Ticagrelor Approval: US and Europe React

US Approval of Ticagrelor

Lisa Nainngolan and Michael O'Riordan

July 21, 2011

July 21, 2011 — After a protracted approval process in which the Food and Drug Administration (FDA) twice postponed a decision on the drug, experts are reacting to news of the US approval of ticagrelor (Brilinta, AstraZeneca), the newest antiplatelet agent to hit the market. The drug was given the all-clear from the agency yesterday, and is currently approved to reduce the risk of cardiovascular death and MI in patients with acute coronary syndromes (ACS).

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

This warning was likely included in the labeling as a response to 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 aspirin doses were generally higher, as previously covered by heartwire . This discrepancy between geographic regions in PLATO is believed to be the reason it took so long to approve ticagrelor in the US, but many are still not convinced that the "aspirin theory" adequately explains the anomaly.

Dr Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD), who was involved in the early pharmacodynamic studies of ticagrelor that were reviewed by the FDA, called the new drug an "advance in therapy."

Gurbel continued: "I wouldn't be so confident to say that you lose the effect of ticagrelor with high-dose aspirin. . . . It's an issue that deserves further study, and something we don't understand." He noted, however, that it is unlikely the boxed warning will affect uptake of the ticagrelor by US physicians, given the drug's effect on cardiovascular mortality observed in the overall trial and in various patient subgroups.

Other cardiologists have similar mixed views on the boxed warning. Dr Anthony Gershlick (University of Leicester, UK) told heartwire that the boxed warning offers just "one answer to the US paradox." Likewise, Dr Dirk Sibbing (German Heart Center, Munich) agrees with Gurbel that plausible explanations are still lacking, as are mechanistic studies that specifically investigate this issue. Before conclusions can be drawn, these studies need to be performed, said Sibbing.

Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who recently published a critique of the PLATO data analysis, and questioned whether the different results in US were the result of independent site monitoring, said he hopes the FDA verified the integrity of the outcome data. "If no further incriminating evidence becomes public, ticagrelor approval is appropriate," he told heartwire . "It seems the FDA has no doubt in the quality of the data granting ticagrelor extremely favorable labeling."

Ticagrelor an important addition to armamentarium

Apart from the aspirin issue, Sibbing said the addition of ticagrelor to the other available P2Y12 receptor blockers--clopidogrel and prasugrel--is important because of its beneficial pharmacologic properties and strong results in the PLATO trial.

"For future treatment of ACS patients it will now also be left to the decision of the attending physician which drug to choose for the individual patient, by balancing the risk of thrombotic and bleeding events," he told heartwire . "I believe that the more drugs we have here the more guidance to tailor antiplatelet treatment will be necessary. Platelet function testing to assess the level of P2Y12 receptor inhibition will help in this setting to sort out the best drug for the individual patient," he added.

Dr Giuseppe Biondi-Zoccai (University of Modena and Reggio Emilia, Italy) expressed similar views, calling the US approval of ticagrelor a success for patients and physicians alike. The drug is more potent than clopidogrel and as effective as prasugrel, but with an shorter half-life in comparison to both, making it an ideal option for patients with acute coronary syndromes considered for medical therapy, bypass surgery, or in whom bleeding might occur, he said.

"Of course, we now eagerly await a head-to-head comparison of prasugrel and ticagrelor within the context of a randomized trial, but I doubt such a trial will be available before the next five to ten years," he told heartwire . "Thus, our belief that our recent adjusted indirect comparison may guide physicians in choosing when to use prasugrel versus ticagrelor."

Sibbing reports fees for advisory board activities from Eli Lilly, AstraZeneca, and Dynabyte. Biondi-Zoccai has lectured for AstraZeneca, Bristol-Myers Squibb, and Sanofi-Aventis, consulted for AstraZeneca and Eli Lilly, and received research grants from Eli Lilly.