Ticagrelor reduces death rate in patients with adult coronary syndrome

Treatment with ticagrelor compared with clopidogrel in patients with acute coronary syndromes significantly reduced the death rate from vascular causes, myocardial infarction (MI), or stroke, according to the Study of Platelet Inhibition and Patient Outcomes (PLATO), a multicenter, randomized, double-blind trial. PLATO’s results were published in a recent issue of The New England Journal of Medicine.

In addition, a similar benefit was observed for the individual components of death from vascular causes and MI, but not for stroke.

Ticagrelor’s beneficial effects were achieved without a significant increase in the rate of major bleeding; the benefits of ticagrelor over clopidogrel occurred in patients with acute coronary syndrome with or without ST-segment elevation.

Ticagrelor is a reversible and direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. It provides faster, greater, and more consistent P2Y12 inhibition than clopidogrel.

Hospitalized patients were eligible for enrollment in the study if they had acute coronary syndrome, with or without ST-segment elevation, with an onset of symptoms during the previous 24 hours. Patients either received ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). The researchers recruited 18,624 patients from 862 centers in 43 countries from October 2006 through July 2008.

The primary end point-death from vascular causes (death from cardiovascular or cerebrovascular causes or death without another known cause), MI, or stroke-occurred significantly less often in those taking ticagrelor (9.8%) than those taking clopidogrel (11.7%) at 12 months (HR=0.84; 95% CI, 0.77–0.92; P.001).

The researchers performed predefined hierarchical testing of secondary end points. These showed significant differences in the rates of other composite end points, as well as MI alone (5.8% in those taking ticagrelor vs 6.9% in those taking clopidogrel, P=.005) and death from vascular causes (4.0% vs 5.1%, P=.001) but not stroke alone (1.5% vs 1.3%, P=.22). In those taking ticagrelor the death rate from any cause was reduced (4.5% vs 5.9% with clopidogrel; P.001).

In patients for whom invasive treatment was planned, the rate of the primary end point was lower with ticagrelor (8.9% vs 10.6% with clopidogrel; P=.003). The rate of stent thrombosis was lower in those receiving ticagrelor than those receiving clopidogrel (1.3% vs 1.9%, P=.009) among patients who received a stent during the study.

Major life-threatening bleeding was defined as fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery, a decline in the hemoglobin level of 5.0 g/dL or more, or the need for transfusion of at least 4 units of red cells. Other major bleeding was considered to be bleeding that led to clinically significant disability (eg, intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in the hemoglobin level ≥3.0 g/dL but
There was no significant difference between the ticagrelor and clopidogrel groups with regard to major rates of bleeding (11.6% and 11.2%, respectively, P=.43). Although there was no significant difference between the 2 treatment groups in the rates of coronary artery bypass graft (CABG)-related major bleeding or bleeding requiring transfusion of red cells, in those receiving ticagrelor, there was a higher rate of non-CABG related major bleeding (4.5% vs 3.8%, P=.03). There was also more episodes of intracranial bleeding with ticagrelor compared with clopidogrel (0.3% vs 0.2%, P=.06), including fatal intracranial bleeding (0.1% vs 0.01%, P=.02). There were, however, fewer episodes of other types of fatal bleeding in those taking ticagrelor than those taking clopidogrel (0.1% vs 0.3%, P=.03).

Regarding other adverse effects, dyspnea was more common in the ticagrelor group than in the clopidogrel group (13.8% of patients vs 7.8%). However, few patients discontinued the study because of dyspnea-0.9% of patients in the ticagrelor group and 0.1% in the clopidogrel group.

CONCLUSION

The authors conclude that there was an absolute reduction of 1.4% and a relative reduction of 22% in rate of death from any cause at 1 year in those treated with ticagrelor. They add that this survival benefit from ticagrelor’s more intense platelet inhibition is consistent with reductions in the mortality rate obtained by platelet inhibition with aspirin in patients with acute coronary syndrome and with clopidogrel in patients who had an MI with ST-segment elevation. They add that in contrast to the experience with prasugrel, which is a more effective platelet inhibitor than clopidogrel, but is irreversible, there was no increased risk of CABG-related bleeding with ticagrelor.

Source

Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.