TARGET and TACTICS Clinical Trial Commentary Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Do Tirofiban And ReoPro Give similar Efficacy Trial This trial was the first of the glycoprotein (gp) IIb/IIIa inhibitor comparative trials. TARGET enrolled 4812 patients from 18 countries who were undergoing coronary stenting. Patients were randomized to tirofiban or abciximab. Tirofiban was given at the dose previously tested in the RESTORE trial and abciximab was given at the normal dose used in clinical practice. TARGET

Primary endpoint The primary endpoint, 30-day outcomes of death, MI, and urgent revascularization, was powered to detect noninferiority of tirofiban. TARGET TirofibanAbciximabORp-value 7.55%6.01% OR odds ratio

Individual outcomes Effects of individual components on the primary endpoint TARGET EndpointTirofibanAbciximab Death0.5%0.4% MI6.9%5.4% Urgent revascularization 0.8%0.7%

Class effect TARGET directly addresses the issue of class effect. Class effect seems to be called upon as a reason to use a drug when it's to the advantage of the manufacturer of that drug. The absence of class effect is similarly given as a reason to use a drug when that is to the manufacturer’s advantage. TARGET calls into question any presumptions that one makes about whether 2 different drugs attacking the same mechanism may be different. TARGET

Points of discussion In TARGET, as in many interventional trials done in the recent past, patients who were randomized and then found not to be suitable for intervention or treatment were not counted in the primary endpoint. This comprised a total of 496 patients. The dosing of tirofiban may also not have been adequate, although an aggressive dosing regimen was used compared to the currently recommended label dosing. TARGET

Intention to treat? Most of the 496 patients (9% total) who were randomized but not treated were enrolled before any knowledge of their coronary anatomy had been obtained - they either had a coronary anatomy requiring surgical intervention or had no significant disease. The trial protocol included only patients who were randomized and received study drug. The trial was designed using a rigorous double-dummy, double-blind format. TARGET

Dose of tirofiban? The dose of tirofiban was the same dose used in the RESTORE trial. At this dose, it had previously been shown that the platelet inhibition at 5 minutes into the procedure and right before the end of the infusion and several hours into the procedure was approximately 95% to 5 μmol ADP as an agonist. The benefit seen in the abciximab group may have been due to additional effects at the level of integrin interactions. TARGET

Subgroup analysis Non-US patients (approximately 1000) had a more pronounced benefit in the trial as a subgroup. Non-ACS (acute coronary syndrome) patients receiving tirofiban showed a trend toward benefit. TARGET Primary composite endpoint at 30-days Treatment groupTirofibanAbciximab ACS9.3%6.3% Non-ACS4.5%5.6% ACS acute coronary syndrome

Clinical implications From the results of TARGET, the use of tirofiban in the cath lab should now be restricted to the following: 1) patients in randomized trials with new dosing regimens or 2) in financially constrained healthcare environments with insufficient funding to pay for abciximab TARGET

Treat angina with Aggrastat and determine the Cost of Therapy with Invasive or Conservative Strategies This study, also known as TIMI-18, looked at an early invasive strategy incorporating upstream gp IIb/IIIa inhibition with tirofiban and catheterization for the treatment of patients with unstable angina (UA) and non- ST segment elevation MI (NSTEMI). This is one of a series of trials trying to establish a place and need for aggressive intervention in clinical practice. TACTICS

Design 2220 patients with UA or NSTEMI received medical treatment with aspirin, heparin, beta blockers as well as tirofiban (administered for 48 to 108 hours). They were then randomized to catheterization within 4 to 48 hours or to a more conservative strategy where they were referred for catheterization only for recurrent rest pain or a positive functional test. The trial's primary endpoint was the combined incidence of death, MI or rehospitalization for ACS at 6 months follow- up. TACTICS

Primary endpoint TACTICS Cardiac events at 6 months Outcome Conservative (n=1106) % Invasive (n=1114) % Odds ratio p-value Primary endpoint Death/MI <0.05 Death MI Rehosp ACS

Troponin subgroup TACTICS The researchers also tested blood levels of troponin, which have been shown to predict a high increased risk of adverse outcome in acute coronary syndromes, upon arrival to hospital. Patients who had a positive troponin had an absolute 10% reduction in the trial's primary endpoint, from 24% down to 14%.

Points of discussion This is the only contemporary trial that reflects (and now validates) the US practice of the invasive interventional approach. The trial did not address the question of whether or not you have to have the gp IIb/IIIa inhibitor on board, since both arms received tirofiban. It did not address the controversy surrounding the use of low-molecular weight heparin. TACTICS

Clinical implications No benefit to the invasive approach was seen in patients who had no ST changes, and there was no benefit in patients who were troponin negative. Abciximab is still the only gp IIb/IIIa inhibitor to date that has been shown to reduce mortality. Despite validation of the treatment of ACS from these trials, there are still a large number of events in the longer term follow- up of patients with ACS that need to be studied. TACTICS

The role of eptifibatide There are no troponin or foundation strategy data on eptifibatide. Data from the PURSUIT trial, using eptifibatide, are similar to the results from TACTICS. Direct comparative data and data from an aggressive versus waiting approach using eptifibatide are necessary.