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The benefit of ticagrelor (Brilinta) monotherapy following a short course of dual antiplatelet therapy (DAPT) was upheld in various high-risk populations undergoing percutaneous coronary intervention (PCI), researchers reported.

The double-blind TWILIGHT trial previously showed that a person's antithrombotic strategy after PCI may be optimized by dropping aspirin after 3 months of DAPT with ticagrelor.

Now, two substudies of TWILIGHT -- one in diabetic patients and the other in people receiving complex PCI -- also show reduced major bleeding without an increase in thrombotic events among high-risk patients.

Furthermore, the TICO trial yielded similar findings for those undergoing PCI with a bioresorbable-polymer drug-eluting stent (DES).

These studies were presented during the same late-breaking trial session at the .

TWILIGHT-DM

People with diabetes, a group known to be at particularly high risk for both ischemic and bleeding complications after PCI, reaped the same benefits of ticagrelor monotherapy as the overall TWILIGHT cohort, a prespecified subanalysis found.

TWILIGHT participants underwent a 3-month course of DAPT; those who were event-free and showed adequate compliance to medication were subsequently randomized to an additional 12 months of ticagrelor monotherapy (ticagrelor plus placebo) or continued DAPT (ticagrelor and aspirin).

For the 2,620 diabetes patients randomized in the trial, Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding in the 12 months following randomization reached 4.5% and 6.7% of groups, respectively, handing ticagrelor monotherapy a significant safety advantage on intention-to-treat analysis (HR 0.65, 95% CI 0.47-0.91).

There was no effect modification for ticagrelor monotherapy by diabetes status (P=0.23 for interaction), according to Dominick Angiolillo, MD, PhD, of the University of Florida College of Medicine -- Jacksonville. The full TWILIGHT-DM manuscript was published online in the .

The rates of death, myocardial infarction (MI), or stroke were similar between arms in the per-protocol cohort (4.6% vs 5.9%, HR 0.77, 95% CI 0.55-1.09). Effect modification by diabetes status was arguably borderline for this endpoint (P=0.05 for interaction).

Altogether, net adverse clinical event rates favored the group that dropped aspirin (4.5% vs 8.7%, HR 0.61, 95% CI 0.45-0.82) with a number needed to treat of 30.

"These findings support such a bleeding avoidance strategy, which can be implemented without any signals for harm even in high-risk patients such as those with DM [diabetes mellitus]," Angiolillo told ACC meeting attendees.

Diabetic patients made up more than a third of the overall TWILIGHT cohort. Mean age was 65 years, and 23% were women. Just over a quarter were insulin users.

"Although this was a pre-specified analysis, randomization was not stratified by DM status and we did not account for multiplicity thereby increasing the chance for a type 1 error," Angiolillo's group cautioned.

Other caveats were that serum glucose and hemoglobin A1c were not collected in TWILIGHT, and the trial was not powered to detect differences in rare events such as stent thrombosis and stroke in diabetes patients.

TWILIGHT-COMPLEX

Aspirin cessation after DAPT was also shown to be safer in the subgroup of patients undergoing complex PCI, according to a post hoc analysis of TWILIGHT.

The incidence of BARC 2, 3, or 5 bleeding in the 12 months after randomization was significantly lower with ticagrelor monotherapy (4.2% vs 7.7% with continued DAPT, HR 0.54, 95% CI 0.38-0.76). This benefit was consistent between complex and non-complex PCI groups (P=0.79 for interaction).

As in the main TWILIGHT cohort, neither group had a higher risk of death, MI, or stroke (3.8% vs 4.9%, HR 0.77, 95% CI 0.52-1.15) -- type of PCI again making no difference in the ischemic endpoint (P=0.13), according to George Dangas, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City.

Like TWILIGHT-DM, TWILIGHT-COMPLEX was also simultaneously published in the .

There were 2,620 people randomized to ticagrelor with or without aspirin after complex PCI in the trial. Most of these cases were said to be complex because total stent length exceeded 60 mm (51.8%). Less common were multivessel PCI, bifurcation with two stents implanted, left main PCI, and chronic total occlusions.

Compared with the overall TWILIGHT trial group, the complex PCI subgroup was significantly older, included fewer women, and had more non-white patients and those with previous coronary artery bypass grafting.

On subgroup analysis, there was a signal that people who had atherectomy devices used during PCI actually had reduced death, MI, or stroke if randomized to ticagrelor monotherapy instead of DAPT (HR 0.16, 95% CI 0.04-0.73).

However, Dangas and colleagues acknowledged the trial's lack of power to draw definite conclusions about outcomes in complex vs non-complex PCI groups. Randomization in the trial was not stratified by complex PCI either, they also said.

Nevertheless, this was "the best one can do given the circumstances of the post hoc nature of the study," commented Glenn Levine, MD, of Baylor College of Medicine in Houston, during the ACC session.

Levine asked Dangas if the guidelines should recommend that patients undergoing complex PCI, including unprotected left main PCI, get 3 months of DAPT followed by ticagrelor monotherapy.

"The most prudent would be a more general guideline ... I don't think there should be a left main-specific guideline [recommendation]," Dangas responded, noting that there were small numbers of these cases in TWILIGHT.

TICO

Finally, people undergoing PCI with a new-generation DES also benefited from ticagrelor monotherapy after a brief period of DAPT, according to the TICO trial from Korea.

Unlike TWILIGHT, however, this trial randomized patients at PCI (without a 3-month enrollment period) and looked at net adverse clinical events (NACE) at 12 months (Thrombolysis in Myocardial Infarction major bleeding plus major adverse cardiac and cerebrovascular events) (MACCE; all-cause death, MI, stent thrombosis, stroke, or target vessel revascularization).

The primary endpoint occurred in 5.9% of patients who received 12 full months of DAPT. For those randomized to 3 months of DAPT followed by 9 months of ticagrelor monotherapy, the rate was a significantly reduced 3.9% (HR 0.66, 95% CI 0.48-0.92).

This advantage was driven by a reduction in major bleeding (1.7% vs 3.0%, HR 0.56, 95% CI 0.34-0.91), reported Yangsoo Jang, MD, PhD, of Yonsei University Severance Cardiovascular Hospital College of Medicine in Seoul.

During the virtual ACC session, Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital in Boston, called TICO "an independent confirmation of TWILIGHT" in its finding that the strategy of ticagrelor monotherapy "essentially cuts major bleeding in half."

TICO had an open-label design and included 3,056 acute coronary syndrome patients undergoing PCI with the Orsiro ultrathin bioresorbable-polymer sirolimus-eluting stent.

For this kind of patient, ticagrelor monotherapy, therefore, "could be an optimal strategy, balancing both ischemic and bleeding risks," Jang said.

The average age of trial participants was 61, and 80% were men. Patients at high-risk of bleeding had been excluded from TICO.

"Study power was calculated by estimating the occurrence of NACE. Thus, comparisons of the occurrence of each component, particularly MACCE, could be underpowered," Jang cautioned.

And even though ticagrelor monotherapy met superiority for the primary outcome, the trial overall suffered from event rates that were lower than expected, he added.