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260 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
therapy with intravenous GPIIb/IIIa antagonists. These agents reduce the 30-d occurrence
of death or MI by approx 10% and this benefit is durable at late (6-mo to 1-yr) follow-up.
These concepts are embodied within the most recent ACC/AHA treatment guidelines
for patients with an ACS (51). Intravenous GPIIb/IIIa antagonists have a class I recommen-
dation (majority of evidence and agreement supporting use) for patients in whom catheter-
ization and percutaneous coronary intervention are planned. A class IIa recommendation
(conflicting evidence or opinion although weight of evidence/opinion favors usefulness)
is given for eptifibatide and tirofiban for high-risk patients (i.e., continuing ischemia or
troponin-positive) in whom an invasive strategy is not planned or percutaneous coronary
intervention patients who are already receiving aspirin and clopidogrel. Abciximab receives
similar recommendation for percutaneous coronary intervention patients but receives a
class III recommendation (evidence that it is not useful) for patients in whom percutaneous
coronary intervention is not planned. In short, the benefit of GPIIb/IIIa agents appears to
be highest among patients who have active atherothrombotic plaques, evidence of myonec-
rosis, or diabetes or who are treated aggressively with early percutaneous revascularization.
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262 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
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45. Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for
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Chapter 11 / Platelet GPIIb/IIIa Inhibitors and an Invasive Strategy 263
263
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
11 Platelet Glycoprotein IIb/IIIa
Inhibitors and an Invasive Strategy
CONTENTS
INTRODUCTION
CLINICAL TRIALS
BENEFITS OF GPIIb/IIIa INHIBITION BY TREATMENT STRATEGY
TARGETING HIGH-RISK ACS PATIENTS
TACTICS-TIMI 18
A
NGIOGRAPHIC OBSERVATIONS:
E
STABLISHING THE MECHANISM OF BENEFIT
SAFETY ISSUES
COST EFFECTIVENESS
CONCLUSIONS
REFERENCES
Christopher P. Cannon, MD
INTRODUCTION
With the importance of plaque rupture and thrombosis in acute coronary syndromes
(ACS) and the problem of distal embolization during percutaneous coronary intervention
(PCI) (1), inhibition of platelet aggregation by platelet glycoprotein (GP) IIb/IIIa recep-
tor antagonists has taken on a central role. By preventing the final common pathway of
platelet aggregation, i.e., fibrinogen-mediated crosslinkage of platelets via the GPIIb/IIIa
receptor, these agents can potently inhibit platelet aggregation caused by all types of stim-
uli (e.g., thrombin, ADP, collagen, and others). Three agents, abciximab, tirofiban, and
eptifibatide, are now approved for use in coronary angioplasty, and the latter two are also
approved for treatment of unstable angina/non-ST elevation myocardial infarction (UA/
NSTEMI) in patients not necessarily undergoing angioplasty. Abciximab is a monoclonal
antibody Fab fragment directed at the GPIIb/IIIa receptor. Eptifibatide, a synthetic hepta-
peptide, and tirofiban, a nonpeptide molecule, are antagonists of the GPIIb/IIIa receptor
whose structure mimics the arginine-glycine-aspartic acid (abbreviated RGD) amino acid
sequence by which fibrinogen binds to the GPIIb/IIIa receptor.
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264 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
CLINICAL TRIALS
Several trials have shown benefit of GPIIb/IIIa inhibition in UA/NSTEMI in patients
managed predominantly with medical management (2,3), early interventional manage-
ment (4) or, both (5–8). In the Platelet Receptor Inhibition for Ischemic Syndrome Man-
agement in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, tirofiban
plus heparin and aspirin significantly reduced the odds of death, myocardial infarction
(MI), or refractory ischemia at 7 d by 32% compared with heparin plus aspirin (5). In the
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin
Therapy (PURSUIT) trial, involving 10,948 patients, eptifibatide also significantly reduced
the rate of death or MI at 30 d (6). A meta-analysis of the first 10 trials, involving over 30,000
patients, found that treatment with a GPIIb/IIIa inhibitor led to a 21% reduction in death
or MI at 30 d (7,8).
More recently the Global Utilization of Strategies to Open Occluded Coronary Arteries
(GUSTO) IV-ACS trial, no benefit was observed with abciximab treatment in patients man-
aged conservatively (9). One explanation put forth to explain these results is that the dose
of the abciximab infusion may have been too low, which led to suboptimal levels of plate-
let inhibition. When this trial was added to the meta-analysis, along with the the Platelet IIb/
IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Orga-
nization Network (PARAGON) B trial (10), the overall benefit of the GPIIb/IIIa inhibitors
in ACS became only 9% reduction in death or MI overall (3). However, the GUSTO-IV-
ACS trial and the recent meta-analysis have led some to question the overall efficacy of
GPIIb/IIIa inhibition in patients treated medically.
BENEFITS OF GPIIb/IIIa
INHIBITION BY TREATMENT STRATEGY
In the overall trial results and the meta-analyses, it has been noted that in general, the
relative treatment benefit of GPIIb/IIIa inhibition appears to be greater in those under-
going PCI vs those having medical therapy alone. For example, in the EPISTENT trial
of abciximab, there was a relative 50% benefit regarding death or MI (11), vs a 10% over-
all benefit in the PURSUIT trial (6). Similarly, in the PURSUIT trial, in an unadjusted anal-
ysis, a greater benefit was observed in patients who underwent early PCI on eptifibatide
(31% reduction in death or MI at 30 d, 16.7% vs 11.6%, p = 0.01), whereas the relative ben-
efit was less (7% reduction, p = 0.23) in those treated medically, with late PCI or coronary
artery bypass graft (CABG).
However, much of this apparent difference may have been caused by confounding,
i.e., the patients selected for PCI may have been those with a greater thrombotic burden
and thus more to gain from this antithrombotic therapy. Indeed, a more careful statistical
analysis, counting all patients up to the time of a procedure, found no significant interac-
tion of PCI vs no PCI in the relative benefit of the GPIIb/IIIa inhibitor (12). In addition, a
dramatic benefit has been seen in patients who eventually went on to bypass surgery (13).
In the PRISM-PLUS trial, the overall reduction in death or MI at 30 d was 30% (p = 0.03),
with improvement being consistent across management strategies: medical therapy (25%
reduction), PCI (35% reduction), and bypass surgery (30% reduction).
The relative benefits of GPIIb/IIIa inhibition in regard to medical vs interventional treat-
ment have been examined in a pooling of data from PRISM-PLUS, PURSUIT, and CAP-
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Chapter 11 / Platelet GPIIb/IIIa Inhibitors and an Invasive Strategy 265
TURE involving 12,296 patients; there was a 34% relative reduction in death or MI during
a period of 24 h of medical management only (3.8% vs 2.5%, p = 0.001) (Fig. 1) (14).
An additional benefit was seen when the agents were continued during angioplasty (8.0%
vs 4.9%, p = 0.001). Looking more broadly at the trials, among patients who undergo PCI,
in those with ACS the benefit of GPIIb/IIIa inhibition is quite dramatic, with reductions
of death or MI ranging from 30 to 70% (Fig. 2). Thus, GPIIb/IIIa inhibition is beneficial
for the medically treated patients and appears to have an additional benefit in patients in
whom the drug is continued through PCI.
TARGETING HIGH-RISK ACS PATIENTS
The overall benefit of early GPIIb/IIIa inhibition in UA/NSTEMI can be increased when
it is applied to appropriately risk-stratified patients. This has been seen most dramatically
in patients with elevated troponin values. These patients are at a two- to threefold higher
risk of subsequent cardiac complications, including mortality (15–20). Elevated markers
have been shown to correlate with a higher rate of thrombus at angiography (21,22), and
worse TIMI flow grade in the culprit artery, as well as worse myocardial perfusion (22).
It has further been observed that a greater antithrombotic effect is observed in these groups:
for example, the degree of resolution of thrombus after 24 h of therapy with abciximab
in the CAPTURE trial was greater in those who were troponin-T-positive vs negative (19).
Clinical benefits have followed the same pattern. The reduction in death or MI at 6 mo
in the CAPTURE trial was 70% in those who were troponin-T-positive vs no significant
benefit for those who were troponin-T-negative (p < 0.001) (19) (Fig. 3A). These find-
ings have been duplicated with tirofiban vs heparin in the PRISM trial (Fig. 3B) (23,24).
Idendical findings of a 50–70% reduction in death or MI was seen in the PARAGON B and
PRISM-PLUS troponin substudies (24,25). Thus, four independent trials confirmed the
very large (approx 70%) benefit of GPIIb/IIIa inhibition in troponin-positive patients.
A similar pattern of benefit has been seen with other markers of increased risk, including
the TIMI risk score, ST-segment changes, and diabetes in the PRISM-PLUS trial (5,26,27).
Fig. 1. Pooled data from CAPTURE, PRISM-PLUS, and PURSUIT trials of unstable angina, show-
ing benefit of GPIIb/IIIa inhibition during medical therapy only (left) and during and immediately fol-
lowing PCI (right). (From ref. 14, with permission.)
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266 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
Another important point, however, is that the dramatic benefit of GPIIb/IIIa inhibition
found in the high-risk patient groups is seen regardless of the treatment strategy. In the
PRISM study, there was the same approx 70% reduction in death or MI at 30 d in patients
who had baseline positive troponin values, regardless of whether or not they underwent
revascularization (23). Similarly, and more recently, the benefit of GPIIb/IIIa inhibition
was seen in those with a TIMI risk score of 4 or higher, regardless of whether they had
PCI or not (26). Thus, in ACS, the benefit of GPIIb/IIIa inhibition appears to relate to the
patient’s risk and not necessarily to the treatment strategy used.
TACTICS-TIMI 18
Further validation of the benefit of GPIIb/IIIa inhibition in the overall management of
UA/NSTEMI comes from the Treat Angina with Aggrastat
and Determine Cost of Ther-
apy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial. In this trial, patients
with a typical history of UA/NSTEMI, with either electrocardiographic changes, positive
cardiac markers, or a history of coronary disease were all treated with aspirin, heparin, and
the GPIIb/IIIa inhibitor tirofiban for 48 h, including ≥12 h following PCI. Patients were
randomized to either an early invasive strategy with coronary angiography between 4 and
48 h after randomization and revascularization when feasible, or to a conservative strategy
whereby angiography was reserved only for patients with rest ischemia or a positive stress
test (which included nuclear perfusion imaging or echocardiography in approx 85% of
patients).
Overall, there was a significant reduction with the invasive approach in the primary end-
point, death, MI, or rehospitalization for an ACS at 6 mo: 15.9% in early invasive strategy
Fig. 2. Benefit of GPIIb/IIIa inhibition among patients with UA/NSTEMI treated with percutaneous
coronary intervention across all large trials. As shown, both the relative benefit and the absolute bene-
fit are quite substantial, ranging from 50 to 100 deaths or MIs prevented for every 1000 patients
treated. (Adapted from ref. 50, with data from ref. 51.)
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Chapter 11 / Platelet GPIIb/IIIa Inhibitors and an Invasive Strategy 267
vs 19.4% in the conservative group [odds ratio (OR) 0.78, p = 0.025] (28). Death or MI at
30 d was also significantly reduced at 30 d, (4.7% vs 7.0%, respectively, p = 0.02), as well
as at 6 mo (p = 0.0498).
When comparing these data with those of the four prior randomized trials of invasive
vs conservative strategies (29–34), an interesting difference emerges. In the trials without
GPIIb/IIIa inhibition, the rate of MI tended to be higher in the invasive group over the
first 2 wk, consistent with an “early hazard” associated with coronary interventions. In con-
trast, in TACTICS-TIMI 18, there was a significantly lower rate of MI over the first weeks,
an effect that is probably owing to the well-documented protection afforded by GPIIb/IIIa
inhibition during PCI (8).
As seen for GPIIb/IIIa inhibition, a significantly greater benefit was found in patients with
positive troponin values compared with those who had negative values (28). In patients with
a troponin T > 0.01 ng/mL (54% of the population) or in those with troponin T ≥ 0.1 ng/mL
(60% of the population), there was a relative 39% risk reduction in the primary endpoint
with the invasive vs conservative strategy (each p < 0.001), whereas patients with a nega-
tive troponin level had similar outcomes with either strategy (35). Death or nonfatal MI also
followed the same pattern, with a significant reduction with the invasive strategy in patients
with positive troponin levels vs no benefit in those with negative troponin levels. The same
pattern of benefit was seen in higher risk patients, defined by the presence of ST-segment
changes or a TIMI risk score of 3 or higher.
This study demonstrates that among patients with UA/NSTEMI who were treated with
the GPIIb/IIIa inhibitor tirofiban, an early invasive strategy was superior to a conservative
strategy in reducing major cardiac events at 30 d and 6 mo. In addition, the absolute rate
of death or MI at 30 d in the invasive group, 4.7%, is the lowest observed rate in any UA/
NSTEMI trial to date (5,6,8,36). Thus, this strategy of using “upstream” GPIIb/IIIa inhibi-
tion with tirofiban in combination with early invasive treatment leads to excellent out-
comes and could be considered the treatment of choice for most UA/NSTEMI patients.
Fig. 3. Benefit of abciximab in the CAPTURE trial of patients with refractory unstable angina treated
with angioplasty in those with positive vs negative troponin T (TnT) levels at study entry (left). Greater
benefit of tirofiban vs heparin in patients with UA/NSTEMI was also seen those with positive tropo-
nin I values in the PRISM trial, with a nearly 70% reduction in death or MI at 30 d with the GPIIb/IIIa
inhibitor (right). (Data from refs. 19 and 23.)
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268 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
An analysis of the contribution of GPIIb/IIIa inhibition toward improving outcomes
in high-risk ACS patients was done by comparing results from TIMI III (the first trial of
an invasive vs conservative strategy) with those from TACTICS-TIMI 18. In both TIMI
III and TACTICS-TIMI 18, inclusion and exclusion criteria were similar, but in TIMI III,
the medical treatment consisted of only aspirin, heparin, and antiischemic therapy. In
TACTICS-TIMI 18, patients also received tirofiban. In addition, stents were used in 85%
of the patients undergoing PCI in TACTICS-TIMI 18 vs none of the patients in TIMI III.
When patients were stratified by the TIMI risk score, an interesting pattern emerged:
a consistently better outcome was seen in the TACTICS-TIMI 18 trial compared with the
TIMI III trial in each of the risk strata (Fig. 4) (37). In low-risk patients in TIMI III, the
incidence of death, MI, or rehospitalization after 6 mo was significantly worse among
patients randomized to the invasive strategy arm, whereas in TACTICS-TIMI 18, event
rates among low-risk patients were approximately the same for both treatment strategies.
For intermediate-risk patients, outcomes for the invasive vs the conservative group were
roughly equal in TIMI III, whereas they were significantly better for the invasive vs con-
servative strategy in TACTICS-TIMI 18. Finally, although a trend was seen for improved
outcomes among high-risk patients treated invasively in the TIMI III trial, in TACTICS-
TIMI 18, there was a dramatic, 10% absolute reduction in events. These differences are
consistent with the main hypothesis of the trial, that the new advances in cardiology of coro-
nary stenting and GPIIb/IIIa inhibition would improve the safety of the early invasive strat-
egy and lead to an overall benefit compared with a conservative approach.
ANGIOGRAPHIC OBSERVATIONS:
ESTABLISHING THE MECHANISM OF BENEFIT
Angiographic data from three trials show that the GPIIb/IIIa inhibitors lead to greater
resolution of thrombus and improved coronary flow compared with aspirin and heparin
Fig. 4. Comparison of event rates in the TIMI 3 vs TACTICS-TIMI 18 trials stratified by the TIMI
risk score (TRS). ACS, acute coronary syndrome; CONS, conservative; INV, invasive; MI, myocar-
dial infarction. (Data from ref. 37.)
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Chapter 11 / Platelet GPIIb/IIIa Inhibitors and an Invasive Strategy 269
alone (38–40). In the PRISM-PLUS trial, the percentage of patients who had definitive
thrombus was reduced from 24 to 17%, and there was a 23% improvement in overall throm-
bus grade (p = 0.022) (39). In addition, administration of tirofiban led to a 35% overall
improvement in TIMI flow grade ( p = 0.002), with TIMI grade 3 flow improving from 74.5
to 81.9% (39). Similar data have recently been found in the TACTICS-TIMI 18 trial, in
which longer duration of therapy produced greater resolution of thrombus (40). Together,
these data establish the pathophysiologic link among the potent platelet inhibition achieved
by the GPIIb/IIIa inhibitors, reduction in thrombus, improvement in coronary blood flow,
and consequent improvement in clinical outcome for patients.
GPIIb/IIIa inhibitors have also been shown to reduce the size of an evolving non-ST-
elevation MI, with evidence from three trials. In the PRISM-PLUS troponin substudy,
among patients with a positive troponin at study entry, those randomized to tirofiban plus
heparin had a significantly lower peak troponin (41). In the PURSUIT trial, when looking
at either index or recurrent MI during the first 72 h, it was observed that the size of the MI,
measured by peak creatine kinase (CK)-MB, was significantly smaller in patients treated
with eptifibatide (42). In the prospective EARLY trial, preliminary data show that among
those treated within the first 8 h, the infarct size determined by CK-MB curve fitting was
smaller in those treated with early eptifibatide (43). Thus, aggressive GPIIb/IIIa inhibition
appears to be able to reduce the size of the infarct among patients with evolving non-ST-
elevation MI.
Interestingly, GPIIb/IIIa inhibition appears to have a greater benefit when treatment
is initiated earlier relative to the onset of pain. In an analysis from PURSUIT, the absolute
reduction in death or MI of eptifibatide was 2.8% for patients treated within 6 h from the
onset of pain and was lower for those treated between 6 and 12 and 12 and 24 h after onset
of pain (44). No benefit was observed in patients treated 24 h after onset of pain.
SAFETY ISSUES
As for all antithrombotic agents, the risk of major hemorrhage is modestly increased for
patients treated with GPIIb/IIIa inhibitors. In PRISM-PLUS, major bleeding occurred in
4.0% of patients treated with tirofiban plus heparin plus aspirin vs 3.0% for heparin plus
aspirin, p = NS (5). For eptifibatide, the rates of severe or moderate bleeding for eptifiba-
tide vs placebo were 12.8% vs 9.9% (p < 0.001) (6).
Thrombocytopenia is another side effect with GPIIb/IIIa inhibitors. For tirofiban in
PRISM-PLUS, the rate of severe thrombocytopenia (<50,000 cells/mm
3
) was 0.5% vs
0.3% for heparin, p = 0.44). The latter event is associated with increased bleeding and (in
a smaller proportion of patients) recurrent thrombotic events (45,46). This syndrome bears
a resemblance to heparin-induced thrombocytopenia and indicates a need to monitor
platelet count daily during the GPIIb/IIIa infusion.
COST EFFECTIVENESS
Thus, evidence from the major trials has shown that GPIIb/IIIa inhibition in patients with
UA/NSTEMI leads to significant reductions in major cardiac events, regardless of whether
an invasive or conservative strategy is employed. In the trials to date, patients enrolled have
been at medium to higher risk, on the basis of rest pain and either electrocardiographic
changes or positive cardiac markers. Although these agents are more expensive than heparin
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