The ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) Trial: What`s the Next Step for Bivalirudin After R

What is the basic study strategy behind the ACUITY trial? ACUITY will enroll 13,800 patients with moderate-to-high unstable angina, all of whom are intended to undergo an invasive strategy. These patients will usually be in the cath lab within 48 hours for diagnostic evaluation and then triage to either surgery, angioplasty, or medical therapy, as best dictated by their anatomy. We’re randomizing trial patients to create three arms up front. Everything starts in the emergency room when the patients present, and they will undergo one of three options: 1. The current standard, which is a heparin (in this case, the low-molecular weight heparin enoxaparin) and a IIb/IIIa inhibitor; 2. Bivalirudin plus a IIb/IIIa inhibitor, or; 3. Bivalirudin alone. The therapy will be continued throughout catheterization and any interventional procedures. In addition, there is a second randomization for the first two groups of patients who received either enoxaparin plus a IIb/IIIa inhibitor or bivalirudin plus IIb/IIIa inhibitor. The IIb/IIIa inhibitor will be randomized as well, either to be started up front at the time of randomization, or withheld and only started in the cath lab at the time of angioplasty, if angioplasty occurs. The principal endpoints are at 30 days, and the patients will be followed for one year. The primary endpoint is a composite of death, myocardial infarction, unplanned revascularization for ischemia, or major hemorrhage. We’ll be looking at those individual components as well in the short term, long term, and numerous other endpoints. What are some of the major clinical questions that are going to be answered in this trial? The principal question is how to best anticoagulate patients with acute coronary syndromes (ACS). The best approach includes an early invasive strategy, without question. There are still major questions that exist, however. The first question is whether heparin, either unfractionated or low-molecular weight heparin such as enoxaparin, both of which are class I indications in ACS, is indeed the best drug to use. The ideal anticoagulant should minimize ischemic complications, i.e. myocardial infarctions and recurrent ischemia requiring unplanned revascularization procedures. At the same time, minimizing major bleeding is crucial. Major bleeding is an iatrogenic side effect of all anticoagulants. ACS patients are placed on several anticoagulants simultaneously, including aspirin, clopidogrel or ticlopidine, on top of which they receive heparin and a IIb/IIIa inhibitor. There are three main questions we hope to answer in ACUITY: 1. Currently, the most widely accepted class I anti-thrombin is enoxaparin. Is this, however, truly the best regimen to use, or is the direct thrombin inhibitor bivalirudin superior? In the REPLACE-2 trial, bivalirudin, when compared to unfractionated heparin and a IIb/IIIa inhibitor in patients undergoing elective angioplasty, was associated with similar prevention in ischemic complications, but also provided significant reduction in major bleeding. Will bivalirudin alone result in similar outcomes (when compared to enoxaparin and a IIb/IIIa inhibitor) in patients with acute coronary syndromes who are on the drugs for a day or two before undergoing angiographic triage, and then possibly revascularization? If so, this would markedly streamline care and decrease costs, as well as reduce major hemorrhagic complications. 2. Will bivalirudin plus a IIb/IIIa inhibitor be even more effective in preventing ischemic complications in patients with unstable angina than enoxaparin and a IIb/IIIa inhibitor, while at the same time slightly decrease or at least not increase major bleeding? 3. Glycoprotein IIb/IIIa inhibitors also enjoy a class I indication in all patients with unstable angina. Is it best to start these agents up front at the time of presentation, or is it preferable to wait until angiography, define the anatomy, and then start IIb/IIIa inhibition just prior to angioplasty in those patients treated in this fashion? The proponents of starting these agents up front would say this is best, because during the day or so you’re waiting prior to catheterization and definitive revascularization, some patients will infarct die, events which a IIb/IIIa inhibitor might prevent. The proponents of waiting would say that doesn’t happen very often, that bleeding might occur while you’re on these agents, and that they’re expensive. Moreover, the people who benefit the most from IIb/IIIa inhibitors are those undergoing angioplasty. IIb/IIIa inhibitors may not be necessary in patients treated medically or surgically. To address this unsettled issue, patients in the IIb/IIIa inhibitor arms will be randomized to either upfront initiation, or restricted to the cath lab, just in those patients undergoing angioplasty. How important is bleeding in this patient population? Bleeding is very important. We’re learning more and more that significant bleeding is a major cause of mortality. In the REPLACE-2 study, major bleeding was a greater predictor of long-term mortality than was detecting evidence of peri- procedural myonecrosis or infarction. Obviously they’re both undesirable, but major bleeding is not uncommon, especially in patients undergoing angioplasty and surgery, and should be avoidable. The risk of major bleeding on all of the anticoagulants in ACUITY is relatively low while the patient is maintained on intravenous infusions and waiting for his or her procedure to take place. Once the procedure begins, however, the risk of major bleeding is not trivial and the rate may significantly vary with different agents. Are there features of bivalirudin that make it a good anticoagulation option for patients? Yes. By not activating heparin and blocking the PAR receptor on the platelet surface, bivalirudin has an intrinsic anti-platelet effect in blocking thrombin-induced platelet aggregation. As thrombin is the most potent endogenous stimulus of platelet clotting, bivalirudin, in combination with aspirin and a thienopyridine to inhibit the other arms of platelet aggregation, is approximately as effective as a IIb/IIIa inhibitor and unfractionated heparin in preventing the ischemic complications of angioplasty, as seen in REPLACE-2. Moreover, bivalirudin has a short half-life of approximately 25 minutes, and thus when this agent is turned off, hemostatic function quickly returns, minimizing bleeding and allowing early sheath withdrawal. This is probably the main reason that major bleeding was reduced approximately 40% in REPLACE-2. Bivalirudin is also a very cost-effective option. We expect these benefits to accrue to ACS patients in addition to those undergoing elective angioplasty, and we hope to demonstrate this in ACUITY. Can you talk a little about how clopidogrel will be used in this trial? Clopidogrel will be used per institutional standards. The study does not specify when clopidogrel should be initiated, which is the central question. There are varying ways that physicians use clopidogrel in patients with unstable angina. Some feel very strongly, on the basis of studies such as CREDO and CURE, that clopidogrel should be administered up front and as soon as possible, with a large loading dose. Such early therapy is the best way to prevent ischemic complications, especially in patients undergoing angioplasty. On the other hand, if clopidogrel is given before the coronary anatomy is known, and then the results of cardiac catheterization dictate bypass surgery, having taken clopidogrel prior to surgery is a significant risk factor of bleeding. A 5-to-10 day waiting period may be necessary for the clopidogrel to wash out. Most physicians are very polarized on this issue. Some feel strongly that all patients, at the time of diagnosis of unstable angina, should be given a thienopyridine such as clopidogrel, even before the anatomy is known. Others feel just as strongly that you should wait until the coronary anatomy is known, then give clopidogrel at the time of angioplasty, even though it’s not going to be effective for the first couple of hours, and some benefit may be lost. However, this approach will minimize bleeding and facilitate early surgery in those patients requiring operative revascularization. We actually considered randomizing this issue in ACUITY, but most investigators felt so strongly that their way was right, that they didn’t want to participate! Thus, we decided to leave the timing of clopidogrel up to the local standard of care. Can you talk about some of the ongoing issues you have in trial management overall? I’m pleased to say that after 2 years of planning, we’ve just started enrolling in this trial. ACUITY is a large, global trial with approximately 600 sites. Clearly, managing a trial of this size is a very significant undertaking. An excellent clinical trial infrastructure is required, starting with the steering committee of the trial, extending to the monitoring systems, the data collection and analysis systems, and the core laboratories. We believe all these elements are in place. Are there any other ongoing trials that involve bivalirudin? We have also just announced a study called HORIZONS, which is currently in the planning stages. This 3400-patient trial in patients undergoing primary angioplasty for evolving acute myocardial infarction will be comparing unfractionated heparin plus a IIb/IIIa inhibitor, versus bivalirudin alone with a bailout IIb/IIIa inhibitor in patients undergoing stenting in acute myocardial infarction. The stent will be either a bare metal stent or a drug-eluting stent, using the Boston Scientific TAXUS Liberte stent. HORIZONS will most likely begin in the first or second quarter of 2004. Why should facilities pay attention to this trial, and how can they get involved as one of the 600 sites? ACUITY is a seminal trial that will answer many of the outstanding unsettled questions in the management of patients with acute coronary syndromes. Our hypothesis is that the bivalirudin-only arm will be as effective as enoxaparin plus IIb/IIIa inhibitors at preventing ischemic complications in patients with acute coronary syndromes and, at the same time, will markedly reduce bleeding, the demonstration of which would represent a major advance. On the other hand, we also believe that when compared to enoxaparin plus IIb/IIIa inhibitors, bivalirudin plus IIb/IIIa inhibitors will significantly reduce ischemic complications while maybe slightly reducing bleeding. The trial is powered to demonstrate both of these findings. This study will also answer the question of the timing of IIb/IIIa inhibitor initiation in unstable angina. It is our hope that this landmark trial will set the standards for many years to come regarding how patients with acute coronary syndromes should be optimally treated. This is a major global initiative with 600 sites, and I believe it is the most exciting ongoing or planned study in acute coronary syndromes. The sponsor of the study is The Medicines Company, and for sites that wish to participate, they should contact their local Medicines Company representative. Interested persons are also welcome to contact me directly at gstone@crf.org