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Acute Coronary Syndromes
In the last few years, growing interest has focused on the role of distal Reperfusion AlternatiVes Evaluation (BRAVE-3) trial
83
showed no
embolisation as a major determinant of poor reperfusion. Based on the benefits in infarct size and 30-day mortality when a clopidogrel-loading
histological analysis of retrieved debris, the Enhanced Myocardial dose of 600mg was administered. Keeping in mind the relationship
Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) between the risk profile and mortality benefits from abciximab
trial
34
showed visible debris in 78% of patients. Henriques et al.
35
administration, it could be claimed that the absence of benefits would
reported that the incidence of angiographically detectable distal have been expected in a population with the mortality lower than 3%,
embolisation was 16%, and this was associated with poor reperfusion, as observed in the BRAVE-3 trial.
83
larger infarct size and unfavourable five-year survival compared with
patients without angiographic signs of distal embolisation. Limited data have been reported on eptifibatide and tirofiban.
82,84–88
Steen
et al.
82
did show in a small randomised trial (53 patients) significantly
Inter-individual Variability in the Response to improved epicardial and myocardial perfusion by adjunctive tirofiban. In
Conventional Antiplatelet Therapies the randomised Zwolle study,
84
the data showed that high-dose tirofiban
High inter-individual variability in response to antiplatelet therapies has was associated with better platelet inhibition compared with abciximab
been demonstrated.
36–42
The percentage of non-responders ranges or a standard dose of tirofiban. In the STRATEGY trial,
86
no difference in
between 5 and 50% (according to different laboratory tests) for aspirin death and/or re-infarction was observed between high-dose tirofiban
and between 20 and 30% for clopidogrel.
36–42
Several mechanisms have and abciximab. Data from the Multi-STRATEGY trial
87
have shown a
been proposed.
43–58
The question of the optimal pharmacological therapy similar outcome (non-inferiority) between tirofiban and abciximab in 745
for reperfusion before and in conjunction with primary PCI, especially STEMI patients undergoing primary angioplasty, and no difference in
when there is a delay in the initiation of therapy, remains unanswered. major bleeding complications. In the eptifibatide versus abciximab in
Fibrinolytic therapy alone was found to be harmful among patients in primary PCI for acute ST elevation MI (EVA-AMI) trial,
88
400 STEMI
the Assessment of the Safety and Efficacy of a New Treatment Strategy patients were randomly assigned to peri-procedural administration of
with PCI (ASSENT-4 PCI) trial, possibly owing to the deleterious effects of eptifibatide or abciximab, with a similar outcome between the two
early activation of platelets by the fibrinolytic agents without effective molecules. The major limitation of the study is that the primary end-point
antiplatelet treatment or plaque haemorrhage at the time of PCI. GPIs (ST resolution at 60–90 minutes) was available in only 50% of patients.
alone, and especially in conjunction with fibrinolytic therapy, have been
evaluated in relatively small numbers of patients. The results of these Further benefits may be expected by adjunctive intracoronary
studies have been inconclusive,
59–64
although there is evidence of an administration of GPIs. A small randomised trial
89
showed that selective
increase in major bleeding, particularly among the elderly.
65
intracoronary administration of abciximab distally to the occlusion
(through an over-the-wire balloon) was associated with a significant
Bleeding Complications improvement in myocardial perfusion and smaller infarct size.
Aggressive antithrombotic therapy carries a risk of bleeding and blood
transfusion. Although the true incidence of bleeding depends on the Pharmacological Facilitation
population studied (i.e. clinical trial versus registry) and the definition Several randomised trials have been conducted to evaluate the
used,
66,67
it is clear that bleeding is associated with an increased risk of benefits of early GPI administration in patients undergoing primary
adverse outcomes including MI and death.
66,68
Therefore, therapies that angioplasty.
60,77,91–101
In the ongoing tirofiban in MI evaluation (On-TIME)
provide an adequate level of anticoagulation to reduce ischaemia while trial,
92
a total of 507 STEMI patients transferred to a PCI centre were
simultaneously minimising the risk of bleeding and transfusion have the randomised to early, pre-hospital initiation of tirofiban (early) or to its
potential to improve outcomes among patients with STEMI, especially initiation in the catheterisation laboratory (late). Early tirofiban was
in those patients at higher risk of bleeding complications, such as those associated with a better pre-procedural thrombolysis in MI (TIMI) grade
with low bodyweight, female gender and impaired renal function.
66–69
2–3 flow (43 versus 34%; p=0.04) and myocardial perfusion (myocardial
blush grade 2–3: 30 versus 22%; p=0.04). However, no benefits were
Glycoprotein IIb/IIIa Inhibitors observed in post-procedural TIMI grade 3 flow, myocardial perfusion,
Several randomised trials have been conducted in primary angioplasty, mortality (4.5 versus 3.7%; p=0.66) and re-infarction (2.4 versus 3.7%;
the vast majority of them on abciximab.
31,70–82
In the largest trial, p=0.43) at one-year follow-up. Similar results have been observed in the
Controlled Abciximab and Device Investigation to Lower Late Time to Integrilin Therapy in Acute MI (TITAN)-TIMI,
34
where 316 STEMI
Angioplasty Combinations (CADILLAC),
79
a total of 2,082 patients were patients were randomised to early or late eptifibatide.
93
randomised to stent or balloon with or without peri-procedural
administration of abciximab. Abciximab did not improve myocardial In the on-TIME 2 trial,
102
the data pertaining to 984 patients with STEMI
perfusion as evaluated by myocardial blush grade and ST-segment were examined. In the ambulance en route to receiving primary PCI,
resolution.
81
Some benefits in mortality with abciximab were observed patients were randomised to receive either tirofiban (25µg/kg bolus
in patients undergoing balloon angioplasty only, whereas no benefits plus 0.15µg/kg/minute infusion for 18 hours) or a placebo, in addition to
were observed in terms of re-infarction. Abciximab did not increase aspirin (500mg), heparin (5,000IU) and clopidogrel (600mg). The median
the risk of bleeding complications; however, a major limitation of this time from symptom onset to initial electrocardiogram (ECG) diagnosis
study was the relatively low-risk population. In fact, in trials without was 76 minutes, and the median time from pre-hospital drug
strict patient selection, as conducted by Antoniucci et al., abciximab administration to angioplasty was 55 minutes. The baseline clinical and
was associated with benefits in terms of death and re-infarction.
79
A angiographic characteristics of the two patient arms were similar.
recent meta-analysis of randomised trials has shown that peri-
procedural abciximab administration is associated with a significant Early tirofiban was associated with a better median ST deviation one
reduction in mortality and re-infarction, without an increased risk of hour after angiography/PCI (4.8 versus 3.6mm; p=0.003), but there was
major bleeding complications.
70
However, data from the Bavarian no difference in 30-day mortality (2.3 versus 4%; p=NS), recurrent MI
86 EUROPEAN CARDIOLOGY
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