ACUITY Published: Bivalirudin—An Alternative to Heparin Plus IIb/IIIa Blocker in ACS Patients Undergoing An Early Invasive Strategy

November 22, 2006

New York, NY - The ACUITY trial, suggesting that bivalirudin is an alternative to heparin/enoxaparin plus a glycoprotein (GP) IIb/IIIa inhibitor in moderate- or high-risk ACS patients undergoing an early invasive strategy, is published in the November 23, 2006 issue of the New England Journal of Medicine[1].

The trial--which was first presented, and reported by heartwire , last March at the American College of Cardiology meeting--showed a slight nonsignificant increase in ischemic events but a large reduction in bleeding with bivalirudin, compared with heparin plus a IIb/IIIa blocker, which translated into a net clinical benefit for bivalirudin.

Lead investigator Dr Gregg Stone (Columbia University Medical Center, New York), says: "After testing several different combinations of drug therapies, we found bivalirudin delivered by itself is as effective as combination drugs and results in less bleeding, which may lead to improved outcomes. Use of bivalirudin alone, rather than the more traditional anticoagulants, in ACS patients could prevent a significant number of major bleeding episodes and blood transfusions every year."

In an accompanying editorial[2], Dr John A Bittl ( Ocala Heart Institute, FL) says ACUITY provides "strong support" for the use of bivalirudin. Two other experts, who were not involved in the trial, told heartwire that, in their view, bivalirudin did not set a new standard but was definitely another option for some ACS patients.

In the ACUITY paper, investigators explain that an early invasive strategy--consisting of angiography followed by PCI, CABG, or medical management--is recommended for patients with moderate- or high-risk ACS, but that this strategy requires an intensive pharmacologic regimen, including aspirin, clopidogrel, a GP IIb/IIIa inhibitor, and an antithrombotic agent (either unfractionated heparin [UFH] or low-molecular-weight heparin), which together cause frequent hemorrhagic complications. They point out that bivalirudin is an alternative to heparin and that the ACUITY trial was designed to establish the usefulness of this new agent in this patient group.

The trial randomized 13 819 ACS patients to one of three antithrombotic regimens: UFH or enoxaparin plus a GP IIb/IIIa inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin alone (with provisional use of GP IIb/IIIa blockers only if required; they were actually used in 9% of this group).

The primary end points were a composite ischemia end point (death, MI, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding at 30 days.

Bivalirudin plus a GP IIb/IIIa inhibitor, compared with heparin plus a GP IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point, major bleeding, and the net clinical outcome end point.

Major results for bivalirudin + GP IIb/IIIa blocker vs UFH/enoxaparin + GP IIb/IIIa

End point
UFH/enoxaparin + GP IIb/IIIa inhibitor (%)
Bivalirudin + GP IIb/IIIa inhibitor (%)
Relative risk (95% CI)
p for superiority
p for noninferiority
Composite ischemic end point
7.3
7.7
1.07 (0.92–1.23)
0.39
<0.007
Major bleeding
5.7
5.3
0.93 (0.78–1.10)
0.38
<0.001
Net clinical outcome
11.7
11.8
1.01 (0.90–1.12)
0.93
<0.001

Bivalirudin alone, compared with heparin plus a GP IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point and significantly reduced rates of major bleeding and the net clinical outcome end point.

Major results for bivalirudin alone vs UFH/enoxaparin + GP IIb/IIIa

End point
UFH/enoxaparin + GP IIb/IIIa inhibitor (%)
Bivalirudin alone (%)
Relative risk (95% CI)
p for superiority
p for noninferiority
Composite ischemic end point
7.3
7.8
1.08 (0.93-1.24)
0.32
0.01
Major bleeding
5.7
3.0
0.53 (0.43-0.65)
<0.001
<0.001
Net clinical outcome
11.7
10.1
0.86 (0.77-0.97)
0.015
<0.001

Clopidogrel treatment: The only subgroup that shows an interaction

Stone et al note that subgroup analysis revealed no significant interactions between the primary study end points and numerous demographic and treatment variables, with the possible exception of the administration of clopidogrel before angiography or PCI. They report that clopidogrel was given to 64% of patients before angiography or PCI. In these patients, the point estimate for composite ischemic events was similar with bivalirudin monotherapy and with heparin plus GP IIb/IIIa inhibitors.

In contrast, in patients who were not pretreated with clopidogrel, the point estimate for adverse ischemic events was slightly higher with bivalirudin monotherapy than with heparin plus GP IIb/IIIa inhibitors.

Addressing this difference, Stone et al say: "Given the borderline statistical significance of the interaction (p=0.054) and the risk of a spurious finding from examination of multiple subgroups, caution against overinterpretation is warranted. Nonetheless, the administration of a thienopyridine before angiography may be desirable to optimize outcomes with a regimen of bivalirudin monotherapy."

Short time to angiography

One point that has been the subject of discussion was the short time from administration of the study drug to angiography (median: 3.5-4 hours). The authors agree that the time to angiography was relatively short but point out that bivalirudin monotherapy was also associated with a significantly lower risk of bleeding and similar rates of ischemia in the subgroup of patients for whom the interval from randomization to angiography or intervention was more than 24 hours.

Some caveats

The researchers point out that the results of this study do not apply to ACS patients who are managed solely with a noninvasive strategy or for a prolonged period (>72 hours) before catheterization or to patients with severe renal insufficiency, who were excluded from enrollment.

Another issue that has been raised is the 25% noninferiority margin used, which is wider than in many other studies. Although conceding that the noninferiority margin might be considered wide, the ACUITY investigators state: "As the rate of ischemic events in the control group was 7.3%, an estimated ischemic-event rate as high as 9.1% in the test groups would have been considered noninferior, even though it might be regarded as clinically important. However, given the observed event rates and confidence intervals, there was a 95.0% likelihood that the incidence of composite ischemia in the bivalirudin-monotherapy group was less than 20% higher than the incidence in the control group."

Positive editorial

In the accompanying editorial, Bittl says the main results of the ACUITY trial are clear. "The nominal 7% decrease in bleeding events seen with bivalirudin plus a glycoprotein IIb/IIIa inhibitor offset the nominal 7% increase in ischemic events, which resulted in a near-perfect balance in the composite event rates. . . . The significant 47% reduction in bleeding seen with bivalirudin monotherapy offset the noninferior 8% increase in ischemic events and produced a small significant 14% reduction in net clinical outcomes at 30 days, which corresponded to an absolute decrease of 1.6 percentage points from the control group."

He says the trial provides strong support for the use of bivalirudin as a substitute for heparin plus GP IIb/IIIa inhibitors in ACS patients who undergo early invasive management, particularly if they are pretreated with clopidogrel.

Bittl says that the clopidogrel-subgroup findings suggest but do not prove conclusively that patients treated with bivalirudin monotherapy should be pretreated with clopidogrel in a dose of 300 mg six hours before PCI, but a dose of 600 mg as early as two hours before PCI remains controversial. Patients who require urgent PCI but have not been adequately pretreated with aspirin or clopidogrel should receive a GP IIb/IIIa inhibitor, he adds.

Experts in the field were asked by heartwire for their opinion on the ACUITY results, now that they are published and, on the whole, the comments were relatively positive.

Steinhubl: "Major step forward"

Dr Steven Steinhubl (University of Kentucky, Lexington), who was cochair of the ACUITY inflammation substudy, says the trial is a "major step forward" in improving the treatment of patients with an acute coronary syndrome in whom invasive management is planned. "I believe it provides reassurance in the one important group of patients not well represented in REPLACE-2--the higher-risk ACS patients--that bivalirudin alone is an effective alternative to heparin plus a GP&#160;IIb/IIIa antagonist," he told heartwire .

He adds that troponin-positive patients are really the only subgroup of possible ACS patients in whom antithrombotic therapy has been shown to make a difference, and although the 1% absolute increase in ischemic events with bivalirudin in this arm is a concern, the 2.6% absolute decrease in major bleeding suggests that long-term cardiovascular outcomes will favor the bivalirudin arm. He thinks too much is being made of the clopidogrel pretreatment issue. "The timing, dose, and duration of clopidogrel pretreatment is not well documented and may be just a chance finding. The ISAR-REACT trial will help determine whether bivalirudin plus P2Y12 blockade have complementary roles, but until then I will not let the lack of clopidogrel pretreatment influence my use of bivalirudin."

Harrington/Ferguson more guarded

Drs Robert Harrington (Duke University, Durham, NC) and James Ferguson (Texas Heart Institute, Houston ), neither of whom were involved in the study, were slightly more guarded in their response to ACUITY.

Harrington has some reservations about the study, including the fact that the results apply to just a select group of moderate- to high-risk patients who are managed in an expedited fashion with an invasive strategy and that the noninferiority margin was large. He says the clopidogrel data are "intriguing" and "yet another factor that must be considered in selecting an antithrombotic strategy for these patients." He concluded: "The bottom line for me is that unfractionated heparin, low-molecular-weight heparin, fondaparinux, and bivalirudin all appear to have a role as anticoagulants in the treatment of NSTE ACS. How one chooses largely depends on the local practice style, including the use and timing of an invasive strategy. There is still much work to be done to determine optimal combinations of drugs, including antiplatelet therapies, because 30-day event rates, including bleeding, remain high."

Ferguson, who was the chief investigator of the SYNERGY trial of enoxaparin in ACS, takes a similar line, saying: "For me, ACUITY does not define a new standard but gives us another pharmacological option that physicians can consider in treating ACS patients." He notes: "What we saw in ACUITY is pretty much identical to what we saw in REPLACE-2--less bleeding and generally similar clinical outcomes. But "generally similar" becomes a somewhat slippery slope, depending on whether you were a bivalirudin believer or not going into the trial." On the clopidogrel difference, he states: "Bivalirudin advocates say this means we need to use more clopidogrel early, and anybody who has received clopidogrel should get bivalirudin monotherapy. The bivalirudin skeptics will suggest that if you have not already loaded with clopidogrel you should not use bivalirudin alone." Although acknowledging that ACUITY solidifies the role of bivalirudin in the cath lab, Ferguson feels that patients with a positive troponin would still benefit from GP&#160;IIb/IIIa antagonists.

"The message for me is not necessarily that bivalirudin needs to be the drug you start in the ER and carry forward all the way until the patient comes to the cath lab--instead, what ACUITY tells me is that bivalirudin monotherapy is a reasonable option to consider when you have made the decision to go to the cath lab in the very near future. But ACUITY has also taught me that if you have already decided to give a GPIIb/IIIa antagonist, there is no advantage whatsoever in choosing bivalirudin over a heparin," he adds.

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