Ventricular Arrhythmias
Conditions
Keywords
Anti-Arrhythmia Agents, Ventricular Fibrillation, Ventricular Tachycardia, Defibrillators, Implantable
Brief summary
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
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.
Interventions
DRUGspironolactone
aldosterone blocker
DRUGplacebo
identical in appearance to spironolactone study drug
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
All participants, providers, investigators, and outcome assessors were blinded to treatment assignment. The pharmacy maintained a key to randomization that was not broken until the study was completed and all outcomes had been assessed.
Intervention model description
This was a prospective, double-blind, randomized trial that assigned patients to receive either spironolactone 25 mg/day or a placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy | through study completion, an average of 35 months | Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Cause Hospitalization | through study completion, an average of 35 months | Number of patients hospitalized for any reason during study follow-up. |
| Ventricular Refractoriness | measured 3 months after randomization | 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. |
| Short Form Health Survey Adapted for Veterans (SF36V) | 12 months after enrollment | 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. |
| Patient Concerns Assessment (PCA) | 12 months | 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. |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | through study completion, an average of 35 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Spironolactone Patients randomized to active therapy with spironolactone
spironolactone: aldosterone blocker | 44 |
| Placebo patients randomized to placebo
placebo: identical in appearance to spironolactone study drug | 46 |
| Total | 90 |
Baseline characteristics
| Characteristic | Placebo | Total | Spironolactone |
|---|---|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 9.3 | 66.5 years STANDARD_DEVIATION 10 | 66.6 years STANDARD_DEVIATION 10.9 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 46 Participants | 90 Participants | 44 Participants |
| Sex: Female, Male Female | 42 Participants | 86 Participants | 44 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 44 | 12 / 46 |
| other Total, other adverse events | 44 / 44 | 46 / 46 |
| serious Total, serious adverse events | 39 / 44 | 37 / 46 |
Outcome results
Primary
Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy
Time to first documented ICD therapy for ventricular tachycardia or ventricular fibrillation after randomization
Time frame: through study completion, an average of 35 months
Population: all enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Spironolactone | Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy | 8.8 months |
| Placebo | Time to First Appropriate Implantable Cardioverter Defibrillator (ICD) Therapy | 12.3 months |
p-value: 0.71Log Rank
Secondary
All Cause Hospitalization
Number of patients hospitalized for any reason during study follow-up.
Time frame: through study completion, an average of 35 months
Population: all randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Spironolactone | All Cause Hospitalization | 28 Participants |
| Placebo | All Cause Hospitalization | 24 Participants |
p-value: 0.07Log Rank
Secondary
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.
Time frame: through study completion, an average of 35 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Kansas City Cardiomyopathy Questionnaire (KCCQ) | 57.35 score on a scale | Standard Deviation 28.59 |
| Placebo | Kansas City Cardiomyopathy Questionnaire (KCCQ) | 68.67 score on a scale | Standard Deviation 22.55 |
Secondary
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Patient Concerns Assessment (PCA) | 22.15 score on a scale | Standard Deviation 12.28 |
| Placebo | Patient Concerns Assessment (PCA) | 18.42 score on a scale | Standard Deviation 10.06 |
Secondary
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.
Time frame: 12 months after enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Short Form Health Survey Adapted for Veterans (SF36V) | 54.87 score on a scale | Standard Deviation 22.5 |
| Placebo | Short Form Health Survey Adapted for Veterans (SF36V) | 63.31 score on a scale | Standard Deviation 20.35 |
Secondary
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.
Time frame: measured 3 months after randomization
Population: Patients randomized at the Portland VA Hospital that consented to testing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Ventricular Refractoriness | 294.2 milliseconds | Standard Deviation 40.8 |
| Placebo | Ventricular Refractoriness | 278.3 milliseconds | Standard Deviation 24.1 |
p-value: 0.42t-test, 2 sided