Colchicine in Patients at Cardiac Risk Undergoing Major Non-Cardiac Surgery: Prospective, Randomized, Triple-blinded, Placebo-controlled, Multi-centre Study
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 880
- 试验地点
- 1
- 主要终点
- Major Adverse Cardiovascular Events
研究概览
简要总结
Perioperative myocardial injury/infarction (PMI) 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 PMI/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 PMI/MACE.
详细描述
This triple-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 third 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 PMI 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Patients, anaesthesia providers and all other health care workers involved in the treatment and the study personal will be blinded to the group allocation by provision of equal looking study drugs (verum and placebo), which are repacked for blinding.
入排标准
- 年龄范围
- 45 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Colchicine
The first dose of the IMP is administered in the evening prior to the surgical procedure. Administrations of the study drug follow a 1-0-1 schedule (colchicine 0.5 mg per intake). The last study drug is administered in the evening of the third postoperative day.
干预措施: Colchicine (Drug)
Control (Placebo)
Patients in the control group will receive the same perioperative anaesthetic, surgical and medical treatment as patients in the experimental group, the sole difference being that patients will be given a placebo instead of the IMP colchicine.
The first dose of the placebo is administered in the evening prior to the surgical procedure. Administrations of the placebo follow a 1-0-1 schedule. The last placebo is administered in the evening of the third postoperative day.
干预措施: Placebo (Drug)
结局指标
主要结局
Major Adverse Cardiovascular Events
时间窗: until postoperative day 30
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
Myocardial Injury
时间窗: until postoperative day 4
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).
次要结局
- postoperative high sensitive cardiac Troponin T concentrations(until postoperative day 4)
- New onset Atrial fibrillation(From beginning of surgery/surgical procedures until the date of first documented occurrence or until postoperative day 30/discharge from hospital, whatever comes first)
- long term cardiovascular outcome(until 1 year after surgery)
研究者
Dr. Timur Yurttas
Principal Investigator, Senior Anaesthesiologist
Cantonal Hospital of St. Gallen