Elderly patients with cardiovascular disease face a high risk of both thrombotic and bleeding events when receiving antithrombotic therapy. The optimal dose of aspirin for secondary prevention in this population remains uncertain, particularly in Chinese elderly individuals. This multicenter, prospective cohort study aims to evaluate the effectiveness and safety of a lower dose of aspirin (50 mg daily) compared with the standard dose (100 mg daily) for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in Chinese patients aged 60 years and older. The study is an extension of the existing LAPIS cohort (ChiCTR1900021980), which has enrolled 5,448 participants receiving long-term aspirin for secondary prevention. Participants will be followed for an additional 2 years (total follow-up up to approximately 6 years) through telephone, clinic visits, and electronic medical records. The primary effectiveness outcome is the first occurrence of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, unstable angina, need for revascularization, non-fatal stroke, transient ischemic attack, and cardiovascular death (excluding intracranial bleeding). The primary safety outcome is the first occurrence of bleeding events (classified by BARC criteria). A secondary aim is to develop and validate a risk prediction model (nomogram) for thrombotic and bleeding events specifically for elderly Chinese patients receiving antithrombotic therapy, using LASSO regression and Cox proportional hazards models. The study will provide real-world evidence to guide individualized antithrombotic management in the aging Chinese population.

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).

Inclusion Criteria:

1. Age ≥ 60 years.
2. Diagnosis of established atherosclerotic cardiovascular disease (ASCVD), including acute coronary syndrome, stable coronary artery disease, post-revascularization (percutaneous coronary intervention or coronary artery bypass grafting), ischemic cardiomyopathy, ischemic stroke, transient ischemic attack, or peripheral artery disease.
3. Long-term use of aspirin (≥1 year) for secondary prevention of ASCVD.
4. Available laboratory tests (within the past 3 months): complete blood count, urinalysis, routine stool examination and occult blood test, liver and kidney function, electrolytes, glucose, lipids, uric acid, coagulation function, etc.
5. Willing to provide written informed consent.

Exclusion Criteria:

1. Hypersensitivity to aspirin or other salicylates, or any other component of the drug product; history of asthma induced by salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs), or any other condition that, in the clinical judgment, makes the patient unsuitable for study participation.
2. Life expectancy ≤ 2 years due to non-cardiovascular causes.
3. Poor compliance (unable to adhere to prescribed medication or follow scheduled follow-up visits as judged by the investigator).

Chinese patients aged ≥60 years with established ASCVD receiving long-term aspirin (50 mg or 100 mg daily) for secondary prevention. This population is a subset (N=5,448) of the LAPIS multicenter prospective cohort, enrolled from 71 centers across China between April 2019 and the end of recruitment. No new enrollment is ongoing; participants are followed prospectively.

Individual participant data (IPD) will not be shared at this time due to the following considerations: (1) The study is an extension of an existing observational cohort (LAPIS, ChiCTR1900021980) and data sharing was not included in the original informed consent obtained from participants; (2) No infrastructure or funding has been established to support the de-identification, curation, and secure dissemination of IPD. However, requests for de-identified aggregate data or collaboration on secondary analyses may be considered and should be directed to the Principal Investigator.