THEMIS - Main results of the effect of Ticagrelor on health outcomes in diabetes mellitus patients intervention study

Reported from the European Society of Cardiology ESC Congress 2019 in Paris

At the ESC Congress 2019 in Paris, Deepak Bhatt presented the results of the THEMIS study. Giuseppe de Gioia provides his analysis of this study, while Pierre Sabouret summarises THEMIS-PCI.

Why is this study important?

Ticagrelor in Patients with Stable Coronary Disease and Diabetes (THEMIS) has been one of the most awaited trials of the year, and rightly so. Randomizing 19,220 patients in little more than 2 years is not an easy task, but with industry support the investigators managed to have 1315 enrolling sites in 42 countries. Moreover, a press release in February communicated to the world that THEMIS had met its primary endpoint, further increasing the hype around this trial.

The background that led to this study being performed was the evidence of increased platelet activation in diabetic patients, at least partly responsible for the higher rates of ischemic cardiovascular events associated with the disease. Thus, the investigators’ main hypothesis was that a potent P2Y12 inhibitor, such as ticagrelor, would reduce ischemic events in diabetic patients with coronary disease.

THEMIS was a randomized, double-blind, placebo-controlled trial, including diabetic patients 50 years of age with coronary artery disease (defined as prior PCI, prior CABG, or known DS 50%) but no prior myocardial infarction or stroke. Enrolled patients were randomized to receive Ticagrelor 90 mg twice daily or matching placebo, on top of low-dose Aspirin (75-150 mg/day). Shortly after the start of enrollment, and on the aftermath of the results of the PEGASUS-TIMI 54 trial, protocol was amended and ticagrelor daily dose was reduced to 60 mg twice daily.

The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. Hierarchical secondary endpoints included cardiovascular death, myocardial infarction, ischemic stroke, and death from any cause. The primary safety outcome was TIMI-defined major bleedin

What were the results?

At a median follow-up of 39.9 months (max 57 months), the Kaplan-Meier rates for the primary outcome were significantly lower in the ticagrelor group [6.9% vs. 7.6% in the placebo group. HR (95% CI) 0.90 (0.81-0.99)]. This benefit in ischemic events was driven by lower rates of myocardial infarction and ischemic stroke.

Conversely, there was a higher frequency of TIMI major bleeding in the ticagrelor group than in the placebo group [(2.2% vs. 1.0%. HR (95% CI) 2.32 (1.82 to 2.94)].

At 3 years, the number needed to treat to prevent 1 ischemic event was 136, while the number needed to cause 1 major bleeding was 93.

The exploratory endpoint of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was not different between the 2 groups.

My take on this study

In conclusion, perhaps betraying expectations, THEMIS represents a punch given and a punch taken in the endless boxing match between ischemia and bleeding. The authors conclude that the addition of ticagrelor to aspirin might be considered in high ischemic and low bleeding risk patients. Despite the absence of significant subgroups interaction, the trialists investigated the impact of this strategy specifically in patients with prior PCI (THEMIS-PCI study), but that is another story.

Watch this short interview of Giuseppe Di Gioia providing a summary of the THEMIS trial: