New data from the Phase III PLATO trial with AstraZeneca’s oral antiplatelet therapy ticagrelor (Brilinta) have shown that Brilanta can reduce the risk of cardiovascular events in acutely ill heart-attack patients compared with the current standard treatment, clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb).
What is more, Brilinta achieved this without any increase in major bleeding episodes, said researchers presenting the late-breaking clinical data at the American Heart Association’s Scientific Sessions 2009 in Orlando, Florida.
AstraZeneca plans to file Brilinta for approval in the US and Europe before the end of the year. At the beginning of September, the company presented data from the 18,642-patient PLATO (PLATelet inhibition and patient Outcomes) study at the European Society of Cardiology meeting in Barcelona, Spain.
These results showed that after 12 months of treatment, 9.8% of patients with acute coronary syndromes who were given Brilinta experienced cardiovascular events compared with 11.7% of patients on Plavix, again without any increase in major bleeding.
STEMI patients
The new data presented in Orlando came from a subset of 8,430 PLATO patients who had ST Segment Elevated Myocardial Infarction (STEMI) and were scheduled for primary percutaneous coronary intervention (PCI or balloon angioplasty) with stenting, a procedure that involves clearing and keeping open a blocked artery.
According to Dr Philippe Gabriel Steg, lead investigator in the PLATO study and professor of cardiology at Hôpital Bichat-Claude Bernard in Paris, STEMI “is really the most acute form of coronary disease” and is “a high-risk condition for which the standard of care, clopidogrel, has clear drawbacks”.
In the subset analysis, 4,201 STEMI patients were allocated to a 180mg loading dose of ticagrelor during PCI, followed by 90mg ticagrelor twice daily plus aspirin, while 4,229 STEMI patients received a 300mg loading dose of clopidogrel, with provision for another 300mg during PCI, followed by 75mg clopidogrel daily plus aspirin.
Treatment was continued for 6-12 months and the primary endpoint was a composite of cardiovascular death, myocardial infarction (MI) and stroke (i.e., cardiovascular events).
With follow-up to one year, 9.3% of the ticagrelor group experienced cardiovascular events compared with 11% of the clopidogrel group, a relative risk reduction of 15%, the researchers said. There was a statistically significant reduction in MI (4.7% in the ticagrelor group versus 6.1% on clopidogrel) and an 18% relative reduction in all-cause mortality at one year (4.9% on ticagrelor, 6.0% on clopidogrel).
Brilinta also demonstrated favourable effects in secondary efficacy endpoints such as stent thrombosis and a composite of MI, stroke and all-cause mortality, Astra Zeneca reported. Major bleeding was seen in 9% of ticagrelor patients and in 9.3% of clopidogrel patients.
The downsides of clopidogrel therapy include slower onset of effectiveness, “which is not suited to the need for rapid effect in STEMI”, and a “modest but inconsistent anti-platelet effect – many patients respond well, but a sizeable unresponsive group remains at high risk of blood clots despite therapy”, Steg commented.
Moreover, unlike clopidogrel, ticagrelor does not bind permanently to the platelets’ P2Y12 receptors, with the result that normal platelet clotting function returns in around four days, Steg noted. This may account for the absence of increased bleeding with the more potent ticagrelor, he suggested.
Ticagrelor does, however, produce some off-target effects, which probably explains the increased incidence of dyspnoea or breathlessness (12.9% of patients) seen on the AstraZeneca drug compared with clopidogrel (8.3%), Steg added.
