Aspirin Discontinuation Safe, Effective Strategy in ACS Subset: TWILIGHT

PHILADELPHIA, PA—In line with results from the primary TWILIGHT trial, an analysis looking only at patients with ACS, albeit excluding those with STEMI, confirms that dropping aspirin after 3 months of dual antiplatelet therapy (DAPT) with ticagrelor (Brilinta, AstraZeneca) following PCI lowers bleeding risk without increasing the rate of ischemic events. Additionally, the benefit seen with ticagrelor monotherapy is uniform across different levels of risk and regardless of NSTEMI or unstable angina presentation.

“The basis for dual antiplatelet therapy in ACS really comes from trials conducted almost 20 years ago showing that DAPT is superior to aspirin,” Usman Baber, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who presented the findings here today at the American Heart Association (AHA) Scientific Sessions 2019, told TCTMD. The results indicate that, aside from STEMI patients and those who have adverse events within 3 months of PCI, dropping aspirin “might be a strategy that could be applicable for a large population of patients,” he said.

Baber noted that “one of the challenges we have with provision of antiplatelet therapy right now is a lot of patients who should be getting probably potent agents are not getting them due to concerns of bleeding. Clopidogrel remains the most commonly used antiplatelet agent for ACS despite guideline recommendation to the contrary, and if we're able to identify strategies such as use of ticagrelor monotherapy that lowers bleeding, maybe we can obviate that concern and allow patients to get the benefits from strong P2Y12 inhibition that may not be getting.”

Results from the primary analysis of TWILIGHT were presented in September at TCT 2019, and showed a 3.1% absolute reduction in BARC 2, 3, or 5 bleeding with no increase in death, MI, or stroke among a population of high-risk PCI patients in the ticagrelor and placebo arm compared with those on ticagrelor and continued aspirin. These findings contrasted with what was shown last year in GLOBAL LEADERS, where ticagrelor monotherapy after 1 month of DAPT was not associated with any benefit compared with continued DAPT over 2 years. Notably, a post hoc analysis of GLOBAL LEADERS suggested that patients undergoing complex PCI might benefit from dropping aspirin.

ACS Outcomes

For this analysis, Baber and colleagues included the 4,614 patients from the main trial who presented with ACS, including 2,494 with unstable angina and 2,120 with NSTEMI. Roughly one-third of patients (34.2%) had between one and three clinical and angiographic high-risk features, 48.6% had four or five, and 17.3% had six or more. Mean patient age was 64.2 years, more than one-third had diabetes, and about one-quarter each were current smokers or had a previous MI. Total stent length was about 40 mm in both study groups, and treatment adherence was high and similar overall.

The primary endpoint of BARC 2, 3, or 5 bleeding was significantly lower at 1 year in the ticagrelor monotherapy group compared with continued aspirin (3.6% vs 7.6%; HR 0.47; 95% CI 0.36-0.61). Additionally, there was no difference between the study groups in the secondary outcome of death, MI, and stroke at 1 year (4.3% vs 4.4%; HR 0.97; 95% CI 0.74-1.28). Both of these findings remained consistent regardless of risk factor burden and presentation with unstable angina or NSTEMI.

1-Year Outcomes by Risk Factor Burden and Presentation

Ticagrelor monotherapy was also associated with less bleeding compared with continued DAPT with regard to all prespecified bleeding endpoints including BARC 3 or 5 (0.8% vs 2.1%; P < 0.0001), TIMI major (0.5% vs 1.0%; P = 0.08), GUSTO moderate or severe (0.6% vs 1.6%; P = 0.002), and ISTH major (0.9% vs 2.2%; P = 0.001). All individual prespecified ischemic endpoints were similar between the study cohorts including CV death, MI, or stroke; all-cause death; any MI; ischemic stroke, and definite/probable stent thrombosis.

Independent predictors of death, MI, or stroke were identified as positive troponins (HR 1.77), established vascular disease (HR 2.77), atherectomy use (HR 2.46), and BARC 3 or 5 bleeding (HR 6.7).

Baber said the main limitations of the study were that it excluded STEMI patients and also that the results cannot be extrapolated to other P2Y12 inhibitors since only ticagrelor was used in the analysis. Also, “as with any subgroup analysis, rare events like stent thrombosis and stroke are pretty infrequent.”

The findings were “overall consistent” with what was shown in the primary trial, he concluded.

The Findings in Context

Discussing the study during the main session, Michelle O’Donoghue, MD, MPH (Brigham and Women’s Hospital, Boston, MA), explained how these results fit in the context of prior studies that looked at a strategy of aspirin discontinuation.

“Prior to TWILIGHT, we had GLOBAL LEADERS, SMART-CHOICE, and STOPDAPT-2, all of which are relatively recent publications that have tested similar strategies of discontinuing aspirin either at month 1 or month 3 for patients who were undergoing PCI either for stable coronary disease or with ACS,” she said. “Importantly, these other studies did include patients with STEMI, and all of them had different strategies of a P2Y12 monotherapy, some of which were clopidogrel, prasugrel, or ticagrelor. Importantly, TWILIGHT was the first double-blind design that we have.”

O’Donoghue presented data that combined the results of all four studies and showed that a strategy of P2Y12 monotherapy with aspirin discontinued at month 1 or 3 “reduces bleeding overall by about 40%” with consistency in terms of MACE. Looking specifically at post-ACS patients, she showed a 51% reduction in bleeding also with “favorable trends for reducing MACE” with P2Y12 inhibitor monotherapy.

Following this study, the first remaining question is which P2Y12 inhibitor is optimal to use, O’Donoghue said. Given that that there exists significant interpatient variability in terms of pharmacodynamic response to clopidogrel monotherapy, she asked, “should you be considering genotyping or platelet function testing in these patients?” It’s also unknown whether aspirin could be safely discontinued before 1 to 3 months or whether a P2Y12 inhibitor be continued indefinitely without aspirin beyond month 12, O’Donoghue said.

What’s more, she noted, “with any type of trial, there is some selection that goes into which patients are enrolled, so it always raises questions about universal generalizability. The current study excluded STEMI patients, but as I previously noted, STEMI patients were included in the other trials that were included in my meta-analysis.”

Ultimately, O’Donoghue said she believes “that discontinuation of aspirin markedly reduces bleeding when stopped 1 to 3 months post-PCI and/or ACS for patients initially started on DAPT. The evidence to date does not indicate that stopping aspirin leads to any increase in major adverse cardiovascular events. These findings now extend to patients with acute coronary syndromes, including those with high-risk clinical and angiographic features.”