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Text sizeNew Orleans, LA - The first major head-to-head trial of two gp IIb/IIIa blockers has shown clear superiority of abciximab (ReoPro® - Centocor) over tirofiban (Aggrastat® - Merck) in coronary stenting.
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Dr Eric Topol (Cleveland Clinic Foundation)
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The TARGET trial1 is being presented today at the at the American Heart Association Scientific Sessions 2000 in New Orleans, LA by Dr Eric Topol (Cleveland Clinic Foundation). The trial, sponsored by Merck, was intended to prove that tirofiban gave similar benefits in the setting of coronary stenting to abciximab, which is widely regarded as the gold-standard gp IIb/IIIa blocker in this setting. However, this goal was not achieved, and tirofiban was actually associated with a significantly worse outcome than abciximab, with a 26% relative increase in the primary endpoint of death/MI/urgent revascularization.
TARGET enrolled 4812 patients from 18 countries who were undergoing coronary stenting. They were randomized to tirofiban or abciximab. Tirofiban was given at the dose previously tested in the RESTORE trial and abciximab was given at the normal dose used in clinical practice. The primary endpoint is shown in the table below:
Death/MI/urgent revascularization at 30 days (primary endpoint)|
Tirofiban |
Abciximab |
OR |
p value |
| 7.55% | 6.01% | 1.26 | 0.037 |
The difference in the primary endpoint was driven by MI, as shown below:
Effects on individual components of primary endpoint|
Endpoint |
Tirofiban |
Abciximab |
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Death | 0.5% | 0.5% |
|
MI | 6.9% | 5.4% |
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Urgent revascularization | 0.9% | 0.7% |
The results were consistent across subgroups, with a similar 25-30% worse effect seen with tirofiban in most cases. The one exception was the presence or absence of acute coronary syndromes. Abciximab showed even more benefit over tirofiban in patients with acute coronary syndromes, whereas tirofiban showed a trend towards a better outcome in patients without ACS. However, this needs to be interpreted with caution as it was not a prespecified subgroup.
ACS subgroup analysis (primary composite endpoint at 30 days)|
Treatment group |
Tirofiban |
Abciximab |
|
ACS | 9.3% | 6.3% |
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Non-ACS | 4.5% | 5.6% |
Topol said he was "surprised" by the results. "They are not at all what we expected, but they clearly show that abciximab should remain the standard of care in patients undergoing interventions."
Excluded patients
Addressing questions raised about 500 patients excluded in the analysis of the TARGET results, Topol said, "these patients were randomized but never received any study drug because they, for the most part, didn't undergo an intervention. It was prespecified to exclude such patients from the analysis owing to lack of fitting inclusion criteria once the coronary anatomy was defined."
Explanations for tirofiban failure
Topol said it was not clear why tirofiban failed to show a similar benefit to ReoPro. "Maybe we needed to use a higher dose or maybe abciximab works better in stenting because it has other anti-inflammatory effects. We just don't know at present." Further studies are now underway to look at the dosing issue and whether the dose used actually did inhibit platelet aggregation enough. "We did do studies that showed a good degree of platelet inhibition with the tirofiban dose used, but we need to look into this again," he added.
What about eptifibatide?
Another question is how this new data affects the third IIb/IIIa blocker, eptifibatide (Integrilin® - COR). This agent has shown a benefit over placebo in coronary stenting (in the ESPRIT) trial, but Topol says it can't be assumed to be as effective as abciximab without a head-to-head trial. In addition, he points out that the ESPRIT data is nowhere near as robust as that for abciximab. "The benefit of eptifibatide in ESPRIT seen at 48 hours is already reduced somewhat at 30 days, and we haven't yet seen any longer-term follow-up. That just cannot compare with 8-year follow-up with abciximab."
ACS - acute confusional state
However, the data for abciximab are not as encouraging as the data for the other IIb/IIIa blockers in patients with acute coronary syndromes not undergoing interventions. The GUSTO-4 trial showed no benefit of abciximab in this population, whereas the other two agents - tirofiban and eptifibatide - both have good data in this indication.
The latest thinking on GUSTO-4 is now leaning towards the hypothesis that the unique characteristics of abciximab may have caused the negative result in the noninterventional setting, with new data showing that longer infusions of abciximab as used in GUSTO-4 could cause a paradoxical activation in platelets, and may therefore be harmful.
This has led to a very complicated situation, where abciximab looks like the best IIb/IIIa inhibitor for stenting, but the worst for use in ACS patients not having an intervention. Topol thus now refers to ACS as "acute confusional state."
Two-compartment model
He says the use of gp IIb/IIIa blockers in acute coronary syndromes now has to be viewed as a "two-compartment model," with patients undergoing interventions considered differently from those not receiving an intervention. "It appears that the huge insult to the artery wall that occurs during stenting is very different from the endogenous process ongoing in an ACS patient not receiving an intervention, and that these two situations need to be treated differently."
However, this leads to some debate as to how to treat the high-risk ACS patient turning up at the emergency room, and who is likely to be heading for the cath lab. If a gp IIb/IIIa blocker is initially given but, as is common, the patient may not go to the cath lab until the next day, either tirofiban or eptifibatide should be given, and continued into the procedure. Thus when this patient arrives at the cath lab, he would not be on the best IIb/IIIa blocker for the setting of stenting. Alternatively, IIb/IIIa blocker therapy could be delayed until the intervention is performed and then abciximab could be used.
Dr Robert Califf (Duke University, Durham, NC) believes a trial of these two strategies needs to be performed. Until such a trial is conducted, cardiologists will just have to use personal preference to decide which to follow. Califf says the data supporting the use of IIb/IIIa blockers in the noninterventional setting is much weaker than that in the interventional setting and that, in reality, IIb/IIIa blockers are not being used widely as purely medical therapy. Therefore many patients will probably arrive in the cath lab without having received such an agent and could be started on abciximab at the time of the procedure.
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[Dr Topol is the editor-in-chief of theheart.org. Dr Califf is a member of the editorial board of theheart.org.]
