Efficacy and safety of the platelet glycoprotein IIb/IIIa inhibitors in acute
coronary syndromes: a meta-analysis
Bento M., Borges M., Brandão M., Figueiredo L., Jácome J., Neves J., Oliveira M., Sousa L.,
Sousa M., Vilaça M.
Biostatistics and Medical Informatics Department of Medicine Faculty of Porto University
Abstract
Background: Several studies have strengthened the benefits of glycoprotein IIb/IIIa
(GPIIb/IIIa) inhibitors in the prevention of platelet aggregation, characteristic of acute coronary
syndromes (ACSs). However, many questions related to the efficacy and safety of these agents
are still raised. Objectives: Study the efficacy and safety of platelet GPIIb/IIIa inhibitors in
ACSs. Methods: The selected studies correspond to randomised clinical trials with an enrolment
of at least 500 patients who presented ACSs without persistent ST elevation, comparing the
GPIIb/IIIa inhibitors with placebo or control therapy. Trials with patients recommended to
percutaneous coronary intervention during study-drug infusion were excluded. Results: In 49316
patients, the use of GPIIb/IIIa inhibitors in conservative treatment strategies showed a 3% OR
reduction of death or myocardial infarction (MI) at 30 days (IC 95% 0.91 to 1.03) with no
statistic significance and no significant between-study heterogeneity. There is significant
evidence of increased risk of major bleeding (OR 1.32 [IC95% 1.19 to 1.46]) and minor bleeding
(OR 1.89 [IC95% 1.75 a 2.05]). The analysis of categories favours significantly the intravenous
inhibitors (OR of death and MI at 30 days of 0.92 [IC95% 0.86 to 0.99]). Oral inhibitors not only
increase this incidence (OR 1,12 [IC95% 0.98 to 1.27]), but also that of major (OR 1.51 [IC95%
1.27 to 1.81) and minor bleeding (OR 1.92 [IC95% 1.75 to 2.12]). In diabetic patients, mortality
or MI at 30 days was significantly reduced in 26% (OR 0.74 [IC95% 0.59 to 0.92]) by
intravenous inhibitors. Conclusion: Although intravenous GPIIb/IIIa inhibitors present
advantages preventing ACSs, these drugs are, globally, less safe and apparently less effective
than conventional therapies.
Introduction
The ACSs (Acute Coronary Syndromes), like myocardial infarction (MI), which results
from the atherosclerosis plaque disruption, promote the formation of thrombus by platelet
aggregation [1]. The platelet activation leads to a conformational change in the platelet
glycoproteins IIb/IIIa (GPIIb/IIIa) receptors on the platelet surface, which increases the receptors
affinity to fibrogen and others compounds and, consequently, promotes the platelet aggregation.
In pathological situations, this platelet aggregation can be the responsible for the thrombus
formation. Nevertheless, the GPIIb/IIIa receptors activation is the final common ending for more
than 100 different pathways of platelet aggregation [2]. There are two spots of GPIIb/IIIa union,
one of them is the amino acid sequence Arginine – Glycine - Aspartic acid, called the RGD
sequence. The GPIIb/IIIa inhibitors are drugs that bind the platelet receptors for GPIIb/IIIa and
inhibit the platelet aggregation. In this way, these drugs inhibit the thrombus formation in
patients who undergo percutaneous coronary intervention (PCI) protecting them from
myocardial infarction and death [3].
The GPIIb/IIIa inhibitors can be classified in four different groups according to their
pathway of action. The first group contains the drug abciximab, a monoclonal chimerical
antibody that acts in an irreversible way. The peptidic inhibitors (or integrilins) like eptifibatide,
a cycle heptapeptide with a KGD sequence (Lysine – Glycine – Asparagine), interact with the
RGD sequence referred above. The third family of inhibitors considered in the study is the
nonpeptidic group, including tirofiban and lamifiban [4]. The oral GPIIb/IIIa are considered to
be “pre-drugs”, because are only activated when administrated to patients (orofiban,
xemilofiban, sibrafiban, roxifiban, ledrafiban…) [5]. In a general way, the GPIIb/IIIa can be
distinguished, according to their way of administration, in oral and intravenous drugs [6]. The
efficiency of these drugs is evaluated in placebo/control trials, being the placebo aspirin or other
drug from the anticoagulants family usually used in the conventional therapy. This family
includes the anticoagulants which need co-factors and those that act directly over the thrombus.
The first has two subgroups: the non-fractioned heparins (they are administrated intravenously
and reduce, in a significant manner, the occurrence of death, myocardial infarction and acute
refractory angina, belonging such beneficial action only between the 30 and 90 days – heparin)
and the low-molecular weight heparins (dalteparin and enoxaparin) with a longer life expected
and a bigger biodisponibility. The direct inhibitors of the thrombus are a group of drugs which
act either in a free state, either connected to the thrombus, without needing a cofactor, although
several of them, as hirudin, have an higher molecular weight than heparin [7].
Previous clinical trials have showed that the GPIIb/IIIa inhibitors, compared with placebo
and/or control therapeutic, reduced the frequency of the infarction in 38% [8].
We sought to realize a systematic revision with the primary objective of analysing the
effect of the GPIIb/IIIa inhibitors based in randomised clinical trials.
Methods
I. Selection and description of the studies
1. Bibliographical research
We proceeded to a research whose target population corresponded to MEDLINE
catalogued randomized clinical trials. It was used the query: ("Platelet Aggregation
Inhibitors"[MeSH] AND "Platelet Glycoprotein GPIIb-IIIa Complex"[MeSH]) AND (("Angina,
Unstable"[MeSH] OR "Myocardial Infarction"[MeSH] OR "Myocardial Ischemia"[MeSH]) OR
"acute coronary syndromes"), considering as limits "Randomized Controlled Trials" and
"Humans" in order to get articles that explored the function of platelet GPIIb/IIIa inhibitors in
acute coronary syndromes. The term "acute coronary syndrome" is relatively recent, from that
the use of the disjunction of this word-key with its specifications. A total of 162 articles was
obtained.
2. Systematic revision of the studies
These articles were divided by 2 groups of revisers. With the application of previously
defined exclusion and inclusion criteria, 8 articles were considered valid.
a) Exclusion criteria
Studies that did not evaluate the effectiveness of GPIIb/IIIa inhibitors were rejected,
since its acceptance would violate the primary objective inherent to this systematic revision.
Also, the studies whose patients were recommended for surgery of precocious revascularization
were ignored as well the studies that compared conservative strategies with interventive ones. In
these cases, the use of inhibitors is total dependent of a revascularisation intervention, which
could never, for the pointed reasons, be considered a primary endpoint in this systematic
revision. The studies with less than 500 patients were also rejected, in order to guarantee an
higher generalization reliability.
b) Inclusion criteria
The selection of studies was processed through the choice of randomized clinical trials
whose patients had non-ST segment elevation acute coronary syndromes. When such happens,
the patient immediately is recommended for revascularisation due to the seriousness of the
situation. It also interested the comparison of the GPIIb/IIIa inhibitors with placebo or with
control therapy.
c) Quality analysis of the studies
To evaluate the quality of the studies it was used a system of classification for
experimental studies [10]. This evaluation of quality had in account some criteria, namely the
sample formation, the baseline differences and its adjustment, the unit of allocation, the outcome
measures and the follow up rate. All of the 8 studies selected held the indispensable requirements
to proceed to its integration in a meta-analysis.
d) Agreement
It was used a test for the evaluation of agreement (Cohen Kappa agreement test – 1960)
to study this property between the choices of different revisers. As two groups of article revisers
were formed, this analysis was made separately for the 2 groups. The obtained results were: 0,74
for first group and 0,46 for the second one. Based on the conclusions of Landis and Koch (1977),
we may classify these agreements, respectively, as substantial and moderate.
II. Data management
1. Definition of variables
We considered individuals’ variables, potentially useful in the evaluation of outcomes,
such as: age, sex, weight, arterial pressure, cholesterol levels, cardiac antecedents and cardiac
medication. We also defined variables related to clinical trials like their primary endpoints, the
study drug, its type and the number of patients.
2. Definitions of efficacy (primary) and safety (secondary) endpoints
Endpoints (variables used to evaluate the therapy’s effectiveness) may be classified as
efficacy endpoints (the therapy is interrupted due to unequivocal disadvantages compared to
placebo) or security endpoints (impossibility of proceeding the study because the therapy is
inappropriate for the study or due to changes in the study conditions). As efficacy endpoint we
considered “death or myocardial infarction at 30 days”. On the other hand, safety endpoints
include various types of complications, namely “bleeding”. Both major and minor haemorrhages
are defined by the TIMI criteria [9]. Blood transfusion (made when necessary) and situations in
which platelet counting is less than 50000/mm3 of blood were also defined as safety endpoints.
3. Making a database
Data of the selected studies was compiled in a database, using “SPSS 12.0 for Windows”
software.
III Statistical analysis
1. Meta-analysis
Included studies were similar, this is, the sample, the intervention and clinical outcomes
were uniform, which made possible the meta-analysis. So, using Review Manager 4.2.3 software
(RevMan 4.2), we made appropriated statistical calculations of the odds ratio (OR) and the
confidence interval at 95% (95% CI) of many variables, which we considered important for
analysis. We also used tests of heterogeneity to evaluate the validity of generalizations.
In these analysis, a significance level of 0,05 was always considered.
Results
1. Characteristics of patients
The 8 selected studies included 49316 patients (29744 in the experimental group and
19579 in the control group). The average population age was 64,5 years old, while 68 % were
men and 21% were diabetic (Table 1).
2. Efficacy endpoints
At 30 days, the number of patients that died or suffered myocardial infarction in the
experimental group were 2545 (8,6 %) and 1894 (9,8 %) in the control one. However, difference
is not statistically significant (p=0,31). In order to determine if there was, in this result,
interference from one or more discrepant studies, a heterogeneity test was applied (p=0,12). No
significant heterogeneity among studies was found (Figure 1).
A comparison among different groups and classes of inhibitors was carried out, as far as
the same variable is concerned. The only GP IIb/IIIa inhibitors category with relevant statistical
difference between placebo and inhibitors is the peptidic one (p=0,04). Only the difference
between non-peptidic and oral inhibitors was considered significant (p=0,03), as treatment with
non-peptidic inhibitors is better than control therapy.
Intravenous and oral GP IIb/IIIa inhibitors were compared (p=0,002). Moreover, the
administration of intravenous inhibitors is significantly more favourable than control therapy
(p=0,03 for OR 0,92 [IC95% 0,86 to 0,99]), oppositely to oral inhibitors which, although there is
no statistically relevant difference between placebo and inhibitor (p=0,09), seem clinically less
effective.
3. Safety endpoints
Glycoproteins IIb/IIIa inhibitors intake is associated with added risk of major and minor
bleeding, when compared with the control group (Figure 3) (p<0,0001, for any case). Both
bleeding major and minor present homogeneous groups. We can view the odds ratio and
confidence interval for 95%, to all considered safety endpoints (Table 2).
In this matter, bleeding is less frequent with conventional therapy rather than the
inhibitor, for all cases (OR>1), but only in a significant manner for oral and peptidic inhibitors.
For intravenous ones, there is a significant increase in the incidence of major (OR 1,21
[1,07 to 1,38]) and minor bleeding (OR 1,78 [1,56 to 2,03]).
There were also verified significant differences between oral and peptidic inhibitors
relatively to major haemorrhage were verified (p=0,02). Their OR and IC95% are 1,52 [1,27 to
1,82] and 1,19 [1,03 to 1,36], respectively.
Considering minor haemorrhage, we could only verify significant difference between oral
and non-peptidic (p=0,02), and between peptidic and non-peptidic (p=0,03).
The difference related to platelet concentration inferior to 50000/mm³ for oral class is
statistically relevant (p=0,03; OR 1,83 [IC95% 1,07 to 3,13]). Patients that undergone treatment
with placebo required less blood transfusion (p<0,001; OR 1,44 [IC95% 1,22 to 1,70]), when
compared to those that used inhibitor.
4. Treatment effects on subgroups
Diabetic patients analysis revealed a significant difference (p=0,007;OR 0,74 [IC95%
0,59 to 0,92]) (Figure 4). This variation was not verified for non-diabetic patients (p=0,99). This
was confirmed by the relevant statistically difference between the effects of inhibitors in diabetic
and non-diabetic patients (p=0,03). Apparently, inhibitors are beneficial for diabetic patients, but
that does not happen for non-diabetic ones.
Discussion
Considering our primordial objective, it was verified that the GPIIb/IIIa inhibitors don’t
show, in their all, significant advantages facing conventional therapy. Indeed, it is suggested a
light benefit of these (Fig. 1) in death or myocardial infarction at 30 days. The use of these
agents is translated in a significant raise of major (1,32 times) and minor (1,89 times)
haemorrhage.
The analysis of intravenous inhibitors let us conclude that these are more efficient than
conventional therapeutics (p=0,03), since there is a significant reduction of OR in 8%. However,
we must underline the raise of the bleeding rate (21% to major and 78% to minor) when
compared with placebo, although safety endpoint OR determination does not carry the
monoclonal antibodies.
Other studies revealed that the intravenous inhibitors used after PCI (Percutaneous
Coronary Intervention) drop the risk of death in 20 to 30%. In fact, this effect is more significant
at short term (30 days) that at 6 months or superior periods [18].
The comparison between inhibitors families showed more relevant conclusions: at first,
the use of peptidic inhibitors is really more effective than usual therapy, due to a reduction of
death or MI incidence at 30 days by 11%; however, patients treated with these drugs show a
significant raise of bleeding than the respective controls (19% raise for major and 85% for
minor). In counterpoint, it is important to note that monoclonal antibodies reveal disadvantages
(only apparent: p=0.36) fighting ACS.
Abciximab was the first inhibitor to be used. The first clinical trials about its effect in
humans gave an idea about the importance for ACS treatment. GUSTO-IV ACS, the first study
of considerable dimensions with posthumous following of the participants, suggested that these
inhibitors could not be so advantageous in the ACS treatment as it should be expected (Fig. 5)
Oral inhibitors proved to be those who have more disadvantages relatively to the control:
they don’t show a significant grow of 30 days death or MI (p=0.09). Furthermore, there is a
considerable increase in the incidence of primary endpoints in those patients who were treated
with this kind of inhibitors (1,12 [0,98; 1,28]). They also promote an higher incidence of major
(51%) and minor bleeding (92%). In fact, the comparison between these and the intravenous
inhibitors significantly favours the last ones, in efficacy (p=0,002) and safety (major
haemorrhage – p=0,009). The patients treated with oral inhibitors also showed a platelet number
lesser than 50.000 for mm3 significantly inferior to the respective control, which is due probably
to collateral effects of this kind of administration in some metabolic pathways. Although, other
studies demonstrated that the oral inhibitors use promotes the reduction of PCI, and at the same
time, stimulate mortality [19]. So, it is comprehensible the disuse of these drugs, in exchange for
intravenous inhibitors.
Curiously the studies that test non peptidic inhibitors (PRISM), show different results
than all the other trials, as it is underlined the efficiency and mainly their safety, being the safest
class of inhibitors. The comparison between both groups of participants is the only non
significant achievement.
The results obtained (Fig. 4) are very promising for diabetic patients. Despite being
included exclusively the trials using intravenous inhibitors, their use in these patients reflects a
26% decrease in the primary endpoint. So, it is understandable that, although they are undeniably
a risk group, are recommended to inhibitors’ administration in detriment of usual therapeutics.
Certain studies that have analyzed this relative inhibitors advantage conclude that, in fact, the
presence of inhibitors GP IIb/IIIa significantly reduce the platelet activation which stimulate the
ACS in diabetic patients (p=0,02), proposing that the decreased connection between fibrinogen
to platelets is due to the platelet membrane proteins glication which, by the way, is greater in
diabetic patients than in those who do not have this pathology. [21]
Limitations
This review was submitted to several methodological and statistical limitations. At first,
the limitations related with the bibliographic search were due not only to the task of defining a
good query, but also to the non-cataloguing of all eligible trials at MEDLINE. On other hand, at
statistic level, for example, PRISM study considers both primary endpoints at 48 hours after
randomisation, while PRISM-PLUS considers them at 7 days (although every event is referred at
30 days). Furthermore, some endpoints were not conveniently referred in all clinical trials.
Consequently, the results obtained from each study are, in some way, very rigid, as the fact of
considering exclusively “death and MI at 30 days” as primary endpoint conditioned the
possibility of making temporal assumptions related to the effect of platelet GPIIb/IIIa at short,
medium and long term. In fact, other reviews [20], by considering the primary endpoints at
different times, are able to preview the dynamic effect of GPIIb/IIIa inhibitors: for example, it is
noteworthy that tirofiban (non-peptidic inhibitor used in PRISM) favour treatment at 30 days,
but does not between 48 a 96 hours after randomisation. Despite being less clear, the opposite is
verified with lamifiban in PARAGON and with eptifibatide in PURSUIT (Fig 6).
On other hand, the heterogeneity between protocols, therapeutic agents, regimes and
population limited the inferential ability of this review, as it was confirmed with heterogeneity
tests which led us to make other kind of statistic analysis. In subgroup analysis, the trials were
not designed to evaluate the potential benefits of these drugs in diabetic patients, although some
information has been acquired.
The results allow us to state that the clinical application of platelet GPIIb/IIIa inhibitors
is, generally, uncertain when compared with conventional therapeutics. However, this reality is
conditioned by the inclusion of several studies with patients submitted to oral inhibitors, since
previous studies with no administration of such family of inhibitors have shown that GPIIb/IIIa
inhibitors are significantly favoured, decreasing in 9% the mortality and MI at 30 days [3]. So,
the administration of certain intravenous categories of inhibitors like peptidics or non-peptidics
and specifically of intravenous inhibitors in diabetic patients reveals as a promissory method in
the combat of disruption of atherosclerotic plaque that leads to ACSs. In face of this, it may be
said that the primary aim of this review was accomplished.
References
1 The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary
syndromes. The New England Journal of Medicine. 1998 Aug 13; 339(7): 436-43
2 Chanu B. Inhibitors of GP IIb/IIIa platelet receptors. Arch Mal Couer Vaiss. 1999; 92(7):893-902
3 Boersman E et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major
randomised clinical trials. Lancet. 2002 Jan 19; 359:189-98
4 Sebastian M, Makkar R . Glycoprotein IIb/IIIa receptor antagonists: clinical pharmacology in cardiovascular diseases of aging.
Drugs Aging. 1999; 15(3):207-18
5 Reimann JD et al. Pharmacokinets and Pharmacodynamics of Sibrafiban, an Orally Administered GP IIb/IIIa Antagonist,
following Coadministration of Aspirin and Heparin. J Clin Pharmacol. 2000; 40:488-495
6 Roe MT, Moliterno JD. Emerging Tratment of Acute Coronary Syndromes with Platelet Glycoprotein IIb/IIIa Inhibitors.
Journal of Thrombosis and Thrombolysis. 1999; 7:247-57
7 Cohen M. New therapies for unstable angina and non-Q-wave myocardial infarction: recent clinical trials. Am Heart J. 1998
Jun; 135:343-52
8 Kang DF, Calliff, RM et al. Clinical outcomes of therapeutic agents that block the platelet glycoproteins IIb/IIIa integrin in
ischemic heart disease. Circulation. 1998:2829-35
9 Chesebro JH et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue
plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation. 1987; 76:142-54
10 Mitchell E, Sullivan F. A descriptive feast but an evaluative famine: systematic review of published articles on primary care
computing during 1980-97. Information in practise. 2001;322: 279-282
11 The PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. Platelet
Receptor Inhibition in Ischemic Syndrome Management. N Engl J Med. 1998 May 21; 338:1498-505
12 The PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in Unstable
Angina and non Q-wave Miocardial Infarction. Platelet Receptor Inhibition In Ischemic Syndrome Management in Patients
Limited by Unstable Signs and Symptoms. N Engl J Med. 1998 May 21; 338:1488-97
13 The PARAGON Investigators. International, Randomized, Controlled Trial of Lamifiban (a Platelet Glycoprotein IIb/IIIa
Inhibitor), Heparin, or Both in Unstable Angina. Circulation. 1998; 97:2386-95
14 The OPUS-TIMI 16 Trial Investigators. Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Pacients With Unstable
Coronary Syndromes. Circulation. 2000 Jul 11; 102:149-56
15 The SYMPHONY Investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute
coronary syndromes: a randomised trial. Lancet. 2000 Jan 29; 355:337–345.
16 The GUSTO-IV ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in pacients with
acute coronary syndromes without early coronary revascularization. Lancet. 2001 Jun 16; 357:1915-24
17 The PARAGON-B Investigators. Randomized, placebo controlled trial of titrated intravenous lamifiban for acute coronary
syndromes. The Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome in a Global Organization Network.
Circulation. 2002 Jan 22; 105:316-21
18 Karvouni E et al. Intravenous Glycoprotein IIb/IIIa Receptor Antagonists Reduce Mortality After Percutaneous Coronary
Interventions. Journal of the American College of Cardiology. 2003 Jan 1; 41(1):26-32
19 Chew D et al. Increased Mortality With Oral Platelet Glycoprotein IIb/IIIa Antagonists – A Meta-analysis of Phase III
Multicenter Randomized Trials. Circulation. 2001 Jan 16; 103:201-206
20 Kong D et al. Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic
Heart Disease. Circulation. 1998 Dec 22/29; 98: 2829-35
21 Keating FK et al. Augmentation of inhibitory effects of glycoprotein IIb/IIIa antagonists in patients with diabetes. Thromb
Res. 2004; 113(1):27-34
Figure 1 – Death or MI at 30 days
Figure 2 – Death or MI at 30 days for each class of inhibitor
Figure 3 – Major bleeding (down) and minor for each clinical trial.
Figure 4 – Death or MI at 30 days in diabetic patients.
Figure 5 – Death or MI at 30 days for studies that
use the monoclonal antibody abciximab (in 16).
Figure 6 – OR and CI95% for risk of death between 48 and 96 hours after randomization of inhibitors vs. placebo (at left)
and at 30 days (in 20).
Nonpeptidics
Peptidics
Orals
OR [IC 95%] (Major
bleeding)
1.47 [0.99, 2.17]
OR [IC 95%] (Minor
bleeding)
1.03 [0.63, 1.70]
1.19 [1.03, 1.36]
1.85 [1.61, 2.13]
1.52 [1.27, 1.82]
1.95 [1.77, 2.15]
Table 2 – OR and CI 95% for all secondary endpoints (Inhibitor vs. Control)
OR [IC 95%]
(platelet)
2.54 [0.80, 8.12]
OR [IC 95%]
(transfusion)
1.57 [1.19, 2.07]
------------- ------------------------- ------------1.84 [1.07, 3.14] 1.37 [1.11, 1.69]