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Abstract
In the 30 years since the original description of ischaemic preconditioning, understanding
of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection
have been revolutionised. In the same period of time, management of patients with
coronary artery disease has also been transformed: coronary artery and valve surgery
are now deemed routine with generally excellent outcomes, and the management of acute
coronary syndromes has seen decade on decade reductions in cardiovascular mortality.
Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart
disease in particular, remain the leading cause of death and a significant cause of
long-term morbidity (with a concomitant increase in the incidence of heart failure)
worldwide. The need for effective cardioprotective strategies has never been so pressing.
However, despite unequivocal evidence of the existence of ischaemia/reperfusion in
animal models providing a robust rationale for study in man, recent phase 3 clinical
trials studying a variety of cardioprotective strategies in cardiac surgery and acute
ST-elevation myocardial infarction have provided mixed results. The investigators
meeting at the Hatter Cardiovascular Institute workshop describe the challenge of
translating strong pre-clinical data into effective clinical intervention strategies
in patients in whom effective medical therapy is already altering the pathophysiology
of ischaemia/reperfusion injury—and lay out a clearly defined framework for future
basic and clinical research to improve the chances of successful translation of strong
pre-clinical interventions in man.
The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types. In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.) 2009 Massachusetts Medical Society
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