The TENACITY Trial

About TENACITY TENACITY (Tirofiban Novel Dosing vs. Abciximab with Evaluation of Clopidogrel and Inhibition of Thrombin Study) is a multi-center, double-blind, randomized comparison of tirofiban (Aggrastat®, Guilford Pharmaceuticals) and abciximab (ReoPro®, Eli Lilly and Co.) that is expected to enroll at least 8,000 patients in approximately 200 centers across the United States. The Cleveland Clinic Cardiovascular Coordinating Center (C5) and Duke Clinical Research Institute (DCRI) will coordinate the trial, which is sponsored by Guilford Pharmaceuticals. The primary objective is to determine whether the 30-day efficacy of a single high-dose bolus regimen of tirofiban is non-inferior to abciximab in patients undergoing PCI with coronary stent placement. In addition, TENACITY will, for the first time, evaluate the 30-day safety and efficacy of bivalirudin (Angiomax®, The Medicines Company) versus heparin among patients receiving tirofiban or abciximab. Key points of TENACITY First large-scale trial with single high-dose bolus tirofiban First large-scale study using a 12-hour infusion of tirofiban along with a 600mg loading dose of clopidogrel First factorial designed large-scale study of a IIb/IIIa inhibitor with a direct thrombin inhibitor The largest study using drug-eluting stents What should we know about platelet inhibition and its role in outcomes after PCI? It is clear now that platelets have multiple effects in vascular biology, reaching beyond the coagulation cascade. For example, platelets importantly contribute to the response to vascular injury by being involved in inflammation and vessel wall repair. Anti-platelet therapy has been a cornerstone of PCI therapy for many years. It was appreciated that the relatively high ischemic event rate of approximately 15-20% among patients undergoing PCI could be reduced by roughly one-half with the addition of aspirin. This was accomplished by decreasing thrombus formation at the site of vascular injury, thereby preventing abrupt vessel closure. Since then, it has been appreciated that aspirin is a relatively weak anti-platelet agent, and that more recently developed therapies have shown to provide benefit beyond aspirin and heparin alone. Systematic evaluation of intravenous platelet IIb/IIIa inhibitors has shown another halving of peri-procedural myocardial infarctions as compared with placebo. As such, in contemporary practice using several anti-platelet drugs, the adverse ischemic event rate has been reduced to approximately 6-7%. The third class of anti-platelet drugs studied in the setting of coronary intervention involves thienopyridines, which includes ticlopidine and clopidogrel. These two drugs have shown benefit in reducing ischemic events beyond aspirin alone. In addition to their effect on platelet aggregation, these agents have anti-inflammatory effects. Even among patients receiving aspirin and IIb/IIIa inhibitors, several studies have suggested an added benefit of preprocedural clopidogrel administration. In addition to anti-platelet therapy, several different antithrombins have been tested as compared with unfractionated heparin in the setting of PCI. Bivalirudin, for example, has been studied in several large-scale studies and has been shown to be similarly effective to heparin and potentially lowers the risk of bleeding events. Considering these several drug classes together, there have been very few or limited studies which have compared anticoagulant drugs during PCI in a head-to-head fashion. TENACITY is factorially designed such that patients will be randomized to either tirofiban or abciximab and then separately randomized to receive either heparin or bivalirudin. All patients will receive aspirin and clopidogrel. This design feature is unique and represents cutting-edge therapies found in previous studies. Can you discuss further why you believe TENACITY is important? There are several unique features of the TENACITY trial which make it important. To begin, this is only the second large-scale, head-to-head trial comparing IIb/IIIa inhibitors. The one previous study, TARGET, compared a lower bolus dose of tirofiban versus abciximab. All patients in TARGET received heparin and aspirin. The TARGET trial showed the lower bolus dose of tirofiban to be inferior to that of abciximab regarding adverse ischemic events. TENACITY will be the first large-scale study testing the single high-dose bolus of tirofiban versus abciximab. Eptifibatide (Integrilin®, Millenium Pharmaceuticals), the other approved intravenous IIb/IIIa inhibitor in the U.S., went through a similar development story. The investigators for eptifibatide initially used a relatively low dose in a single-bolus fashion. After a series of studies, a double-bolus of higher dose eptifibatide evolved and is now used in clinical practice. Considering the most recent developments with tirofiban, there has been a series of studies showing that the low dose of tirofiban, as used in TARGET, was inadequate. Most recently, approximately 600 patients have been studied worldwide with the high-dose single-bolus of tirofiban and data have shown it to be strikingly effective versus placebo and at least as good as abciximab. Each of these studies, however, was too small or a single-center study, and could not be fully conclusive. Hence the need for TENACITY, which will include over 8,000 patients at more than 200 sites for patients with moderate-to-high risk characteristics for adverse events during PCI. What are the primary differences between the three IIb/IIIa platelet inhibitors on the market in the U.S. today? Abciximab is a monoclonal antibody, which is expensive to make. The small molecules, tirofiban and eptifibatide, are less expensive to make because they are either very small proteins or peptidomimetics. Another difference (beyond their cost) would be the mechanism of disabling the IIb/IIIa receptor. With abciximab being a monoclonal antibody, the majority of the drug is given during a bolus. Roughly 75% of the drug is given as a bolus, because as an antibody, it literally binds to the IIb/IIIa receptor in a nearly irreversible fashion. As a result, abciximab is administered in a concentration of drug-to-receptor ratio of about 2:1. In contrast, the small molecules, eptifibatide and tirofiban, are given at a several hundred-fold ratio of drug to receptor. For every IIb/IIIa receptor, there are several hundred tirofiban molecules given, because it is competitive with fibrinogen for the IIb/IIIa receptor. The small molecules bind reversibly, remaining bound to the receptor for seconds to minutes. Only about 5% of the total dose of small molecules is given in the bolus, whereas the remaining 95% is given during the infusion. It is very important to have the right amount of bolus of small molecule until the infusion can reach a high enough level in the blood. What are the current issues in regards to administration of heparin or bivalirudin with GP IIb/IIIas? In the past, most PCI studies have isolated one anticoagulant agent and studied it versus placebo. In most prior abciximab studies, for example, it was abciximab versus placebo. The other drugs in the polypharmacy of anti-coagulation were not randomized, but rather they were left to the discretion of the investigator. Many studies were either trying to get their initial FDA approval or had very specific patient groups they were studying. The difference with those trials, as compared with TENACITY, is that TENACITY is several orders of magnitude larger than most previous placebo-controlled studies in interventional cardiology and is considering combinations of different drugs. While the study is not particularly powered for superiority, we will have the ability to assess the different combinations of anti-coagulant therapy. In the REPLACE-1 study, the combination of bivalirudin with a IIb/IIIa inhibitor was associated with an approximately 20% reduction in ischemic events as compared with patients receiving heparin with a IIb/IIIa inhibitor. These data considering a combination of potent anti-platelet and potent anti-thrombin therapy are considered encouraging; however, such findings need to be studied among a larger number of patients. TENACITY will provide us that opportunity to study the combination of bivalirudin with either abciximab or tirofiban. Some criticisms of recent trials involve new definitions for major and minor bleeding. What definitions will TENACITY use? TENACITY will use two different sets of definitions for major and minor bleeding to allow comparison with recent previous trials. Specifically, we will use the TIMI classification for major and minor bleeding as was done in EPISTENT and TARGET. In addition, we will use the definitions for major and minor bleeding as used in the REPLACE-2 trial. There has been some criticism that bivalirudin was tested against too high a dose of unfractionated heparin in the REPLACE-2 trial. Do you think this issue can be clarified by TENACITY? I think TENACITY will provide valuable information for several reasons. One, it is a very large study, so we will have the opportunity to look at particularly large subgroups. The second thing is that TENACITY will have blinded activated clotting times (ACTs), so that the investigators will not be able to see what the procedural ACT is. Hopefully this will add an extra level of scientific rigor to the study. TENACITY is using a lower dose of heparin as compared with other recent trials. Even though the study is targeting a very similar extent of anti-coagulation (as measured by the ACT), we will be starting out with a lower dose of heparin trying to approach the targeted ACT without overshooting so markedly. In REPLACE-2, while the ACT target was similar to that in TENACITY, the overshoot was by approximately one-hundred seconds, or roughly 30% of the target. As such, some have criticized REPLACE-2, saying that too much heparin was administered to the control group. Other studies have also used 60-70 units per kilogram of heparin as the initial bolus. In TENACITY, the initial dose of heparin will be less than or equal to 50 units per kilogram, and hopefully the resultant ACT will be closer to the target of 225 seconds. Will patients all receive the same post-procedure course of clopidogrel for the same time frame? They likely will not. We will make recommendations as to how long patients should receive clopidogrel post-procedure. On the other hand, we have not prospectively randomized patients to different durations of clopidogrel. The protocol recommends that patients receiving a bare-metal stent also receive at least one month of clopidogrel and consideration should be given for treatment to one year. For patients receiving a drug-eluting stent, the protocol recommends a minimum of three months of clopidogrel, again with consideration for therapy to one year. Are all patients in TENACITY receiving a stent? The protocol requests that the intent be to stent the primary target vessel for which the patient is enrolled into study. As in TARGET and EPISTENT, there is an intent-to-stent inclusion for the culprit lesion. If a secondary lesion needs to be treated, it is not mandated that this lesion receive a coronary stent. We know in contemporary practice that approximately 80% of patients are likely to receive a coronary stent for the second lesion treated. With this in mind, we believe that it is likely more than 90% of all lesions treated in the TENACITY study will include a coronary stent. Will TENACITY sub-analyze the Taxus and Cypher drug-eluting stent groups to account for potential drug-interaction differences? The TENACITY study will collect data on the type of stent whether bare metal or drug eluting and data will be additionally collected for the type of drug-eluting stent. We therefore will have the ability to perform sub-analyses according to stent type. This is of particular interest, since this trial will likely include several thousand patients receiving a drug-eluting stent and potentially be one of the largest studies including such patients to date. Currently, only 23% of 150 Primary PCI institutions in NRMI currently meet the 90-minute median door-to-balloon specification, and only 3% of all PCIs in NRMI 4 were completed in 90 minutes or less. How much complexity do you realistically think the ACS-primary PCI process can stand? The TENACITY trial will include all patients at moderate-to-high risk for adverse events and as such will include patients with an acute coronary outcome. The study will include patients with ST-elevation acute myocardial infarction. We expect this cohort to only comprise approximately 10% of the study. As with other ST-elevation MI trials, we will make all efforts to minimize trial complexity. For example, the study does not contain a double-dummy, meaning that all patients will get a single bolus of IIb/IIIa inhibitor and a single infusion of therapy for 12 hours. So, too, patients will all receive a single bolus and infusion of anti-thrombin therapy. For the heparin-treated group, the infusion of anti-thrombin therapy will actually be placebo. These efforts hopefully will minimize the study complexity. For the roughly 90% of the study's patients, the procedures will be performed on a non-emergent basis and there should be no concern regarding urgency of time to treatment. We have put other mechanisms in place to facilitate enrollment and speed of study drug administration. An example would include the ability to randomize patients in advance of enrollment. As such, if a patient qualifies for study enrollment based on high-risk demographic characteristics, the patient can be randomized prior to coronary angiography. If a patient’s coronary anatomy is appropriate for TENACITY, the patient can then be enrolled into the trial and promptly receive the study drug. A patient is not considered enrolled into TENACITY until they receive the study drug. This ability to randomize patients in advance allows the pharmacists and the study team the ability to prepare materials for this patient, thereby saving time in the catheterization laboratory. Could you summarize the potentially unique features of TENACITY and the potential ramifications to the study? The potential advantages to doing a study like TENACITY are many-fold. As mentioned, it is hoped this trial will help us understand an optimal strategy to minimize ischemic events, reduce bleeding events, or both among patients undergoing PCI. A second advantage is that our efforts are to make patient treatments simpler or potentially safer than in the past. While the protocol design is more complex than some prior trials, to find an optimal strategy or another tact may be helpful. For example, the recently completed SYNERGY trial also attempted to find an anti-coagulant treatment strategy that would potentially be safer or easier for practicing cardiologists. The trial had some outcomes of parity, such as ischemic events, but on the other hand, more bleeding was associated with the enoxaparin strategy. It was clearly important to learn the advantages and potential disadvantages to using enoxaparin. With TENACITY, investigators have the ability to test bivalirudin, a short-acting drug, in an attempt to decrease bleeding as was seen in REPLACE-2. In addition, by using a short-acting IIb/IIIa inhibitor such as tirofiban superimposed on a background of high-dose clopidogrel, we may have a potentially better strategy cost-wise and regarding bleeding events. This will be the first large-scale study not only testing the high-dose single-bolus of tirofiban, but also giving the tirofiban infusion for only 12 hours, as compared with 18-24 hours for the small molecule eptifibatide in ESPRIT or the longer infusion of tirofiban in TARGET. With the addition of high-dose clopidogrel loading, it is believed that the tirofiban infusion for 12 hours after coronary intervention will provide an abciximab-like effect. These advantages may have a good impact on contemporary interventional cardiology, where more specific and short-acting intravenous agents can be used in the catheterization laboratory when coupled with long-acting oral agents such as clopidogrel. In addition since many patients will be receiving a drug-eluting stent, an arteriotomy closure devices, and other approved devices, the study will provide the opportunity for a careful look at contemporary PCI practice.

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