Remote Ischemic Preconditioning for Aute Type A Aortic Dissection Surgery

Study Design and Rationale

This study is a multicenter, prospective, double-blind, randomized, sham-controlled clinical trial designed to evaluate the organ-protective efficacy and safety of remote ischemic preconditioning (RIPC) in patients undergoing emergency surgery for acute type A aortic dissection (ATAAD).

Primary Objective

The primary objective of this study is to determine whether RIPC reduces the incidence of the primary composite endpoint of major adverse outcomes occurring from the time of surgery until hospital discharge (or up to 30 days postoperatively if hospitalization exceeds 30 days). This composite endpoint includes perioperative all-cause mortality and severe complications requiring invasive intervention or resulting in organ failure.

Key Interventions and Methodology Intervention Group

After induction of general anesthesia, patients in the intervention group will undergo RIPC. RIPC will be performed alternately on one upper arm and one thigh for a total of four cycles, beginning with cuff inflation on the upper arm.

Each cycle consists of 5 minutes of cuff inflation (baseline pressure of 200 mm Hg; or at least 15 mm Hg above systolic pressure if systolic pressure exceeds 185 mm Hg), followed by 5 minutes of cuff deflation to allow reperfusion. The first cycle of the thigh cuff is initiated after completion of the first inflation cycle of the upper arm cuff.

Control Group

Patients in the control group undergo a sham procedure identical in timing and application sites to the RIPC intervention. However, the cuff is inflated to a low, non-ischemic pressure of 20 mm Hg for 5 minutes, followed by 5 minutes of deflation in each cycle.

Blinding

This study employs a double-blind design. Study participants, surgical teams, postoperative care providers, outcome assessors, and data analysts/statisticians are all blinded to treatment allocation. Only an independent researcher, who does not participate in subsequent patient assessment or data collection, is unblinded in order to perform the assigned intervention.

Standardization

All surgical procedures and perioperative care are conducted in accordance with standardized protocols at each participating center.

Study Endpoints Primary Endpoint

The incidence of the primary composite endpoint of major adverse outcomes from surgery until hospital discharge (or up to 30 days postoperatively).

Secondary Endpoints

Secondary endpoints include the incidence of each individual component of the primary composite endpoint at 30 days, 3 months, and 12 months after surgery; Sequential Organ Failure Assessment (SOFA) scores recorded during the first 3 postoperative days; the incidence of postoperative delirium; durations of surgery, cardiopulmonary bypass, and mechanical ventilation; lengths of intensive care unit (ICU) and hospital stay; cardiac troponin and serum creatinine levels within the first 3 postoperative days; 12-month survival; and the incidence of unplanned rehospitalization within 12 months.

Quality Assurance and Data Management Site Selection and Training

Participating centers are required to have substantial experience in emergency ATAAD surgery. All investigators undergo centralized training on the study protocol and Standard Operating Procedures (SOPs), with a focus on the standardized RIPC procedure and data collection.

Clinical Monitoring

Clinical Research Associates (CRAs) conduct periodic on-site monitoring visits to ensure adherence to the study protocol and to verify consistency between data entered in the electronic Case Report Forms (eCRFs) and source documents.

Statistical Analysis

The primary analysis will be conducted in the intention-to-treat (ITT) population. Continuous variables will be compared using appropriate parametric or non-parametric tests, and categorical variables will be compared using the chi-square test or Fisher's exact test, as appropriate.

Sample Size Justification

Based on previously reported literature indicating an incidence of major adverse outcomes of approximately 25.8% after ATAAD surgery, and assuming an anticipated relative risk reduction of 26.5% with RIPC, sample size calculations using a two-sided alpha level of 0.05 and 80% statistical power determined that 589 evaluable patients are required per group. Allowing for an estimated dropout rate of 10%, the final target enrollment for this study is 1,312 patients.

Interim Analysis and Data Safety Monitoring

An independent Data and Safety Monitoring Board (DSMB) will oversee participant safety throughout the study and periodically review aggregated safety data.

A pre-specified blinded sample size re-estimation will be performed when approximately 600 participants have completed assessment of the primary endpoint. This analysis will be based on the pooled event rate and observed dropout rate only, without unblinding treatment allocation or conducting between-group efficacy comparisons. Therefore, the interim analysis will not affect the overall type I error rate.