ISAR-COOL

Late-Breaking Trials from the European Society of Cardiology Congress

Source: Neumann F, Kastrati AP-MG. JAMA. 2003;290:1593-1599.

The Intracoronary Stenting with Antithrombotic Regimen Cooling Off (ISAR-COOL) study results were initially presented at the 2002 American Heart Association Scientific Session. This study randomized high-risk acute coronary syndrome (ACS) patients (those with elevated troponin or ST-segment depression) to receive antithrombotic pretreatment for 3-5 days or for less than 6 hours prior to catheterization and intervention. The antithrombotic regimen studied consisted of intravenous heparin and tirofiban, ASA (500 mg IV bolus, followed by 100 mg PO twice daily), and clopidogrel (600 mg loading dose followed by 75 mg twice daily). The primary end point was the composite of large nonfatal MI (Q-waves, new LBBB or CKMB 5 × normal) or death at 30 days. Bleeding complications were also assessed and defined using standard TIMI trial definitions.

A total of 410 patients were randomized between February 2000 and April 2002. The antithrombotic pretreatment and early intervention groups were well matched in terms of baseline clinical characteristics, entry criteria, and CAD burden. Definitive treatment (method of revascularization) was comparable between the 2 groups. Of the antithrombotic pretreated patients, 64.3% underwent PCI (91.7% received stents), and 7.7% underwent CABG; of the early intervention patients, 70.4% underwent PCI (86.7% received stents), and 7.9% underwent CABG. The primary end point was reached in 11.6% (21 MIs, 3 deaths) of the antithrombotic pre-treatment group and in 5.9% (12 MIs, no deaths) of the early intervention group (P = .04). The difference on outcome between the groups was attributable to events occurring prior to intervention, with equal event rates occurring after intervention was completed. There was no difference in bleeding complication rates between the groups. Neumann and Kastrati concluded that deferral of coronary intervention for prolonged antithrombotic treatment did not improve outcome in ACS patients undergoing revascularization when compared with "immediate" intervention using an early and intense antiplatelet regimen.

Comment by Sarah M. Vernon, MD

The "early invasive" approach to the management of patients with acute coronary syndromes (ACS), particularly in those patients with high-risk features such as positive biomarkers or ST segment depression, has emerged as the superior strategy for reducing adverse cardiac events in this patient population. "Early" catheterization and revascularization, by percutaneous coronary intervention in most cases, has become the standard of care in the management of ACS. At the same time, early administration of increasingly potent antiplatelet and antithrombotic therapies have also been shown to improve outcomes in patients with ACS and in many patients undergoing PCI. The concept of "cooling off" the patient with ACS has considerable appeal, in part because of what we know about the pathobiology of passivation of the unstable coronary plaque, and in part because we know that complication rates of PCI are higher in patients with unstable syndromes. The CREDO1 trial (reviewed in the December 2002 issue of Clinical Cardiology Alert) demonstrated the benefit of clopidogrel administered as a 300-mg loading dose before PCI and continued long term for 1 year, well beyond the standard port-procedural duration of 1 month. Subgroup analysis from CREDO showed that periprocedural outcomes were better when patients were pretreated with clopidogrel more than 6 hours prior to PCI. This has led many of us to initiate clopidogrel loading as early as possible in the management of the ACS patient destined for early invasive management. However, given the CREDO data, should we delay catheterization to give clopidogrel time to work?

ISAR-COOL only partly addresses this issue. The delay to catheterization of 3-5 days was quite long—longer, in fact, than most hospitalizations for ACS in this country (with the exception of the late Friday admission deferred for the weekend for scheduled catheterization on Monday morning). This study doesn’t tell us whether waiting 1 hour or 6 hours or 12 after initiation of antithrombotic therapy yields the best outcomes with PCI. However, the end point of this study is quite "hard" and despite the extremely potent antithrombotic regimen used in this study, 6.3% of patients treated more conservatively experienced a large MI or death while waiting to undergo catheterization and revascularization. This study suggests that high-risk patients should be treated as early as possible with the full complement of antithrombotic and antiplatelet drugs available and should be sent to the cardiac cath lab promptly (and probably not waiting until the following Monday).

Dr. Vernon, Assistant Professor of Medicine Director, VAMC Cardiac Catheterization Laboratory, University of New Mexico Health Sciences Center, Albuquerque, NM, is on the Editorial Board of Clinical Cardiology Alert.

Reference

1. Steinhubl SR, et al. JAMA. 2002;288:2411-2420.