THEMIS: No overall benefit of ticagrelor in people with diabetes, coronary artery disease
medwireNews: Findings from the THEMIS trial suggest that the addition of ticagrelor to aspirin treatment reduces the incidence of ischemic cardiovascular events among people with type 2 diabetes and stable coronary artery disease, but at the cost of an increased risk for major bleeding, resulting in an unfavorable risk:benefit ratio.
However, the investigators found that ticagrelor may be beneficial for the subgroup of patients who had previously undergone percutaneous coronary intervention (PCI), leading them to suggest that the P2Y12 receptor antagonist “should be considered” in this specific group.
THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) involved 19,220 type 2 diabetes patients aged 50 years or older with stable coronary artery disease but no prior myocardial infarction or stroke, who were randomly assigned to receive ticagrelor 90 mg twice daily or placebo alongside low-dose aspirin (75–150 mg/day). The dose of ticagrelor was reduced to 60 mg twice daily following a protocol amendment in 2015.
P Gabriel Steg (Hôpital Bichat, Paris, France) and co-investigators report in The New England Journal of Medicine that participants given ticagrelor were significantly less likely to experience ischemic cardiovascular events – a composite outcome of cardiovascular death, myocardial infarction, or stroke – over a median follow-up of 39.9 months compared with those in the placebo group, at rates of 7.7% versus 8.5% (hazard ratio [HR]=0.90).
These findings translate into a number needed to treat (NNT) to prevent one primary event at 36 months of 138, explain Steg and colleagues.
However, they found that the incidence of TIMI-defined major bleeding was significantly higher among individuals treated with ticagrelor versus placebo (2.2 vs 1.0%; HR=2.32), with an NNT to cause one major bleeding event over 36 months of 93. Patients in the ticagrelor group also had a significantly higher risk for intracranial hemorrhage than those given placebo (0.7 vs 0.5%).
In an exploratory analysis taking both efficacy and safety into account, the incidence of the composite outcome of irreversible harm (all-cause mortality, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was comparable in the ticagrelor and placebo groups, at 10.1% versus 10.8%.
Writing in an accompanying editorial, Eric Bates (University of Michigan, Ann Arbor, USA) says that in light of these findings, “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.”
Nonetheless, he suggests that “[i]t 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.”
Indeed, THEMIS-PCI, a prespecified subgroup analysis of the THEMIS trial from the same team published in The Lancet, demonstrated that among the 11,154 participants with prior PCI, those who were treated with ticagrelor had a significantly lower risk for ischemic cardiovascular events than those given placebo (7.3 vs 8.6%; HR=0.85), but the risk was comparable in the two groups among patients with no prior PCI (8.2 vs 8.4%).
In contrast to the overall findings from THEMIS, ticagrelor was associated with a significant reduction in the composite endpoint of irreversible harm among patients with prior PCI (9.3 vs 11.0%; HR=0.85), report the investigators.
“This effect shows that 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 ischaemic risk, and low bleeding risk,” they write.
However, the authors of an accompanying comment, Marco Valgimigli and Negar Manavifar, both from Bern University Hospital in Switzerland, caution that the test for interaction between prior PCI and the primary efficacy outcome was not statistically significant, “which makes the interpretation of study findings challenging.”
They say that while “[c]linicians would now need to consider the combination of ticagrelor and aspirin as a new treatment option for patients with stable coronary artery disease and diabetes undergoing PCI,” the “optimal patient selection, timing of treatment initiation, and treatment duration remain unclear.”
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