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Cleveland, OH - A subgroup analysis of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) study suggests that the heparin plus IIb/IIIa blocker strategy has a slight efficacy advantage over bivalirudin if abciximab is used, but there is no advantage if eptifibatide is used as the IIb/IIIa blocker. But several experts have pointed out that because the choice of IIb/IIIa blockers was not randomized, this analysis must be interpreted with extreme caution.
The issue of whether different effects are seen with the 2 IIb/IIIa blockers used in REPLACE-2 has been the subject of much interest since the main results were first presented last November. Presented graphically in the paper published in the February 19 issue of the Journal of the American Medical Association,1 the results comparing bivalirudin with planned IIb/IIIa blocker use do seem to change depending on which IIb/IIIa blocker is used, with some benefit suggested in the IIb/IIIa blocker group when abciximab is used, but no benefit when eptifibatide is used.
Lead author Dr Michael Lincoff (Cleveland Clinic, OH) disclosed more of the data on this to heartwire. He said the trial could be conceptually divided into 2 smaller trials1 using eptifibatide as the IIb/IIIa blocker (involving 3300 patients) and 1 using abciximab (involving 2700 patients). He noted that each of these 2 smaller trials would be larger than the ESPRIT trial of eptifibatide or the stent part of the EPISTENT trial of abciximab.
He reported that when the primary triple end point of death/MI/urgent revascularization was considered, there was a 1.5% absolute reduction in the planned IIb/IIIa blocker group compared with the bivalirudin group when abciximab was used, but there was no difference in this efficacy end point when eptifibatide was used as the IIb/IIIa blocker. All results are nonsignificant.
Primary triple efficacy end point: Death/MI/urgent revascularizations|
IIb/IIIa blocker used |
Heparin plus planned IIb/IIIa blocker (%) |
Bivalirudin plus provisional IIb/IIIa blocker (%) |
|
Abciximab | 7.0 | 8.5 |
|
Eptifibatide | 7.1 | 7.0 |
Lincoff noted that the benefit seen with abciximab seemed to be accounted for by a reduction in non-Q-wave infarctions.
He also reported that there was no difference in the reduction in bleeding depending on which IIb/IIIa blocker was used.
Major bleeding, as defined in REPLACE-2 protocol|
IIb/IIIa blocker used |
Heparin plus planned IIb/IIIa blocker (%) |
Bivalirudin plus provisional IIb/IIIa blocker (%) |
|
Abciximab | 4.0 | 2.5 |
|
Eptifibatide | 4.1 | 2.2 |
Lincoff warned that this analysis was not based on randomized comparisons between IIb/IIIa blockers and so had to be interpreted with caution, as some operators may have chosen eptifibatide for different patients from those for abciximab. He added, however, that many hospitals participating in REPLACE-2 just used 1 IIb/IIIa blocker in all patients requiring such an agent.
He concluded that these new data suggest that: "Planned use of abciximab plus heparin may have a slight efficacy advantage over bivalirudin, which has to be balanced against the reduction in bleeding with bivalirudin. But bivalirudin appears to be an excellent replacement for eptifibatide, as the reduction in bleeding does not seem to be accompanied with any loss of efficacy in this group."
Although eptifibatide is the less expensive of the 2 IIb/IIIa blockers, Lincoff pointed out that using bivalirudin instead would still save money, as bivalirudin costs $395 in comparison with $615 for eptifibatide.
He said he hoped to present further details of this analysis at a satellite during the upcoming American College of Cardiology meeting, and the data would eventually be published a separate paper.
Other experts cautious
Commenting on this analysis, Dr Robert Harrington (Duke University, Durham, NC) said that, like most observational secondary analyses arising from a larger randomized trial, these data should be interpreted with caution. "Given the nonrandomized nature of these comparisons, much more analysis needs to be done that would include extensive adjustments for patient characteristics and likely operators/sites. Statistical testing for interaction after appropriate adjustment would be helpful," he added.
Dr Paul Armstrong (University of Alberta, Edmonton) also seemed reluctant to take this new analysis on board without more information. "I think this is probably too much slicing and dicing given the open nature of the IIb/IIIa usage. I would like to see the bleeding broken into TIMI major vs the definition of major in this trial as well to get better a understanding of what happened in this subsidiary analysis," he commented.
Dr Elliott Antman (Brigham and Women's Hospital, Boston) gave a similar view. "The subgroup analysis stratified by GP IIb/IIIa inhibitor must be interpreted with caution since it is not randomized and is underpowered. It also needs to be corrected for baseline characteristics before we can conclude there is any important difference in response based on which GP IIb/IIIa inhibitor was used," he told heartwire.
In response, Lincoff noted that multivariate analyses are under way, but that with a blinded trial, the randomized comparisons between bivalirudin and heparin plus GP IIb/IIIa remain valid for each of the strata defined by the operator's choice of abciximab or eptifibatide. "We are not trying to compare outcome with abciximab vs eptifibatide, which would be invalid due to the nonrandomized choice of GP IIb/IIIa inhibitor. But for a given choice of GP IIb/IIIa inhibitor, the randomized comparison is appropriate," he said.
