CardioBrief

New results from a subset of the PLATO trial show that ticagrelor was more effective than clopidogrel in preventing events in ACS patients undergoing an invasive strategy.

Under development as Brilinta by AstraZeneca, ticagrelor is an oral, reversible antiplatelet drug with a rapid onset of action. The main results of PLATO in 18,624 ACS patients were presented last month at the ESC and published simultaneously in the New England Journal of Medicine. At TCT today, Chris Cannon presented results of the very large, planned substudy of the 72% of PLATO patients for whom an invasive strategy was intended.

The primary endpoint, the rate of CV death, MI, and stroke, was reduced from 10.7% in the clopidogrel arm to 9.0% in the ticagrelor arm, a highly significant (p=0.0025) reduction of 16%. MIs were reduced from 6.6% in the clopidogrel group to 5.3% in the ticagrelor group. CV death was cut from 4.3% to 3.4%. All cause mortality was 5.08% in the clopidogrel group versus 3.94% in the ticagrelor group. Stent thrombosis was also reduced by ticagrelor (definite ST 1% versus 1.6%, probable or definite ST 1.7% versus 2.3%).

The difference between the two arms were not altered by the pre-randomization use of either 300 mg or 600 mg clopidogrel loading dose.

The superior efficacy of ticagrelor was not achieved at the expense of more bleeding. Major bleeds occurred in 11.6% of clopidogrel patients and 11.5% of ticagrelor patients. There were also no significant differences in life threatening of fatal bleeds, or bleeding associated with CABG.

Cannon calculated that treating 59 patients with ticagrelor instead of clopidogrel for one year would prevent one major event of CV death, MI, or stroke.

Here is our coverage of the main PLATO results at the ESC.

Here is the AstraZeneca press release:

Ticagrelor Reduced Cardiovascular Deaths and Heart Attacks in ACS Patients Undergoing Heart Procedures: New Data from PLATO Trial

Significant effects shown with no increase in major bleeding compared to clopidogrel in head-to-head trial

September 24, 2009 – San Francisco, CA – New data from the phase III PLATO study showed that ticagrelor (BRILINTA™) provided greater reduction of cardiovascular (CV) events (composite of CV death, heart attack and stroke) than clopidogrel (9.02% vs. 10.65%, p=0.0025 a 16% Relative Risk Reduction ) in acute coronary syndromes patients undergoing planned invasive treatment  (either PCI or CABG).*  Although patients undergoing invasive procedures are at greater risk of bleeding, these  results were achieved without a significant  increase in major bleeding compared to clopidogrel (11.5% vs 11.6%, p=0.88).  Patients with planned invasive procedures at randomization accounted for more than 70% of the greater than 18,000 patients in PLATO.  These sub-analysis data were presented today at the Transcatheter Cardiovascular Therapeutics (TCT) conference in San Francisco.

Additional findings from this PLATO invasive sub-analysis showed that treatment with ticagrelor, compared to clopidogrel, demonstrated an effect consistent with the results for the entire invasive subgroup across the multiple secondary efficacy endpoints.  The effect was seen regardless of whether a standard 300 mg loading dose of clopidogrel was given, or an additional loading dose of clopidogrel (e.g. 600 mg) was given.  Specifically, results in this subgroup analysis indicated treatment with ticagrelor:

•           Reduced CV death 3.4% vs. 4.3% (p=0.025) Relative Risk Reduction of 18%

•           Reduced myocardial infarction (heart attack, MI)  5.3% vs. 6.6% (p=0.002) Relative Risk Reduction of 20%

•           Reduced definite stent thrombosis  1.0% vs. 1.6% (p=0.003) Relative Risk Reduction of 38%

•           Reduced total mortality 3.9% vs. 5.1% (p=0.01) Relative Risk Reduction of 19%

“The majority of patients rushed to the hospital with severe chest pain or heart attacks will have an invasive procedure,” said Christopher Cannon, M.D., PLATO Executive Committee member, a cardiologist at Brigham and Women’s Hospital in Boston.  “Doctors need to make quick decisions about antiplatelet therapy for patients who are sent for cardiac catheterization and may need angioplasty or surgery.  In this study population, ticagrelor led to fewer heart attacks and deaths without a significant increase in major bleeding versus clopidogrel.”

Similar to the overall PLATO findings, Dyspnoea (shortness of breath) was more common among patients on ticagrelor but less than 1% discontinued ticagrelor treatment in the sub-analysis because of dyspnoea.

The PLATO study was designed to reflect how patients with ACS are currently managed in clinical practice, by including patients who underwent invasive procedures and those who were managed with medication only.

Last month, the primary results from PLATO were presented at the European Society of Cardiology and simultaneously published in The New England Journal of Medicine in August 2009.

AstraZeneca remains on track to submit BRILINTA to regulatory authorities in the fourth quarter of this year.

About PLATO:

PLATO (A Study of PLATelet Inhibition and Patient Outcomes) was a head-to-head 18,624 patient outcomes study of ticagrelor plus aspirin versus the active comparator, clopidogrel plus aspirin, and was designed to establish whether ticagrelor could achieve meaningful cardiovascular and safety endpoints in ACS patients, above and beyond those afforded by clopidogrel, an irreversible therapy in the thienopyridine class of medicines. The study design of PLATO was published in the April 2009 edition of the American Heart Journal.

The bleeding definitions used within the PLATO trial were an evolution from the CURE bleeding definitions and were developed by the PLATO Executive Committee as constituting the most appropriate and clinically meaningful assessment of bleeding complications associated with acute and chronic therapy. The PLATO bleeding definitions provide a framework to allow investigators to record all bleeding events reported by patients in the PLATO trial. The bleeding definitions were developed to characterize bleeding in both the acute and long-term setting.

Given the size of the PLATO database, AstraZeneca will continue to analyze and publish additional PLATO findings.

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