Clinical Efficacy of Potassium Canrenoate in Sinus Rhythm Restoration Among Patients With Atrial Fibrillation.

Study Overview
=================
Brief Summary
-----------------
The purpose of this randomized, double blind, placebo-controlled, superiority clinical trial was to assess clinical efficacy of potassium canrenoate - canrenone in rapid conversion of atrial fibrillation to sinus rhythm.

Detailed Description
-----------------
Canrenone is a specific antagonist of aldosterone. It is a competitive inhibitor of aldosterone receptors and inhibits the effects of aldosterone. Spironolactone is a prodrug which is active after its conversion into canrenone. By inhibiting the effects of aldosterone it increases aqueous and sodium diuresis and is classified as a diuretic. It decreases urinary elimination of potassium and increases urinary excretion of calcium. Canrenone is used for the treatment of primary or secondary hyperaldosteronism, edema and ascites of congestive heart failure and cirrhosis, and in the treatment of the arterial hypertension. Current evidence supports renin-angiotensin-alodsterone (RAAS) inhibition: angiotensin-converting-enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB) or, potentially, mineralocorticoid receptor antagonists (MRA) as an upstream therapy for atrial fibrillation (AF) management. It has been demonstrated that plasma aldosterone concentration may be increased in patients with AF episode, and it lowers after cardioversion. Only canrenone (potassium canrenoate) may be administered intravenously. Canrenone increases plasma level of potassium, lowers blood pressure and reduces preload at the same time. To show superiority of canrenone over placebo a sample size of 80 patients was calculated based on following assumptions: two-tailed test, a type I error of 0.01, a power of 90%, efficacy of placebo 5%, efficacy of canrenone 50% and 20% drop-out rate to fulfill the criteria of intention-to-treat analysis. Due to presumed lack of statistical power the secondary end points and safety endpoints will be considered exploratory.

Official Title
-----------------
Clinical Efficacy of Potassium Canrenoate - Canrenone in Sinus Rhythm Restoration Among Patients With Atrial Fibrillation and Elevated Blood Pressure - a Pilot Randomized Controlled Trial.

Conditions
-----------------
Atrial Fibrillation, Paroxysmal

Intervention / Treatment
-----------------
* Drug: Saline 0.9%
* Drug: Canrenone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: written informed consent for enrolment patients aged between 40 and 75 years atrial fibrillation episode lasting for less than 48 hours, documented by the ECG potassium plasma levels < 4.5 mmol/l blood pressure > 120/80 mmHg stable cardiopulmonary status (according to attending physician's assessment) in case of left ventricle injury suspicion or unclear medical history of cardiac insufficiency, enrolment will be possible after echocardiographic examination Exclusion Criteria: no written informed consent for enrollment allergy to canrenone cardiac insufficiency or LVEF (left ventricular ejection fraction) < 40% systolic BP < 120/80 mmHg history of canrenone treatment in the 30 days before enrollment average QRS rate > 160 p.m. advanced hepatic or renal failure history of acute coronary syndrome, CABG (coronary artery bypass grafting), TIA (transient ischemic attack) or stroke within the previous 30 days pre-excitation syndrome (which has not been treated with accessory pathway ablation). atrial fibrillation due to a valvular heart disease atrial fibrillation episode resulting in myocardial ischemia (chest pain, ischemic changes in the ECG)

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Comparator: Placebo<br>Any patient fulfilling the inclusion criteria will be prepared to pharmacological cardioversion in a standard way comprising of standard baseline 12-lead ECG, continuous ECG monitoring, periodic noninvasive blood pressure monitoring (BP) and iv line. Patients assigned to control group will be administered saline 0.9% in bolus of 10 cm3 within 2-3 minutes. After drug administration the patient will be observed for 2 hours after the last dose with exit ECG and BP measure taken at the end of observation. Further treatment of the patient will depend on clinical condition and will follow appropriate clinical guidelines. | Drug: Saline 0.9%<br>* Patients assigned to control group will be administered saline 0.9% in bolus of 10 cm3 within 2-3 minutes. BP will be measured before injection.<br>* Other names: saline 0.9% in bolus of 10 cm3;|
| Experimental: Experimental: canrenone<br>Any patient fulfilling the inclusion criteria will be prepared to pharmacological cardioversion in a standard way comprising of standard baseline 12-lead ECG, continuous ECG monitoring, periodic noninvasive blood pressure monitoring (BP) and iv line. After administration of canrenone: dose 200 mg (1 ampule a 10 ml) within 2-3 minutes the patient will be observed for 2 hours after the dose with exit ECG and BP measure taken at the end of observation. | Drug: Canrenone<br>* Patients assigned to canrenone group will be administered canrenone in bolus of 200 mg diluted to 10 cm3 within 2-3 minutes in one dose. Drug administration will be stopped in case of serious adverse event. Further treatment of the patient will depend on clinical condition and will follow appropriate clinical guidelines.<br>* Other names: canrenone in bolus of 200 mg diluted to 10 cm3;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conversion of atrial fibrillation to sinus rhythm. | Conversion of atrial fibrillation to sinus rhythm confirmed in standard 12-lead ECG during observation period after first iv bolus. | Time Frame: 2 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to conversion of atrial fibrillation to sinus rhythm. | Time to conversion of atrial fibrillation to sinus rhythm in minutes since injection. | Time Frame: 2 hours. | 
| Atrial fibrillation recurrence within observation period. | Atrial fibrillation recurrence within observation period. | Time Frame: 2 hours. | 
| Serious adverse reactions. | Serious adverse reactions, which refer to every event requiring admission to a hospital or extended observation. | Time Frame: 24 hours. | 
| Safety outcome (exploratory analysis). | hypotension < 90 mm Hg, cardiac conduction abnormalities, new arrhythmia occurrence, other | Time Frame: 24 hours. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pharmacological cardioversion, Canrenone