Arrhythmia, Atrial Fibrillation, Endothelial Dysfunction, Inflammation
Conditions
Keywords
Atrial Fibrillation, Arrhythmia, Pulmonary Vein Isolation, Left atrial catheter ablation, Inflammation, Endothelial dysfunction
Brief summary
To investigate whether statin therapy utilizing the drug Lipitor (atorvastatin) might be effective in preventing short-and long-term atrial fibrillation (AF) following a left atrial ablation procedure. We further hypothesize this reduction will result from diminished peri-procedural inflammation, which will be reflected in lower C-Reactive Protein (CRP) values in the blood.
Detailed description
Although pharmacologic therapy is the traditional mainstay of therapy for AF, curative therapy has recently become possible. There is growing evidence that inflammation may be involved in the pathogenesis of AF. CRP, a sensitive marker of systemic inflammation, is increased in patients with AF compared with patients in sinus rhythm. Elevated CRP levels are associated with increased likelihood of new onset AF and with recurrence of AF after successful cardioversion. Clinical and basic laboratory evidence suggests that, in addition to being potent lipid-lowering agents, statins may also have anti-inflammatory properties and protective effect against AF. 125 eligible patients with AF, undergoing left atrial ablation, will be randomly assigned in a 1:1 ratio to receive daily 80 mg of atorvastatin or placebo in a double-blind fashion for 3 months after their ablation procedure. Patients will have baseline lipids, CRP, endothelial function tests and Quality of Life (QoL) surveys compared with testing at 3 months post ablation.
Interventions
DRUGAtorvastatin
80 mg tablet taken by mouth daily for 90 days
DRUGPlacebo
Placebo tablet taken by mouth once daily for 90 days
Sponsors
Pfizer
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Patients \> or = to 18 years of age * Clinically indicated left atrial ablation procedure for atrial fibrillation
Exclusion criteria
* Known malignancy * Known inflammatory disease * Surgery or trauma or myocardial infarction in the previous month * Known contraindication to statin therapy * Elevated liver enzymes above two times the upper limit of normal * Patients already receiving therapy with any statin, niacin or fibrates at the time of their randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Without Symptoms of Atrial Fibrillation at 3 Months | Baseline through 3 months | Asymptomatic recurrence was defined as any atrial arrhythmia lasting more than 30 seconds. This was assessed by an electrocardiogram (ECG) and 72-hour Holter monitor recordings. At the end of the study, 336 ECG and Holter recordings were available for analysis (172 in the atorvastatin group and 164 in the placebo group). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Without Atrial Arrhythmia at 3 Months | Baseline through 3 months | Percentage of subjects without atrial arrhythmia (as opposed to atrial fibrillation) recurrence, irrespective of symptoms. Atrial arrhythmias included AF, atrial tachycardia and atrial flutter. |
| Change in Mean C-Reactive Protein Level | Baseline and 3 months | — |
| Change in Mean Quality of Life Score | Baseline and 3 months | A visual analogue scale (VAS) was used to collect the subject's perception of their current state of health/quality of life. The VAS consists of a vertical 20 centimeter scored line (like a thermometer) with the ends labelled best imaginable health state at the top (100) and worst imaginable health state at the bottom (0). The subject marked a single line to grade his/her own current level of function at the baseline visit and again at the 3 month visit. The average change in VAS score from baseline to 3 months later is reported for each treatment group. |
| Change in Lipid Levels | Baseline and 3 months | The change from baseline to 3 months in blood cholesterol levels (total cholesterol, LDL or low-density lipoprotein and HDL or high-density lipoprotein) was calculated. |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled in this trial between January 2008 and December 2009 at Mayo Clinic in Rochester, Minnesota (USA).
Pre-assignment details
847 patients were screened and of those, 567 were excluded, primarily because they were already receiving statin therapy (68%) and/or had known inflammatory disease (16%). 280 met entry criteria but 155 were not willing to participate. 125 were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Lipitor (atorvastatin) 80 mg tablet taken once daily by mouth for 90 days | 62 |
| Placebo Placebo (dummy) tablet taken once daily by mouth for 90 days | 63 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | AF returned after ablation | 3 | 2 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Atorvastatin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 10 | 57 years STANDARD_DEVIATION 10 | 57 years STANDARD_DEVIATION 10 |
| Anatomical area of ablation Cavotricuspid isthmus line | 49 Participants | 51 Participants | 100 Participants |
| Anatomical area of ablation LA isthmus | 12 Participants | 7 Participants | 19 Participants |
| Anatomical area of ablation Nonpulmonary vein foci | 7 Participants | 6 Participants | 13 Participants |
| Anatomical area of ablation Roof line | 12 Participants | 8 Participants | 20 Participants |
| Anatomical area of ablation Wide-area circumferential ablation | 44 Participants | 46 Participants | 90 Participants |
| Antiarrhythmic drugs Amiodarone | 1 Participants | 4 Participants | 5 Participants |
| Antiarrhythmic drugs Sodium Channel Blocker Class IC | 13 Participants | 20 Participants | 33 Participants |
| Antiarrhythmic drugs Sotalol/dofetilide | 14 Participants | 9 Participants | 23 Participants |
| Antiarrhythmic drugs Total on any antiarrhythmic drug | 28 Participants | 33 Participants | 61 Participants |
| Concomitant Conditions Chronic kidney disease | 1 Participants | 2 Participants | 3 Participants |
| Concomitant Conditions Chronic lung disease | 1 Participants | 2 Participants | 3 Participants |
| Concomitant Conditions Congestive Heart Failure | 0 Participants | 3 Participants | 3 Participants |
| Concomitant Conditions Coronary Artery Disease | 0 Participants | 0 Participants | 0 Participants |
| Concomitant Conditions Diabetes Mellitus | 1 Participants | 0 Participants | 1 Participants |
| Concomitant Conditions Dilated cardiomyopathy | 1 Participants | 0 Participants | 1 Participants |
| Concomitant Conditions Hypertension | 20 Participants | 16 Participants | 36 Participants |
| Concomitant Conditions Hypertrophic cardiomyopathy | 0 Participants | 0 Participants | 0 Participants |
| Concomitant Conditions Old Cardiovascular Accident/Transient Ischemic Att | 0 Participants | 0 Participants | 0 Participants |
| Concomitant Conditions Sleep apnea | 14 Participants | 12 Participants | 26 Participants |
| Concomitant Conditions Valvular heart disease | 6 Participants | 5 Participants | 11 Participants |
| Duration of Atrial Fibrillation | 4 Months | 4 Months | 4 Months |
| Echocardiographic parameter-LA diameter, long axis | 58.4 millimeters STANDARD_DEVIATION 6.7 | 57.5 millimeters STANDARD_DEVIATION 7.7 | 57.9 millimeters STANDARD_DEVIATION 7.2 |
| Echocardiographic parameter-LA volume index | 40.4 cc/m^2 STANDARD_DEVIATION 0.7 | 39.4 cc/m^2 STANDARD_DEVIATION 13.1 | 39.9 cc/m^2 STANDARD_DEVIATION 13.8 |
| Echocardiographic parameter-LVEF | 60 Percentage STANDARD_DEVIATION 10 | 60 Percentage STANDARD_DEVIATION 9 | 60 Percentage STANDARD_DEVIATION 10 |
| Medication on admission ACE inhibitors/Angiotensin Receptor Blockers | 12 Participants | 7 Participants | 19 Participants |
| Medication on admission Aspirin | 28 Participants | 30 Participants | 58 Participants |
| Medication on admission Beta blocker | 35 Participants | 30 Participants | 65 Participants |
| Medication on admission Oral anticoagulation | 46 Participants | 41 Participants | 87 Participants |
| Paroxysmal Atrial Fibrillation | 44 Participants | 46 Participants | 90 Participants |
| Procedural time | 110 Minutes STANDARD_DEVIATION 39 | 113 Minutes STANDARD_DEVIATION 47 | 111 Minutes STANDARD_DEVIATION 42 |
| Region of Enrollment United States | 62 participants | 63 participants | 125 participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 49 Participants | 49 Participants | 98 Participants |
| Years of Atrial Fibrillation | 5.7 Years STANDARD_DEVIATION 4.9 | 4.9 Years STANDARD_DEVIATION 3.96 | 5.3 Years STANDARD_DEVIATION 4.45 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 62 | 1 / 63 |
| serious Total, serious adverse events | 0 / 62 | 0 / 63 |
Outcome results
Primary
Percentage of Subjects Without Symptoms of Atrial Fibrillation at 3 Months
Asymptomatic recurrence was defined as any atrial arrhythmia lasting more than 30 seconds. This was assessed by an electrocardiogram (ECG) and 72-hour Holter monitor recordings. At the end of the study, 336 ECG and Holter recordings were available for analysis (172 in the atorvastatin group and 164 in the placebo group).
Time frame: Baseline through 3 months
Population: Intent-to-treat analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Percentage of Subjects Without Symptoms of Atrial Fibrillation at 3 Months | 95 Percentage of subjects |
| Placebo | Percentage of Subjects Without Symptoms of Atrial Fibrillation at 3 Months | 93.5 Percentage of subjects |
p-value: 0.75Log Rank
Secondary
Change in Lipid Levels
The change from baseline to 3 months in blood cholesterol levels (total cholesterol, LDL or low-density lipoprotein and HDL or high-density lipoprotein) was calculated.
Time frame: Baseline and 3 months
Population: Intent-to-treat analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Change in Lipid Levels | Change in total cholesterol | -50 mg/dL | Standard Deviation 42 |
| Atorvastatin | Change in Lipid Levels | Change in LDL (low-density lipoprotein) cholestero | -47 mg/dL | Standard Deviation 35 |
| Atorvastatin | Change in Lipid Levels | Change in HDL (high-density lipoprotein) cholest. | 3 mg/dL | Standard Deviation 7 |
| Placebo | Change in Lipid Levels | Change in total cholesterol | 15 mg/dL | Standard Deviation 29 |
| Placebo | Change in Lipid Levels | Change in LDL (low-density lipoprotein) cholestero | 9 mg/dL | Standard Deviation 23 |
| Placebo | Change in Lipid Levels | Change in HDL (high-density lipoprotein) cholest. | 3 mg/dL | Standard Deviation 9 |
Comparison: The change in total cholesterol was compared between treatment groups.p-value: <0.001t-test, 2 sided
Comparison: The change in LDL cholesterol was compared between treatment groups.p-value: <0.001t-test, 2 sided
Comparison: The change in HDL cholesterol was compared between treatment groups.p-value: 0.92t-test, 2 sided
Secondary
Change in Mean C-Reactive Protein Level
Time frame: Baseline and 3 months
Population: Intent-to-treat analysis population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin | Change in Mean C-Reactive Protein Level | -0.75 mg/dL | Standard Deviation 3 |
| Placebo | Change in Mean C-Reactive Protein Level | 2.1 mg/dL | Standard Deviation 19.9 |
p-value: 0.11t-test, 2 sided
Secondary
Change in Mean Quality of Life Score
A visual analogue scale (VAS) was used to collect the subject's perception of their current state of health/quality of life. The VAS consists of a vertical 20 centimeter scored line (like a thermometer) with the ends labelled best imaginable health state at the top (100) and worst imaginable health state at the bottom (0). The subject marked a single line to grade his/her own current level of function at the baseline visit and again at the 3 month visit. The average change in VAS score from baseline to 3 months later is reported for each treatment group.
Time frame: Baseline and 3 months
Population: Intent-to-treat analysis population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atorvastatin | Change in Mean Quality of Life Score | 13 units on a scale | Standard Deviation 18 |
| Placebo | Change in Mean Quality of Life Score | 11 units on a scale | Standard Deviation 18 |
p-value: 0.53t-test, 2 sided
Secondary
Percentage of Subjects Without Atrial Arrhythmia at 3 Months
Percentage of subjects without atrial arrhythmia (as opposed to atrial fibrillation) recurrence, irrespective of symptoms. Atrial arrhythmias included AF, atrial tachycardia and atrial flutter.
Time frame: Baseline through 3 months
Population: Intent-to-treat analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Percentage of Subjects Without Atrial Arrhythmia at 3 Months | 85 Percentage of subjects |
| Placebo | Percentage of Subjects Without Atrial Arrhythmia at 3 Months | 88 Percentage of subjects |
p-value: 0.37Log Rank