ISAR-REACT 3: Less Bleeding, but No Overall Benefit of Bivalirudin Over UFH in Elective PCI After Clopidogrel Preloading

Shelley Wood

March 29, 2008

March 29, 2008 (Chicago, IL) - Low-risk patients undergoing elective PCI who have received a 600-mg preloading dose of clopidogrel derive no overall benefit from bivalirudin compared with unfractionated heparin (UFH), although bleeding may be reduced. Results from the Intracoronary Stenting and Antithrombotic Regimen--Rapid Early Action for Coronary Treatment 3 (ISAR-REACT 3) trial failed to show any difference between bivalirudin- and UFH-treated patients for the primary quadruple composite end point of death, MI, urgent target vessel revascularization (TVR), or major bleeding within 30 days.

According to lead investigator Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany), the results should convince operators who have started using bivalirudin as a substitute for heparin in elective PCI--an increasingly common practice in the US--that there are no solid reasons for doing so.

"That is the message of this study: We don't need to use bivalirudin in patients with stable and unstable angina without elevated troponin," Kastrati told heartwire . Kastrati presented the trial results during the first late-breaking session of the American College of Cardiology 57th Annual Scientific Session/i2 Summit-SCAI Annual Meeting.

But Dr Harvey White (Green Lane Hospital, Auckland, NZ), the scheduled discussant for the trial, had a very different view of the results, emphasizing the importance of reduced bleeding. "Bleeding is important to patients in terms of discomfort, prolonged hospitalizations, and increased costs, and it is independently associated with early and long-term morbidity and mortality," he said. "The ISAR group has shown that bivalirudin is an appropriate antithrombotic choice in elective PCI and in patients with ACS undergoing PCI who are troponin-negative after clopidogrel loading greater than two hours previously with aspirin and 600-mg clopidogrel."

ISAR-REACT 3: No difference in primary, secondary end points

The ISAR-REACT 3 trial enrolled 4570 patients who had received a 600-mg loading dose of clopidogrel at least two hours before PCI and randomized them in a double-blind, double-dummy fashion to either bivalirudin (2289 patients; 0.75-mg/kg bolus followed by an infusion of 1.75 mg/kg per hour, stopped at the end of the procedure) or UFH (2281 patients; 140 units/kg given as a bolus, with no additional boluses and no infusion). All patients were troponin-negative with no ACS, and no GP IIb/IIIa inhibitors were given during the course of the trial. Drug-eluting stents were used during PCI for more than 80% of patients in both arms of the trial.

As Kastrati showed today, the primary end point of the study--a composite of death, MI (CK-MB two times the upper limit of normal), urgent TVR, or major bleeding (using the REPLACE-2 definition, which includes transfusion of >2 units of blood)--was no different between the two groups at 30 days. The secondary end point of the study, a composite of death, MI, or urgent TVR, was no different, either.

When each of the end points was evaluated separately, only major and minor bleeding, according to the study definitions, were statistically different between the groups. Using the TIMI definition of major and minor bleeding, rates of bleeding were also significantly different between the two groups, but the event rate was low in both groups. Of note, there were no significant differences in ischemic events, something hinted to be a risk of bivalirudin use in other trials, although events were numerically lower in the UFH group.

ISAR-REACT 3: Results

End point Bivalirudin (%) UFH (%) p
Primary 8.3 8.7 0.57
Secondary 5.9 5.0 0.23
Major bleeding* 3.1 4.6 0.008
Minor bleeding* 6.8 9.9 0.0001
Transfusion 1.3 1.8 0.15
TIMI major 0.5 1.0 0.04
TIMI minor 1.3 2.2 0.01
*As per ISAR-REACT 3 definition

Looking across subgroups stratified by age, sex, diabetes, creatinine, and angina status, investigators saw no differences between the bivalirudin and UFH groups. To heartwire , Kastrati said it was possible that bivalirudin will turn out to be a good choice in patients at higher risk of bleeding--older patients and those with renal dysfunction--but that sort of analysis has not yet been done.

"You can make clinical decisions only on the basis of the primary end point, and not on the basis of subgroup analyses or on the basis of individual elements of the composite end point," he emphasized. "Major bleeding alone wasn't even a secondary end point in ISAR-REACT 3."

He concluded his presentation saying, "In biomarker-negative patients with stable and unstable angina undergoing PCI pretreated with 600-mg clopidogrel at least two hours before the procedure, bivalirudin does not improve net clinical benefit in terms of the quadruple end point at 30 days compared with UFH, although it significantly reduces bleeding."

Reacting to ISAR-REACT 3

White, discussing the results, noted that although the primary end point of the trial was negative, the event rate tilted in favor of bivalirudin. He also stressed that the bleeding definitions used in the study were outdated; the STEEPLE and ACUITY trials, for example, used a definition of major bleeding based on one unit of blood transfusion, not two. More information on different aspects of the bleeding end point in ISAR-REACT 3, including rate of intracranial bleeding, would have helped clarify the findings, he noted.

"I think the real question in a low-risk ischemic patient group is, does bivalirudin reduce bleeding? And I think this should have been the primary end point."

White's remarks were echoed by Dr Roxana Mehran (Columbia University, New York, NY), who commented on the study for heartwire .

"I don't think this trial was neutral," she said. "I thought that there was a significant reduction in bleeding, which is what we expect to see in patients treated with bivalirudin. We've seen this in every other trial where bivalirudin has been studied."

But Mehran also pointed to the "somewhat obscure" definition of bleeding used in ISAR-REACT 3, saying that the results might have been different if the more current definition of bleeding had been used. She and White also observed that the dose of heparin in ISAR-REACT 3, although common in Europe, is much higher than that used in the US. "That was a major limitation of the study," Mehran commented.

But Dr Peter Berger (Geisinger Health System, Danville, PA), who led the US portion of the trial, emphasized to heartwire that people should not dismiss the results on the basis of a bolus heparin dose not used in the US.

"Any cardiologist thinking about how to interpret these results and whether they ought to influence their practice should know that no additional boluses or infusions of heparin were administered [in ISAR-REACT 3], and the total dose of heparin in ISAR REACT 3 is actually less than the total dose administered in many recent trials, in which lower boluses were given but multiple additional boluses were given based on intraprocedural [activated clotting times]," Berger told heartwire . "It's also not clear whether the numerically lower frequency of procedural MI in heparin-treated patients in this trial is related to or the result of this German practice of giving a large initial bolus."

Worth it?

Also commenting on the study results, Dr Marc Cohen (Newark Beth Israel, NJ) hinted to heartwire that the high bolus dose of UFH might have boosted the bleeding benefit of bivalirudin. "There was a reduction in bleeding complications with bivalirudin, but it was in relation to a dose of heparin that was more than twice as high as what we use in the US. If the standard US dose was used, I think the impact on bleeding would have been more modest. That's just my prediction."

Cohen also said he was "disappointed" by the fact that the issue of cost was not raised by the presenter or the discussant. "You got a reduction in bleeding with bivalirudin, but did that reduction save the hospital administrators any money? Was length of stay reduced? You can't make the statement in the abstract, that bivalirudin is still worthwhile because it reduces bleeding complications. The statement should be, by adding a $500 surcharge, does the difference in bleeding make up for that cost? We need longer-term data, but also data that allow a healthcare administrator to say it's worth it."

The ISAR-REACT 3 investigators reported having no conflicts of interest. White disclosed receiving "significant" research grant support from Sanofi, Eli Lilly, Pfizer, Johnson & Johnson, Merck Sharp Dohme, The Medicines Company, Schering Plough, Roche, AstraZeneca, and consulting fees (modest) from GlaxoSmithKline. Cohen disclosed receiving honoraria and/or consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, and Schering-Plough. Mehran has previously disclosed being on the speakers' bureau for The Medicines Company and receives research support from Tyco/Mallinkradt, Cordis/Johnson & Johnson, and Boston Scientific.

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