When choosing a P2Y12 inhibitor to use in combination with aspirin in patients with diabetes undergoing percutaneous coronary intervention (PCI) for multivessel disease, prasugrel may be preferable to ticagrelor, a new study has suggested. 

In the TUXEDO-2 trial, patients receiving prasugrel in combination with aspirin had a lower rate of the primary outcome (a composite of death, myocardial infarction, stroke, and major bleeding at 1-year follow-up) than those assigned to ticagrelor plus aspirin. 

“Our findings indicate that prasugrel may potentially be the better choice for patients with diabetes,” said lead study author Sripal Bangalore, MD, professor of medicine at NYU Grossman School of Medicine in New York City. 

“We were surprised by the results because we hypothesized that ticagrelor should be as good or perhaps even better than prasugrel. But from our data, we cannot say that ticagrelor and prasugrel are interchangeable,” he added. 

Bangalore presented the results of the TUXEDO-2 trial at the American Heart Association (AHA) Scientific Sessions 2025 this month.

Various Measures Favor Prasugrel

The trial was based in India and had a 2 x 2 factorial design, with the other part of the trial comparing two different stents. 

For the antiplatelet comparison, 1800 patients with diabetes and multivessel coronary disease were randomized to ticagrelor or prasugrel, each in combination with aspirin, as part of dual antiplatelet therapy (DAPT). 

The trial was designed first to try to show noninferiority of ticagrelor to prasugrel, and if that was shown, then to look at superiority.

Baseline characteristics showed 99% of the patients had type 2 diabetes, with a quarter requiring insulin. The mean duration of diabetes was 6 years; 79% of patients had acute coronary syndrome (ACS), and 21% had stable ischemic heart disease; 85% of patients had triple-vessel coronary disease, and 15% had two-vessel disease.

Results showed the primary endpoint occurred in 16.57% in the ticagrelor group, and 14.23% in the prasugrel group. The risk difference was 2.33, and the upper bound of the 95% CI was 6.74, which did not meet the noninferiority margin of 5%. The P value for noninferiority was 0.8365.

“So ticagrelor was not shown to be noninferior when compared to prasugrel,” Bangalore said. 

The ischemic composite endpoint of death, MI, or stroke occurred in 10.43% of those in the ticagrelor group compared with 8.63% of those assigned to prasugrel.

Major bleeding occurred in 8.41% with ticagrelor compared with 7.14% with prasugrel.

“All point estimates for the secondary outcomes favor prasugrel,” Bangalore said.

In the per protocol analysis, the primary endpoint occurred in 15.98% of the ticagrelor group vs 13.52% of the prasugrel group, which again missed the noninferiority margin.

“So the per protocol analysis confirmed that ticagrelor is not noninferior when compared to prasugrel,” Bangalore said.

Confirmed by Results From ISAR-REACT 5

Bangalore pointed out that a previous trial comparing these two antiplatelet agents when used in front loading strategies in patients with ACS, the ISAR-REACT 5 trial, also found a better outcome with prasugrel.

In a meta-analysis of the ISAR-REACT 5 and TUXEDO-2 results, prasugrel resulted in a 22% reduction in the risk for death, MI, or stroke compared to ticagrelor, with a strong trend favoring prasugrel for the endpoint of major bleeding, Bangalore reported.

Jacqueline Tamis-Holland, MD, of the Cleveland Clinic, said the results were interesting. 

“This trial, together with the ISAR-REACT 5 data, has an astounding message: that prasugrel appears to be superior to ticagrelor in these high-risk patients undergoing PCI,” Tamis-Holland, who served as a discussant for the TUXEDO-2 trial, commented.

She said both agents have been shown to be superior to clopidogrel when used as part of a DAPT regimen after PCI in patients with ACS.

“We know that patients with diabetes represent a very high-risk cohort, and we need to be extremely aggressive with preventive therapies,” she said.

She said that while ISAR-REACT 5 had suggested front loading with prasugrel may be preferable to ticagrelor in patients with ACS undergoing PCI, “we didn’t know whether prasugrel itself is truly superior to ticagrelor, and whether this applies across the spectrum of coronary artery disease, including patients with chronic coronary syndromes.” The TUXEDO-2 trial tried to answer those questions.

Tamis-Holland concluded the pooled data from TUXEDO-2 and ISAR-REACT 5, importantly, show a lower rate of major adverse cardiovascular events with prasugrel.

On possible caveats, she wondered whether the low rate of intravascular imaging used in the TUXEDO-2 study may have affected the results, given that the ticagrelor group had a higher rate of small-vessel disease and a higher stent thrombosis rate.

And she also questioned whether patients with diabetes and multivessel disease and left anterior descending artery involvement should be referred to coronary artery bypass grafting rather than PCI.

The TUXEDO-2 trial was funded by Sahajanand Medical Technologies (a device/stent manufacturing company). Bangalore and Tamis-Holland reported having no relevant disclosures.