THEMIS Study: Ticagrelor Plus Aspirin Associated with Lower Ischemic Event Rate but Higher Bleeding Rate Than Aspirin Alone in Patients with Diabetes and Stable Coronary Artery Disease

Use of ticagrelor plus aspirin in patients with stable coronary artery disease and type 2 diabetes significantly lowers the risk of major adverse cardiovascular events compared with aspirin alone, but at the cost of higher major bleeding, according to the THEMIS study. The results were presented at ESC 2019 and published in the New England Journal of Medicine.

THEMIS was a randomized, double-blind trial that included 19,271 patients with stable coronary artery disease and type 2 diabetes mellitus at more than 1000 sites in 42 countries in North America, South America, Asia, Africa, Australia, and Europe. Patients were randomly assigned to receive either ticagrelor plus aspirin or placebo plus aspirin for a median of 40 months. The patients did not have a prior history of myocardial infarction or stroke. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.

The incidence of the primary efficacy outcome (ischemic cardiovascular events) was lower in the ticagrelor group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P=0.04). However, patients receiving ticagrelor had twice as high as the risk of TIMI major bleeding compared with the placebo group (2.2% vs. 1.0%, HR 2.03; 95% CI 1.48-2.76), and there was a higher incidence of intracranial hemorrhage in the ticagrelor group (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P=0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P=0.11).

In an exploratory analysis that weighed both efficacy and safety events, there was no reduction in the composite outcome of irreversible harm, defined as death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02). The results propose that that ticagrelor therapy does not seem to have a favorable risk-benefit ratio in this trial population. However, according to THEMIS-PCI substudy, published recently in The Lancet, a significant net-clinical benefit was observed in patients with prior PCI (9.3% with ticagrelor vs. 11.0% with placebo; hazard ratio, 0.85; 95% CI, 0.75 to 0.95; P=0.005), but not in those without prior PCI (P interaction=0.012).

In conclusion, ticagrelor may be considered in addition to aspirin in diabetics with a history of PCI who have a high ischemic risk and low bleeding risk.