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440 Part IV / Practical Issues and Future Applications
97). A prospectively defined metaanalysis of the two enoxaparin trials, ESSENCE and
TIMI-11B, showed
consistent reductions in the composite endpoints of death, MI, or
urgent revascularization and
death or MI in favor of enoxaparin over UFH through 43 d
(98). The benefits
of enoxaparin reflected similar, proportionate reductions
in each ele-
ment of the composite endpoints, indicating
that the results were not driven by any individ-
ual event. At 1 yr,
the rate of death, MI, or urgent revascularization remained significantly
lower in enoxaparin-treated patients (23.3% vs 25.8%; p = 0.008). In contrast to enoxap-
arin, greater efficacy with dalteparin and fraxiparine compared with UFH has not been
confirmed (99,100). Possible reasons for the benefit of enoxaparin include more selec-
tive anti-Xa/anti-IIa activity and inactivation of platelet-released von Willebrand factor.
Clinical experience with combined LMWH and GPIIb/IIIa inhibition is limited. Results
from the ongoing SYNERGY and A to Z trials in patients with NSTE-ACS and PCI should
help delineate the safety and efficacy of this combination. The need for therapeutic mon-
itoring of LMWH activity during PCI also remains controversial. Standard measurements
of anticoagulation during PCI (e.g., activated clotting time) are unreliable with LMWHs,
and devices that measure factor Xa activity directly may be a solution for those who believe
therapeutic monitoring is indicated.
W
ARFARIN
Like unfractionated heparin, warfarin treatment requires laboratory monitoring to
remain within a therapeutic window. Although initial studies of warfarin showed a reduc-
tion in recurrent cardiac ischemia and embolic cerebrovascular events, the long-term
benefit of warfarin with aspirin appears limited. The CARS trial compared aspirin alone
with a combined regimen of aspirin and fixed, low-dose warfarin in 8803 patients after MI
(101). Fixed-dose warfarin (1 or 3 mg) combined with low-dose aspirin (80 mg) did not
surpass the efficacy achieved with 160 mg aspirin alone (8.6% with aspirin vs 8.8% with
3 mg warfarin/80 mg aspirin for the composite endpoint of reinfarction, nonfatal ische-
mic stroke, or cardiovascular death; p = ns). Similarly, the CHAMP study randomized 5059
patients to low-dose warfarin (mean international normalized ratio [INR], 1.8) plus 81 mg
aspirin or aspirin 162 mg monotherapy within 14 d after MI (102). At a median 2.7 yr of
follow-up, the rates of death, MI, or stroke were nearly identical, with significantly more
major bleeding events in the combination-therapy group (1.28 vs 0.72 events per 100 per-
son-years; p < 0.001).
These findings were further supported by the OASIS study in unstable angina, in which
treatment with moderate-dose warfarin and aspirin was associated with a small, nonsignif-
icant reduction in recurrent ischemic events (7.6% with warfarin and aspirin vs 8.3% with
aspirin alone; p = ns) at the expense of significantly greater bleeding (2.7% vs 1.3%, respec-
tively; p < 0.05) (103). On the other hand, the WARIS-II study showed a significant reduc-
tion in cardiac and cerebrovascular events among patients randomized to receive warfarin
plus aspirin after MI vs aspirin alone (104). Given the increased risk of bleeding and need
for monitoring, warfarin is unlikely to become routine therapy for patients with ischemic
heart disease. Like warfarin, combined antiplatelet therapy with aspirin and clopidogrel
has been associated with reduced ischemic outcomes but greater bleeding risk (94). Future
studies should determine the most appropriate balance between safety and efficacy.
D
IRECT THROMBIN INHIBITORS
Direct antithrombins have several advantages over UFH for use in ACS or PCI. These
include (1) high specificity and potency for thrombin
inhibition, (2) a lack of dependence
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Chapter 21 / Summary and the Future 441
on antithrombin III for
anticoagulant activity, (3) the ability to inactivate both clot-bound
and free thrombin, and (4) a lack of aggregatory effects on
platelets. Pooled data from the
GUSTO-IIb and TIMI-9B studies comparing hirudin with UFH as an adjunct to fibrinol-
ytic therapy showed no significant reduction in mortality and a nonsignificant 14% reduc-
tion in recurrent infarction at 30 d (105). In the recent HERO-2 trial of UFH vs bivalirudin
as adjunctive therapy to streptokinase for acute MI, 30-d mortality was not significantly
reduced with bivalirudin (10.5% with bivalirudin vs 10.9% with heparin; p = 0.46),
although reinfarction was significantly reduced by 30% (1.6% vs 2.3%; p = 0.001) (106).
Compared with UFH, significantly fewer bleeding and ischemic adverse events have
been observed among patients undergoing angioplasty with adjunctive bivalirudin (107).
In a systematic overview of four trials comparing bivalirudin with UFH in PCI or ACS,
bivalirudin was associated with a significant reduction in the
composite of death or infarc-
tion (odds ratio, 0.73; 95% confidence interval, 0.57–0.95;
p = 0.02) at 30–50 d, or 14
fewer events per 1000 patients treated (108). There also was a significant reduction in
major
hemorrhage for the same trials (odds ratio, 0.41; 95% confidence interval, 0.32–
0.52;
p < 0.001, or 58 fewer events per 1000 patients treated). In a systematic overview
of 11 randomized trials involving nearly 36,000 patients, direct thrombin inhibitors were
associated with a lower risk of death or MI at 30 d compared with UFH (7.4% vs 8.2%;
p = 0.02) (109). Subgroup analyses indicated a benefit with direct thrombin inhibitors in
both ACS and PCI. Of note, there was an apparent reduction in ischemic events with bival-
irudin and hirudin, but not with univalent agents. More recent studies of bivalirudin in PCI
have suggested reduced ischemic adverse events compared with UFH and GPIIb/IIIa inhi-
bition with the potential for equivalent outcomes without the use of GPIIb/IIIa inhibitors.
Results from the REPLACE-2 trial, comparing UFH plus mandatory GPIIb/IIIa inhibi-
tion with bivalirudin plus provisional GPIIb/IIIa inhibitors in PCI, are eagerly awaited.
F
ACTOR Xa INHIBITORS
Molecules that directly inhibit factor Xa are in development, and early clinical results
appear promising. Fondaparinux is a synthetic, highly sulfated pentasaccharide that mimics
the biologically active region of heparin but specifically inhibits factor Xa. Early studies
of patients at high risk for developing deep-vein thrombosis showed the superiority of
fondaparinux over enoxaparin (110). In a dose-finding study among patients with ACS,
fondaparinux was associated with fewer early adverse ischemic events compared with
enoxaparin (111). Although bleeding was not significantly increased with fondaparinux
therapy, no dose response was observed for ischemic outcomes, suggesting that further
studies to characterize its effects are required.
In a Phase I trial of patients with ST-elevation MI, adjunctive administration of SR9010A/
ORG31540, a synthetic pentasaccharide that selectively inhibits factor Xa, with standard
fibrinolytic therapy resulted in no excess bleeding and similar rates
of TIMI grade 3 flow
at 90 min and 6 d compared with UFH,
with trends toward less reocclusion and urgent
revascularization (57). Results from ongoing evaluations of other factor Xa inhibitors
performed in various clinical settings are forthcoming.
I
NHIBITORS OF THE TISSUE FACTOR PATH WAY
Considering the central role of tissue
factor in initiating the coagulation cascade at sites
of vascular injury, interest has arisen in the possible clinical effects of its inhibition. Ade-
noviral
gene transfer of recombinant tissue factor pathway inhibitor (TFPI) in animals
has been shown
to prevent local arterial thrombus formation and the neointimal response
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442 Part IV / Practical Issues and Future Applications
after balloon-induced injury without impairing hemostasis (112). At present, however, no
studies of TFPI have been performed in patients with cardiovascular disease.
FUTURE DIRECTIONS
Pharmacodynamics and Monitoring of Therapy
DOSING AND INTENSITY OF PLATELET INHIBITION
Despite more recent attention to the relationship between the pharmacodynamics of
GPIIb/IIIa inhibition and clinical outcomes, the most effective intensity of platelet inhi-
bition remains unknown. In the GOLD trial evaluating the intensity of platelet inhibition
with GPIIb/IIIa therapy in patients undergoing PCI, <70% platelet inhibition after steady-
state drug infusion was associated with a higher incidence of ischemic adverse events
(113). More adverse events likewise occurred among the 25% of patients who did not
achieve >95% inhibition within 10 min of administration. Based on preclinical studies with
abciximab, at least 80% receptor occupancy was required to maintain continuous arterial
perfusion. Notably, the use of a calcium-chelating anticoagulant (such as citrate) in ex vivo
platelet aggregation studies overestimates the in vivo inhibitory effects of GPIIb/IIIa inhib-
itors. This phenomenon confounded the search for optimal dosing of eptifibatide and
tirofiban. Doses of eptifibatide used in the IMPACT-II study (15) achieved 50–60% inhi-
bition by standard platelet aggregometry. This finding led to higher dosing in the PURSUIT
and ESPRIT trials and may partly explain the larger clinical benefit observed in these
studies compared with IMPACT-II.
Similarly, variable platelet inhibition may have contributed to the negative findings
of the TARGET (26) and RESTORE (16) trials of tirofiban and the GUSTO-IV study
of abciximab (60). In the COMPARE trial, serial platelet aggregometry was performed
in 73 patients randomized to receive either abciximab, eptifibatide, or tirofiban using
doses established in contemporary ACS trials (W. Batchelor, personal communication).
Platelet aggregation in the first 30 min after administration was reduced least with tiro-
fiban (RESTORE dose regimen). The greatest variability in platelet aggregation was
observed with abciximab during late infusion (≥4 h). In contrast, the most consistent
inhibition of platelet aggregation occurred with the eptifibatide regimen (PURSUIT dose
regimen). Although the RESTORE-tirofiban dosing regimen provided platelet inhibition
comparable with that of eptifibatide and abciximab with extended infusion, it did not pro-
duce a similar degree of platelet inhibition during immediate PCI. Consistent platelet inhi-
bition after several hours of continued infusion may account for the efficacy observed when
PCI is delayed 4–48 h after administration, as in the PRISM-PLUS and TACTICS-TIMI
18 (114) studies. Alternatively, the finding of platelet recovery (i.e., reduced platelet inhi-
bition) after several hours of abciximab therapy may in part explain the negative findings
with abciximab in the GUSTO-IV trial, which discouraged early revascularization.
Further studies in ACS and PCI are required to determine how pharmacodynamic dif-
ferences may influence the efficacy of GPIIb/IIIa antagonists. In addition, reasons for inter-
patient variability in response to GPIIb/IIIa inhibition need to be clarified. Potential contrib-
uting factors include individual cardiovascular risk profiles (e.g., diabetes, age), resistance
to adjunctive antiplatelet therapies (e.g., aspirin), or inherited genetic polymorphisms
regarding platelets. Moreover, there is a need for standardized, accurate methods of deter-
mining platelet inhibition, because current measures of platelet inhibition are imprecise
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Chapter 21 / Summary and the Future 443
(115). Based on these findings, however, potent platelet inhibition at the time of intentional
vessel injury probably determines benefit during PCI, whereas a more prolonged and con-
sistent reduction in platelet aggregation may be required for ACS applications.
M
ONITORING
The relationship between GPIIb/IIIa receptor occupancy and physiologic measures of
platelet function varies. Platelet aggregometry has been the accepted standard for deter-
mining the intensity of antiplatelet therapies, but this technique is limited by intra- and
interindividual variation, the need for fresh samples, and excessive time and cost to com-
plete the assay. Moreover, this method does not specifically measure GPIIb/IIIa binding
activity but rather global platelet function.
Newer assays such as the Ultegra Rapid Platelet Function Assay (RPFA, Accumetrics,
Inc.) have provided a more rapid and specific assessment of GPIIb/IIIa receptor occu-
pancy. By measuring the interaction between GPIIb/IIIa and fibrinogen-coated beads,
the RPFA offers an efficient, bedside method for determining the specific receptor inhibi-
tion with GPIIb/IIIa blockade. Interpretation of RPFA results differs from that of aggre-
gometry results, creating a need to reconcile the disparate results before a uniform method
is adopted. Clinicians accustomed to giving antiplatelet therapy without monitoring may
be slow to adopt routine platelet assays during PCI. For these reasons, routine platelet
monitoring will probably be used to support clinical trial results, but routine clinical use
is unlikely.
Whether other measures of platelet function yield more consistent results than aggre-
gometry has not been well studied. Studies examining the effects of GPIIb/IIIa antagonists
on inflammation—for example, inhibition of the α
v
β
3
or Mac-1 integrin receptors—may
instead provide more reliable and yet clinically relevant assessments of platelet activity.
As an antagonist of both GPIIb/IIIa and α
v
β
3
with equal affinity, abciximab may provide
additional benefit in preventing α
v
β
3
-mediated thrombin generation and smooth muscle
cell migration (116), Mac-1-regulated platelet-leukocyte interaction, or both (117).
B
LEEDING AND THROMBOCYTOPENIA
Although further studies are needed to clarify the relationship between ischemic events
and the level of platelet inhibition with GPIIb/IIIa blockade, the likelihood of bleeding
complications correlates more directly with the level of impaired platelet activity. In the
EPILOG study, a nonsignificantly lower bleeding rate was observed with abciximab and
low-dose heparin vs standard heparin (13), and bleeding may even be further reduced with
thrombin inhibitors such as bivalirudin.
All GPIIb/IIIa inhibitors are associated with some risk of thrombocytopenia, which occurs
in 0.4–4% of patients. The precise mechanism and optimal treatment remain unknown,
and treatment is usually limited to platelet transfusions. Thrombocytopenia is associated
with not only a greater risk of hemorrhage but also a paradoxically greater likelihood of
ischemic adverse events (118). Pseudothrombocytopenia, or artifactual platelet clumping
in vitro owing to autologous antibodies, may occur in up to 1% of patients receiving abcixi-
mab but does not affect clinical outcome (119).
Except for abciximab, readministration of GPIIb/IIIa antagonists remains uncertain. In
the ReoPro Readministration Study (28), overall rates of thrombocytopenia with abciximab
were similar to rates for first-time administration, yet there appeared to be a greater inci-
dence of profound thrombocytopenia as well as delayed presentations of thrombocytopenia
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444 Part IV / Practical Issues and Future Applications
after hospital discharge. Despite the development of human antichimeric antibodies in a
small number of patients after initial exposure to abciximab, neither hypersensitivity reac-
tions nor neutralization of the abciximab effect were observed.
For most patients, the risk of thrombocytopenia will not preclude the use of a GPIIb/IIIa
inhibitor. Instead, the uncertainty about which patients will develop thrombocytopenia and
our inability to prevent it should reinforce the need for vigilant periprocedural monitor-
ing of platelet counts. Advanced age and lower body weight are associated with a greater
likelihood of thrombocytopenia, although no risk factor has been established with any
certainty to preclude GPIIb/IIIa inhibitor administration. Importantly, the ReoPro Read-
ministration Study did not include patients who developed thrombocytopenia with initial
therapy, such that potential risks from readministration to this particular subgroup are not
well understood. Although it is customary among patients with abciximab-associated
thrombocytopenia to avoid GPIIb/IIIa inhibition altogether or substitute a small-mole-
cule inhibitor, there are few prospective data to support this practice.
New Strategies for NSTE-ACS: “Upstream” Therapy
Recent trials have supported the idea that the optimal management strategy for patients
with ACS involves a combination of pharmacologic therapy and PCI. Despite earlier
studies (TIMI-IIIB [49], VANQWISH [120]) that failed to show a clinical benefit with the
routine use of an early invasive strategy vs a more conservative approach that involved
noninvasive testing, more recent trials of GPIIb/IIIa inhibitors with early revascularization
have supported a combined approach to reduce ischemic adverse events. Whether the
mechanism of benefit with early GPIIb/IIIa inhibition is passivation of an unstable plaque,
improved microvascular function, or greater epicardial patency, recent trials of early GPIIb/
IIIa inhibition followed by PCI have fueled enthusiasm for this complementary approach.
The clinical benefit of GPIIb/IIIa inhibitors before revascularization is not because of
PCI alone. In recent trials of patients with NSTE-ACS, most MIs have not been related to
revascularization procedures, underscoring the benefit of GPIIb/IIIa inhibition beyond
the catheterization laboratory (121). A consistent reduction in death or MI with GPIIb/IIIa
inhibition exists, regardless of management with an early invasive strategy or early con-
servative approach (61).
In the TACTICS-TIMI 18 study, upfront administration of tirofiban coupled with an
early invasive strategy resulted in lower rates of death and MI (4.7% with early invasive
strategy vs 7.0% with conservative management at 30 d; p = 0.02) (114). The highest-risk
patients (e.g., troponin-positive, ST-segment depression) derived the greatest benefit from
the early invasive strategy combined with GPIIb/IIIa inhibition. An important limitation
of this study, however, is that all patients received tirofiban, precluding comparisons with
early revascularization without GPIIb/IIIa inhibition.
Alternative early revascularization strategies might be considered before advance ther-
apy with GPIIb/IIIa inhibition becomes common. In the FRISC-II trial, an early invasive
approach, similar to that taken in TACTICS-TIMI 18, showed a lower incidence of death
or MI among patients randomized to early revascularization and treatment with daltepa-
rin. Six-month rates of death or MI were 9.4% for the early invasive approach vs 12.1%
for the conservative strategy (p = 0.03). The results were independent of dalteparin treat-
ment (122). In the observational PCI-CURE trial, treatment with clopidogrel an average
6 d before PCI followed by long-term clopidogrel therapy was associated with a signifi-
cant reduction in the rate of cardiovascular death, MI, or revascularization at 30 d (rela-
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Chapter 21 / Summary and the Future 445
tive risk, 0.70; p = 0.03) (123). In this study, use of GPIIb/IIIa inhibitors was infrequent,
and the apparent benefit of early combined aspirin and clopidogrel has advanced the notion
that GPIIb/IIIa inhibitors may not be warranted in some cases. Still, the PCI-CURE strategy
has not been prospectively tested against the use of GPIIb/IIIa inhibitors in a randomized
fashion, and current evidence suggests that the two therapies appear more complementary
than exclusionary in contemporary practice. Although clinicians may favor prescribing a
GPIIb/IIIa inhibitor without early clopidogrel treatment, the available evidence supports
the use of a GPIIb/IIIa inhibitor during PCI with both aspirin and a thienopyridine. A trial
that measures the clinical and economic outcomes of early aspirin/clopidogrel treatment and
aspirin/GPIIb/IIIa inhibitor treatment is required to clarify this important issue. Remain-
ing issues for advance therapy include identifying which patients benefit most from GPIIb/
IIIa inhibition and early revascularization and the interaction of GPIIb/IIIa inhibitor phar-
macodynamics with timing of revascularization.
New Strategies for ST-Elevation MI: “Facilitated PCI”
Facilitated PCI, or the strategy of planned early PCI after pharmacologic reperfusion
therapy, fuses the best aspects of fibrinolysis and primary angioplasty in the management
of ST-elevation MI. On the one hand, fibrinolysis can result in TIMI grade 3 flow as early
as 60 min after administration. On the other hand, primary angioplasty achieves higher
rates of normal epicardial artery blood flow but generally at later times. As a combined
approach, facilitated PCI may provide the best outcomes based on TIMI flow and clinical
events.
In the ADMIRAL trial, nearly one-fourth of patients received early administration of
abciximab in either the emergency room or the ambulance (33). Baseline TIMI grade 3 flow
was significantly more common among patients receiving abciximab both immediately
before and after revascularization (Fig. 8), a finding consonant with prior studies showing
a 25–35% rate of TIMI grade 3 flow with abciximab when given 60–90 min before angio-
graphy (41,42). These data are also consistent with (1) a previous report from 2507 patients
in the PAMI trials, in which early and late mortality were strikingly reduced for patients
with spontaneously recovery of TIMI 3 flow before the procedure, independent of the final
TIMI flow grade (Fig. 8) (124); (2) the randomized PACT trial, in which early reperfusion
with reduced-dose alteplase resulted in greater early recovery of left ventricular function
(125); and (3) a metaanalysis showing that mortality is reduced when thrombolytic therapy
is started before arrival at the hospital rather than in the emergency room (126). In compar-
ison, abciximab was given only in the catheterization laboratory to patients in the CADILLAC
trial, which may account for the lack of improvement in epicardial flow. Although some
of the marked benefit in the early-treatment group in ADMIRAL may reflect the play of
chance, resulting in an inexplicably high rate of adverse events in the placebo-treated
patients, these data support ongoing trials of pharmacologic reperfusion before mechani-
cal revascularization.
The GUSTO IV SPEED investigators described the outcomes of 323 patients who under-
went PCI about 1 h after reperfusion therapy and compared them with a similar cohort who
did not undergo early revascularization (127). For the facilitated-therapy group, procedu-
ral success was 88%, and the 30-d composite endpoint of death, reinfarction, or urgent TVR
occurred in 5.6% of patients (Fig. 9). Although these findings are more descriptive than
comparative, they are encouraging, because earlier trials consistently showed lower imme-
diate procedural success rates, higher mortality, and higher rates of reinfarction, bypass
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446 Part IV / Practical Issues and Future Applications
surgery, and bleeding than with a conservative approach. With a greater likelihood for
epicardial artery patency, facilitated PCI may also improve patient stability and reduce
periinfarction complications such as shock. Still more trials are under way, including
the ADVANCE MI trial (with eptifibatide/tenecteplase followed by early PCI) and the
FINESSE trial (abciximab/reteplase followed by early PCI).
Targeting Patient Populations
As the approach to treating ACS patients with GPIIb/IIIa inhibitors becomes further
refined, so does our understanding of which patients benefit from therapy most. For exam-
ple, several studies have suggested that troponin-positive patients who are at higher risk for
death and myocardial (re)infarction may show an enhanced treatment effect with GPIIb/
IIIa inhibitors. In the CAPTURE study, the incidence of death or nonfatal MI at 6 mo was
reduced by 60% among abciximab-treated patients who were troponin-positive at random-
ization, whereas troponin-negative patients showed no treatment effect of abciximab (128).
In a recent systematic overview of GPIIb/IIIa inhibition in NSTE-ACS trials (including
the GUSTO-IV study), patients with elevated baseline troponin levels showed a consistent
reduction in ischemic events (Fig. 7) (60). These findings were supported in the PRISM
(129) and PARAGON-B (57) trials, which not only reaffirmed the higher clinical risk asso-
ciated with elevated troponin levels but also showed that treatment with GPIIb/IIIa inhibi-
tors in such patients appeared to reduce adverse outcomes to a rate nearly identical to that
of troponin-negative patients.
Further investigations should define the interactions of other clinical characteristics with
GPIIb/IIIa administration. In a systematic overview of GPIIb/IIIa therapies in patients with
NSTE-ACS, for example, features such as younger age and male sex were consistently
associated with a greater treatment effect (61). Whether this latter observation is related
to sex-related differences in treatment response or whether troponin-positive patients in
trials are more likely to be male will require further study. Similarly, the magnitude of
Fig. 8. Benefit of early abciximab administration as an initial reperfusion therapy in the ADMIRAL
trial. PCI, percutaneous coronary intervention. (Adapted from ref. 33.)
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Chapter 21 / Summary and the Future 447
benefit from treatment with eptifibatide in the PURSUIT trial was greater in the United
States than elsewhere in the world (130). In the absence of dedicated, prospective rando-
mized trials, however, the certainty of these results is limited by the possibility of chance
findings when multiple comparisons are performed.
New Indications
CEREBROVASCULAR DISEASE
Fibrinolytic therapy is approved for the treatment of acute ischemic stroke, yet few
patients are eligible for treatment. Although efficacious, the practical use of fibrinolytic
therapy is confined by a short treatment window of 3 h from stroke onset and the risk of
intracranial hemorrhage, which can occur in nearly 10% of patients. Recent trials suggest-
ing a clinical benefit of aspirin therapy given within 48 h of stroke onset raise the possi-
bility of improved efficacy with more potent platelet inhibitors (131). Further support of
safety with GPIIb/IIIa inhibition is derived from the low risk of intracranial hemorrhage
(approx 0.15%) in the PCI setting. Treatment of ischemic cerebrovascular events with
GPIIb/IIIa inhibitors, alone or combined with reduced-dose fibrinolytic therapy, there-
fore may improve reperfusion, reduce the risk of intracranial hemorrhage, and extend the
time frame for therapeutic benefit. Among 74 patients arriving within 24 h of symptom
onset, randomization to abciximab resulted in a trend toward lesser disability with no cases
of major intracranial hemorrhage (132). Patients did not receive adjunctive aspirin or
heparin, however. Although preliminary, these findings are encouraging, considering the
paucity of effective therapies for acute ischemic stroke.
H
EART FAILURE
Heart failure remains an important public health concern in the United States, accounting
for over 1 million hospitalizations each year. Although considerable attention has been given
to the contribution of neurohormonal activation and loading conditions to ventricular
Fig. 9. Influence of TIMI grade status immediately before percutaneous coronary intervention (PCI)
for acute MI and the reduction in clinical events observed with facilitated PCI in the SPEED (GUSTO-
IV Pilot) trial (43,127). ReMI, reinfarction.
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448 Part IV / Practical Issues and Future Applications
dysfunction, the role of atherosclerotic disease should not be underestimated, since acute
myocardial ischemia or infarction contributes to 30–50% of sudden-death events in
patients with heart failure (133). Up to one-third of patients with heart failure who suffered
a sudden death and who had significant coronary disease on autopsy were misdiagnosed
as having “nonischemic” cardiomyopathy in life (134). These findings suggest that acute
coronary thrombosis and the accompanying ischemia are important contributors to sudden
cardiac death and that these events often are unrecognized during life among patients with
advanced heart failure.
Aside from the reduction in ischemic events by treatment with angiotensin-converting
enzyme inhibitors and β-blockers, evidence supports a neurohormonal mechanism of
platelet activation in heart failure. In addition, chronic aspirin use is associated with a
reduced risk of hospital admission and all-cause mortality, regardless of the etiology of
cardiomyopathy (135). As a result, platelet activation and resultant myocardial ischemia
may contribute to elevated levels of cardiac troponin T observed in patients with worsen-
ing heart failure (136). Not only may elevations of markers of myocardial injury identify
a population of patients who may specifically benefit from antiplatelet therapy, but the
use of GPIIb/IIIa inhibitors may reduce ischemic complications, thereby possibly reduc-
ing the risk of sudden death. Forthcoming trials of GPIIb/IIIa inhibition in patients with
advanced heart failure should clarify potential applications for these agents.
P
ERIPHERAL ARTERIAL DISEASE
The relative risk of cardiovascular death for patients with peripheral arterial disease
(PAD) alone approximates that of patients with known coronary or cerebrovascular dis-
ease (137). The severity of PAD is closely associated with the risk of MI, ischemic stroke,
and death from vascular causes. The lower the ankle-brachial index, the greater the like-
lihood for cardiovascular events, such that patients with critical limb ischemia have an
annual mortality rate of nearly 25%.
Clinical experience with GPIIb/IIIa inhibition in patients with PAD is limited. Studies
of these agents in catheter-based carotid interventions, although showing some benefit,
are restricted by their lack of randomized design and small sample sizes (138). Consider-
ing the lower incidence of periprocedural ischemic events relative to PCI, definitive ran-
domized trials are unlikely to be performed because their design would require substantial
numbers of patients. Alternatively, randomized trials of GPIIb/IIIa inhibition may be pos-
sible if limited to high-risk patients with a greater likelihood of ischemic events, such as
those with critical limb ischemia. Roxifiban, an oral agent with a longer half-life and greater
receptor affinity, has shown an acceptable safety profile with reduced ischemic events
(139), yet its evaluation in PAD patients was halted based on the general negative findings
with other oral GPIIb/IIIa inhibitors.
C
ORONARY ARTERY BYPASS GRAFTING
An increasing number of patients have undergone bypass surgery after treatment with
GPIIb/IIIa inhibitors. To date, there appears to be no major increase in the risk of bleed-
ing, although many patients have received perioperative platelet transfusions. Formal
randomized trials are needed to investigate whether GPIIb/IIIa inhibitors reduce platelet
consumption during cardiopulmonary bypass and whether these drugs ameliorate the
effect of platelet activation on systemic outcomes.
Despite recent advances in the medical stabilization of patients with recent ACS, those
who require bypass surgery during the initial admission have increased perioperative
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Chapter 21 / Summary and the Future 449
morbidity and mortality. Pretreatment with GPIIb/IIIa inhibition may attenuate some
risk, however. In the PURSUIT trial, for example, eptifibatide administration in patients
with ACS undergoing bypass surgery during the index hospitalization resulted in both early
and late reductions in the occurrence of death or MI (32.7% with placebo vs 27.6% with
eptifibatide for the composite of death or MI at 6 mo; p = 0.029) (140).
Effect of Genetics on Dosing
The role of platelets in unstable coronary syndromes and adverse events after coronary
intervention are typical examples of the interplay between genetic and environmental fac-
tors. A number of genetic polymorphisms within the subunits of platelet receptors may
induce gain or loss of function, thereby predisposing some individuals to thrombotic events.
Platelet function may reflect variations that either encode a missense mutation (the result-
ing codon changes the amino acid) or modify the level of expression of the gene product.
The Pl
A2
polymorphism of the GPIIIa is the first genetic variant that has been shown
to modify the platelet response to antiplatelet therapy. Pl
A2
does not destroy the activity
of GPIIb/IIIa but can affect its properties, thereby affecting the responsiveness and adhe-
sive properties of platelets (140,141). Compared with Pl
A1,A1
platelets (wild type), Pl
A2
-
positive platelets express significantly more P-selectin, GP IIb/IIIa-bound fibrinogen, and
activated
GPIIb/IIIa in vitro in response to platelet agonists (142).
Pl
A2
has been implicated in arterial thrombosis and the development of unstable coro-
nary syndromes. Specifically, a high prevalence of the Pl
A2
allele has been reported in
patients with unstable angina or MI and in siblings of patients with a history of premature
ischemic heart disease (143,144). Mikkelson et al. (145) reported a higher prevalence of
Pl
A2
among victims of sudden cardiac death whose coronary arteries contained thrombus.
The Pl
A2
polymorphism has also been related to a higher incidence of adverse ischemic
events after catheter-based procedures, in particular subacute stent thrombosis (146–148).
The Pl
A2
polymorphism may thus represent a major risk for the development of coronary
thrombosis in susceptible individuals.
Because many case-control studies have reported varied findings about the clinical rele-
vance of the Pl
A2
polymorphism, further studies are needed to define prospectively the
effect of this genetic variant on clinical outcomes and response to drug therapies. Recent
studies examining the effect of GPIIb/IIIa inhibition on Pl
A2
-positive platelets with various
agonists have yielded conflicting results (141,149). Incorporation of mechanistic studies,
such as genotyping and platelet function, should further define clinical outcomes data and
enable specific antithrombotic regimens to be tailored to individual patients.
CONCLUSIONS
Alone and combined with other pharmacologic and mechanical interventions, the use
of GPIIb/IIIa inhibitors reflects considerable progress in the treatment of patients with
ACS. From early benchwork and clinical development to primary indications for therapy,
GPIIb/IIIa inhibitors are transitioning from an era of rapid growth (e.g., adoption into
routine therapy) to maturity (e.g., novel indications, new trials). Prescription of GPIIb/
IIIa inhibitors remains surprisingly infrequent despite established benefit and cost effec-
tiveness in various clinical settings. Between 50 and 75% of the patients who would derive
a benefit from GPIIb/IIIa inhibitors do not receive this therapy. The limited efficacy of
“standard” antithrombotic and anticoagulant therapy with aspirin and heparin alone should
remind clinicians of the continued need to apply therapies with proven benefit. Based on
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