Diabetes Duration and Meds Don’t Impact Ticagrelor Effects in THEMIS

For patients with type 2 diabetes and stable coronary disease who have not had an MI or stroke, specific factors related to their diabetes should not necessarily come into play when physicians are deciding whether they should add ticagrelor (Brilinta; AstraZeneca) to the treatment regimen, a post hoc analysis of the THEMIS and THEMIS-PCI studies indicates. Nor did they influence the trial findings, investigators say.

The complex balance between efficacy and safety demonstrated in the overall trial cohort as well as in the subset with a history of PCI was not significantly influenced by diabetes duration, baseline HbA1c, or background glucose-lowering medications, researchers led by Lawrence Leiter, MD (St. Michael’s Hospital and University of Toronto, Canada), report.

That’s important, not only because diabetes patients face a much higher risk of cardiovascular disease and events than nondiabetic subjects, but also because the prothrombotic milieu conferred by their disease, or secondary effects of other diabetes medications, may make them respond differently to antiplatelet therapies. Prior studies have indicated that diabetes duration likely influences risk of subsequent CV events, while certain diabetes medications—most notably, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists—may reduce those risks.

When the results of THEMIS and THEMIS-PCI were released in 2019, investigators reached a two-part conclusion: in stable CAD patients with diabetes and no prior stroke or MI, the significant increase in major bleeding seen with ticagrelor plus aspirin outweighed the more-modest reduction in MACE achieved. A more-favorable benefit-risk balance, however, was seen in the PCI subset, echoing earlier studies in higher risk patients. As such, investigators concluded that patients with diabetes and a history of PCI might represent an “easy to identify” patient group in whom extended dual antiplatelet therapy with ticagrelor could be considered.

What can be taken away from this new analysis, published in the May 18, 2021, issue of the Journal of the American College of Cardiology, is a message of consistency, senior author Philippe Gabriel Steg, MD (Hôpital Bichat, Paris, France), told TCTMD. The lack of significant interactions with the diabetes-related factors in this post hoc analysis “suggests that the overall interpretation does apply to the various subsets that we’ve look at, and that there’s no particular reason to use duration of diabetes, glucose control, or types of background glucose-lowering agents as a method for selection of patients,” Steg said. “We still stick with the idea that the best population [for the addition of ticagrelor] are THEMIS-PCI-type patients.”

No Significant Interactions

The THEMIS investigators set out to examine the influence of diabetes-related factors when it came to the effects of ticagrelor plus low-dose aspirin in the trial, which included 19,271 patients who had type 2 diabetes and stable CAD without a history of MI or stroke; most (58%) had a history of PCI. Median duration of diabetes among the participants was 10 years, and the median HbA1c at baseline was 7.1%.

I would be much more aggressive in my management in general of a diabetic patient who has coronary artery disease and 20 years of diabetes as opposed to a patient who was recently diagnosed with diabetes and has evidence of coronary artery disease. Philippe Gabriel Steg

The primary efficacy outcome was MACE (CV death, MI, or stroke), and this occurred in 8.1% overall in THEMIS and 7.3% in THEMIS-PCI. The primary safety outcome was TIMI major bleeding, and this was observed in 1.6% in the overall trial and in 2.0% in the PCI subset.

Compared with aspirin alone, the combination of ticagrelor and low-dose aspirin reduced MACE at the cost of more TIMI major bleeding in both cohorts, as previously reported. These effects were not significantly modified by the duration of diabetes, HbA1c level, or use of various key antihyperglycemic medications (P = NS for all interactions).

The researchers also assessed a net clinical outcome encompassing all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding, finding no difference between treatment arms in the overall THEMIS trial (HR 0.93; 95% CI 0.86-1.02), but an advantage for ticagrelor plus aspirin in the PCI subset (HR 0.85; 95% CI 0.75-0.95). These findings also did not differ based on the diabetes-related factors evaluated in this post hoc analysis (P = NS for all interactions).

“This adds to the robustness of the THEMIS-PCI findings and the suggestion that this is the optimal group to treat with ticagrelor added to aspirin,” Steg said.

Modifying Treatment Decisions

Though the information in this study should not be used to make decisions about the use of ticagrelor in these types of patients, the results do provide physicians with influential data, Steg said, noting that MACE risk was strongly related to both a longer duration of diabetes and a higher HbA1c in THEMIS and THEMIS-PCI. The association with duration in particular is not well appreciated, and should be taken into account when managing patients, he said.

“I would be much more aggressive in my management in general of a diabetic patient who has coronary artery disease and 20 years of diabetes as opposed to a patient who was recently diagnosed with diabetes and has evidence of coronary artery disease,” Steg advised. “And I think we need to be more stringent with all avenues for prevention, whether it’s lifestyle, control of lipids or blood pressure, investigation of the extent of disease, and so on and so forth.”

As for where ticagrelor fits in, “I think it’s probably not a treatment for everybody who fits the criteria,” Steg said. “I think that even in patients who look like THEMIS-PCI patients, it probably has to be a physician decision given that you have risks and you have benefits, so you probably need to weigh that for every patient based on your perception of the bleeding risk and the ischemic risk.”

Jean-Guillaume Dillinger, MD, PhD, and Patrick Henry, MD, PhD (both Hôpital Lariboisière, Paris, France), make a similar point in an accompanying editorial. “The combination of ticagrelor and aspirin is a new treatment option for selected diabetes mellitus patients who are at high CV risk, and this option should be considered after a careful evaluation of the bleeding risk and consideration of several factors such as diabetes mellitus duration, HbA1c level, and previous PCI,” they write.