Overview
The goal of this clinical trial is to learn if a technique called remote ischemic preconditioning (RIPC) helps protect organs during emergency surgery for acute type A aortic dissection (ATAAD). The main questions it aims to answer are:
Does RIPC reduce the risk of major complications after surgery, such as heart, brain, or kidney problems?
Is RIPC safe to use during emergency ATAAD surgery?
Researchers will compare the RIPC group to a control group (who will receive a placebo) to see if RIPC can reduce complications after surgery.
Participants will:
Receive either RIPC or a sham intervention during their surgery.
Be monitored for up to 30 days after surgery for complications.
Have follow-up visits at 3 months, 1 year, and then yearly for up to 5 years to track their recovery.
Description
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 receive the RIPC procedure. On the non-arterial cannulation side, alternating RIPC cycles are applied to both the upper arm and thigh, for a total of four cycles. The protocol begins with the upper arm cuff.
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, 90 days, and 12 months postoperatively; the maximum SOFA-2 score within the first 3 postoperative days; surgery- and cardiopulmonary bypass-related times; duration of mechanical ventilation; lengths of intensive care unit (ICU) and hospital stay; postoperative all-cause mortality; and the rate of unplanned rehospitalization.
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 1,296 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.
Eligibility
Inclusion Criteria:
- Age ≥18 years, with no restriction on sex;
- Diagnosis of acute Type A aortic dissection requiring emergency surgery (symptom onset \<14 days);
- Ability to understand the study objectives, voluntary provision of written informed consent by the patient or a legally authorized representative, and willingness to comply with follow-up.
Exclusion Criteria:
- Traumatic or iatrogenic aortic dissection;
- Previous open cardiac or thoracic aortic surgery;
- Severe preoperative dysfunction of vital organs, such as persistent deep coma, abdominal compartment syndrome, or circulatory failure;
- Severe comorbidities, including myocardial infarction within the past 7 days, stroke within the past 2 months; end-stage renal disease (eGFR \<30 ml/min/1.73 m²); end-stage liver disease (total bilirubin \>342 μmol/L or INR \>2.0);
- Evidence of ischemia in the limb planned for intervention, such as decreased skin temperature, pain, pallor, with or without sensory disturbance, paralysis, or diminished/absent pulses; or severe deformity or prior arteriovenous surgery at the intervention site;
- Peripheral arterial disease involving the limbs, Raynaud phenomenon, active phlebitis, or a history of deep vein thrombosis of the lower extremities;
- Current use of sulfonylurea oral hypoglycemic agents or nicorandil;
- Life expectancy \<1 year (e.g., advanced malignancy);
- Participation in another clinical trial without having reached its primary endpoint;
- Pregnancy or lactation; immunodeficiency (e.g., HIV positivity, history of organ transplantation); known bleeding disorders, coagulation abnormalities, or sickle cell anemia; active or uncontrolled infection;
- Other severe physical or psychiatric disorders, or laboratory abnormalities, which in the investigator's judgment may increase risk or interfere with study outcomes, rendering the patient unsuitable for enrollment.
