Post-Operative Atrial Fibrillation After Coronary Artery Bypass Grafting (CABG)
Conditions
Keywords
colchicine, postoperative atrial fibrillation, coronary artery bypass grafting, off-pump surgery, cardiopulmonary bypass, pharmacokinetics, inflammation, neutrophil extracellular traps
Brief summary
Post-operative atrial fibrillation after coronary artery bypass grafting (CABG)
Detailed description
This single-center, prospective, randomized, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy of colchicine in preventing post-operative atrial fibrillation (POAF) following coronary artery bypass grafting (CABG) and to compare its pharmacologic and clinical effects between different surgical strategies - off-pump CABG (OPCAB) and on-pump CABG (ONCAB). Post-operative atrial fibrillation is one of the most common arrhythmias after CABG, with an incidence of approximately 50%, and is associated with prolonged ICU and hospital stay and increased healthcare utilization. Intravenous amiodarone is commonly used for POAF treatment but may increase the risk of catheter-related infection. Colchicine, an anti-inflammatory and immunomodulatory agent, has shown potential to reduce postpericardiotomy syndrome and POAF in small-scale studies, but existing evidence remains inconsistent, and most prior trials did not distinguish between surgical strategies. In this trial, 400 adult patients undergoing elective CABG will be enrolled and randomized in a 1:1 ratio within each stratum (OPCAB and ONCAB) to receive either colchicine or placebo. The treatment group will receive colchicine 0.5 mg orally twice daily, starting on postoperative day -3 and continuing through postoperative day 7. The placebo group will receive identically appearing tablets on the same schedule. The primary endpoint is the incidence of new-onset atrial fibrillation within 14 days after surgery, defined as any episode lasting ≥30 seconds documented by 12-lead ECG, continuous telemetry, or Holter monitoring. Secondary outcomes include the incidence and management of other arrhythmias (atrial flutter, supraventricular tachycardia), total dose and duration of intravenous amiodarone, ICU and total hospital length of stay, ischemic stroke or TIA, infection events (including catheter-related infection), and 30-day readmission. Safety outcomes will include gastrointestinal intolerance, hepatic enzyme elevation, creatine kinase elevation with myalgia, hematologic abnormalities, and serious adverse events (SAE). Pharmacokinetic (PK) and pharmacodynamic (PD) analyses will measure colchicine concentrations in plasma and pericardial fluid and correlate these with inflammatory biomarkers (CRP, IL-6, TNF-α, white blood cell profile, and immune cell phenotyping by flow cytometry). This integrated approach aims to elucidate the relationship between colchicine exposure, inflammation, and POAF occurrence. Statistical analyses will primarily follow an intention-to-treat (ITT) approach. The primary endpoint will be evaluated using a log-binomial or Poisson-robust model to estimate relative risk (RR) with 95% confidence intervals, including treatment, surgical strategy, and their interaction terms. Time-to-event outcomes will be analyzed using Cox proportional hazards or Kaplan-Meier methods, and continuous variables by linear mixed-effects models. Missing data will be handled conservatively with multiple imputation where appropriate. An independent Data and Safety Monitoring Board (DSMB) will review blinded safety data once 50% of subjects have been enrolled. The trial is expected to clarify the pharmacokinetic and clinical effects of colchicine in different CABG surgical strategies. If colchicine is shown to effectively reduce POAF in OPCAB patients or in those achieving sufficient plasma concentrations, it may provide a simple, low-cost preventive strategy that reduces the need for intravenous amiodarone, lowers infection risk, and shortens ICU and hospital stay. The results could guide future optimization of dosing and timing strategies in ONCAB patients and improve perioperative management and resource utilization in cardiac surgery.
Interventions
Colchicine 0.5 mg administered orally twice daily beginning 3 days before surgery and continuing through postoperative day 7. Temporary interruption or discontinuation is permitted for clinically significant adverse events according to the study safety protocol.
DRUGPlacebo Oral Tablet
Matching placebo tablet administered orally twice daily beginning 3 days before surgery and continuing through postoperative day 7 under double-blind conditions.
Sponsors
National Taiwan University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults aged 20 years or older scheduled to undergo elective coronary artery bypass grafting (CABG), including either off-pump CABG or on-pump CABG. * Ability to receive oral study medication before and after surgery. * Provision of written informed consent before randomization.
Exclusion criteria
* History of atrial fibrillation or atrial flutter before surgery. * Severe renal impairment (estimated glomerular filtration rate \<30 mL/min/1.73 m²) or chronic dialysis. * Severe hepatic dysfunction. * Known hypersensitivity or previous severe adverse reaction to colchicine. * Pregnancy or breastfeeding. * Current use of strong CYP3A4 or P-glycoprotein inhibitors that cannot be safely discontinued or substituted. * Any condition judged by the investigators to interfere with study participation or safety assessment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of new-onset atrial fibrillation within 14 days after CABG surgery | From the day of surgery through postoperative day 14. | New-onset atrial fibrillation (AF) or atrial flutter (AFL) lasting ≥30 seconds, documented by 12-lead ECG, continuous telemetry monitoring, or 24-hour Holter recording, occurring within 14 days after coronary artery bypass grafting (CABG). Events are adjudicated by blinded cardiologists according to prespecified criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total duration of post-operative atrial fibrillation (POAF) | From the day of surgery through postoperative day 14. | Cumulative duration (in hours) of all atrial fibrillation or atrial flutter episodes documented by telemetry or ECG monitoring within 14 days after surgery. |
| Proportion of patients requiring cardioversion for POAF | From the day of surgery through postoperative day 14. | Percentage of patients who undergo pharmacologic or electrical cardioversion for atrial fibrillation/flutter occurring within 14 days after surgery. |
| Total dose of intravenous amiodarone used for POAF treatment | From the day of surgery through postoperative day 14. | Total cumulative intravenous amiodarone dose (mg) administered for POAF management during the first 14 postoperative days. |
| Length of stay in the intensive care unit (ICU) | From the date of surgery until discharge from the intensive care unit or death, whichever occurred first, assessed up to 30 days after surgery. | Duration (days) of ICU hospitalization from the date of surgery until discharge from the intensive care unit. |
| Total hospital length of stay | From hospital admission until hospital discharge or death, whichever occurred first, assessed up to 60 days after surgery. | Total number of days from hospital admission for CABG surgery until hospital discharge. |
| 30-day hospital readmission | From hospital discharge until 30 days after discharge. | Incidence of unplanned hospital readmission for any cause within 30 days after discharge from index CABG hospitalization. |
| Plasma and pericardial fluid colchicine concentrations | From preoperative day 1 through postoperative day 7. | Measured colchicine concentrations (ng/mL) in plasma and pericardial fluid at predefined perioperative time points(preoperative baseline, end of surgery, postoperative day 1, postoperative day 3, and postoperative day 7)for pharmacokinetic analysis. |
Countries
Taiwan
Outcome results
None listed