Compared with placebo plus aspirin, ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding in patients with stable coronary artery disease (CAD) and diabetes without a history of myocardial infarction (MI) or stroke, said researchers presenting on the THEMIS trial at ESC Congress 2019. However, in patients with diabetes, stable CAD and previous PCI, findings from the THEMIS-PCI trial found ticagrelor plus aspirin provided a "favorable net clinical benefit."

In the broader THEMIS study – simultaneously published in the New England Journal of Medicine – 19,220 patients (50+ years of age) with stable CAD and type 2 diabetes were randomly assigned to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous MI or stroke were excluded. Patients were from 42 countries in North America, South America, Asia, Africa, Australia and Europe. The primary efficacy outcome was a composite of cardiovascular death, MI or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. The median follow-up time was 39.9 months.

Results showed the incidence of ischemic cardiovascular events was lower in the ticagrelor group (7.7 percent) than in the placebo group (8.5 percent), while the incidence of major bleeding and of intracranial hemorrhage, respectively, was higher in the ticagrelor group (2.2 percent and 0.7 percent) compared with the placebo group (1.0 percent and 0.5 percent). Researchers found no significant difference in the incidence of fatal bleeding between the two groups.

Additionally, the incidence of an exploratory composite outcome of irreversible harm (death from any cause, MI, stroke, fatal bleeding or intracranial hemorrhage) was similar in both groups (10.1 percent vs. 10.8 percent). In other findings, Deepak L. Bhatt, MD, MPH, FACC, and colleagues noted the rates of discontinuation were high across both groups, but higher in the ticagrelor group largely due to an increased risk of bleeding and dyspnea. "These findings are likely to reflect the side-effect profile that would be observed in clinical practice," they said.

In a related New England Journal of Medicine editorial comment, Eric R. Bates, MD, FACC, writes that "PARTHENON investigators and the sponsor deserve great credit for testing ticagrelor in five major trials [including THEMIS] enrolling more than 80,000 patients during the past dozen years." In many cases, he notes, findings from these trials suggest the risk of bleeding, possible additional side effects and increased costs outweigh the benefits. However, while "it may be possible to identify individual patients who have an increased risk of thrombotic events and a reduced risk of bleeding for whom this trade-off may be advantageous, … for most patients with type 2 diabetes and known coronary disease who fit the THEMIS enrollment criteria, the addition of ticagrelor to aspirin is not recommended," he writes.

Meanwhile, in the THEMIS-PCI study – simultaneously published in the Lancet – 11,154 patients with a history of previous PCI were randomly assigned to either ticagrelor or placebo. The primary efficacy outcome was a composite of cardiovascular death, MI or stroke. Median follow-up was 3.3 years. Results found ticagrelor improved net clinical benefit (9.3 percent vs. 11.0 percent), although with increased major bleeding, compared with patients without prior PCI where it did not. Bhatt, et al. noted the benefit was present "irrespective of time from the most recent PCI." Based on these findings, "long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischemic risk, and low bleeding risk," they said.

Keywords: ESC 19, ESC Congress, Adenosine, Primary Prevention, Angiography, Percutaneous Coronary Intervention, Diabetes Mellitus, Coronary Artery Disease

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