Download Platelet glycoprotein IIb/IIIa receptor blockade in coronary

Journal of the American College of Cardiology
© 2000 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 35, No. 5, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(00)00554-4
REVIEW ARTICLE
Platelet Glycoprotein IIb/IIIa
Receptor Blockade in Coronary Artery Disease
A. Michael Lincoff, MD, FACC,* Robert M. Califf, MD, FACC,† Eric J. Topol, MD, FACC*
Cleveland, Ohio and Durham, North Carolina
New strategies for profound inhibition of platelet activity at the injured coronary plaque focus
on blockade of the platelet surface membrane glycoprotein IIb/IIIa receptor, which binds
circulating fibrinogen or von Willebrand factor and crosslinks platelets as the final common
pathway to platelet aggregation. Intravenous agents directed against this receptor include the
chimeric monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and
nonpeptide mimetics tirofiban and lamifiban. Over 33,000 patients have been evaluated in 11
large-scale, placebo-controlled trials of these agents.
During percutaneous coronary intervention, an absolute reduction of 1.5% to 6.5% in the
30-day risk of death, myocardial infarction or repeat urgent revascularization has been
observed, with some variability in treatment effect among the agents tested (abciximab,
eptifibatide and tirofiban). Treatment effect is achieved early with every modality of
revascularization and is maintained over the long-term (up to three years). Increased bleeding
risk may be minimized by reduction and weight-adjustment of concomitant heparin dosing.
In the acute coronary syndromes without ST segment elevation, absolute 1.5% to 3.2%
reductions in 30-day rates of death or myocardial (re-) infarction have been achieved with two
to four day courses of eptifibatide or tirofiban. Clinical benefit accrues during the period of
drug infusion and is durable. Treatment effect may be enhanced among patients undergoing
early coronary revascularization, with evidence of stabilization before intervention and
suppression of postprocedural ischemic events. Thus, blockade of the platelet glycoprotein
IIb/IIIa receptor reduces ischemic complications when used as an adjunct to percutaneous
coronary intervention or the management of acute ischemic syndromes. (J Am Coll Cardiol
2000;35:1103–15) © 2000 by the American College of Cardiology
Plaque fissure is a key initiating component in the pathogenesis of unstable angina (1,2) and the ischemic complications of percutaneous coronary revascularization (3,4).
The central role of platelet activity in these settings is
highlighted by consistent clinical benefit derived from
aspirin therapy (5–10). Newer strategies for more profound
platelet inhibition at the injured coronary plaque focus on
the integrin glycoprotein IIb/IIIa receptor (alphaIIbbeta3) on
the platelet surface membrane, which binds circulating
fibrinogen or von Willebrand factor and cross-link platelets
as the final common pathway to platelet aggregation (11).
Pharmacologic compounds directed against glycoprotein
IIb/IIIa block this receptor, prevent binding of adhesion
molecules and potently inhibit platelet aggregation (12).
Three intravenous IIb/IIIa receptor antagonists are ap-
From the *Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio and the †Duke Clinical Research Institute, Duke University, Durham,
North Carolina. The authors have received research grant support for clinical trials in
this field sponsored by Centocor, Inc. (Malvern, Pennsylvania), Eli Lilly and
Company (Indianapolis, Indiana), COR Therapeutics (South San Francisco, California), Schering-Plough (Kenilworth, New Jersey), Hoffmann LaRoche (Basel,
Switzerland) and Merck (White House Station, New Jersey).
Manuscript received July 1, 1999; revised manuscript received November 9, 1999,
accepted January 5, 2000.
proved for clinical use, and this class of therapy has, thus,
entered the pharmacologic armamentarium of physicians
providing care to a broad spectrum of patients with cardiovascular disease. This review is a systematic overview of the
efficacy and safety of the intravenous IIb/IIIa receptor
antagonists in the approved clinical settings of percutaneous
coronary revascularization and unstable ischemic syndromes, providing practical guidelines based upon randomized trial data for patient selection, choice of agent and
clinical use.
THE AGENTS
Four intravenous glycoprotein IIb/IIIa antagonists have
undergone large-scale trial evaluation in the settings of
percutaneous coronary revascularization or unstable ischemic syndromes (Table 1). Abciximab (c7E3 Fab, ReoPro,
Centocor, Malvern, Pennsylvania) is a human-murine chimeric monoclonal antibody fragment that binds with high
affinity for and a slow dissociation rate from the glycoprotein IIb/IIIa receptor (13,14). Abciximab is cleared rapidly
from the plasma (15) but is detectable bound to circulating
platelets for at least 21 days (16). Abciximab is not specific
for the platelet glycoprotein IIb/IIIa receptor; this agent has
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April 2000:1103–15
equal affinity for the vitronectin receptor (alphavbeta3),
which plays a role in cell adhesion, migration and proliferation. Eptifibatide (Integrilin, COR Therapeutics, South
San Francisco, California), a cyclic heptapeptide based upon
the Lys-Gly-Asp (KGD) amino acid sequence, tirofiban
(Aggrastat, Merck, White House Station, New Jersey), a
tyrosine-derivative nonpeptide mimetic and lamifiban (Ro
44-9883, Hoffman-La Roche, Basel, Switzerland), another
nonpeptide mimetic, are highly-specific competitive inhibitors of the glycoprotein IIb/IIIa complex with rapidly
reversible pharmacodynamics and short (2 to 2.5 h) plasma
half-lives (17–19). Abciximab has been available for clinical
use since 1995; eptifibatide and tirofiban were approved in
1998. Platelet aggregation is inhibited by these agents in a
dose-related manner, with nearly complete abolition of
platelet thrombosis at levels of receptor occupancy ⬎80%
(14). After discontinuation of abciximab, platelet aggregation returns toward baseline over the subsequent 12 to 36 h
(14); normalization of platelet function occurs much more
quickly (over 30 min to 4 h) after discontinuation of the
reversible inhibitors (17,18).
Abbreviations and Acronyms
CAPTURE
⫽ C7E3 AntiPlatelet Therapy in
Unstable REfractory angina
EPIC
⫽ Evaluation of c7E3 for Prevention of
Ischemic Complications
EPILOG
⫽ Evaluation in PTCA to Improve
Long-term Outcome with abciximab
GP IIb/IIIa blockade
EPISTENT
⫽ Evaluation of Platelet Inhibition in
STENTing
HACA
⫽ human antichimeric antibody
IMPACT II
⫽ Integrilin to Minimize Platelet
Aggregation and Coronary
Thrombosis-II
MI
⫽ myocardial infarction
PARAGON
⫽ Platelet IIb/IIIa Antagonism for the
Reduction of Acute Coronary
Syndrome events in the Global
Organization Network
PRISM
⫽ Platelet Receptor Inhibition in Ischemic Syndrome Management
PRISM PLUS ⫽ Platelet Receptor Inhibition in Ischemic Syndrome Management in
Patients Limited by Unstable Signs
PURSUIT
⫽ Platelet IIb/IIIa in Unstable angina:
Receptor Suppression Using Integrilin
Therapy
RAPPORT
⫽ ReoPro And Primary PTCA
Organization and Randomized Trial
RESTORE
⫽ Randomized Efficacy Study of
Tirofiban for Outcomes and
REstenosis
TRIALS OF PERCUTANEOUS
CORONARY REVASCULARIZATION
The role of periprocedural glycoprotein IIb/IIIa inhibition
in the setting of percutaneous coronary revascularization
was established by seven randomized, placebo-controlled
trials enrolling, in total, over 15,000 patients (Table 2)
Table 1. Intravenous Glycoprotein IIb/IIIa Receptor Antagonists
Brand name
Structure
Molecular weight (kD)
Plasma half-life
Excretion
Approved indications*
Approved dose*
Abciximab
Eptifibatide
Tirofiban
Lamifiban
ReoPro
Antibody Fab fragment
47.6
10–30 min
Unknown
PCI
Integrilin
Cyclic heptapeptide
0.832
⬃2.5 h
⬃50% renal
ACS (unstable angina
and non-Q wave MI)
PCI
Aggrastat
Nonpeptide
0.495
⬃2 h
39–69% renal
ACS (unstable angina and
non-Q wave MI)
—
Nonpeptide
0.468
⬃2 h
90% renal
Not approved
For ACS: 180 ␮g/kg
bolus, 2.0 ␮g/kg-min
infusion ⫻ 72–96 h
(PURSUIT dose)
†For PCI: 135 ␮g/kg
bolus, 0.5 ␮g/kg-min
infusion for 20–24 h
(IMPACT II dose)
For ACS: 0.4 ␮g/kg-min
⫻ 30 min, then 0.1 ␮g/
kg-min ⫻ 48–108 h
Not approved
Refractory unstable
angina when PCI is
planned within 24 h
For PCI: 0.25 mg/kg
bolus, 0.125 ␮g/kgmin (max 10 ␮g/min)
infusion ⫻ 12 h
†For unstable angina:
0.25 mg/kg bolus, 10
␮g/min infusion ⫻
18–24 h before PCI,
continued 1 h after
PCI
ACS ⫽ acute coronary syndromes; IMPACT II ⫽ Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II; kD ⫽ kilodalton; MI ⫽ myocardial infarction;
PCI ⫽ percutaneous coronary intervention; PURSUIT ⫽ Platelet IIa/IIIb in Unstable angina: Receptor Supression Using Integrilin Therapy.
*Approved indications and approved dose according to label of United States Food and Drug Administration (FDA); †FDA approved dose for indication, but may not be
optimal (see text). For abciximab in unstable angina, an infusion of 12 h after PCI is recommended. For eptifibatide during PCI, the PURSUIT dose of 180 ␮g/kg bolus and
2.0 ␮g/kg-min infusion is recommended.
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Table 2. Randomized Interventional Trials—Patient Populations
Agent
Tested
Trial
Number of
Patients
Enrollment
Period
abciximab
EPIC
2,099
11/91–11/92
abciximab
EPILOG
2,792
2/95–12/95
abciximab
EPISTENT
2,399
7/96–9/97
eptifibatide
tirofiban
IMPACT II
RESTORE
4,010
2,139
11/93–11/94
1/95–12/95
abciximab
CAPTURE
1,265
5/93–12/95
abciximab
RAPPORT
483
11/95–2/97
Entry Criteria
High risk PTCA or DCA:
Acute MI — within 12 h (direct or rescue PTCA)
Recent MI — within prior 7 days
Unstable angina — within 24 h of chest pain (rest or
postinfarction angina with ischemic ECG changes)
Clinical-morphologic criteria (ACC/AHA lesion score B2 or C,
ACC/AHA score B1 with DM or with women of age ⬎65)
Urgent or elective PTCA, DCA, TEC or laser:
Excluding unstable angina or acute MI (EPIC criteria) within
prior 24 h, elective stents, rotational atherectomy
Coronary intervention suitable for PTCA or elective stent:
Excluding acute MI within 24 h, rotational atherectomy
All clinical indications, all approved interventions
High risk PTCA or DCA:
Acute MI — within 72 h (Q wave or non-Q wave)
Unstable angina — within 72 h (chest pain at rest or on
minimal effort with ECG changes, hemodynamic changes or
angiographic thrombus)
Refractory unstable angina:
Unstable angina — within 48 h (chest pain with ECG changes)
despite IV heparin and nitroglycerin
Primary PTCA for acute ST elevation MI — within 12 h
ACC/AHA ⫽ American College of Cardiology/American Heart Association modified lesion complexity score (58); DCA ⫽ directional coronary atherectomy; DM ⫽ diabetes
mellitus; ECG ⫽ electrocardiographic; MI ⫽ myocardial infarction; PTCA ⫽ coronary balloon angioplasty; TEC ⫽ transluminal extraction catheter atherectomy. For Trial
Acronyms see “Abbreviations and Acronyms.”
(20 –26). The efficacy of abciximab in reducing ischemic
complications among patients at high risk, a broad spectrum
of patients undergoing elective or urgent revascularization
and patients suitable for stent implantation was assessed in
Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) (20), Evaluation in PTCA to Improve Longterm Outcome with abciximab GP IIb/IIIa blockade (EPILOG) (21) and Evaluation of Platelet Inhibition in
STENTing (EPISTENT) (22), respectively. C7E3 AntiPlatelet Therapy in Unstable REfractory angina (CAPTURE) tested abciximab as treatment before and during
angioplasty among patients with refractory unstable angina
(25), while ReoPro And Primary PTCA Organization and
Randomized Trial (RAPPORT) focused on angioplasty as
primary reperfusion therapy for acute myocardial infarction
(MI) (26). Eptifibatide was evaluated among all patients
undergoing coronary intervention in Integrilin to Minimize
Platelet Aggregation and Coronary Thrombosis-II (IMPACT II) (23). Randomized Efficacy Study of Tirofiban for
Outcomes and REstenosis (RESTORE) assessed tirofiban
during revascularization for acute ischemic syndromes
(24,27).
Trial designs. All trials were blinded throughout longterm follow-up. End points were adjudicated by review of
primary data by independent blinded clinical events committees, although the level of adjudication varied among the
trials. Myocardial infarction was identified by new Q waves
or creatine kinase-MB elevations ⱖ3 times the control.
Aside from CAPTURE, all trials evaluated a strategy
whereby study drug (glycoprotein IIb/IIIa inhibitor or
placebo) was administered as a bolus immediately before
coronary intervention, followed by infusions of varying
durations. The durations of study drug infusion were based,
in part, upon pharmacodynamic differences among the
agents: 24-h or 36-h infusions of the competitive inhibitors
eptifibatide and tirofiban were chosen for the IMPACT II
and RESTORE trials, respectively, whereas the slowly
reversible abciximab was evaluated with a 12-h infusion. In
CAPTURE, study drug was administered for 20 to 24 h
before angioplasty and 1 h thereafter. All patients received
aspirin. In EPISTENT, patients received ticlopidine for
four weeks after stenting, according to contemporary interventional practice (28,29).
As described below, excess hemorrhagic risk was observed
with abciximab in EPIC, apparently linked to the level of
intraprocedural heparin dosing as well as the practice of
leaving vascular access sheaths in place with ongoing heparin infusion for the entire 12-h study drug infusion period.
A pilot study showed that the blood loss associated with
abciximab might be attenuated by weight-adjustment and
reduction of heparin doses and by early vascular sheath
removal (30). Based upon these findings, the EPILOG trial
explicitly tested low-dose versus standard-dose weight-
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Figure 1. Composite 30-day end point (death, myocardial infarction or urgent repeat revascularization) event rates for the seven
glycoprotein IIb/IIIa interventional trials. This was not the prespecified primary end point of RESTORE or RAPPORT. RESTORE trial
end points listed here are for the published post-hoc analysis including only urgent repeat revascularization. RESTORE trial end points
listed here differ from those of the other trials in that only patients with successful crossing of the lesion with the guidewire were included
in the efficacy analysis of RESTORE, whereas all randomized patients were included in the other studies. RAPPORT trial end points
listed here are for secondary end point of death, myocardial infarction or urgent repeat target vessel revascularization. *EPISTENT trial
groups compared with reference group of Placebo ⫹ Stent; thus, the “placebo control” for the Abciximab ⫹ PTCA group underwent
stenting rather than PTCA. B ⫽ bolus; B ⫹ I ⫽ bolus plus infusion; CAPTURE ⫽ C7E3 AntiPlatelet Therapy in Unstable REfractory
angina; EPIC ⫽ Evaluation of c7E3 for Prevention of Ischemic Complications; EPILOG ⫽ Evaluation in PTCA to Improve Long-term
Outcome with abciximab GP IIb/IIIa blockade; EPISTENT ⫽ Evaluation of Platelet Inhibition in STENTing; IMPACT ⫽ Integrilin
to Minimize Platelet Aggregation and Coronary Thrombosis; LDH ⫽ low-dose, weight-adjusted heparin; MI ⫽ myocardial infarction;
PTCA ⫽ percutaneous transluminal coronary angioplasty; RAPPORT ⫽ ReoPro And Primary PTCA Organization and Randomized
Trial; RESTORE ⫽ Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis; SDH ⫽ standard-dose, weight-adjusted
heparin; 135/.5 and 135/.75 ⫽ eptifibatide doses: 135 ␮g/kg bolus, followed by infusions of 0.5 or 0.75 ␮g/kg-min.
adjusted heparin regimens with abciximab, and the other
trials incorporated some form of protocol-directed limitation or weight-adjustment of heparin dosing. Trials after
EPIC and CAPTURE recommended that no heparin
infusion be administered after the procedure and that
vascular sheaths be removed early (usually during study drug
infusion).
Efficacy. Event rates for the composite 30-day end point of
death, MI or urgent repeat revascularization are summarized in Figure 1.
In the EPIC (20), EPILOG (21) and EPISTENT trials
(22), abciximab therapy was associated with absolute 4.5 to
6.5% reductions in the 30-day composite end point. The
magnitude of treatment effect was independent of the
modality of revascularization (balloon angioplasty, directional atherectomy or stenting) (22,31). In the specific
disease states assessed in CAPTURE (refractory unstable
angina) and RAPPORT (acute MI), therapy with abciximab conferred a similar reduction in ischemic end points
(absolute 4.6% to 5.4% risk reduction) (25,26). In CAPTURE, clinical benefit from abciximab began to accrue
during the pretreatment phase before angioplasty (preprocedural MI rate reduced from 2.1% to 0.6%; p ⫽ 0.029)
(25). The IMPACT II and RESTORE trials provided
evidence that eptifibatide and tirofiban, respectively, also
diminish periprocedural ischemic events, but the magnitude
of treatment effect with these agents (absolute 1.5% to 2.5%
risk reductions) was less than in the abciximab trials and did
not reach conventional levels of statistical significance
(23,24). Ischemic events were reduced considerably by
eptifibatide or tirofiban at 24 to 48 h, but attenuation of
clinical benefit occurred over the subsequent 30 days.
Across the interventional trials, the treatment effect of
glycoprotein IIb/IIIa blockade was similar for each of the
components (death, MI or urgent revascularization) of the
30-day composite end point. Moreover, clinical benefit was
generally consistent among all subgroups of patients, although apparently enhanced in certain settings. In particular, the composite end point rate was decreased from 13.1%
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Figure 2. Composite six-month end point of death or myocardial (re-) infarction event rates for the glycoprotein IIb/IIIa interventional
trials. *EPISTENT trial groups compared with reference group of Placebo ⫹ Stent. Abbreviations as in Figure 1.
to 3.8% (p ⫽ 0.004) with abciximab (absolute 9.3% risk
reduction) among those patients in EPIC with unstable
angina and ischemic electrocardiographic changes (32).
Rates of death or MI at six months are summarized in
Figure 2. The suppression of acute ischemic events achieved
within 30 days by glycoprotein IIb/IIIa blockade was
maintained without attenuation over the long term
(21,23,25–27,33–36). Evidence of long-term suppression of
mortality by GP IIb/IIIa blockade has been derived from
the three trials that reported results of follow-up at one year
or longer: EPIC, EPILOG and EPISTENT. Nonsignificant trends were observed among the overall trial populations in EPIC (8.6% vs. 6.8% at three years, p ⫽ 0.20) and
EPILOG (2.6% vs. 1.7% at one year, p ⫽ 0.07) (34,35)
although mortality at three years in EPIC was significantly
reduced by abciximab from 12.7% to 5.1% (p ⫽ 0.01)
among the 555 highest risk patients enrolled with unstable
angina or acute MI (34). In the EPISTENT trial, mortality
at one year was significantly reduced by 60% with the
combination of abciximab with stenting relative to either
therapy alone: 1% in the stent plus abciximab group compared with 2.4% in the stent plus placebo group (p ⫽ 0.04)
and 2.1% in the balloon angioplasty plus abciximab group
(37).
In EPIC, therapy with abciximab was associated with a
reduction in target vessel revascularization procedures at six
months, from 22.3% to 16.5% (p ⫽ 0.007), a finding that
led to speculation that this agent may reduce restenosis (33).
A significant decrease in the need for late target vessel
revascularization procedures was not observed with glyco-
protein IIb/IIIa blockade in the subsequent EPILOG trial,
however, nor in any of the other balloon angioplasty trials.
Yet among patients undergoing elective stenting in
EPISTENT, treatment with abciximab was associated with
reduction in six-month target vessel revascularization rates
from 10.6% to 8.7% (p ⫽ 0.22) and a significant halving of
this end point among the prespecified subgroup of patients
with diabetes mellitus (16.6% to 8.1%, p ⫽ 0.021) (36).
Thus, in the setting of stenting, wherein the processes of
recoil and remodeling are not operative and neointimal
hyperplasia is the predominant mechanism of luminal renarrowing, abciximab may reduce restenosis, particularly
among diabetic patients, who are known to be at elevated
risk for this late complication (38).
Hemorrhagic risk. The major limitation of abciximab
therapy in the first interventional trial, EPIC, was a substantially increased risk of bleeding (Fig. 3) (20). During
subsequent trials, in which heparin dosing was limited and
vascular sheaths removed early, bleeding rates were diminished in all treatment groups, and no significant increase in
hemorrhagic risk was associated with glycoprotein IIb/IIIa
therapy. A trend toward lower rates of bleeding in the
abciximab groups compared with placebo was observed
when the low-dose, weight-adjusted heparin regimen was
used (in EPILOG and EPISTENT). The high rates of
bleeding in RAPPORT and CAPTURE were likely related
to long vascular access sheath dwell times. Rates of intracranial hemorrhage were not increased by glycoprotein
IIb/IIIa blockade (39).
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Figure 3. Rates of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major bleeding in the glycoprotein IIb/IIIa interventional
trials. *EPISTENT trial groups compared with reference group of Placebo ⫹ Stent. Major bleeding defined as intracranial hemorrhage
or a fall in hemoglobin by ⱖ5 mg/dl (57). Abbreviations as in Figure 1.
TRIALS OF UNSTABLE ISCHEMIC SYNDROMES
The role of intravenous glycoprotein IIb/IIIa antagonists in
the setting of unstable ischemic syndromes, independent of
the use of coronary revascularization, was tested among over
18,000 patients in four placebo-controlled trials (40 – 43).
These trials focused on patients with unstable symptoms
without persistent ST segment elevations, a proportion of
whom would subsequently be determined on the basis of
cardiac enzyme elevations to have suffered MI. Patients with
persistent ST segment elevations suitable for reperfusion
therapy were not eligible for enrollment. These studies
assessed the competitive reversible inhibitors: eptifibatide in
Platelet IIb/IIIa in Unstable Angina: Receptor Suppression
Using Integrilin Therapy (PURSUIT) (40), tirofiban in
Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs (PRISM
PLUS) and Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) (41,42) and lamifiban in
Platelet IIb/IIIa Antagonism for the Reduction of Acute
Coronary Syndrome events in the Global Organization
Network (PARAGON) (43).
Trial designs. Entry criteria were comparable, although a
lower risk patient population was included in PRISM
(Table 3). There were substantial differences among the
trials with regard to treatment strategy. Platelet IIb/IIIa in
Unstable Angina: Receptor Suppression Using Integrilin
Therapy was a broad “mega-trial,” assessing eptifibatide
superimposed upon the spectrum of different practice patterns throughout the world. Thus, the protocol did not
specify pharmacologic therapies aside from the study agent
and did not mandate a particular strategy of coronary
angiography and revascularization. In contrast, a 48-h study
drug pretreatment period was specified in PRISM PLUS,
after which catheterization and revascularization were encouraged to be performed while study drug therapy was
ongoing. PARAGON and PRISM focused on patients for
whom a conservative strategy of medical therapy was
planned, and angiography and revascularization during
study drug infusion were discouraged.
All patients received aspirin. Approaches to heparinization varied. In PURSUIT, treatment with intravenous or
subcutaneous heparin was encouraged during study drug
infusion. PRISM PLUS and PARAGON explicitly tested
the interaction between heparin and glycoprotein IIb/IIIa
inhibition, with patients in the active study drug arms
(tirofiban or lamifiban) randomized to either heparin or no
heparin. PRISM tested the strategy of glycoprotein IIb/IIIa
blockade by tirofiban compared with heparinization in lower
risk patients.
Efficacy. Event rates for the composite and individual end
points at various time points are presented in Table 4; the
trials are compared on the basis of the 30-day composite of
death or MI in Figure 4. As with the interventional trials,
ischemic event rates were generally reduced by glycoprotein
IIb/IIIa blockade among patients with unstable ischemic
syndromes.
In PURSUIT, treatment with eptifibatide was associated
with absolute 1.2 to 1.5% reductions in the incidence of
death or MI at 96 h, seven days, 30 days and six months
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Table 3. Randomized Acute Ischemic Syndrome Trials—Patient Populations
Agent
Tested
Trial
Number of
Patients
Enrollment
Period
10,948
11/95–1/97
Eptifibatide
PURSUIT
Tirofiban
PRISM PLUS
1,915
11/94–9/96
Tirofiban
PRISM
3,232
3/94–10/96
Lamifiban
PARAGON
2,282
8/95–5/96
Entry Criteria
CP at rest within 24 h and either: ECG
changes (ST depression, T inversion or
transient ST elevation) or CK-MB elevation
CP at rest or minimal exertion within 12 h and
either: ECG changes (ST depression, T
inversion or transient ST elevation) or CKMB elevation
CP at rest or minimal exertion within 24 h
and: ECG changes (ST depression, T
inversion or transient ST elevation) or CKMB elevation or history of coronary disease
or positive stress test
CP at rest within 12 h, and: ECG changes
(ST depression, T inversion or transient ST
elevation)
Angiography and
Revascularization
Discretion of
attending
physician
Deferred for first
48 h, then
performed
during study
drug infusion
Discouraged
Discouraged
CK-MB ⫽ creatine kinase MB isoenzyme fraction; CP ⫽ chest pain (or ischemic symptoms); ECG ⫽ electrocardiographic. For Trial Acronyms see “Abbreviations and
Acronyms.”
(40,44). The observed treatment effect varied considerably
among the four predefined geographic regions involved in
the trial, with the greatest benefit observed in North
America (30-day end point reduced from 15.0% to 11.7%).
Similarly, although the reduction in ischemic events was
equivalent among men and women in North America, no
treatment effect was observed for women in other regions of
the world. Such geographic variations in outcome have been
observed in other international randomized trials (45) and
may have been related to substantial differences in patient
baseline characteristics and treatment strategies (including
the use of heparin and the performance and timing of
coronary revascularization).
Therapy with tirofiban plus heparin in PRISM PLUS
resulted in a significant and durable reduction in ischemic
end points as compared with heparin alone (41). The
composite end point of death, MI or refractory ischemia was
diminished at seven days, with preservation of the absolute
treatment effect to 30 days. Death and MI rates were
reduced at 30 days (although the p ⫽ 0.03 did not reach the
prespecified level of p ⫽ 0.025 for a three group trial) and
at six months (absolute 3.0%–3.2% risk reduction). Tirofiban alone (without heparin) was found at the first interim
analysis to be associated with an apparent increased risk of
death by seven days, leading to early discontinuation of this
group and precluding formal comparison of heparin versus
no heparin arms.
In PRISM, a significant reduction in the composite end
point of death, MI or refractory ischemia was observed at
the end of study drug infusion (48 h) among patients
receiving tirofiban rather than heparin (42). There was a
nonsignificant trend toward suppression of this end point, as
well as the composite of death or MI, by 30 days.
The results of PARAGON differed somewhat from the
pattern of efficacy seen in the other three trials (43). By
30 days, there was no significant effect of lamifiban at either
dose, with or without heparin, on the incidence of death or
MI compared with placebo. Event rates diverged after
30 days, however, and, by six months, there was a significant
treatment effect of low-dose lamifiban (⫾ heparin). No
influence of heparin on clinical outcome could be discerned.
The interaction between glycoprotein IIb/IIIa blockade
and coronary revascularization was not tested in a randomized fashion in these trials. In PURSUIT and PRISM
PLUS, however, a substantial number of patients underwent percutaneous revascularization during study drug infusion, although selection for these procedures was a postrandomization event and may have been influenced by the
occurrence of ischemic end points. Nevertheless, the consistent finding in these two trials, as in CAPTURE, was
that glycoprotein IIb/IIIa blockade was effective in stabilizing patients before the performance of coronary intervention
and in reducing ischemic events after revascularization. In
PURSUIT, 1,228 patients underwent percutaneous revascularization within the first 72 h (40). Eptifibatide therapy
in these patients was associated with a reduction in the risk
of MI before revascularization (5.5% vs. 1.7%, p ⬍ 0.001) as
well as a significant reduction in the composite end point of
death or MI by 30 days (16.7% vs. 11.6%, 5.1% absolute risk
reduction, p ⫽ 0.01). Without coronary intervention, the
treatment effect was somewhat less (30 day end point rates
of 15.6% vs. 14.5% in placebo and eptifibatide groups,
respectively, p ⫽ NS). During the first 48 h in PRISM
PLUS (while angiography and revascularization were discouraged), death or MI rates were reduced from 2.6% to
0.9% by tirofiban in the overall 1,570 patient cohort (p ⫽
0.01); among the 475 patients undergoing intervention
thereafter on study drug, 30-day rates of death or MI were
RI
RI
RI
RI
7.6
—
0.9
7.1
10.1
—
1.5
9.3
14.2
—
3.5
12.6
17.8
—
6.4
14.7
9.1
—
1.2
8.3
11.6
—
2.0
10.4
15.7
—
3.7
13.5
19.0
—
6.2
15.7
Eptifibatide
ⴙ Heparin
(n ⴝ 4,722)
15.3
32.1
7.0
10.5
11.9
22.3
4.5
9.2
8.3
17.9
1.9
7.0
2.6
7.8
0.3
2.6
Placebo ⴙ
Heparin
(n ⴝ 797)
12.3
27.7
6.9
8.3
8.7
18.5
3.6
6.6
4.9
12.9
1.9
3.9
0.9
5.7
0.1
0.9
Tirofiban
ⴙ Heparin
(n ⴝ 773)
PRISM PLUS*
—
—
—
—
7.1
17.1
3.6
4.3
4.2
11.2
1.6
3.1
1.4
5.6
0.4
1.4
Heparin
(n ⴝ 1,616)
—
—
—
—
5.8
15.9
2.3
4.1
3.3
10.3
1.0
2.6
0.9
3.8
0.2
0.9
Tirofiban
(n ⴝ 1,616)
PRISM
17.9
—
6.6
14.3
11.7
—
2.9
10.6
6.6
—
1.3
9.1
3.7
—
0.5
3.3
Placebo ⴙ
Heparin
(n ⴝ 758)
13.7
—
5.2
10.8
10.6
—
3.0
9.4
6.8
—
1.1
7.9
3.5
—
0.3
3.5
Lamifiban
Low-Dose
(ⴞ Heparin)
(n ⴝ 755)
PARAGON
16.4
—
6.8
12.9
12.0
—
3.6
10.9
7.0
—
1.7
9.5
2.6
—
0.4
2.5
Lamifiban
High Dose
(ⴞ Heparin)
(n ⴝ 769)
Lincoff et al.
Platelet Glycoprotein IIb/IIIa Blockade
*Efficacy data are not provided for the low-dose eptifibatide group of PURSUIT and the tirofiban plus placebo group of PRISM PLUS treatment arms, which were discontinued before completion of the trials, to avoid inappropriate
comparisons of patients who were not contemporaneously enrolled.
48 –96 h end point: assessed in PURSUIT at 96 h, assessed in PRISM PLUS, PRISM and PARAGON at 48 h.
Heparin use in PURSUIT was encouraged, but not mandated, and was administered to 89.9% and 89.7% of patients randomized to placebo and eptifibatide, respectively.
MI ⫽ myocardial infarction; RI ⫽ refractory ischemia. For Trial Acronyms see “Abbreviations and Acronyms.”
48–96 h
Death or MI
Death, MI or
Death
MI
7 Days
Death or MI
Death, MI or
Death
MI
30 Days
Death or MI
Death, MI or
Death
MI
6 Months
Death or MI
Death, MI or
Death
MI
End Point (% of
Patients)
Placebo ⴙ
Heparin
(n ⴝ 4,739)
PURSUIT*
Table 4. Randomized Acute Ischemic Syndrome Trials—Efficacy End Points
1110
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April 2000:1103–15
Lincoff et al.
Platelet Glycoprotein IIb/IIIa Blockade
1111
Figure 4. Composite 30-day composite end point of death or myocardial (re-) infarction in the four glycoprotein IIb/IIIa unstable
ischemic syndrome trials. Efficacy data are not provided for the low-dose eptifibatide group PURSUIT and the tirofiban plus placebo group
PRISM PLUS treatment arms, which were discontinued before completion of the trials. *p ⫽ 0.03 in PRISM PLUS did not reach the
prespecified level of p ⫽ 0.025 for a three group trial; †Heparin use in PURSUIT was encouraged, but not mandated, and was administered
to 89.9% and 89.7% of patients randomized to placebo and eptifibatide, respectively. PARAGON ⫽ Platelet IIb/IIIa Antagonism for the
Reduction of Acute Coronary Syndrome events in the Global Organization Network; PRISM PLUS ⫽ Platelet Receptor Inhibition in
Ischemic Syndrome Management in Patients Limited by Unstable Signs; PURSUIT ⫽ Platelet IIb/IIIa in Unstable Angina: Receptor
Supression Using Integrilin Therapy.
10.2% and 5.9% in the placebo and tirofiban groups,
respectively (4.3% absolute risk reduction, p ⫽ 0.12). With
medical management, 30-day end point rates were reduced
from 10.1% to 7.8% (p ⫽ NS).
Hemorrhagic risk. Rates of hemorrhagic complications
(unassociated with coronary artery bypass surgery) are summarized in Table 5. The excess bleeding risk associated with
glycoprotein IIb/IIIa blockade ranged from 0 to 30 events
per 1,000 patients treated. Variability in the incremental
risks of bleeding among the trials likely reflects differences
in underlying patient risk factors, protocols for heparin
dosing and monitoring, schedules for ascertainment of
hemoglobin values during and after study drug infusion and
utilization of invasive revascularization procedures. Despite
the prolonged duration of glycoprotein IIb/IIIa therapy in
these trials, no increase in the risk of intracranial hemorrhage was observed (39).
SYNTHESIS OF THE CLINICAL TRIALS
Efficacy. The consistent finding among over 33,000 patients is a reduction in important acute ischemic events by
glycoprotein IIb/IIIa receptor blockade during percutaneous
coronary revascularization or in the management of unstable
angina or MI without ST elevation. The greatest magnitude
of clinical benefit with these agents appears to be achieved
in patients undergoing coronary intervention (up to 65 acute
ischemic events prevented per 1,000 patients treated),
wherein the timing of plaque injury and the role of acute
platelet aggregation are precisely defined. Inhibition of
acute ischemic events is achieved primarily in the first 12 to
48 h after revascularization and maintained over long-term
(up to three year) follow-up. No demographic, clinical,
angiographic or procedural characteristic has been observed
that will identify patients who do not benefit from glycoprotein IIb/IIIa blockade during coronary revascularization.
The clinical efficacy of abciximab after stenting is incremental to that achieved with conventional antiplatelet therapy
with theinopyridines and aspirin (28,29).
In contrast, patients with unstable ischemic syndromes
are more heterogeneous with regard to pathophysiology,
duration of plaque erosion and the extent of established
thrombosis versus ongoing platelet aggregation and, consequently, may be somewhat less responsive to empiric glycoprotein IIb/IIIa receptor blockade. Nevertheless, the observed absolute treatment effect of 15 to 32 events prevented
per 1,000 patients treated represents an incremental therapeutic advance over aspirin and heparin. Clinical benefit
1112
Lincoff et al.
Platelet Glycoprotein IIb/IIIa Blockade
JACC Vol. 35, No. 5, 2000
April 2000:1103–15
Table 5. Randomized Acute Ischemic Syndrome Trials—
In-Hospital Bleeding (Unassociated with CABG)
PURSUIT Trial‡
Placebo
Eptifibatide
PRISM PLUS Trial‡
Heparin
Tirofiban ⫹
heparin
PRISM Trial
Heparin
Tirofiban
PARAGON Trial
Placebo
Lamifiban low dose
Lamifiban high dose
Major
Bleeding
(%)
Blood
Transfusion
(%)
Intracranial
Hemorrhage
(%)
1.3
3.0*
1.8
4.4*
0.1
0.1
0.8
1.4
2.8
4.0
0
0
0.4
0.4
1.4
2.4
0.1
0.1
3.0
3.0
6.0*
4.5†
4.5†
9.3†
0
0
0.1
Major Bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria
(57) as intracranial hemorrhage or bleeding associated with a decrease in hemoglobin
of ⱖ5 gm/dl.
*p ⬍ 0.05; †times of transfusions and relationship to CABG were not recorded in
PARAGON, thus, total transfusion rates (including CABG-associated) are provided;
‡safety data are not provided for the low-dose eptifibatide group of PURSUIT and
the tirofiban plus placebo group of PRISM PLUS treatment arms, which were
discontinued before completion of the trials to avoid inappropriate comparisons of
patients who were not contemporaneously enrolled.
CABG ⫽ coronary artery bypass surgery. For Trial Acronyms see “Abbreviations
and Acronyms.”
accrues during the two to four day period of drug infusion
and is durable over late (six month) follow-up. The treatment effect of these agents appears to be greatest among
those who undergo early percutaneous coronary revascularization, with clear evidence of stabilization during the
period before intervention as well as suppression of postprocedural ischemic events. Glycoprotein IIb/IIIa blockade
with a less aggressive strategy of medical management also
appears to provide benefit.
Differences in efficacy among the agents. Although all of the
agents tested reduce ischemic risk, there does seem to be
heterogeneity among the drugs with regard to the magnitude and durability of treatment effect, at least in the setting
of percutaneous coronary revascularization. Importantly,
direct comparative trials have not been performed. Apparent
variability among agents in efficacy may, in part, be due to
pharmacodynamics of receptor binding, with the slow
dissociation of abciximab contrasting with the rapid reversibility of the other agents. Additionally, the nonspecific
blockade by abciximab of both the IIb/IIIa receptor, and the
alphavbeta3 receptor may theoretically provide an advantage
over the specific agents, as ex vivo studies have suggested
that dual receptor blockade more completely suppresses
platelet-mediated thrombin generation than does inhibition
of either receptor alone (46).
For eptifibatide, the relatively modest treatment effect in
IMPACT II was almost certainly due, in part, to inadequate
dosing based upon Phase II studies that used sodium citrate
as an anticoagulant for platelet aggregation measurements.
Subsequent to IMPACT II, it was observed that the
binding of eptifibatide to the glycoprotein IIb/IIIa receptor
was exaggerated in blood anticoagulated by citrate (which
chelates calcium) relative to that which would occur at
physiologic calcium concentrations (47). The potential for
higher doses of eptifibatide to more effectively reduce
ischemic complications is suggested by the substantial treatment effect among patients in PURSUIT who underwent
early percutaneous coronary revascularization.
In the trials of acute ischemic syndromes without mandated percutaneous revascularization, the greatest treatment
effect was observed in PRISM PLUS among patients
receiving tirofiban combined with heparin (Fig. 4). Confidence intervals around this estimate were wide, however,
and the magnitude of risk reduction was not statistically
different from that seen in other trials. It is likely that similar
outcomes would be obtained with any of the reversible
IIb/IIIa inhibitors in this clinical setting.
Safety. The reduction in bleeding risk with IIb/IIIa inhibitors during the trials of percutaneous coronary revascularization demonstrates that reduction of concomitant heparin
doses, as well as early vascular sheath removal, ameliorate
excess hemorrhagic risk in this setting. Bleeding may
nevertheless occur in certain patients, such as those who
receive these agents as an unplanned or “bailout” intervention in the setting of full-dose heparinization or fibrinolytic
therapy.
For patients who develop refractory or life-threatening
bleeding, the antiplatelet effect of abciximab may be reversed by discontinuation of drug infusion and by platelet
transfusion after the ⬃10 to 30 min required for clearance of
circulating drug. After transfusion, abciximab redistributes
from old to new platelets, reducing the mean level of
receptor blockade (R. Jordan, Centocor, Inc., personal
communication). Platelet transfusions should rarely be necessary with the rapidly reversible agents eptifibatide and
tirofiban and, in fact, might not be expected to be effective
during the ⬃2 h required for elimination of these agents
from the circulating plasma phase.
Emergency coronary artery bypass surgery. There has been
concern regarding the risk of excessive perioperative bleeding among patients who require urgent coronary artery
bypass surgery after administration of a glycoprotein IIb/
IIIa inhibitor. In this regard, the rapidly reversible agents
eptifibatide and tirofiban present little in the way of bleeding risk (40,41). With abciximab, platelet transfusions (after
discontinuation of abciximab infusion) appear to reduce
hemorrhagic risk (48,49), and blood loss was only modestly
increased among patients who required emergency surgery
in the EPILOG and EPISTENT trials (50).
Thrombocytopenia. Thrombocytopenia occurs infrequently with glycoprotein IIb/IIIa inhibition but may be
precipitous and profound (platelet count ⬍50,000 mm⫺3);
the excess risk of profound thrombocytopenia associated
JACC Vol. 35, No. 5, 2000
April 2000:1103–15
with abciximab (0.4% to 1.1%) is higher than with eptifibatide (0%– 0.2%), tirofiban (0.1% to 0.3%) or lamifiban
(0% to 0.1%). The mechanism of thrombocytopenia is
unknown, but there is little evidence of ongoing platelet
clearance after discontinuation of the glycoprotein IIb/IIIa
antagonist. Platelet transfusions are protective for profound
thrombocytopenia with or without serious bleeding induced
by glycoprotein IIb/IIIa inhibitors. Platelet counts should,
therefore, be measured early (within the first 2 to 4 h) after
administering these agents and followed for the duration of
therapy.
Readministration. The development of a human antichimeric antibody (HACA) response in approximately 5% to
6% of patients within the first month after receiving
abciximab (20) raises the question of safety of readministration of this agent. No antibodies have been observed to
develop in response to treatment with eptifibatide, tirofiban
or lamifiban. A prospective abciximab readministration
registry of 500 patients found no instances of hypersensitivity or anaphylactic reactions after abciximab readministration, and efficacy of the agent in reducing ischemic
complications appears to be similar with readministration as
with first-time use (51). Rates of thrombocytopenia after
readministration were somewhat higher, however, than
those seen with first time administration, although the
presence or absence of a positive HACA titer was not
predictive of a lack of clinical effectiveness, development of
thrombocytopenia or other sequelae in patients undergoing
readministration.
Indications for therapy and choice of agent. Although
trial data support the use of glycoprotein IIb/IIIa inhibitors
in virtually all patients undergoing percutaneous coronary
revascularization, these agents are not universally employed
in clinical practice due, in part, to economic considerations
and concerns regarding safety issues. Although the economic aspects of GP IIb/IIIa blockade are beyond the scope
of this review, it is important to recognize that cost savings
derived from reduction in ischemic events offset much of the
acquisition cost of these agents. Moreover, the costeffectiveness of abciximab in reducing mortality during
coronary stenting appears quite favorable, in the range of
other accepted medical therapies (37). Economic considerations aside, the benefits of this therapy should certainly be
provided to patients at elevated risk for periprocedural
complications, such as those with unstable angina or acute
MI, complex lesion morphology, extensive myocardium at
jeopardy, multivessel or multilesion interventions or diabetes mellitus. The current efficacy standard during and after
percutaneous coronary intervention is abciximab administered as a bolus followed by a 12-h infusion. Aspirin,
heparin and ticlopidine or clopidogrel (in patients receiving
stents) should also be administered (52). A pretreatment
regimen of abciximab is effective in stabilizing patients
before coronary revascularization, but offers no clear advantage in stable patients or even in unstable patients for whom
Lincoff et al.
Platelet Glycoprotein IIb/IIIa Blockade
1113
revascularization can be immediately performed. Regardless
of whether or not a period of pretreatment with abciximab
is used, the 12-h postprocedural infusion appears to be
necessary for optimal clinical benefit. Although anecdotal
data suggest that abciximab may be useful in an unplanned
or “bailout” fashion to reverse thrombotic complications of
coronary intervention (53), this approach has never been
tested in a randomized fashion and must be regarded as
suboptimal relative to planned use.
Eptifibatide or tirofiban are effective as empiric therapy
among patients with unstable ischemic symptoms associated
with either electrocardiographic or enzymatic evidence of
myocardial ischemia or necrosis, particularly if revascularization is subsequently performed. Given the heterogeneity
of acuity and risk for complications of patients admitted
with the diagnosis of “unstable angina,” these agents will
likely prove most beneficial if focused on those with high
risk features such as recurrent or prolonged rest symptoms,
ischemic heart failure, dynamic electrocardiographic
changes, hemodynamic instability (54), elevated troponin or
creatine kinase (55) or prior aspirin use. Treatment with
abciximab in this setting has not yet been evaluated and
cannot be recommended. Once a course of empiric therapy
with eptifibatide or tirofiban is initiated, it should be
continued for 24 h after percutaneous coronary intervention
(if performed). The available pharmacodynamic and clinical
data strongly suggest that, with eptifibatide, the dose of
180 ␮g/kg bolus and 2.0 ␮g/kg-min infusion be utilized.
Conjunctive heparin. During coronary intervention, the
low-dose, weight-adjusted heparin regimen (initial bolus of
70 U/kg, maximum 7000 U, adjusted to maintain an
activated clotting time ⱖ200 s) is safe and effective with
abciximab therapy (21). Postprocedural heparin likely provides no additional benefit, even in patients with acute
ischemic syndromes, and vascular access sheaths can typically be removed 2 to 6 h after the procedure. Optimal
heparin dosing during coronary intervention in patients
receiving eptifibatide or tirofiban has not been investigated,
but a dose of 100 U/kg (maximum 10,000 U) adjusted to an
activated clotting time ⱖ300 s is currently recommended.
The role of heparin among patients receiving glycoprotein
IIb/IIIa antagonists during the medical management of
unstable angina remains unresolved. Evidence from the
randomized trials and other studies (56) suggests that
heparin likely adds clinical benefit to glycoprotein IIb/IIIa
blockade in the acute ischemic syndromes, although the
optimal intensity and duration of therapy has not been
defined.
Conclusions. Platelet glycoprotein IIb/IIIa receptor blockade represents a significant advance in the practice of
interventional cardiology and the management of acute
ischemic syndromes. Topics for future study include the role
of these agents among patients treated with thrombolytic
therapy for acute MI, economic aspects and development of
less costly alternatives, the effectiveness of these agents when
1114
Lincoff et al.
Platelet Glycoprotein IIb/IIIa Blockade
used in an unplanned fashion during coronary intervention,
the role of oral glycoprotein IIb/IIIa antagonists and the
potential for combining glycoprotein IIb/IIIa antagonists
with novel inhibitors of thrombin or other components of
the coagulation cascade.
Reprint requests and correspondence: Dr. A. Michael Lincoff,
Department of Cardiology, The Cleveland Clinic Foundation,
9500 Euclid Avenue, Cleveland, Ohio 44195.
JACC Vol. 35, No. 5, 2000
April 2000:1103–15
20.
21.
22.
23.
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