Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study

Myocardial Infarction Clinical Trial

— COPMAN  

Official title:

Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study (COPMAN)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT04139655
• Other study ID #: H19-02858
• Status: Withdrawn
• Phase: N/A
• Start date: September 1, 2020
• Est. completion date: October 1, 2021

Study information

• Verified date: November 2021
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Perioperative Myocardial Infarction (PMI) is a major contributor to perioperative mortality and morbidity with overall incidence of 5-16%. It is associated with increased 30-day mortality of 11.6% vs 2.2% of patients without PMI in non-cardiac surgical patients. However, its recognition and diagnosis remains challenging as the typical symptoms and findings of ischemic MI may be masked by post-operative changes and pain management.

In this study, the investigators hope to determine if colchicine decreases the incidence of MINS in high risk surgical patients undergoing non-cardiac surgery and optimally establish colchicine as a viable therapy to improve perioperative cardiovascular outcome in those patients.

Description:

Perioperative Myocardial Infarction (PMI) is a major contributor to perioperative mortality and morbidity with overall incidence of 5-16%. It is associated with increased 30-day mortality of 11.6% vs 2.2% of patients without PMI in non-cardiac surgical patients. However, its recognition and diagnosis remains challenging as the typical symptoms and findings of ischemic MI may be masked by post-operative changes and pain management.

To support early detection and diagnosis of myocardial injury in the perioperative setting, myocardial injury after non-cardiac surgery (MINS) has been recognized as an important prognostic marker independently associated with mortality and significant morbidity in the perioperative period. MINS is defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. Perioperative screening and monitoring of MINS is recommended by the most recent 2016 Canadian Cardiovascular Society (CCS) Guidelines. One study found of the MINS patients, only 41.8% of which filled universal definition of MI. This may suggest that screening for MINS in the Perioperative setting by detecting post-operative troponin rise is an important marker to prompt further investigation and closer monitoring.

However, despite efforts in recognition and establishment of MINS, there is still no consensus for the optimal management of MINS in addition to routine cardiac risk stratification. Common MI management options may be complicated by post-operative changes such as anemia, hypotension, hypoxemia, and use of routine anti-platelet and anticoagulation agents and invasive intervention is associated with high risk of complication and mortality in the perioperative period.

Colchicine is an alkaloid anti-inflammatory drug with well-established safety and adverse effect profile in various clinical settings including pericarditis and gout flare. Pharmacologically, colchicine inhibits beta-tubulin polymerization into microtubules, preventing activation and migration of neutrophils to achieve its anti-inflammatory effect. Clinically in the cardiac surgery patient population, colchicine has been shown in multiple meta-analyses to be efficacious in preventing post-operative atrial fibrillation, in treatment and prevention of pericarditis and post-pericardiotomy syndrome. In patients who are high risk for cardiovascular events, systemic review has shown reduction in cardiovascular mortality and myocardial infarction in some studies. Colchicine is an ideal agent in the perioperative period as it does not increase the risk of major bleeding, hepatic and renal toxicity, and there is only gastrointestinal discomfort at high doses.

In this study, the investigators hope to determine if colchicine decreases the incidence of MINS in high risk surgical patients undergoing non-cardiac surgery and optimally establish colchicine as a viable therapy to improve perioperative cardiovascular outcome in those patients.

Research Question: In the current clinical setting, is a larger, multi-centre randomised controlled trial comparing effect of perioperative oral colchicine administration versus placebo on incidence of MINS feasible?

This pilot study will inform many aspects of the future multi-centre trial. The pilot study will provide information on the recruitment rate of eligible patients and incidence of MINS on the recruited patient, which will allow the investigators to determine the sample size required in the large multi-centre trial to detect clinically relevant differences.

The pilot study will also provide information on the operational aspect of clinical trial, including initial patient enrolment and consent processes, data collection from electronic chart review. This will help refine the process and improve efficiency of the larger trial.

Lastly, information collected on side-effects of study drug (colchicine) would improve timely detection and treatment of the associated side effects (GI, myopathies, and blood dyscrasias), as well as expected drop-out rate from the larger trial due to intolerance of these side effects.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: October 1, 2021
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years and older

Eligibility

Inclusion Criteria:

Any patient undergoing non-cardiac surgery is eligible if (s)he is:

• Aged 45 years of age or older

• Expected to be admitted for >48 hours

• Have a preoperative Brain natriuretic peptide (BNP) value of 92 or higher, or a N-terminal prohormone brain natriuretic peptide (NT-proBNP) value of 300 or higher,

• If a BNP or NT-proBNP is not available, then the patient must fulfill at least one of the criteria for moderate to high risk of perioperative myocardial injury (see below):

Moderate to high risk for perioperative myocardial injury criteria:

• History of coronary artery disease

• History of peripheral artery disease

• History of stroke

• Undergoing major vascular surgery

• Any 3 of the following 9 criteria:

1. Age 70 years or greater

2. Undergoing intraperitoneal, retroperitoneal, intrathoracic, or major orthopaedic surgery

3. History of heart failure

4. History of transient ischemic attack

5. History of diabetes requiring insulin or oral hypoglycemic medications

6. Hypertension

7. Serum creatinine greater than 170 mmol/mL

8. History of smoking within 2 years of surgery

9. Undergoing urgent or emergent surgery

Exclusion Criteria:

Patients will be ineligible for the study if (s)he has:

• An allergy to colchicine

• Myelodysplastic syndrome

• An estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73m2

• Anticipated post-operative administration of cyclosporine, ketoconazole, itraconazole, protease inhibitors, or clarithromycin

Related Conditions & MeSH terms

• Infarction
• Infectious Complications
• Major Adverse Cardiac Events
• Myocardial Infarction
• Myocardial Injury
• Wounds and Injuries

Intervention

Drug:
• Colchicine 0.6 mg
Oral colchicine given at 0.6 mg 1 hour prior to surgery, then 0.6 mg twice daily starting on the night after surgery for 7 days or until discharge from hospital, whichever occurs earlier. For patient under 60kg in body weight, daily dose will be 0.6 mg once daily. Medical and surgical management of the participant will be carried out under each institute's standard clinical practice.
• Placebo oral tablet
Placebo oral tablet given at 0.6 mg 1 hour prior to surgery, then 0.6 mg twice daily starting on the night after surgery for 7 days or until discharge from hospital, whichever occurs earlier. For patient under 60kg in body weight, daily dose will be 0.6 mg once daily. Medical and surgical management of the participant will be carried out under each institute's standard clinical practice.

Locations

Country	Name	City	State
Canada	St. Paul's Hospital	Vancouver	British Columbia

Sponsors (3)

Lead Sponsor	Collaborator
University of British Columbia	Providence Health & Services, Vancouver Coastal Health

Country where clinical trial is conducted

Canada, 

References & Publications (10)

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Devereaux PJ, Xavier D, Pogue J, Guyatt G, Sigamani A, Garutti I, Leslie K, Rao-Melacini P, Chrolavicius S, Yang H, Macdonald C, Avezum A, Lanthier L, Hu W, Yusuf S; POISE (PeriOperative ISchemic Evaluation) Investigators. Characteristics and short-term prognosis of perioperative myocardial infarction in patients undergoing noncardiac surgery: a cohort study. Ann Intern Med. 2011 Apr 19;154(8):523-8. doi: 10.7326/0003-4819-154-8-201104190-00003. — View Citation

Duceppe E, Parlow J, MacDonald P, Lyons K, McMullen M, Srinathan S, Graham M, Tandon V, Styles K, Bessissow A, Sessler DI, Bryson G, Devereaux PJ. Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery. Can J Cardiol. 2017 Jan;33(1):17-32. doi: 10.1016/j.cjca.2016.09.008. Epub 2016 Oct 4. Review. Erratum in: Can J Cardiol. 2017 Dec;33(12 ):1735. — View Citation

Hemkens LG, Ewald H, Gloy VL, Arpagaus A, Olu KK, Nidorf M, Glinz D, Nordmann AJ, Briel M. Cardiovascular effects and safety of long-term colchicine treatment: Cochrane review and meta-analysis. Heart. 2016 Apr;102(8):590-6. doi: 10.1136/heartjnl-2015-308542. Epub 2016 Feb 1. Review. — View Citation

Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P. Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis. Int J Cardiol. 2017 Dec 15;249:127-137. doi: 10.1016/j.ijcard.2017.08.039. Epub 2017 Sep 1. Review. — View Citation

Papageorgiou N, Briasoulis A, Lazaros G, Imazio M, Tousoulis D. Colchicine for prevention and treatment of cardiac diseases: A meta-analysis. Cardiovasc Ther. 2017 Feb;35(1):10-18. doi: 10.1111/1755-5922.12226. Review. — View Citation

Parashar A, Agarwal S, Krishnaswamy A, Sud K, Poddar KL, Bassi M, Ellis S, Tuzcu EM, Menon V, Kapadia SR. Percutaneous Intervention for Myocardial Infarction After Noncardiac Surgery: Patient Characteristics and Outcomes. J Am Coll Cardiol. 2016 Jul 26;68(4):329-38. doi: 10.1016/j.jacc.2016.03.602. Erratum in: J Am Coll Cardiol. 2016 Sep 13;68(11):1254. — View Citation

Puelacher C, Lurati Buse G, Seeberger D, Sazgary L, Marbot S, Lampart A, Espinola J, Kindler C, Hammerer A, Seeberger E, Strebel I, Wildi K, Twerenbold R, du Fay de Lavallaz J, Steiner L, Gurke L, Breidthardt T, Rentsch K, Buser A, Gualandro DM, Osswald S, Mueller C; BASEL-PMI Investigators. Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization. Circulation. 2018 Mar 20;137(12):1221-1232. doi: 10.1161/CIRCULATIONAHA.117.030114. Epub 2017 Dec 4. — View Citation

Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators, Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger O, Villar JC, Wang CY, Garutti RI, Jacka MJ, Sigamani A, Srinathan S, Biccard BM, Chow CK, Abraham V, Tiboni M, Pettit S, Szczeklik W, Lurati Buse G, Botto F, Guyatt G, Heels-Ansdell D, Sessler DI, Thorlund K, Garg AX, Mrkobrada M, Thomas S, Rodseth RN, Pearse RM, Thabane L, McQueen MJ, VanHelder T, Bhandari M, Bosch J, Kurz A, Polanczyk C, Malaga G, Nagele P, Le Manach Y, Leuwer M, Yusuf S. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012 Jun 6;307(21):2295-304. doi: 10.1001/jama.2012.5502. Erratum in: JAMA. 2012 Jun 27;307(24):2590. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Medical comorbidities	Based on patient charts.	Duration of hospital admission up to 7 days post-operatively
Other	Clinical risk stratification scores	Revised cardiac risk index (RCRI) scores based on patient charts. RCRI score is used and recommended by Canadian Cardiovascular Society as an evidence-based 30-day perioperative cardiovascular mortality and morbidity risk stratification tool. The tool is composed of 6 yes or no questions and provides a score from 0/6 to 6/6 which is interpreted as a percentage of 30-day risk of death, MI, or cardiac arrest. The lowest risk percentage is 3.9% and the highest percentage risk is 15%. A higher percentage indicates a higher risk of death, MI, or cardiac arrest in 30-days post-operatively.	Duration of hospital admission up to 7 days post-operatively
Other	Neutrophil to lymphocyte ratio (NLR)	Based on patient charts, to be obtained from patient's pre-operative bloodwork. NLR is a marker of neutrophil predominant inflammatory state that is associated with Major Adverse Cardiac Events (MACE) in a systemic review	Pre-operatively up to 7 days post-operatively
Primary	Number of Patients Recruited	The number of eligible subjects recruited in 3 months after 2 weeks of run-in period in participating centres	3 months
Secondary	Incidence of Myocardial Injury after Non-Cardiac Surgery (MINS)	The incidence of MINS in the treatment versus placebo group, as defined by high sensitivity troponin T level > 65 ng/L or Troponin level > 0.03 ng/mL. The incidence of MINS will be determined upon review of the troponin assay on post-operative day 0, 1, 2 and 3rd (or according to each participating institution's own MINS pathway) and electrocardiogram (ECG) on post-operative day 1, or as otherwise clinically indicated and ordered by the perioperative team. Information will be obtained by review of blood work results and ECG on institution's electronic health record and patient's bedside chart if necessary by our research team member.	From Post-Operatively day one up to 7 days post-operatively
Secondary	Adverse Events	We will collect adverse effects, whether or not associated with study drug through review of patient's bedside chart and discharge summary.	Duration of hospital admission up to 7 days post-operatively
Secondary	Incidence of premature discontinuation of the study drug and Reasoning	Incidence of premature discontinuation of the study drug will be recorded. If the subject chooses to discontinue the study drug and withdraw from the study, the duration of treatment before withdraw as well as reasons of withdraw will be recorded.	Post-Operatively until date of study drug discontinuation (up to 7 days post-operatively)
Secondary	Incidence of infectious complications	Incidence of infectious complications will also be recorded with review of chart and discharge summary. The determination of the complication will depend on patient's chart review, history and physical assessment by the primary care provider team, and associated imaging and laboratory investigations as clinically indicated. Complications include, but are not limited to: including but not limited to: pneumonia, surgical site infection, urinary tract infection, and sepsis during the hospital admission.	Duration of hospital admission up to 7 days post-operatively