European Heart Journal Supplements (2008) 10 (Supplement A), A4–A12
doi:10.1093/eurheartj/sum078
Antiplatelet therapy in acute coronary syndromes
Anselm K. Gitt1* and Amadeo Betriu2
1
Institut fuer Herzinfarktforschung Ludwigshafen an der Universitaet Heidelberg, Bremser Str. 79,
67063 Ludwigshafen, Germany
2
Universitat de Barcelona, Villarroel, 170, Barcelona 8036, Spain
KEYWORDS
Antiplatelet agents are an essential component of the treatment of acute coronary
syndromes (ACS). In numerous clinical trials, aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors have been shown to reduce the incidence of ischaemic
events in patients with unstable angina, non-ST-elevation myocardial infarction, and
ST-elevation myocardial infarction. Aspirin is appropriate for lifelong therapy in
patients with ACS. Clopidogrel is recommended for most patients with ACS for
short- or long-term therapy, depending on the patient’s level of risk. New antiplatelet
agents with distinct pharmacological properties may offer advantages, including
faster onset of action, greater potency, and reversibility of effects. The treatment
of ACS has evolved considerably in the past decade, with a trend towards greater
consistency of care and more widespread provision of evidence-based therapies.
Registries and surveys offer opportunities to educate health care providers on compliance with current guideline recommendations for the management of patients with
ACS, which should lead to improved clinical outcomes.
Introduction
Thrombosis occurring in the presence of underlying
atherosclerosis is a key pathological step in the development of acute coronary syndromes (ACS)—unstable
angina (UA), ST-elevation myocardial infarction (STEMI),
and non-STEMI (NSTEMI).1 Because platelets play an
important role in the development of thrombosis,2 antiplatelet agents are a mainstay of the treatment of ACS.
This article will review the recommendations for the
use of antiplatelet agents and the evidence demonstrating their contribution to favourable outcomes.
Current use of antiplatelet agents
in ST-elevation myocardial infarction
Guideline recommendations
Guidelines from the European Society of Cardiology
(ESC)3 and the American College of Cardiology and the
* Corresponding author. Tel: þ49 621 503 4000; fax: þ49 621 503 4044.
E-mail address: [email protected]
American Heart Association (ACC/AHA)4 recommend
routine use of aspirin as soon as possible after the
onset of symptoms of acute myocardial infarction (MI)
and as lifelong therapy thereafter. Clopidogrel is recommended as an alternative in patients who cannot tolerate aspirin.3 Clopidogrel is recommended in addition
to aspirin in patients in whom percutaneous coronary
intervention (PCI) is planned, for 3–4 weeks after placement of a bare-metal stent (BMS),5 and by the ESC and
the US Food and Drug Administration for 12 months
after placement of a drug-eluting stent (DES).6,7 The glycoprotein IIb/IIIa inhibitor (GPI) abciximab, with tiroﬁban
and eptiﬁbatide as alternatives, is recommended for
patients undergoing PCI, with or without stenting.3,4
Aspirin in patients with ST-elevation
myocardial infarction
Lifelong aspirin therapy is appropriate for all patients
with STEMI in whom it is not contraindicated. A metaanalysis of trials comprising 19 302 patients with acute
MI found that antiplatelet therapy—primarily with
aspirin—resulted in an approximately 25% reduction in
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2007.
For permissions please email: [email protected].
Downloaded from by guest on October 15, 2014
Aspirin;
Clopidogrel;
Myocardial infarction;
Percutaneous coronary
intervention;
Stroke;
Drug-eluting stent
Antiplatelet therapy in ACS
serious vascular events with a small risk of bleeding complications.8 Aspirin doses of 75–100 mg appear to be as
effective as higher doses and less likely to cause
bleeding.8,9
Thienopyridines in patients with ST-elevation
myocardial infarction
Glycoprotein IIb/IIIa inhibitors in patients with
ST-elevation myocardial infarction
A meta-analysis of 11 trials that included 27 115 patients
with STEMI showed that abciximab treatment reduced
the rate of 30-day re-infarction in all trials combined,
in primary angioplasty trials, and in ﬁbrinolysis trials.16
Overall, abciximab treatment did not result in a
reduction in 30-day or 1-year mortality. However,
abciximab-treated patients who underwent primary
angioplasty did have lower 30-day mortality (2.4 vs.
3.4%, odds ratio [OR] 0.68, 95% conﬁdence interval [CI]
0.47–0.99, P ¼ 0.047) and lower 1-year mortality (4.4
vs. 6.2%, OR 0.69, 95% CI 0.52–0.92, P ¼ 0.01). Abciximab
had no effect on mortality when used in patients treated
with ﬁbrinolysis.
A more recent meta-analysis pooled long-term data
from three trials that included 1101 high-risk patients
with STEMI who underwent primary PCI with stenting
and were randomized to abciximab or placebo.17 After
up to 3 years of follow-up, the frequency of death or
re-infarction was reduced from 19.0% in the placebo
group to 12.9% in the abciximab group (relative risk
[RR] 0.633, 95% CI 0.452–0.887, P ¼ 0.008). Analysed
separately, the rate of re-infarction was signiﬁcantly
reduced by abciximab treatment, and the rate of death
nearly so, with no signiﬁcant increase in bleeding.
Current use of antiplatelet agents in
non-ST-elevation-acute coronary syndromes
Guideline recommendations
Because it has been shown to reduce death and MI in
patients with UA or NSTEMI and is associated with a low
incidence of adverse effects, aspirin is recommended
by guidelines as acute and long-term treatment for all
patients with NSTE-ACS unless it is contraindicated.18,19
Clopidogrel in combination with aspirin, or as monotherapy if aspirin is not tolerated, is similarly recommended
for acute treatment at a dose of 300 mg, followed by
12 months of treatment at 75 mg/day.6 Because of
increased risk of surgical bleeding, clopidogrel should
be withheld for 5 days before coronary artery bypass
grafting (CABG) if clinically feasible.6 Treatment with
eptiﬁbatide or tiroﬁban in addition to oral antiplatelet
therapy is recommended for initial early treatment in
patients at intermediate to high risk; in high-risk patients
undergoing PCI not pre-treated with a GPI, abciximab
is recommended immediately following angiography.6
Bivalirudin may be considered an alternative to GPIs
plus unfractionated heparin (UFH)/low-molecular-weight
heparin (LMWH).6
Aspirin in patients with non-ST-elevation-acute
coronary syndromes
Aspirin therapy reduces the risk of MI, ischaemic stroke,
and cardiovascular death in patients with NSTE-ACS and
is an essential component of therapy for all patients in
whom it is not contraindicated.18 The ideal aspirin
dosage is unknown, but 75–150 mg/day is effective,8
whereas higher doses have not been shown to provide
additional beneﬁt and may carry an increased risk of
bleeding.19 The beneﬁts of daily aspirin administration
persist for at least 2 years; given its relative safety,
there appears to be no reason not to recommend lifelong
aspirin therapy.19
Clopidogrel in patients with
non-ST-elevation-acute coronary syndromes
Like aspirin, clopidogrel has an established role in
NSTE-ACS, based, to a large degree, on the results of
the CURE trial, which randomized 12 562 patients
with NSTE-ACS to receive clopidogrel or placebo.20
Downloaded from by guest on October 15, 2014
As the use of PCI has grown, thienopyridines have come
to play an increasingly important role in the treatment
of STEMI.10 Clopidogrel has largely replaced ticlopidine
because of its equal efﬁcacy and better safety proﬁle.11
In a dose of 75 mg/day, clopidogrel is as effective as
aspirin at preventing ischaemic events in patients with
a history of recent MI, with a similar safety proﬁle.12
Greater effectiveness can be obtained from combining
clopidogrel and aspirin. In the COMMIT trial, the routine
addition of clopidogrel 75 mg/day to aspirin therapy for
4 weeks in patients with acute MI resulted in a 9% proportional reduction in death, re-infarction, or stroke
(P ¼ 0.002) and a 7% proportional reduction in death
(P ¼ 0.03).13 Even though no loading dose was used, the
beneﬁt of clopidogrel therapy was seen almost immediately in an 11% proportional reduction in mortality
in the ﬁrst 2 days after the initiation of therapy
(P ¼ 0.019).13
Used with ﬁbrinolysis in patients with STEMI, clopidogrel has been shown to reduce the risk of in-hospital
arterial occlusion, death, or recurrent MI by 36%
(P , 0.001) and the 30-day risk of cardiovascular death,
recurrent MI, or urgent revascularization by 20% (P ¼
0.03), with no signiﬁcant increase in major bleeding.2
In patients with STEMI who received ﬁbrinolysis and
then underwent PCI, a 300 mg clopidogrel loading dose
given before ﬁbrinolysis followed by 75 mg/day until coronary angiography reduced by 46% the 30-day occurrence
of the composite endpoint of cardiovascular death,
recurrent MI, or stroke; the beneﬁt was similar whether
patients underwent PCI urgently or electively and was
unrelated to the timing of PCI.14 The ongoing CIPAMI
trial15 will investigate the administration of clopidogrel
as early as possible after the diagnosis of STEMI and
compare it with later administration, after initial
angiography.
A5
A6
All patients received aspirin. Clopidogrel was given in a
loading dose of 300 mg, followed by 75 mg/day for 3–12
months. The composite of cardiovascular death, nonfatal MI, or stroke occurred signiﬁcantly less often in
the clopidogrel group (9.3 vs. 11.4%, RR 0.80, 95% CI
0.72–0.90, P , 0.001) (Figure 1).20 Major bleeding
occurred in 3.7% of patients in the clopidogrel group
and 2.7% of patients in the placebo group (RR 1.38, 95%
CI 1.13–1.67, P ¼ 0.001), although the rates of fatal
bleeding, bleeding requiring surgical intervention, and
haemorrhagic stroke did not differ signiﬁcantly.20
Among the 2658 patients in the CURE trial who underwent PCI, the incidence of cardiovascular death or MI
was reduced by a third in the clopidogrel group.21
The appropriate dose of clopidogrel before PCI has
been the subject of debate. Given its slow onset of
action and the variability of patient response to the
drug, a 300 mg loading dose may be insufﬁcient. When
patients undergoing planned PCI were randomized to
loading doses of 300 or 600 mg of clopidogrel, the
higher dose was associated with a .50% risk reduction
in the 30-day incidence of MI, a difference due entirely
to a reduction in peri-procedural MI, with no excess of
bleeding.22 A 900 mg loading dose appears to offer no
additional advantage.23
Large trials have examined the use of GPIs in patients
with NSTE-ACS whose treatment plan called for medical
management. In the GUSTO IV-ACS trial,24 7800 patients
with NSTE-ACS not scheduled for PCI and receiving
aspirin and either UFH or LMWH were randomized to an
abciximab bolus and 24 h infusion, an abciximab bolus
and 48 h infusion, or placebo. The trial found no beneﬁt
and an increase in bleeding from abciximab treatment.
The PURSUIT trial25 found a signiﬁcant 1.5% absolute
reduction in the 30-day rate of death or non-fatal MI in
patients with NSTE-ACS receiving eptiﬁbatide compared
with patients receiving placebo (P ¼ 0.04); most patients
did not undergo PCI. In the PRISM trial,26 3232 patients
with UA already taking aspirin were randomized to
receive tiroﬁban or heparin for 48 h. Tiroﬁban treatment
resulted in a 32% reduction in the composite of death, MI,
or refractory ischaemia at 48 h compared with heparin
treatment (P ¼ 0.01). At 30 days, there was no difference
between treatment groups in the occurrence of the
composite endpoint, although mortality was lower in
the tiroﬁban group (2.3 vs. 3.6%, P ¼ 0.02). Thrombocytopenia occurred signiﬁcantly more often in the
tiroﬁban group (1.1 vs. 0.4%, P ¼ 0.04).
A meta-analysis of six trials that included 31 402
patients with NSTE-ACS for whom an intervention strategy was not planned found a 9% reduction in the risk of
death or MI at 30 days in patients given a GPI (10.8 vs.
11.8%, OR 0.91, 95% CI 0.85–0.98, P ¼ 0.015).27 The
beneﬁt was conﬁned to patients with an elevated troponin level. There was a signiﬁcantly higher frequency
of major bleeding in patients given GPIs (2.4 vs. 1.4%,
P , 0.0001).
GPIs have been shown to improve outcomes when used
in patients undergoing PCI. The ISAR-REACT 2 trial28 randomized 2022 patients undergoing planned PCI to abciximab (0.25 mg/kg bolus followed by 0.125 mg/kg/min
infusion for 12 h) plus heparin (70 U/kg) or placebo plus
Figure 1 Cumulative hazard rates for the composite of cardiovascular death, non-fatal myocardial infarction, or stroke in patients with
non-ST-elevation-acute coronary syndromes randomized to clopidogrel or placebo in the CURE trial. Used with permission from The Clopidogrel in
Unstable Angina to Prevent Recurrent Events Trial Investigators.20 Copyright 2001 Massachusetts Medical Society. All rights reserved.
Downloaded from by guest on October 15, 2014
Glycoprotein IIb/IIIa inhibitors in patients with
non-ST-elevation-acute coronary syndromes
A.K. Gitt and A. Betriu
Antiplatelet therapy in ACS
Antiplatelet agents in patients receiving stents
Controversy has surrounded the use of DES since reports
of subacute stent thrombosis, manifesting as sudden
death or acute MI, appeared soon after their approval.
Late stent thrombosis appeared to be associated with
the implantation of DES in complex lesions and in
patients with complicating conditions such as renal dysfunction or diabetes, not with approved uses, and with
premature withdrawal of antiplatelet agents.34 A recent
meta-analysis found that the long-term incidence of the
combination of death and Q-wave MI is 16–38% higher
in patients who receive DES than in patients who
receive BMS,35 although another meta-analysis of 14
trials found that patients who received sirolimus-eluting
stents had the same risk of stent thrombosis, death, or
MI as patients who received BMS but required
re-intervention less often.36
Clopidogrel therapy for 6–12 months in addition to lifelong aspirin has been the standard of care in patients
receiving DES.5 An observational study found that, for
patients who were event-free at 6 or 12 months after
implantation of a DES, clopidogrel therapy was a signiﬁcant predictor of lower risk for death or MI at 24
months; clopidogrel therapy had no such predictive
effect in patients who received BMS.37 In contrast, discontinuation of clopidogrel therapy within 30 days after
implantation of a DES has been shown to increase the
1-year mortality rate to 7.5% from the 0.7% found in
patients
who
continued
clopidogrel
therapy
(P , 0.0001).38 On the basis of these data, recommendations have been made that clopidogrel therapy be continued for up to 12 months after stent implantation in
patients not at high risk for bleeding.6,7
A recent meta-regression of seven trials that randomized a total of 3382 patients receiving stents to clopidogrel or ticlopidine focused on the effects on death or
non-fatal MI of a clopidogrel-loading dose.39 Overall,
the two drugs were equally effective, but clopidogrel
was found to be superior to ticlopidine in the ﬁve trials
in which a 300 or 600 mg clopidogrel loading dose was
used and inferior to ticlopidine in the two studies in
which a loading dose was not used.
New antiplatelet agents
Despite high clopidogrel loading doses and concomitant
use of aspirin, ischaemic events continue to occur. For
maximum beneﬁt, clopidogrel should be given at least
6 h before PCI40; it may contribute to bleeding complications in patients who undergo CABG within 5 days of
its administration,41 and there is signiﬁcant variability
in patient response.42 These limitations have led to a
search for alternative antiplatelet agents.
Prasugrel
Prasugrel is a new thienopyridine that has been shown to
be more potent than clopidogrel in pre-clinical studies,
with a lower rate of non-responders43 and a faster
onset of action.44 In the TRITON-TIMI 38 trial, 13 608
moderate- to high-risk patients with NSTE-ACS or STEMI
undergoing PCI were randomized to receive prasugrel
(60-mg loading dose followed by 10 mg/day) or clopidogrel (300-mg loading dose followed by 75 mg/day) for 6
to 15 months.45 The composite end point of death from
cardiovascular causes, nonfatal MI, or nonfatal stroke
occurred in 12.1% of patients randomized to clopidogrel
and 9.9% of patients randomized to prasugrel (hazard
ratio [HR] 0.81, 95% CI 0.73–0.90, P , 0.001). There
were also signiﬁcant reductions in the rates of MI,
urgent target-vessel revascularization, and stent thrombosis among patients randomized to prasugrel. The rate
of major bleeding was higher in the prasugrel group
(2.4 vs. 1.8%, HR 1.32, 95% CI 1.03–1.68, P ¼ 0.03), as
were the rates of life-threatening bleeding (1.4 vs. 0.9%,
Downloaded from by guest on October 15, 2014
heparin (140 U/kg). All patients had been pre-treated
with a 600 mg loading dose of clopidogrel and 500 mg of
oral or intravenous aspirin. In the abciximab group,
there was a 25% reduction in the composite of death,
MI, or urgent revascularization within 30 days of randomization (P ¼ 0.03), but the beneﬁt was conﬁned to
patients with an elevated troponin level.28
In the ESPRIT trial,29 2064 patients undergoing PCI with
stenting were randomized to receive placebo or eptiﬁbatide given as two 180 mg/kg boluses 10 min apart and an
infusion of 2.0 mg/kg/min for 18–24 h or until hospital
discharge, whichever came ﬁrst; patients also received
aspirin, a thienopyridine, and, at the investigator’s discretion, heparin. At 48 h, the rate of death, MI, urgent
target-vessel revascularization, or thrombotic bailout
with a GPI was signiﬁcantly reduced in the eptiﬁbatide
group, from 10.5 to 6.6% (P ¼ 0.0015). The 30-day rate
of death, MI, or urgent target-vessel revascularization
was also signiﬁcantly reduced in the eptiﬁbatide group,
from 10.5 to 6.8% (P ¼ 0.0034).
Tiroﬁban was compared with abciximab in 4809
patients undergoing elective or urgent PCI with stenting
in the TARGET trial.30 All patients received aspirin and,
when possible, clopidogrel. At 30 days, the incidence of
death, MI, or urgent target-vessel revascularization was
signiﬁcantly lower in the abciximab group (6.0 vs. 7.6%,
P ¼ 0.038), primarily due to a lower rate of MI.30 At
1-year follow-up, mortality rates in the two treatment
groups were similar.31
Current guidelines recommend administering GPIs
either ‘upstream’, usually in the emergency department,
or later, in the catheterization laboratory.5 In a substudy
of the ACUITY trial,32 upstream use of either eptiﬁbatide
or tiroﬁban was compared with the administration of
either eptiﬁbatide or abciximab in the catheterization
laboratory. Upstream use resulted in a lower rate of
ischaemic events but a higher rate of bleeding, such
that the net clinical beneﬁt was similar for the two strategies.32 The ongoing EARLY ACS trial33 will compare
placebo treatment with the administration of eptiﬁbatide 25 h before catheterization, allowing provisional
use of eptiﬁbatide in the catheterization laboratory, in
10 500 patients with UA or NSTE-ACS undergoing an
early invasive treatment strategy.
A7
A8
P ¼ 0.01) and fatal bleeding (0.4 vs. 0.1%, P ¼ 0.002).
Ongoing trials of prasugrel are studying its effect on
platelets in patients already taking clopidogrel, patients
with ACS, and patients undergoing PCI.
AZD6140
AZD6140 is the ﬁrst platelet aggregation inhibitor of
the cyclopentyltriazolopyrimidine class. In doses of
200 or 400 mg daily given for 28 days to patients
with atherosclerosis, AZD6140 exhibits greater inhibition
of platelet aggregation than clopidogrel 75 mg once
daily.46 Bleeding times were higher in AZD6140-treated
patients than in clopidogrel-treated patients, but no signiﬁcant increase in major or minor bleeding events was
recorded.
Cangrelor
Evolving patterns of treatment of acute
coronary syndromes
Given that many questions and controversies surround
the treatment of ACS, it comes as no surprise that it
has undergone considerable change in recent years. Evidence from registries provides a real-world picture of
how clinicians approach patients with ACS and where
educational efforts should be directed to improve the
care of such patients.
Euro Heart Survey on acute coronary syndromes
Within the Euro Heart Survey (EHS) Programme of the
ESC, two ACS surveys (ACS I and II) collected data in
Europe and the Mediterranean Basin in 2000–2001 and
in 2004,10 and the ESC-ACS registry will continue to do
so until November 2008. EHS-ACS I collected data on
10 484 patients in 25 countries, and EHS-ACS II collected
data on 6385 patients in 32 countries. The proportion of
patients with ST-elevation ACS rose from 42% in
EHS-ACS I to 47% in EHS-ACS II, and the proportion of
patients with a history of MI fell. The use of coronary
angiography, PCI, and intra-coronary stents all increased
in EHS-ACS II. Among patients with ST-elevation, the use
of PCI increased from 40.4 to 57.8% and the use of stents
increased from 31.0 to 52.4%, whereas the use of ﬁbrinolysis declined. Among patients without ST-elevation, the
use of PCI increased from 25.4 to 37.1% and the use of
stents increased from 18.1 to 33.8%.
More patients received guideline-recommended medications in EHS-ACS II than in EHS-ACS I. The most striking
change was in the use of thienopyridines, which
increased from 36.1 to 69.8% in patients with
ST-elevation and from 27.6 to 67.4% in patients without
ST-elevation. There was also a signiﬁcant increase in
the use of statin agents. The use of aspirin, GPIs,
angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers, and beta-blockers all
increased, whereas the use of heparins declined.10
Presumably as a result of these improvements in
therapy, there was a signiﬁcant decline in mortality
rates from EHS-ACS I to EHS-ACS II. In-hospital mortality
occurred in 4.9% of EHS-ACS I patients and 4.0% of
EHS-ACS II patients (adjusted OR 0.86, 95% CI 0.73–
1.01, P ¼ 0.07). Thirty-day mortality occurred in 6.2%
of EHS-ACS I patients and 5.1% of EHS-ACS II patients
(adjusted OR 0.85, 95% CI 0.73–0.99, P ¼ 0.04).10
ACOS registry
The ACOS registry gathered data from 16 817 patients
treated in Germany at facilities with intensive care
units and offering early reperfusion therapy.48 An analysis
of ACOS patients with STEMI demonstrated the beneﬁt of
clopidogrel therapy. One-year mortality was lower in
STEMI patients treated with clopidogrel than in those
not treated with clopidogrel (3.7 vs. 12.4%, OR 0.27,
95% CI 0.22–0.33, P , 0.001) whether they underwent
ﬁbrinolysis, primary PCI, or no reperfusion.
GRACE registry
The GRACE registry has continuously collected data on
patients with ACS since 1999.49 Comparison of 6-month
periods during 1999 and 2005 showed that use of PCI
increased from 32.4 to 63.5% among patients with
STEMI and from 16.9 to 34.6% among patients with
NSTE-ACS. Use of guideline-recommended medications,
including aspirin, beta-blockers, statins, ACE-inhibitors
or angiotensin-receptor blockers, LMWH, thienopyridines, and GPIs, signiﬁcantly increased. Figure 2 displays
this improved adherence to guideline-recommended
therapies in patients with NSTE-ACS.49
Greater adherence to guidelines was paralleled by
improved outcomes. Among STEMI patients, the
in-hospital rate of death declined by 3.9 percentage
points, congestive heart failure (CHF) or pulmonary
oedema declined by 9.0 percentage points, MI . 24 h
after presentation or recurrent MI declined by 1.6 percentage points, and cardiogenic shock declined by 2.4
percentage points. At 6 months, the rates of stroke and
MI, but not of death, had declined signiﬁcantly.49
Among patients with NSTE-ACS, the in-hospital rate of
death declined by 0.7 percentage points, CHF or pulmonary oedema declined by 6.5 percentage points, MI . 24 h
after presentation or recurrent MI declined by 1.3
Downloaded from by guest on October 15, 2014
Cangrelor is an intravenous P2Y12 antagonist that was
studied in a phase II safety trial47 of patients undergoing
PCI. In the ﬁrst part of the randomized, open-label study,
three doses (1, 2, or 4 mg/kg/min) of cangrelor were
given with aspirin and heparin for 18–24 h beginning
before PCI; in the second part of the study, the 4 mg/
kg/min dose of cangrelor was compared with abciximab
(0.25 mg/kg bolus followed by 0.125 mg/kg/min). No signiﬁcant difference in major or minor bleeding or in major
adverse cardiac events was seen in either part of the
study. Cangrelor treatment resulted in similar levels of
inhibition of platelet aggregation as abciximab treatment
and trends towards less prolongation of bleeding time
and more rapid return to baseline platelet function.
A.K. Gitt and A. Betriu
Antiplatelet therapy in ACS
A9
Table 1 Changes in clinical outcomes in 27 558 patients with non-ST-elevation-acute coronary syndromes included in the GRACE
registry49
Number/total (%) of patients
In-hospital outcomesb
Death
CHF or pulmonary oedema
MI .24 h after presentation or
recurrent MIc
Cardiogenic shock
Stroke
Six-month outcomesb
Death
Stroke
MIc
% difference in rates
(95% CI)
P-value for linear trendsa
0.02
,0.001
0.03
July–December 1999
July–December 2005
2213 (2.9)
2228 (13)
696 (3.0)
1566 (2.2)
1564 (6.1)
1556 (1.7)
20.7 (21.7 to 0.3)
26.5 (28.4 to 24.7)
–1.3 (22.7 to 0.1)
2230 (2.1)
2227 (0.2)
1565 (1.8)
1559 (0.6)
20.2 (21.1 to 0.7)
0.3 (20.1 to 0.7)
0.01
0.18
1942 (4.9)
1901 (1.4)
2.5
998 (3.3)
957 (0.7)
2.9
21.6 (23.0 to 20.1)
20.7 (21.4 to 0.1)
0.4 (21.7 to 2.5)
0.04
0.01
0.43
Adapted with permission from Fox et al.49 Copyright&2007. American Medical Association. All rights reserved.
a
Double-sided Cochran–Armitage test or logistic regression using data for all time periods.
b
Risk adjustment was applied as the risk proﬁle increased over time.
c
First time period was for July–December 2002.
percentage points, and cardiogenic shock declined by 0.2
percentage points. At 6 months, the rates of death and
stroke had declined signiﬁcantly (Table 1).49
CRUSADE registry
In the US, the beneﬁts of guideline-recommended therapies for NSTE-ACS have been documented in the CRUSADE
initiative, which collected data from 501 hospitals.50
Analysis of the records of 113 595 patients showed that,
during the 4 years following the release of the ACC/
AHA guidelines,4 adherence to class I recommendations
for the use of drug therapy improved; there were
steady increases in the use of antiplatelet agents, betablockers, clopidogrel, heparin, and GPIs, both in-hospital
and at discharge. The proportion of patients who
Downloaded from by guest on October 15, 2014
Figure 2 Temporal trends in the use of guideline-recommended therapies in patients with non-ST-elevation-acute coronary syndromes included in the
GRACE registry, January 2000–June 2005. ARB, angiotensin receptor blocker. Used with permission from Fox et al.49 Copyright&2007. American Medical
Association. All rights reserved.
A10
received all guideline-recommended medications
increased from 30 to 48% for in-hospital medications
and from 30 to 50% for discharge medications.50 The
use of PCI increased by 8%; however, the increase was
greater in low-risk than in high-risk patients.51 After
risk adjustment, every 10% increase in adherence to
guidelines was associated with a 10% decrease in
in-hospital mortality.52
A.K. Gitt and A. Betriu
5.
6.
Conclusion
The improved outcomes now being obtained in patients
with ACS can be attributed to the publication of comprehensive,
authoritative
guidelines
recommending
evidence-based therapies. Important among these recommendations are those pertaining to the short- and
long-term use of antiplatelet agents, which have been
shown to signiﬁcantly reduce mortality and ischaemic
events in patients with UA, NSTEMI, and STEMI. New antiplatelet agents that may provide greater potency, faster
onset of action, and less variability in patient response
will soon be available.
7.
8.
9.
10.
11.
12.
Funding
This work was supported by an educational grant from
Daiichi Sankyo Europe GmbH and Eli Lilly and Company.
13.
14.
References
1. Libby P. Current concepts of the pathogenesis of the acute coronary
syndromes. Circulation 2001;104:365–372.
2. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G,
Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH,
Braunwald E, for the CLARITY–TIMI 28 Investigators. Addition of clopidogrel to aspirin and ﬁbrinolytic therapy for myocardial infarction
with ST-segment elevation. N Engl J Med 2005;352:1179–1189.
3. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KAA,
Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C,
Underwood SR, Vahanian A, Verheugt FWA, Wijns W. Management of
acute myocardial infarction in patients presenting with ST-segment
elevation. The Task Force on the Management of Acute Myocardial
Infarction of the European Society of Cardiology. Eur Heart J 2003;
24:28–66.
4. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M,
Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ,
Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS,
Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G,
Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK. ACC/AHA guidelines
for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart
15.
16.
17.
18.
Downloaded from by guest on October 15, 2014
Conﬂict of interest: A.B. declares he has received support from
the following companies: sanoﬁ-aventis, Schering-Plough, and
Daiichi Sankyo.
A.K.G. declares he has worked as a consultant for and/or
received honoraria from the following companies: S.O., Eli
Lilly, Essex Pharma, GlaxoSmithKline, MSD, Pﬁzer, sanoﬁaventis, Servier, Schering-Plough, NovoNordisk, and Amgen.
A.K.G. has also received grants and/or sponsorships from
sanoﬁ-aventis, Thrombsdorff, S.O., GlaxoSmithKline, MSD,
Nycomed, and Servier.
Association Task Force on Practice Guidelines (Committee to Revise
the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1–E211.
Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C,
Jorgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P,
Stone GW, Wijns W. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of
the European Society of Cardiology. Eur Heart J 2005;26:804–847.
Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A,
Fernandez-Aviles F, Fox KAA, Hasdai D, Ohman EM, Wallentin L,
Wijns W. Guidelines for the diagnosis and treatment of
non-ST-segment elevation acute coronary syndromes. The Task
Force for the Diagnosis and Treatment of Non-ST-Segment Elevation
Acute Coronary Syndromes of the European Society of Cardiology.
Eur Heart J 2007;28:1598–1660.
Food and Drug Administration. Update to FDA statement on coronary
drug-eluting stents. http://www.fda.gov/cdrh/news/010407.html
(17 July 2007).
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis
of randomised trials of antiplatelet therapy for prevention of
death, myocardial infarction, and stroke in high risk patients. BMJ
2002;324:71–86.
Peters RJG, Mehta SR, Fox KAA, Zhao F, Lewis BS, Kopecky SL, Diaz R,
Commerford PJ, Valentin V, Yusuf S, for the Clopidogrel in Unstable
angina to prevent Recurrent Events (CURE) Trial Investigators.
Effects of aspirin dose when used alone or in combination with
clopidogrel in patients with acute coronary syndromes: observations
from the Clopidogrel in Unstable angina to prevent Recurrent Events
(CURE) study. Circulation 2003;108:1682–1687.
Mandelzweig L, Battler A, Boyko V, Bueno H, Danchin N, Filippatos G,
Gitt A, Hasdai D, Hasin Y, Marrugat J, Van de Werf F, Wallentin L,
Behar S, on behalf of the Euro Heart Survey Investigators. The
second Euro Heart Survey on acute coronary syndromes: characteristics, treatment, and outcome of patients with ACS in Europe and
the Mediterranean Basin in 2004. Eur Heart J 2006;27:2285–2293.
Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for the CLASSICS
Investigators. Double-blind study of the safety of clopidogrel with
and without a loading dose in combination with aspirin compared
with ticlopidine in combination with aspirin after coronary stenting:
the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–629.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
Lancet 1996;348:1329–1339.
COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial)
collaborative group. Addition of clopidogrel to aspirin in 45 852
patients with acute myocardial infarction: randomised placebocontrolled trial. Lancet 2005;366:1607–1621.
Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G,
Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E, for the
Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in
patients with ST-elevation myocardial infarction treated with ﬁbrinolytics: the PCI-CLARITY study. JAMA 2005;294:1224–1232.
Zeymer U, Arntz HR, Darius H, Huber K, Senges J. Efﬁcacy and safety
of Clopidogrel 600 mg administered pre-hospitally to Improve Primary
percutaneous coronary intervention in patients with Acute Myocardial Infarction (CIPAMI): study rationale and design. Cardiology
2007;108:265–272.
De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE,
Neumann FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as
adjunctive therapy to reperfusion in acute ST-segment elevation
myocardial infarction: a meta-analysis of randomized trials. JAMA
2005;293:1759–1765.
Montalescot G, Antoniucci D, Kastrati A, Neumann FJ, Borentain M,
Migliorini A, Boutron C, Collet JP, Vicaut E. Abciximab in primary coronary stenting of ST-elevation myocardial infarction: a European
meta-analysis on individual patients’ data with long-term follow-up.
Eur Heart J 2007;28:443–449.
Bertrand ME, Simoons ML, Fox KAA, Wallentin LC, Hamm CW,
McFadden E, De Feyter PJ, Specchia G, Ruzyllo W. Management of
acute coronary syndromes in patients presenting without persistent
ST-segment elevation. Eur Heart J 2002;23:1809–1840.
Antiplatelet therapy in ACS
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
Cohen DJ, Mehran R, White HD, for the ACUITY Investigators.
Routine upstream initiation vs deferred selective use of glycoprotein
IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing
trial. JAMA 2007;297:591–602.
Giugliano RP, Newby LK, Harrington RA, Gibson CM, Van de Werf F,
Armstrong P, Montalescot G, Gilbert J, Strony JT, Califf RM,
Braunwald E, on behalf of the EARLY ACS Steering Committee. The
Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation
Acute Coronary Syndrome (EARLY ACS) trial: a randomized placebocontrolled trial evaluating the clinical beneﬁts of early front-loaded
eptiﬁbatide in the treatment of patients with non-ST-segment
elevation acute coronary syndrome—study design and rationale. Am
Heart J 2005;149:994–1002.
Farb A, Boam AB. Stent thrombosis redux—the FDA perspective. N
Engl J Med 2007;356:984–987.
Nordmann AJ, Briel M, Bucher HC. Safety of drug-eluting stents:
insights from a meta-analysis. Presented at European Society of Cardiology Meeting, September 2006, Barcelona, Spain, Session 707009.
Kastrati A, Mehilli J, Pache J, Kaiser C, Valgimigli M, Kelbaek H,
Menichelli M, Sabate M, Suttorp MJ, Baumgart D, Seyfarth M,
Pﬁsterer ME, Schomig A. Analysis of 14 trials comparing
sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;
356:1030–1039.
Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB,
Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED,
Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:
159–168.
Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS,
Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM,
Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent
placement: results from the PREMIER registry. Circulation 2006;
113:2803–2809.
Biondi-Zoccai GGL, Lotrionte M, Agostoni P, Valgimigli M, Abbate A,
Sangiorgi G, Moretti C, Sheiban I. Beneﬁts of clopidogrel in patients
undergoing coronary stenting signiﬁcantly depend on loading dose:
evidence from a meta-regression. Am Heart J 2007;153:587–593.
Steinhubl SR, Berger PB, Mann JT III, Fry ETA, DeLago A, Wilmer C,
Topol EJ, for the CREDO Investigators. Early and sustained dual oral
antiplatelet therapy following percutaneous coronary intervention:
a randomized controlled trial. JAMA 2002;288:2411–2420.
Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002;40:231–237.
Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary
stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908–2913.
Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT,
Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L. Prasugrel
achieves greater inhibition of platelet aggregation and a lower rate
of non-responders compared with clopidogrel in aspirin-treated
patients with stable coronary artery disease. Eur Heart J 2006;27:
1166–1173.
Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS,
Jakubowski JA, Naganuma H, Winters KJ. A comparison of prasugrel
and clopidogrel loading doses on platelet function: magnitude of
platelet inhibition is related to active metabolite formation. Am
Heart J 2007;153:66.e9–66.e16.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W,
Gottlieb S, Neumann F-J, Ardissino D, De Servi S, Murphy SA,
Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, for the TRITONTIMI 38 Investigators. Prasugrel versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med 2007;357:2001–2015.
Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M,
Peters G. Pharmacodynamics, pharmacokinetics, and safety of the
oral reversible P2Y12 antagonist AZD6140 with aspirin in patients
with atherosclerosis: a double-blind comparison to clopidogrel with
aspirin. Eur Heart J 2006;27:1038–1047.
Greenbaum AB, Grines CL, Bittl JA, Becker RC, Kereiakes DJ,
Gilchrist IC, Clegg J, Stankowski JE, Grogan DR, Harrington RA,
Emanuelsson H, Weaver WD. Initial experience with an intravenous
P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II,
Downloaded from by guest on October 15, 2014
19. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD,
Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN,
Pepine CJ, Schaeffer JW, Smith EE III, Steward DE, Theroux P,
Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G,
Hiratzka LF, Jacobs AK, Smith SC Jr. ACC/AHA 2002 Guideline
Update for the Management of Patients With Unstable Angina and
Non–ST-Segment Elevation Myocardial Infarction. http://www.acc.
org (2002) (30 July 2007).
20. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial
Investigators. Effects of clopidogrel in addition to aspirin in patients
with acute coronary syndromes without ST-segment elevation. N Engl
J Med 2001;345:494–502.
21. Mehta SR, Yusuf S, Peters RJG, Bertrand ME, Lewis BS, Natarajan MK,
Malmberg K, Rupprecht HJ, Zhao F, Chrolavicius S, Copland I,
Fox KAA, for the Clopidogrel in Unstable angina to prevent Recurrent
Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
Lancet 2001;358:527–533.
22. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G.
Randomized trial of high loading dose of clopidogrel for reduction
of periprocedural myocardial infarction in patients undergoing
coronary intervention: results from the ARMYDA-2 (Antiplatelet
therapy for Reduction of MYocardial Damage during Angioplasty)
study. Circulation 2005;111:2099–2106.
23. von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A,
Schomig A. Absorption, metabolization, and antiplatelet effects of
300-, 600-, and 900-mg loading doses of clopidogrel: results of the
ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen:
Choose Between 3 High Oral Doses for Immediate Clopidogrel
Effect) Trial. Circulation 2005;112:2946–2950.
24. The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary
syndromes without early coronary revascularisation: the GUSTO
IV-ACS randomised trial. Lancet 2001;357:1915–1924.
25. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein
IIb/IIIa with eptiﬁbatide in patients with acute coronary syndromes.
N Engl J Med 1998;339:436–443.
26. The Platelet Receptor Inhibition in Ischemic Syndrome Management
(PRISM) Study Investigators. A comparison of aspirin plus tiroﬁban
with aspirin plus heparin for unstable angina. N Engl J Med 1998;
338:1498–1505.
27. Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de
Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J,
Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–198.
28. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H,
Graf I, Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J,
Berger PB, Schomig A, for the Intracoronary Stenting Antithrombotic
Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2)
Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after
clopidogrel pretreatment: the ISAR-REACT 2 randomized trial.
JAMA 2006;295:1531–1538.
29. The ESPRIT Investigators. Novel dosing regimen of eptiﬁbatide in
planned coronary stent implantation (ESPRIT): a randomised,
placebo-controlled trial. Lancet 2000;356:2037–2044.
30. Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL,
Cohen DJ, Cohen EA, Bertrand M, Neumann FJ, Stone GW,
DiBattiste PM, Demopoulos L, for the TARGET Investigators. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tiroﬁban and
abciximab, for the prevention of ischemic events with percutaneous
coronary revascularization. N Engl J Med 2001;344:1888–1894.
31. Mukherjee D, Topol EJ, Bertrand ME, Kristensen SD, Herrmann HC,
Neumann FJ, Yakubov SJ, Bassand JP, McClure RR, Stone GW,
Ardissino D, Moliterno DJ, for the TARGET Investigators. Mortality
at 1 year for the direct comparison of tiroﬁban and abciximab
during percutaneous coronary revascularization: do tiroﬁban and
ReoPro give similar efﬁcacy outcomes at trial 1-year follow-up. Eur
Heart J 2005;26:2524–2528.
32. Stone GW, Bertrand ME, Moses JW, Ohman EM, Lincoff AM, Ware JH,
Pocock SJ, McLaurin BT, Cox DA, Jafar MZ, Chandna H, Hartmann F,
Leisch F, Strasser RH, Desaga M, Stuckey TD, Zelman RB, Lieber IH,
A11
A12
multicenter, randomized, placebo- and active-controlled trial. Am
Heart J 2006;151:689.e1–689.e10.
48. Zeymer U, Gitt AK, Junger C, Heer T, Wienbergen H, Koeth O,
Bauer T, Mark B, Zahn R, Gottwik M, Senges J, for the Acute COronary
Syndromes (ACOS) registry investigators. Effect of clopidogrel on
1-year mortality in hospital survivors of acute ST-segment elevation
myocardial infarction in clinical practice. Eur Heart J 2006;27:
2661–2666.
49. Fox KAA, Steg PG, Eagle KA, Goodman SG, Anderson FA Jr,
Granger CB, Flather MD, Budaj A, Quill A, Gore JM, for the GRACE
Investigators. Decline in rates of death and heart failure in acute coronary syndromes, 1999–2006. JAMA 2007;297:1892–1900.
50. Mehta RH, Roe MT, Chen AY, Lytle BL, Pollack CV Jr, Brindis RG,
Smith SC Jr, Harrington RA, Fintel D, Fraulo ES, Califf RM,
Gibler WB, Ohman EM, Peterson ED. Recent trends in the care of
A.K. Gitt and A. Betriu
patients with non–ST-segment elevation acute coronary syndromes:
insights from the CRUSADE initiative. Arch Intern Med 2006;166:
2027–2034.
51. Tricoci P, Peterson ED, Mulgund J, Newby LK, Saucedo JF, Kleiman NS,
Bhatt DL, Berger PB, Cannon CP, Cohen DJ, Hochman JS, Ohman EM,
Gibler WB, Harrington RA, Smith SC Jr, Roe MT, for the CRUSADE
Investigators. Temporal trends in the use of early cardiac catheterization in patients with non-ST-segment elevation acute coronary syndromes (results from CRUSADE). Am J Cardiol 2006;98:1172–1176.
52. Peterson ED, Roe MT, Mulgund J, DeLong ER, Lytle BL, Brindis RG,
Smith SC Jr, Pollack CV Jr, Newby LK, Harrington RA, Gibler WB,
Ohman EM. Association between hospital process performance and
outcomes among patients with acute coronary syndromes. JAMA
2006;295:1912–1920.
Downloaded from by guest on October 15, 2014