Many experts not involved in ACUITY are reluctant to comment on the trial, saying they need to see more of the data before making any decisions about the results. But a few cardiologists did venture some preliminary opinions, and many appear to be cautiously positive about bivalirudin monotherapy. One view seems to be that a combination of bivalirudin and clopidogrel is a good strategy for troponin-negative patients, while the jury is still out for troponin-positive patients. But the ACUITY investigators claim that bivalirudin monotherapy is the optimal approach for all patients, even those with elevated troponins.

The view of the ACUITY steering committee is that bivalirudin will now become the antithrombin of choice for upstream use in ACS patients in whom early intervention is the planned strategy. Principal investigator Dr Gregg Stone said: "The bottom line is that bivalirudin monotherapy is as good as UFH or enoxaparin plus a IIb/IIIa blocker, but with far less bleeding. Bivalirudin monotherapy will facilitate care tremendously. We can now use one IV instead of two, and we don't need any monitoring."

Dr Jeffrey Moses, who is also on the ACUITY steering committee, agrees: "The trial is complicated, but the message is simple: the best therapy for hot ACS is upfront bivalirudin, with a clopidogrel loading dose and early intervention." Moses also noted that, as well as major bleeding being almost halved with bivalirudin monotherapy, minor bleeding was also significantly reduced. "While a reduction in minor bleeding may not save lives, it will make life much easier and shorten hospital stays."

Moses pointed out to heartwire that the one subgroup in which there did appear to be an interaction in ACUITY was the group pretreated with clopidogrel. "Bivalirudin monotherapy showed a greater relative risk reduction in events in the patients who received clopidogrel than in those who did not get clopidogrel. This is probably because the combination of the antiplatelet effect and the antithrombin effect is the optimal combination for efficacy and safety."

Dr Harvey White (Green Lane Cardiovascular Service, Auckland City Hospital, New Zealand), also a member of the ACUITY steering committee, makes some additional points: "I think the ACUITY trial results need to be considered in the light of the patient risk and the early time of going to the cath lab after randomization. For patients going to the cath lab early, bivalirudin without IIb/IIIa antagonists is as effective as unfractionated heparin or enoxaparin plus IIb/IIIa antagonists, and there is significantly less bleeding, including transfusions; it is easier to use and sheaths can be pulled early. And bivalirudin given together with aspirin and clopidogrel is a particularly attractive option," he told heartwire. "It seems that early in the cath lab an antithrombin effect is important, and if you use unfractionated heparin a IIb/IIIa antagonist may be required. Later on, a factor Xa inhibitor such as fondaparinux, which decreases the production of thrombin, seems to work well, if a small amount of unfractionated heparin is also given to reduce the incidence of catheter thrombus formation. Enoxaparin, which has both upstream inhibition of factor Xa and antithrombin effects, also works well, but it may need the first dose to be given intravenously if the strategy is to go to the cath lab very early (ie, in the first six hours)," he added.

Speculating on why the combination of bivalirudin plus a IIb/IIIa blocker was no better than bivalirudin alone, White said: "Adding a IIb/IIIa antagonist to bivalirudin had no effect of efficacy and just increased bleeding. This may be because, whereas unfractionated heparin and enoxaparin activate platelets, bivalirudin inhibits thrombin-mediated platelet activation."

Cardiologists who were not involved in the trial were more guarded in their opinions. Dr Bob Harrington (Duke University, Durham, NC) summed up many observers' feelings that it was premature to be making any recommendations based on ACUITY before the paper had been published. "This is a complex trial to understand, and the presentations at the ACC were packed with information. But there was not enough time for detailed discussion in a public forum. We need to see the peer-reviewed publications before recommending any immediate change in practice," he commented to heartwire. "A recent JAMA paper showed how abstracts and late-breaking clinical-trial results evolve from presentation to publication. It is always good practice to await the full publication of data," he added.

Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA) said: "Overall, the bivalirudin-alone strategy has some appeal, since avoiding bleeding is growing in importance as a goal of therapy in ACS. Now we all have to integrate the four different options we now have for anticoagulation (UFH, enoxaparin, fondaparinux, and bivalirudin) to see what should be used in different patients."

Dr Matt Wolff, who was one of the moderators of the late-breaking-trial session at which ACUITY was presented, noted: "The problem with ACUITY in my view is that it was so complicated—it was trying to address many different issues—so that the results become difficult to interpret. And in ACUITY Timing, looking at early vs late use of IIB/IIIa blockers, there were only five hours separating the two groups, which is not really enough for a meaningful comparison."

He added: "On the whole, I think bivalirudin looks pretty good. But I would like to see more of the data before I know for sure. In particular, I would like to see the specifics of the bleeding information. As a reduction in bleeding is responsible for the benefit with bivalirudin compared with heparin plus a IIb/IIIa blocker, it really depends on what sort of bleeding was reduced. If really important bleeding like transfusions was reduced, that may be good enough to switch to bivalirudin alone instead of heparin plus a IIb/IIIa blocker, but I would be reluctant to make that switch if it was just the less-severe bleeding that was reduced, unless there was also improved efficacy in terms of fewer ischemic events or reduced cost.

"I will also want to study exactly what doses of heparin and the IIb/IIIa blockers were used before making up my mind about this trial. But I would say that if all these caveats are met, the ACUITY results probably will influence clinical practice," Wolff said.

Stone responded to heartwire that "bivalirudin monotherapy was associated with significant reductions in retroperitoneal bleeding, major organ bleeding, and other types of bleeding that almost all caregivers would agree are clinically relevant, including blood transfusions. Given numerous recent studies showing the prognostic importance of major bleeding and transfusions, the reduction in major bleeding and transfusions with bivalirudin is a significant advance in the care of patients with acute coronary syndromes."

But several experts have highlighted the fact that bivalirudin did not actually reduce bleeding compared with UFH or enoxaparin in the direct head-to-head comparison (with both groups receiving IIb/IIIa blockers). One of these, Dr Shamir Mehta (McMaster University, Hamilton, ON), says: "The PR on bivalirudin is that it reduces bleeding compared with UFH, but in the comparison in which both groups received IIb/IIIa inhibitors (which is the fairest comparison), there was no significant difference between bivalirudin and UFH/enoxaparin in major bleeding, and the net clinical outcome (composite of ischemic and bleeding end points) was virtually the same." Cannon makes the same point: "What I found interesting is that relative to heparin (with all patients getting IIb/IIIa inhibition), there was no advantage of bivalirudin on bleeding," he commented.

Mehta added: "It is only when bivalirudin alone is compared with UFH/enoxaparin plus a IIb/IIIa blocker that a reduction in bleeding is seen, but this is an expected finding. Any comparison of one antithrombotic drug vs two antithrombotic drugs is bound to show less bleeding in the monotherapy group."

Another issue highlighted by many is the observation that the main benefit of bivalirudin monotherapy compared with UFH plus IIb/IIIa blocker occurred in the lower-risk patients (those without raised troponins) and that there was no significant difference in the net clinical outcome between the two groups in high-risk patients (those with raised troponins), the population in whom the IIb/IIIa blockers are used most and for which they have a class 1A recommendation.

Mehta commented: "As bleeding was probably reduced in all groups, as would be expected when pitting one agent against two, the fact that there was no net clinical benefit in troponin-positive patients leads one to wonder whether ischemic events may have been increased with bivalirudin monotherapy in this subgroup." Noting that these data have not yet been presented, he says: "It will be key to see the ischemic events/bleeding data in the high-risk (troponin-positive) subgroup, as this group benefits from IIb/IIIa blockers the most. Until we are reassured that ischemic events in this group are not increased, I'm not sure I'd feel comfortable using bivalirudin alone in high-risk patients."

Harrington made a similar point: "There were insufficient data to understand the issue of ischemic events among troponin-positive patients. This is an important high-risk group who we know get preferential benefit to platelet inhibition with a IIb/IIIa blocker," he noted.

Others to mention troponin status as a possible caveat to the ACUITY results were Dr Steven Steinhubl (University of Kentucky, Lexington) and Dr Dan Simon (Brigham and Women's Hospital). Steinhubl commented to heartwire: "In general, I think the ACUITY data are very encouraging for bivalirudin, although I would like to see the data based on troponin status before I completely give up on IIb/IIIa antagonists in NSTEMI patients." And Simon said: "Bivalirudin use will undoubtedly increase on the basis of ACUITY—we use it in about 35% of our ACS patients at present, and I would predict that this will now increase to about 50%, as it will probably capture most of the troponin-negative patients. But I'm not sure if doctors will want to stop using IIb/IIIa blockers in troponin-positive patients on the basis of this data. IIb/IIIa blockers have a class IA recommendation for troponin-positive patients, and doctors generally follow class IA recommendations."

Stone responded on this issue: "The effects of bivalirudin monotherapy compared with heparin plus IIb/IIIa inhibitors regarding all three primary end points, including reducing net clinical outcomes, being noninferior for composite ischemia, and reducing major bleeding, were consistent in all risk categories, including baseline elevated troponins or biomarkers, baseline ST deviation, and TIMI low- vs moderate- vs high-risk-score patients. We only had time at the ACC to show the composite-outcomes subgroups. Thus bivalirudin monotherapy is the optimal approach for all patients, even those with elevated troponins. All these data will appear in great detail in the manuscript."

The time at which bivalirudin was started and how long it was given for before the patient went to the cath lab are other points of discussion.

Dr Doug Weaver (Henry Ford Heart and Vascular Institute, Detroit, MI), another of the moderators at the late-breaking clinical-trial session, commented to heartwire: "The ACUITY findings suggest that bivalirudin can be used in the hours prior to cath instead of the combination of heparin and a IIb/IIIa antagonist in ACS patients, but the treatment time was relatively short (five hours). I'd like to know if the findings would have been similar if the treatment had been started 12 to 30 hours prior to cath, which probably more closely reflects the typical delays and precath times in the US."

Harrington made a similar point: "There was a long period between presentation and randomization with a very short time on treatment to cath. This won't be standard practice—treatment will usually be initiated much earlier, so ACUITY selected a group of patients who survived the early high-risk hours. This notion of true upstream treatment requires a bit more reflection." He added that costs will also be important, "given that much longer infusions than used in ACUITY are what will be needed in practice, where time to cath averages just short of a day."

Stone responded to heartwire that the way the data were reported might have led to some confusion about exactly when treatment was started. "The data were reported in medians, and when dealing with medians, one cannot simply add or subtract subintervals to determine the differences. Thus, the median time from admission to randomization in ACUITY was 6.0 hours; the median time from randomization to study antithrombin drug administration was 0.5 hours; the median time from study drug to angiography was 4.1 hours; and the median time from admission to angiography was 19.7 hours," he reported. "We didn't have time to show all these data at the ACC, but bottom line, there was not a long time between admission and randomization or treatment. Thus, it is not true that ACUITY selected just patients that survived the early high-risk hours. Also, these are not STEMI patients—not many unstable-angina patients are dying within the first six hours of admission. All these data will appear in the manuscript," he added

And what about ISAR-REACT 2? How does this trial fit together with the ACUITY results?

Moses suggested to heartwire that the heparin-plus-abciximab arm in ISAR-REACT 2 was similar to the control arm (heparin or enoxaparin plus a IIb/IIIa blocker) in ACUITY, and so bivalirudin monotherapy given upstream still looks like the superior strategy. "ACUITY suggests that if bivalirudin had been used as the antithrombotic instead of heparin in ISAR-REACT 2, abciximab would not have shown the same benefits," he commented. He added: "The ISAR-REACT 2 results show that we used the correct regimen of a heparin plus a IIb/IIIa blocker as our control arm in ACUITY. If no additional benefit had been shown with abciximab in ISAR-REACT 2, people would have said that we should have used heparin alone as our control group. But as it is, the heparin/abciximab arm came out better in ISAR-REACT 2, and bivalirudin alone beat this combination in ACUITY."

But Mehta and Harrington both make the point that the ISAR-REACT 2 results reinforce the question of whether bivalirudin monotherapy would be sufficient in troponin-positive patients. Mehta says: "ISAR-REACT 2 confirms previous data showing that we do need to use IIb/IIIa blockers in troponin-positive patients. So this highlights the fact that in ACUITY the group we really need to focus on are those with raised troponins, and ACUITY actually showed no benefit from bivalirudin in that group." Harrington agrees: "Troponin-positive patients are an important high-risk group, and ISAR REACT 2 is the latest trial to show that this group gets preferential benefit to platelet inhibition with a IIb/IIIa blocker," he noted.

Chief investigator of ISAR-REACT 2, Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany), points out that there were many differences between his trial and ACUITY, and he believes the two studies cannot be directly compared. "In ACUITY, patients were randomized on first presentation, and 43% of them never even received a PCI. Patients who do not undergo PCI need neither IIb/IIIa blockers nor bivalirudin. Whereas in ISAR-REACT 2, we randomized patients in the cath lab and all patients received a PCI. Also, our patients were a higher-risk group than those in ACUITY. And the control group in ACUITY was a mixture of all sorts—two different types of heparin, three different IIb/IIIa blockers given at two different times (prior to cath lab and in the cath lab). In our trial, the heparin/IIb/IIIa-blocker arm was one regimen—unfractionated heparin and abciximab given in the cath lab," he told heartwire. Kastrati believes that another trial is probably needed in which high-risk ACS patients with raised troponins are randomized in the cath lab to heparin plus abciximab or bivalirudin alone.

But one of the moderators of the session at which ISAR-REACT 2 was presented, Dr Bernard Gersh (Mayo Clinic, Rochester, MN) was not convinced such a study is necessary. He commented to heartwire: "Okay, there are subtle differences between the two trials, but bivalirudin showed a clear benefit over heparin plus a IIb/IIIa blocker in ACUITY and was even better in the presence of clopidogrel. So I would feel comfortable not giving abciximab in the cath lab even after the ISAR-REACT 2 results."