March 14, 2006. Lisa Nainggolan

The new regimen of enoxaparin involves lower doses in elderly patients and those with renal dysfunction, and this translated into a reduction in bleeding compared with previous trials of enoxaparin in thrombolysis patients. However, it was still associated with an increase in major bleeding compared with UFH in this study.

Enoxaparin did not reduce mortality alone in EXTRACT-TIMI 25, but it did reduce the primary end point of death or nonfatal recurrent MI and was associated with a net clinical benefit when the efficacy and bleeding results were combined.

"It is our judgment that despite the increase in episodes of major bleeding, the early and sustained reduction in ischemic events and the balance of efficacy and safety . . . demonstrate the advantage of the regimen of enoxaparin over 48 hours of UFH as the adjunctive antithrombin regimen to support fibrinolysis," Antman and colleagues state.

The results of EXTRACT will undoubtedly be compared with those of the OASIS-6 study, also reported today at a late-breaking session at the meeting.

OASIS-6 is comparing another strategy of prolonged antithrombin therapy—this time with the factor Xa inhibitor fondaparinux—with 48 hours of UFH therapy in all patients with STEMI, including those undergoing primary PCI, those receiving no reperfusion therapy, and those undergoing thrombolysis.

The results of the subgroup of patients with STEMI who receive thrombolysis in OASIS-6 will thus be the most interesting to compare with the EXTRACT findings.

In the paper, Antman and colleagues explain that thrombolysis is the most common method of reperfusion worldwide for patients with STEMI, and contemporary guidelines recommend the routine administration of UFH for 48 hours, along with the thrombolytic agent and aspirin. But the use of UFH requires frequent monitoring to adjust the infusion rate to maintain a therapeutic range of anticoagulation.

LMWHs such as enoxaparin provide a reliable level of anticoagulation without the need for therapeutic monitoring and offer the advantage of subcutaneous administration.

In the study, 20 506 patients with STEMI who were scheduled to undergo fibrinolysis were randomized to receive enoxaparin (until hospital discharge or for a maximum of eight days, whichever came first) or UFH heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent MI through 30 days.

The dose of enoxaparin was reduced accordingly for those aged 75 years or older (they were given three quarters of the normal dose and the bolus was omitted) and in those who had clinically significant impairment in renal function (enoxaparin was given once a day, rather than twice).

The primary end point was significantly reduced in those patients who received enoxaparin—this was primarily driven by a 33% reduction in the rate of nonfatal MI in the enoxaparin group, as there was no significant difference in mortality between the two arms. A significant 26% reduction in urgent revascularization was also seen with the low-molecular-weight heparin.

"Our results suggest that a strategy of administering enoxaparin throughout the index hospitalization is superior to the current strategy of administering UFH for 48 hours as adjunctive therapy for patients with STEMI who undergo pharmacologic reperfusion with a fibrinolytic agent," say Antman and colleagues

Three factors may have contributed to the effects observed, they add. First, the superior antithrombotic effect of enoxaparin "may be explained, in part, by its greater ratio of anti-factor Xa to anti-factor IIa activity," they note. Second, a longer duration of treatment with enoxaparin may have helped, and finally, a possible rebound increase in thrombotic events after the discontinuation of UFH could have contributed.

However, they note, "We are unable to determine definitively the relative contributions of each of these factors to the results observed."

Major bleeding was significantly increased with enoxaparin, by 53%, but there was no significant increase in the rate of intracranial hemorrhage with the low-molecular-weight heparin (0.8% vs 0.7% with UFH; p=0.14), the investigators note.

"For every 1000 patients treated with the enoxaparin strategy, there would be 15 fewer nonfatal reinfarctions, seven fewer episodes of urgent revascularization, and six fewer deaths, at the cost of four additional episodes of nonfatal major bleeding (with no increase in the number of nonfatal intracranial hemorrhages)," they conclude.

1. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006; DOI: 10.1056/NEJMoao6o898. Available at: http://www.nejm.org.

Atlanta, GA - The thrombin inhibitor bivalirudin (Angiomax, The Medicines Company) was associated with significantly less bleeding than and a similar rate of ischemic events as a combination of heparin or enoxaparin plus a GP IIb/IIIa blocker in the ACUITY trial in patients with moderate- to high-risk non-ST-segment-elevation ACS heading to the cath lab. This gives a net clinical benefit in favor of bivalirudin alone.

However, bivalirudin plus a GP IIb/IIIa blocker failed to show superiority over heparin/enoxaparin plus a GP IIb/IIIa blocker; both bleeding and ischemic events were similar in these two groups, giving an almost identical result for the composite end point of ischemic events and major bleeding.

Lead investigator Dr Gregg Stone (Columbia University Medical Center Cardiovascular Research Foundation, New York, NY), who presented the data at the American College of Cardiology (ACC) 2006 Scientific Sessions, believes that bivalirudin monotherapy should replace heparin or enoxaparin and GP IIb/IIIa blockers in ACS patients heading to the cath lab. He told heartwire: "Bivalirudin monotherapy can markedly simplify and streamline our approach to ACS treatment. You can do away with the monitoring necessary with heparin, the increased bleeding shown with enoxaparin in SYNERGY, and the prolonged infusion and excess bleeding with the IIb/IIIa blockers."

One of the moderators of the late-breaking clinical-trial session at which the trial was presented said it is far too soon to be making that sort of statement. Dr Paul Armstrong (University of Alberta, Edmonton) commented to heartwire: "It is impossible to draw any firm take-home messages from the ACUITY trial based on this presentation. This is a very complicated trial presented in too short a time for people to make sense of it. To make recommendations on these results, we need to take a detailed look at the data, which has not been possible so far."

One of Armstrong's concerns focused on the dosage of enoxaparin used in the trial. "This trial suffers from the same problem that OASIS-5 did. It used enoxaparin at the package-insert dose, but we all know that this can cause excess bleeding in patients with reduced creatinine clearance. I need to study the data on these patients carefully before making any recommendations based on this study. This is the first time anyone outside the trial has seen any of the data, and there are too many pieces of information missing at this stage to know for sure whether bivalirudin monotherapy is actually the superior strategy."

Stone responded that there certainly needed to be more exploration of the data, but that there was no interaction with creatinine clearance. "We did not find a subgroup that did not benefit from the bivalirudin-monotherapy approach. The only subgroup that was different in any material way was [the one in which] clopidogrel [was used], and that suggested that if you pretreat with clopidogrel, the results look even better," he told heartwire.

Others said they would like to see data on unfractionated heparin (UFH) and enoxaparin separately before making any decisions about whether to change clinical practice. Dr Dan Simon (Brigham and Women's Hospital, Boston, MA) commented to heartwire: "The biggest issue for me about this trial is that they used a control group that is a blended mix of therapies. After SYNERGY, I don't use enoxaparin any more in ACS [patients] because there was no additional benefit and increased bleeding in that trial. Also, we go to the cath lab fast with these patients, and you need at least two doses of enoxaparin to get maximum therapeutic efficacy; there may not be time for that. I want to know how bivalirudin compares with unfractionated heparin without the enoxaparin patients included." Simon consults for Schering Plough (the manufacturer of eptifibatide) but receives research funding from both Schering Plough and The Medicines Company.

Stone responded to heartwire that data comparing UFH and enoxaparin will be presented at a later date. Preliminary data show that there was no difference in outcomes between patients receiving UFH and those given enoxaparin, but this was not a randomized comparison so must be subjected to multivariate analysis, he said.

Introducing his presentation, Stone explained that ACS patients are at significant risk for death and myocardial infarction. Many patients, especially those in the US, now undergo angiography and usually revascularization within the first 24 hours; an intensive drug regimen is given as soon as the patient arrives at the hospital before angiography. This includes aspirin, clopidogrel, UFH or low-molecular-weight heparin, and GP IIb/IIIa inhibitors to try to stabilize the disrupted atherosclerotic plaque. But these medications are associated with a high rate of bleeding complications, and the rate of adverse ischemic events still remains unacceptably high, Stone said.

The ACUITY trial was conducted to see whether the use of bivalirudin in place of UFH or low-molecular-weight heparin improves outcomes. The trial also examines whether the use of bivalirudin eliminates the need for the routine use of a GP IIb/IIIa blocker or whether the combination of bivalirudin and a GP IIb/IIIa blocker will improve outcomes further.

The ACUITY trial involved 13 819 patients with moderate- to high-risk ACS who all underwent cardiac catheterization within 72 hours; percutaneous or surgical revascularization was performed when appropriate. Patients were randomized to one of three arms: UFH or enoxaparin plus routine GP IIb/IIIa inhibition; bivalirudin plus routine GP IIb/IIIa inhibition; or bivalirudin alone, with GP IIb/IIIa inhibition only given as bailout (in this arm, around 7% of patients actually received a bailout GP IIb/IIIa blocker).

In the UFH/enoxaparin + GP IIb/IIIa inhibition arm, it was left to individual investigators to choose which agent to use; about half used UFH and half enoxaparin. Clopidogrel was recommended, but the dosage and timing was left to the individual investigators. A total of 60% of patients actually received clopidogrel: 30% came in already on it, 20% were given it before randomization, and 10% received the drug before going to the cath lab.

A second part of the trial involves a 2x2 randomization in the groups receiving routine GP IIb/IIIa blockers and looks at whether these are better started early (on presentation) or late (just before the patient goes to the cath lab). Of patients given a GP IIb/IIIa blocker up front, two thirds received eptifibatide and one third received tirofiban. Of those given a GP IIb/IIIa blocker in the cath lab, 60% received eptifibatide and 40% received abciximab. The results of this part of the trial will be reported at a separate presentation.

For the main part of the trial, the primary study end point is the composite of death, myocardial infarction, unplanned revascularization for ischemia, and major bleeding at 30 days.

The ACUITY trial had its own definition of major bleeding, which comprised the following: intracranial bleeding; intraocular bleeding; access-site hemorrhage requiring intervention; hematoma more than 5 cm in diameter; reduction in hemoglobin concentration of more than 4 g/dL without an overt source of bleeding; reduction in hemoglobin concentration of more than 3 g/dL with an overt source of bleeding; reoperation for bleeding; and use of any blood-product transfusion.

Results were presented for each bivalirudin arm separately compared with the UFH/enoxaparin arm.

When bivalirudin alone was compared with heparin/enoxaparin plus a GP IIb/IIIa blocker, there was a slight but nonsignificant increase in ischemic events; these results fell within the prespecified levels for noninferiority. However, the bivalirudin group showed significantly less major bleeding.

When UFH/enoxaparin plus a GP IIb/IIIa blocker was compared with bivalirudin plus a GP IIb/IIIa blocker, the bleeding advantage for bivalirudin disappeared; the primary composite end point was almost identical in the two arms. Thus, the trial failed to show superiority of the bivalirudin + GP IIb/IIIa blocker combination.

To make things even more complicated, the ISAR-REACT-2 trial, being presented later at the ACC, will also affect these results. That study is looking at whether GP IIb/IIIa blockade is needed if clopidogrel is already on board in patients similar to those studied in ACUITY.