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After one month of dual antiplatelet therapy (DAPT) with aspirin and ticagrelor (Brilinta) post-percutaneous coronary intervention for an acute coronary syndrome, dropping aspirin cut bleeding risk without any increase in the risk for ischemic events, new randomized trial results show. 

The findings, from the ULTIMATE-DAPT trial, showed that, as expected, stopping aspirin reduced the risk for major and minor bleeding by about 55%, and major bleeding by about 60%. The question was whether it was safe to stop aspirin in terms of increased ischemic events, said Gregg W. Stone, director of academic affairs for the Mount Sinai Health System, New York City, and professor of medicine (Cardiology) and population health science and policy at Icahn School of Medicine. Stone, the study's co-chair, presented the results at the American College of Cardiology Scientific Session 2024 in Atlanta.

"There was absolutely no difference between the groups, 3.7% vs 3.6%, and with 3400 randomized patients, that confidence interval is quite tight, so you can have good certainty that there's not more than really a 1% at worst, increase in major adverse ischemic events," Stone told an ACC press conference.

The researchers conclude that "it's time to change the guidelines and it's time to change clinical practice pattern," he said. Most patients with ACS treated with successful PCI using contemporary stents should switch after 1 month from DAPT to monotherapy using a potent P2Y12 inhibitor, "and the best data so far is with ticagrelor." 

He said there would be a "reasonable expectation" that prasugrel (Effient) might be an option, but not clopidogrel (Plavix), Stone added.

These results provide important information on the safety and reduced bleeding risk associated with this monotherapy approach, study author Shao-Liang Chen, MD, PhD, professor in internal medicine and cardiology at Nanjing Medical University, and director of cardiology at Nanjing First Hospital, China, told theheart.org | Medscape Cardiology.

"Further analyses are warranted to identify groups of patients according to varying bleeding and ischemic risk that may particularly benefit from ticagrelor monotherapy," he said.

These findings from the ULTIMATE-DAPT trial were also published online today in The Lancet.

Following PCI for acute coronary syndromes, current guidelines recommend most patients receive DAPT for 12 months to reduce the risk for myocardial infarction (MI) and stent thrombosis. However, increased risk for potentially life-threatening bleeding has been a concern.

Previous studies looking at P2Y12 inhibitor monotherapy lacked robust data, the authors note. For example, they were open-label and used variable definitions of bleeding.

ULTIMATE-DAPT included 3400 patients with an acute coronary syndrome such as unstable angina, non-ST-segment elevation MI, or ST-segment elevation MI, from 58 centers in China, Pakistan, the UK, and Italy. 

Patients had to remain event-free on DAPT, consisting of oral ticagrelor (90 mg twice daily) plus oral enteric-coated aspirin (100 mg daily), for 1 month after PCI with contemporary drug-eluting stents.

The mean age of study participants was 63 years and 74.1% were men. Almost one third (31.6%) had diabetes and 59.5% presented with acute MI.

Researchers then randomly assigned these patients to receive ticagrelor plus placebo, or to continue on ticagrelor plus aspirin therapy, for 11 months.

Visits after PCI were scheduled for 1, 4, 6, and 12 months. The study was double-blind, but unmasking was allowed if knowing the antiplatelet agent was necessary for managing major adverse events.

The study had two primary outcomes: the superiority outcome was clinically relevant bleeding, Bleeding Academic Research Consortium (BARC) types 2, 3, or 5; the non-inferiority endpoint was major adverse cardiovascular or cerebrovascular events (MACCE), which was a composite of cardiac death, MI, ischemic stroke, definite stent thrombosis, and clinically driven target vessel revascularization.

All primary endpoints were adjusted for ACS type, diabetes, and geographical region.

Bleeding Rate More Than Halved

Up to 12 months after PCI, clinically relevant bleeding occurred in 2.1% of the ticagrelor plus placebo group and 4.6% of the ticagrelor plus aspirin group (hazard ratio [HR] 0.45; 95% CI, 0.30 - 0.66; P < .001).

Major bleeding (BARC types 3 or 5) also occurred less frequently with ticagrelor plus placebo compared with ticagrelor plus aspirin (0.7% vs 1.7%). This was also the case for other measures of bleeding, including Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding (0.7% vs 16%), Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) moderate, severe or life-threatening bleeding (0.5% vs 1.1%), and International Society on Thrombosis and Hemostasis (ISTH) major bleeding (0.5% vs 1.2%)

MACCE rates were similar, occurring in 3.6% of those treated with ticagrelor plus placebo and 3.7% in those treated with ticagrelor plus aspirin (absolute difference, –0.1%; 95% CI, –1.4% to 1.2%; HR, 0.98; 95% CI, 0.69 - 1.39; P for non-inferiority: < .0001 and P for superiority = .89).

Rates of individual components of the primary non-inferiority endpoint were also similar between the two groups as were mortality rates.

There was no significant interaction for age with respect to clinically relevant bleeding. However, among patients older than 65, those in the ticagrelor monotherapy group had elevated rates of MACCE (5.3%) compared to the ticagrelor plus aspirin group (3.7%) in contrast to younger patients.

The new results suggest clinicians can safely stop DAPT after a month in this patient population to reduce bleeding risk, and to reduce MACCE they should consider risk stratification, particularly for older patients, said Cheng.

Refining Decision-Making

During a press briefing, Wayne Batchelor, MD, director of interventional cardiology, associate director, Inova Heart and Vascular Institute, Fairfax, Virginia, called the study "terrific" and "yet another" example of new research that will likely affect clinical practice.

"This study should have an impact on guidelines." It shows "we can actually get away with one month of dual antiplatelet therapy followed by just a single antiplatelet therapy, at least in the form of ticagrelor, and that's an important development," said Batchelor, also an adjunct professor of medicine at Duke University.

"We are finally refining our decision-making based on this data and others, to the point where we can actually start to withdraw some of these medications that are causing extra bleeds, and aspirin on top of P2Y12 is one of those scenarios."

He noted the "absolutely phenomenal" findings regarding MACCE. "There was not a single hint of detection in the difference of MACCE."

But he pointed out that patients on dual therapy who had a bleeding or major adverse cardiovascular event during the first 30 days post-PCI were excluded. "We have to be cautious that we don't apply this to all patients and expect the exact same results on day one."

Crucial Component

This "well-designed investigation" adds "another crucial component" to the ongoing research into optimal antiplatelet therapy strategies, commented Gloria M. Steiner-Gager and Jolanta M. Siller-Matula, both from the Medical University of Vienna, Austria, in an accompanying editorial.

However, inclusion of target-vessel revascularization as a co-primary endpoint of MACCE, which accounts for about 50% of ischemic events, "might be debatable," they write. "The ischemic events rates in the trial were lower than anticipated. Therefore, without inclusion of target-vessel revascularization in the primary endpoint, the study would be largely underpowered."

But although dual antiplatelet therapy effectively mitigates the risk for stent thrombosis and MI, "it is unlikely that the antiplatelet agents diminish the odds of re-stenosis, the main driver of target-vessel revascularization," they add.

The finding of elevated rates of MACCE in the older ticagrelor plus placebo group "is remarkable considering age itself is a risk factor for bleeding events and calls for further investigation to understand the underlying causal relationships between age and the risk of MACCE while on ticagrelor monotherapy," they write.

The editorial also noted 98.7% of study participants were from China or Pakistan with only 1.3% from Europe. "Given the acknowledged higher bleeding risk observed in patients from eastern Asia, the applicability of a 1-month dual antiplatelet therapy regimen followed by ticagrelor monotherapy to other regions necessitates evaluation."

The question regarding appropriate therapy 12 months after PCI remains unanswered, the editorial concludes. "Which antiplatelet regimen (eg, ticagrelor, aspirin or even clopidogrel monotherapy) should be prescribed to patients following that transition is still unclear."

Chen reports speaker honoraria from Microport, Pulnovo, Boston International Scientific, Medtronic, Sanofi, and BioMed; grants from the National Scientific Foundation of China; and is a fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University. Siller-Matula declares speaker bureaus from Chiesi and Daiichi Sankyo and research grants from AOP Orphan Pharmaceuticals GmbH, Novartis, and Chiesi.