Boston, MA - Results of the ISAR-REACT 3 trial, supporting a role for a cheap standby—unfractionated heparin (UFH)—over the more expensive newcomer, bivalirudin, in low-risk patients undergoing elective PCI—have now been published in the August 14, 2008 issue of the New England Journal of Medicine [1]. As previously reported by heartwire when Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany) presented the results at the 2008 ACC meeting, the trial looked at the primary quadruple composite end point of death, MI, urgent target-vessel revascularization (TVR), or major bleeding within 30 days in patients with no biomarker elevation who did not receive GP IIb/IIIa inhibitors during the course of the trial.

"Expensive therapies need stronger evidence to get applied in clinical practice," Kastrati told heartwire this week. "I believe we look more carefully at the evidence if a therapy is expensive, and if it is lacking, as it is in ISAR-REACT 3, then I think the implication of the trial will be that interventional cardiologists will use more and more UFH in patients similar to the ones in this study."

When the results were first unveiled during the ACC, several commentators suggested to heartwire that the reduced bleeding tilted the trial in favor of bivalirudin. "I don't think this trial was neutral," Dr Roxana Mehran (Columbia University, New York, NY) told heartwire at the ACC. "I thought that there was a significant reduction in bleeding, which is what we expect to see in patients treated with bivalirudin."

But Kastrati disagrees. "Those people forget why the combined composite end point of ischemia and bleeding complications came out, in the end, to be similar. If there is a reduction in bleeding complications, you should realize that something happened to the ischemic complications that balanced things again. We should not forget that there was a trend to more myocardial infarction with bivalirudin, as compared with heparin. . . It's always difficult in evaluating such composite end points in which the components are moving in two different directions. That's why I say that we should evaluate the trial on the basis of the primary end point; any other considerations are not sound."

He also points out that the price difference alone means the results can't be "neutral." UFH, he points out, costs about €5 per patient, while bivalirudin is more in the range of €400.

"The lack of benefit in terms of the primary end point, the much lower price of unfractionated heparin, and the much larger experience with unfractionated heparin should make interventionalists use UFH during PCI in patients similar to those included in the ISAR-REACT 3 trial," he told heartwire.

Asked whether the choice of anticoagulant could be made on the basis of individual patient risk, Kastrati said that his group has already addressed this question and submitted their findings for publication. "The hypothesis is that patients at high risk for bleeding might benefit from bivalirudin and that those at higher risk for MI or ischemic complications might benefit from a more potent therapy in this direction, such as UHF—we're looking at both of these issues," he said.

Trial coinvestigator Dr Peter Berger (Geisinger Health System, Danville, PA), commenting on the paper for heartwire, suggested that cardiologists can already draw conclusions from the trial. "Many clinicians did not know—they could not have known—that bivalirudin does not reduce procedural thrombotic complications in low-risk (troponin-negative) patients. Accordingly, bivalirudin, which is much more expensive than unfractionated heparin, need not be administered to all such patients," he said. "However, clinicians will undoubtedly value the small but statistically significant reduction in bleeding with bivalirudin differently, and that is appropriate. In patients in whom the fear of bleeding is great and the potential consequences profound, bivalirudin ought to be preferred. It causes less bleeding than heparin, as administered in this trial."

Another issue debated in the wake of the trial's presentation last March was the choice of a 140-unit/kg heparin dose—a much higher bolus than is commonly used in the US. At the time, Berger pointed out to heartwire that while the bolus was higher than the US standard, the total dose administered was actually lower than that used in many recent trials, where multiple additional boluses of heparin are given.

Nonetheless, Kastrati told heartwire that his group is attempting to clarify this question in a study dubbed ISAR-REACT 3a, using a 100-unit/kg dose of heparin. Investigators will then compare these outcomes with those seen with 140-unit/kg heparin bolus and bivalirudin in the main ISAR-REACT 3 trial. While nonrandomized, Kastrati believes the information will prove key to understanding the optimal use of UFH in this patient group.

"No one knows the optimal dose of heparin. We have reduced the dose of heparin without any evidence, along with adding very effective antiplatelet therapies such as clopidogrel, which we hadn't used before, Kastrati explained. "Before the use of a loading dose of clopidogrel, it was always a relationship between dose of heparin, increased risk of bleeding, and reduced risk of ischemic complications. But maybe with the systematic use of clopidogrel loading, we don't need such a high dose of UFH."