By TCT Daily Staff

First-generation and second-generation thienopyridines such as clopidogrel come with a number of limitations that are significantly ameliorated by the third-generation agent prasugrel. However, patients with prior stroke or TIA are exceptions to prasugrel’s general superiority over clopidogrel, according to Franz-Josef Neumann, MD, of Herz-Zentrum Bad Krozingen (Bad Krozingen, Germany).

According to Dr. Neumann, who discussed the “state of the art” of thienopyridine therapy at the recent TCT 2008 symposium in Washington, DC, the first limitation of clopidogrel is its delayed onset of action. Only 15% of clopidogrel is metabolized in a 2-step process in the liver, which takes considerable time. With a 600-mg dose, a substantial inhibitory effect is not seen for 2 to 4 hours, Dr. Neumann said. And in the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, the clinical benefit did not become clinically significant until 15 hours after loading with 300 mg.
Another problem with clopidogrel is its irreversible action. This can be a serious drawback if a patient has to undergo emergency cardiac surgery, Dr. Neumann noted.

Still another important limitation of clopidogrel is the variability in patient response. Four hours after clopidogrel administration, some patients have virtually normal platelet reactivity, while others are profoundly inhibited, Dr. Neumann said. The difference can have a major impact on clinical outcome. Patients with low residual platelet reactivity have a very low incidence of periprocedural events, whereas those with high residual reactivity have substantially more events, said Neumann. The same pattern holds for maintenance doses. In addition, the RECLOSE (low REsponsiveness to CLOpidogrel and Sirolimus- or paclitaxel-Eluting stent thrombosis) trial showed that high responders have an increased incidence of stent thrombosis compared to nonresponders.

Prasugrel to the Rescue?

After asking whether prasugrel solves these problems, Dr. Neumann presented a strong case for the medication. Although prasugrel is chemically similar to clopidogrel, there are major differences in how the drug is metabolized that may account for its differential effect. For example, in a study in which patients receiving clopidogrel were switched to prasugrel, all the clopidogrel nonresponders turned into responders, Dr. Neumann said.

In addition, the PRINCIPLE-TIMI 44 study showed that prasugrel has a much faster onset of action compared to clopidogrel. Its effect is both stronger and more consistent for both loading and maintenance doses. The clinical benefit, meanwhile, was clearly seen in the TRITON-TIMI 38 study. Patients with ACS about to undergo PCI were randomized to clopidogrel (300 mg loading dose, 75 mg maintenance dose) or prasugrel (60 mg loading dose, 10 mg maintenance dose). For the primary endpoint of death, nonfatal MI, and nonfatal stroke, there was a 20% relative reduction among patients receiving prasugrel vs. clopidogrel. The difference was apparent from the third day until the end of follow-up, showing a benefit both periprocedurally and in secondary prevention, observed Dr. Neumann. And importantly, patients who did experience 1 event benefited most from secondary prevention. There was also a more than 50% reduction in both short-term and long-term stent thrombosis.

There was a price to pay, though, in safety, Dr. Neumann said. Nevertheless, the 2.2% reduction in the primary ischemia endpoint trumps the 0.6% increase in bleeding; for every 1,000 patients treated with prasugrel, 23 MIs can be prevented at the expense of only 6 major non-CABG bleeds, Dr. Neumann said.

But this net clinical benefit did not hold across all patient subsets. Among patients with a prior stroke or transient ischemic attack, patients receiving prasugrel experienced a significantly higher rate of major bleeding (2.4% vs. 1.8%, P=0.03) and life-threatening bleeding (1.4% vs. 0.9%, P=0.01) compared with those taking clopidogrel. For this reason, prasugrel should be avoided in such patients, Dr. Neumann said. In addition, elderly and underweight patients did not benefit. Whether these patients should be given a reduced maintenance dose is under investigation.

Even so, Dr. Neumann concluded, in the majority of ACS patients, the superior efficacy of prasugrel far outweighs the increased risk of bleeding.