the
site of injury in a paracrine fashion. This is mediated through platelet-derived factors such as adeno-
sine diphosphate (ADP) and thromboxane A2 (TXA-2). Platelet activation results in a conformational
change that includes the externalization of glycoprotein IIb/IIIa (GP IIb/IIIa) receptors, essential
receptors that facilitate the cross-binding of platelets to fibrinogen and the formation of a stable
thrombus. Since there are several pathways that facilitate platelet activation, different antiplatelet
therapies are often used in combination to optimize outcomes.
In addition to their prothrombotic properties, platelets can exert potent inflammatory effects
through a variety of platelet-derived receptors, adhesion molecules, and mediators including CD40L
and P-selectin. Interactions between these molecules and receptors on the surface of other cell types
ultimately leads to the recruitment of leukocytes, further release of inflammatory mediators, and the
perpetuation of a prothrombotic state
(5,6).
Clinically, sCD40L has been related to adverse outcomes in patients presenting with ACS (7) and
following presentation for ACS (8). The use of glycoprotein IIb/IIIa inhibitors, such as abciximab, has
been shown to be of benefit in those with ACS, especially with elevated levels of sCD40L (7). P-selectin
has also been shown to predict adverse cardiovascular events in otherwise healthy patients
(9).
CURRENT ANTIPLATELET THERAPIES IN NON-ST-SEGMENT
MYOCARDIAL INFARCTION
Aspirin
The intra-platelet metabolism of arachadonic acid into TXA2 facilitates activation of other plate-
lets. These steps are driven by the action of the enzyme, cyclo-oxygenase-1 (COX-1). Aspirin is a
well-known irreversible inhibitor of the COX-1 enzyme and, subsequently, of TXA2 production and
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platelet activation. Because of its potent antithrombotic properties, aspirin use in coronary atheroscle-
rosis has been studied extensively.
The beneficial effects of aspirin in unstable angina/NSTEMI have been demonstrated across broad
populations of patients, with either short or long-term administration, and in comparison to other anti-
thrombotic therapies. A few landmark trials, conducted prior to the widespread use of clopidogrel, glyco-
protein IIb/IIIa inhibitors, and an early invasive approach, established aspirin as the backbone of therapy
for patients with an ACS. The Veterans Administration (VA) Cooperative Study was one of the first multi-
center, double-blinded, randomized trials examining the use of 324
mg of aspirin vs. placebo for 12 weeks
in 1,266 men with unstable angina
(10). The use of aspirin was associated with a significant reduction in
the rate of death or myocardial infarction (p
= 0.0005). The beneficial effects of aspirin were shown to be
durable, despite cessation of aspirin therapy at 12
weeks, with a significantly lower mortality at 1 year in
those treated with aspirin (p
= 0.008). One caveat of this study was the introduction of beta-blocker ther-
apy during the study period and the fact that it was not accounted for in the study protocol.
Cairns et al. reported the results of the Canadian Multicenter Trial in 1985 (11). Five hundred fifty five
patients with unstable angina were enrolled in this randomized, double-blinded, prospective study and
received 325 mg of aspirin (4×/day), sulfinpyrazone 200 mg, a combination of both therapies, or placebo
(11). While enrollment was not limited to men and follow up was over a longer period, the results were
equally dramatic with a significant reduction in the composite of death and nonfatal myocardial infarction
over a mean of 18 months (p = 0.008). There was no apparent benefit with sulfinpyrazone.
Aspirin has also been examined in comparison to heparin in patients with NSTEMI. The Research
Group on Instability in Coronary Artery Disease (RISC) study examined 796 Swedish men with unsta-
ble angina and compared the effects of intravenous heparin therapy for 5
days after presentation, lower
dose aspirin (75
mg/day oral) for 1 year, both the above, or neither (12). Over a follow-up period of
3
months, there was a clear reduction in the rate of death or non-fatal myocardial infarction in those
patients who received aspirin. The use of IV heparin alone did not confer any obvious benefit; however,
during the first 5 days of the study, the combination of heparin and aspirin together resulted in a signifi-
cant reduction of the primary combined endpoint as compared to heparin or placebo. The benefit of
heparin in ACS was, however, observed in a study by Theroux et al., examining the benefit of intrave-
nous heparin, aspirin (325
mg oral 2×/daily), the combination, or placebo in patients with ACS (13).
Despite the obvious benefit of aspirin in these patients, many patients do not receive appropriate
antiplatelet therapy. The Reduction of Atherothrombosis for Continued Health (REACH) Registry
reported that among 40,450 patients with established CAD, between 10 and 15% of those previously
revascularized were not on any antiplatelet therapy. Furthermore, of those only on medical therapy for
atherosclerotic disease, more than 20% did not receive any antiplatelet therapy (14).
Aspirin Dosing
Aspirin is likely to be one of the most widely used drugs in the world. There are many indications
for its use in cardiovascular disease – it has been shown to be of benefit in the setting of ACS, in
chronic stable coronary disease, and in high-risk primary prevention. However , the optimal dosing
strategy for each of these situations is unknown. The studies described above vary in the dosing of
aspirin used in ACS. The benefit, however, appears to be similar and lasting despite the wide variation
in dosing. The benefit of aspirin in preventing myocardial infarction and ischemic stroke may be
countered by an increased risk of bleeding (primarily gastrointestinal) and hemorrhagic stroke
(15,16). In gastric mucosa, the inhibition of cyclo-oxygenase-1 (COX-1) results in a reduction in
prostaglandin production. Subsequent studies have documented that long term aspirin use has been
associated with increased risk of gastric and duodenal ulceration (17). Data from healthy adult volun-
teers suggest that very high doses of aspirin (2,600 mg/day) can lead to gastric mucosal injury
independent of a prostaglandin-mediated mechanism (18). It has been previously demonstrated
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Antithrombotic Drug Therapy in Cardiovascular Disease
that inhibition of platelet-derived thromboxane occurs at considerably lower doses of aspirin (19,20).
To optimize the dose of aspirin would involve selecting a dose low enough to ensure proper and complete
platelet inhibition without significantly increasing the risk of bleeding.
The optimal dosing of aspirin in the setting of primary prevention of coronary atherosclerosis has
been examined. A systematic review examining aspirin use in the prevention of cardiovascular disease
has concluded that the optimal daily dose of aspirin should be between 75 and 81 mg daily to optimize
antiplatelet activity without substantially increasing the risk of bleeding complications
(21).
In the setting of higher risk patients, aspirin dosing becomes a more critical issue. Often, in these
patients, antiplatelet agents or antiplatelet and antithrombotic agents in combination are used. The risk
of bleeding increases substantially with the combination of these agents
(22). Furthermore, elderly
patients appear to be at significantly higher risk of bleeding complications, primarily gastrointestinal
bleeding, with a combination of agents vs. aspirin alone
(23). Data from this same observational
cohort identified age, renal failure, peptic ulcer disease, diabetes, and bleeding during hospitalization
for acute MI as risk factors for bleeding in elderly patients.
The Antithrombotic Trialists’ Collaboration (ATC) examined the question of aspirin dosing in
patients at higher risk of arterial or venous thrombosis, or in those with an acute thrombotic event.
A meta-analysis of 287 studies examining 135,000 patients was conducted to examine the benefit of
various types of antiplatelet and antithrombotic therapies in reducing non-fatal myocardial infarction,
non-fatal stroke, or vascular death. In terms of efficacy, there appeared to be no difference in the pro-
portional reduction in serious vascular events when comparing doses of 75–150
mg (32% ± 6%) to
higher daily doses such as 160–325
mg (26% ± 3%) or 500–1,500 mg (19% ± 3%). Daily doses less
than 75
mg/day appeared to have a slightly smaller benefit (24).
In a substudy of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial,
investigators examined the question of aspirin dosing (£100 mg, 101–199 mg, and ³199 mg) in the
setting of clopidogrel vs. placebo ACS
(25). In 12,562 patients with ACS, an increasing dose of aspi-
rin resulted in a higher risk of major bleeding, without an increase in efficacy and authors conclude
that dosing between 75 and 100 mg/day may be optimal, irrespective of clopidogrel use.
The DUTCH TIA Trial Study Group reported that 30
mg of aspirin per day was as effective in
reducing recurrent events as 283
mg of aspirin per day. In 3,131 patients with a prior TIA, 30 mg of
aspirin was also associated with fewer side effects, including a significant reduction in minor bleeding
complications (26).
Despite the data from these studies, it appears that practice trends are quite different. The Can
Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early
Implementation of the American College of Cardiology/American Heart Association Guidelines
(CRUSADE) initiative suggested that up to 24.1% of patients hospitalized for ACS did not receive
aspirin at discharge and of those who did, the majority of patients received 325 mg/day dosing (27).
For post elective PCI or PCI for ACS, the ACC/AHA/ESC guidelines recommend 325 mg of aspi-
rin once daily for those patients with evidence of aspirin resistance. In addition, it is recommended
that the aspirin be dosed at the 325 mg level for 1 month following bare metal stent implantation, for
3 months following sirolimus-eluting stent implantation and for 6 months following paclitaxel-eluting
stent implantation prior to decreasing the dose to 81 mg indefinitely.
ADP Receptor Blockade (Thienopyridines)
Clopidogrel and ticlopidine are the two currently available drugs, which act to inhibit the function
of the ADP receptor, P2Y
12
. Both of these drugs are present as pro-drugs and require metabolism into
an active form by the liver. ADP mediated activation of the P2Y
12
receptor results in further platelet
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activation in the form of platelet aggregation and response to other platelet stimuli resulting in a
heightened prothrombotic state. Ticlopidine use has been limited given the association with serious
side effects including neutropenia and thrombotic thrombocytopenic purpura
(28).
Ticlopidine
Ticlodipine has been examined in the context of acute coronary syndromes and in the setting of
elective percutaneous coronary intervention (PCI). A randomized, multicenter trial examined patients
with unstable angina randomized to conventional therapy alone (n
= 338) vs. conventional therapy
plus ticlopidine 250
mg b.i.d. (n = 314). The investigators followed patients for 6 months and found
that those treated with a combination of conventional therapy and ticlopidine had a relative risk reduc-
tion of 46.8% in vascular death whereas a relative risk reduction in non fatal myocardial infarction of
46.1% was noted in the group treated with combination therapy
(29).
Ticlopidine was also examined in the context of acute myocardial infarction following thromboly-
sis in 1,470 patients randomized to either aspirin (160
mg/day) or ticlopidine (500 mg/day). There
was a similar rate of death, recurrent myocardial infarction, angina or stroke in both of these groups
(8.0%, p = 0.966). Furthermore there was no significant difference in the rate of adverse reactions
between the two groups
(30).
In the setting of PCI, the use of ticlopidine has been examined (Table
1). A meta-analysis examined
13,955 patients enrolled in these trials and found that clopidogrel provided an advantage with regard
to major adverse cardiac events and notably all cause mortality at 30 days (p = 0.001), suggesting
improved efficacy of clopidogrel over ticlopidine in the setting of PCI
(31).
Clopidogrel
The use of clopidogrel in both secondary prevention and ACS been extensively examined. In the
Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel was com-
pared to aspirin for purposes of secondary prevention. In 19,185 patients, the use of clopidgrel was
associated with an 8.7% reduction in the risk of ischemic stroke, vascular death, or myocardial infarc-
tion without an increase in adverse events (32).
Given the potential complimentary role of ADP receptor inhibitors to aspirin in platelet inhibition,
it is no surprise that the combination serves as a potent antithrombotic entity (33). In the setting of
PCI, the Clopidogrel for Reduction of Events During Observation (CREDO) study examined the
combination of clopidogrel and aspirin in 2,116 patients undergoing PCI with patients randomized to
either a 300 mg-loading dose of clopidogrel followed by 75 mg/day for 1 year vs. 75 mg/day for
28 days (34). At 28 days, the group receiving the loading dose of clopidogrel had an 18.5% relative
risk reduction in a combined endpoint of death, myocardial infarction, or urgent target vessel revas-
cularization (p
= 0.23). At 1 year, there was an observed 26.9% relative risk reduction in the same
combined endpoint (p = 0.02) and the curves started to separate quite early from randomzation.
Interestingly, a post-hoc analysis suggested that patients randomized to a loading dose of 300 mg of
clopidogrel greater than 6 h before PCI experienced a 38.6% relative risk reduction in the combined
endpoint vs. no benefit in those receiving the loading dose <6 h to PCI.
In the setting of ACS, clopidogrel has been examined in many trials. In acute ST elevation myo-
cardial infarction (STEMI), the use of clopidogrel has been examined in two large trials. The
Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) assessed the effect of either
aspirin or aspirin and clopidogrel in 45,852 patients with AMI. In those receiving both aspirin and
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Table 1
Trials of ticlopidine in the setting of percutaneous coronary intervention
Trial # of Pts Treatment groups Primary endpoint Results Comments
CLASSICS
(66)
n = 1,020 Randomized to:300 mg
Clopidogrel loading then
75 mg/day/325 mg ASA
vs. 75 mg Clopidogrel and
ASA 325 vs. 250 mg bid
Ticlopidine/325 mg ASA
Combined: major
bleeding complications,
neutropenia,
thrombocytopenia, or
discontinuation due to
noncardiac adverse event
Primary endpoint
occurred in 9.1% of
ticlopidine group vs.
4.6% of clopidogrel
(p = 0.005)
No difference in
major adverse
cardiac events
between the
groups noted
FANSTASTIC
Study (67)
n = 485 Randomized to ASA (100–
325 mg/day) and:Ticlopidine
250 mg bid × 6 weeks vs.
oral anticoagulants for
6 weeks
Combined: bleeding, or
peripheral vascular
complications, secondary
include cardiac events
and duration of
hospitalization
Primary endpoint: 13.5%
of ticlopidine vs. 21%
of oral anticoagulation
(p = 0.03). MACE
and hospital duration
were shorter in
the ticlopidine
group (p
= 0.01 and
p = 0.0001)
Muller et al.
(68)
n = 700 Randomized to 4 weeks of
500 mg/day of ticlopidine
or 75 mg/day of clopidogrel
after elective/urgent PCI
(ASA as standard of care)
Combined primary cardiac:
of death, urgent TVR,
stent thrombosis, or non
fatal MI within 30 days
No difference in the
primary cardiac
endpoint which
occurred in 1.7%
on ticlopidine and
3.1% on clopidogrel
(p = 0.24)
Noncardiac events
were higher in
the ticlopidine
population
(p
= 0.01)
Taniuchi et al.
(69)
n = 1,016
(522 to
clopidogrel
and 494 to
ticlopidine)
Randomized to either
clopidogrel or ticlopidine
after PCI. Patients on
325 mg/day of ASA and GP
IIb/IIIa inhibitor at discretion
of operator
Primary: Failure to
complete thienopyridine
therapy in addition
to ASA. Secondary
combined endpoints
were thrombocytopenia,
bleeding, cardiac
death, NSTEMI, stent
thrombosis or TVR
The primary endpoint
occurred in more
patients on ticlopidine
(p = 0.04). There were
no differences in
the other outcomes
between groups
No significant
differences
in rates of
thrombocytopenia
between groups
using GPIIb/IIIa
inhibitors
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Dangas et al.
(70)
n = 827 Retrospective, examining
those having undergone PCI
and then received either
clopidogrel or ticlopdine in
addition to ASA. Ticlopidine
was loaded at 500 mg pre
PCI and then 250 mg bid for
2–4 weeks
30-day follow up to
examine the incidence
of stent thrombosis
While not statistically
significant, there was
a slightly higher rate
of subacute stent
thrombosis with ASA
and clopidogrel
A total of only
6 episodes of
subacute stent
thrombosis
occurred in the
study at 30 days
Berger et al.
(71)
n = 500
consecutive
patients with
clopidogrel
and 827
consecutive
patients
receiving
ticlopidine
Comparison of consecutive
patients having received
clopidogrel after PCI vs.
those having received
ticlopidine (non randomized)
30-day incidence of adverse
cardiac events including
death, non-fatal MI,
repeat PCI or bypass
surgery
There was no significant
difference in outcomes
between the two
groups with regards
to adverse cardiac
outcomes
Patients treated with
clopidogrel were
older, had more
severe angina and
more frequent MI
within preceding
24 h
CLASSICS Clopidogrel Aspirin Stent International Cooperative Study; FANTASTIC full anticoagulation vs. aspirin and ticlopidine after intracoronary stenting; MACE
Major adverse cardiac events; TVR target vessel revascularization; MI myocardial infarction; ASA aspirin; GP IIb/IIIa glycoprotein IIb/IIIa inhibitor; PCI percutane-
ous coronary intervention; NSTEMI non-ST segment elevation myocardial infarction
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Antithrombotic Drug Therapy in Cardiovascular Disease
clopidogrel, there was a significant reduction in mortality (p = 0.03) and in the risk of death, reinfarc-
tion, and stroke (p
= 0.002) (35).
The other large study examining the efficacy of clopidogrel in AMI was the Clopidogrel as
Adjunctive Reperfusion Therapy Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28)
Trial, which randomized 3,491 patients with AMI to clopidogrel vs. placebo following fibrinolysis for
AMI. In those receiving clopidogrel in addition to fibrinolysis and aspirin, there was a 20% risk reduc-
tion of a combined endpoint of 30
day death from cardiovascular causes, myocardial infarction, or
need for urgent revascularization
(36).
In the setting of unstable angina/NSTEMI, the CURE trial examined the question of whether the addi-
tion of clopidogrel to aspirin in the setting of unstable angina or NSTEMI led to a reduction in the first primary
outcome, a combination of death from cardiovascular causes, non fatal myocardial infarction, or stroke.
A second primary endpoint consisting of the first primary endpoint or recurrent ischemia was also
examined. In total 12,562 patients were randomized to either aspirin and placebo or aspirin and clopi-
dogrel (300
mg loading dose and then 75 mg/day). Patients were eligible if they presented within 24 h
of onset of symptoms
(37). Patients randomized to clopidogrel and aspirin were noted to have a 20%
relative risk reduction in the first primary outcome (p
< 0.001). Within this first primary outcome,
patients receiving clopidogrel and aspirin had a 40% reduction in ST elevation myocardial infarctions.
Furthermore, the same group had a 14% relative risk reduction in the second primary endpoint. This
benefit came at the expense of a significant increase in major bleeding in the treatment group
(p = 0.001), although not in life threatening bleeding (p = 0.13) (37).
The benefit of clopidogrel therapy in ACS was noticeable in the first 24
h following treatment.
At this time point there was a statistically significant reduction in the combined second primary
endpoint. Withholding clopidogrel treatment by even 1
day resulted in a significant loss in the benefit
observed during the first day of treatment. It is unclear if part of the short term benefit is due to the
possibility of prevention of rebound hypercoagulability following heparin cessation (38). Incremental
benefit of clopidogrel therapy was noted between 30
days and 12 months from randomization with an
18% relative risk reduction in the combined primary endpoint
(39).
PCI-CURE was a planned prospective substudy of the original CURE trial. This intention to treat
analysis examined 2,658 patients with UA or NSTEMI who underwent PCI. Patients were pretreated
with a combination of aspirin and placebo or clopidogrel for a median of 6
days prior to PCI.
Following PCI, >80% of patients were placed on an “open-label” thienopyridine for 4
weeks, after
which the original study drug (placebo or clopidogrel) was resumed. The primary combined endpoint
of cardiovascular death, myocardial infarction, or urgent target-vessel revascularization was seen in
6.4% of the placebo group vs. 4.5% for the treatment group (p = 0.03) (40). This benefit was observed
at both 30 days post-PCI and up to 8 months post-PCI for cardiovascular death and myocardial infarction.
Interestingly, the group randomized to clopidogrel showed less utilization of a glycoprotein IIb/IIIa
inhibitor. Furthermore, the benefit of clopidogrel was realized regardless of the timing of PCI following
presentation (41).
In summary, the current data on thienopyridine, primarily clopidogrel, use suggests that their efficacy
is about equivalent to that of aspirin. Furthermore, the combination of dual antiplatelet therapy (aspirin
and thienopyridine) provides an incremental benefit beyond either of them alone in elective PCI and
across the spectrum of ACS (NSTEMI and STEMI). In the setting of elective PCI, early pretreatment
with a thienopyridine may provide more benefit than starting at or after the time of PCI. It is also impor-
tant to realize that the effects of this therapy begin early after initiation and last up to 1 year.
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Drug Eluting Stent Thrombosis and Clopidogrel Therapy
Recent enthusiasm for the use of drug eluting stents (DES) in reducing clinical and angiographic
restenosis seen with bare metal stents has been dampened by the very real and catastrophic risk of
stent thrombosis. Stent thrombosis, both subacute and late, in DES has been observed following PCI.
McFadden et
al. reported four cases of angiographically confirmed late stent thrombosis following
PCI with DES
(42). Nasser et al. also reported two cases of stent thrombosis occurring in the setting
of non-cardiac surgery following cessation of all antiplatelet therapy
(43).
The Basel Stent Kosten Effektiviats Trial – Late Thrombotic Events (BASKET-LATE) study exam-
ined this question in patients randomized to either bare metal stents or drug eluting stents. Following
PCI, patients were treated with dual antiplatelet therapy for 6
months and after this time clopidogrel was
discontinued. The rates of nonfatal myocardial infarction and cardiac death or nonfatal myocardial
infarction were significantly higher in the group receiving DES after dual antiplatelet therapy was
stopped. Furthermore, cardiac death or the combination of cardiac death and nonfatal MI were more
frequently related to thrombosis
(44).
However, the issue regarding the true incidence of stent thrombosis remains controversial. This was
partly driven by the lack of a consistent definition of stent thrombosis, be it angiographic or clinical.
There have been several studies, including many meta-anlayses of larger clinical trials of drug eluting
stents, attempting to quantify the risk associated with DES use vs. bare metal stents and they are
described in Table 2. The rate of DES stent thrombosis after 1 year remains low overall. In some of
these studies, the rate remains even lower than others. This may, in part, be due to “off label” vs. “on
label” usage of these coronary devices. “Real world” or increased off-label usage of DES appears to
confer a higher risk of stent thrombosis as noted in the Swedish Coronary Angioplasty and
Angiography Registry (SCAAR) study, which used propensity analysis to compare 19,771 patients,
who had undergone PCI with either BMS or DES
(45). They concluded that over a 3-year period the
risk of death was significantly higher with DES use. Although the specifics relating to duration of
clopidogrel therapy were not reported, the excess mortality as compared to the large-scale clinical
trials raises concern. Iakovou and colleagues examined this question of predictors of stent thrombosis
in a “real world” population and at 9
months follow up found that there was a higher rate of stent
thrombosis than noted in the clinical trial data and that premature discontinuation of antiplatelet
therapy, the presence of diabetes, left ventricular dysfunction, renal failure, and bifurcation lesions
were predictive of stent thrombosis
(46).
The role of dual antiplatelet therapy following PCI with DES appears to have meaningful signifi-
cance in reducing clinical events associated with DES. In an observational study of 4,666 patients
undergoing PCI with either DES (n
= 1,501) or BMS (n = 3,165), the ongoing use of clopidogrel
therapy was associated with lower rates of death up to 1 year and death or MI up to 2 years (47).
Similar findings were seen in a prospective analysis of 500 patients having received DES for acute
MI where cessation of thienopyridine therapy by 30 days post PCI was associated with higher mortal-
ity rates (48). These findings are in contrast to clinical trial data, which tested the duration of dual
antiplatelet therapy for either 3 or 6 months. Currently, the optimal duration of dual antiplatelet
therapy following PCI with DES is not known. Although recommendations currently call for dual
antiplatelet therapy for at least 1 year following PCI with DES, the optimal duration of therapy, in
terms of risks and benefits, is not known.
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Table 2
Studies examining the risk of stent thrombosis associated with drug eluting stent vs. bare metal stent use with at least 1 year of follow up
Study # of patients Design Follow up Results Comments
Stone et al. (72) 1,748 for sirolimus vs.
placebo and 3,513
for paclitaxel vs.
placebo
Pooled analysis of 4 tri-
als of sirolimus stents
vs. BMS and 5 trials
of paclitaxel stents vs.
BMS
4 years After 1 year, rates of ST
were higher vs. BMS in
both types of DES, how-
ever, no increase in death
or MI at 4 years
While rates of TVR
were lower in either
DES group, after
1 year, there was
significantly higher
rates of ST in both
the DES groups
Bavry et al. (73) 6,675 Meta-analysis on 14
clinical trials of either
paclitaxel or sirolimus
eluting stents
>1 year follow up Rates of ST were sig-
nificantly higher in both
DES types vs. BMS,
although overall rates
remained low
The true risk of ST
with DES increased
>6–12
months after
procedure
Kastrati et al. (74) 4,958 Meta-analyis of 14 clini-
cal trials of sirolimus
vs. BMS with primary
endpoint of all cause
mortality, but also
examining ST
12.1–58.9 months
mean follow up
interval
Rates of death, myocardial
infarction, and need for
revasc were all lower
with sirolimus eluting
stents
While the overall risk
of ST was no differ-
ent, after 1 year, the
risk of ST with SES
was slightly higher
Mauri et al. (75) 878 with SES
1,400 with PES
2,267 with BMS
Pooled analysis of 8
trials of both PES
and SES vs. BMS.
Readjudicated out-
comes according to the
ARC definition of ST
4 years Rates of ST by ARC defini-
tion did not differ sig-
nificantly between either
DES group and BMS
group
Authors suggest that
differences in mor-
tality rates between
DES and BMS are
not all attributable
to ST
Airoldi et al. (76) 3,021 with DES
vs. BMS at 4
institutions
Prospective observational
cohort, examining the
incidence of ST
18 months Within 6 months, discon-
tinuation of thienopyrid-
ine therapy was strongest
predictor of ST. At
18 months, 1.9% had ST
Discontinuation of
thienopyridine ther-
apy did not predict
ST beyond 6 months
154
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Antiplatelet Therapies in Unstable Angina and Non-ST Segment Elevation Myocardial Infarction
Ong et al. (77) 2,006 patients with
SES or PES
Prospective observational
cohort examining angi-
ographically proven ST
Mean of 1.5 years Angiographically proven
late ST occurred with an
incidence of 0.35%
ST occurred in this
population in
patients on only
antiplatelet mono-
therapy
Lagerqvist et al.
(45)
6,033 with DES,
13,738 with BMS
Retrospective, propensity
matched study compar-
ing outcomes between
DES and BMS usage
3 years After 6 months, there was a
significantly higher mor-
tality rate with DES use
Reflects “off label” use,
however, unclear
if the early gain
observed with DES
is due to clopidogrel
use at this time, not
accurately quantified
BMS Bare metal stent; ST stent thrombosis; TVR target vessel revascularization; DES drug eluting stent; SES sirolimus eluting stent; PES paclitaxel eluting stent; ARC
academic research consortium
155
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