Colchicine in Patients at Cardiac Risk Undergoing Major Non-Cardiac Surgery

Phase 3RecruitingNCT06279000

Cantonal Hospital of St. Gallen880 enrolled

Overview

Perioperative myocardial injury and major adverse cardiovascular events (MACE) are common causes of morbidity and mortality in patients at increased cardiovascular risk undergoing non-cardiac surgery. However, research in recent years has yielded limited preventive and therapeutic measures for myocardial injury/MACE. Recent studies in patients with chronic and acute coronary artery disease have shown that colchicine administration can reduce the risk of cardiovascular events. These encouraging results in non-surgical patients ask for a similar investigation in patients undergoing major non-cardiac surgery. The aim of the proposed study is to investigate the effects of perioperative colchicine administration on the incidence of myocardial injury/MACE.

This double-blind, placebo-controlled study is conducted at the Cantonal Hospital St. Gallen and the University Hospital Basel, Switzerland. The investigators intend to expand the participant recruitment to other centers. Inclusion criteria encompass patients' cardiovascular risk profile and vascular, orthopedic, visceral, and thoracic surgical procedures with a high risk as determined by the recognized incidence of troponin dynamics. Patients are informed during preoperative consultation and provide consent prior to randomization to the colchicine or placebo groups. The preoperative assessment includes medical history, medication use and physical capacity. Baseline values and cardiac biomarkers, are determined through routine laboratory tests. Study medication is administered from the evening before surgery until the third postoperative day. Daily high-sensitivity cardiac troponin T (hs-cTnT) testing is performed until the fourth day. Visits monitor primary, secondary, and safety endpoints, with standard treatment for complications. Post-hospitalization, cardiovascular events will be recorded until postoperative day 30 and for one year post-surgery to assess long-term outcomes. The primary objective is to evaluate the efficacy of perioperative colchicine administration in cardiac-risk patients undergoing major non-cardiac surgery, with the aim of reducing the myocardial injury incidence until postoperative day 4 and mitigate postoperative MACE until postoperative day 30. Secondary objectives include whether perioperative administration of colchicine reduces new-onset atrial fibrillation incidence postoperatively (until discharge) compared to placebo, to quantify the maximum increase in postoperative hs-cTnT concentrations until postoperative day 4 and to assess the impact of perioperative colchicine administration on long-term survival and morbidity (composite of MACE) after one year. The safety objectives are the incidence of gastrointestinal adverse events and clinically adverse events attributable to the administration of colchicine.

Interventions

ColchicineDRUG

Colchicine Group: IMP = Colchicine (0.5 mg, enteral) first application in the evening before day of surgery, following a 1-0-1 regimen until the third postoperative day, ending with the application of the ninth dose. Colchicine tablets are provided as 1 mg tablets with a score, which must be divided before ingestion.

PlaceboDRUG

Placebo Group: Placebo (identical to IMP in appearance and application) first application in the evening before day of surgery, following a 1-0-1 regimen until the third postoperative day, ending with the application of the ninth dose. Placebo tablets are provided as tablets with a score, which must be divided before ingestion.

Eligibility

Sex: ALLMin age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: undergoing major non-cardiac surgery in general anaesthesia will be included. Major non-cardiac surgery is defined as: * vascular surgery (with the exception of arteriovenous shunt, vein stripping procedures and carotid endarterectomies) * intraperitoneal surgery * intrathoracic surgery * major orthopaedic surgery (spinal surgery or joint replacement surgery) * at cardiovascular risk, defined as meeting at least 1 of the following 6 criteria: * preoperative n-terminal pro brain natriuretic peptide (NT-proBNP) ≥ 200 ng/l * history of coronary artery disease * history of peripheral vascular disease * history of stroke * undergoing major vascular surgery, with the exception of arteriovenous shunt, vein stripping procedures and carotid endarterectomies * fulfilment of any 3 of the 8 following criteria: * undergoing major surgery (intrathoracic, intraperitoneal or supra-inguinal vascular surgery) * any history of congestive heart failure or history of pulmonary oedema * anamnestic transient ischemic attack (TIA) * diabetes under treatment with either oral antidiabetic agent or insulin * age \> 70 years * history of hypertension * serum creatinine \> 175 mumol/l or calculated creatinine clearance \< 60 ml/min/1.73m2 (cockcroft gault) * history of smoking within 2 years of surgery * planned surgical time ≥ 90 minutes * planned postoperative hospital stay at least 1 night Exclusion Criteria: * no written consent * inclusion in other clinical trial with direct impact on perioperative medication * previously reported side effects or reported intolerance from colchicine (e.g., allergic reaction or significant sensitivity to colchicine or an auxiliary substance of the IMP) * pregnancy or planned pregnancy and/or breast feeding * clinically significant history of drug or alcohol abuse within the last year * very severe frailty (≥ 8 clinical frailty scale) * patient with inflammatory bowel disease (e.g., Morbus Crohn or Colitis ulcerosa) * patient taking colchicine for other indications (e.g., familial Mediterranean fever, gout) * severe renal impairment (eGFR \< 30 ml min -1 1.73 m2 -1) or end-stage renal disease with indication for haemodialysis * history of solid organ or bone marrow transplantation * systemic immune-suppression (medication (steroids \>30mg cortisol-equivalent per day, tacrolimus etc...) or disease (e.g., myelodysplastic syndrome) * severe hepatic impairment with history of cirrhosis * chronic active hepatitis or functional disorders defined as alanine aminotransferase greater than three times the upper limit of normal * anticipated post-operative administration of CYP3A4 metabolized substances like cyclosporine, ketoconazole, clarithromycin, verapamil, quinidine, diltiazem or ritonavir * Any other condition that the investigator would consider a risk to the patient if the latter were to participate in the study.

Outcomes

Primary Outcomes

Major Adverse Cardiovascular Events

Proportion of patients developing MACE in the peri- postoperative course. MACE is defined as a composite of any of the following within 30 days following surgery: * Acute coronary syndrome * New/worsening congestive heart failure * Coronary revascularization * Stroke * All-cause mortality * Cardiovascular death

Time frame: until postoperative day 30

Myocardial Injury

Proportion of patients developing myocardial injury in the peri- postoperative course. The primary outcome is a composite of myocardial injury and 30-day MACE. Myocardial injury is defined as an absolute perioperative rise in hs-cTnT of ≥ 14 ng/l above preoperative values (or between two postoperative measurements, if preoperative hs-cTnT is missing).

Time frame: until postoperative day 4

Secondary Outcomes

New onset Atrial fibrillation

Proportion of patients developing new-onset atrial fibrillation in the peri- postoperative course. The time frame includes the time from beginning of surgery (ECG monitoring in the peri- and early postoperative course on postoperative care unit/intensive care unit) until the date of first documented occurrence of atrial fibrillation (perioperative monitoring by daily nurse-controlled pulse examination, verified by an ECG in case of suspected arrhythmia/atrial fibrillation). These monitoring procedures take place until the discharge from the hospital.

Time frame: From beginning of surgery/surgical procedures until the date of first documented occurrence or until postoperative day 30/discharge from hospital, whatever comes first

postoperative high sensitive cardiac Troponin T concentrations

Comparison of postoperative hs-cTnT concentrations (maximal increase from individual baseline \& the area under the curve) until postoperative day 4 between the study groups

Time frame: until postoperative day 4

long term cardiovascular outcome

Proportion of patients developing MACE in regard of long term cardiovascular outcome after surgery.1-year composite endpoint of MACE (composite of acute coronary syndrome, new or worsening congestive heart failure, coronary revascularization, stroke, all-cause mortality and cardiovascular mortality) as a marker of long-term postoperative outcome.

Time frame: until 1 year after surgery