Cath Lab Digest

September 24, 2012, WILMINGTON, Del. — AstraZeneca announced results from a sub-analysis of PLATO that evaluated the effects of age on clinical outcomes in patients with acute coronary syndrome (ACS). Results of this analysis suggest the overall findings from the PLATO study of a greater reduction in thrombotic cardiovascular (CV) events with ticagrelor (BRILINTA®) tablets plus aspirin compared to clopidogrel plus aspirin were consistent regardless of age. These data are now published in the September print and online issues of Circulation: Cardiovascular Quality and Outcomes, and were presented at the American College of Cardiology 2011 meeting.

This PLATO age sub-analysis is important because approximately 33% of all ACS episodes occur in patients over 75 years.

“Elderly patients with ACS are at high risk for recurrent ischemic events and treatment-related complications,” stated James Ferguson, MD, Executive Director, Medical Affairs and Strategic Development, and Vice President for Global Medical Affairs. “This PLATO sub-analysis suggests that the clinical benefits of ticagrelor vs. clopidogrel on thrombotic CV events were not significantly affected by age, and were similar in patients 75 years of age and older and younger patients.”

Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). In PLATO, ticagrelor has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. In PLATO, the difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with an artery-opening procedure known as percutaneous coronary intervention (PCI), ticagrelor reduces the rate of stent thrombosis.

Ticagrelor has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Avoid maintenance doses of aspirin above 100 mg daily.

Specific data from this sub-analysis showed:

· In PLATO, higher overall rate of thrombotic CV events (adjusted hazard ratio [HR], 1.48 [95% CI, 1.32-1.66]) were associated in patients ≥75 years (n=2,878); Higher rates of Plato-defined Overall Major Bleeding were also associated with this patient population (adjusted HR, 1.11 [95% CI, 0.97-1.26]).

· The effects of ticagrelor compared to clopidogrel were consistent for thrombotic CV events, regardless of age. Thus, there was a similar reduction in the primary composite end point for patients aged ≥ 75 years of age (adjusted HR, 0.89 [95% CI, 0.74 -1.08]) and for patients < 75 years of age (adjusted HR, 0.84 [95% CI, 0.75 - 0.93]) (interaction p= 0.56).

· There was no significant interaction between age and the effects of treatment on Overall Major Bleeding and Non-CABG Major Bleeding. For PLATO-defined Overall Major Bleeding the adjusted HRs for ticagrelor vs. clopidogrel were 1.02 (95% CI, 0.82–1.27) and 1.04 (95% CI, 0.94–1.15) for patients aged ≥75 years and in younger patients, respectively (interaction P=0.89). For Non-CABG related Major Bleeding events, the adjusted HRs for ticagrelor vs. clopidogrel were 1.18 (95% CI, 0.87–1.59) in patients aged ≥75 years and 1.19 (95% CI, 0.99–1.43) in younger patients. (interaction P=0.96).

· Dyspnea and ventricular pauses were more common with ticagrelor than with clopidogrel treatment. With regards to dyspnea, rates were higher in elderly vs. younger patients in both treatment groups. In this analysis, dyspnea showed no evidence of an age by treatment interaction (P=0.21). Similarly, ventricular pauses showed no evidence of an age-by treatment interaction.

About PLATO

PLATO (PLATelet Inhibition and Patient Outcomes) was a large (18,624 patients in 43 countries), head-to-head patient outcomes study of ticagrelor versus clopidogrel, both given in combination with aspirin and other standard therapy. The study was designed to establish whether ticagrelor could achieve a clinically meaningful reduction in cardiovascular (CV) events in acute coronary syndrome (ACS) patients, above and beyond that afforded by clopidogrel. Patients were treated for at least 6 months and up to 12 months.

PLATO demonstrated that treatment with ticagrelor led to a significantly greater reduction in the primary end point – a composite of CV death, MI, or stroke – compared to patients who received clopidogrel (9.8% vs 11.7% at 12 months; 1.9% absolute risk reduction [ARR]; 16% relative risk reduction [RRR]; 95% CI, 0.77 to 0.92; P<0.001). The difference in treatments was driven by CV death and MI with no difference in stroke. In PLATO, the absolute difference in treatment benefit versus clopidogrel was seen at 30 days and the Kaplan-Meier survival curves continued to diverge throughout the 12-month treatment period.

The PLATO study also demonstrated that treatment with ticagrelor for 12 months was associated with a 21% RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16% RRR in MI compared to clopidogrel at 12 months (5.8% vs 6.9%; 1.1% ARR; P<0.005).

The primary safety end point in the PLATO study was Total Major Bleeding (11.6% for ticagrelor and 11.2% for clopidogrel). In PLATO, non-CABG major + minor bleeding events were more common with ticagrelor versus clopidogrel (8.7% vs 7% respectively). The rate of non-CABG-related major bleeding was higher for ticagrelor (4.5%) vs clopidogrel (3.8%).

Dyspnea was reported in 14% of patients treated with ticagrelor and in 8% of patients treated with clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment.