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430 Part IV / Practical Issues and Future Applications
In the RAPPORT trial, patients with acute MI given abciximab before primary angio-
plasty had a >70% relative reduction in the primary endpoint of death, reinfarction, or
revascularization (5.6% vs 11.2% at 30 d; p = 0.03) (30). In the single-center, open-label,
randomized STOP-AMI trial, the combination of stenting plus abciximab was shown to
enhance myocardial salvage and markedly improve event-free survival at 30 d and 1 yr
compared with accelerated alteplase (31). These investigators also explored the benefits
of adding abciximab to early stenting in MI in the ISAR-2 trial (32). In that study, 200
patients within 48 h of onset of acute MI in whom primary or rescue stenting was planned
were randomized to receive a bolus and 12-h infusion of abciximab, or control. Patients
Fig. 2. Hazard ratios for 30-d clinical endpoints with tirofiban vs placebo in the TARGET trial. MI, myo-
cardial infarction; TVR, target vessel revascularization. (From ref. 26, with permission.) Copyright
©2001 Massachusetts Medical Society. All rights reserved.
Fig. 3. Sixty-minute angiographic TIMI grade 3 flow rates with contemporary fibrinolytic agents in
patients with acute MI (44–46).
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Chapter 21 / Summary and the Future 431
treated with abciximab had a lower composite rate of in-hospital death, reinfarction, or
urgent TVR (9.2% vs 2.0%; p < 0.05). Regional wall motion, global left ventricular
function, and peak coronary blood flow velocity by Doppler angiography were better in
abciximab-treated patients, consistent with improved distal microcirculatory function,
presumably owing to reduced distal thromboemboli or capillary plugging. The rate of
clinical events or angiographic restenosis did not differ at 6 mo, however (24).
The ADMIRAL study showed that abciximab was associated with a higher rate of early
TIMI grade 3 flow (95.1% vs 86.7% for placebo, p = 0.04), greater left ventricular ejec-
tion fractions (57.0 ± 10.4% vs 53.9 ± 10.4%; p < 0.05), and a significantly lower rate of
the primary composite endpoint of death, reinfarction, and urgent TVR at 30 d after enroll-
ment (14.6% vs 6.0%; p = 0.01; Fig. 4) (33). In the CADILLAC trial (Fig. 4), 2081 patients
with acute ST-segment elevation MI were randomized to receive one of four treatment
strategies: (1) balloon angioplasty alone, (2) balloon angioplasty plus abciximab, (3) stent-
ing alone, or (4) stenting plus abciximab (34). Although TIMI grade 3 flow was not signif-
icantly improved in the abciximab group compared with the stenting-alone group, abciximab
administration was associated with significant reductions in recurrent ischemia, subacute
thrombosis, and length of hospitalization.
Facilitated Fibrinolysis: GPIIb/IIIa Inhibitors in ST-Elevation MI
In addition to their antiplatelet effects, GPIIb/IIIa inhibitors also augment intrinsic
fibrinolysis, creating a dual rationale for their application in acute MI. GPIIb/IIIa inhibitors
independently exhibit some intrinsic clot-dissolving activity (35). Early animal studies
showed the benefit of combining GPIIb/IIIa blockade with heparin and fibrinolytic therapy
in acute coronary occlusion (36,37). Theoretical advantages of “facilitated fibrinolysis”
include a reduction in plasminogen activator-mediated platelet aggregability, earlier infarct-
vessel patency, increased safety, and less reocclusion.
Fig. 4. Thirty-day and 6-mo outcomes of patients undergoing primary angioplasty, stenting, or both
in the CADILLAC (33) and ADMIRAL (34) trials. reMI, reinfarction; TVR, target vessel revascularization.
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432 Part IV / Practical Issues and Future Applications
Contemporary trials combining GPIIb/IIIa blockade with reduced-dose fibrinolytic
therapy have shown a higher rate of TIMI grade 3 flow with acceptable bleeding risk (38–
43). In the ASSENT-3 trial, two new therapies were compared with unfractionated heparin
and full-dose fibrinolytic therapy (44). The experimental arms consisted of (1) low-molec-
ular-weight heparin (enoxaparin) plus full-dose tenecteplase and (2) reduced-dose tenec-
teplase, abciximab, and unfractionated heparin. Among 6095 patients, the incidence of
30-d mortality, in-hospital reinfarction, or in-hospital recurrent ischemia was 11.2% in
the enoxaparin group, 11.4% in the abciximab group, and 15.4% in the full-dose tenectep-
lase plus unfractionated heparin group (p = 0.0001).
In the largest trial of “facilitated fibrinolysis” to date, the GUSTO-V study compared
standard-dose reteplase alone with half-dose reteplase plus full-dose abciximab in 16,588
patients with acute MI (Fig. 5) (45). For the primary endpoint of 30-d survival, combined
treatment with reteplase and abciximab offered no significant advantage over reteplase
alone (5.9% with reteplase vs 5.6% with combined therapy; p = 0.43). Combination ther-
apy was associated with fewer nonfatal ischemic complications (28.6% vs 31.7% for any
complication; p < 0.0001) but also significantly greater bleeding complications (4.6% vs
2.3%; p < 0.0001 for moderate and severe nonintracranial bleeding). The rate of stroke
(both ischemic and hemorrhagic) did not differ significantly between the groups. In a sub-
group analysis, elderly patients receiving combination therapy tended to have more intracra-
nial hemorrhages (2.1% with combination therapy vs 1.1% with alteplase alone; p = 0.069)
compared with younger patients. The INTRO-AMI trial likewise showed a 3% intracranial
hemorrhage rate among patients receiving the higher-dose eptifibatide regimen (46). Before
combination therapy is adopted into routine clinical practice, the reduction in post-MI com-
plications must be balanced against the increased risk of bleeding, complexity of dosing,
and potentially higher costs.
Fig. 5. Death and ischemic complications in patients receiving abciximab or reteplase plus abciximab
for acute MI in the GUSTO V trial (45). PCI, percutaneous coronary intervention.
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Chapter 21 / Summary and the Future 433
GPIIb/IIIa Inhibition in Non-ST Elevation ACS
In the United States, non-ST-elevation (NSTE) ACS remains a leading cause of cardio-
vascular-related hospitalizations, accounting for more than 750,000 annual admissions
(47). More than one-third of admissions for acute MI are related to NSTE infarctions
(48). Although NSTE-ACS manifests as heterogeneous combinations of clinical symp-
toms, electrocardiographic changes, and biochemical markers of myocardial injury, treat-
ment remains directed at the common underlying event of platelet activation and thrombus
formation.
In the past decade, patients with NSTE-ACS were at substantial risk for adverse clinical
outcome events even after intensive in-hospital treatment. Among such patients enrolled
in the TIMI-IIIB trial, 6.2% died or had an MI by 42 d, and more than half required revas-
cularization (49). In addition, in the GUSTO-IIb study, 9.8% of patients had an MI or died
within 30 d (50).
The substantial benefit with adjunctive GPIIb/IIIa blockade for PCI has been established
for several years. More recently, the importance of GPIIb/IIIa antagonism for patients
presenting with ACS has also become clear. Unlike coronary intervention, in which the
presence of coronary artery disease and the timing of intentional intimal injury are both
known, the broad treatment of patients presenting with chest pain symptoms is less certain.
Unstable angina remains a clinical diagnosis, relying on patient symptoms that may be
atypical and electrocardiographic changes and serum cardiac markers that may be incon-
sistent. Extending the application of GPIIb/IIIa inhibitors to patients based on imprecise
initial symptoms may not provide the same benefit as administration before PCI of a known
coronary lesion. Despite these challenges, large randomized trials have shown the effi-
cacy of GPIIb/IIIa antagonists for patients with NSTE-ACS (Fig. 6).
The PRISM trial, the first large trial of GPIIb/IIIa inhibitors, randomly assigned 3232
patients with ACS to intravenous tirofiban or heparin for 48 h (51). At 48 h, the primary
composite endpoint of death, MI, or refractory ischemia was reduced in the tirofiban group
(3.8% vs 5.9%; p = 0.014). This benefit did not persist at 30 d, however (12.8% vs 13.9%;
p = ns) despite an unexpected, significant reduction in mortality (2.3% vs 3.6%; p = 0.02).
Among troponin I-positive patients, treatment with tirofiban was also associated with sig-
nificant reductions in the composite of death or MI and length of hospitalization com-
pared with heparin treatment alone (46).
The PRISM-PLUS trial enrolled 1915 high-risk patients with ACS to test tirofiban as
part of a comprehensive strategy of standard therapy with heparin and aspirin and the selec-
tive use of PCI (52).
As part of the study design, PRISM-PLUS examined an aggressive
strategy with angiography performed in 90% of patients and revascularization in 54%, typi-
cally after at least 48 h of study drug treatment. Patients received heparin, tirofiban plus
heparin, or tirofiban alone for a mean of 71 h. Notably, the tirofiban monotherapy arm was
stopped prematurely because of excess mortality at 7 d (4.6% vs 1.1%; p = 0.012). At 7 d,
tirofiban plus heparin reduced the primary composite endpoint of death, MI, or refractory
angina compared with heparin alone (12.9% vs 17.9%; p = 0.004). The benefit of com-
bination therapy persisted at both 30 d (22.3% vs 18.5%; p =0.03) and 6 mo (32.1% vs
27.7%; p = 0.02).
The PARAGON-A (53) trial was a dose-ranging pilot study of lamifiban in NSTE-ACS.
Nearly 2300 patients were treated with one of two doses of lamifiban, with or without hep-
arin, or heparin alone. All patients received aspirin. At 30 d, the composite endpoint of
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434 Part IV / Practical Issues and Future Applications
death or nonfatal MI was not reduced with either dose of lamifiban therapy. By 6 mo,
patients assigned to low-dose lamifiban showed a lower incidence of death or MI than
those treated with heparin alone (12.6% vs 17.9%; p = 0.025). High-dose lamifiban therapy,
however, did not confer any advantage with regard to ischemic events and, when combined
with heparin, was associated with more bleeding. No clear explanation exists for the lack
of benefit and potential harm of high-dose therapy, particularly because a much smaller
study preceding PARAGON-A reported greater platelet inhibition and lower 30-d event
rates with higher doses (54).
Retrospective analyses of patients enrolled in PARAGON-A indicated improved out-
comes among patients with plasma levels of lamifiban between 18 and 42 ng/mL (55). The
effect of optimally dosed lamifiban (based on renal function) and concomitant heparin
therapy therefore was assessed in the placebo-controlled PARAGON-B trial (56). Unlike
previous trials of GPIIb/IIIa inhibition in NSTE-ACS, PARAGON-B was powered to
detect a more ambitious 25% relative reduction in the primary endpoint of death, MI, or
urgent revascularization at 30 d. A total of 5225 patients with NSTE-ACS were randomized
to receive either placebo or dose-adjusted lamifiban. GP IIb/IIa inhibition with intravenous
lamifiban was associated with an approximate 10% relative reduction in the primary end-
point, but this difference was not statistically significant (11.8% with lamifiban vs 12.8%
with placebo; p = 0.329). In a prespecified substudy of 1160 patients with elevated tro-
ponin T levels, lamifiban was associated with a significant reduction in death or MI at
Fig. 6. Odds ratios for death or MI at 30 d; contemporary trials of GPIIb/IIIa inhibition vs placebo
for NSTE-ACS. (Data from ref. 61.)
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Chapter 21 / Summary and the Future 435
30 d compared with placebo (11.0% vs 19.4%; p = 0.018), reaffirming that GPIIb/IIIa
inhibition improves the outcomes of high-risk patients (57).
In the largest investigation of GPIIb/IIIa antagonists in ACS, the PURSUIT trial, 10,948
patients in 28 countries were randomly assigned to receive eptifibatide or placebo with
adjunctive heparin and aspirin therapy (58). Entry criteria included either dynamic ST-seg-
ment shift or enzyme evidence of myocardial injury, establishing the study population
as a relatively high-risk group. Previous experience with eptifibatide showed a reduction
in the frequency and duration of ischemic events detected by Holter monitoring (59). In
PURSUIT, eptifibatide was associated with an absolute 1.5% reduction in the primary end-
point of death or MI at 30 d (14.2% vs 15.7%; p = 0.04). The benefit was apparent by 96 h
and persisted through the 30-d follow-up. Bleeding was more common in patients assigned
eptifibatide, but there was no increase in hemorrhagic stroke.
In contrast to previous trials showing a benefit with intravenous GPIIb/IIIa inhibition
in NSTE-ACS, the GUSTO-IV trial showed no clinical advantage in treating such patients
with abciximab compared with placebo (60). Specifically, 7800 patients were randomly
assigned to treatment with placebo, a 24-h abciximab infusion, or a 48-h abciximab infu-
sion. The primary endpoint of 30-d death or MI occurred in 8.0, 8.2, and 9.1% of patients,
respectively (p = ns). Only 1.6% of patients underwent revascularization within the 48-h
treatment period. In contrast to PARAGON-B, GUSTO-IV did not detect a particular bene-
fit from GPIIb/IIIa inhibition among patients with elevated troponin levels. The reasons
for this discrepancy are unclear, but they may relate to paradoxical platelet activation with
abciximab, a lower risk study population, or heterogeneity in platelet inhibition among
patients treated over a period of days. Another explanation may be the absence of early
revascularization. A modest but distinct clinical benefit of early or “upstream” treatment
with GPIIb/IIIa inhibitors before PCI has been established in ACS trials, however, such
that the benefit of an invasive strategy is not strictly because of PCI alone. More likely,
GUSTO-IV did not have adequate statistical power to detect a realistic effect of GPIIb/IIIa
inhibition as medical therapy alone—10% relative reduction in death or MI, consonant
with GPIIb/IIIa inhibition as medical therapy in previous studies, vs the intended 20%
event-rate reduction.
Compared with previous studies, patients in the GUSTO-IV trial also were at lower risk,
having the lowest incidence of death or MI at 30 d. Furthermore, GUSTO-IV enrolled more
women (38%). Whether this observation relates to a sex-related difference in treatment
response or the fact that troponin-positive patients in trials are more often male requires fur-
ther study. Factors such as being younger and male have consistently been associated with
greater treatment effects in ACS patients, however, and a systematic overview of GPIIb/
IIIa inhibition in NSTE-ACS has shown consistently reduced ischemic events among tro-
ponin-positive patients (Fig. 7) (61). Alternatively, abciximab may promote an inflamma-
tory reaction by aiding P-selectin-mediated leukocyte adhesion (62), although studies of
abciximab therapy for PCI suggest early, but nonsustained, suppression of C-reactive pro-
tein, tumor necrosis factor, and interleukin-6 (63).
PROGRESSION AND REGRESSION:
DEVELOPMENT AND FAILURE OF ORAL GPIIb/IIIa INHIBITORS
Prevention of recurrent events after patients are admitted for ACS poses a continuing
challenge. Activation of the coagulation system and inflammation within the coronary
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436 Part IV / Practical Issues and Future Applications
artery plaque may persist up to several months after the initial event (64,65). Clinical expe-
rience supports these observations with high rates of recurrent cardiac events in this pop-
ulation. For example, in the GUSTO-IIb study, >6% of patients with NSTE-ACS died,
>10% had an MI, and >45% were readmitted by 6-mo follow-up (66). Although the abso-
lute benefit of eptifibatide in the PURSUIT trial was preserved at 6 mo, there were no
additional reductions in death or infarction between 1 and 6 mo. This suggests that most
of the benefit occurs in the early phase of treatment, with no further effect after the drug
infusion ends (67).
Several studies have examined both the safety and clinical benefit of sustained platelet
suppression with oral GPIIb/IIIa antagonists for secondary prevention after a cardiac event.
In the TIMI-12 study, major bleeding occurred among those treated with oral sibrafiban to
nearly the same extent as those receiving aspirin alone (68). Minor bleeding, however,
particularly mucocutaneous bleeding, was more common with increasing doses of sibrafi-
ban. The safety profile and risk for bleeding appeared to be largely determined by total daily
dose, renal function, and daily dosing frequency. Other trials of oral GPIIb/IIIa inhibition
after PCI also seemed promising at first. The ORBIT investigators reported effective long-
term suppression of platelet aggregation with xemilofiban after angioplasty, with a trend
toward fewer cardiovascular events at early (3-mo) follow-up (69). Clinical development
of xemilofiban was discontinued, however, after publication of the EXCITE trial results
(70). Among 7232 patients undergoing PCI and randomized to receive one of two doses
of xemilofiban or placebo for 6 mo, the incidence of death or MI did not differ signifi-
cantly, although bleeding rates were higher with both low- and high-dose xemilofiban.
Fig. 7. Odds ratios for death or myocardial infarction at 30 d by sex and troponin status; contem-
porary trials of GPIIb/IIIa inhibition in NSTE. (Data from ref. 61.)
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Chapter 21 / Summary and the Future 437
Development of other oral GPIIb/IIIa inhibitors has been abandoned because of lack
of efficacy and potential harm. Results of the SYMPHONY and 2nd SYMPHONY trials
evaluating sibrafiban alone and with aspirin showed no clinical benefit and significantly
higher rates of ischemic events with high-dose sibrafiban (71,72). The OPUS-TIMI 16
study was terminated early because of an unexpectedly higher mortality among patients
treated with orbofiban (73). Finally, the BRAVO trial
(74) was stopped early for significant
increases in death, serious thrombocytopenia, and major bleeding associated with lotrafi-
ban use. In a systematic overview of four randomized trials of oral GPIIb/IIIa inhibition
enrolling more than 33,000 patients, treatment with oral GPIIb/IIIa agents was associated
with a 31% increase in mortality (odds ratio, 1.31; 95% confidence interval, 1.12–1.53;
p = 0.0001) (75). Results were similar whether the agent was added to or substituted for
aspirin. Ischemic events or sudden death tended to be increased (odds ratio, 1.22; 95%
confidence interval, 0.91–1.63), and among patients with ACS, the incidence of MI was
increased (odds ratio, 1.16; 95% confidence interval, 1.03–1.29).
Although many potential explanations exist for the poorer clinical outcomes associ-
ated with oral GPIIb/IIIa inhibition, a prothrombotic effect most likely contributes to the
observed higher rate of ischemic events (75,76). Oral GPIIb/IIIa inhibitors may paradox-
ically activate platelets, enhance fibrinogen binding, or potentiate inflammation (76–78).
In contrast to intravenous agents given at doses that achieve sustained levels of receptor
occupancy, oral agents are used at lower doses, and plasma levels may vary considerably
between doses (78,79). Supporting this theory, the Phase II FROST trial showed that clin-
ical outcomes with the oral GPIIb/IIIa antagonist lefradafiban related directly to the degree
of platelet inhibition, suggesting that longer-acting drugs with more effective platelet inhi-
bition may offer clinical benefit (80). Finally, based on the association of oral GPIIb/IIIa
inhibitors with increased mortality despite a reduction in urgent revascularization, a direct
toxic effect of these agents also been has suggested (75).
ALTERNATIVE ANTIPLATELET AND ANTITHROMBOTIC THERAPIES
Antiplatelet Therapies
ASPIRIN
Aspirin is the “wonder drug” of cardiovascular medicine. Introduced as a medicine over
100 years ago, this drug has a significant beneficial effect—reducing ischemic events in
patients with atherosclerosis—at a cost of less than a penny a day. Aside from its effect on
platelet aggregation, aspirin’s antiinflammatory effects also may contribute to its observed
reduction in ischemic events.
Aspirin has a dramatic effect on the risk of vascular events in patients with known athero-
sclerosis. The Antiplatelet Trialists’ Collaboration showed a 20–40% reduction in the risk
of death, MI, or stroke (81). This benefit is clear for patients with primary disease in the
coronary and cerebrovascular beds and for patients after MI, unstable angina, transient
ischemic attacks, or stroke. More recently, aspirin has been associated with lower all-cause
mortality over the long term. Among 6174 patients undergoing stress echocardiography
to evaluate known or suspected coronary artery disease, aspirin therapy was associated
with reduced all-cause mortality over an approximate 3-yr follow-up period (hazard ratio,
0.67; 95% confidence interval, 0.51–0.87; p = 0.002). After adjusting for the propensity
for using aspirin, as well as other possible interactions, aspirin use remained associated with
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438 Part IV / Practical Issues and Future Applications
a lower risk of death (hazard ratio, 0.56; 95% confidence interval, 0.40–0.78; p < 0.001).
Although this multicenter observational study cannot be definitive, its findings are con-
sistent with data from randomized trials.
Recent analyses also have stressed the benefit of aspirin in primary prevention. Both the
HOT Trial (82) and the Primary Prevention Project (83) showed that relatively low doses
of aspirin (80–100 mg/d) were effective in preventing cardiovascular events in patients
with at least one risk factor but no overt coronary disease. In the Physicians’ Health Study,
primary prevention with 325 mg every other day resulted in a significant reduction in MI
but no overall reduction in cardiovascular mortality (84). A recent review of aspirin ther-
apy in primary prevention trials involving more than 50,000 patients showed a reduction
in the relative risk of ischemic adverse events in all trials except one (85).
Despite dozens of clinical trials involving over 100,000 patients, the most effective
aspirin dose has not been identified. A broad clinical consensus has developed, nonetheless,
with recommendations for aspirin dosing between 75 and 325 mg/d in patients with coro-
nary disease. Overall, this practice has been primarily driven by simplicity, commercial
availability, physician preference, and concerns about the adverse effects such as abdom-
inal discomfort and gastrointestinal bleeding associated with higher doses. Although this
dose range has developed empirically over time, evaluation of the optimal dose for aspirin
therapy (balancing clinical benefit with adverse effects) has largely resulted from indirect
comparisons among multiple trials performed in various clinical settings.
Varied results from previous trials addressing aspirin dosing have underscored the uncer-
tainty with regard to aspirin dosing in reducing secondary vascular events. In the largest
experience to date, the Antiplatelet Trialists’ Collaboration performed a systematic over-
view of 11 trials of antiplatelet therapy, suggesting no dose relationship of aspirin in the
secondary prevention of cardiovascular events (80). Alternatively, a recent analysis of
aspirin dosing in the CURE trial (S. Mehta, personal communication) showed the lowest
rates of bleeding and ischemic events among patients taking <100 mg/d of aspirin. For
patients receiving combined aspirin and clopidogrel (75 mg/d), adverse events were lowest
among those patients taking <100 mg/d of aspirin compared with 100–200 mg/d and
>200 mg/d, such that the benefit of combination therapy was largely owing to the reduction
in ischemic events compared with aspirin alone at doses >100 mg/d. Similarly, two recent
systematic overviews of aspirin trials showed a greater benefit of lower doses of aspirin
in reducing ischemic adverse events in ACS (86; D. Kong, personal communication).
Accordingly, there is a clear need to define the optimal dose of aspirin therapy in an ade-
quately powered, randomized controlled trial with reference to prevention of both ische-
mic vascular events and excess bleeding. Despite its widespread availability and low cost,
identifying the optimal dose of aspirin will have major effects, considering the potential
reduction in both ischemic and bleeding events. Bleeding is slightly but significantly
increased with 75 mg of aspirin per day compared with placebo, but gastric bleeding is
doubled with 300 mg/d and increased fivefold with 1.8–2.4 g/d (87). Potential implica-
tions of aspirin dosing underscore the need for a large, randomized clinical trial.
T
HIENOPYRIDINES: TICLOPIDINE AND CLOPIDOGREL
Thienopyridine platelet inhibitors have been in clinical use for over a decade. Ticlopidine,
the prototype, was shown in a series of clinical trials to reduce ischemic events compared
with placebo (88,89), to be marginally superior to aspirin in one trial of cerebrovascular
disease (90), and to provide additive benefit to aspirin in PCI (91). Clopidogrel is struc-
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Chapter 21 / Summary and the Future 439
turally similar to ticlopidine but is associated with a much lower rate of adverse events.
Most notably, ticlopidine treatment carries troublesome rates of neutropenia, thrombo-
cytopenia, and thrombotic thrombocytopenic purpura (92). In comparison, these events
have not been identified with clopidogrel in large clinical trials.
The first major study with clopidogrel was the CAPRIE trial, which showed a modest
benefit over aspirin (relative reduction, 8.7%; p = 0.043) in the secondary prevention of
ischemic stroke, MI, or vascular death among patients with vascular disease (93). These
results were important in providing substantial evidence that aspirin-intolerant patients
could take clopidogrel with at least equal clinical benefit. The substantially higher cost
of clopidogrel, however, has inhibited most health care providers from substituting clo-
pidogrel for aspirin in routine secondary prevention.
Recently, the CURE trial compared the combination of aspirin and clopidogrel with
aspirin alone in patients with ACS (94). The trial showed a 22% relative reduction in the
composite endpoint of death, MI, or stroke with combined aspirin and clopidogrel therapy
(9.3% with clopidogrel and aspirin vs 11.4% with aspirin alone; p < 0.001). Although major
bleeding occurred significantly more often with combined therapy (3.7% with aspirin
and clopidogrel vs 2.7% with aspirin alone; p = 0.001), there was no difference in major
bleeding after 30 d. This relationship suggests that most of the hemorrhagic risk occurred
with revascularization procedures.
As a result of these findings, contemporary guidelines for the treatment of non-ST-
elevation ACS emphasize prompt administration of clopidogrel and aspirin for patients
in whom a noninvasive strategy is planned and for patients scheduled to undergo PCI.
Because of an increased risk of perioperative bleeding, clopidogrel should be discontinued
a minimum of 5 d before elective bypass surgery (47). Although CURE was not designed
as a long-term prevention study (follow-up period of 1 yr), it might be reasonable to con-
tinue clopidogrel beyond this period.
Thrombin Inhibitors
UNFRACTIONATED AND LOW-MOLECULAR-WEIGHT HEPARINS
A mainstay of conventional therapy in ACS patients has been adjunctive antithrombin
treatment. In clinical trials, however, the addition of heparin or direct thrombin inhibitors
has conferred only a modest benefit with regard to clinical outcomes. Oler and colleagues
performed a systematic overview of six trials of aspirin alone vs aspirin and unfractionated
heparin (UFH). No individual trial reached statistical significance, and the pooled risk of
MI or death was reduced by a relative 33% (p = 0.06) in patients with unstable angina given
aspirin alone (95).
Even though UFH appears to provide a benefit in ACS, event rates increase when it
is discontinued, although GPIIb/IIIa inhibition appears to attenuate this rebound effect
(96). Heparin is also associated with thrombocytopenia and the potential to cause malig-
nant thrombosis. Finally, it is difficult to titrate heparin dosing within a therapeutic range,
and both insufficient and excessive doses are associated with worse clinical outcomes.
Low-molecular-weight heparins (LMWHs) offer several conceptual advantages over
UFH. First, through preferential inhibition of factor Xa over thrombin, LMWHs produce
more effective anticoagulation earlier in the coagulation cascade. They also are less likely
to cause heparin-induced thrombocytopenia, and current standards do not require thera-
peutic monitoring. In several direct comparative trials of patients with NSTE-ACS and
ST-elevation ACS, the LMWHs have been at least as effective, if not superior to, UFH (44,
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