Less Bleeding by Omitting Aspirin in Non-ST-segment Elevation Acute Coronary Syndrome Patients

Approximately 15,000 patients with non-ST-segment elevation acute coronary
syndrome (NSTE-ACS) are admitted to Dutch hospitals each year. The vast
majority of these patients is treated with percutaneous coronary intervention
(PCI) using intracoronary stents. Dual antiplatelet therapy (DAPT), consisting
of aspirin and a P2Y12-inihibitor, reduces the risk of stent thrombosis,
myocardial infarction (MI) and stroke as compared to aspirin monotherapy after
coronary stent implantation. However, DAPT inevitably increases the risk of
bleeding, which in turn is associated with increased mortality, morbidity and
reduced quality of life (all associated with high healthcare costs). In recent
decades, improvements in stent design, interventional technique and
antithrombotic therapy have substantially reduced the risk of stent thrombosis
and subsequent ischemic complications.

Among these improvements is the development of new generation drug-eluting
stents (DES). The bulky, thick-strut bare-metal stents that were used when DAPT
was introduced, have therefore become obsolete. The advent of safer,
thinner-strut, new generation DES equipped with biocompatible coatings has led
to low rates of stent thrombosis. These DES are now commonly used in all
patients. Pharmacological therapy has improved as well. New P2Y12-inhibitors,
i.e. prasugrel and ticagrelor, which result in a more potent and reliable
inhibition of platelet activity, have been shown to significantly reduce the
incidence of stent thrombosis as compared to clopidogrel. These novel agents
are currently used alongside aspirin as the standard-of-care for acute coronary
syndrome (ACS) patients. The combined improvements in stent design and
antithrombotic therapy have led to very low rates of stent thrombosis.

Consequently, the status of aspirin as the cornerstone of antithrombotic
therapy has been challenged. Aspirin use is associated with an increased risk
of bleeding (in particular gastrointestinal bleeding), especially when combined
with other antithrombotic agents (e.g. a P2Y12-inhibitor). The advent of potent
P2Y12-inhibitors has raised questions as to whether the additional
antithrombotic benefit of aspirin outweighs the increase in bleeding
complication. Ex-vivo data on thrombogenicity under dynamic flow conditions
have shown that the antithrombotic potency of P2Y12-inhibitor monotherapy is
similar to that of a P2Y12-inhibitor combined with aspirin in high-risk
patients who underwent PCI with DES. Furthermore, contemporary pharmacologic
therapies for cardiovascular risk factors, such as hypertension, dyslipidemia
and impaired glucose metabolism, have led to reductions in an individual*s
cardiovascular risk. These therapies were not available at the time of the
pivotal studies evaluating aspirin in the setting of secondary prevention.
Therefore, relative benefits of adding aspirin might translate into much
smaller absolute risk reductions in current clinical practice as compared to
several decades ago.

In recent years, multiple randomized controlled trials (RCT) have evaluated the
efficacy and safety of P2Y12-inhibitor monotherapy, but this always involved
concurrent aspirin use during at least 1-3 month(s). A recent meta-analysis of
these trials investigating P2Y12-inhibitor monotherapy after PCI concluded that
P2Y12-inhibitor monotherapy preceded by a short period of DAPT was associated
with a 40% lower incidence of major bleeding compared to standard DAPT without
a significant differences in cardiovascular events after one year. In fact,
even complete omission of aspirin after PCI is now a topic of investigation.
Recently, the Acetyl Salicylic Elimination Trial (ASET) pilot has shown that an
aspirin-free strategy directly following PCI was feasible in chronic coronary
syndrome patients. Besides improving clinical outcomes, omitting aspirin can
reduce healthcare costs (e.g. by reducing costs associated with bleeding
complications). Likewise, omitting aspirin might reduce polypharmacy and
therefore improve medication adherence.

This study has been transitioned to CTIS with ID 2023-504360-42-00 check the CTIS register for the current data.

The Less Bleeding by Omitting Aspirin in Non-ST-segment Elevation Acute
Coronary Syndrome Patients (LEGACY) trial will investigate whether omitting
aspirin reduces the rate of major or minor bleeding while remaining
non-inferior to the current standard of care, DAPT, with respect to the rate of
ischemic events in NSTE-ACS patients undergoing PCI. Importantly, we
hypothesize that omitting aspirin will vastly improve the cost-effectiveness of
the care for these patients. Our study addresses an important gap in evidence
as highlighted by the European Society of Cardiology (ESC). Completely omitting
aspirin is unique and could positively alter the treatment of a large number of
patients.

Open-label, multicenter randomized controlled trial

No aspirin during 12 months

Patients will be contacted by phone after 1, 3, 6 and 12 month(s) for
follow-up. Omitting aspirin may lead to a reduction in (major) bleeding events,
while reducing the number of medications patients use. However, it is unknown
if omitting aspirin affects the risk of ischemic events.