Washington, DC - Bivalirudin has now proved itself in acute-MI patients undergoing primary angioplasty, results from the HORIZONS AMI trial indicate. According to Dr Gregg Stone (Columbia University, New York, NY), who presented the results during the TCT 2007 meeting, bivalirudin significantly reduced net adverse clinical events at 30 days—a composite of major bleeding and major adverse cardiovascular events (MACE)—as well as major bleeding alone, also 30 days out, as compared with heparin plus a GP IIb/IIIa inhibitor. That reduction in bleeding appeared to drive the most surprising result from the study: a significant reduction in cardiac deaths at 30 days.

"Right now, it certainly looks like [bivalirudin] would apply to the vast majority if not all the patients undergoing primary angioplasty," Stone said.

Dr Gregg Stone

A panel discussing the results following the presentation as well as other experts contacted by heartwire were largely in agreement that the trial results were overwhelmingly positive and an important step forward, although some of the findings will need further scrutiny.

"At first blush, it seems like the entire spectrum of ischemic disease that comes to the cardiac catheterization laboratory is now effectively treated with bivalirudin, in contrast to heparin and GP IIb/IIIa inhibitors," Dr Jeff Popma (Caritas St Elizabeth's Medical Center, Boston, MA) commented in a press conference. "We have stable disease and non-STEMI, and the only arena that was not tested in a randomized controlled trial was STEMI. It seems as if now the bookend is complete."

"It's going to be hard to find anyone who will have anything critical to say about this," Dr Deepak Bhatt (Cleveland Clinic, OH) commented to heartwire, adding that he had expected bleeding rates and net adverse clinical events to be reduced, but not for cardiac deaths also to be reduced. "When there's a reduction in cardiac mortality, that kind of trumps everything else," he said.

Even Dr Sanjay Kaul (Cedars-Sinai, Los Angeles, CA), whose critique of the statistical assumptions in the ACUITY trial made waves at last year's AHA meeting, told heartwire he believed the HORIZONS AMI trial, as presented at TCT, looked statistically more sound. "Overall, the results appear to look quite favorable for bivalirudin," he said. But he also added that he is curious to know how bivalirudin would compare with heparin alone, without GP IIb/IIIa inhibitors, in primary PCI. "It is reasonable to ask whether bivalirudin alone would provide superior outcomes compared with heparin alone during contemporary management of STEMI with primary PCI. This has important implications for clinical practice."

A new horizon for bivalirudin?

More than 3600 patients took part in HORIZONS AMI, from 123 centers in 11 countries. All patients had STEMI with a symptom onset of less than 12 hours and were randomized in a 1:1 fashion to unfractionated heparin (UFH) 60 U/kg IV, with subsequent boluses titrated by nomogram to activated clotting time (ACT) of 200 to 250 seconds, plus a GP IIb/IIIa inhibitor (abciximab or eptifibatide), or to bivalirudin monotherapy (0.75 mg/kg bolus; infusion 1.75 mg/kg per hour), stopped at the end of the procedure, plus provisional GP IIb/IIIa inhibitors for large thrombus or refractory no-flow. In all, only 7.2% of patients in the bivalirudin-treated group also received GP IIb/IIIa inhibitors in the cath lab.

The trial was powered to test for noninferiority and superiority, but for both the primary end points, bivalirudin was significantly better than the UFH-GP IIb/IIIa-inhibitor strategy. At 30 days, investigators saw a 24% reduction in net adverse clinical events and a 40% reduction in major bleeding—the primary end points of the study. MACE, defined as all-cause death, reinfarction, ischemic target vessel revascularization (TVR), or stroke, were no different between the two groups. Investigators saw no significant differences between any of the individual event rates that made up the MACE end point, with the exception of cardiac mortality, which was significantly reduced in patients in the bivalirudin arm of the study.

Major outcomes in HORIZONS AMI

End point	UFH-GP IIb/IIIa inhibitors (%)	Bivalirudin (%)	Absolute difference (%)	Relative risk reduction (%)	p, noninferiority	p, superiority
NACE*	12.1	9.2	-2.9	24	<0.0001	0.006
Major bleeding	8.3	4.9	-3.3	40	<0.0001	<0.0001
MACE	5.5	5.4	—	—	—	NS

Death at 30 days

End point	UFH-GP IIb/IIIa inhibitors (%)	Bivalirudin (%)	p
All death	3.1	2.1	0.058
Cardiac death	2.9	1.8	0.035

To heartwire, Kaul raised a red flag about the cardiac-mortality numbers. While it is "reassuring" to see all-cause mortality and cardiac mortality tracking in the right direction, Kaul said he "would not make too much" of what could essentially be a false-positive error from an underpowered comparison within an unadjusted, post hoc analysis.

Investigators also reported data for stent-thrombosis rates out to 30 days, which were the same for the two groups, with the exception of acute stent thrombosis (<24 hours), which was higher for the bivalirudin-treated patients at 1.3% vs 0.3% for the UFH-GP IIb/IIIa-inhibitor-treated patients.

Discussing the results after the formal presentation, Dr Michel E Bertrand (Hospital Cardiologique, Lambersart, France) expressed enthusiasm for the trial findings and particularly the reduction in cardiac mortality but also raised questions about stent-thrombosis data. One explanation, he suggested, might be the shorter half-life of bivalirudin and the fact that, in HORIZONS AMI, the drug was stopped at the end of the procedure.

One of the study coauthors, Dr Roxana Mehran (Columbia University, New York, NY), agreed to heartwire that the best duration of therapy with bivalirudin is not yet known. "Are we giving bivalirudin enough time, or should we give it in the ER, through the procedure, and then maybe a few hours afterward, instead of stopping it as we did in this trial? I think those are the kind of questions we still don't have answers for. This worked very well, but maybe it could be even better."

In HORIZONS AMI, roughly 65% of patients received heparin in the emergency room, with those in the bivalirudin arm switching therapies. While the study findings were no different in patients who had started on heparin, Mehran pointed out that future studies should look into whether bivalirudin alone could be started when patients first arrive in the emergency room.

Others told heartwire that they would wait to see the full results, in print, before embracing the HORIZON AMI results. Dr Marc Cohen (Beth Israel Medical Center, Newark, NJ) commented, "This is a positive study in the sense that it establishes bivalirudin as an alternative for patients with STEMI, but I'm not convinced that it's a seismic change."

He points out that while the stent thrombosis seen in the bivalirudin arm did not seem to translate into more deaths, it is enough to convince him to "think twice" about the type of patients in whom he'd use the drug. "If you had a patient who is at risk for stent thrombosis, a patient with a lot of intraluminal thrombus or with a very angulated lesion, or a patient who has a long segment of disease, the data on acute stent thrombosis may make you think twice before just jumping to the conclusion that either of these approaches are fine."

But others, like Bhatt, say the HORIZONS AMI is likely to make them more comfortable using bivalirudin, not less: "This trial appears to provide a clear-cut answer as to the preferred antithrombotic strategy for primary PCI," Bhatt commented. "The results of HORIZONS make me far more confident in the results of ACUITY as well. It would appear that bivalirudin really is the preferred anticoagulant across PCI, with GP IIb/IIIa reserved for bailout use."

Stone disclosed receiving research support from The Medicines Company and Boston Scientific and honoraria from Eli Lilly. Bhatt disclosed being on the pharmacology committee for the HORIZONS AMI trial and receiving research grants (directly to his institution) from Bristol-Myers Squibb, Eisai, Ethicon, Sanofi-Aventis, and The Medicines Company; honoraria (donated to nonprofits for more than two years) from AstraZeneca, Bristol-Myers Squibb, Centocor, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL, Sanofi Aventis, Schering-Plough, The Medicines Company, and TNS Healthcare; being on the speaker's bureau (more than two years ago) for Bristol-Myers Squibb, Sanofi Aventis, The Medicines Company; being a consultant/advisory board member(any honoraria donated to nonprofits) for AstraZeneca, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi-Aventis, Schering-Plough, The Medicines Company, TNS Healthcare, and Vertex; giving expert testimony regarding clopidogrel (the compensation was donated to a nonprofit organization). Cohen disclosed receiving honoraria and or consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, Schering-Plough, and ("occasionally") The Medicines Company. Mehran is on the speaker's bureau for The Medicines Company and receives research support from Tyco/Mallinkradt, Cordis/Johnson & Johnson, and Boston Scientific. Bertrand disclosed being on the speaker's bureau or receiving grant support from Servier, Nycomed, and Sanofi-Aventis; Popma is on the speaker's bureau for Sanofi-Aventis, The Medicines Company, Bristol-Myers Squibb, and Pfizer.