Aspirin 50 mg vs. 100 mg in Elderly Cardiovascular Disease Patients

Background:

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of mortality and disability in elderly individuals in China. Antithrombotic therapy, particularly aspirin, is the cornerstone of ASCVD secondary prevention. However, advancing age increases both thrombotic and bleeding risks. Current guidelines recommend aspirin 75-100 mg daily for secondary prevention, but evidence from Western populations may not fully apply to Chinese elderly, who have different body weights, comorbidities, and polypharmacy patterns. Preliminary data from the investigators' prior single-center studies suggested that a lower dose of aspirin (40-50 mg daily) provides comparable antiplatelet effects with fewer gastrointestinal adverse events in Chinese elderly. The ongoing LAPIS study (Low-dose Aspirin in the Prevention and Management of Cardiovascular Disease in Elderly Patients; ChiCTR1900021980) is a nationwide, multicenter, prospective cohort that has enrolled 7,611 participants (including 5,448 for secondary prevention) since April 2019. This protocol represents a 2-year extension of the LAPIS secondary prevention cohort to further assess the long-term effectiveness and safety of 50 mg daily versus 100 mg daily aspirin, and to develop a risk prediction model tailored to elderly Chinese patients receiving antithrombotic therapy.

Primary Objectives:

To compare the effectiveness (prevention of major adverse cardiovascular events, MACE) and safety (bleeding events) of aspirin 50 mg daily versus 100 mg daily in elderly Chinese patients (≥60 years) with established ASCVD receiving long-term aspirin for secondary prevention.

Secondary Objective:

To develop and internally/externally validate a prognostic model (nomogram) for predicting thrombotic events (MACE) and bleeding events in elderly Chinese patients on antithrombotic therapy, integrating demographic characteristics, comorbidities, polypharmacy, laboratory parameters, and other risk factors.

Study Design:

Multicenter, prospective, observational cohort study. No intervention is assigned; aspirin dose is determined by routine clinical practice.

Study Population:

Chinese patients aged ≥60 years with established ASCVD (including acute coronary syndrome, stable coronary artery disease, post-revascularization, ischemic cardiomyopathy, ischemic stroke, transient ischemic attack, or peripheral artery disease) who are on long-term aspirin (≥1 year) for secondary prevention. Participants were previously enrolled in the LAPIS study.

Exposure:

Participants are categorized into two groups according to their long-term daily aspirin dose:

50 mg daily group

100 mg daily group

Dose categorization is based on the stable dose taken at baseline and maintained for at least 1 year.

Number of Participants:

5,448 participants from the LAPIS secondary prevention cohort.

Follow-up Duration:

An additional 2 years of follow-up (after the original LAPIS follow-up), leading to a total follow-up period of up to approximately 6 years (since first enrollment in April 2019). Follow-up visits occur at 1 month, 3 months, 6 months post-enrollment, and then every 6 months thereafter until study completion. Mixed modes (telephone, WeChat, outpatient clinic, hospital records) are used to minimize loss to follow-up.

Outcome Measures:

Primary Effectiveness Endpoint (composite):

First occurrence of major adverse cardiovascular events (MACE) including: non-fatal myocardial infarction, unstable angina, need for surgical or percutaneous revascularization, non-fatal stroke, transient ischemic attack, and cardiovascular death (excluding intracranial bleeding).

Secondary Effectiveness Endpoints:

Composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death (excluding intracranial bleeding)

Individual components of the primary composite endpoint

First occurrence of unstable angina

First occurrence of revascularization

First occurrence of transient ischemic attack

All-cause mortality

Primary Safety Endpoint (composite):

First occurrence of bleeding events classified by BARC (Bleeding Academic Research Consortium) criteria:

Fatal bleeding (type 5)

Major bleeding (type 3-4)

Minor bleeding (type 1-2)

Secondary Safety Endpoints:

Gastrointestinal adverse events including newly diagnosed gastroduodenal ulcer, reflux esophagitis, erosive gastritis, abdominal pain, diarrhea, nausea, vomiting, acid regurgitation, heartburn, abdominal discomfort, and constipation.

Data Collection:

Baseline data include demographics, vital signs, medical history (cardiovascular events, bleeding history, digestive system diseases, comorbidities such as hypertension, diabetes, dyslipidemia), laboratory tests (complete blood count, urinalysis, stool occult blood, liver/kidney function, electrolytes, glucose, HbA1c, lipid profile, coagulation function, platelet aggregation rate), and concomitant medications (antiplatelet agents, anticoagulants, beta-blockers, statins, ACEIs, ARBs, CCBs, diuretics, PPIs, H2RAs, NSAIDs, corticosteroids, etc.). Follow-up data include changes in aspirin dose, new comorbidities, concomitant medications, MACE, bleeding events, gastrointestinal symptoms, hospitalizations, and procedures. All suspected clinical events are adjudicated by an independent Clinical Events Committee.

Data Management:

An electronic data capture (EDC) system (www.91trial.com) is used. Each site has a dedicated data manager. Remote source data verification is performed weekly by a third-party CRO (30% random sampling). On-site monitoring occurs every 6 months. The database will be locked after all data are cleaned.

Statistical Analysis:

Analyses will be performed using R 4.3.3.

For effectiveness and safety comparison (aspirin 50 mg vs. 100 mg):

Propensity score matching (1:3 ratio) will be applied to balance baseline characteristics (age, sex, comorbidities, etc.). Kaplan-Meier curves with log-rank tests will compare event-free survival. Cox proportional hazards regression will estimate hazard ratios (HR) with 95% confidence intervals, adjusting for residual confounding.

For risk prediction model development:

The cohort will be split temporally into a training set (first 70% of enrolled participants, i.e., enrolled before September 1, 2022) and an internal validation set (remaining 30%). An independent external validation cohort (participants from other centers or geographic regions) will also be used. Candidate predictors are selected based on literature review and the LAPIS interim analysis. Least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation will be applied for predictor selection. Multivariable Cox models will be used to construct risk scores and nomograms for MACE and bleeding events. Model performance will be assessed by discrimination (C-statistic, AUC of ROC curves), calibration (calibration plots, Brier score), and clinical utility (decision curve analysis).

Sample Size Justification:

Based on LAPIS interim data (as of October 2023, 4,951 secondary prevention participants):

For safety comparison (two-proportion test, two-sided α=0.05, power=0.8, 1:3 ratio): estimated 1,661 participants (415 in 50 mg group, 1,246 in 100 mg group). Allowing 5% loss to follow-up: 1,749 participants.

For effectiveness non-inferiority test (one-sided α=0.025, power=0.8, non-inferiority margin Δ=0.02, 1:3 ratio): estimated 4,508 participants (1,126 in 50 mg group, 3,382 in 100 mg group). Allowing 5% loss: 4,745 participants.

For prediction model (assuming 15 predictors, events per variable ≥10): MACE model requires ≥5,660 participants; bleeding model requires ≥1,823 participants. The available 5,448 secondary prevention participants meet these requirements.

Study Period:

2025-2027 (2-year extended follow-up, plus final data analysis). Primary completion date (final data collection for primary outcome): April 2027. Study completion date (completion of all analyses): December 2027.

Ethics and Dissemination:

The study is approved by the Biomedical Research Ethics Committee of Peking University First Hospital. All participants provided written informed consent. Results will be published in peer-reviewed journals and presented at international conferences.

Trial Registration:

Chinese Clinical Trial Registry: ChiCTR1900021980 (original LAPIS study). This extension is registered with ClinicalTrials.gov (NCT number pending).