Clinical Trial Commentary GUSTO-IV 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

Modest benefit of gp IIb/IIIa inhibitors in other clinical trials Trial gp IIb/IIIa inhibitor PRISM/PRISM Plus tirofiban Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms PURSUIT eptifibatide Platelet IIb/IIIa in unstable angina: receptor suppression using integrilin therapy PARAGON lamifiban Platelet IIb/IIIa antagonism for the reduction of acute coronary syndrome events in a global organization network

GUSTO-IV, initial questions 1) Does abciximab benefit unstable angina patients who are not undergoing interventions? 2) What is the best dosing regimen to use in this setting? 3) Is it safe to combine use of abciximab with low molecular weight heparin? 4) Is troponin the best marker of who will benefit most?

GUSTO-IV, protocol 7800 patients believed to have unstable angina and receiving conventional therapy were randomized to: placebo, or abciximab bolus + 24 hour infusion, or abciximab bolus + 48 hour infusion. The trial was designed to test the drug in the absence of interventions. Fewer than 5% of patients underwent revascularizations during the treatment period. The primary endpoint was death/MI at 30 days.

GUSTO-IV Primary outcomes Figure 1 Primary endpoint, death or MI at 30 days

GUSTO-IV Deaths over time Figure 2 Death at 48 hours

GUSTO-IV Troponin results Table 1 Death/MI at 30 days in patients with and without elevated troponin levels Death/MI Placebo Abciximab 24 hours Abciximab 48 hours With elevated troponin 9.7% 10.2% 11.7% Without elevated troponin 5.3% 5.9% 6%

GUSTO-IV Explanations? Possible explanations for the absence of benefit (and trend toward harm) in the GUSTO-IV include: 1) The trial may have been insufficiently powered to pick up the small benefit (say a 10% reduction in events) likely to be seen in medically treated patients. 2) GUSTO-IV may have had a different population of patients compared to other unstable angina trials (in retrospect, many patients may not have had true coronary disease). 3) Fewer interventions were performed compared to other trials. 4) Prolonged platelet inhibition may actually have an untoward effect in the inflammatory cascade.

Pro-inflammatory effect GUSTO-IV Pro-inflammatory effect GUSTO-IV was the first trial to look at 48 hour abciximab infusions. A longer infusion time with no intervention is being compared to much shorter infusion times with PCI in other trials. There may be a pro-inflammatory effect of abciximab at longer infusion times comparable to the effect seen with oral gp IIb/IIIa inhibitors. These results suggest that you may not be able to passivate an artery with drug therapy alone.

On GUSTO-IV “Abciximab clearly works in an interventional setting. We have many trials that have consistently shown that. The GUSTO-IV results show that abciximab does not work in a non-interventional setting…I no longer believe that IIb/IIIa blockers should be used outside the angioplasty setting. The GUSTO-IV results are therefore good news for healthcare providers as they will save millions on the cost of these drugs.” Dr Martin Simoons (Chief investigator, GUSTO-IV) Erasmus University Hospital Rotterdam, Netherlands heartwire. Aug 30, 2000. GUSTO-4 results - What went wrong and what do they mean?

On GUSTO-IV “The trial unexpectedly entered lower risk patients than anticipated. In all subgroups where the risk was higher (eg, elderly, male sex and diabetics) there was a trend towards benefit with abciximab. The lower risk groups trended towards harm…At the start I was shocked, but now I'm not so much. I will still use these agents for high-risk non-revascularized patients.” Dr Eugene Braunwald Harvard Medical School, Boston, MA heartwire. Aug 30, 2000. GUSTO-4 results - What went wrong and what do they mean?

PARAGON B Troponin results Table 2 30 day outcomes in a prospective troponin substudy (n=1200) Death/MI Placebo Lamifiban Troponin T positive 19% 11%* Troponin T negative 10.3% 9.6% *p<0.05

GUSTO-IV Recommendations? 1) This trial does not affect the use of abciximab in the interventional setting, where it has consistently shown benefit and reduced mortality. 2) The use of IIb/IIIa blockers can still also probably be justified in patients with refractory ischemia in spite of aspirin and heparin, as these patients are generally on their way to revascularization. 3) The data is not clear for other patients. …recommendations made by Dr Rob Califf at the 2000 meeting of the European Society of Cardiology. heartwire. Aug 30, 2000. GUSTO-4 results - What went wrong and what do they mean?

GUSTO-IV, substudy LMWH protocol 974 patients received dalteparin open label at a dose of 120 IU/kg sc twice daily for five to seven days. Patients were then randomized per the main study to placebo or abciximab for 24 or 48 hours. The substudy happened to recruit patients at higher risk than those generally enrolled into GUSTO-4 (more older patients, more males and more patients with raised troponin levels). Abciximab in this group was associated with a trend towards benefit, with a death/MI rate of 9.6% versus 11.3% on placebo.

GUSTO-IV, substudy Bleeding outcomes Table 3 Dalteparin vs unfractionated heparin Bleeding UF heparin LMW heparin Placebo Abciximab Major bleeding 0.2% 0.8%* 0.7% 1.3% Minor bleeding 1.6% 3.2%* 4.0%* Thrombocytopenia 0.9% 6.3%* 1.5% 3.1% Intracranial hemorrhage 0.1% 0.15% 0% 0.31% * p<0.05 compared to placebo UF unfractionated LMW low molecular weight