Ticagrelor Approved at Last for US Market: FDA

Lisa Nainngolan

July 20, 2011

July 20, 2011 (Silver Spring, Maryland) — AstraZeneca's new antiplatelet agent, ticagrelor (Brilinta), has finally been cleared for marketing in the US after a protracted approval process in which the Food and Drug Administration twice postponed a decision on the drug [1].

The approval comes with a boxed warning, however, stating that use of ticagrelor with aspirin doses above 100 mg/day decreases the effectiveness of the medication.

Health Canada recently approved ticagrelor for the Canadian market, specifying that the drug "be coadministered with low maintenance dose ASA (75–150 mg).”

A discrepancy between geographic regions in a pivotal trial of ticagrelor is thought to be the reason the US regulatory body had stalled on its verdict, despite its advisory committee voting to recommend approval of the agent a year ago, in July 2010, and ticagrelor having been approved in the European Union, Canada, and other markets.

This "aspirin theory" is believed to explain the so-called "North American anomaly," in which outcomes were superior with ticagrelor vs clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) across the entire international PLATO trial but not in North America, where the aspirin doses were generally higher, as previously covered by heartwire .

US Must Move to Low-Dose Aspirin for ACS Patients

PLATO enrolled >18 000 patients in 43 countries on nearly every continent. In it, as heartwire has reported extensively, ticagrelor was associated with a 16% reduction in the composite primary end point vs clopidogrel, with both drugs accompanied by aspirin, over a mean of 12 months. In the overall trial, the absolute rates were 9.8% for those taking ticagrelor and 11.7% for the clopidogrel group (p<0.001).

But in a prospectively defined subgroup analysis, the rates were 11.9% and 9.6%, respectively, for US and Canadian patients; the difference didn't reach significance.

The newest regional analysis compared the 1413 patients randomized in the US with 17 211 randomized in other countries and found geographic variation in the relative ticagrelor-vs-clopidogrel effect on outcomes was evident for the composite primary end point, for some of its components, and for all-cause mortality, but not for major bleeding.

PEGASUS Trial Will Provide Further Details on Ticagrelor

Another ongoing trial may shed some more light on the ASA issue. The Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin (PEGASUS)-TIMI 54 trial will enroll 21 000 stable patients, post–acute coronary syndrome (ACS), from 30 countries, with 25% of those recruited expected to be from the US [2].

Only patients taking 75–150 mg/day of aspirin will be enrolled in PEGASUS, and they will be randomized to one of two doses of ticagrelor (60 mg or 90 mg twice daily) or placebo. The primary end point will be any event after randomization from the composite of cardiovascular death, nonfatal MI, or nonfatal stroke.

AstraZeneca stressed earlier this year that the FDA had not requested the PEGASUS-TIMI 54 study as part of the approval process for ticagrelor.

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