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Arrhythmia Watch Editorial Staff

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Atrial Fibrillation high on ESC agenda

A record number of 31,371 delegates attended the European Society of Cardiology (ESC)Congress in Barcelona this week. Clinical trials in atrial fibrillation were among the most well attended sessions, receiving worldwide news coverage within minutes of presentation. Principal among these were RE-LY and PLATO, details of which we feature here.

Dabigatran vs warfarin as long-term anticoagulant therapy in atrial fibrillation: results from the RE-LY study

The anticoagulant dabigatran is more effective than warfarin in the prevention of stroke in patients with atrial fibrillation, according to results from the RE-LY study (Randomized Evaluation of Long-term anticoagulant therapy).

“Although researchers have been looking for a replacement for warfarin for several decades, nothing has been successful as an oral blood thinner,” says Professor Stuart Connolly, Director of the Division of Cardiology at McMaster University, Canada, and one of the leading investigators of the study.
The RE-LY study 1 compared two doses of dabigatran with the current standard therapy, warfarin, in 18,113 patients with atrial fibrillation at increased risk of stroke. The study included more than 951 centres in 44 countries. Patients were enrolled over a two-year period and then followed for one further year. The study was designed to evaluate whether either of two doses of dabigatran were non-inferior to warfarin (ie, at least as good as warfarin). The results show, however, that the higher dose of dabigatran, 150 mg twice daily, significantly reduces the risk of stroke by 34% compared to warfarin. The lower dose, 110 mg twice daily, had a similar effect to warfarin in the prevention of stroke, but with significantly less major bleeding.

According to Professor Connolly, although warfarin has been the gold standard for reducing stroke in atrial fibrillation for more than 20 years, it has many problems; these include a need for monitoring by blood test measurement, and a significant risk of increased bleeding, which makes it unsuitable for many patients. “Several new drugs have been recently studied to see if they could replace warfarin,” says Professor Connolly. “None, however, has been satisfactory. Either they were not effective enough, they had too many side effects or they caused too much bleeding. This is the first time in more than 50 years that a new oral blood thinner has been developed which has been found to be both safer and more effective than existing therapy.”
Atrial fibrillation is a common disorder of the heart rhythm that affects about 1% of the population and up to 10% of people over the age of 80. The major complication of atrial fibrillation is stroke. About one in six strokes are caused by atrial fibrillation. Patients with atrial fibrillation have an annual risk of stroke of 1-10%. Anticoagulants such as warfarin are the only way to prevent these strokes.

PLATO trial; Ticagrelor in acute coronary syndrome

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®) (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®).


About Ticagrelor

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.

About the PLATO study

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).

Published on: September 7, 2009

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