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WASHINGTON -- The third time proved to be the charm for the long-awaited new entry into the antiplatelet market dominated by clopidogrel (Plavix) as ticagrelor (Brilinta) today won FDA marketing approval for reducing thrombotic events in patients with acute coronary syndrome, including unstable angina, and MI who are candidates for stenting.
Ticagrelor was studied as part of a dual antiplatelet regimen, and the FDA said the drug's label will include a "boxed warning to healthcare professionals and patients warning that aspirin doses above 100 milligrams per day decrease the effectiveness of the medication."
The boxed warning also states that, just like other blood thinning agents, ticagrelor "increases the rate of bleeding and can cause significant, sometimes fatal, bleeding."
As with most recent approvals, the FDA ordered a Risk Evaluation and Mitigation Strategy, as part of the approval message. "As part of that plan, the company must conduct educational outreach to physicians to alert them about the risk of using higher doses of aspirin, " the FDA said.
A year ago an FDA advisory committee voted 7-1 to recommend approval for ticagrelor, and the FDA was expected to issue a decision by mid-September 2010. But the agency postponed its decision by three months and then in December 2010 the FDA told drugmaker AstraZeneca that it needed more information before it could approve the drug.
The FDA December response stunned the cardiology community because the drug was almost universally lauded based on positive results -- including a survival benefit -- from the pivotal PLATO trial.
The other widely touted benefit of ticagrelor is that its effect can be quickly switched off because it has a much shorter half life than either of the two approved antiplatelets -- market-leader clopidogrel and prasugrel (Effient).
PLATO was a head-to-head trial with clopidogrel that randomized 18,624 ACS patients to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 to 600 mg loading dose, 75 mg thereafter). Patients were followed for 12 months.
Some 9.8% of patients randomized to ticagrelor reached the composite endpoint of cardiovascular death, stroke, or MI versus 11.7% of those randomized to clopidogrel. That was a relative reduction of 16% (P<0.001).
But one of the difficulties with those data was the fact that most of the patients came from Europe, the Middle East, or Africa. Only 11% of the patients were recruited in North America. In that cohort, ticagrelor-treated patients were 27% more likely to suffer one of the endpoint events, although the difference fell short of statistical significance (HR 1.27, 95% CI 0.92 to 1.75).
When the PLATO results were initially reported in Barcelona at the European Society of Cardiology meeting in 2009, the results from North America were regarded as a play of chance rather than a significant finding.
Another issue that emerged early on -- but was also downplayed amidst the generally unbridled enthusiasm from researchers viewing the PLATO results -- was excess bleeding events seen with ticagrelor across the entire PLATO sample. Some 14.5% of patients in the ticagrelor group experienced bleeding, compared with 13.2% in the clopidogrel group (P=0.0083).
The timing of the FDA decision is also interesting since it came when clopidogrel faces just 10 remaining months of patent protection -- protection that the FDA extended to May 2012.