ARTICLE IN PRESS
Journal of the American College of Cardiology
© 2005 by the American College of Cardiology Foundation
Published by Elsevier Inc.
YEAR IN CARDIOLOGY SERIES
The Year in Non–ST-Segment
Elevation Acute Coronary Syndromes
Robert P. Giugliano, MD, SM, FACC,*† Eugene Braunwald, MD, MACC*†
Boston, Massachusetts
Non–ST-segment elevation acute coronary syndrome
(NSTE-ACS), which comprises unstable angina and non–
ST-segment elevation myocardial infarction (NSTE-MI),
accounted for approximately 1.7 million discharges (primary
or secondary diagnoses) from U.S. hospitals in 2002, with
NSTE-ACS accounting for approximately 1.2 million of
these discharges (1). The year 2004 marked the tenth
anniversary of the publication of a guideline for manage-
ment of patients with NSTE-ACS—the first such
evidence-based guideline to establish clearly detailed diag-
nostic criteria, to provide a scheme for risk stratification, and
to recommend diagnostic procedures and treatment for
patients with this condition (2). In the subsequent decade, a
large body of literature and many clinical trials (Table 1)
have further refined and improved the approach to these
patients. Given the broad nature of this topic and extensive
number of publications in the past year, we have elected to
focus on important observations in the following areas: 1)
risk assessment and risk scores, 2) biomarkers, 3) platelet
P2Y12 receptor blockers, 4) glycoprotein (GP) IIb/IIIa
blockers, 5) anticoagulants, 6) early invasive treatment
strategy, and 7) lipid therapy.
RISK ASSESSMENT AND RISK SCORES
A number of scores derived from clinical trials (3,4) and
registries (5–7) have been developed to assess the risk of
patients with NSTE-ACS and to help identify patients
most likely to benefit from aggressive therapy (Table 2). An
analysis comparing three risk scores (the TIMI, PURSUIT,
and GRACE scores) (8) concluded that all three demon-
strated good predictive accuracy for death or MI at one year,
thus identifying patients who might be likely to benefit from
aggressive therapy, including early myocardial revasculariza-
tion. A second comparison of risk scores (9) demonstrated
better clinical outcomes among patients whose treatment
From the *TIMI Study Group, Cardiovascular Division, Brigham and Women’s
Hospital and the †Department of Medicine, Harvard Medical School, Boston,
Massachusetts. Dr. Giugliano reports the following potential conflicts and financial
disclosures: Millennium, research grant support, Speaker’s Bureau; Schering-Plough,
research grant support, Speaker’s Bureau; Nuvelo, research grant support; Merck/
Schering-Plough, research grant support; Sanofi-Aventis, Speaker’s Bureau; Bristol
Myers Squibb, Speaker’s Bureau; Pfizer, Speaker’s Bureau. Dr. Braunwald reports the
following potential conflicts and financial disclosures: research grant support from:
Millennium, Aventis, Nuvelo, Astra-Zeneca, Eli Lilly, and Merck/Schering-Plough.
Manuscript received May 2, 2005; revised manuscript received May 23, 2005,
accepted June 1, 2005.
Vol. 46, No. 5, 2005
ISSN 0735-1097/05/$30.00
doi:10.1016/j.jacc.2005.06.051
was compliant with current guideline recommendations,
regardless of the risk group.
The TIMI unstable angina risk score also was found to be
useful in the prediction of angiographic severity and extent
of coronary artery disease (10), including greater intracoro-
nary thrombus burden and impaired flow (11). Analyses of
the TIMI risk index (12), which uses only age, systolic
blood pressure, and heart rate, demonstrated that this
simple risk index not only predicted short-term mortality in
ST-segment elevation myocardial infarction (STEMI) ACS
but also was a useful tool for predicting 30-day and 1-year
mortality across the spectrum of patients with ACS, includ-
ing patients with NSTE-ACS (13). Although initially
applied to patients with STEMI, the concept of a “risk score
profile” (14), a novel approach to characterize the risk of a
population, was also shown to be applicable in patients with
NSTE-ACS (15). Analyses of subgroups of patients at
high-risk, including women (16), the elderly (17), non-
whites (18,19), as well as those with positive troponin or
ST-segment depressions (20), heart failure (21), or renal
failure (22), showed that paradoxically, these patients, who
stand to benefit the most from proven therapies recom-
mended in existing treatment guidelines, are less likely to
receive them than are patients at lower risk. Underuse of
cardiac catheterization, particularly in patients with elevated
troponin, was observed, with only 45% of such patients
undergoing an early invasive strategy with catheterization
within 48 h (23). Patients who underwent early catheter-
ization within 48 h were more likely to receive guideline-
recommended treatments and had a significantly lower risk
of adjusted in-hospital mortality (2.5% vs. 3.7%) (24).
These observations present a major opportunity for improv-
ing the care of patients with NSTE-ACS.
BIOMARKERS
Considerable research on five groups of biomarkers that had
been shown previously to be useful in prognostication of
patients with ACS (markers of necrosis, inflammation,
natriuretic factors, renal dysfunction, and glucose tolerance),
and multimarker approaches were reported during the past
year (Fig. 1) (25).
Troponin. Elevation of troponin, an accurate marker of
cardiac necrosis, even if only marginal (26), is correlated
with worse clinical outcomes in NSTE-ACS. An elevation
of troponin correlated strongly with intracoronary thrombus
 ARTICLE IN PRESS
JACC Vol. 46, No. 5, 2005 Giugliano and Braunwald 907
September 6, 2005:906–19 The Year in Non–ST-Segment Elevation Acute Coronary Syndromes

Table 1. Acronyms of Clinical Trials and Registries

A to Z Aggrastat to Zocor
ACUITY Acute Catheterization and Urgent Intervention Triage strategY
ALBION Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation, and Ongoing Necrosis
ANTHEM-TIMI-32 Anticoagulation with rNAPc2 To Help Eliminate MACE-TIMI 32
CLEAR PLATELETS Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets
CREDO Clopidogrel for the Reduction of Events During Observation
DISPERSE 2-TIMI-33 Does greater Inhibition of platelet aggregation lead to Superior Prevention of thrombotic Events afteR Non-ST
Elevation? 2-TIMI-33
GRACE Global Registry of Acute Coronary Events
GUSTO-IV ACS Global Use of Strategies To improve Outcomes-IV ACS
ICTUS Invasive Versus Conservative Treatment in Unstable Coronary Syndromes
IMPROVE IT IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
ISAR-COOL Intracoronary Stenting with Antithrombotic Regimen COOLing-off
JUMBO Joint Utilization of Medications to Block platelets Optimally
OASIS Organisation to Assess Strategies for Ischemic Syndromes
PEACE Platelet Activity Extinction in non–Q-wave Myocardial Infarction with Aspirin, Clopidogrel, and Eptifibatide
PROTECT-TIMI-30 A randomized trial to evaluate the relative PROTECTion against post-PCI microvascular dysfunction and post-PCI
ischemia among anti-platelet and anti-thrombotic agents-TIMI-30
PROVE IT-TIMI-22 Pravastatin or Atorvastatin Evaluation and Infection Therapy-TIMI-22
PURSUIT Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using InTegrilin
REPLACE-2 Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2
REVERSAL Reversal of Atherosclerosis with Aggressive Lipid Lowering
SYNERGY Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors
TACTICS-TIMI-18 Treat angina with Aggrastat ⫹ determine Cost of Therapy with an Invasive or Conservative Strategy-TIMI-18
TIMI Thrombolysis In Myocardial Infarction
TRITON-TIMI-38 TRial to assess Improvement in Therapeutic outcomes by Optimizing platelet inhibitioN with prasugrel-TIMI-38

as visualized by angioscopy (27). This finding may explain
the particular benefit of GP IIb/IIIa receptor blockers in
such patients (see “Glycoprotein IIb/IIIa Blockers”). Ele-
vated troponin levels after percutaneous coronary interven-
tion (PCI) were associated with short-term complications
(28) and mortality at two years (29). Mechanistic insight
into the relationship between elevation of post-PCI tropo-
nin and worse clinical outcomes were provided by demon-
stration of impaired myocardial contrast enhancement and
myocardial tissue perfusion (30), as well as new irreversible
myocardial injury on delayed-enhancement magnetic reso-
nance imaging (31).
Markers of inflammation. High-sensitivity C-reactive
protein (hs-CRP) is a measure of inflammation that predicts
cardiovascular risk above and beyond traditional risk factors
and adds independent prognostic information to long-term
risk assessment in normal subjects as well as in those with
coronary artery disease (32). Patients with NSTE-ACS had
higher levels of hs-CRP and more complex angiographic
stenoses than did patients with chronic stable angina (33).
The hs-CRP ordinarily rises after the implantation of both
bare metal and sirolimus-eluting stents (34), but these
elevations can be attenuated by two-thirds with clopidogrel
pretreatment (35).
Myeloperoxidase is an enzyme secreted during leuko-
cyte activation that possesses proinflammatory properties
and predicts an increased risk for cardiovascular events
independently of other biomarkers (36). A close link
between myeloperoxidase-mediated endothelial dys-
function, oxidation, inflammation, and cardiovascular
disease has been demonstrated (37), and a common
myeloperoxidase-promoter polymorphism present in
two-thirds of the Western population, which is associ-
ated with higher myeloperoxidase levels, has been iden-
tified (38).
At present, both hs-CRP and myeloperoxidase appear to
be of clinical value in risk stratification. Ongoing research is
being conducted to clarify the value of the broad array of
these and other inflammatory markers in understanding the
pathobiology of NSTE-ACS and in determining whether
they add to hs-CRP and myeloperoxidase in clinical assess-
ment and risk stratification.

Table 2. Comparison of Risk Scores

Externally
Name (Ref. No.) Variables Included Advantages Disadvantages Validated Useful to Select Tx
GRACE (7) 8 clinical variables Accuracy Very complex No Unknown
PREDICT (5) 6 clinical, 1 detailed ECG Accuracy Very complex No Unknown
PURSUIT (4) 5 clinical variables Weighting used Mod complexity No Unknown
RUSH (6) 6 clinical variables Accuracy Logistic regression No Unknown
TIMI risk score (3) 7 clinical variables Simple Equal weighting Yes Yes
TIMI risk index (12) Age, SBP, HR Very simple Need chart Yes Unknown
ECG ⫽ electrocardiogram; HR ⫽ heart rate; PREDICT ⫽ Predicting Risk of Death in Cardiac Disease Tool; SBP ⫽ systolic blood pressure; Tx ⫽ therapy.
 ARTICLE IN PRESS
908 Giugliano and Braunwald
The Year in Non–ST-Segment Elevation Acute Coronary Syndromes
Figure 1. Multimarker approach for risk stratification in acute coronary syndromes, adapted from Morrow and Braunwald (25). *Glucose metabolism ⫽
hyperglycemia or elevated hemoglobin (HB) A1C. BNP ⫽ B-type natriuretic peptide; CrCl ⫽ creatine clearance; CRP ⫽ C-reactive protein; hs-CRP ⫽
high sensitivity C-reactive protein.
Natriuretic peptides. Plasma B-type natriuretic peptide
(BNP) has been shown to be an independent predictor of
mortality in patients with NSTE-ACS (39), and recent
analyses extended these findings by demonstrating the
utility of plasma BNP even among patients without the
presence of markers of necrosis (40) and in an apparently
asymptomatic community population (41). The N-terminal
fragment of its prohormone, N-terminal-pro-BNP (Nt-
proBNP), was found to be the strongest independent
biochemical predictor of in-hospital and 180-day mortality,
adding substantial information after adjustment for baseline
risk (42). Dynamic changes of Nt-proBNP were associated
with marked increases in adverse outcome (43). Levels of
Nt-proBNP were shown to parallel the severity of angio-
graphic disease (44) and to correlate independently with
death or nonfatal MI during the year after PCI in patients
with NSTE-ACS (45). Nt-pro-atrial natriuretic peptide is
an independent predictor of mortality at two years in
patients with NSTE-ACS with normal levels of Nt-
proBNP (46).
The elevation of circulating concentrations of natriuretic
peptides is associated with increased ventricular wall stress.
Although such elevations clearly identify high-risk patients,
they have not yet been shown to be useful in identifying
patients in whom revascularization, intensive anti-ischemic
therapy, or other therapeutic maneuvers improve outcome.
Nonetheless, it appears logical to treat such patients with
agents such as angiotensin-converting enzyme inhibitors to
reduce ventricular wall stress in an effort to reduce the
concentration of natriuretic peptide levels.
Impaired glucose tolerance. Although it has been clear
that upwards of 75% of patients with diabetes die of
cardiovascular complications, the reverse, i.e., the high
prevalence of impaired glucose tolerance in patients present-
ing with ACS has been underappreciated until recently. In
JACC Vol. 46, No. 5, 2005
September 6, 2005:906–19
the Euro Heart Survey, 58% of patients with acute coronary
artery disease had an abnormal oral glucose tolerance test
(22% new diabetes, 36% pre-existing impaired glucose
regulation) (47). Among diabetics with ACS, both hyper-
glycemia and hypoglycemia were associated with significant
higher all-cause mortality (48). Thus, careful assessments of
glucose concentration, glucose tolerance, and the presence
of the metabolic syndrome among patients with NSTE-
ACS should be obtained, and these conditions should be
treated vigorously.
Renal dysfunction. Impaired renal function is an indepen-
dent predictor of poor short-term outcomes (in-hospital
death, bleeding, and contrast-induced nephropathy) (49) as
well as mid-term outcomes (death at 30 days and 6 months,
stroke and recurrent ischemia at 30 days) (50). Increased
levels of cystatin C, a more accurate marker of renal function
than serum creatinine, are associated with a graded increase
in the risk of death (51). Renal dysfunction is a marker of
vascular damage; patients with NSTE-ACS having this
common and serious risk factor require close follow up.
Multimarker approach. With the proliferation of biomark-
ers, combinations of two (52) or more (53) individual
markers, or classes of markers (e.g., necrosis, inflammation,
coagulation) (54) are being pursued. The importance of
various marker combinations should now be assessed in
various key subgroups of patients, particularly in light of the
observation that women with ACS have a different pattern
of biomarker expression (higher hs-CRP and BNP, but
lower troponin) than do men (55).
Genetic markers. Genetic markers have the potential to be
even more powerful risk markers than the classical pheno-
typic markers described previously. For example, polymor-
phisms of the cytochrome P450 epoxygenase CYP2J2 gene
(56) were associated with a doubling of the risk of coronary
artery disease. Identification of genetic polymorphisms also
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may allow the tailoring of drug therapies according to
individual genotype. For example, patients with one of two
common polymorphisms in the 3-hydroxy-3-methylutaryl-
CoA reductase gene demonstrated reduced efficacy of cho-
lesterol lowering with pravastatin (57).
PLATELET P2Y12 RECEPTOR BLOCKERS
Clopidogrel. The stimulation of the platelet P2Y12 recep-
tor leads to sustained platelet aggregation. Thienopyridines,
such as ticlopidine and now clopidogrel, irreversibly block
these receptors. Although the clinical value of the P2Y12
receptor blocker clopidogrel in patients with NSTE-ACS
has been well-established, determination of the appropriate
loading dose (58) and the variability of responsiveness (59)
recently have received considerable attention.
Inhibition of platelet aggregation with 75 mg of clopi-
dogrel daily in healthy volunteers achieves a steady state in
five days, and it is not until day 8 that the fluctuation
between peak and trough platelet inhibition becomes neg-
ligible (60). Administration of a 300-mg loading dose
shortens the time to peak effect to 12 h (61), which is
consistent with a clinical treatment effect at approximately
15 h in the CREDO trial, which compared a 300-mg
pretreatment loading dose with no clopidogrel load before
PCI (62). Increasing the loading dose to 600 mg achieves
the full antiplatelet effect of clopidogrel by 2 h (63), whereas
300 mg, the dose approved by the Food and Drug Admin-
istration, fails to enhance platelet inhibition in 40% of
patients at 2.5 h (64). A loading dose of 600 mg also reduces
the incidence of clopidogrel nonresponsiveness to one-
quarter the rate observed with 300 mg of clopidogrel (65).
Furthermore, loading with 600 mg compared with 300 mg
of clopidogrel 4 to 8 h before PCI was safe and reduced the
primary composite of death, MI, or target vessel revascu-
larization significantly from 12% to 4%, with all of the
difference attributed to a reduction in post-PCI myonecrosis
(66). Finally, a 600 mg reload in patients on maintenance
(75 mg/day) clopidogrel achieved additional inhibition of
adenosine diphosphate-induced expression of GP IIb/IIIa
and P-selectin receptors, even among patients who were
chronically taking 75 mg of clopidogrel daily (67). An even
higher loading dose (900 mg) of clopidogrel is being
compared with 300 and 600 mg in a French trial known as
ALBION that is due to report initial results in May 2005 at
the EUROPCR scientific sessions (G. Montalescot, per-
sonal communication, 2005.). Although the loading dose of
clopidogrel approved by the Food and Drug Administration
is 300 mg, the recently released guidelines for PCI, released
by the European Society of Cardiology (68), recommend
600 mg in patients with NSTE-ACS undergoing immedi-
ate (⬍6 h) PCI. Because there appears to be little extra risk
to the higher loading dose, it is likely that it will be used
increasingly widely before PCI in patients with NSTE-
ACS.
The first extensive report exploring the interindividual
Giugliano and Braunwald 909
response to clopidogrel demonstrated marked variability in
the degree of inhibition of platelet aggregation, with 31%
and 15% of patients at 5 and 30 days exhibiting “resistance”
(69), which was defined as ⬍10% reduction in platelet
aggregation compared with baseline using light transmis-
sion aggregometry in response to platelet stimulation with 5
␮mol/l adenosine diphosphate. Emerging data link clopi-
dogrel hyporesponsiveness in patients undergoing primary
PCI with recurrent cardiovascular events (70), and in a
broader group of patients undergoing stenting to a higher
risk of stent thrombosis (71) and postdischarge ischemic
events (72). Assays measuring the phosphorylation of
vasodilator-stimulated phosphoprotein, an inhibitor protein
that is predominantly expressed in platelets, may be useful in
the identification of patients at risk for subacute stent
thrombosis. Thus, patients who are hyporesponsive to
clopidogrel as determined by flow cytometric measurement
of vasodilator-stimulated phosphoprotein phosphorylation
were shown to be at very high risk for subacute stent
thrombosis (73).
Increased bleeding at the time of cardiac surgery after the
recent use of clopidogrel remains a challenging clinical issue
because preoperative clopidogrel use is associated with
increased odds of reoperation for bleeding and for transfu-
sion (74). However, the risk of perioperative bleeding must
be weighed against the benefits of beginning clopidogrel
early in patients presenting with NSTE-ACS, as one
analysis revealed a 44% reduction in cardiovascular death,
MI, or stroke in patients treated with clopidogrel preoper-
atively (75). One approach to deal with this issue is to hold
clopidogrel on admission if patients are scheduled for
coronary angiography within 24 h but to pretreat patients in
whom cardiac catheterization is likely to be deferred.
Combination treatment with a thienopyridine and a GP
IIb/IIIa blocker has received considerable attention. The
possible additional benefits of abciximab in patients under-
going elective PCI pretreated with 600 mg of clopidogrel
were evaluated in three trials (76 –78) and included one-year
follow-up in one of the studies (79). In each of these three
trials, there was no benefit of adding abciximab to clopi-
dogrel. However, these results should be interpreted with
caution in light of the lower than anticipated event rates in
patients undergoing elective PCI. Furthermore, it is unclear
if these findings apply to other GP IIb/IIIa blockers which,
in fact, did demonstrate a benefit when added to clopidogrel
in other studies (see “Glycoprotein IIb/IIIa Blockers”).
Other P2Y12 receptor blockers. Prasugrel is a thienopyri-
dine under development that has several potential advan-
tages over clopidogrel, including 1) a more rapid and
efficient generation of an active metabolite, leading to a
faster onset of action (80); 2) a 10-fold greater potency in
the inhibition of adenosine-induced platelet aggregation;
and 3) a more consistent antiplatelet response without the
unresponsiveness or hyporesponsiveness to clopidogrel
noted previously. In a phase II dose-ranging trial of patients
with stable atherosclerosis, prasugrel added to aspirin
 ARTICLE IN PRESS
910 Giugliano and Braunwald
The Year in Non–ST-Segment Elevation Acute Coronary Syndromes
Table 3. New Antiplatelet Agents Targeting the P2Y12 Receptor
Name (Ref. No.) Class
Prasugrel (81,82) Thienopyridine
AZD6140 (84) Cyclolpentyltriazolopyrimidine
Cangrelor (83) ATP derivative
achieved higher platelet inhibition than clopidogrel (81). In
a phase II dose-ranging study of prasugrel in PCI
(JUMBO-TIMI-26), prasugrel was associated with rates of
bleeding similar to clopidogrel while resulting in lower rates
of target vessel thrombosis and recurrent ischemia (82).
Prasugrel currently is being compared with clopidogrel in a
phase III trial of patients with ACS undergoing PCI
(TRITON-TIMI-38).
Two reversible blockers of the P2Y12 receptor in devel-
opment include cangrelor (AR-C69931MX) and AZD6140
(Table 3) (80). Cangrelor is an intravenous ATP derivative
with a plasma half-life of 5 min that achieves 90% inhibition
of platelet aggregation, with recovery of platelet function 20
min after termination of infusion. In a pilot, dose-ranging
study of patients with STEMI, cangrelor and half-dose
alteplase achieved similar rates of epicardial and myocardial
reperfusion, ST-segment resolution, and bleeding compared
to a full dose of alteplase (83). Cangrelor is being compared
with abciximab in a phase II trial of patients undergoing
PCI. AZD6140 is an orally active, directly acting, cyclo-
pentyltriazolopyrimidine that also reversibly blocks the
P2Y12 receptor and can achieve high levels of platelet
inhibition (84). A phase II dose-ranging clinical trial (DIS-
PERSE 2-TIMI-33) is compared AZD6140 to clopidogrel
in NSTE-ACS and results are anticipated late in 2005.
GLYCOPROTEIN IIb/IIIa BLOCKERS
Although GP IIb/IIIa blockers have been available clinically
for more than a decade, several pharmacodynamic studies
Figure 2. Measures of platelet (PLT) activation and aggregation in the platelet activity extinction in non–Q-wave myocardial infarction with aspirin (ASA),
clopidogrel (Clopid), and eptifibatide (PEACE) study (88) demonstrated the incremental benefit of adding clopidogrel to ASA and enoxaparin (Enox) and
then the further incremental benefit of eptifibatide (Ept). ADP ⫽ adenosine diphosphate; GP ⫽ glycoprotein; PAC ⫽ activated GP IIb/IIIa.
JACC Vol. 46, No. 5, 2005
September 6, 2005:906–19
Formulation Reversibility Comparison With Clopidogrel
Oral No Higher-level inhibition
Fewer hypo/non-responders
Oral Yes Higher-level inhibition
Intravenous Yes Shorter half life (3 to 5.5 min)
Higher-level platelet inhibition
during the past year have helped to shed additional light on
their mechanism of action and their incremental effects in
combination with other antiplatelet drugs. Tirofiban blunts
the rise in hs-CRP after presentation with NSTE-MI (85)
and after PCI (86) and reverses the endothelial dysfunction
induced by PCI (87).
The PEACE study (88) compared platelet activation by a
panel of agonists with three combinations of antithrombotic
agents: 1) aspirin and enoxaparin; 2) aspirin, enoxaparin,
and clopidogrel; and 3) aspirin, enoxaparin, clopidogrel, and
eptifibatide. Relative reductions in activated GP IIb/IIIa
receptor expression of 33% to 48% (depending upon the
type of agonist) were observed after the addition of clopi-
dogrel, whereas additional reductions of 72% to 80% were
observed after eptifibatide (Fig. 2). The CLEAR PLATE-
LETS study (89) was a 2 ⫻ 2 factorial study (300 mg or 600
mg clopidogrel with or without eptifibatide) of patients
undergoing elective stenting, assessed platelet reactivity, and
release of cardiac markers. Eptifibatide more than doubled
platelet inhibition when added to 600 mg of clopidogrel
whereas the latter dose achieved significantly higher levels of
platelet inhibition than did 300 mg (Fig. 3). Compared with
clopidogrel alone, eptifibatide was associated with lower
rates of release of CK-MB, troponin, and myoglobin after
PCI. Clearly, GP IIb/IIIa blockers are more powerful
inhibitors of platelet aggregation than are thienopyridines,
but the clinical relevance of these findings remains contro-
versial because some analyses have demonstrated incremen-
tal benefit of eptifibatide when added to clopidogrel (90 –
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Figure 3. In the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study (90) (2 ⫻ 2 randomization
to clopidogrel [clop] 300 vs. 600 mg and no eptifibatide vs. eptifibatide [ept]), the use of 600 mg of clopidogrel achieved a higher level of platelet inhibition
than 300 mg of clopidogrel using standard light transmission platelet aggregometry with 5 ␮mol/l adenosine diphosphate as the stimulus. *p ⱕ 0.001. The
release of troponin and myoglobin after PCI among the four treatment groups from highest to lowest were as follows: clopidogrel 300 mg without
eptifibatide, clopidogrel 600 mg without eptifibatide, clopidogrel 300 mg with eptifibatide, clopidogrel 600 mg with eptifibatide. ADP ⫽ adenosine
diphosphate; CK-MB ⫽ creatine kinase-myocardial band; ULN ⫽ upper limit of normal.

92), whereas the three aforementioned trials with abciximab
(76 –78) failed to do so.
Several studies have explored the clinical efficacy of GP
IIb/IIIa blockers in patients undergoing PCI. Longer du-
rations of infusion (⬎16 h) both before (93) and after (94)
PCI were associated with better clinical outcomes than
shorter infusions. A meta-analysis of five studies involving
6,766 patients with NSTE-ACS that were assigned ran-
domly to routine invasive versus conservative therapy
demonstrated improved survival with an early invasive
approach that includes stenting with adjunctive GP IIb/IIIa
blockade in men and in patients of both genders who
present with an elevated troponin (95). A comparison of
two trials (TIMI-3B and TACTICS-TIMI-18) comparing
an early invasive to an early conservative strategy demon-
strated better outcomes with the early invasive strategy only
in the trial that mandated use of an upstream GP IIb/IIIa
blocker (TACTICS-TIMI-18), suggesting a potential pos-
itive interaction between these two therapies (15).
Several articles have reported new information regarding
the safety of GP IIb/IIIa blockers. In patients in the
GUSTO IV ACS trial using abciximab in whom early
revascularization was not planned, major bleeding was rare
(1.2%), and when it did occur, it was associated with a
longer duration of abciximab infusion, performance of
nonplanned revascularization, and older age (96). One
approach to minimize the incremental increased risk of
bleeding with the addition of a GP IIb/IIIa blocker to
aspirin and clopidogrel (so-called “triple antiplatelet ther-
apy”) may be to utilize vascular closure devices (97).
Despite the wealth of new information about the use of
GP IIb/IIIa blockers, the recommendations provided in the
updated American College of Cardiology/American Heart
Association guidelines (98) remain pertinent (Table 4).
ANTICOAGULANTS
Interest in lowering the dose or even eliminating the use of
unfractionated heparin (UFH) in an attempt to minimize
bleeding is of great interest, given the increasing tendency to
administer triple antiplatelet therapy (aspirin, clopidogrel,
and a GP IIb/IIIa blocker) to many patients with ACS. A
consecutive case series of 500 patients undergoing elective
PCI received aspirin, clopidogrel, eptifibatide, and no rou-
tine heparin resulted in 100% technical success of PCI, with
no major adverse events in the first 24 h, and low rates of
non–Q-wave MI (1.6%), thrombocytopenia (0.6%), and
major (0.2%) and minor (0.6%) bleeding complications (99).
Data from larger randomized trials are needed to establish
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Table 4. American College of Cardiology/American Heart Association Guidelines (98) Regarding GP IIb/IIIa Blockers
Class I
A platelet GP IIb/IIIa antagonist should be administered, in addition to aspirin and heparin, to patients in whom catheterization and PCI are
planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI (Level of Evidence: A)
Class IIa
Eptifibatide or tirofiban should be administered, in addition to aspirin and low molecular weight heparin or unfractionated heparin, to patients with
continuing ischemia, an elevated troponin or with other high-risk features in whom an invasive m anagement is not planned. (Level of Evidence: A)
Class IIa
A platelet GP IIb/IIIa antagonist should be administered to patients already receiving heparin, aspirin, and clopidogrel in whom catheterization and
PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: B)
GP ⫽ glycoprotein; PCI ⫽ percutaneous coronary intervention.

the safety and efficacy of reducing or eliminating adjunctive
heparin in patients with ACS undergoing PCI.
Low molecular weight heparin. Two large-scale open-
label clinical trials, A to Z (100) and SYNERGY (101)
compared the low-molecular weight heparin, enoxaparin,
with UFH in patients with NSTE-ACS and concluded that
enoxaparin is not inferior to UFH and is, in fact, a safe,
effective alternative. Petersen et al. (102) provided a system-
atic evaluation of the outcomes in 21,946 patients in six
randomized controlled clinical trials that compared enox-
aparin and UFH in patients with NSTE-ACS (Table 5).
There was a 9% significant reduction in the composite of
death or nonfatal MI after 30 days with enoxaparin and no
differences in major bleeding or blood transfusions. Patients
who received an antithrombin before randomization ap-
peared to experience higher absolute rates of bleeding.
Thus, the practice of switching between antithrombins in
the same patient in the course of a single hospitalization
should be avoided whenever possible.
Since current practice has resulted in shorter intervals
between presentation and PCI, the question of whether an
adequate level of anticoagulation is achieved with fewer than
three doses of enoxaparin (without an initial bolus) is
important, particularly because lower anti-Xa activity on
enoxaparin is independently associated with higher rates of
30-day mortality (103). However, a retrospective analysis of
patients who went rapidly to PCI (after only two injections
of enoxaparin with a 12-h interval) demonstrated a level of
anti-Xa activity similar to those referred later to PCI (104).
In a subgroup analysis of the patients enrolled in the A to
Z trial managed with a conservative strategy, those random-
ized to enoxaparin experienced a significant 28% reduction
in the primary triple composite end point of death, new MI,
or documented refractory ischemia within seven days com-
pared with patients randomized to UFH, with no difference
in safety (105).
In conclusion, enoxaparin appears to result in similar or
slightly better efficacy than UFH in patients with NSTE-
ACS and a similar safety profile (Table 5). Given the greater
convenience (twice-daily subcutaneous injections), absence
of the need for routine monitoring, and simple weight-
based dosing that does not require subsequent dose-
adjustment with enoxaparin, we believe that enoxaparin
generally should be preferred over UFH in most patients
with NSTE-ACS.
Bivalirudin. The REPLACE-2 trial demonstrated that
the direct antithrombin bivalirudin (with provisional use of
a GP IIb/IIIa blocker) achieved comparable results to the
combination of UFH and a GP IIb/IIIa blocker, as assessed
by the quadruple composite end point of death, MI, urgent
target vessel revascularization, and major bleeding in 6,010
patients undergoing urgent or elective PCI (106). A major
feature of bivalirudin with provisional GP IIb/IIIa blocker
in this trial was reduced bleeding. No differences emerged in
long-term efficacy (death, MI, or repeat revascularization)
(106). A subgroup analysis (107) revealed that clopidogrel
pretreatment was associated with a trend toward lower
adverse events in both treatment arms, but no significant

Table 5. Systematic Overview of Six Randomized Trials Comparing Enoxaparin With

Unfractionated Heparin in NSTE-ACS (102)
End Point N Enoxaparin (%) UFH (%) Odds Ratio (95% CI)
All-cause mortality at 30 days
All patients 21,945 3.0 3.0 1.00 (0.85–1.17)
No pre-randomization antithrombin 9,833 2.8 3.2 0.88 (0.69–1.11)
Death or MI at 30 days
All patients 21,946 10.1 11.0 0.91 (0.83–0.99)
No pre-randomization antithrombin 9,835 8.0 9.4 0.81 (0.70–0.94)
Transfusions up to 7 days
All patients 16,650 7.2 7.5 1.01 (0.89–1.14)
No pre-randomization antithrombin 8,401 5.0 5.5 0.94 (0.77–1.16)
Major bleeding up to 7 days
All patients 16,650 4.7 4.5 1.04 (0.89–1.30)
No pre-randomization antithrombin 8,401 3.8 3.4 1.15 (0.86–1.55)
CI ⫽ confidence interval; MI ⫽ myocardial infarction; NSTE-ACS ⫽ non–ST-segment elevation acute coronary syndrome;
UFH ⫽ unfractionated heparin.
 ARTICLE IN PRESS
JACC Vol. 46, No. 5, 2005
September 6, 2005:906–19 The Year in Non–ST-Segment Elevation Acute Coronary Syndromes
treatment interaction was observed. A registry of 6,996
consecutive patients undergoing PCI at a single tertiary care
center during a four-year period confirmed that the results
of REPLACE 2, i.e., fewer bleeding events and no evident
increase in the incidence of ischemic complications with
bivalirudin compared with heparin with or without a GP
IIb/IIIa blocker (108).
Among moderate- and high-risk patients with ACS
undergoing PCI in the PROTECT-TIMI-30 trial (109)
that compared bivalirudin with the combination of the GP
IIb/IIIa blocker with UFH or enoxaparin, bivalirudin was
associated with a lower rate of normal myocardial perfusion,
a longer duration of ischemia on Holter monitoring among
patients with ischemia, and a trend toward a higher com-
posite rate of death, MI, or ischemia but no difference in
coronary flow reserve. Again, there were fewer episodes of
transfusion or serious bleeding with bivalirudin.
Taken together, the available results indicate that biva-
lirudin appears to be a safer and equally or perhaps slightly
less effective alternative to the combination of heparin with
a GP IIb/IIIa blocker. The ACUITY trial is randomizing
13,800 patients with NSTE-ACS undergoing an invasive
strategy randomly to 1) UFH or enoxaparin with a GP
IIb/IIIa blocker versus 2) bivalirudin with a GP IIb/IIIa
blocker versus 3) bivalirudin with provisional use of a GP
IIb/IIIa blocker (110). This large trial should provide
important guidance regarding the necessity for and timing
of heparin, bivalirudin, and GP IIb/IIIa blockade.
Other anticoagulants. The synthetic factor Xa inhibitor
fondaparinux was comparable with UFH in a pilot study of
350 patients undergoing PCI as a potential replacement for
heparin (111). Ongoing large phase III trials are evaluating
fondaparinux versus enoxaparin in patients with NSTE-
ACS (OASIS-5) and fondaparinux versus UFH (if indi-
cated) in patients with STE-MI treated with either fibrino-
lytic therapy or primary PCI (OASIS-6).
The first clinical study of a monoclonal antibody to tissue
factor (Sunol-cH36), blocking the most proximal step in the
extrinsic coagulation pathway, demonstrated dose-
dependent anticoagulant effects, although mucosal bleeding
was observed at higher doses (112). An inhibitor of the
tissue factor-factor VIIa complex, recombinant nematode
anticoagulant protein c2 (113), is being evaluated in patients
with NSTE-ACS in the phase II ANTHEM-TIMI-32
trial with preliminary results expected in late 2005.
Aptamers, single-stranded three-dimensional nucleic ac-
ids bind to target molecules (analogous to antibodies),
directed at thrombin represent another promising class of
anticoagulants. The RNA aptamer Ch-9.3t (114) and
ARC183, a DNA-based direct thrombin inhibitor, are two
such aptamers currently in early clinical trials. Given the
great importance of interfering safely with the clotting
system in patients with NSTE-ACS, further exploration of
these novel anticoagulants is welcome.
Giugliano and Braunwald 913
EARLY INVASIVE TREATMENT STRATEGY
A comprehensive summary of the year in interventional
cardiology was published in the Journal earlier this year
(115). Here, we focus on new findings with respect to the
early invasive management of patients with NSTE-ACS.
Each of three meta-analyses (95,116,117) concluded that
an early routine invasive strategy is superior to a selectively
invasive approach. Mehta et al. (116) analyzed data from
seven trials involving 9,212 patients and concluded that a
routine invasive strategy was associated with a significant
18% relative reduction in death or MI, a nonsignificant
trend toward fewer deaths, and a significant 25% relative
reduction in MI alone through the end of follow-up.
Although an early invasive strategy was associated with
excess mortality during the inhospital phase (1.8% vs. 1.1%),
this was more than offset by a significant reduction in
mortality between discharge and the end of follow-up (3.8%
vs. 4.9%). A routine invasive strategy also was associated
with relative reduction in angina and rehospitalizations of
33% and 34%, respectively. A meta-regression analysis
(117) showed that the most significant predictors of the
benefits of an early invasive strategy on survival free of
infarction were the use of an aggressive antiplatelet treat-
ment (defined as use of a GP IIb/IIIa blocker or thieno-
pyridine in addition to aspirin) and intracoronary stenting in
the early invasive group which was associated with a
substantial improvement in health-related quality of life.
These meta-analyses have strengthened further the case for
a routine early invasive strategy.
Additional support for an early invasive strategy in
patients with NSTE-ACS came from ISAR-COOL (118),
a trial comparing prolonged antithrombotic pretreatment
(median 86 h) with aspirin, heparin, clopidogrel, and
tirofiban before intervention with early intervention (me-
dian 2.4 h after presentation) with the same background
antithrombotic therapies. Patients randomized to the
“cooling-off” strategy had a significantly increased risk of
death or large nonfatal MI at 30 days. This difference in
outcome was attributed to events occurring before catheter-
ization in the group receiving prolonged antithrombotic
pretreatment. Furthermore, patients undergoing an early
invasive management have improved functional status and
quality of life, including greater treatment satisfaction and
lower disease perception (119).
Subgroup analyses from elderly patients with NSTE-
ACS enrolled in the TACTICS-TIMI-18 trial demon-
strated that a routine early invasive strategy was associated
with relative reductions of 39% (patients age ⬎65 years) and
56% (patients age ⬎75 years) in the rates of death or MI at
six months (120). Men appear to benefit more than women
from an early invasive strategy (121), although much of this
difference may be related to a lower incidence of positive
baseline markers of myonecrosis in women compared with
men (55).
In contrast to these studies and analyses favoring an early
 ARTICLE IN PRESS
914 Giugliano and Braunwald
The Year in Non–ST-Segment Elevation Acute Coronary Syndromes
invasive strategy, in the ICTUS trial of 1,200 patients with
NSTE-ACS, an elevated troponin T, and either ischemic
electrocardiographic changes or a documented history of
coronary artery disease, randomization to an early invasive
versus a selective invasive strategy demonstrated no differ-
ence in the composite end point of death, MI, or rehospi-
talization for ACS at one year (122). One potential expla-
nation for the lack of benefit with an early invasive approach
was the high rate of catheterization (67%) and revascular-
ization (47%) in the “selective” invasive strategy, thereby
markedly reducing the differences between the treatment
arms.
LIPID-LOWERING THERAPY AFTER ACS
Two large, double-blind, randomized controlled trials have
compared early intensive lipid lowering statin regimens with
more standard statin regimens in patients after NSTE-ACS
or STEMI. In the PROVE IT-TIMI-22 trial, 4,162
patients hospitalized with ACS within 10 days were ran-
domized to either 40 mg of pravastatin or 80 mg of
atorvastatin daily and followed for a mean of 24 months
(123). The median low-density lipoprotein (LDL) achieved
during treatment was significantly lower in patients ran-
domly assigned to high-dose atorvastatin (62 mg/dl vs. 95
mg/dl, p ⬍ 0.001), which translated into a 16% significant
relative reduction in the primary composite end point of
all-cause mortality or major cardiovascular events with the
more intensive lipid-lowering regimen (Fig. 4). Consistent
reductions were observed across a variety of cardiac events
except stroke. Furthermore, the reduction in clinical events
became apparent quite early, with event curves diverging
within 30 days after the initiation of therapy (124). These
findings led to a modification of the recommendations of
the Adult Treatment Panel III guidelines of the Cholesterol
Education Program in very high-risk patients, providing an
optional LDL cholesterol goal of ⬍70 mg/dl (125).
In the Z phase of the A to Z trial, 4,487 post-ACS
patients were randomized to an early initiation of intensive
statin (simvastatin 40 mg/day for one month followed by 80
mg/day thereafter) or a delayed conservative statin regimen
consisting of diet with placebo for four months followed by
20 mg/day thereafter for an average of two years (126). At
one month, the mean LDL cholesterol levels were reduced
to 68 mg/dl in the simvastatin 40 mg group compared with
122 mg/dl in the group randomly assigned to placebo,
whereas at eight months the mean LDL cholesterols were
77 versus 63 mg/dl in the simvastatin 20- and 80-mg
groups, respectively. A favorable trend toward a lower rate
of the primary composite end point of cardiovascular death,
nonfatal MI, readmission for ACS, and stroke was observed
with more intensive statin arm (14.4% vs. 16.7% in the
delayed conservative arm). No difference between these
arms was evident during the first four months after random-
ization. However, from four months through the end of the
JACC Vol. 46, No. 5, 2005
September 6, 2005:906–19
Figure 4. The composite of death or major cardiovascular events were
reduced by 16% in patients after acute coronary syndromes who were
randomized to high-intensity statin (atorvastatin 80 mg/day) compared
with standard-dose statin (pravastatin 40 mg/day) in the PROVE IT-
TIMI-22 trial (123).
study, the primary composite was reduced significantly by
25% in the high-dose simvastatin group.
The findings of the PROVE IT-TIMI-22 and A to Z
trials were supported by an intracoronary ultrasound study,
REVERSAL, that demonstrated slower progression of
atherosclerosis in 502 patients with chronic coronary artery
disease undergoing coronary angiography with intensive
lipid lowering with atorvastatin 80 mg/day compared to
pravastatin 40 mg/day (127). A second smaller study dem-
onstrated a reduction in plaque volume of nonculprit lesions
by serial volumetric intravascular ultrasound assessments six
months after an admission for ACS in patients who were
managed with PCI and treated with atorvastatin 20 mg/day
versus placebo (128). Similar findings of plaque regression
and reverse remodeling were observed by serial magnetic
resonance imaging of the aorta; plaque regression correlated
strongly with the degree of LDL reduction in patients
treated with simvastatin at doses of 20 to 80 mg/day (129).
An important additional lesson learned from the studies
of early intensive statin therapy is the achievement of an
acute anti-inflammatory effect and its association with
better clinical outcomes. In the PROVE IT-TIMI-22 trial,
patients who achieved hs-CRP levels ⬍2 mg/l had lower
event rates than those who had higher hs-CRP levels
regardless of the LDL achieved (Fig. 5) (130). The dual
goals of LDL ⬍70 mg/dl and hs-CRP ⬍2 mg/l were more
likely to be achieved with atorvastatin 80 mg/day than with
pravastatin 40 mg/day (131). A second randomized trial
comparing atorvastatin 40 mg/day with placebo in patients
with ACS also showed the rapid reduction in hs-CRP seen
in PROVE IT-TIMI-22 (132). In the REVERSAL trial,
hs-CRP levels were independently and significantly corre-
lated with the rate of progression of atherosclerosis (133).
The data now available support the use of an intensive
statin regimen, such as atorvastatin 80 mg/day in patients
after ACS, preferably commencing in the hospital. The
reduction of CRP appears to be an equally useful goal. The
IMPROVE IT trial is comparing Vytorin (MSP Singapore
LLC, Merck/Schering-Plough Pharmaceuticals, North
 ARTICLE IN PRESS
JACC Vol. 46, No. 5, 2005
September 6, 2005:906–19
Figure 5. An analysis (130) from the PROVE IT-TIMI-22 trial of achieved low-density lipoprotein (LDL) and achieved high-sensitivity C-reactive
protein (hs-CRP), stratified at cutpoints of 70 mg/dl and 2 mg/l respectively, identified four groups of patients. Event rates were highest in the group with
“high” LDL and “high” hs-CRP, and lowest in the group with “low” LDL and “low hs-CRP.”
Wales, Pennsylvania) the combination of simvastatin with
ezetimibe, an inhibitor of cholesterol absorption, with
simvastatin alone in patients early after ACS. In addition,
more potent therapies to raise HDL, such as combinations
of existing therapies (134), inhibitors of cholesterol ester
transfer protein (135), and infusions of apoA-1 Milano and
phospholipids (136) are also on the horizon. The pharma-
ceutical industry is now focusing appropriate attention on
anti-inflammatory drug development as well. Interestingly,
long-term treatment with gatifloxacin, an antibiotic that is
bactericidal against Chylamydia pneumoniae, did not reduce
the rate of cardiovascular events compared with placebo in
the PROVE IT-TIMI-22 trial, even among patients with
elevated titers to C. pneumoniae or hs-CRP (137).
CONCLUSIONS
Because analyses of combinations of proven therapies dem-
onstrate that each additional treatment provides incremental
benefit (138,139), we end this Year in Review with a
simplified “ABCDE” mnemonic approach to the manage-
ment of NSTE-ACS recently proposed by Gluckman et al.
(140). This can be used as a checklist of proven therapies.
A: Antiplatelet therapy, Anticoagulation, Angiotensin-
converting enzyme inhibition
B: Beta-adrenergic receptor blocker, Blood pressure control
C: Cholesterol lowering, Cigarette smoking cessation
D: Diet, Diabetes management
E: Exercise
Reprint requests and correspondence: Dr. Eugene Braunwald,
TIMI Study Group, Brigham and Women’s Hospital, 350 Long-
wood Avenue, 1st Floor Offices, Boston, Massachusetts 02115.
E-mail: ebraunwald@partners.org.
Giugliano and Braunwald 915
The Year in Non–ST-Segment Elevation Acute Coronary Syndromes
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