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Drug Evaluation medicure publication
10.1517/17425255.3.2.275 © 2007 Informa UK Ltd ISSN 1742-5255 275
Current strategies with
high-dose tirofiban
Debabrata Mukherjee † & Marco Roffi
† Gill Heart Institute, University of Kentucky, 326 Wethington Bldg, 900 S. Limestone, Lexington,
Kentucky 40436-0200, USA
The glycoprotein (GP) IIb/IIIa receptor is a platelet-specific adhesion receptor
that mediates the formation of platelet aggregates. Pharmacologic blockade
of the receptor is associated with a reduction in major cardiovascular adverse
events after percutaneous coronary interventions and in the setting of acute
coronary syndromes. Three intravenous GP IIb/IIIa receptor inhibitors are
available: abciximab, tirofiban and eptifibatide. Tirofiban is a small, synthetic
non-peptide, competitive GP IIb/IIIa antagonist with high specificity and high
affinity for the GP IIb/IIIa receptor. In a head-to-head comparison, tirofiban
10-µg/kg bolus followed by a 0.15-µg/kg/min infusion was found to be infe-rior
to standard dose of abciximab in patients undergoing percutaneous cor-onary
intervention. Insufficient platelet inhibition with low-dose tirofiban
may likely explain these results. Subsequently, a high-bolus dose of tirofiban
(25 µg/kg bolus) followed by standard infusion was tested and evidence sug-gest
that in this dosing tirofiban may be as effective as abciximab and have a
comparable safety profile. Therefore, high-bolus dose tirofiban may be an
appealing and cost-effective alternative to abciximab. However, further test-ing
is warranted given the short follow up and limited statistical power of
the available data.
Keywords: abciximab, acute coronary syndromes, glycoprotein IIb/IIIa receptor inhibition,
percutaneous coronary intervention, tirofiban
Expert Opin. Drug Metab. Toxicol. (2007) 3(2):275-280
1. Introduction
A large body of evidence supports the notion that platelet glycoprotein (GP) IIb/IIIa
receptor inhibitors effectively reduce major cardiovascular adverse events (MACE)
including death, myocardial infarction (MI) and urgent target vessel revasculariza-tion
(TVR) in patients undergoing percutaneous coronary intervention (PCI) [1].
Similarly, these agents have proven to be efficacious in the setting of acute coronary
syndromes (ACS) [2] and particularly for patients undergoing early PCI [3]. Three
GP IIb/IIIa inhibitors are available on the market namely, abciximab, tirofiban and
eptifibatide. In this review, the authors focus on tirofiban, a small-molecule GP
IIb/IIIa inhibitor, and address laboratory and clinical evidence supporting the newer
high-bolus dose (HBD) regimen.
2. Platelet glycoprotein IIb/IIIa receptor antagonists
The GP IIb/IIIa receptor, or α IIB/β 3 integrin, is the most abundant platelet mem-brane
GP found in humans and, as a platelet-specific adhesion receptor, has a broad
specificity for a number of ligands, most notably fibrinogen, von Willebrand factor
and prothrombin. Approximately 60,000 – 80,000 copies of the integrin are present
per platelet and the number increases as an internal pool becomes available during
platelet activation. The GP IIb/IIIa receptor mediates the formation of platelet
aggregates via von Willebrand factor and soluble fibrinogen. Platelet stimulation by
1. Introduction
2. Platelet glycoprotein IIb/IIIa
receptor antagonists
3. Dosing and
administration strategy
4. Clinical efficacy of high-bolus
dose tirofiban
5. Safety
6. Conclusion
7. Expert opinion

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Tirofiban
276 Expert Opin. Drug Metab. Toxicol. (2007) 3(2)
soluble agonists, such as thrombin, ADP and thromboxane
A2, causes conformational changes of the receptor with subse-quent
transformation from a low- into a high-affinity state,
allowing for ligand binding. This conformational change of
the receptor is not due to direct action of the agonists on the
receptor, but results from receptor-mediated stimulation of
intracellular signaling pathways that enhance ligand affinity.
GP IIb/IIIa antagonists are qualitatively different from classi-cal
antiplatelet agents, such as aspirin or clopidogrel. They do
not inhibit platelet activation (i.e., intraplatelet signal genera-tion
or conduction), but primarily act outside the platelet by
competing with ligand binding that is essential for platelet
bridging and aggregate formation [4].
2.1 Tirofiban
Tirofiban (L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidine-butyl)])
is a nonpeptide tyrosine derivative with a molecular
weight of 495 Da that is administered as an intravenous
infusion [5]. The volume of distribution is in the range of
21 – 87 l, and binding to human plasma proteins is modest at
64%. Metabolism in humans is negligible, and most drug
(.65%) is excreted renally with systemic clearance in the
range of 4.8 – 25.8 l/h. Renal function influences the excretion
of tirofiban and halving of the dose is recommended in
patients with creatinine clearance < 30 ml/min. Conversely,
concurrent disease or other drugs generally used in patients
affected by coronary artery disease do not seem to affect its
metabolism. The IC 50 value of tirofiban for inhibition of plate-let
aggregation is 0.011 µmol/l (5.45 µg/l) [6]. Following intra-venous
administration, tirofiban inhibits platelet aggregation
dose dependently, but dissociates rapidly from platelets and its
effect is reversed within 3 – 4 h after the end of infusion [6].
3. Dosing and administration strategy
Tirofiban has been tested in patients with ACS, administered
soon after hospital admission as part of the medical manage-ment
(upstream therapy) and at the time of PCI in patients
with stable and unstable coronary artery disease (downstream
therapy). The bolus regimen of tirofiban differed in the
upstream and downstream setting. For the upstream setting,
tirofiban was administered as 0.6 µg/kg of body weight/min
for 30 min in the Platelet Receptor Inhibition in Ischemic
Syndrome Management in Patients (PRISM) study [7] and
0.4 µg/kg/min for 30 min with heparin in the Platelet Recep-tor
Inhibition in Ischemic Syndrome Management in Patients
Limited by Unstable Signs and Symptoms (PRISM-PLUS) [8]
study. The tirofiban-only arm (without heparin) of the
PRISM-PLUS trial used a dose of 0.6 µg/kg, but was pre-maturely
stopped due to lack of efficacy. A total dose of
10 µg/kg, administered over 3 min, was used in the down-stream
setting in the Randomized Efficacy Study of Tirofiban
for Outcomes and Restenosis (RESTORE) [9] and in the Do
Tirofiban and ReoPro Give Similar Efficacy Outcomes
(TARGET) [10] trial. The PRISM study compared tirofiban
alone with heparin alone, and found a significant reduction in
the incidence of the composite primary end point of death,
MI, or refractory ischemia at 48 h in the tirofiban group [7],
and the PRISM-PLUS study showed that tirofiban with
heparin and aspirin was associated with a lower incidence of
ischemic events in patients with ACSs [8]. There was no bene-fit
with tirofiban alone in the PRISM-PLUS study [8]. Early
dose-finding studies of tirofiban did show > 85% ex vivo inhi-bition
of platelet aggregation by light transmission aggrego-metry
in response to a 10-µg/kg bolus plus a 0.15-µg/kg/min
infusion [11]. In the RESTORE trial, the primary composite
end point at 30 days was reduced from 12.2% in the placebo
group to 10.3% in the tirofiban group, a 16% relative reduc-tion
that was not statistically significant (p = 0.160). Thus,
the trial did not meet its primary end point at 30 days.
Nevertheless, the same bolus dose regimen was used in the
TARGET trial .
Despite a large body of evidence demonstrating improved
outcomes with the use of GP IIb/IIIa receptor inhibitors in
ACS patients undergoing PCI [7-9], head-to-head data among
the three available agents in this setting are lacking. In the only
comparative trial, the TARGET trial, the primary end point of
30 day composite end point of death, MI and urgent TVR was
significantly reduced with standard dose of abciximab
(0.25 µg/kg bolus and 0.125 µg/kg/min [maximum of
10 µg/min] infusion) compared with tirofiban (10 µg/kg bolus
followed by a 0.15 µg/kg/min infusion) in patients undergoing
PCI [10]. The lower incidence of adverse events was reflected,
in large part, by a reduction in periprocedural MI observed in
the first 12 – 24 h after PCI in the abciximab group. At 6- and
12-month follow up in the TARGET trial, tirofiban provided
a similar level of protection to abciximab against the composite
of death, MI and any target-vessel revascularization, but these
were secondary end points [12]. Mechanistic studies have sug-gested
that the reduced efficacy observed with tirofiban is
related to the inadequate platelet inhibition level achieved and
that a HBD of tirofiban (25 µg/kg) may be more clinically
effective. Accordingly, a study demonstrated that the inhibi-tion
of platelet function within 60 min of PCI was greater with
abciximab than with tirofiban given at the dose used in the
TARGET tri al [13], whereas other investigators showed that
after 2 h comparable inhibition of platelet function was
achieved with the two agents [14].
3.1 Platelet aggregation inhibition
On the base of these observations, recent mechanistic studies
have addressed higher doses of tirofiban in patients
undergoing PCI. Dose-finding studies demonstrated that a
25- µg/kg bolus plus the standard 0.15-µg/kg/min infusion of
tirofiban produced > 90% platelet inhibition by light trans-mission
aggregometry 15 – 60 min after the onset of treat-ment
[15]. Others have showed that the administration of the
same HBD of tirofiban was associated with a mean periproce-dural
level of platelet aggregation inhibition of > 80% [16].
Furthermore, comparable angiographic outcomes andMukherjee & Roffi
Expert Opin. Drug Metab. Toxicol. (2007) 3(2) 277
left-ventricular function recovery in ST-segment elevation MI
have been described with HBD tirofiban and abciximab
[16,17]. The prospective randomized Multicenter Registry of
High-Risk Percutaneous Coronary Intervention and Ade-quate
Platelet Inhibition (MR PCI) study was the first
head-to-head study comparing HBD tirofiban with dou-ble-
bolus eptifibatide and demonstrated greater platelet inhi-bition
with high-dose tirofiban compared with double-holus
eptifibatide (twice 180 µg/kg administration 10 min apart)
and standard infusion at 10 min and at 8 h [18].
4. Clinical efficacy of high-bolus dose tirofiban
Based on the suboptimal platelet inhibition detected after the
10-µg/kg-bolus regimen in ACS patients and improved inhi-bition
of platelet aggregation on subsequent dose-ranging
studies with HBD tirofiban, the tirofiban bolus dose was
raised from 10 to 25 µg/kg in the clinical setting, whereas the
infusion dosing, which demonstrated a good safety profile in
all previous clinical experience, remained unchanged. One
observational study reported that HBD tirofiban, followed by
0.15 µg/kg infusion, was well tolerated and resulted in no
excess of bleeding complications among 133 patients under-going
PCI [19]. The same investigators addressed safety and
efficacy of HBD tirofiban in 274 patients undergoing PCI
with HBD and found comparable results to a historical
cohort of abciximab-treated patients [20].
In the double-blind, placebo-controlled The Additive Value
of Tirofiban Administered With the High-Dose Bolus in the
Prevention of Ischemic Complications During High-Risk Coro-nary
Artery Angioplasty (ADVANCE) trial, 202 consecutive
patients pretreated with thienopyridines undergoing high-risk
PCI were randomized to HBD tirofiban or placebo immediately
before the procedure and then followed for a median time of
6 months for the occurrence of primary composite end point
(death, MI, TVR, and bailout use of GP IIb/IIIa inhibitors) [21].
The cumulative incidence of the primary end point was 35 and
20% in placebo and HBD tirofiban groups, respectively (hazard
ratio [HR]: 0.51; 95% confidence interval [CI]: 0.29 – 0.88;
p = 0.01). This difference was mainly due to the reduction of
MI and bailout use of GP IIb/IIIa inhibitors, with no significant
effect on TVR or death. The safety profile did not differ
between tirofiban and placebo. Importantly, the beneficial effect
of tirofiban was additive to thienopyridines and was consistent
across the whole spectrum of patients enrolled, with those
affected by ACS or diabetes showing a relatively greater benefit
from therapy. Again in the setting of ACS, there was no differ-ence
in 6-month MACE rates between HBD tirofiban and
abciximab among 229 non-randomized consecutive patients
undergoing early invasive strategy [22], and in the Randomized
Comparison of Upstream Tirofiban Versus Downstream High
Bolus Dose Tirofiban or Abciximab on Tissue-Level Perfusion
and Troponin Release in High-Risk Acute Coronary Syndromes
Treated With Percutaneous Coronary Interventions
(EVEREST) trial, tissue-level perfusion and extent myocardial
salvage were comparable in patients randomized to either HBD
tirofiban or abciximab (n = 61) [23].
With respect to acute MI and emergent coronary inter-vention
in this setting (primary PCI), Danzi et al. have
recently published the first head-to-head comparison between
HBD tirofiban and abciximab [17]. Abciximab, by virtue of its
salutary effect on tissue perfusion and coronary artery pat-ency,
is part of the recommended treatment strategy in acute
MI patients. In the study, 100 patients were randomized to
receive standard dose of abciximab or HBD tirofiban. The
end points, namely the change in infarct-zone wall motion
score index and left-ventricular ejection fraction at 30 days on
echocardiography, did not differ among the two groups. In
addition, in the HBD tirofiban group no major bleeding or
severe thrombocytopenia were observed and there was no
need for red blood cell transfusions.
One study addressed, in a randomized fashion, the efficacy
in terms of platelet-aggregation inhibition of four different
antiplatelet regimens in 112 patients with acute MI under-going
primary PCI [16]. The study showed that the mean
periprocedural platelet aggregation inhibition exceeded 80%
only in the HBD tirofiban group, further supporting the
appropriateness of the revised bolus dose of tirofiban also in
the primary PCI setting.
A strategy of HBD tirofiban-supported drug-eluting stent
implantation to abciximab plus bare-metal stent implantation
was compared among 175 patients undergoing primary PCI for
acute MI in terms of angiographic and clinical outcomes in the
High-Dose Bolus Tirofiban and Sirolimus Eluting Stent versus
Abiciximab and Bare Metal Stent in Acute Myocardial Infarc-tion
(STRATEGY) trial [24]. The investigators concluded that a
strategy of tirofiban-supported drug-eluting stent implantation
during primary PCI was safe and resulted in improved clinical
(decreased need for TVR) and angiographic (decreased resteno-sis
rate) outcomes compared with a strategy of abciximab-sup-ported
bare-metal stent implantation. Moreover, the HBD
tirofiban group had less thrombocytopenia. The cumulative
incidence of 8-month MACE (death, MI or TVR) was signifi-cantly
lower in the HBD tirofiban drug-eluting stent group than
in the abciximab bare-metal stent group (18 versus 32%, respec-tively;
HR: 0.53; 95% CI: 0.28 – 0.92; p = 0.043). The
composite end point of death/MI was similar in the two groups
(13 and 17%, respectively), but there was a significant reduction
in the HBD tirofiban drug-eluting stent group in the need for
TVR (7 and 20%, respectively; HR: 0.30; 95% CI: 0.12 – 0.77;
p = 0.01). However, much of the benefit in terms of MACE
reduction observed in the HBD tirofiban drug-eluting stent
groups was derived by the reduction in TVR expected with
drug-eluting stents and can, therefore, not be used to support
the HBD strategy. Markers of reperfusion, such as thrombolysis
in myocardial infarction (TIMI) flow patterns and cumulative
ST-segment resolution on echocardiogram, did not differ
between treatment arms, further supporting HBD tirofiban as
alternative GP IIb/IIIa antagonist to the current ‘gold standard’
abciximab in the setting of acute MI. The differential effects ofTirofiban
278 Expert Opin. Drug Metab. Toxicol. (2007) 3(2)
GP IIb/IIIa receptor inhibitors (HBD tirofiban versus abcixi-mab)
and stent types (bare-metal versus drug-eluting) is being
tested in the Multicentre 2x2 Factorial Randomised Study Com-paring
Tirofiban Administered With the Single High-Dose
Bolus Versus Abciximab and Sirolimus Eluting Stent Versus Bare
Metal Stent in Acute Myocardial Infarction (MULTI-STRAT-EGY)
trial, a multicenter, 2×2 factorial, randomized study
enrollling 600 patients with acute MI undergoing primary PCI.
The Tirofiban Evaluation of Novel Dosing versus Abcixi-mab
with Clopidogrel and Inhibition of Thrombin (TENA-CITY)
trial was designed to prospectively compare clinical
outcomes between HBD tirofiban and abciximab in > 4000
patients undergoing PCI, but was terminated prematurely
after enrolling 383 patients due to lack of funding [25]. This
was the only trial powered to address clinical equivalence
between the two GP IIb/IIIa receptor inhibitors. An analysis
of the available data showed no differences between HBD
tirofiban and abciximab (Tabl e 1 ) [25].
A meta-analysis of the available data suggested that HBD
tirofiban may be as effective as abciximab in patients under-going
PCI with a comparable safety profile [26]. The primary
end point in the analysis was the composite of death, MI and
urgent TVR at 30 days. Major and minor bleeding and the
incidence of thrombocytopenia were also assessed. A total of
1392 patients (689 allocated to tirofiban, 703 randomized to
abciximab) were included. The incidence of the combined
end point was 6.1% with HBD tirofiban and 7.3% with
abciximab (p = 0.46). There were also no differences between
the two groups in the individual end points of death, MI,
TVR, major or minor bleeding, or thrombocytopenia.
5. Safety
The most serious and frequent adverse effect related to the use
of GP IIb/IIIa receptor antagonists are bleedings and
thrombocytopenia. Risk of bleeding can be reduced by the use
of low-dose adjunctive unfractionated heparin, early sheath
removal and meticulous postprocedure care. In studies involv-ing
tirofiban, the incidence of any bleeding complications was
more frequent than heparin alone, but major bleeding com-plications
were not significantly different. Most of the
increases in bleeding occurred in patients who underwent
diagnostic catheterization or PCI, primarily at the femoral
artery access site. The incidence of thrombocytopenia,
defined as an absolute platelet count < 90,000/mm 3 , was
0.4% in PRISM and 1.9% in PRISM-PLUS trials. As a com-parison,
in patients receiving abciximab, the incidence of mild
thrombocytopenia (< 100,000/mm 3 ) is known to be in the
range 2.6 – 5.6%, whereas that of severe thrombocytopenia
(< 20,000/mm 3 ) is .0.1 – 0.5% of patients. In the TARGET
trial, there was no difference in terms of major bleeding
between the two study drugs, whereas minor bleeding and
thrombocytopenia were both lower in the tirofiban group [10].
In the STRATEGY trial, the use of tirofiban was associated
with a trend towards lower bleeding and to a statistically sig-nificant
reduction in the incidence of thrombocytopenia as
compared to abciximab, which suggests that increasing the
bolus dose of the drug, but not the infusion rate, has no or
negligible effect on the safety profile of the drug [24]. However,
the safety of the HBD tirofiban needs to be further tested in
larger, prospective trials. Importantly, HBD tirofiban has not
been tested in patients with renal insufficiency. For patients
with creatinine clearance < 30 ml/min, both in the upstream
and in the downstream setting, it is recommended to halve
the dose of the standard bolus and of the infusion.
6. Conclusion
Based on the available data, in patients undergoing PCI both
in the setting of stable and unstable coronary artery disease,
the use of HBD tirofiban (25-µg/kg bolus plus a
0.15-µg/kg/min infusion) appears to convey similar outcomes
Table 1. HBD tirofiban versus abciximab use or placebo in randomized studies.
Trials Population study Design Key information
ADVANCE [21] 202 high-risk patients undergoing
PCI
HBD tirofiban versus placebo Reduction of ischemic/thrombotic
complications
Danzi et al. [17] 100 STEMI treated with primary PCI HBD tirofiban versus abciximab Similar effects on angiographic results
and in the left-ventricular function
recovery
STRATEGY [24] 175 STEMI treated with primary PCI HBD tirofiban plus drug-eluting
stent versus abciximab plus
bare-metal stent
Similar effect and bleeding rate, but less
thrombocytopenia in the tirofiban group
EVEREST [23] 93 high-risk ACS patients
undergoing PCI
HBD tirofiban versus
standard-dose tirofiban versus
abciximab
Similar tissue-level perfusion and
myocardial salvage
TENACITY [25] 383 patients undergoing PCI HBD tirofiban versus abciximab Comparable safety and efficacy, but
underpowered
ACS: Acute coronary syndromes; HBD: High-bolus dose; PCI: Percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction. Mukherjee & Roffi
Expert Opin. Drug Metab. Toxicol. (2007) 3(2) 279
to standard-dose abciximab, with a comparable safety profile
and at lower costs. However, the short follow up and limited
sample size of the studies performed thus far do not allow for
established clinical equivalence. To that purpose, an
adequately powered randomized trial is needed.
7. Expert opinion
The data discussed herein suggest that HBD tirofiban effec-tively
inhibits platelet aggregation and appears at least equiva-lent
in efficacy to abciximab and double-bolus eptifibatide.
Despite lack of adequately powered, randomized, comparative
data, many clinicians are already using HBD tirofiban as
adjunct to PCI based on preclinical mechanistic data and
available clinical data. Although a meta-analysis of
.800 patients demonstrated no significant differences in
efficacy between HBD tirofiban and abciximab, adequately
powered, randomized clinical trials would provide more
definitive evidence. Furthermore, the landscape for optimal
antithrombotic therapy in the setting of PCI and ACS is rap-idly
changing with the introduction of newer agents, such as
bivalirudin and fondaparinux, and any incremental benefits of
GP IIb/IIIa inhibitors on top of these agents will need to be
reassessed in the future.
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Affiliation
Debabrata Mukherjee †1 MD &
Marco Roffi 2 MD
† Author for correspondence
1 Gill Heart Institute, University of Kentucky,
326 Wethington Bldg, 900 S. Limestone,
Lexington, Kentucky 40436-0200, USA
Tel: [phone]; Fax: [phone];
E-mail: [e-mail]
2 University Hospital, Department of Cardiology,
Zurich, Switzerland