Carotid Ultrasound-Based Strategy for Primary Prevention of Cardiovascular Events in Inflammatory Rheumatic Disease (PREVENER)

Background:

Patients with chronic inflammatory rheumatic diseases (RA, PsA, AxSpA, SLE) carry a significantly increased risk of atherosclerotic cardiovascular events compared to the general population. This excess risk is largely attributed to the pro-atherogenic effect of chronic inflammation. Despite this, conventional CV risk stratification tools such as SCORE2/OP do not account for inflammation-related risk, leading to systematic underestimation of CV risk in these patients. Data from the CARMA project demonstrated that 53% of CV events in Spanish patients with IRD occurred in those classified as low-to-moderate risk by SCORE2/OP, highlighting the urgent need for improved risk stratification strategies.

Carotid ultrasound for the detection of subclinical atherosclerosis (carotid plaques) has been proposed as a modifier of CV risk in the ESC 2021 guidelines. The presence of carotid plaques automatically reclassifies individuals to very high CV risk, warranting intensive lipid-lowering therapy. However, no randomized clinical trial has evaluated the efficacy of this strategy in patients with IRD.

Study Design:

PREVENER is an open-label, randomized, multicenter, phase IV clinical trial. Patients aged ≥50 years with IRD (RA by ACR/EULAR 2010 criteria, PsA by CASPAR criteria, AxSpA by ASAS criteria, or SLE by ACR/EULAR 2019 criteria) and low-to-moderate CV risk according to SCORE2/OP will be enrolled across 17 Spanish hospitals.

Eligible patients will be randomized 1:1 to:

* Experimental group: carotid ultrasound performed within 30 days of randomization. Patients with carotid plaques (defined by Mannheim consensus criteria) will be classified as very high CV risk and initiated on high-intensity statin therapy (LDL target \<55 mg/dL). Patients without plaques will be managed according to ESC 2021 guidelines. * Control group: standard management according to ESC 2021 guidelines throughout the study.

Randomization will be performed using REDCap, stratified by age, sex, classic CV risk factors, lipid-lowering treatment, rheumatic disease, and advanced therapy use.

Primary Endpoint:

Incidence of major adverse cardiovascular events (MACE), defined as: acute myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization for peripheral arterial disease, or CV death.

Secondary Endpoints:

1. Efficacy of the strategy analyzed individually by rheumatic disease (RA, PsA, AxSpA) 2. Comparison of efficacy between men and women 3. Safety comparison of adverse events between groups

Follow-up:

All patients will be followed for 48 months. Patients on lipid-lowering treatment will have monthly visits during the intensification phase (maximum 5 visits) until therapeutic target is achieved, followed by semi-annual visits until month 48. Patients not requiring lipid-lowering treatment will have semi-annual visits throughout.

Statistical Analysis:

The primary analysis will follow an intention-to-treat approach. Cox regression models will be used to calculate Hazard Ratios with 95% confidence intervals, adjusted for relevant covariates. Kaplan-Meier survival curves will be compared using the log-rank test. A sample size of 1,944 patients provides 80% power to detect a 50% reduction in CV events in the experimental group (alpha=0.05). An interim analysis will be performed at 50% of expected events using the O'Brien-Fleming stopping rule, reviewed by an independent Data Safety Monitoring Board (DSMB).

• Number of Participants Experiencing an Acute Myocardial Infarction or Stroke [Срок оценки: 48 months]
• Number of Participants Hospitalized for Unstable Angina [Срок оценки: 48 months]
• Number of Participants Requiring Arterial Revascularization for Peripheral Arterial Disease [Срок оценки: 48 months]
• Number of Participants Experiencing Cardiovascular Death [Срок оценки: 48 months]
• Number of Participants Experiencing a Major Cardiovascular Event. Stratified by Rheumatic Disease Subgroup [Срок оценки: 48 months]
• Number of Participants Experiencing a Major Cardiovascular Event. Analyzed by Sex [Срок оценки: 48 months]
• Incidence of adverse events [Срок оценки: 48 months]
• LDL cholesterol levels [Срок оценки: 48 months]