New antiplatelet agents face hurdles in clopidogrel-dominated market

For the treatment of patients with acute coronary syndrome or percutaneous coronary intervention, the antiplatelet therapy of choice has been consistent among physicians since it was first approved in 1997 — clopidogrel.

“[Clopidogrel (Plavix, Sanofi-Aventis)] was the first safe thienopyridine in the marketplace, so in a sense, it had a huge head start over a lot of other drugs in the field that are now available or about to be available,” David P. Faxon, MD, vice chair of medicine for strategic planning at the Brigham and Women’s Hospital, Boston, and Cardiology Today Editorial Board member, said in an interview. “So, for that reason, there hasn’t been much competition for it, and it has taken over the marketplace.”

David P. Faxon, MD, says that even though clopidogrel is the current leader in antiplatelet therapies, other alternatives may soon be available. Photo coutesy of: David P. Faxon, MD

The substantial, high-level evidence that supports the use of clopidogrel for reduction of morbidity and mortality in patients with ACS, MI and many other indications has helped the drug develop its formidable presence, said Rhonda M. Cooper-DeHoff, PharmD, MS, associate professor in the colleges of pharmacy and medicine at University of Florida, Gainesville, and a Cardiology Today Editorial Board member.

“Additionally, its relative ease of use, good tolerability and low incidence of adverse reactions have made it the antiplatelet agent of choice for reduction of atherosclerotic events in patients with MI or stroke since its approval,” she said.

Yet, despite its strengths, shortcomings with clopidogrel are still hindering its use in all patients in need of therapy. At the top of this list, according to Cooper-DeHoff, is clopidogrel resistance, which is the result of a patient’s genetic makeup, “whereby they are not able to adequately convert the prodrug to the active metabolite, resulting in inadequate protection, or they over-convert to the active metabolite, resulting in increased risk of bleeding,” she said.

Other shortcomings, according to Gilles Montalescot, MD, PhD, professor of cardiology at the Pitié-Salpêtrière Hospital in Paris, include poor predictability of the effect, slow onset of action, possible interactions with proton pump inhibitors, as well as recent negative studies on double doses of clopidogrel, including the CURRENT and GRAVITAS trials.

In response to these limitations, new agents have and are continuing to be developed that could potentially change the paradigm of the antiplatelet market by providing answers to several of these concerns.

Adoption of prasugrel inhibited by risks

After its approval in 2009, prasugrel (Effient, Daiichi Sankyo/Eli Lilly) became the only other available thienopyridine compound, which is still true today. Similar to clopidogrel, prasugrel is an indirect platelet inhibitor. However, platelet inhibition with prasugrel is observed after only 15 or 30 minutes and at a significantly lower loading dose compared with clopidogrel (60 mg vs. 300 mg), which occurs within 1 to 2 hours after a single-loading dose.

Rhonda M. Cooper-DeHoff

“While both compounds are prodrugs, clopidogrel requires a two-step enzymatic conversion to the active metabolite, while prasugrel only has to undergo a single conversion,” Cooper-DeHoff said. “However, prasugrel must be used with caution in the very elderly and/or lean population.”

This issue with the elderly, Faxon said, stems from the risk for bleeding with the drug, which he cited as the greatest obstacle currently inhibiting its widespread use. “They say patients have to be off [prasugrel] for 7 days, even longer for surgery. For people who are older, with stroke risk and prior transient ischemic attacks, you get higher risk of intracranial bleeding. This is serious because half the patients with [intracranial bleeding] die and the other half are severally disabled,” he said.

There is even some concern stemming from a study that found a link between prasugrel use and cancer, but Faxon said the study was not powered to look at the connection, and as a result, the finding has not made a huge effect on the drug’s usage.

“It needs to be evaluated, but the incidence was tiny,” he said. “If you’re going to do a study to determine whether prasugrel has any relation to cancer, you need a study of 22,000 patients. You can forget about that. … Personally, I think it was purely by chance because there is no plausible explanation.”

Upcoming trials for prasugrel that will help expound upon current knowledge of the drug, according to Montalescot, include the TRILOGY trial, which will be looking at a new regimen of the drug in ACS, as well as the ACCOAST trial, which will examine pretreatment with the drug in non-STEMI.

Need for data halts ticagrelor

With the FDA panel’s vote of 7-1 in July to recommend approval of the direct-acting P2Y12 inhibitor ticagrelor (Brilinta, AstraZeneca) for the reduction of thrombotic events in patients with ACS, it seemed an almost sure thing that clopidogrel would soon face one of its greatest challenges yet. However, less than 5 months later, the momentum of the drug was halted when the FDA issued a complete response letter to AstraZeneca declining the approval of the drug without additional analysis of the PLATO trial.

“There are a certain number of questions around the [PLATO] results that need to be answered. They are different from country to country,” Montalescot said. “Even if the results look impressive, this is not a home run. Heterogeneity in the results, same safety issues (bleeding) as prasugrel, side effects, reality of the death effect … all this needs to be answered.”

Yet, as many cardiologists agree, even these obstacles seem to be only a temporary setback to the drug’s ultimate approval.

“Ticagrelor is the only one in the group that has shown a reduction in mortality, and I always put a lot of weight into that. Saving lives is what you want to do,” Faxon said. “The bleeding rates are probably more significant than the papers would have you realize, but it seems to have a better profile than prasugrel. It has a relatively short half-life. So you can administer the drug and it works right away, and you can stop it and it goes away very quickly.”

Other promising agents

Although prasugrel and ticagrelor may currently have most of the spotlight in the category of newer antiplatelet therapies, others have emerged that are giving physicians a reason to take notice, including cangrelor, an IV-administered thienopyridine that is a direct and reversible P2Y12 inhibitor. This drug has the advantage of having an even more rapid onset and offset than ticagrelor due to IV administration.

However, the 2009 CHAMPION-PCI trial showed that cangrelor did not reduce the primary endpoint of a composite of death, MI or ischemia-driven revascularization at 48 hours after PCI compared with clopidogrel.

Still, these findings should not rule out possible use, Faxon said. “In some instances, a patient comes in with unstable coronary syndrome and has to go right to the cath lab, and you don’t know if they are going to be a surgical candidate or not. Here’s a drug that you could give them intravenously, cath them and if they don’t have the procedure, you can stop the drug. It wears right off, and you can take them to surgery,” he said. “So, it has a potential place, but if the next trial is negative, then it should be written off. But not quite yet.”

Also of interest to Faxon are protease-activated receptor-1 (PAR-1) drugs, which go to work on the platelet’s thrombin receptor.

“PAR-1 drugs are going to be interesting. There are some big studies with PAR-1 antagonist, including the TRACER study,” he said. “You might think it would only be good by itself, but since it works differently, it might be useful to combine it with clopidogrel or ticagrelor. This is true in general, as it might be good to combine different drugs that work in different ways for patients who want to have the most powerful effect.” – by Brian Ellis

For more information:

• Bellemain-Appaix A. J Am Coll Cardiol. 2010;56:1542-1551.
• Wallentin L. Eur Heart J. 2009;30:1964-1977.

Disclosures: Drs. Cooper-DeHoff and Faxon report no relevant financial disclosures. Dr. Montalescot and his research units report several relationships from the past year, including receiving research grants and consulting or lecture fees from AstraZeneca, Eli Lilly and Sanofi-Aventis.