REPLACE-2 published: More controversy over the role of bivalirudin vs IIb/IIIa blockers in PCI

February 18, 2003

Cleveland, OH - The REPLACE-2 study, which suggests that using bivalirudin (Angiomax®, The Medicines Company) instead of heparin may do away with the need for routine use of IIb/IIIa blockers in certain PCI patients, is published in the February 19 issue of the Journal of the American Medical Association[1].

The trial was first reported last November at the American Heart Association. The implications of the trial are commercially very sensitive, with The Medicines Company and the manufacturers of both IIb/IIIa blockers used in the trial all fighting for the PCI market. This, together with the complex nature of the trial and the differing directions of the safety and efficacy results, has led to much heated discussion of the data, with different angles being emphasized or downplayed by the various interested parties.

Different effects with different IIb/IIIa blockers: Eptifibatide in the firing line?

The controversy surrounding the results continues with the publication of the paper and a challenging editorial from Dr Elliott Antman (Brigham and Women's Hospital, Boston)[2]. But fuel has definitely been added to the fire by a new analysis of the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) results, exclusively revealed by heartwire , suggesting that different effects are seen with the 2 IIb/IIIa blockers used in REPLACE-2. This analysis suggests a slight advantage for abciximab over bivalirudin, but the same advantage was not observed when eptifibatide was the planned IIb/IIIa blocker. (See separate news article.)

The REPLACE-2 trial was a randomized double-blind active controlled study in 6010 patients undergoing PCI in 233 centers in 9 countries during 2001 and 2002. Patients were randomized to bivalirudin plus provisional IIb/IIIa blocker use or heparin plus planned IIb/IIIa blocker use. Operators could choose to use abciximab or eptifibatide. In the provisional IIb/IIIa blocker group, 7.2% of patients actually received 1 of these agents.


The primary composite end point included both measures of efficacy and safety30-day death/MI/urgent revascularization or in-hospital major bleedingand suggested a slight advantage for bivalirudin over heparin plus a IIb/IIIa blocker. But the secondary end point, which was solely an efficacy measuredeath/MI/ urgent revascularization at 30 daystrended in the other direction, suggesting a slight advantage for the heparin plus IIb/IIIa blocker group.

REPLACE-2: Primary and secondary composite end points

End point

Heparin plus planned IIb/IIIa blocker

Bivalirudin plus provisional IIb/IIIa blocker


Death/MI/urgent revascularization/ major bleeding 10.0% 9.2% 0.32
Death/MI/urgent revascularization 7.1% 7.6% 0.40


The REPLACE-2 authors, led by Dr Michael Lincoff (Cleveland Clinic, OH), note that prespecified statistical criteria for noninferiority of bivalirudin to heparin plus IIb/IIIa blocker use were satisfied for both end points.

In-hospital major bleeding rates were significantly reduced by bivalirudin. Major bleeding was experienced by 4.1% of patients taking heparin plus planned IIb/IIIa blockers vs 2.4% of those taking bivalirudin plus provisional IIb/IIIa blockers (p<0.001).

In the paper, the researchers conclude that: "Bivalirudin with provisional IIb/IIIa blockade is statistically not inferior to heparin plus planned IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding."

They note that there was a statistically nonsignificant 0.5% excess in ischemic events (primarily non-Q-wave infarctions) in the bivalirudin group and that 6-month and 1-year follow-up is under way to examine the consequences of this. They add, however, that even larger differences in early infarction rates have not consistently translated into detectable differences in 1-year mortality in other studies. And they add that major bleeding, transfusions, and thrombocytopenia are also clinically relevant complications associated with patient discomfort, prolonged hospitalization, infection risk from blood products, and increased cost. "The significant absolute 1.7 major bleeding events, 1 thrombocytopenia episode, or 0.8 transfusions prevented for every 100 patients treated with bivalirudin in this trial may be a reasonable balance against a nonsignificant 0.5% ischemic risk (1 additional event per 200 patients treated)," they state.

They point out that at $395 per patient, bivalirudin is likely to prove economically more attractive than IIb/IIIa blocker use (which ranges from $615 for eptifibatide to $1300 for abciximab). Bivalirudin also has the added advantage of a short infusion time (less than 1 hour), while IIb/IIIa blockers are infused for 12 to 18 hours, which may prolong hospitalization and patient immobilization times in an era of expedited care following PCI, Lincoff et al note.

They comment that: "These findings validate bivalirudin with selective GP IIb/IIIa blockade as an effective and safe anticoagulation strategy during PCI, with advantages with regard to bleeding risk, cost, and ease of administration."

Noting that patients with acute MI or unstable angina requiring empiric IIb/IIIa blockade were not included in REPLACE-2, they say that IIb/IIIa inhibitors should not be withheld in high-risk patients (which include urgent ACS and treated diabetics), in whom distinct benefits of these agents have been shown.

"But certainly, the sizable number of patients with low- or moderate-risk characteristics for periprocedural or long-term complications of PCI are appropriate candidates for bivalirudin with provisional GP IIb/IIIa inhibition, especially if there is a heightened likelihood of bleeding," the authors comment. "What remains to be investigated is whether outcome during PCI may be further optimized in a cost-effective manner by routine combination of bivalirudin and GP IIb/IIIa blockade in high-risk patients," they add.

Issues for discussion

In his accompanying editorial, Antman explores several issues that have provoked discussion about the REPLACE-2 trial. These include the quadruple primary end point, the definition of major bleeding, the noninferiority statistical analysis, and the dose-ACT (activated-clotting-time) range in the heparin group.

On the quadruple end point, he notes that combining safety and efficacy results in this way "can be problematic from a regulatory perspective because drugs that are ineffective but have safety advantages can appear to be better than drugs with proven efficacy." In this case, he notes that there was a net excess of 23 non-Q-wave infarctions (predominantly in the intermediate and large categories as ascertained by creatine kinase-MB elevations) but 52 fewer major bleeding events in the bivalirudin group. And because the difference in bleeding events was greater than the difference in efficacy events, the quadruple end point favored bivalirudin.

On the subject of the noninferiority analyses, Antman explains that this shows that bivalirudin plus provisional IIb/IIIa blockade preserves at least 50% of the treatment effect of combining GP IIb/IIIa inhibition with heparin for the triple efficacy end point and 50% to 75% for the quadruple safety and efficacy end point. He says that while the statistical analysis satisfies quite a conservative definition in terms of the quadruple end point, the triple end point does not satisfy such rigorous criteria, with the upper confidence limit suggesting that bivalirudin could have been up to 32% worse with regard to this efficacy measure.

He says "the benefit of bivalirudin pivots around the difference in the frequency of major bleeding." Noting that the criteria for major bleeding in REPLACE-2 were similar to the combination of TIMI major and minor bleeds, he points out that the drivers for the difference in major bleeding in the trial were vascular access puncture and gastrointestinal tract bleeding episodes. He further elaborates that there was little difference between the 2 groups in terms of TIMI major bleeding and the quadruple end points would have been quite similar if that definition of bleeding had been used.

Noting that there was a significant increase in TIMI minor bleeding in the heparin plus IIb/IIIa blocker group, Antman puts forward the possibility that this may have been due to high ACTs in REPLACE-2, which exceeded those recommended in the prescribing information for both eptifibatide and abciximab.

Antman concludes that bivalirudin is an attractive anticoagulant for PCI patients with renal failure or heparin-induced thrombocytopenia, and he agrees with the REPLACE-2 authors that it should not replace GP IIb/IIIa blockers in high-risk patients. He says that whether bivalirudin should be used in more elective PCI cases, which made up about 56% of the REPLACE-2 population, will depend on whether interventionalists (and the FDA) will accept the quadruple end point, the definition of major bleeding, the noninferiority analysis, and the heparin dose and ACT data. "The trade-off appears to be fewer non-life-threatening bleeding events with bivalirudin compared with heparin at the cost of a few more moderately sized myocardial infarctions when GP IIb/IIIa inhibitors are used provisionally rather than routinely," he adds.

Armstrong also wary of trade-off

Having seen the full published data on REPLACE-2, Dr Paul Armstrong (University of Alberta, Edmonton) still has concerns about the trade-off between increased MIs and reduced bleeding.

"In my view the differences in bleeding were largely procedural related, and the failure to demonstrate a meaningful difference in TIMI major bleeding between the 2 strategies makes this argument for bivalirudin less compelling. The heparin dosing and high ACTs achieved also raise the question of whether the increased bleeding in the heparin group is potentially avoidable with lower doses of heparin," he commented to heartwire . "As for the increase in infarctions in the bivalirudin group, they do seem to be of substantial size and we know that isn't good for youthe more CK rises, the worse the long-term outcome from large-scale analyses," he added.

He believes that "bivalirudin remains an interesting alternative in selected situations, and its economic attraction is also a genuine point in its favor."

Armstrong also pointed out that there appeared to be different results according to gender. "Although not statistically significant, the results in women favor bivalirudin on the quadruple end point, but they don't seem to show the same trend toward benefit with heparin plus IIb/IIIa blocker as the men on the triple efficacy end point. This builds on other data from a recent meta-analysis by Boersma et al where IIb/IIIa blockers had increased bleeding and little benefit in women unless they had elevated troponins. Clearly the IIb/IIIa story in women continues to be an interesting one."

Lincoff responds

In response to Antman's and Armstrong's comments, Lincoff told heartwire that while some of these issues were valid points of discussion, such as whether the trade-off between the bleeding reduction and MI increase was worthwhile or not, many of the issues raised were "invalid arguments." These include the inference that the bleeds that were reduced were not that meaningful. "Puncture site and GI bleeds are a major morbidity issue. They prolong hospitalization and increase patient discomfort for weeks. Patients remember these bleeds much more than a nonsymptomatic increase in CK levels," he commented.

He also believes that the debate over the ACT values is not valid, as there is substantial variation in ACT measurements between machines so it is wrong to compare these values between studies.

Lincoff concedes that that the statistical analysis "may deserve discussion," but he points out that this same method of defining "noninferiority" has been used to approve other drugs, 1 of which was the thrombolytic reteplase. "If we are willing to accept that 2 agents just have to be shown to be roughly similar, then we have to accept a value less than 100%, and 50% does have some precedent."


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