New oral antiplatelet agent ticagrelor first to show reduction in cardiovascular death

Barcelona, Spain, 30 August: The presentation of the PLATO (A Study of Platelet Inhibition and Patient Outcomes), showed that ticagrelor (Brilinta®) reduced the rate of cardiovascular (CV) events (CV death, myocardial infarction or stroke) from 11.7% to 9.8% compared clopidogrel (Plavix®) XX% (p<0.001, RRR = 16%), without an increase in major bleeding. This efficacy endpoint was driven by a statistically significant reduction in both CV death and myocardial infarction (MI) with no difference in stroke. Ticagrelor is the first antiplatelet agent to demonstrate a reduction in CV death across all major acute coronary syndromes (ACS) patient types.

For every 1,000 patients admitted to the hospital because of an ACS event, use of ticagrelor instead of clopidogrel, for up to one year, led to 14 fewer deaths, or 11 fewer MI's, or 8 fewer cases of stent thrombosis, without an increase in major bleeds. In the PLATO study, the reduction in risk of cardiovascular events appears early and the benefit over clopidogrel grows with time. Ticagrelor demonstrated a consistent benefit across multiple secondary efficacy endpoints including CV death and total mortality; myocardial infarction; the composite of myocardial infarction, stroke, and total mortality; and a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, recurrent cardiac ischemia, severe recurrent cardiac ischemia, and other arterial thrombotic events.

"Ticagrelor is the first antiplatelet therapy to achieve a significant reduction in CV mortality in ACS patients versus clopidogrel and perhaps most importantly without an increase in major bleeding," commented Professor Lars Wallentin, co-chair of the PLATO Executive Committee. "PLATO has redefined what is possible in the prevention of recurrent events in patients with acute coronary syndromes."

The PLATO study confirmed the clinical safety profile of previous ticagrelor studies by showing an efficacy advantage without an increase in major bleeding. Across all the important patient subgroups (e.g. gender, weight, history of stroke/TIA) in PLATO, ticagrelor showed no difference versus clopidogrel in the incidence of major bleeding. When minor bleeding was added, ticagelor showed a small increase in PLATO defined major plus minor bleeding versus clopidogrel. At continuous ECG monitoring wile in hospital, but not at later followup in the outpatient setting, pauses in the heart rhythm were seen more frequent with ticagrelor. However such pauses were not associated with any symptoms or clinical consequences for the patient. Transient symptoms of dyspnoea were reported more often by patients on ticarelor but only one in 100 ticagrelor treated patients overall stopped taking study medication due to dyspnoea.

PLATO was a head-to-head outcomes study of ticagrelor plus aspirin versus the active comparator, clopidogrel plus aspirin, and was designed to establish whether ticagrelor could achieve meaningful cardiovascular endpoints in ACS patients. 18,624 patients at 893 sites in 43 countries across all continents were sucessfully recruited. All patients were admitted to hospital because of acute coronary syndrome, one third with ST-elevation myocardial infarction and two thrirds without ST-elevation. Shortly after admission to hospital, the patients started their long-term anti-platelet treatment with either ticagrelor (90 mg twice daily) or clopidogrel (75 mg daily) in a randomized, double-blind fashion for 6 - 12 months. The PLATO study was led by the Executive Committee co-chairs, Professor Lars Wallentin, Sweden (Uppsala Clinical Research Center) and Professor Robert Harrington, USA (Duke Clinical Research Institute).

The PLATO study was sponsored by AstraZeneca which has developed and manufactures ticagrelor (Brilinta®). AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services.

Ticagrelor is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events. Ticagrelor is the first in a new chemical class, the CPTPs (cyclopentyl-triazolo-pyrimidines) and is chemically distinct from the thienopyridines, such as clopidogrel and prasugrel. AstraZeneca has proposed the name BRILINTATM. If approved by the FDA and the EMEA, it will serve as the trade name for ticagrelor / AZD6140.

PLATO was an international head-to-head outcomes study of ticagrelor plus aspirin, versus clopidogrel plus aspirin. The PLATO study was designed to establish whether ticagrelor could achieve clinically meaningful cardiovascular and safety endpoints in ACS patients, above and beyond those afforded by clopidogrel, an irreversible therapy in the thienopyridine class of medicines.

In PLATO, patients randomised to treatment with ticagrelor received a single 180 mg loading dose of ticagrelor followed by a twice-daily 90 mg maintenance dose. For those patients randomised to receive clopidogrel, a loading dose of 300 mg, which could be adjusted as necessary to 600 mg to reflect current clinical practice seen across the world, was followed by a twice-daily 75 mg maintenance dose. All patients received concomitant aspirin unless intolerant. The study design of PLATO was published in the April 2009 edition of the American Heart Journal (James, S. et al. in Am. Heart J. 2009; 157: 599-605).

'Acute coronary syndromes' (ACS) is an umbrella term for conditions that can suddenly cause chest pain due to an insufficient blood supply to the heart muscle. ACS is divided into two conditions – unstable angina (which is not associated with heart muscle damage) or heart attack (also known as myocardial infarction, where the heart muscle is damaged). ACS is the most common reason for cardiac hospitalisation in the world. It is estimated that one in three ACS patients will die, have a recurrent heart attack or be readmitted to hospital within six months of their first cardiovascular event so preventing reoccurrence is vital in ACS patient treatment.

The two principal goals of ACS treatment are restoration of blood flow to the heart muscle and reduction of the risk of recurrent CV events. Depending on the severity of the underlying condition, the patient will either need to undergo surgical intervention (e.g. stent placement or surgery) or be managed with prescription medicines. Interventional options may include percutaneous coronary intervention (PCI), a procedure to open existing blocked arteries (also known as angioplasty). During this procedure, a stent (a tube, normally made of metal) may be inserted to keep the arteries open. Patients may undergo coronary artery bypass graft (CABG), a procedure where surgeons bypass the affected artery in the heart so that blood can flow around the heart more easily.