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Antiplatelet Therapies: Aspirin, Clopidogrel and Thienopyridines
American Heart Association/American College of Cardiology (AHA/ACC) practice guidelines give
a Class I (evidence that treatment is beneficial and effective) recommendation for aspirin to be chewed
by patients who have not taken the medication before presentation with STEMI
(7). The initial dose
should be between 162 and 325
mg and continued indefinitely at a daily dose of 75–162 mg (8). For
initial dosing, non-enteric-coated formulations are favored due to more rapid buccal absorption
(9). The
main contraindication to aspirin use is a hypersensitivity to salicylate. In patients with true aspirin allergy
(hives, nasal polyps, bronchospasm, or anaphylaxis), clopidogrel or ticlopidine may be substituted,
although likely a thienopyridine may already be indicated itself as adjunctive therapy (see below).
Failure to respond to aspirin may be caused by an inadequate primary pharmacological effect,
known as “aspirin resistance.” Depending on the population studied, the assay used, and the definition
applied, the prevalence of aspirin resistance has ranged from 5% to 65%
(10). Aspirin resistance, as
defined by an aggregation-based rapid platelet function assay, was associated with an increased risk of
adverse clinical outcomes in stable patients with coronary artery disease
(11). Furthermore, in high-risk
aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 (a marker of in
vivo
thromboxane generation and therefore aspirin resistance) predicted the future risk of myocardial infarction
(MI) or cardiovascular death (12). The clinical ramifications of aspirin resistance in STEMI management
have not yet been clearly defined, although it is unlikely to play a major role
(13). Monitoring of
antiplatelet activity is mainly done for investigational purposes at the present time
(14).
THIENOPYRIDINES
As more has become known about the pathogenesis of plaque rupture and clot formation, there has
been increasing interest in evaluating more potent antiplatelet agents. The thienopyridine derivative
clopidogrel is an oral antiplatelet agent that inhibits platelet activation and aggregation by targeting
the P2Y
12
ADP receptor (15). Ticlopidine, another thienopyridine and quite similar chemically to
clopidogrel, can cause the adverse effects of neutropenia and thrombotic thrombocytopenic purpura.
Both agents are prodrugs requiring hepatic metabolism to form their active metabolites that irreversibly
bind to the P2Y
12
receptor. Given the fewer side effects, lack of need for laboratory monitoring, and
once-daily dosing clopidogrel is the preferred agent
(16).
Dual antiplatelet treatment, with aspirin and a thienopyridine, decreases the incidence of death or
ischemic complications in the setting of percutaneous coronary intervention (PCI) (17) and when
given upstream in patients presenting with non ST-segment elevation (NSTE) ACS
(18).
Pharmacologic Reperfusion
The CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in
Myocardial Infarction 28) trial was a placebo-controlled, double blinded trial that enrolled 3,491
patients worldwide, aged 18–75 years, within 12 h of STEMI symptom onset (19). Patients were
randomly assigned to receive either clopidogrel (300 mg loading dose, followed by 75 mg once daily)
or placebo at presentation. All patients were to be treated with aspirin (150–325 mg on the first day
and 75–162
mg daily thereafter) and a fibrinolytic. Patients who received a fibrin-specific lytic (69%
of patients) were to receive heparin (unfractionated or low-molecular weight). As per trial protocol,
all patients were to undergo coronary angiography during the index hospitalization (48–192 h after
randomization) in order to assess for late patency of the infarct-related artery.
The primary efficacy endpoint was the composite of an occluded infarct-related artery (defined by
a TIMI flow grade of 0 or 1) at angiography or death or recurrent MI prior to angiography. The last
two served as surrogate markers for failed reperfusion or reocclusion of the infarct-related artery. The
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Antithrombotic Drug Therapy in Cardiovascular Disease
rates of the primary efficacy endpoint were 21.7% in the placebo group and 15.0% in the clopidogrel
group, representing an absolute risk reduction of 6.7% and an odds reduction of 36% with treatment
with clopidogrel (p
< 0.001; Fig. 2). Among the individual components of the primary endpoint, clopi-
dogrel had the greatest effect on reducing the rate of an occluded infarct-related artery (18.4% to
11.7%; p
< 0.001) and the rate of recurrent MI prior to angiography (3.6% to 2.5%; p = 0.08). The
benefit of clopidogrel in reducing the risk of the primary endpoint was observed across all prespeci-
fied subgroups including age, sex, type of heparin, type of fibrinolytic, and infarct location. At 30
days’ follow-up treatment with clopidogrel prior to angiography had significantly reduced the odds of
cardiovascular death, recurrent MI, or recurrent ischemia leading to urgent revascularization by 20%
(from 14.1% to 11.6%; p = 0.03; Fig. 3).
The addition of clopidogrel to fibrinolytic therapy did not significantly increase the risk of TIMI
major bleeding (1.3% with clopidogrel vs. 1.1% with placebo; p
= 0.64), including a similar risk of
intracranial hemorrhage (ICH), (0.5% with clopidogrel vs. 0.7% with placebo; p
= 0.38). Importantly,
of the 136 patients who underwent coronary artery bypass graft (CABG) surgery during their index
Fig. 3. Cumulative incidence curves in the CLARITY-TIMI 28 trial for the endpoint of death from cardiovascular causes,
recurrent MI, or recurrent ischemia leading to the need for urgent revascularization through 30 days’ follow-up.
Fig. 2. Incidence of the primary endpoint, a composite of an occluded infarct-related artery (defined as a TIMI flow
grade of 0 or 1), or death or recurrent MI prior to coronary angiography, in the CLARITY-TIMI 28 trial.
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Antiplatelet Therapies: Aspirin, Clopidogrel and Thienopyridines
hospitalization, there was no excess in major bleeding through 30 days (7.5% with clopidogrel vs. 7.2%
with placebo; p
= 1.00), and there was a trend toward reduction in 30-day ischemic events (20).
In the CLARITY-TIMI 28 trial, clopidogrel therapy did not significantly improve the mean degree
of ST-segment elevation (a non-invasive marker of early reperfusion) at 180
min. However, clopidogrel
was found to improve late angiographical outcomes, including a 36% increase in the odds of optimal
epicardial flow (a TIMI flow grade of 3; p
< 0.0001), a 21% increase in the odds of optimal microv-
ascular perfusion (a TIMI myocardial perfusion grade of 3; p
= 0.008), and a 27% reduction in the
odds of intracoronary thrombus (p
< 0.001), when angiography was performed 2–8 days after randomi-
zation. Furthermore, the largest treatment benefit with clopidogrel was observed in patients who
achieved initial vessel reperfusion, as suggested by either partial (30–70%) or complete (>70%)
ST-segment resolution at 90
min, whereas angiographical or clinical benefit with clopidogrel was not
apparent in patients in the absence of initial ST-segment resolution (p for interaction 0.003)
(21).
These data suggest that clopidogrel appears to improve late coronary patency and clinical outcomes
by preventing reocclusion of the infarct-related artery rather than by facilitating reperfusion.
The second major trial examining the role of clopidogrel in the setting of pharmacologic reperfusion
for STEMI was COMMIT/CCS-2 (the Clopidogrel and Metoprolol Infarction Trial/the Second
Chinese Cardiac Study) (22). This was a randomized trial that used a 2 × 2 factorial design to evaluate
the addition of clopidogrel (75
mg daily, without a loading dose) and metoprolol, both compared with
placebo, in patients with a suspected STEMI within 24
h of symptom onset. The trial enrolled 45,852
patients in China and had two prespecified co-primary endpoints: the composite of death, reinfarction,
or stroke; and death from any cause. Patients were followed until hospital discharge or day 28, which-
ever occurred sooner. Ninety-three percent of patients had evidence of ST-segment elevation or left
bundle branch block on their electrocardiogram at the time of randomization. In comparison with the
CLARITY-TIMI 28 trial, there was no upper age limit to the trial and 26% of enrolled patients were
greater than 70 years old. All patients were treated with aspirin 162 mg daily; only 54% received a
fibrinolytic, 75% received an anticoagulant, and less than 5% of patients underwent PCI.
Fig. 4. Cumulative incidence curves for the endpoint of death prior to discharge in COMMIT/CCS-2.
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Antithrombotic Drug Therapy in Cardiovascular Disease
In COMMIT/CCS-2, treatment with clopidogrel resulted in a significant 9% reduction in the incidence
of death, reinfarction, or stroke (10.1% vs. 9.2%; p
= 0.002) and a significant 7% reduction in the risk of
death alone (8.1% to 7.5%; p
= 0.03; Fig. 4). The benefit of clopidogrel on the incidence of the
composite primary endpoint was observed independent of age, sex, or the use of fibrinolytic therapy.
Despite the absence of a loading dose, the clinical benefit of clopidogrel emerged rapidly, with a
significant 11% reduction in the incidence of death, reinfarction, or stroke by the end of the second
hospital day (p
= 0.014), driven predominantly by an 11% reduction in the risk of death (3.2% vs.
3.6%; p
= 0.019).
The rates of major bleeding (defined as requiring transfusion, fatal, or cerebral) in COMMIT/
CCS-2 were low and similar in the two treatment groups (0.58% with clopidogrel vs. 0.55% with
placebo; p
= 0.59), including participants receiving concomitant fibrinolytic therapy and older patients.
The rates of ICH were identical across treatment arms (0.2%). Treatment with clopidogrel was associated
with a higher incidence of minor bleeding, including bruising and dental bleeding (3.6% vs. 3.1%;
p
= 0.005).
The CLARITY-TIMI 28 trial and COMMIT/CCS-2 demonstrate that the addition of clopidogrel to
aspirin in patients with STEMI receiving fibrinolytic therapy helps to maintain infarct-related artery
patency and reduce the rate of ischemic complications, including mortality. The trials had several differ-
ences, including the use of a loading dose of clopidogrel and the performance of angiography
(Table 1), yet both studies support the use of clopidogrel as adjunctive therapy in the setting of phar-
macologic reperfusion for STEMI.
The duration of treatment in these trials was brief (up to and including the day of coronary angi-
ography or day 8/hospital discharge in CLARITY-TIMI 28; until hospital discharge or up to 4 weeks
Table 1
Comparison of the CLARITY-TIMI 28 trial and COMMIT/CCS-2
CLARITY-TIMI 28 COMMIT/CCS-2
Number of patients 3,491 45,852
Primary endpoint Occluded infarct-related artery or death or
recurrent MI before angiography
Death, reinfarction or stroke; mortality
Inclusion STEMI < 12 h, age £ 75 Acute MI < 24 h, no age limit (maxi-
mum age was 99 years)
Trial location International (predominantly North
America and Europe)
China
Percentage receiving
fibrinolysis
99% 54% (Predominantly urokinase)
Clopidogrel dosing Loading dose (300 mg), followed
by 75 mg daily
75 mg Daily (no loading dose)
Angiography Routine (94%) Rare
Percentage
undergoing PCI
53.4% <5%
Results Clopidogrel improves patency rate
of infarct-related artery and reduces
ischemic complications
Clopidogrel reduces mortality and
major vascular events
Safety No increase in TIMI major bleeding or ICH No increase in major bleeding or ICH
CLARITY-TIMI 28: Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction 28
COMMIT/CCS-2: the Clopidogrel and Metoprolol in Myocardial Infarction Trial/the Second Chinese Cardiac Study
MI myocardial infarction, TIMI thrombolysis in myocardial infarction, ICH intracranial hemorrhage, CABG coronary
artery bypass grafting
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Antiplatelet Therapies: Aspirin, Clopidogrel and Thienopyridines
in the hospital in COMMIT/CCS-2). Thus, there is a lack of long-term data regarding the duration of
clopidogrel therapy in STEMI patients receiving thrombolysis. However, extrapolation of data from
patients with NSTE ACS treated with clopidogrel over 12 months
(18) and a subset of patients with
prior MI, ischemic stroke, or symptomatic peripheral arterial disease (PAD) treated with long-term
therapy
(23) indicate that extended treatment can reduce ischemic complications or death.
The most recent iteration of the STEMI practice guidelines
(7) is several years old and predates the
CLARITY-TIMI 28 trial and COMMIT/CCS-2. However, based on those trials, a clopidogrel loading
dose of 300
mg would be reasonable for patients aged less than 75 years receiving fibrinolytic therapy,
followed by a daily dose of 75
mg. For patients aged greater than 75 years, the addition of clopidogrel
75
mg daily (without a loading dose) to fibrinolytic therapy appears to be well tolerated and improves
clinical outcomes without any significant excess in bleeding. These recommendations are supported
by the 2007 STEMI focused update
(24). Determination of the optimal duration of therapy will
require further study, although, as noted above, data from other patient populations suggest that 12
months of therapy may be beneficial.
Mechanical Reperfusion
Although not focused on patients with STEMI, there is data to support the use of thienopyridines
with PCI. Several initial trials examined the use of ticlopidine in conjunction with aspirin in patients
treated with PCI (17,25) and demonstrated the synergistic benefit of thienopyridine and aspirin therapy.
The aspirin–ticlopidine combination, as compared to aspirin–warfarin, demonstrated a decrease in a
combined primary endpoint of death, MI, angiographically evident thrombosis, or revascularization
of the target lesion within 30 days (0.5% for aspirin–ticlopidine vs. 2.7% for aspirin–warfarin;
p < 0.001) (26). Studies have shown clopidogrel to have comparable if not better efficacy and a superior
safety profile compared with ticlopidine
(27,28). Thus, clopidogrel is the preferred thienopyridine and
the use of clopidogrel is considered the standard of care in patients undergoing primary PCI for
STEMI (7), despite a lack of clinical trial data specific to this population.
However, a key question is when to initiate clopidogrel therapy relative to the timing of PCI:
upstream or at the start of PCI. Even when a 300-mg loading dose is used, it requires at least 4–6 h
for clopidogrel to approach its maximal antiplatelet effect
(29). Although CLARITY-TIMI 28 enrolled
patients receiving pharmacologic reperfusion therapy rather than primary PCI, the upstream initiation
of clopidogrel and the protocol-mandated coronary angiography 2–8 days thereafter permitted the
assessment of the benefit of pretreatment in the 53.4% of all randomized patients who underwent PCI,
who thereafter were to receive open-label clopidogrel (30). In PCI-CLARITY, pretreatment with
clopidogrel was found to significantly reduce the odds of cardiovascular death, recurrent MI, or stroke
by 46% following PCI through 30 days from randomization (3.6% vs. 6.2%; adjusted p = 0.008),
without a significant increase in bleeding rate. The Kaplan-Meier estimated event rate curves for the
two treatment groups separated soon after PCI and continued to diverge over time (Fig. 5). The ben-
efit of clopidogrel pretreatment was observed across all patient subgroups, including patients who
received a GP IIb/IIIa receptor inhibitor at the time of PCI
(31). Analogously, the benefit of clopidogrel
pretreatment has also been demonstrated in patients with NSTE ACS undergoing PCI (32). Some
clinicians are reluctant to administer clopidogrel before angiography because of concerns that the
patient will be found to have disease requiring coronary artery bypass grafting (CABG). Nonetheless,
data from both CLARITY-TIMI 28 and CURE suggest that even for patients requiring CABG there
is a benefit to upstream clopidogrel initiation and minimal risk of bleeding, especially if one waits 5
days after discontinuing clopidogrel (20,33).
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Determination of the optimal loading dose of clopidogrel with PCI is under active investigation.
Higher loading doses of clopidogrel have been shown to achieve more rapid and consistent platelet
inhibition as compared with the standard 300-mg loading dose (29,34–36). In the ARMYDA-2
(Antiplatelet Therapy for Reduction of Myocardial Damage during Angioplasty) trial, a 600-mg loading
dose of clopidogrel, as compared to 300 mg, significantly reduced the incidence of periprocedural
MI by 50% in patients undergoing PCI for indications other than STEMI (p
= 0.041) (37). The 600 mg
loading dose had an acceptable safety profile during short-term follow-up. Data also suggest that a
600 mg loading dose may improve cardiovascular outcomes at 1 month of follow-up in NSTE ACS
patients undergoing PCI
(38). Whether any additional benefit is gained with the use of loading doses
higher than 600
mg is yet to be determined as trials have revealed somewhat discordant results
(29,35). Evidence also suggests that a higher maintenance dose of clopidogrel with 150 mg daily
provides more effective platelet inhibition than the currently recommended dose of 75
mg daily (39).
Whether this will reduce complications, including late stent thrombosis, has not yet been determined.
The clinical effects of higher loading and early maintenance doses of clopidogrel in patients with
unstable angina and NSTE ACS undergoing early invasive therapy is being evaluated in the
CURRENT/OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/
Optimal Antiplatelet Strategy for Interventions) trial.
For patients with STEMI proceeding directly to primary PCI, the ACC/AHA guidelines recommend
a clopidogrel loading dose of 300 mg after diagnostic angiography and prior to PCI (7). The 2005
ACC/AHA/SCAI (Society for Cardiovascular Angiography and Interventions) guidelines recommend
a 300
mg loading dose of clopidogrel at least 6 h before PCI and support a loading dose of greater than
300 mg for patients undergoing PCI who need to achieve a greater degree of platelet inhibition more
rapidly, as would be the case in primary PCI for STEMI (40). Most recently, the 2007 guidelines from
the European Society of Cardiology suggest a 600-mg loading dose of clopidogrel in patients with
STEMI undergoing primary PCI (41).
As is the case with pharmacologic reperfusion, the optimal duration of clopidogrel therapy follow-
ing mechanical reperfusion in STEMI remains unknown. Extrapolation of data from patients undergoing
elective PCI suggests that 12 months of therapy is beneficial (42). The type of stent (bare metal stent
Fig. 5. Cumulative incidence curves of cardiovascular death, recurrent MI, or stroke following PCI through 30 days’
follow-up in the PCI-CLARITY-TIMI 28 study.
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Antiplatelet Therapies: Aspirin, Clopidogrel and Thienopyridines
[BMS] or drug eluting stent [DES]) deployed at the time of PCI affects arterial healing by several
mechanisms
(43). Data suggest that premature discontinuation of clopidogrel after DES implantation
can be associated with an increase in late cardiac death or nonfatal MI, possibly related to late stent
thrombosis
(44). Observational data suggest a benefit of dual antiplatelet therapy for more than 1 year
following DES placement
(45). A current scientific advisory document stresses the importance of 12
months of dual antiplatelet therapy after placement of a DES, and education of the patient and health
care provider about hazards of premature discontinuation
(46). ACC/AHA/SCAI guidelines recom-
mend daily clopidogrel for at least 1 month following BMS implantation
(40).
Similar to aspirin resistance, the concept of “clopidogrel resistance” has been gaining interest. The
definition of clopidogrel resistance and assay specifications varies from study to study and nonstand-
ardized methods and use of varying doses of ADP makes comparison of study results difficult
(10).
However, it is believed that several factors, typically divided into those intrinsically or extrinsically
related to the platelet, are responsible for the phenomenon of clopidogrel resistance
(47). Intrinsic
mechanisms include variability of P2Y
12
receptor affinity for the active metabolite of clopidogrel,
variable receptor number, and variability in the response to binding (internal signaling, secondary
messenger release). Several genetic mutations that modulate both P2Y
12
function and expression have
been identified
(48,49). Extrinsic mechanisms include any factor that affects platelet aggregation
response other than the direct interaction of the active metabolite of clopidogrel with the P2Y
12
receptor
and the subsequent downstream signaling. Examples include noncompliance, drug–drug interactions,
and variability in absorption or metabolism. Potential for interaction exists with clopidogrel and the
3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins), as in
vitro, clopidogrel
metabolism is inhibited by more than 90% when clopidogrel and atorvastatin are present at equi-
molar concentrations
(50). However, there was no evidence of an interaction clinically in a large
placebo-controlled trial with long-term follow-up
(51).
Patient variability in platelet response to clopidogrel has been demonstrated, and resistance portends
worse clinical outcomes in patients, particularly in those who undergo coronary stenting (52–55).
Furthermore, incomplete inhibition of ADP-induced platelet aggregation has been demonstrated after
stent thrombosis has occurred (55).
The optimal management strategy for patients deemed to have response variability to clopidogrel
is not well defined. The possibility of higher loading or maintenance doses, as discussed previously,
may be a reasonable treatment strategy. Alternatively, other P2Y
12
receptor antagonists are under
development and may provide more predictable levels of ADP inhibition. There are also reports of
ticlopidine serving as an alternative therapy in cases of clopidogrel resistance (56).
GLYCOPROTEIN (GP) IIB/IIIA RECEPTOR INHIBITORS
The platelet GP IIb/IIIa receptor mediates platelet aggregation induced by all physiologic agonists.
Activation of intracellular signaling pathways within the platelet causes the resting GP IIb/IIIa receptor
to undergo a conformational change allowing it to bind to fibrinogen. Platelet aggregation then occurs
via the cross-linking of two separate platelets by fibrinogen. Blockade of the receptor, either by mono-
clonal antibodies or by small molecules patterned after the arginine glycine-aspartic acid (RGD) cell
recognition domain, prevents arterial thrombosis in animal models better than aspirin (57).
The first of these inhibitors to be developed was abciximab, a chimeric monoclonal antibody that
binds nonspecifically to the GP IIb/IIIa receptor (58). With concerns relating to irreversibility, non-
specificity for the GP IIb/IIIa receptor and immunogenicity, small molecule GP IIb/IIIa receptor
inhibitors were developed, including eptifibatide and tirofiban.
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Antithrombotic Drug Therapy in Cardiovascular Disease
Pharmacologic Reperfusion
The role of GP IIb/IIIa receptor inhibitors as an adjunct to pharmacologic reperfusion for STEMI
has been evaluated. Combination therapy of GP IIb/IIIa receptor inhibitors and reduced-dose fibrino-
lytic therapy has been the subject most extensively studied. Early studies showed encouraging findings
that GP IIb/IIIa receptor inhibition might offer incremental benefit and it was believed that it may
help to minimize the risk of bleeding by allowing reduction in the dose of the co-administered lytic
(59–62). The GUSTO-V (Global Utilization of Strategies to Open Occluded Coronary Arteries – V)
trial was a randomized, open-label trial to compare the effect of reteplase alone with reteplase plus
abciximab in patients with STEMI
(63). A total of 16,588 patients in the first 6 h of evolving STEMI
were randomly assigned standard-dose reteplase or half-dose reteplase and full-dose abciximab. The
primary endpoint was 30-day mortality, and secondary endpoints included various complications of
MI. The combination of reteplase and abciximab did not offer a significant survival benefit (5.6%
mortality in the combined group vs. 5.9% in the reteplase group; p
= 0.43), but it did decrease the risk
of nonfatal reinfarction, as well as other complications of MI (including ventricular tachycardia and
fibrillation, high-grade atrioventricular block, and septal or free wall rupture). However, this occurred
at the cost of twice the rate of major bleeding, including an increased risk of ICH in patients over the
age of 75 years (2.1% vs. 1.1%; p
= 0.069). Furthermore, the ASSENT-3 (Assessment of the Safety
and Efficacy of a New Thrombolytic Regimen – 3) trial evaluated abciximab and half-dose tenect-
eplase as compared with standard dose thrombolytics. The findings were consistent with GUSTO-V
as this trial showed reduced MI, but doubled bleeding, and had no effect on mortality
(64).
Based on the available data, ACC/AHA practice guidelines provide a Class IIb (usefulness/efficacy
less well established) recommendation for the consideration of combination pharmacological reper-
fusion with abciximab and half-dose reteplase or tenecteplase for prevention of reinfarction and other
complications of STEMI in selected patients (anterior location of MI, age less than 75 years, and no
risk factors for bleeding) (7). Specific mention is given to the lack of a mortality benefit at both 30
days and 1 year with this treatment strategy. A Class III (evidence that treatment is not effective or
harmful) recommendation is given to the combination of abciximab and half-dose reteplase or tenect-
eplase in patients aged greater than 75 years, due to the increased risk of ICH
(7).
Mechanical Reperfusion
In the management of STEMI, the role of GP IIb/IIIa receptor inhibitors in primary PCI was evaluated
in the ADMIRAL (Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction
Regarding Acute and Long Term Follow-up) trial
(65). Of the 300 patients, those randomized to
abciximab and PCI as compared with PCI alone had a significant 59% reduction in the rate of death,
recurrent MI, or urgent target vessel revascularization at 30 days (6.0% vs. 14.6%; p = 0.01). At 6
months, the corresponding figures were 7.4% and 15.9% (p = 0.02; Fig. 6). The better clinical out-
comes in the abciximab group were related to the greater frequency of a TIMI flow grade of 3 before
the procedure (16.8% vs. 5.4%, p = 0.01), immediately afterward (95.1% vs. 86.7%, p = 0.04), and 6
months afterward (94.3% vs. 82.8%, p
= 0.04). One major bleeding event occurred in the abciximab group
and none occurred in the placebo group. A significant mortality benefit in the ADMIRAL trial per-
sisted at 3-year follow-up (66).
The beneficial results of the ADMIRAL trial were not replicated in the larger CADILLAC
(Controlled Abciximab Device Investigation to Lower Late Angioplasty Complications) trial, as
abciximab did not produce a significant additive benefit to primary stenting (67). However, in a meta-
analysis, in which 11 trials involving 27,115 patients were analyzed, a significant benefit with the use
of adjunctive abciximab therapy during primary PCI for STEMI was demonstrated, and this was not
seen when abciximab was used as an adjunct to fibrinolysis (68). When compared with the control
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Antiplatelet Therapies: Aspirin, Clopidogrel and Thienopyridines
group, abciximab was associated with a significant reduction in short-term (30 days) mortality (2.4%
vs. 3.4%, p
= 0.047) and long-term (6–12 months) mortality (4.4% vs. 6.2%; p = 0.01) in patients
undergoing primary angioplasty but not in those treated with fibrinolysis.
ACC/AHA guidelines state that it is reasonable to start treatment with abciximab as early as
possible before primary PCI (with or without stenting) in patients with STEMI (Class IIa, weight of
evidence is in favor of efficacy) (7). The data on eptifibatide and tirofiban are more limited than for
abciximab, but given the common mode of action and general clinical experience these agents are
given a Class IIb indication to support primary PCI in STEMI (7).
The timing of adjunctive GP IIb/IIIa receptor inhibitor administration relative to PCI has been an
area of recent investigation. In the RELAx-AMI (Randomized Early versus Late Abciximab in Acute
Myocardial Infarction treated with primary coronary intervention) trial early abciximab administration
improved pre-PCI angiographic findings, post-PCI tissue perfusion, and 1-month left ventricular
function recovery (69). Furthermore, in the TITAN (Time to Integrilin Therapy in Acute Myocardial
Infarction) – TIMI 34 trial, initiation of eptifibatide in the emergency department was shown to
improve myocardial perfusion without a significant increase in major bleeding (70).
However, neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab
alone significantly improved clinical outcomes in the much larger FINESSE (Facilitated Intervention
with Enhanced Reperfusion Speed to Stop Events) trial (71,72).
Fig. 6. Incidence of death, reinfarction, and urgent target-vessel revascularization at 30 days and at 6 months after
randomization to abciximab or placebo in patients with acute MI undergoing primary PCI in the ADMIRAL trial.
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FUTURE DIRECTIONS
The issues of variability in response, irreversibility of inhibitor effects and length of time required
for maximum platelet inhibition has fostered the search for newer antiplatelet agents. The third generation
oral thienopyridine, prasugrel, was shown to be ten times more potent than clopidogrel in animal studies
(73). The JUMBO-TIMI 26 (Joint Utilization of Medications to Block Platelets Optimally – TIMI 26)
trial, was a phase 2, randomized, dose-ranging, double-blinded safety trial of prasugrel versus clopi-
dogrel in 904 patients undergoing elective or urgent percutaneous coronary intervention
(74). A loading
dose followed by 1 month of maintenance therapy with prasugrel was just as safe as clopidogrel.
Although not specifically designed to assess efficacy, prasugrel-treated patients had a non-significant
decrease in the incidence of death, MI, stroke, or target vessel thrombosis at 30-day follow-up. The
TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet
Inhibition with Prasugrel) trial was a phase III study evaluating prasugrel against clopidogrel in
patients presenting with ACS with PCI as the planned management strategy (75). In this trial, prasugrel
therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis,
but with an increased risk of major bleeding (76).
AZD6140 is an orally active, non-thienopyridine reversible inhibitor of the platelet P2Y
12
receptor.
This agent is a cyclopentyl triazolopyrimidine that provides more rapid and complete antiplatelet
effect than clopidogrel
(77). The PLATO (Platelet Inhibition and Patient Outcomes) trial will compare
the efficacy of AZD6140 and clopidogrel in patients with STEMI and NSTE ACS.
Cangrelor is an intravenous non-thienopyridine reversible inhibitor of the P2Y
12
receptor. The very
short half-life of this agent makes it an attractive alternative and it has been shown to be safe and well
tolerated in patients with acute coronary syndromes
(78).
Other novel classes of agents being explored include protease-activated receptor antagonists and
platelet adhesion antagonists (16).
Adjunctive antiplatelet therapy in pharmacologic or catheter-based reperfusion for STEMI has
produced improved cardiovascular outcomes, including mortality benefits. The novel agents under
investigation will likely better refine the role of antiplatelet therapy in this clinical setting and lead to
further improvement in patient outcomes.
REFERENCES
1. Ruggeri ZM (2002) Platelets in atherothrombosis. Nat Med 8(11):1227–1234
2.
Offermanns S (2006) Activation of platelet function through G protein-coupled receptors. Circ Res 99(12):1293–1304
3. Campbell CL, Smyth S, Montalescot G et al (2007) Aspirin dose for the prevention of cardiovascular disease: a systematic
review. JAMA 297(18):2018–2024
4. ISIS-2 (second international study of infarct survival) Collaborative Group (1988) Randomised trial of intravenous strep-
tokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet
2(8607):349–360
5.
Roux S, Christeller S, Ludin E (1992) Effects of aspirin on coronary reocclusion and recurrent ischemia after thromboly-
sis: a meta-analysis. J Am Coll Cardiol 19(3):671–677
6. Baigent C, Collins R, Appleby P et al (1998) ISIS-2: 10 year survival among patients with suspected acute myocardial
infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second In-
ternational Study of Infarct Survival) Collaborative Group. BMJ 316(7141):1337–1343
7. Antman EM, Anbe DT, Armstrong PW et al (2004) ACC/AHA guidelines for the management of patients with ST-
elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial
Infarction). Circulation 110(9):e82–e292
8. Antithrombotic Trialists’ Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy
for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324(7329):71–86
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