Atorvastatin Therapy for the Prevention of Atrial Fibrillation (SToP-AF)

• Sponsor: Emory University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00252967
• Collaborator: Pfizer (Industry)
• Enrollment: 64
• Locations: 3
• Arms: 2
• Duration (Months): 48
• Patients Per Site: 21.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to test whether the drug, atorvastatin, will be able to reduce the rate of return of the abnormal beats after using cardioversion. Atorvastatin is a drug approved by the Food and Drug Administration (FDA) for the treatment of high cholesterol but is not approved for preventing abnormal heartbeats. In addition to lowering cholesterol, the drug reduces inflammation. Inflammation seems to help cause atrial fibrillation, a certain type of abnormal heartbeat. In animals, atorvastatin reduces the risk of this type of abnormal beats, and preliminary data in humans supports an effect of atorvastatin and other similar drugs that have the same action on reducing the risk of this type of abnormal beats. We, the researchers at Emory University, would like to learn if this drug could prevent the return of these abnormal heartbeats.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation; Inflammation	Drug: Atorvastatin; Drug: Placebo	Phase 3

Detailed Description

Atrial fibrillation (AF) and its related disorder, atrial flutter (AFlut), are common abnormal heartbeats. Because they are similar and AFlut is rare compared to AF, they are usually treated similarly and discussed as one disorder. AF is an extremely common arrhythmia affecting more that 5% of the population over 65 years of age. It is an independent risk factor for death. AF is considered a progressive disease increasing in prevalence with age and converting from paroxysmal to permanent within a single individual. The projected lifetime risk of AF is 1 in 4 for men. AF occurs when there is an electrical short circuit in the top parts of the heart (atria). This causes the atria to beat at >300 times per min in an irregular and ineffective manor. This has two consequences. The blood tends to pool in the atria allowing for clotting. Second, the bottom parts of the heart (ventricles) beat too rapidly in response to impulses arising in the atria. The rapid ventricular contraction without adequate filling time results in a reduced ejection of blood. This can cause heart failure symptoms such as shortness of breath and reduced blood flow to organs resulting in lightheadedness or collapse.

One logical therapy to correct the defects arising from AF is return the abnormal heartbeats back to the normal rhythm. This can be done with electrical shock therapy (cardioversion) or by drugs called antiarrhythmic agents. Often, they are used together. While its stands to reason that using these techniques to restore rhythm to normal would be beneficial, clinical trials show that leaving patients in AF and thinning the blood to prevent blood clots is equally efficacious to trying to restore normal beating (sinus rhythm). The common explanations for this are that AF returns rapidly despite antiarrhythmic drugs and that antiarrhythmic drugs can make worse abnormal heart beats, a phenomenon known as proarrhythmia.

Based on the lack of efficacy of current therapies and similarities between risk factors for atherosclerosis (hardening of the arteries) and AF, we began to investigate whether oxidative stress, a mechanism similar to inflammation thought to be responsible for atherosclerosis, might be playing a role in causing AF. We studied this in pigs first and found that when we put pigs into AF, they had a large increase in oxidative stress markers. Then, we made a mouse that had too much oxidative stress in the heart, and this mouse developed AF. Based on this and other data in humans, we hypothesized that oxidative stress can cause AF.

Atorvastatin is a cholesterol lowering medication that works by blocking production of cholesterol at an early stage. This has the effect of preventing the synthesis of molecules required to assemble the most common enzymatic source of oxidative stress, the NADPH oxidase. Therefore, atorvastatin decreases oxidative stress in addition to reducing cholesterol, and if our hypothesis is correct, atorvastatin should reduce the incidence of AF.

In this study we chose to look at patients undergoing cardioversion. This is because this group has a high likelihood of recurrence of AF and would benefit most by an effective drug. Once the decision is made to have the patient undergo cardioversion, we will approach the patient about enrolling in this trial. The only change in their medical therapy will be the addition of the study drug. The study requires no other alterations to the standard of care. If patients agree to participate, then they will be started on the study drug and followed for recurrence of AF by a variety of surface electrocardiogram techniques. All of which are noninvasive. To insure the medicine is not causing side effects, examinations and blood tests will be done, and to study whether the drug actually affects oxidative stress, blood will be analyzed. The subjects participation ends when AF recurs or after 1 year. This will be a double blind, placebo controlled trial and will be analyzed on an intention to treat basis.

The risks of this study to the patient are likely to be small compared to the potential benefit of reduced AF burden. Based on a previous trial using the same dose of study medication, the risks of all study drug related adverse events is likely to be <3%. All of these are expected to be reversible with discontinuation of the drug.

The significance of this research is that currently treatments to address AF are less than optimal. Antiarrhythmic drugs are variably effective and are associated with potentially lethal proarrhythmic side effects. The common treatment to prevent strokes in subjects with AF is chronic warfarin administration, but warfarin therapy requires frequent monitoring and adjustment of dose and is associated with bleeding complications. This research may provide the first new therapeutic strategy in many years for AF and the most serious consequence of AF, stroke.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Atorvastatin Therapy for the Prevention of Atrial Fibrillation (SToP-AF)
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Oct 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo taken daily	Drug: Placebo
Experimental: Atorvastatin Atorvastatin at a dose of 80 mg daily	Drug: Atorvastatin; 80 mg of Atorvastatin

Outcome Measures

Primary Outcome Measures

1. Time of Atrial Fibrillation Recurrence [Upon recurrence, up to 12 months]

Secondary Outcome Measures

1. Comparison of Redox Potential for Cysteine Values [Baseline and 30 days]

2. Comparison of Redox Potential for Glutathione Values [Baseline and 30 days]

3. Comparison of Derivatives of Reactive Oxygen Metabolites Values [Baseline and 30 days]

4. Comparison of Isoprostanes Values [Baseline and 30 days]

5. Comparison of Interleukin-6 Values [Baseline and 30 days]

6. Comparison of Interleukin-1 Values [Baseline and 30 days]

7. Comparison of High Sensitivity C-reactive Protein [Baseline and 30 days]

8. Comparison of Tumor Necrosis Factor Alpha Values [Baseline and 30 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• or = 18 years of age

• Clinical diagnosis-abnormal heart beat known as atrial fibrillation/flutter (ECG documentation)

• Able to swallow pill form of drug

Exclusion Criteria:

• < 18 years of age

• enrollment in another ongoing trial

• paroxysmal atrial fibrillation

• hemodynamic instability

• atrial fibrillation ablation within 6 months of enrollment

• a contraindication for anticoagulation

• severe valvular heart disease

• presence of single lead implantable cardioverter defibrillator

• unstable angina

• New York Heart Association (NYHA) Class IV heart failure

• hyperthyroidism

• uncontrolled hypertension (blood pressure > 180/100 at rest) on medications

• an illness that would limit life expectancy to less than 1 year

• use of statins within the previous 30 days

• significant coronary artery disease or lipid abnormalities necessitating statin therapy

• implanted devices for active management of arrhythmias by pacing or defibrillation

• lack of access to a telephone

• illicit drug use

• alcohol abuse

• hypersensitivity to atorvastatin by history

• pregnancy

• sexually active female subjects not on contraception or surgically sterilized

• nursing mothers

• chronic liver disease or abnormal liver function (elevated transaminases 1.5 times the upper limit of normal [ULN] of laboratory reference range)

• severe renal disease (creatinine > 200 mmol/L)

• inflammatory muscle disease or creatine kinase (CK) > 3 times ULN

• concurrent treatment with cyclosporine, fibrates, or high-dose niacin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veteran Administration Medical Center/Emory University	Atlanta	Georgia	United States	30033
2	Crawford Long Hospital	Atlanta	Georgia	United States	30322
3	The Emory Clinic	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• Pfizer

Investigators

• Principal Investigator: Samuel D. Dudley, Jr., MD, PhD, US Department of Veterans Affairs

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Samuel C. Dudley, Jr., MD, Emory University
• ClinicalTrials.gov Identifier: NCT00252967
• Other Study ID Numbers: IRB00024771; 1137-2004
• First Posted: Nov 15, 2005
• Last Update Posted: Sep 3, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Samuel C. Dudley, Jr., MD, Emory University: Reactive Oxgen Speers; Atrial Fibrillation; Oxidative Stress; Inflammation
• Additional relevant MeSH terms: Atrial Fibrillation; Inflammation; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Period Title: Overall Study
STARTED	31	33
COMPLETED	31	33
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Atorvastatin	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	31	33	64
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.9 (13.9)	58.2 (11.6)	58.5 (12.8)
Sex: Female, Male (Count of Participants)
Female	5 16.1%	6 18.2%	11 17.2%
Male	26 83.9%	27 81.8%	53 82.8%

Outcome Measures

1. Primary Outcome

Title	Time of Atrial Fibrillation Recurrence
Time Frame	Upon recurrence, up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Median (Inter-Quartile Range) [days]	22	29

2. Secondary Outcome

Title	Comparison of Redox Potential for Cysteine Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	-61.2	-65.3
1 month (30 day follow-up)	-64.5	-62.6

3. Secondary Outcome

Title	Comparison of Redox Potential for Glutathione Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	-116.7	-125.3
1 month (30 day follow-up)	-124.3	-129.0

4. Secondary Outcome

Title	Comparison of Derivatives of Reactive Oxygen Metabolites Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	384	382
1 month (30 day follow-up)	400	345

5. Secondary Outcome

Title	Comparison of Isoprostanes Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	1259	1062
1 month (30 day follow-up)	1146	1240

6. Secondary Outcome

Title	Comparison of Interleukin-6 Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	5.3	4.0
1 month (30 day follow-up)	5.6	2.2

7. Secondary Outcome

Title	Comparison of Interleukin-1 Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	0.29	0.30
1 month (30 day follow-up)	0.25	0.28

8. Secondary Outcome

Title	Comparison of High Sensitivity C-reactive Protein
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	9.6	6.3
1 month (30 day follow-up)	12.3	2.3

9. Secondary Outcome

Title	Comparison of Tumor Necrosis Factor Alpha Values
Time Frame	Baseline and 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Atorvastatin
Arm/Group Description
Measure Participants	31	33
Baseline	2.0	1.8
1 month (30 day follow-up)	2.6	1.5

Adverse Events

Arm/Group Title	Placebo		Atorvastatin
Arm/Group Description
All Cause Mortality
	Placebo		Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/31 (83.9%)		22/33 (66.7%)
Cardiac disorders
Atrial fibrillation	26/31 (83.9%)		22/33 (66.7%)

Limitations/Caveats

Limited enrollment; recurrence rate of AF was slightly higher than other trials indicated that the study sample may be a high-risk population.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.