Colchicine for Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement

Study Overview
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Brief Summary
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Transcatheter aortic valve implantation (TAVI) is a well-established alternative to surgical aortic valve replacement for the treatment of patients with symptomatic severe aortic stenosis. While peri-procedural complications such as stroke, vascular complications and bleeding have substantially declined with the refinement of transcatheter valves and increasing experience, new-onset atrial fibrillation (NOAF) or atrioventricular conduction disturbances continue to occur in almost half of all patients. Colchicine is a well-known substance that has been approved for the treatment of acute gout flares and familial Mediterranean fever in many countries. Colchicine has proven safe and effective in the prevention of atrial fibrillation after cardiac surgery. The anti-inflammatory effects of colchicine may mitigate the occurrence of atrioventricular conduction disturbances and thus the need for the implantation of a permanent pacemaker post transcatheter aortic valve implantation. The objective of the Co-STAR-Trial is to investigate the efficacy of colchicine for the prevention of new-onset atrial fibrillation and conduction disturbances requiring the implantation of a permanent pacemaker in patients undergoing transcatheter aortic valve implantation. Co-STAR is an investigator-initiated, randomized, double blind, placebo-controlled trial. A total of 200 patients referred for treatment of symptomatic severe aortic stenosis and selected to undergo TAVI will be randomized in a 1:1 ratio to the treatment with Colchicine or placebo for 30 days post transcatheter aortic valve implantation.

Official Title
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Colchicine for Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement (Co-STAR): a Randomized-controlled Trial

Conditions
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Pacemaker, Transcatheter Aortic Valve Replacement, Atrial Fibrillation New Onset, Colchicine

Intervention / Treatment
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* Drug: Colchicine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 65 years Symptomatic severe aortic stenosis defined by an aortic valve area (AVA) ≤1.0 cm2 or an AVA indexed to body surface area <0.6cm2/m2 Selected to undergo transfemoral TAVI based on heart team decision Exclusion Criteria: Life expectancy <1 year irrespective of valvular heart disease Kidney disease with a creatinine clearance ≤30 ml/min Known severe liver disease Known neuromuscular disease Clinically significant anaemia with haemoglobin <80g/L Known inflammatory bowel disease or chronic diarrhea Known ongoing bacterial infection Known galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption Current treatment with colchicine, steroids or biologicals for any indication Concomitant intake of Cyclosporine, Amiodarone, Clarithromycin, Erythromycin, Omeprazole, Verapamil or other strong inhibitors of CYP3A4 or P-Glycoprotein Concomitant intake of Carbamazepin, Phenobarbital, Phenytoin, Rifampicin or other strong inductors of CYP3A4 and P-Glycoprotein Permanent pacemaker or implantable cardioverter defibrillator History of atrial fibrillation Absence of sinus rhythm on hospital admission Planned non-cardiac surgery within 30 days Known intolerance to colchicine Inability to provide written informed consent Known or suspected non-compliance, drug or alcohol abuse Participation in another clinical trial with an active intervention Any other planned cardiac intervention performed in the 7 days before TAVI, concomitantly with TAVI or in the 30 days after TAVI except for percutaneous coronary interventions.

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colchicine<br> | Drug: Colchicine<br>* Colchicine in a loading dosage of 1mg single dose per os the day before TAVI and 1mg single dose at the day of procedure. Thereafter, colchicine 0.5mg once daily per os up to post-procedural day 12.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo once daily per os the day before TAVI and once at the day of procedure. Thereafter, once daily per os up to post-procedural day 12.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of the composite of new onset atrial fibrillation or occurrence of conduction disturbances requiring the implantation of a permanent pacemaker | Assessed based on extended rhythm monitoring performed until 7 days post-discharge as well as clinically or incidentally captured episodes of NOAF captured during routine care thereafter. NOAF is defined as at least one episode of atrial fibrillation with a duration >30s. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single components of primary composite endpoint | Including predefine sensitivity analysis using the alternative definition of NOAF: At least one episode of atrial fibrillation with a duration >6 min. | 30 days and 1 year | 
| The incidence of conductance disturbances | New or worsened first-degree atrioventricular (AV) block, second-degree AV block (Mobitz I or Mobitz II), high-grade atrioventricular block, third-degree AV block, right bundle branch block, left bundle branch block, left anterior fascicular block, left posterior fascicular block, intraventricular conduction delay | 30 days, 1 year | 
| The predictors of conductance disturbances | New or worsened first-degree atrioventricular (AV) block, second-degree AV block (Mobitz I or Mobitz II), high-grade atrioventricular block, third-degree AV block, right bundle branch block, left bundle branch block, left anterior fascicular block, left posterior fascicular block, intraventricular conduction delay | 30 days, 1 year | 
| The incidence of new arrhythmias resulting in hemodynamic instability or requiring therapy | Defined as electrical/medical cardioversion or initiation of a new medication e.g. oral anticoagulation, rhythm, or rate controlling therapy | 30 days, 1 year | 
| Inflammatory marker levels | IL-6, IL-8, TNF-alpha, IL-1β, CRP, high-sensitivity CRP | at day 1 | 
| The proportion of patients with at least one prosthetic leaflet with > 50% motion reduction or with at least one prosthetic leaflet with thickening | Based on a study-specific cardiac computed tomography angiography | 30 days | 
| The proportion of prosthetic leaflets with > 50% motion reduction or leaflet thickening | Based on a study-specific cardiac computed tomography angiography | 30 days | 
| The incidences of major clinical adverse events | All-cause mortality, stroke, systemic embolism, myocardial infarction, infections, clinical valve thrombosis | 30 days, 1 year |