TICAKOREA: Ticagrelor Ups Bleeding Over Clopidogrel in Korean ACS Patients

SAN FRANCISCO, CA—Korean ACS patients who are slated for early invasive management are more likely to bleed over the next year if their dual antiplatelet therapy (DAPT) regimen includes ticagrelor (Brilinta; AstraZeneca) instead of clopidogrel, with no ischemic benefit, according to the randomized TICAKOREA study.

Through 12 months, clinically significant bleeding occurred in 11.7% of patients who received ticagrelor and 5.3% of those treated with clopidogrel in addition to aspirin (HR 2.26; 95% CI 1.34-3.79).

That elevated bleeding risk was not offset by a lower risk of MACE; the composite of CV death, MI, or stroke was numerically—but not significantly—higher in the ticagrelor group (9.2% vs 5.8%; HR 1.62; 95% CI 0.96-2.74).

Duk-Woo Park, MD (Asan Medical Center, Seoul, Korea), presented the results here at TCT 2019 last week. The study was published simultaneously online in Circulation, with Park and Osung Kwon, MD (Eunpyeong St. Mary’s Hospital, Seoul), as lead authors.

“The present study identified safety concerns regarding bleeding complications of standard-dose ticagrelor in East Asian/Korean patients with acute coronary syndrome,” the authors conclude in their paper. “Large, adequately powered randomized trials are needed to determine the optimal antithrombotic regimen in this population.”

Speaking with TCTMD, Park said: “Our trial suggests that tailored antiplatelet therapy to balance the risk of bleeding and ischemia is required to improve the safety and efficacy of ACS treatment in East Asian patients.”

Some medications have dose-modification criteria, but ticagrelor does not, he noted, adding that the full 90-mg dose of ticagrelor might be too strong for some East Asian patients.

But despite the fact that the TICAKOREA findings are similar to those from the PHILO study, which included mostly Japanese patients, it would be premature to recommend changes to practice at this time, Park said. “It’s not enough to dramatically change the current practice. It’s going to take time. We definitely need more evidence and more trials.”

‘East Asian Paradox’

The pivotal ticagrelor trial was PLATO, which showed that the more potent P2Y12 inhibitor reduced the rate of death from vascular causes, MI, or stroke without increasing major bleeding in an international cohort of ACS patients. Those findings supported changes to US and European guidelines to include a preference for ticagrelor over clopidogrel as the P2Y12 inhibitor in antiplatelet regimens for ACS.

Only 6% of patients in the PLATO population were Asian, however, which leaves open the question of the relative safety and efficacy of ticagrelor versus clopidogrel in East Asians, who have a greater susceptibility to bleeding and a lower likelihood of ischemic events for any given level of platelet inhibition compared with Western populations. That’s called the “East Asian paradox,” Park said.

TICAKOREA, conducted at 10 Korean centers, was designed to explore the safety and efficacy of ticagrelor in an East Asian population. Investigators randomized 800 patients who were hospitalized for ACS and were planned for invasive management to receive ticagrelor (180-mg loading dose followed by 90 mg twice daily) or clopidogrel (600-mg loading dose followed by 75 mg daily) on top of aspirin (100 mg daily) for 1 year. Mean patient age was 62.4, and about three-quarters were men.

The most common presentation was STEMI (40.7%), followed by NSTEMI (37.8%) and unstable angina (21.3%). All patients underwent diagnostic coronary angiography, with most (77.5%) undergoing PCI with stent implantation. Another 6% were treated with balloon angioplasty alone, with 2.1% undergoing CABG and 14.4% receiving medical therapy alone. Some patients (4.3%) had no evidence of obstructive coronary disease and discontinued the study medications.

The primary safety outcome was clinically significant bleeding, a composite of major bleeding or minor bleeding according to PLATO criteria. This was more common in ticagrelor-treated patients in the main analysis and in a landmark analysis starting at 30 days. Major, minor, and fatal bleeds all were more frequent with ticagrelor.

Though numerically higher, MACE was not significantly increased with ticagrelor. Much of the apparent difference was related to an imbalance in periprocedural MI, and a composite endpoint of CV death, spontaneous MI, or stroke occurred at similar rates in the ticagrelor and clopidogrel groups (5.4% vs 4.3%; P = 0.47).

Park cautioned that the study was not powered to detect meaningful differences in ischemic events, and pointed out the numerical increase in events in the ticagrelor arm could be a chance effect. It could be, too, that patients who bled stopped taking their medications and thus had an increased risk of ischemic events moving forward, he said. Indeed, premature discontinuation of the study drugs was more common in the ticagrelor group (11.5% vs 6.8%).

More Evidence Is Coming

Commenting on the TICAKOREA results for TCTMD, David Moliterno, MD (University of Kentucky, Lexington), editor-in-chief of JACC: Cardiovascular Interventions, said the increased bleeding risk with ticagrelor was believable but added that the magnitude of the difference was surprising. There’s no clear explanation, but the rate of bleeding in the clopidogrel arm was also lower than expected, he pointed out.

“We do know that the Asian population is more likely to have loss-of-function alleles for clopidogrel, so it would be believable they would be less likely to bleed with clopidogrel, therefore maybe accentuating the risk to bleed with ticagrelor versus clopidogrel,” Moliterno said.

Ultimately, TICAKOREA “adds more fuel to the fire that we need to rethink using one drug, one dose for all populations,” but it does not justify a change to recommendations, he said.

“What I think it rather begs is, should we now use this information combined with the present studies of taking aspirin out of the formula sooner? So maybe this would be a place that you would say this cohort should have aspirin withdrawn sooner because it’s probably the combination of ticagrelor and aspirin that’s leading to the heightened bleeding risk, if in fact it does exist,” Moliterno said. “Personally, if I were practicing in Asia, I would probably take away the aspirin versus not using ticagrelor or lowering my dose of ticagrelor.”

Personally, if I were practicing in Asia, I would probably take away the aspirin versus not using ticagrelor or lowering my dose of ticagrelor. David Moliterno

Park agreed that more research is needed before recommending use of adjusted-dose ticagrelor to mitigate the excess bleeding risk in East Asian patients with ACS. To that end, his group is currently conducting the TAILORED-CHIP trial, which is evaluating a tailored antithrombotic strategy using low-dose ticagrelor in high-risk patients.

In an accompanying editorial, Shinya Goto, MD, PhD (Tokai University School of Medicine, Isehara, Japan), echoes the idea that the evidence from TICAKOREA is not sufficient to change practice.

“Even after TICAKOREA, it remains unclear whether there is a large enough difference in the response to antiplatelet therapy in East Asian patients to justify a different dosing strategy as compared with the dose used globally,” he says.