Study Summary

THEMIS, and its substudy THEMIS-PCI, sought to evaluate whether diabetic patients with a history of stable coronary artery disease (CAD) would benefit from dual anti-platelet therapy with ticagrelor plus aspirin. The study was a randomized, double-blind, placebo-controlled, multi-center, international trial. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke, and the primary safety outcome was TIMI major bleeding. Overall, 19,271 patients were randomized to receive either aspirin plus ticagrelor versus aspirin plus placebo. Baseline characteristics did not differ significantly between the two groups, with a median age of 66 years. The primary efficacy outcome occurred in 7.7% of patients in the ticagrelor group, and 8.5% in the placebo group (P = 0.04), driven mostly by a lower incidence of myocardial infarction and stroke in the ticagrelor group. The primary safety outcome analysis showed a higher frequency of TIMI major bleeding in the ticagrelor group, as compared with the placebo group (2.2% versus 1.0%, P <0.001). Overall, there was no significant between-group difference in the net clinical event rate (i.e. death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage).

In the THEMIS-PCI substudy, 11,154 patients from the THEMIS trial with a history of previous PCI were studied. In this population, the primary efficacy outcome was improved in the ticagrelor group (7.3% versus. 8.6%, P = 0.013). TIMI major bleeding occurred in 2.0% of patients receiving ticagrelor versus 1.1% in the placebo group (P<0.0001). Overall, net clinical benefit was improved in the ticagrelor group with prior PCI compared to placebo (9.3% versus 11.0%, P = 0.005), though TIMI major or minor bleeding occurred at a higher rate in patients receiving ticagrelor versus placebo (2.8% versus 1.4%, P<0.0001).

In patients without prior PCI, there was no significant difference in the primary efficacy outcome when comparing ticagrelor versus placebo (8.2% versus 8.4%, P = 0.76), though there was a reduction in TIMI major bleeding in patients receiving placebo (2.4% versus 1.0%, p <0.0001).

Commentary

Study Strengths: The study was very large, multi-center, placebo-controlled, double blind, randomized trial. Mean duration of diabetes was 10 years with 25% of patients having complications from diabetes, indicating a significant burden of disease. Follow-up was a median of 39.9 months, which would be long enough to capture significant events post-randomization. There was a mix of patients who had previously received PCI (58%), CABG (22%), or no revascularization (20%).

Study Limitations: The study was industry sponsored. The study drug dose was decreased from 90 mg twice daily to 60 mg twice daily for all patients approximately 15 months into enrollment due to the results of PEGASUS-TIMI 54. While clinically appropriate, this change of protocol introduced an opportunity for issues with applicability and analysis.

Next Steps/Clinical Perspective: Although there was a statistically significant difference in the primary endpoint for ticagrelor, the risk of non-fatal bleeding was significant. The discontinuation rate of ticagrelor was higher than placebo (34.5% versus 25.4%) due to dyspnea and major bleeding, which likely reflects real-world clinical practice. The benefit for ticagrelor plus aspirin dual therapy in patients with stable CAD and diabetes was focused in patients with a prior PCI. Patients with stable CAD who are at high risk for bleeding are not good candidates for ticagrelor. In patients with stable CAD and prior PCI, the use of 60 mg ticagrelor dosing may be considered.