ACUITY: Less bleeding with bivalirudin

Treatment associated with reduction in 30-day clinical outcome.

ATLANTA – Patients with acute coronary syndromes who were given bivalirudin had superior clinical outcomes at 30 days compared with those who were given unfractionated heparin or enoxaparin along with a GPIIb/IIIa inhibitor, or a combination of bivalirudin and GPIIb/IIIa inhibition.

Bivalirudin (Angiomax, The Medicines Co.) was associated with a reduction in bleeding compared with the other treatment regimens. Bleeding was reduced even further when interventionists delayed the administration of GPIIb/IIIa inhibitors until the patient was in the catheterization lab.

Those who received the GPIIb/IIIa inhibitors earlier, however, had lower rates of unplanned revascularization for ischemia.

Dan Simon, MD, said he attended both the main ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy Trial) and the ACUITY Timing trial, which were presented by Gregg W. Stone, MD, director of cardiovascular research and education at Columbia University Medical Center’s Center for Interventional Vascular Therapy.

“An interventional cardiologist may come away from these trials confused,” said Simon, associate director of interventional cardiology at Brigham and Women’s Hospital. “On the one hand, you don’t need the addition of GPIIb/IIIa inhibitors when you use bivalirudin, but if you do use them it’s probably better to use them upstream.”

ACUITY design

ACUITY was designed to determine the best adjunct pharmacologic treatment strategy for patients with moderate to high-risk acute coronary syndromes who had presented at the emergency department for an invasive strategy.

Researchers enrolled 13,819 patients from 448 centers in 17 countries and randomized them to one of three strategies: unfractionated heparin or enoxaparin (Lovenox, Sanofi-Aventis) plus a GPIIb/IIIa inhibitor; bivalirudin plus a GPIIb/IIIa inhibitor; or bivalirudin alone.

For a secondary timing analysis, the patients in the two arms who had received a GPIIb/IIIa inhibitor were further randomized to receive the GPIIb/IIIa inhibitor immediately upon presentation or to delayed administration in the cath lab. Choice of GPIIb/IIIa inhibitor was based on operator discretion, and a majority of the clinicians chose eptifibatide (Integrilin, Millennium/Schering).

To be enrolled in the trial, patients had to present with unstable angina or non ST-segment elevation MI with 10 minutes of cardiac chest pain within 24 hours plus either biomarker elevation, electrocardiogram changes or documented prior disease.

All randomization was done on a one-to-one ratio. The mean age of the patient cohort was 63 years, 30% were women and 20% had diabetes.

Main ACUITY trial

For the larger ACUITY trial, Stone presented a number of comparisons.

Compared with the unfractionated heparin or enoxaparin plus GPIIb/IIIa inhibition, treatment with bivalirudin alone was associated with a significant reduction in the 30-day clinical outcome from 11.7% to 10.1% (P=.015). However, the bivalirudin plus GPIIb/IIIa inhibitor group was only noninferior to unfractionated heparin or enoxaparin plus GPIIb/IIIa inhibition at 11.8%.

A 30-day composite ischemic outcome was similar in all three groups at approximately 7.5%.

Major bleeding was significantly lower in the bivalirudin alone group at 3% compared with 5.7% in the unfractionated heparin or enoxaparin plus GPIIb/IIIa inhibitor group. Patients given bivalirudin plus a GPIIb/IIIa inhibitor had a 5.3% rate of major bleeding, which was noninferior to the rate seen in the unfractionated heparin or enoxaparin plus a GPIIb/IIIa inhibitor group.

Conclusion in ACUITY trial raises questions by Walter Alexander Today in Cardiology CORRESPONDENT ATLANTA — Gregg W. Stone, MD, derived a definitive conclusion from the ACUITY trial: “Compared to either unfractionated heparin or enoxaparin with GPIIb/IIIa inhibition or bivalirudin with GPIIb/IIIa inhibition, a bivalirudin-alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days.” Other experts at the American College of Cardiology Scientific Session 2006 were hesitant about that conclusion or asked for more time to study the ACUITY findings. ACUITY was a prospective, randomized comparison of unfractionated heparin or enoxaparin plus a GPIIb/IIIa inhibitor, and bivalirudin with or without a GPIIb/IIIa inhibitor in patients with acute coronary syndromes. Stone said that for all three endpoints, bivalirudin (Angiomax, The Medicines Co.) plus a GPIIb/IIIa inhibitor met criteria for noninferiority but not superiority compared with unfractionated heparin or enoxaparin (Lovenox, Sanofi-Aventis) plus a GPIIb/IIIa inhibitor. Bivalirudin alone also met noninferiority criteria for all three endpoints compared with unfractionated heparin or enoxaparin plus a GPIIb/IIIa inhibitor. It met superiority criteria for net clinical outcome and major bleeding, he said. None of the arms met superiority criteria for any of the components of the ischemic composite. Net clinical outcome included an ischemic composite (death, MI, or unplanned revascularization for ischemia) and major bleeding. During an interview, Eric D. Peterson, MD, associate professor of cardiology, Duke University Medical Center, said that almost half of ACUITY patients “ruled out for MI” based on serial cardiac markers. “In that population, it’s hard for any antithrombotic regimen to make well patients better.” “We don’t know yet if there was a differential effect for the more intensive regimens in patients with positive markers. If there is, then ACUITY has been very helpful in targeting where we should be more intensive and where less. If there isn’t, then Gregg’s conclusion that bivalirudin is an excellent and perhaps safer alternative to unfractionated heparin and low molecular weight heparin is reasonable,” Peterson said. Session moderator Paul Armstrong, MD, professor of medicine at University of Alberta, Edmonton, Canada, was uncomfortable with Stone’s firm take-home message because of the lack of time available for analysis of the large and complex trial containing multiple subgroups. He said in an interview that “ACUITY’s use of enoxaparin at the package insert dose may be problematic, given that in patients with reduced creatinine clearance, for example the elderly, excretion of enoxaparin is likely impaired and can contribute to excess bleeding. The profile of elderly patients in OASIS-5 recently published in the New England Journal of Medicine supports this message.” Peterson receives research support from Schering-Plough, Bristol-Myers Squibb, and Sanofi-Aventis.

Timing trial

For the timing portion of the trial, researchers further randomized those patients who had received GPIIb/IIIa inhibition to upstream use or delayed use. Those who received the agents upstream received them 0.6 hours after randomization, whereas the delayed patients waited 4.6 hours. Nearly all of the patients in the upstream arm received a GPIIb/IIIa inhibitor, whereas only 55.7% of patients in the delayed arm received the agents.

No differences were noted in either the net clinical outcome or the composite ischemic outcome.

However, delayed use of GPIIb/IIIa inhibition was associated with a reduction in ACUITY-defined major bleeding from 6.1% in the upstream group to 4.9% in the delayed group (P=.009). TIMI minor bleeding was also lower in the delayed group at 5.4% compared with 7.2% (P<.001).

When researchers measured the components of the clinical outcome, there was no difference in mortality or MI, but unplanned revascularization for ischemia was lower in the upstream group at 2.1% compared with 2.8% in the delayed group (P=.03).

“The problem right now is that we don’t have all the data. Once we have the peer-reviewed manuscript, it will make more sense,” Simon said. “In the meantime, the use of bivalirudin in our cath lab is likely to go from about 30% to 35% of cases to about 50% to 55%, and I think that’s reasonable.” – by Jeremy Moore

Simon is a consultant and member of the speaker bureau for Cordis/Johnson&Johnson and Schering and he receives research support from Schering and The Medicines Co.

For more information:

• Stone GW, McLaurin BT, Ware JH, et al. Prospective, randomized comparison of heparin plus IIb/IIIa inhibition and bivalirudin with or without IIb/IIIa inhibition in patients with acute coronary syndromes: the ACUITY trial.
• Stone GW, Cox DA, Pocock SJ, et al. Prospective, randomized comparison of routine upfront initiation versus selective use of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes: the ACUITY timing trial. Both presented at the American College of Cardiology Scientific Session 2006. March 11-14, 2006. Atlanta.