TICO: Ticagrelor Monotherapy After 3 Months of DAPT Curbs Bleeding in Stented ACS Patients

Switching to ticagrelor (Brilinta; AstraZeneca) monotherapy after 3 months of dual antiplatelet therapy (DAPT) reduces major bleeding without increasing ischemic risk compared with 12 months of DAPT in ACS patients implanted with a second-generation DES, results of the TICO trial show.

Dropping aspirin after 3 months reduced the risk of net adverse clinical events (NACE), a composite of TIMI major bleeding and major adverse cardiac and cerebrovascular events, through 1 year (3.9% vs 5.9%; HR 0.66; 95% CI 0.48-0.92), according to Yangsoo Jang, MD, PhD (Yonsei University College of Medicine, Seoul, Korea).

The difference was mainly driven by a reduction in major bleeding  (1.7% vs 3.0%; HR 0.56; 95% CI 0.34-0.91), he reported at the virtual American College of Cardiology (ACC) 2020 Scientific Session.

“This finding indicates that ticagrelor monotherapy could be an optimal strategy, balancing both ischemic and bleeding risks for patients with ACS treated by ultrathin, biodegradable-polymer, sirolimus-eluting stents,” Jang concluded.

Commenting during a panel discussion after Jang’s presentation, Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), gave a nod toward some of the trial’s limitations cited by Jang—it was open-label, lacked a placebo control, and had limited statistical power—but said TICO “is an important independent confirmation of TWILIGHT.” That trial also showed that going with ticagrelor monotherapy after 3 months of DAPT reduced bleeding without increasing ischemic events, albeit in a broader population of high-risk PCI patients.

“To have two independently done trials essentially reaching the same conclusion that this strategy of ticagrelor monotherapy essentially cuts major bleeding in half is very comforting,” Bhatt said. “So I think that core finding is a true one.”

But, he asked Jang, how does one reconcile these findings with prior trials indicating that longer durations of DAPT improve outcomes?

Jang said that if you prolong DAPT, especially with clopidogrel, you may reduce ischemic events. With more-potent P2Y12 inhibitors like ticagrelor and prasugrel, however, in vitro studies show that adding aspirin doesn’t enhance the suppression of platelet activity, and thus the duration of DAPT with aspirin can be shortened, he said. “I think the aspirin makes the bleeding.”

The TICO Trial

TICO, conducted at 38 Korean centers, included 3,056 patients with ACS (mean age 61 years; 79% men) who underwent PCI with the ultrathin-strut, bioresorbable-polymer, sirolimus-eluting Orsiro stent (Biotronik); those at high bleeding risk were excluded. Investigators randomized patients to 12 months of DAPT with ticagrelor plus aspirin or to 3 months of DAPT followed by 9 months of ticagrelor monotherapy. Overall, 36% of patients presented with STEMI, 34% with NSTEMI, and 30% with unstable angina.

Landmark analyses showed that the reductions in NACE and TIMI major bleeding seen in the primary results were also seen between 3 and 12 months:

• NACE (1.4% vs 3.5%; HR 0.41; 95% CI 0.25-0.68)
• TIMI major bleeding (0.2% vs 1.6%; HR 0.13; 95% CI 0.04-0.44)

The MACCE component of the primary endpoint did not, however, show a significant difference, either overall (2.3% vs 3.4%; HR 0.69; 95% CI 0.45-1.06) or in the 3-month landmark analysis (1.2% vs 2.1%; HR 0.58; 95% CI 0.33-1.04). None of the individual components of that endpoint (all-cause death, MI, stent thrombosis, stroke, and TVR) differed either.

Jang noted that the trial, in which overall event rates were lower than expected, could have been underpowered for the components of the primary NACE endpoint.

Post-PCI Antithrombotic Therapy in the Modern Stent Era

When interpreting the implications of trials like TICO and TWILIGHT, it’s important to think about the advances that have been made in PCI over the years, moving from plain balloon angioplasty to BMS to DES, according to Elliott Antman, MD (Brigham and Women’s Hospital, Boston, MA). In the early days, stents had thicker struts and generally were not drug-eluting. Introduction of DES brought down in-stent restenosis rates, and now newer-generation devices have much thinner struts, improved polymers (bioresorbable in some cases), and better drug coatings.

To have two independently done trials essentially reaching the same conclusion that this strategy of ticagrelor monotherapy essentially cuts major bleeding in half is very comforting. Deepak Bhatt

“In general, the technology of stenting has improved, so it is logical that in parallel with that we should be addressing what is the appropriate antithrombotic support to be giving a patient who’s had a stent,” Antman told TCTMD.

But he urged caution when interpreting the results of TICO in particular, because it was conducted in a single country, included about half the number of patients that were included in TWILIGHT, was open-label (TWILIGHT was double-blind), and had overall low numbers of ischemic events. “We have to navigate our way very carefully as we think about these trials and how they inform us,” Antman said.

What can be taken from the two trials, he said, “is a strong suggestion that it is possible to reduce the risk of bleeding by eliminating dual antiplatelet therapy after 3 months, and it does seem that that does not cost very much in terms of the risk of ischemic events, which is comforting.”

More-definitive trials, however, would be needed before making major changes to practice guidelines, Antman argued. “The writing committee would look at these trials, in my opinion, and say these are important trials to inform the clinical community, and exactly where we would land in terms of a recommendation or how they would move recommendations isn’t entirely obvious by just looking at the individual trial reports.”

Practicing physicians, on the other hand, might incorporate information from TICO and TWILIGHT into their discussions with patients in this era of personalized medicine, noting that if he had patients who fit the criteria for either trial, he would discuss the findings with them. “This will influence the clinical thinking of practitioners,” Antman said. “It will have a more limited impact on clinical practice guideline recommendations.”

One other issue to consider, he said, is the possibility that aspirin might be sufficient when considering antiplatelet monotherapy after an initial period of DAPT.

“Maybe the more-general question here is how long is dual antiplatelet therapy to be given and then what antiplatelet agent should be used as the monotherapy to support patients in an era now where we have significant advances in the technology of stenting,” Antman said. If that were to be explored in a future trial, he added, an important question would be whether aspirin alone is enough to maintain protection against ischemic events.