Antiarrhythmic Effects of Spironolactone in Patients With ICDs

Study Overview
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Brief Summary
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This study will test whether spironolactone, an approved drug for among other things hypertension, will reduce the risk of severe arrhythmias in patients with implanted defibrillators. Half the patients in the study will get spironolactone and half will get a placebo. Neither the patients or their providers will know if they are getting spironolactone or placebo.

Detailed Description
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Objectives: This study is designed to determine whether spironolactone at a dose of 25 mg per day in patients with implanted cardioverter defibrillators (ICD) will 1) Reduce the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF), 2) Improve health related quality of life, 3) Reduce the need for hospitalization, and 4) Change ventricular refractoriness. Plan: The study was a randomized double blind placebo controlled multi-center trial. Patients were randomized to either 25 mg per day of spironolactone or placebo and followed for 2 years each. The primary endpoint is time to the first episode of VT/VF. Secondary endpoints will include changes in health related quality of life, frequency of hospitalization, and in a subset of patients the effect of spironolactone on the ventricular effective refractory period measured through the ICD 3 months after starting the study medication. All data analyses will be conducted on intent to treat basis. Methods: Patients were recruited at the Portland VA ICD clinics, the Seattle VA ICD clinics, Oregon Health and Sciences University ICD clinics and the Little Rock, Arkansas VA ICD clinics. Randomization and drug preparation were done by the Portland VA Medical Center research pharmacy. For safety purposes serum potassium will be measured at 1, 2, 3, 6, 12, 18, and 24 months. Patients will undergo ICD interrogation to document the occurrence of ICD therapy for VT or VF and will be screened for potential drug side effects every 3 months during the study. Health related quality of life will be measured at baseline, 3, 6, 12, 18, and 24 months using Short Form Health Survey adapted for veterans (SF36V) Veterans Health Study Version, the Patients Concerns Assessment, and the Kansas City Cardiomyopathy Questionnaire. Hospitalizations will be tracked throughout the study. In the subset of patient enrolled at the Portland VA the ventricular effective refractory period will be measured via single extra stimuli pacing through the ICD at 3 months after randomization.

Official Title
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Antiarrhythmic Effects of Spironolactone in Patients With ICDs

Conditions
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Ventricular Arrhythmias

Intervention / Treatment
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* Drug: spironolactone
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Patients were considered eligible for enrollment only if they had received an ICD therapy, either a shock or antitachycardia pacing (ATP), VT/VF in the previous 2 years or received an ICD for secondary prevention of sustained VT/VF in the previous 6 months. Exclusion Criteria: -Important exclusion criteria were an indication for spironolactone based on the RALES trial (EF of <35% and -New York Heart Association (NYHA) class III or IV), unstable angina, primary hepatic failure, known intolerance to spironolactone, a serum creatinine concentration of >2.5 mg/dL, a serum potassium concentration of >5.0 mmol/L, and a life expectancy of <2 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This was a prospective, double-blind, randomized trial that assigned patients to receive either spironolactone 25 mg/day or a placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spironolactone<br>Patients randomized to active therapy with spironolactone | Drug: spironolactone<br>* aldosterone blocker<br>* Other names: Aldactone;|
| Placebo Comparator: placebo<br>patients randomized to placebo | Drug: placebo<br>* identical in appearance to spironolactone study drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy | Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization | through study completion, an average of 35 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause Hospitalization | Number of patients hospitalized for any reason during study follow-up. | through study completion, an average of 35 months | 
| Ventricular Refractoriness | The right ventricular effective refractory period (ERP) will be measured at 3 month in patients enrolled at the Portland VA Medical Center by single extra stimuli via their implanted defibrillator. The ERP is defined as the shortest paced beat coupling interval that fails to produce ventricular capture after a baseline stable pacing train. | measured 3 months after randomization | 
| Short Form Health Survey Adapted for Veterans (SF36V) | Short Form Health Survey adapted for veterans (SF36V) is a 36 item questionnaire that measures general physical and mental health [17]. The SF36V is a reliable and valid questionnaire, containing eight constructs of health status: physical functioning (PF), role limitations due to physical problems (RP), bodily pain (BP), general health perceptions (GH), energy/vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). These eight dimensions can be summarized numerically into two scores, the physical component summary (PCS) and the mental component summary (MCS). Range 0-100 higher score is better Health Related Quality of Life (HRQOL). We are reporting the Mental Component Summary score at 12 months here. | 12 months after enrollment | 
| Patient Concerns Assessment (PCA) | Patient Concerns Assessment (PCA) is a symptom checklist that measures physical symptoms and fears that are common after ICD implantation. The PCA is a disease-specific instrument for ICD QOL, symptoms, and distress, with a reliability of ( = 0.88). Range 0-44, a higher score reflects more concerns and fears. | 12 months | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item reliable and valid questionnaire, which evaluates HRQOL in heart failure. It quantifies, in a disease-specific fashion, physical limitations, symptoms, quality of life, social interference and self-efficacy. KCCQ provides the calculation of 2 main scores, the overall score and the clinical summary score, which includes functional status, social limitation and quality of life domains scores. Range 0-100, higher scores represent higher HRQOL. | through study completion, an average of 35 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Arrhythmia Agents, Ventricular Fibrillation, Ventricular Tachycardia, Defibrillators, Implantable