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

Official title

Colchicine in Patients at Cardiac Risk Undergoing Major Non-Cardiac Surgery: Prospective, Randomized, Double-blinded, Placebo-controlled, Multi-centre Study

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.

Detailed description

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

• Drug Colchicine
  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.
• Drug Placebo
  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.

Primary outcome measures

• Major Adverse Cardiovascular Events [Time frame: until postoperative day 30]
• Myocardial Injury [Time frame: until postoperative day 4]

Secondary outcome measures (3)

• New onset Atrial fibrillation [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 [Time frame: until postoperative day 4]
• long term cardiovascular outcome [Time frame: until 1 year after surgery]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Switzerland · 1 center

• Cantonal Hospital St. Gallen — Sankt Gallen

Identifiers

NCT: NCT06279000 · CTU 22/025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗