Lifelong aspirin has been a cornerstone of secondary prevention after coronary artery disease (CAD), based on trials conducted 40-50 years ago. Since then, major advances in coronary reperfusion and risk factor management have significantly improved outcomes. At the same time, aspirin is clearly associated with an increased risk of major bleeding, including intracranial haemorrhage. This raises a critical, yet unanswered question: in patients more than 2 years after a CAD event, does the benefit of continued aspirin still outweigh its bleeding risk? RELEASE-Norway is an investigator-initiated, registry-based, randomised trial with blinded endpoint assessment (PROBE design) designed to determine whether patients with chronic CAD can safely stop aspirin without losing cardiovascular protection. The trial will randomise 7,000 patients from all major hospitals in Norway. Together with a similar trial (RELEASE-Denmark, n≈7,000) planned in Denmark, the study will provide definitive evidence on the long-term net clinical benefit versus harm of aspirin in stable CAD and most likely directly inform future guidelines and clinical practice worldwide. Imaging and PROMS sub-studies will explore clinical and psychosocial mechanisms, providing insight into treatment heterogeneity and enabling future personalised antiplatelet therapy. Additionally, a health-economic analysis will assess the cost-effectiveness of discontinuing aspirin for healthcare systems.
Age ≥65 years at randomization treated with low-dose (≤150 mg/day) aspirin
An ACS event treated with PCI 2-8 years prior to randomisation and no ischemic cardiovascular event (MI or stroke) or any coronary revascularization procedure (PCI/coronary artery bypass grafting) since index event
Signed informed consent and expected cooperation according to ICH/GCP and national/local regulations
Indication for antiplatelet treatment other than secondary prevention of CAD (i.e. haematological diseases, stroke, PAD)
Active treatment with or indication for anti-coagulant or P2Y12-inhibitor therapy
Left main stenosis or any history of stent thrombosis, or other contraindications to discontinuation of aspirin according to treating physician
Any condition (e.g. drug/alcohol abuse, dementia) or situation, that in the investigator's opinion could put the subject at signifi-cant risk directly related to the randomized aspirin strategy, confound the results, interfere significantly with participation, or render informed consent unfeasible. Investigators are explicitly encouraged not to exclude patients solely due to advanced age, frailty or polypharmacy if equipoise exists regarding aspirin continuation vs. discontinuation and informed consent is feasible.
Parallel
Discontinuation of aspirin (ATC-code B01AC06 and N02BA01)
DrugPatients will be randomized open-label 1:1 to either continuation of low-dose oral aspirin (Anatomical Therapeutic Chemical codes B01AC06 and N02BA01) at a daily dose of ≤150 mg (no intervention group) or discontinuation of aspirin therapy (intervention group). If the patient is randomized to discontinuing aspirin the treatment will be discontinued from their medical list. All participants will receive lifestyle advice and appropriate follow-up, as recommended.
Hierarchical composite endpont
The net clinical benefit of discontinuing versus continuing aspirin in patients randomized 2-8 years after an index ACS event, using a hierarchical composite endpoint with a win-ratio framework that includes: 1. Cardiovascular death, 2. Intracranial bleeding, 3. Myocardial infarctions including stent thrombosis, 4. Ischemic stroke, 5. Major bleeding (BARC 3 and 5) requiring hospitalization. The components of the endpoints will be identified in The Norwegian Patient Registry and Cause of Death Registry using procedure and diagnostic codes.
Risk of ischaemic disease
The cumulative risk of a composite of recurrent myocardial infarction including stent thrombosis, ischemic stroke, and cardiovascular death by randomization group. Events will be identified in the Norwegian Patient Registry and the Norwegian Cause of Death registry using procedure and diagnostic codes.
Risk of major bleedings
The cumulative risk of major bleedings, including intracranial and other major (BARC 3, 5) bleeding events requiring hospitalization by randomization group. Events will be identified in The Norwegian Patient Registry and the Cause of Death registry data with procedure and diagnostic codes.
Subgroup analyses
The net clinical benefit of discontinuing versus continuing aspirin across subgroups by age, sex, Clinical Frailty Scale score \<4 vs. ≥4 (mild frailty), single vs. multi-vessel disease, and discontinuation 2-4 years vs. 4-8 years after index event. The net clinical benefit will be analyzed the same way as for the primary endpoint: a win-ratio framework using a hierarchical composite endpoint including both ischemic events and major bleeding events.
Risk of individual components of the primary endpoint
The cumulative risk of the individual components of the primary endpoint by randomization group. Events will be identified in The Norwegian Patient Registry and The Norwegian Cause of Death Registry using procedure and diagnostic codes.
Recurrent CVD hospitalisations
The cumulative risk of recurrent hospitalization for (any) cardiovascular disease by randomization status. Hospitalizations will be identified in registry data using diagnostic and procedure codes.
All-cause mortality
The cumulative risk of all-cause mortality by randomization group. All-cause mortality will be obtained from the Cause of Death Registry
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Vestre Viken Hospital Trust
Lead sponsor
Oslo Universitetssykehus Hospital Trust
Collaborator
Akershus University Hospital Trust
Collaborator
Sorlandet Hospital HF
Collaborator
Helse Stavanger HF
Collaborator
Helse-Bergen HF
Collaborator
St. Olavs Hospital
Collaborator
Norwegian Health Association
Collaborator
Landsforeningen for hjerte og lungesyke (LHL)
Collaborator
Bispebjerg Hospital
Collaborator
Odense University Hospital
Collaborator
University of Oslo
Collaborator
University Hospital of North Norway
Collaborator
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