New York, NY - Following the seemingly dazzling results of the HORIZONS AMI trial, presented last week at the TCT meeting, heartwire asked several cardiologists whether bivalirudin (Angiomax, The Medicines Company) would now be their antithrombotic of choice in primary PCI.

While the trial results are undoubtedly impressive, a few issues are still up for discussion before some make up their minds.

The HORIZONS AMI trial randomized 3600 STEMI patients to unfractionated heparin plus a GP IIb/IIIa inhibitor or to bivalirudin monotherapy plus provisional GP IIb/IIIa inhibitors for large thrombus or refractory no-flow. GP IIb/IIIa inhibitors were actually received by 7.2% of patients in the bivalirudin-treated group. Results showed significant reductions for the bivalirudin group in both primary end points—net adverse clinical events (a composite of major bleeding and major adverse cardiovascular events [MACE]) and major bleeding alone (both at 30 days). An added bonus of the study was a significant reduction in cardiac deaths at 30 days in the bivalirudin group, which was somewhat of a surprise.

Dr James Ferguson (Texas Heart Institute, Houston) sums up the results as follows: "Less bleeding—no particular surprise. More early stent thrombosis—a little bit of a surprise, but not unexpected. Similar clinical outcomes—a bit of a surprise and somewhat expected. Reduced mortality and lower death/MI—a big surprise and completely unexpected."

"I think a lot of people were looking to HORIZONS to cloud the issue more than answer the questions and were expecting it to be too complicated and too underpowered. Lo and behold, it gives us a fairly resounding message. With bivalirudin, as given in this study, you seem to pay a slight price in early stent thrombosis but get back a reduction in subsequent mortality accumulated over the next 30 days. The decreased bleeding is a message that has been consistent across all the trials. The reduction in mortality has always been lurking in the background, but we were never sure whether it was signal or noise. After HORIZONS I can't help but think that there is something real there, which becomes even more dramatic in the face of the higher rate of early stent thrombosis," Ferguson added. 

The reduction in bleeding with bivalirudin now appears to be universally accepted. Dr Robert Harrington (Duke University, Durham, NC) notes: "The marked difference in major bleeding is quite impressive and now a very consistent finding across the bivalirudin studies. We could argue about the definitions of bleeding used in these studies, but it really doesn't matter, as the bleeding is less with the bivalirudin strategy across multiple definitions/parameters (HORIZONS, TIMI, GUSTO, transfusions, thrombocytopenia)."

And reduced bleeding also now appears to be linked to a reduction in mortality. On this, Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA) says: "The link between less bleeding and lower mortality in HORIZON is very interesting—and consistent with what was seen in OASIS-5 and in good part with REPLACE-2. We also have a wealth of studies of the converse: increased bleeding associated with increased mortality. Thus, I have taken one major lesson from HORIZONS and recent trials—avoiding bleeding can potentially improve mortality."

But despite these positive findings, the early increase in stent thrombosis in the bivalirudin group (1.3% vs 0.3% in the first 24 hours) remains a concern for some. Dr Shamir Mehta (McMaster University, Hamilton, ON), who has been conducting studies with the competitor antithrombotic, fondaparinux (Arixtra, GlaxoSmithKline), commented to heartwire: "The fourfold higher rate of acute stent thrombosis in the bivalirudin group is definitely concerning. Although the rates are low, the increase is highly significant and probably real. The time-to-event curves show initially higher mortality in the bivalirudin group, and then the curves cross at about one week. The same is true for major adverse cardiac events, where the rates were much higher in the bivalirudin group early, with later catch-up in the heparin/GP-IIb/IIIa group. It would be interesting to see if the late benefit with bivalirudin was due to reduced bleeding early on."

Harrington also highlights the crossing over of the event curves. "As with most of the other bivalirudin trials (REPLACE 2, ACUITY), there are more early ischemic events associated with the bivalirudin strategy. In this study, that also includes early stent thrombosis. But in this study, we see something very curious: a recrossing of the Kaplan-Meier death curves and a convergence of the overall ischemic-event curves. There could be a few things at play here, including chance, given the relatively modest sample size and the small number of deaths overall. The intriguing question is whether the early bleeding in the GP-IIb/IIIa arm is translating into more ischemic events over the next 30 days. This is consistent with observations by Dr Sunil Rao [Duke University Medical Center] from our group and from the recent OASIS-5 data. It will be interesting to see in the HORIZONS analyses how much of the mortality risk is explained by the early bleeding."

In response, chief investigator of HORIZONS AMI, Dr Gregg Stone (Columbia University, New York, NY), says: "There was no significant overall increase in stent thrombosis in patients assigned to bivalirudin rather than heparin plus IIb/IIIa inhibitors, although there was an absolute 1% increase within 24 hours. However, this was offset by a 0.5% decrease in the bivalirudin arm after 24 hours, so within 30 days the rates were nonsignificantly different (p=0.33), and cardiac mortality (including deaths due to stent thrombosis) was lower with bivalirudin."

Stone further points out that a preliminary analysis to be presented at the George Washington symposium at the upcoming American Heart Association meeting shows that the mortality benefit of bivalirudin compared with heparin plus IIb/IIIa inhibitors was in large part due to the prevention of bleeding. "Major bleeding as defined in HORIZONS had virtually the same impact on mortality as did definite stent thrombosis, and since major bleeding was more common than stent thrombosis, bivalirudin-assigned patients had lower mortality," he commented to heartwire.

On the crossing of the Kaplan-Meier curves, he says: "ACUITY (and other trials) have shown that the impact of major bleeding is extended and explain why the MACE curves cross. The lower mortality with bivalirudin compared with heparin plus IIb/IIIa inhibitors can't be ignored and points to the importance of preventing iatrogenic bleeding complications in high-risk ACS patients. Even REPLACE-2 and ACUITY had lower point estimates for mortality at one year with bivalirudin monotherapy compared with heparin plus IIb/IIIa inhibitors, so the results are highly consistent."

Another issue highlighted was that many patients in the study received unfractionated heparin (UFH) before being given bivalirudin. Mehta points out: "The majority of patients received UFH prior to the PCI, so this is really a trial of bivalirudin on top of UFH, not bivalirudin alone. Does this mean if we use bivalirudin for primary PCI we also need to give a UFH bolus before the procedure? I wonder what the results would have looked like if UFH had not been given, especially with respect to early stent thrombosis and cardiac events." Ferguson also raises this point. "There was a lot of up-front UFH in the study, but in some ways that makes the bivalirudin differences even more striking. It still needs to be sorted out, though," he commented to heartwire.

On this, Stone replies: "There was no significant interaction between heparin strata and bivalirudin safety and efficacy in this trial, and the antithrombin effect of bivalirudin is much greater than heparin. So, actually, receiving heparin ahead of time disadvantaged the bivalirudin arm, potentially by increasing bleeding, and heparin does not need to be given before bivalirudin."

Harrington also said that while the bivalirudin strategy looks reasonable in this setting, he is not ready to completely discount GP IIb/IIIa inhibitors just yet. "There is sizable body of evidence that suggests GP IIb/IIIa inhibitors improve ischemic outcomes. Perhaps what is needed is just more rational UFH use (although this is easier said than done). Remember that this was the situation moving from EPIC to EPILOG with abciximab. Lowering UFH dose not only translated into less bleeding but also better efficacy with abciximab," he noted. "Would much lower UFH added to GP IIb/IIIa blockers lead to less bleeding but still preserve ischemic benefit over the anticoagulant alone? Alternatively, if you could get uniform platelet inhibition on board with better ADP inhibition and then add bivalirudin, could you lower ischemic risk while maintaining benefit with regard to bleeding?" he added. Another suggestion made by Ferguson was that the results could have been even more dramatic with a longer bivalirudin infusion.

Stone replied: "Whether a lower heparin dose could decrease bleeding and thus improve outcomes in the control arm is something to consider, but I doubt it. ACUITY suggests the problem is the IIb/IIIa inhibitor, not the heparin, as the bleeding rates were increased and almost identical with bivalirudin plus IIb/IIIa inhibitors as with heparin plus IIb/IIIa inhibitors." He added that the addition of a rapid-acting P2Y12-inhibitor antiplatelet agent to further decrease ischemia in the early hours after bivalirudin is definitely a rational hypothesis that should be tested in a clinical trial. "Longer bivalirudin infusions or more aggressive antiplatelet therapy to decrease early ischemia within the first 24 hours with bivalirudin are interesting hypotheses but, unless formally tested, must remain as such. The brief bivalirudin regimen as tested in HORIZONS led to overall similar rates of reinfarction and lower mortality than the previous gold standard of heparin plus IIb/IIIa inhibitors, with much lower bleeding and thrombocytopenia, and thus this regimen should be embraced, not altered, unless strong evidence suggests otherwise. Any further attempts to reduce ischemia may again increase bleeding and eliminate the survival advantage," Stone commented.

Other issues raised by Ferguson were possible differences between the IIb/IIIa blockers or type of stent used. "We don't yet have data on the different IIb/IIIa antagonists, but there is not likely to be sufficient statistical power to really say anything. And we are still waiting for the drug-eluting stent vs bare-metal stent shoe to drop, to see whether outcomes are going to be similar and if stent thrombosis was more of a problem with the drug-coated stents."

Stone noted that there were no significant interactions between any of the three major end points and unfractionated heparin strata, GP IIb/IIIa inhibitor choice, or clopidogrel loading dose. "The stent arms remain blinded until next year, but we have not been informed of any major interactions that need to be disclosed. Studies have not shown any difference between drug-eluting stent and bare-metal stent thrombosis rates until beyond one year, anyway," he added.