Prasugrel May Be Better Than Ticagrelor After PCI for Diabetes Patients With MVD

NEW ORLEANS, LA—Ticagrelor did not prove to be noninferior to prasugrel as part of dual antiplatelet therapy (DAPT) following PCI in patients with diabetes and multivessel coronary disease in the TUXEDO-2 trial.

The primary composite outcome of death, MI, stroke, or BARC-defined major bleeding occurred in 16.57% of patients treated with ticagrelor and 14.23% of those treated with prasugrel. The between-group difference was 2.33%, with the upper bound of the 95% confidence interval (6.74%) exceeding the 5% noninferiority margin.

Point estimates for nearly all outcomes suggested better results with prasugrel, study chair Sripal Bangalore, MD (NYU Langone Health, New York, NY), reported earlier this week at the American Heart Association (AHA) 2025 Scientific Sessions.

This is the second head-to-head trial of the potent P2Y12 inhibitors after ISAR-REACT 5, which demonstrated improved outcomes with an up-front strategy involving prasugrel versus ticagrelor in patients with ACS undergoing PCI. “Combined with the results of the ISAR-REACT 5 trial, these findings [from TUXEDO-2] support the use of prasugrel over ticagrelor,” Bangalore concluded.

The TUXEDO-2 Trial

The optimal DAPT regimen following PCI remains unclear for patients with diabetes, and there are limited data comparing ticagrelor and prasugrel in this setting. A hypothesis-generating, prespecified analysis of ISAR-REACT 5 suggested that in the subgroup of patients with diabetes, about 22% of the overall trial cohort, ticagrelor and prasugrel provided similar results.

TUXEDO-2, conducted at 66 centers in India, presented an opportunity to explore the comparative safety and efficacy of these two agents further. The 2x2 factorial trial randomized 1,800 patients (mean age 60 years; 72% men) both to two different DES, with those results presented recently at TCT 2025, and to ticagrelor- or prasugrel-based DAPT with aspirin.

Nearly all patients had type 2 diabetes, with about one-quarter requiring insulin. The mean duration of diabetes was slightly longer in the prasugrel versus ticagrelor group (6.19 vs 5.62 years; P = 0.04). Most patients (59%) presented with MI, 21% with chronic coronary syndrome, and 20% with unstable angina; 85% of patients had triple-vessel coronary disease and the remainder double-vessel disease.

At discharge and through 1 year of follow-up, about 91% of patients took aspirin. At discharge, 51.3% of patients were on ticagrelor, 46.3% were on prasugrel, and 2.5% were on clopidogrel. The respective proportions at 1 year were 44.7%, 43.2%, and 12.0%.

The slightly higher rate of the primary composite outcome among patients treated with ticagrelor versus prasugrel observed at 1 year was generally consistent across various subgroups. There were suggestions, albeit with nonsignificant P values for the interactions, that ticagrelor performed worse than prasugrel in patients with a diabetes duration of less than 5 years and those with high bleeding risk.

Rates of the following outcomes did not differ significantly between the ticagrelor and prasugrel arms at 1 year, although nearly all the numbers favored prasugrel:

• Death, MI, or stroke (10.43% vs 8.63%; P = 0.30)
• Major bleeding (8.41% vs 7.14%; P = 0.19)
• Death (5.03% vs 3.67%; P = 0.34)
• Nonfatal MI (5.96% vs 5.21%; P = 0.53)
• Stroke (0.46% vs 0.68%; P = 0.53)
• Stent thrombosis (1.11% vs 0.56%; P = 0.20)

Bangalore also presented pooled results from the TUXEDO-2 and ISAR-REACT 5 trials, which indicated a significantly higher risk of death, MI, or stroke with ticagrelor than with prasugrel (risk ratio 1.28; 95% CI 1.08-1.51) accompanied by a nonsignificantly greater risk of major bleeding (risk ratio 1.22; 95% CI 0.96-1.54).

A Bump in Prasugrel Use?

Whether there are differences between the potent P2Y12 inhibitors is a clinically relevant question, Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said during an AHA media briefing. Since both, like clopidogrel, are now available in generic formulations, cost differences should be minimal, although side effects come into play.

“On the one hand, ticagrelor tends to have more dyspnea associated with it, and so that can lead to discontinuation,” Kirtane explained. “On the other hand, prasugrel has issues such as a black box warning in the United States for patients above the age of 75, those with a prior history of stroke, or those with low body weight.”

He highlighted some issues to consider when interpreting the results of TUXEDO-2, indicating that there is some uncertainty in the estimates of event rates in a drug therapy trial of this size, in addition to some questions around the impact of the open-label design, endpoint ascertainment, and potential differences in adherence between trial arms.

“I could sort of pick apart the trial in many ways, but we are left with the fact that this is a reasonably sized randomized trial that was powered for an outcome and does not demonstrate any superiority, certainly, of ticagrelor over prasugrel,” Kirtane said. “This is also even more germane in the Indian population, because . . . there’s a much greater incidence of clopidogrel resistance among South Asians. So these agents probably should be used preferentially in an ACS population.”

Ultimately, he said, “I think there’s always resistance to use a drug like prasugrel, and certainly this study combined with ISAR-REACT 5 should hopefully ameliorate that resistance and allow more patients to be treated appropriately for ACS with potent P2Y12 inhibitors.”

He told TCTMD that clopidogrel is still used in many ACS patients likely due to its lower bleeding risk, but said clinicians can always reduce the dose of the potent P2Y12 inhibitors if they are concerned about bleeding. “We wouldn’t do that up front after a stent, but maybe rapidly de-escalate,” he said. “That’s something I do in practice routinely.”

In terms of the potential impact of these TUXEDO-2 results, Kirtane said that in a population of patients with diabetes, “if you were going to use a more potent agent, you might favor prasugrel a little bit.”

Patients with diabetes are a high-risk group and clinicians need to be aggressive with preventive therapies, Jacqueline Tamis-Holland, MD (Cleveland Clinic, OH), said in a discussion following Bangalore’s presentation.

Though she had some questions about TUXEDO-2, she said data from the trial, together with those from ISAR-REACT 5, “suggest that prasugrel is superior to ticagrelor . . . and it really makes us think about what we should be using when [treating] patients, even with chronic coronary syndromes, who undergo PCI who are at high risk.”

Tamis-Holland questioned, however, whether these patients with diabetes, multivessel disease, and LAD involvement (found in 85% of the cohort) should have been referred for CABG rather than PCI, noting that the 2021 coronary revascularization guidelines recommend bypass surgery in this group, for appropriate candidates, to reduce mortality and repeat revascularization.

That guidance is based on the results of the FREEDOM trial. Of note, a secondary objective of TUXEDO-2 is to pool the data from both arms of the trial and compare the results with performance goals derived from the CABG arm of FREEDOM through 5 years of follow-up.