Comparing the Effects of Amiodarone, Sotalol, and Placebo in Maintaining Sinus Rhythm in Patients With Atrial Fibrillation Converted to Sinus Rhythm

Sponsor

US Department of Veterans Affairs (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT00007605

Collaborator

(none)

706

Enrollment

Locations

Arms

Duration (Months)

25.2

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Atrial fibrillation is the most frequently occurring cardiac arrhythmia, with 1.0-1.5 million cases annually. It is a risk factor for congestive heart failure, and stroke, 75,000 cases of the latter occurring annually in patients with atrial fibrillation. The safety of the most widely used antiarrhythmic agent for this group of patients, quinidine, has been called into question. This study seeks to determine whether two other agents, amiodarone and sotalol, are safe and effective treatments for patients with atrial fibrillation.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation Cerebrovascular Accident Death, Sudden	Drug: Amiodarone Drug: Sotalol	Phase 3

Detailed Description

Primary Hypothesis: The primary objective is to compare the effects of amiodarone, sotalol, and placebo in maintaining sinus rhythm in patients with atrial fibrillation converted to sinus rhythm.

Secondary Hypotheses: To compare the three therapies in regard to: 1. Frequency of episodes of major and minor strokes. 2. Frequency of episodes of major and minor bleeds. 3. Frequency of sudden death, cardiac mortality, and total mortality. 4. Frequency of life-threatening pro-arrhythmic reactions. 5. Frequency of episodes of congestive heart failure. 6. Frequency of side effects necessitating discontinuation of therapy. 7. Frequency and mean duration of hospitalization directly related to atrial fibrillation or flutter. 8. Mean change in maximal exercise capacity on treadmill during atrial fibrillation or flutter versus sinus rhythm. 9. Time to the development of sinus rhythm from randomization to day 28 of the study. 10. Mean duration of the intervals between occurrences of atrial fibrillation or flutter after day 28. 11. The mean ventricular response documented on electrocardiogram (ECG) recordings during occurrences of atrial fibrillation or flutter after day 28. 12. Changes in health-related quality of life as measured by the SF-36 and an atrial fibrillation quality of life questionnaire. 13. Time to first occurrence of atrial fibrillation or flutter after day 28 or cessation of treatment due to adverse drug reactions after randomization.

Intervention: Patients are randomized to amiodarone (400mg bid for 14 days, 400mg qam and d200mg qhs for 14 days, 300mg qd for 48 weeks, then 200mg qd), sotalol 80mg bid for 7 days and 160mg bid thereafter) or placebo.

Primary Outcomes: The time from day 28 of randomization to first occurrence of atrial fibrillation or flutter. Failure time will be set at 0 days for patients who fail to cardiovert at day 28.

Study Abstract: Atrial fibrillation is the most frequently occurring cardiac arrhythmia, with 1.0-1.5 million cases annually. It is a risk factor for congestive heart failure, and stroke, 75,000 cases of the latter occurring annually in patients with atrial fibrillation. The safety of the most widely used antiarrhythmic agent for this group of patients, quinidine, has been called into question. This study seeks to determine whether two other agents, amiodarone and sotalol, are safe and effective treatments for patients with atrial fibrillation. All patients will have atrial fibrillation continuously for greater than 72 hours. Background medications will include warfarin for anticoagulation and digoxin plus diltiazem or verapamil for heart rate control. If warfarin is contraindicated, left atrial thrombus must be excluded by transesophageal echo (TEE) and aspirin 325 mg QD may be used. Patients will be randomly assigned to receive sotalol (80 mg bid for 7 days and 160 mg bid thereafter), amiodarone (400 mg bid for 14 days, 400 mg qam and 200 mg qhs for 14 days, 300 mg qd for 48 weeks, then 200 mg qd) or placebo. Treatment assignment will be stratified by participating hospital, whether the patient has ischemic heart disease and whether the patient is symptomatic. After randomization, patients will stay on drugs for rate control until sinus rhythm is restored and on anticoagulation until two months after sinus rhythm has been restored. After four weeks, patients remaining in atrial fibrillation will undergo DC cardioversion. Those patients not on warfarin must undergo another TEE within 48 hours prior to cardioversion. Patients will have their heart rhythm monitored transtelephonically every week and occurrences of atrial fibrillation or flutter will be documented twice within 24 hours. In the case of documented atrial fibrillation or flutter occurrence, the patient will be re-anticoagulated and at appropriate time subjected to a further DC cardioversion to restore sinus rhythm. Patients in sinus rhythm will be followed until the end of the study. Patients relapsing into AF will be followed a minimum of one year or until relapse, whichever is later. Assuming 35% of patients on placebo, 50% on sotalol, and 60% on amiodarone remain in normal sinus rhythm at the end of one year, a sample size of 706 patients, 279 on amiodarone, 279 on sotalol, and 148 on placebo (85% power and two-sided overall alpha level of 0.05 for the set of three pairwise comparisons) will be needed for these group differences to be statistically significant.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

706 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

CSP #399 - The Effects of Antiarrhythmic Therapy in Maintaining Stability of Sinus Rhythm in Atrial Fibrillation

Study Start Date :

Apr 1, 1998

Actual Primary Completion Date :

Oct 1, 2002

Actual Study Completion Date :

Dec 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Amiodarone or Sotalol	Drug: Amiodarone Patients assigned will receive 400 mg bid for 14 days, 400 mg QAM and 200 mg QHS for 14 days, 300 mg qd for 48 weeks, then 200 mg qd.
Active Comparator: 2 Sotalol	Drug: Sotalol Patients assigned will receive 80 mg bid for 7 days and 160 mg bid thereafter.

Arm

Intervention/Treatment

Active Comparator: 1

Amiodarone or Sotalol

Drug: Amiodarone

Patients assigned will receive 400 mg bid for 14 days, 400 mg QAM and 200 mg QHS for 14 days, 300 mg qd for 48 weeks, then 200 mg qd.

Active Comparator: 2

Sotalol

Drug: Sotalol

Patients assigned will receive 80 mg bid for 7 days and 160 mg bid thereafter.

Outcome Measures

Primary Outcome Measures

Treatment failure, defined as occurrence of atrial fibrillation or flutter after day 28 or failure to convert to sinus rhythm. [After day 28]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients who have atrial fibrillation continuously for greater than 72 hours.

Exclusion Criteria:

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southern Arizona VA Health Care System, Tucson	Tucson	Arizona	United States	85723
2	Central Arkansas VHS Eugene J. Towbin Healthcare Ctr, Little Rock	No. Little Rock	Arkansas	United States	72114-1706
3	VA Central California Health Care System, Fresno	Fresno	California	United States	93703
4	VA Medical Center, Loma Linda	Loma Linda	California	United States	92357
5	VA Palo Alto Health Care System	Palo Alto	California	United States	94304-1290
6	VA Greater Los Angeles HCS, Sepulveda	Sepulveda	California	United States	91343
7	VA Greater Los Angeles Healthcare System, West LA	West Los Angeles	California	United States	90073
8	VA Connecticut Health Care System (West Haven)	West Haven	Connecticut	United States	06516
9	VA Medical Center, DC	Washington	District of Columbia	United States	20422
10	VA Medical Center, Bay Pines	Bay Pines	Florida	United States	33708
11	James A. Haley Veterans Hospital, Tampa	Tampa	Florida	United States	33612
12	VA Medical Center, Augusta	Augusta	Georgia	United States	30904
13	Edward Hines, Jr. VA Hospital	Hines	Illinois	United States	60141-5000
14	VA Medical Center, Iowa City	Iowa City	Iowa	United States	52246-2208
15	VA Boston Healthcare System, Brockton Campus	Brockton	Massachusetts	United States	02301
16	VA Medical Center, Minneapolis	Minneapolis	Minnesota	United States	55417
17	VA Medical Center, Kansas City MO	Kansas City	Missouri	United States	64128
18	VA Medical Center, St Louis	St Louis	Missouri	United States	63106
19	New Mexico VA Health Care System, Albuquerque	Albuquerque	New Mexico	United States	87108-5153
20	VA Medical Center, Fargo	Fargo	North Dakota	United States	58102
21	VA Medical Center, Portland	Portland	Oregon	United States	97201
22	VA Pittsburgh Health Care System	Pittsburgh	Pennsylvania	United States	15240
23	VA Medical Center, Providence	Providence	Rhode Island	United States	02908
24	VA Medical Center, Memphis	Memphis	Tennessee	United States	38104
25	VA Medical Center	Nashville	Tennessee	United States	37212-2637
26	VA North Texas Health Care System, Dallas	Dallas	Texas	United States	75216
27	Hunter Holmes McGuire VA Medical Center	Richmond	Virginia	United States	23249
28	Wlliam S. Middleton Memorial Veterans Hospital, Madison	Madison	Wisconsin	United States	53705