RELEASE - Reconsidering Long-Term Aspirin in the Elderly Patients With Stable Ischemic Heart Disease: A Randomized Non-Inferiority Trial

Rationale:

Current guidelines recommend life-long aspirin therapy in patients with chronic coronary syndrome. The evidence supporting long-term aspirin therapy after myocardial infarction (MI) and for chronic coronary syndrome stems primarily from trials conducted in the 1970s and 1980s. Since then, the clinical landscape of MI has evolved markedly: The use of highly sensitive cardiac troponins has led to the diagnosis of smaller MIs, coinciding with a shift from predominantly large ST-segment elevation MI (STEMI) to smaller non-STEMI. Acute revascularization is now a part of the routine care for MI and many patients with stable coronary artery disease undergo percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Population risk factors have improved, and universal use of statins have contributed to plaque stabilization and reduces progression of disease. As a result, long-term prognosis in patients with MI and chronic coronary syndromes has markedly improved.

Therefore, the absolute ischemic benefit of long-term aspirin therapy may be attenuated, while the risk of bleeding, particularly in older patients, remains clinically relevant. These developments warrant a contemporary re-evaluation of the life-long role of aspirin in long-term secondary prevention of cardiovascular disease, especially in elderly patients with stable disease.

Objective:

To evaluate whether discontinuation of long-term aspirin in elderly patients with stable chronic coronary syndrome is non-inferior to continued aspirin therapy with respect to net clinical outcome.

Primary endpoint A hierarchical composite endpoint using a win-ratio framework combining cardiovascular death, fatal bleeding, intracranial bleeding, MI, ischemic stroke, and bleeding events (BARC 3-5).

Secondary endpoints:

Each component of the primary composite outcome, all-cause mortality, hospitalization for cardiovascular causes, peptic ulcer, and patient-reported outcomes (minor bleeding, abdominal pain/discomfort, quality of life and lifestyle behaviour).

All clinical outcomes will be registry based except patient-reported outcomes. They will be assessed using questionnaires measuring bleeding symptoms (ISTH/SSC bleeding assessment tool - The International Society on Thrombosis and Haemostasis - Scientific and Standardization Committee), gastrointestinal discomfort, quality of life (EQ-5D-5L - EuroQol 5 Dimensions, 5 Levels), anxiety and depression (HeartQoL), angina (Seattle Angina Questionnaire), and lifestyle behaviour.

Trial design:

Investigator-initiated, registry-based, prospective, randomized, open-label, blinded endpoint (PROBE) non-inferiority trial with 1:1 allocation. The trial is conducted as a low-intervention clinical trial using nationwide Danish health registries as the primary data source.

Trial population:

Inclusion criteria

• Age ≥65 years at randomization
• Ischemic heart disease with index event (MI, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)) >2 years previously
• Since index event free from ischemic cardiovascular events (MI, ischemic stroke, or transitory ischemic attack) or any coronary revascularization procedure (PCI/CABG)
• Currently treated with low dose aspirin (≤150 mg daily)

Exclusion criteria

• History of ischemic stroke
• Active treatment with or indication for anti-coagulant or P2Y12-inhibitor therapy
• Indication for antiplatelet treatment other than secondary prevention of IHD according to treating physician (i.e. haematological diseases, peripheral artery disease)
• Any revascularization procedure for peripheral artery disease
• Any history of stent thrombosis or stenting of the left main coronary artery
• Other contraindications to aspirin discontinuation according to treating physician
• Not being able to understand Danish

Interventions:

Continuation versus discontinuation of low-dose aspirin therapy (≤150 mg daily).

Ethical considerations relating to the clinical trial including the expected benefit to the individual participant or group of patients represented by the trial participants as well as the nature and extent of burden and risks:

Aspirin is widely used in secondary prevention and is available over the counter, reflecting its well established safety profile and the generally low risk associated with its use. Nevertheless, aspirin is associated with potential adverse effects, including bleeding, gastrointestinal discomfort, and clinically relevant drug interactions, particularly in elderly patients with comorbidities. Based on data from national health registries, the target population - older adults with stable chronic coronary syndrome - represents a clinically stable group with a low event rate of ischemic events. Given that lifelong aspirin therapy is often continued without systematic reassessment, there is a clear ethical justification for evaluating whether continuation remains beneficial - and safe - in an aging population with changing comorbidity profiles.

Inclusion criteria

• Age ≥65 years at randomization
• Ischemic heart disease with index event (MI, percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)) >2 years previously
• Since index event free from ischemic cardiovascular events (MI, ischemic stroke, or transitory ischemic attack ) or any coronary revascularization procedure (PCI/CABG)
• Currently treated with low dose aspirin (≤150 mg daily)

Exclusion criteria

• History of ischemic stroke
• Active treatment with or indication for anti-coagulant or P2Y12-inhibitor therapy
• Indication for antiplatelet treatment other than secondary prevention of IHD according to treating physician (i.e. haematological diseases, peripheral artery disease)
• Any revascularization procedure for peripheral artery disease
• Any history of stent thrombosis or stenting of the left main coronary artery
• Other contraindications to aspirin discontinuation according to treating physician
• Not being able to understand Danish