Antagonist: Available evidence provides a strong rationale for using clopidogrel early in a wide range of patients with acute coronary syndromes. However, platelet glycoprotein IIb/IIIa antagonists should be used in certain patients who present to the emergency department. This includes troponin positive patients, and anyone whose management will include an invasive strategy.

Protagonist: The CURE trial was a randomized, double blind, parallel group trial of acute and long-term clopidogrel therapy vs. placebo. It included 12,562 patients with acute coronary syndromes. Investigators randomized patients to an immediate 300 mg clopidogrel loading dose or placebo, then 75 mg clopidogrel or placebo for up to 1 year.

The primary endpoint of CURE was a composite of myocardial infarction, stroke and cardiovascular death 1 year after randomization. Trial results showed a highly significant 20% relative risk reduction in this endpoint (P = 0.00009).

Statistical analysis showed that the benefit was already apparent as early as 2 hours after the loading dose. This correlated nicely with basic science data showing a rapid rise in platelet inhibition following administration of a loading dose.

Patients benefited regardless of whether they underwent percutaneous coronary intervention or medical therapy. In patients who underwent stenting, there was a 44% relative risk reduction in the primary endpoint.

This effect was also evident across low, medium and high risk patient groups. Absolute risk reduction in patients with low and moderate risk score patients was 1.6%. Absolute risk reduction in high risk patients was almost 5%.

There was a consistent benefit regardless of other standard therapies the patient received, including heparin, aspirin, angiotensin converting enzyme inhibitors, angioplasty, bypass and others.

Results of the major IIb/IIIa antagonist trials are very different. Clearly, these agents benefit patients who undergo intervention. One meta-analysis of 6 interventional trials including 14,706 patients shows a remarkable reduction in death or myocardial infarction at 30 days (8.7% to 5.6%).

However, IIb/IIIa antagonists have shown little efficacy in general trials of acute coronary syndromes. A meta-analysis including approximately 31,000 patients shows only a 9% relative risk reduction.

Furthermore, this effect is not consistent. For example, there is no benefit in patients over 70 years of age. There is a significant 15% excess in death and myocardial infarction in women. That starkly contrasts with the CURE trial of clopidogrel. In more than 50 subgroups examined, every one echoed the significant risk reduction.

There is also a significant 62% excess of bleeding with IIb/IIIa antagonists. On the other hand, the excess bleeding in CURE was lower than in all IIb/IIIa trials individually. Therefore, a strategy of starting this agent in case the patient needs percutaneous coronary intervention later may actually be causing net harm.

Antagonist: Clopidogrel and IIb/IIIa inhibitors are both very effective treatments. To maximize patient outcomes, clinicians should use each agent when appropriate.

Published guidelines now state that acute coronary syndrome patients undergoing percutaneous coronary intervention should receive a IIb/IIIa inhibitor. A dramatically compelling and consistent benefit can be seen across various interventional trials including IIb/IIIa inhibitors. Reductions in death and myocardial infarction are in the range of 50% to 70%.

The IIb/IIIa inhibitors and clopidogrel have not been compared directly in the setting of acute coronary syndromes. However, from review of the available data, it seems reasonable that IIb/IIIa inhibitors would provide a benefit greater than clopidogrel in percutaneous coronary intervention.

However, IIb/IIIa inhibitors are not for everyone. The relative benefit of this approach increases in higher risk patients. Probably the best risk stratifier is troponin status. Many investigators believe troponins particularly suited for identifying patients who will have a major benefit.

Data from the Platelet Receptor Inhibition for Ischemic Syndrome (PRISM) trial showed a 70% reduction in death or myocardial infarction at 30 days for troponin positive patients. Interestingly, this benefit occurred with or without revascularization. In contrast, clopidogrel showed no such relationship in a study of positive and negative markers.

The IIb/IIIa approach also has merit in patients with diabetes. Antiplatelet therapy has a dramatic effect in treating acute coronary syndromes in this rapidly growing population. One recent meta-analysis suggested an approximately 25% reduction in mortality. In the largest clopidogrel study ever, there was a 7% reduction in mortality that did not reach statistical significance.

Some of the most recent data supporting use of IIb/IIIa inhibitors in interventional procedures comes from the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) study.

In this study, investigators evaluated effectiveness in clinical practice of IIb/IIIa inhibitor added to background therapy in an invasive vs. conservative strategy. They saw an early and significant reduction in myocardial infarction. This suggests the benefit of IIb/IIIa seen in clinical trials is also applicable in clinical practice.