ATRIAL FIBRILLATION



























RACE II Study - Strict vs Lenient Rate Control in Permanent A fib, NEJM (2010) [PubMed abstract]
  • The RACE II study enrolled 614 patients with permanent atrial fibrillation
Main inclusion criteria
  • Permanent A fib for 12 months
  • Age ≤ 80 years
  • Average resting heart rate > 80 bpm
  • Current use of anticoagulation or aspirin
Baseline characteristics
  • Average age 68 years
  • Median duration of A fib - 18 months
  • Previous cardioversion - 72%
  • CAD - 18%
  • Valvular heart disease - 20%
  • CHADS2 score: 0 or 1 - 61% | 2 - 26% | 3 to 6 - 13%
  • Average resting heart rate - 96
Randomized treatment groups
  • Group 1 (311 patients) - Lenient rate control (target resting heart rate of < 110 bpm)
  • Group 2 (303 patients) - Strict rate control (target resting heart rate of < 80 bpm, target heart rate of < 110 bpm during moderate exercise)
  • Medications used to control heart rate were beta blockers, calcium channel blockers, and digoxin
Primary outcome: Composite of death from cardiovascular causes, hospitalization for heart failure, stroke, systemic embolism, major bleeding, and arrhythmic events including syncope, sustained ventricular tachycardia, cardiac arrest, life-threatening adverse effects of rate-control drugs, and implantation of a pacemaker or cardioverter–defibrillator
Results

Duration: 3 years
Outcome Lenient rate Strict rate Comparisons
Primary outcome 12.9% 14.9% HR 0.84, 95%CI [0.58 - 1.21]
Heart failure 3.8% 4.1% HR 0.97, 95%CI [0.48 - 1.96]
Stroke 1.6% 3.9% HR 0.35, 95%CI [0.13 - 0.92]
  • The average resting heart rate in the lenient group at the end of the dose adjustment phase was 93 bpm
  • The average resting heart rate in the strict group at the end of the dose adjustment phase was 76 bpm [8]

Findings: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve
AFFIRM Study - Rate Control vs Rhythm Control in A fib, NEJM (2002) [PubMed abstract]
  • The AFFIRM study enrolled 4060 patients with atrial fibrillation
Main inclusion criteria
  • Age ≥ 65 years
  • A fib deemed to be recurrent and likely symptomatic
  • Additional risk factors for stroke or death
Baseline characteristics
  • Average age 70 years
  • Hypertension - 51%
  • CAD - 26%
  • History of CHF - 23%
  • Previously failed antiarrhythmic drug - 17.6%
Randomized treatment groups
  • Group 1 (2027 patients) - Rate control only with beta blockers, calcium channel blockers, and/or digoxin. Target rate was ≤ 80 bpm resting and ≤ 110 bpm with six-minute walk test. Continuous anticoagulation with warfarin was mandated.
  • Group 2 (2033 patients) - Rhythm control with common antiarrhythmic drugs. Cardioversion as needed. Anticoagulation with warfarin could be stopped if sinus rhythm was maintained for 4 - 12 weeks.
Primary outcome: Overall mortality
Results

Duration: Average of 3.5 years
Outcome Rate control Rhythm control Comparisons
Primary outcome 25.9% 26.7% p=0.08
Stroke or brain bleed 7.4% 8.9% p=0.93
Any hospitalization 73% 80% p<0.001
  • The following adverse events were more common in the rhythm control group than the rate control group: pulmonary event 7.3% vs 1.7%; GI event 8% vs 2.1%; bradycardia 6% vs 4.2%; prolonged QT interval 1.9% vs 0.3%
  • During the course of the study, 248 patients crossed over from the rate control group to the rhythm control group. 86 of these patients crossed back over to rate control by the end of the study.
  • During the course of the study, 594 patients crossed over from the rhythm control group to the rate control group. 61 of these patients crossed back over to rhythm control by the end of the study.
  • More than 85% of the patients in the rate control group took warfarin throughout the study. In the rhythm control group, about 70% of patients took warfarin throughout the study

Findings: Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate-control strategy. Anticoagulation should be continued in this group of high-risk patients.
EAST-AFNET 4 trial - Early Rhythm Control vs Rate Control in A fib, NEJM (2020) [PubMed abstract]
  • The EAST-AFNET 4 trial enrolled 2789 patients with A fib diagnosed within the past 12 months
Main inclusion criteria
  • Age ≥ 18 years
  • A fib diagnosed within last 12 months
  • Age > 75 years OR previous TIA/Stroke OR meet two of the following: age > 65 years, female sex, heart failure, hypertension, diabetes mellitus, severe CAD, chronic kidney disease (GFR 15 - 59 ml/min), LVH
Baseline characteristics
  • Average age 70 years
  • Previous stroke or TIA - 12%
  • Stable heart failure - 29%
  • Average CHA2DS2-VASc score - 3.4
  • Median days since A fib diagnosis - 36
  • Absence of A fib symptoms - 30%
  • A fib type: First episode - 38% | Paroxysmal - 36% | Persistent - 26%
Randomized treatment groups
  • Group 1 (1395 patients): Early rhythm control which consisted of antiarrhythmic drugs or ablation, as well as cardioversion of persistent atrial fibrillation soon after randomization
  • Group 2 (1394 patients): Rate control therapy without rhythm control therapy. Rhythm control therapy was used only to mitigate uncontrolled atrial fibrillation–related symptoms during adequate rate control therapy.
  • Treatment of cardiovascular conditions, anticoagulation, and rate control were mandated in all patients in accordance with guideline recommendations
Primary outcomes
  • First: Composite of death from cardiovascular causes, stroke (either ischemic and hemorrhagic), or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis
  • Second: Number of nights spent in the hospital per year
Results

Duration: Median of 5.1 years
Outcome Rhythm control Rate control Comparisons
First primary outcome (%/year) 3.9% 5% HR 0.79 (0.66 - 0.94)
Secondary primary outcome (nights) 5.8 5.1 p=0.23
Stroke (%/year) 0.6% 0.9% HR 0.65 (0.44 - 0.97)
Death from CV causes (%/year) 1.0% 1.3% HR 0.72 (0.52 - 0.98)
Hospitalization for heart failure (%/year) 2.1% 2.6% HR 0.81 (0.65 - 1.02)
Hospitalization for coronary syndrome (%/year) 0.8% 1.0% HR 0.83 (0.58 - 1.19)
Overall mortality 9.9% 11.8% N/A
  • In the rate control group, 85.4% of patients were still not receiving rhythm control therapy at 2 years
  • In the rhythm control group, 8% of patients were initially treated with ablation and 86.8% were treated with antiarrhythmics
  • At 2 years, 88% of the patients in the rhythm control group were still receiving anticoagulants as were 91% in the rate control group
  • At 2 years, sinus rhythm was present in 82.1% of the rhythm control group and 60.5% of the rate control group
  • A secondary analysis that compared outcomes between patients who were asymptomatic at baseline to those who were symptomatic found no difference in the benefit between groups. [PMID 34447995]

Findings: Early rhythm control therapy was associated with a lower risk of cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions









AFFIRM Study - Rate Control vs Rhythm Control in A fib, NEJM (2002) [PubMed abstract]
  • The AFFIRM study enrolled 4060 patients with atrial fibrillation
Main inclusion criteria
  • Age ≥ 65 years
  • A fib deemed to be recurrent and likely symptomatic
  • Additional risk factors for stroke or death
Baseline characteristics
  • Average age 70 years
  • Hypertension - 51%
  • CAD - 26%
  • History of CHF - 23%
  • Previously failed antiarrhythmic drug - 17.6%
Randomized treatment groups
  • Group 1 (2027 patients) - Rate control only with beta blockers, calcium channel blockers, and/or digoxin. Target rate was ≤ 80 bpm resting and ≤ 110 bpm with six-minute walk test. Continuous anticoagulation with warfarin was mandated.
  • Group 2 (2033 patients) - Rhythm control with common antiarrhythmic drugs. Cardioversion as needed. Anticoagulation with warfarin could be stopped if sinus rhythm was maintained for 4 - 12 weeks.
Primary outcome: Overall mortality
Results

Duration: Average of 3.5 years
Outcome Rate control Rhythm control Comparisons
Primary outcome 25.9% 26.7% p=0.08
Stroke or brain bleed 7.4% 8.9% p=0.93
Any hospitalization 73% 80% p<0.001
  • The following adverse events were more common in the rhythm control group than the rate control group: pulmonary event 7.3% vs 1.7%; GI event 8% vs 2.1%; bradycardia 6% vs 4.2%; prolonged QT interval 1.9% vs 0.3%
  • During the course of the study, 248 patients crossed over from the rate control group to the rhythm control group. 86 of these patients crossed back over to rate control by the end of the study.
  • During the course of the study, 594 patients crossed over from the rhythm control group to the rate control group. 61 of these patients crossed back over to rhythm control by the end of the study.
  • More than 85% of the patients in the rate control group took warfarin throughout the study. In the rhythm control group, about 70% of patients took warfarin throughout the study

Findings: Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and there are potential advantages, such as a lower risk of adverse drug effects, with the rate-control strategy. Anticoagulation should be continued in this group of high-risk patients.
EAST-AFNET 4 trial - Early Rhythm Control vs Rate Control in A fib, NEJM (2020) [PubMed abstract]
  • The EAST-AFNET 4 trial enrolled 2789 patients with A fib diagnosed within the past 12 months
Main inclusion criteria
  • Age ≥ 18 years
  • A fib diagnosed within last 12 months
  • Age > 75 years OR previous TIA/Stroke OR meet two of the following: age > 65 years, female sex, heart failure, hypertension, diabetes mellitus, severe CAD, chronic kidney disease (GFR 15 - 59 ml/min), LVH
Baseline characteristics
  • Average age 70 years
  • Previous stroke or TIA - 12%
  • Average CHA2DS2-VASc score - 3.4
  • Median days since A fib diagnosis - 36
  • Absence of A fib symptoms - 30%
  • A fib type: First episode - 38% | Paroxysmal - 36% | Persistent - 26%
Randomized treatment groups
  • Group 1 (1395 patients): Early rhythm control which consisted of antiarrhythmic drugs or ablation, as well as cardioversion of persistent atrial fibrillation soon after randomization
  • Group 2 (1394 patients): Rate control therapy without rhythm control therapy. Rhythm control therapy was used only to mitigate uncontrolled atrial fibrillation–related symptoms during adequate rate control therapy.
  • Treatment of cardiovascular conditions, anticoagulation, and rate control were mandated in all patients in accordance with guideline recommendations
Primary outcomes
  • First: Composite of death from cardiovascular causes, stroke (either ischemic and hemorrhagic), or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis
  • Second: Number of nights spent in the hospital per year
Results

Duration: Median of 5.1 years
Outcome Rhythm control Rate control Comparisons
First primary outcome (%/year) 3.9% 5% HR 0.79 (0.66 - 0.94)
Secondary primary outcome (nights) 5.8 5.1 p=0.23
Stroke (%/year) 0.6% 0.9% HR 0.65 (0.44 - 0.97)
Death from CV causes (%/year) 1.0% 1.3% HR 0.72 (0.52 - 0.98)
Hospitalization for heart failure (%/year) 2.1% 2.6% HR 0.81 (0.65 - 1.02)
Hospitalization for coronary syndrome (%/year) 0.8% 1.0% HR 0.83 (0.58 - 1.19)
Overall mortality 9.9% 11.8% N/A
  • In the rate control group, 85.4% of patients were still not receiving rhythm control therapy at 2 years
  • In the rhythm control group, 8% of patients were initially treated with ablation and 86.8% were treated with antiarrhythmics
  • At 2 years, 88% of the patients in the rhythm control group were still receiving anticoagulants as were 91% in the rate control group
  • At 2 years, sinus rhythm was present in 82.1% of the rhythm control group and 60.5% of the rate control group

Findings: Early rhythm control therapy was associated with a lower risk of cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions
CABANA study - Catheter Ablation vs Antiarrhythmic Drug Therapy in A fib, JAMA (2019) [PubMed abstract]
  • The CABANA study enrolled 2204 patients with symptomatic A fib
Main inclusion criteria
  • New onset or under-treated paroxysmal, persistent, or long-standing persistent A fib
  • Age ≥ 65 years or < 65 years with ≥ 1 stroke risk factor
Main exclusion criteria
  • Failed ≥ 2 antiarrhythmic drugs
  • NYHA class IV heart failure
Baseline characteristics
  • Median age 68 years
  • Median CHA2DS2-VASc score - 3
  • Median length of time since diagnosis - 1.1 years
  • A fib type: persistent 47% | paroxysmal 43% | long-standing persistent 10%
  • Past antiarrhythmic use: one drug 82% | ≥ 2 drugs 18%
Randomized treatment groups
  • Group 1 (1108 patients): Catheter Ablation
  • Group 2 (1096 patients): Drug therapy
  • It was recommended that patients randomized to medical therapy receive rate control medications first. If the patient had previously failed rate control therapy, then rhythm control drug therapy could be initiated in an approach consistent with contemporaneous guidelines.
  • All patients were to receive anticoagulation based on contemporaneous guidelines. Patients who received a catheter ablation were treated with anticoagulation for at least 3 months after the ablation, with a recommendation that this be continued throughout the trial in patients with CHA2DS2-VASc score ≥ 2
Primary outcome: Composite of death, disabling stroke, serious bleeding, or cardiac arrest
Results

Duration: Median of 48.5 months
Outcome Ablation Drug therapy Comparisons
Primary outcome 8% 9.2% HR 0.86 (0.65 - 1.15), p=0.30
Death 5.2% 6.1% HR 0.85 (0.60 - 1.21), p=0.38
Disabling stroke 0.3% 0.6% HR 0.42 (0.11 - 1.62), p=0.19
Serious bleeding 3.2% 3.3% HR 0.98 (0.62 - 1.56), p=0.93
Cardiac arrest 0.6% 1.0% HR 0.62 (0.24 - 1.61), p=0.33
  • In the drug therapy group, 28% of patients crossed over to ablation during the trial. In the catheter ablation group, 9.2% of patients did not receive ablation.
  • In the ablation group, 19.4% had repeat ablations and 44.6% received antiarrhythmic drugs at some point after ablation with 27% still receiving antiarrhythmic drugs at last follow-up
  • In the drug therapy group, 88% of patients received rhythm control drugs during the trial
  • In the ablation group, cardiac tamponade occurred in 0.8% of patients and pulmonary vein stenosis in 0.1% of patients. In the drug therapy group, thyroid disorders occurred in 1.6% of patients and proarrhythmia in 0.8% of patients.
  • A secondary analysis that only included subjects with heart failure (NYHA class ≥ II) at baseline (N=778) found that ablation was superior to antiarrhythmics for the primary outcome and overall mortality [PMID 33554614]

Findings: Among patients with A fib, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite endpoint of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial.
CASTLE-AF - Ablation vs Medical Therapy for A Fib in Heart Failure with Reduced EF, NEJM (2018) [PubMed abstract]
  • The CASTLE-AF trial enrolled 363 patients with NYHA class II - IV heart failure and A fib
Main inclusion criteria
  • Symptomatic paroxysmal or persistent A fib
  • EF ≤ 35%
  • NYHA class ≥ II
  • Dual chamber ICD implanted
Main exclusion criteria
  • Left atrial diameter > 6 cm
  • Previous ablation
Baseline characteristics
  • Median age - 64 years
  • Median EF - 32%
  • NYHA class: I - 11% | II - 59% | III - 28% | IV - 2%
  • A fib type: Paroxysmal - 33% | Persistent - 67%
Randomized treatment groups
  • Group 1 (179 patients): Ablation followed by warfarin for 6 months. After 6 months, treatment was at provider's discretion.
  • Group 2 (184 patients): Medical therapy (rate or rhythm control) at provider's discretion. A rhythm control strategy was used in 30% of patients.
  • All patients were required to have an implantable cardioverter–defibrillator (ICD) device or a cardiac resynchronization therapy defibrillator (CRT-D)
Primary outcome: Composite of death from any cause or hospitalization for worsening heart failure
Results

Duration: Median 37.8 months
Outcome Ablation Medical therapy 1 vs 2
Primary outcome 28.5% 44.6% HR 0.62, 95%CI [0.43 - 0.87], p=0.007
Overall mortality 13.4% 25% HR 0.53, 95%CI [0.32 - 0.86], p=0.01
CHF hospitalization 20.7% 35.9% HR 0.56, 95%CI [0.37 - 0.83], p=0.004
  • In the ablation group, 15.6% of patients did not receive ablation. In the medical therapy group, 9.8% of patients received ablation.
  • In the ablation group, 25% of patients had a repeat ablation

Findings: Catheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy.
EARLY-AF trial - Ablation vs Antiarrhythmics for the Initial Treatment of A Fib, NEJM (2020) [PubMed abstract]
  • The EARLY-AF trial enrolled 303 patients with symptomatic, paroxysmal, untreated atrial fibrillation
Main inclusion criteria
  • Symptomatic A fib
  • Persistent or paroxysmal A fib
  • At least 1 episode on ECG within 24 months
Main exclusion criteria
  • Permanent A fib
  • Daily antiarrhythmic drug therapy
  • NYHA class III - IV heart failure
  • Hypertrophic cardiomyopathy
Baseline characteristics
  • Average age 58 years
  • Male sex - 70%
  • Median years since diagnosis - 1
  • Paroxysmal A fib - 95%
  • Previous cardioversion - 39%
  • Average CHA2DS2-VASc score - 1.9
  • Anticoagulant: Warfarin - 4.5% | Other - 60%
Randomized treatment groups
  • Group 1 (154 patients): Cryoablation. Median time to procedure after randomization was 50 days.
  • Group 2 (149 patients): Antiarrhythmic drug therapy according to local practices
  • After enrollment, all patients underwent insertion of an implantable cardiac monitor that continuously detected A fib
  • Initial antiarrhythmic drugs used: Flecainide - 76.5% | Sotalol - 15.4% | Propafenone - 4.7% | Dronedarone - 3.4%
Primary outcome: First recurrence of any atrial tachyarrhythmia (atrial fibrillation, atrial flutter, or atrial tachycardia) lasting 30 seconds or longer between 91 and 365 days after the initiation of an antiarrhythmic drug or the catheter ablation procedure
Results

Duration: 1 year
Outcome Cryoablation Antiarrhythmics Comparisons
Primary outcome 42.9% 67.8% p<0.001
Symptomatic A fib 11% 26.2% HR 0.39 (0.22 – 0.68)
Average % time in A fib 0.6% 3.9% N/A
  • Serious adverse events occurred in 5 of the 154 patients (3.2%) in the ablation group and in 6 of the 149 patients (4.0%) in the antiarrhythmic drug group. These events included three cases of phrenic-nerve palsy in the ablation group and two cases of wide-complex tachycardia, one case of syncope, and one case of exacerbation of heart failure in the antiarrhythmic drug group.

Findings: Among patients receiving initial treatment for symptomatic, paroxysmal atrial fibrillation, there was a significantly lower rate of atrial fibrillation recurrence with catheter cryoballoon ablation than with antiarrhythmic drug therapy, as assessed by continuous cardiac rhythm monitoring.
EARLY-AF trial - 3-Year Results, NEJM (2023) [PubMed abstract]
  • Patients from the EARLY-AF trial (N=303) were followed for an additional 2 years. Results from 3-years of follow-up are presented below. All patients had implantable loop recorders placed at the beginning of the trial.

Duration: 3 years
Outcome Cryoablation Antiarrhythmics Comparisons
Persistent A fib 1.9% 7.4% HR 0.25, 95%CI (0.09 – 0.70)
Any atrial tachyarrhythmia 56.5% 77.2% HR 0.51, 95%CI (0.38–0.67)
Median % time in A fib 0% 0.24% N/A
  • Over 3 years of follow-up, 63 patients who had been initially assigned to the antiarrhythmic group underwent catheter ablation after arrhythmia recurrence, and 27 patients who had been initially assigned to the ablation group underwent repeat ablation.
  • There were 2 strokes and 1 TIA in the antiarrhythmic group and 0 in the ablation group

Findings: Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs.












  • Scores for each criteria patient meets are summed
  • Reference [1,2]
CHADS2 risk criteria Score
Prior stroke, TIA, or thromboembolism 2
Age ≥ 75 1
Hypertension 1
Diabetes 1
Heart Failure 1

  • Reference [1]
Annual risk of stroke based on CHADS2 score
CHADS2 score Annual Stroke Rate
0 1.9%
1 2.8%
2 4%
3 5.9%
4 8.5%
5 12.5%
6 18.2%


  • Scores for each criteria patient meets are summed
  • Reference [12]
CHA2DS2-VASc risk criteria Score
Prior stroke, TIA, or thromboembolism 2
Age ≥ 75 2
Hypertension 1
Diabetes 1
Heart Failure 1
Vascular disease (CAD or PVD) 1
Age 65 - 74 1
Female sex 1

  • Reference [12]
Annual risk of stroke based on CHA2DS2-VASc score
CHA2DS2-VASc SCORE Annual Stroke Rate
0 0%
1 1.3%
2 2.2%
3 3.2%
4 4.0%
5 6.7%
6 9.8%
7 9.6%
8 6.7%
9 15.2%

AHA stroke prevention recommendations in A fib
CHA2DS2-VASc score
Men Women Treatment
≥ 2 ≥ 3
  • Treat with one of the following: Warfarin, Dabigatran, Rivaroxaban, Apixaban, Edoxaban
  • NOTE: Dabigatran, Rivaroxaban, Apixaban, and Edoxaban are preferred over warfarin except in patients with moderate-to-severe mitral stenosis or a mechanical heart valve
1 2
  • Prescribing an oral anticoagulant to reduce thromboembolic stroke risk may be considered
0 1
  • It is reasonable to omit anticoagulant therapy except in cases of moderate-to-severe mitral stenosis or a mechanical heart valve
Patients with mechanical heart valves
  • Warfarin is recommended

AHA recommendations for anticoagulation before and after cardioversion
Duration of A fib CHA2DS2-VASc score Recommendation
≥ 48 hours or unknown Any score
  • Stable patients: anticoagulation is recommended for at least 3 weeks before and at least 4 weeks after cardioversion regardless of method (electrical or pharmacological)
  • Unstable patients: anticoagulation should be initiated as soon as possible and continued for at least 4 weeks after cardioversion unless contraindicated
< 48 hours Men ≥ 2
Women ≥ 3
  • Administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor is reasonable as soon as possible before cardioversion, followed by long-term anticoagulation therapy
< 48 hours Men - 0
Women - 1
  • Administration of heparin, a factor Xa inhibitor, or a direct thrombin inhibitor, versus no anticoagulant therapy, may be considered before cardioversion, without the need for postcardioversion oral anticoagulation
≥ 48 hours or unknown and negative TEE Any score
  • It is reasonable to perform TEE before cardioversion and proceed with cardioversion if no left atrial thrombus is identified, including in the LAA, provided that anticoagulation is achieved before TEE and maintained after cardioversion for at least 4 weeks
  • Studies: In 2016, a study was published that compared edoxaban to enoxaparin-warfarin in patients undergoing electrical cardioversion for A fib. The study found that edoxaban was equivalent in both efficacy and safety to enoxaparin-warfarin. [PMID 27590218]




PROTECT AF Study - Atrial Appendage Closure with the Watchman Device vs Warfarin in Nonvalvular A Fib, Lancet (2009) [PubMed abstract]
  • The PROTECT AF study enrolled 707 adults with nonvalvular A fib
Main inclusion criteria
  • Paroxysmal, persistent, or permanent nonvalvular AF
  • CHADS2 score ≥ 1
Main exclusion criteria
  • Patent foramen ovale with atrial septal aneurysm and right-to-left shunt
Baseline characteristics
  • Average age 72 years
  • CHADS2 score: 1 ∼ 30% | 2 ∼ 35% | 3 ∼ 20% | 4 ∼ 9% | 5 ∼ 4%
  • A fib category: paroxysmal - 41% | persistent - 21% | permanent - 36% | unknown - 1%
  • A fib onset: < 1 year - 18% | ≥ 1 year - 76% | unknown - 5.5%
Randomized treatment groups
  • Group 1 (463 patients) - Watchman® device insertion + warfarin for 45 days. If device was positioned correctly, then warfarin was stopped and clopidogrel + aspirin was taken up until 6 months post insertion, then aspirin alone indefinitely
  • Group 2 (244 patients) - Warfarin with target INR of 2 - 3
Primary outcomes
  • Efficacy: Composite of stroke, cardiovascular death, or systemic embolism
  • Safety: Composite of major bleeding, pericardial effusion, or device embolization
Results

Duration: Average of 18 months
Outcome Watchman device Warfarin Comparisons
Primary efficacy outcome (%/year) 3% 4.9% Rate ratio 0.62, 95%CI [0.35 - 1.25]
Primary safety outcome (%/year) 7.4% 4.4% Rate ratio 1.69, 95%CI [1.01 - 3.19]
All-cause mortality (%/year) 3% 4.8% Rate ratio 0.62, 95%CI [0.34 - 1.24]
  • In the warfarin group, the INR was therapeutic (between 2 - 3) 66% of the time
  • In the Watchman group, 86% of implanted patients were able to stop warfarin at 45 days. At 6 months, 92% of implanted patients were able to stop.
  • The Watchman device was successfully implanted in 88% of patients (91% of those where implantation was attempted)
  • Risks of the procedure included pericardial effusion (4.8%), procedure-related stroke (1.1%), and device embolization (0.6% of patients) [10]

Findings: The efficacy of percutaneous closure of the LAA with this device was non-inferior to that of warfarin therapy. Although there was a higher rate of adverse safety events in the intervention group than in the control group, events in the intervention group were mainly a result of periprocedural complications. Closure of the LAA might provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with non-valvular atrial fibrillation.
PROTECT AF Study 3.8-Year Results, JAMA (2014) [PubMed abstract]
  • All the participants in the PROTECT AF Study above were followed for an average of 3.8 years. Results from 3.8 years are presented in the table below.

Duration: Average 3.8 years
Outcome Watchman device Warfarin Comparisons
Primary efficacy outcome (%/year) 2.3% 3.8% HR 0.61, 95%CI [0.38 - 0.97], p=0.04
Primary safety outcome (%/year) 3.6% 3.1% HR 1.21, 95%CI [0.78 - 1.94], p=0.41
All-cause mortality 14.5% 21.5% HR 0.66, 95%CI [0.45 - 0.98], p=0.04

Findings: After 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality.
PROTECT AF Study 5-Year Results, JACC (2017) [PubMed abstract]
  • All the participants in the PROTECT AF Study above were followed for an average of 5 years. Results from 5 years are presented in the table below.

Duration: Average 5 years
Outcome Watchman device Warfarin Comparisons
Primary efficacy outcome (%/year) 2.24% 3.66% p=0.04

Findings: These 5-year outcomes of the PREVAIL trial, combined with the 5-year outcomes of the PROTECT AF trial, demonstrate that LAAC with Watchman provides stroke prevention in nonvalvular atrial fibrillation comparable to warfarin, with additional reductions in major bleeding, particularly hemorrhagic stroke, and mortality.






BAFTA study - Aspirin vs Warfarin in Elderly Patients with A Fib (2007) [PubMed abstract]
  • The BAFTA study enrolled 973 elderly patients with atrial fibrillation
Main inclusion criteria
  • Age ≥ 75 years
  • Atrial fibrillation or atrial flutter
Main exclusion criteria
  • Rheumatic heart disease
  • Major nontraumatic hemorrhage within 5 years
  • History of intracranial hemorrhage
  • Peptic ulcer disease
  • BP > 180/110
Baseline characteristics
  • Average age 81 years
  • Taking warfarin - 40%
  • Taking aspirin - 42%
  • History of stroke or TIA - 13%
  • CHADS2 score: 1 to 2 - 72% | 3 to 6 - 28%
Randomized treatment groups
  • Group 1 (488 patients) - Warfarin (target INR 2-3)
  • Group 2 (485 patients) - Aspirin 75 mg once daily
Primary outcome: Composite of any nonfatal disabling stroke (ischemic or hemorrhagic), intracranial hemorrhage, or clinically significant arterial embolism
Results

Duration: Average 2.7 years
Outcome Warfarin Aspirin Comparisons
Primary outcome 4.9% 9.9% HR 0.48, 95%CI [0.28 - 0.80], p=0.0027
Stroke (all) 4.3% 9.1% HR 0.46, 95%CI [0.26 - 0.79], p=0.003
Hemorrhagic stroke 0.5% 0.4% HR 1.15, 95%CI [0.29 - 4.77], p=0.83
Overall mortality 22% 22% HR 0.95, 95%CI [0.72 - 1.26], p=0.73
Major hemorrhage 5.1% 5.2% HR 0.96, 95%CI [0.53 - 1.75], p=0.90
Drug discontinuation 33% 24% N/A
  • In the warfarin group, 26% of the subjects crossed over to aspirin at some point during the study. In the aspirin group, 17% of patients were taking warfarin at some point during the study.
  • In the warfarin group, INR was in the therapeutic range 67% of the time

Findings: These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation, unless there are contraindications or the patient decides that the benefits are not worth the inconvenience.
AVERROES study - Aspirin vs Apixaban in A Fib, NEJM (2011) [PubMed abstract]
  • The AVERROES study enrolled 5599 patients with atrial fibrillation who were at increased risk of stroke
Main inclusion criteria
  • Age ≥ 50 years
  • Atrial fibrillation
  • Deemed unsuitable for warfarin
  • At least one of the following: prior stroke or TIA, age ≥ 75 years, hypertension, diabetes, NYHA class II - IV heart failure, EF ≤ 35%, or documented PAD
Main exclusion criteria
  • Heart valve disease requiring surgery
  • Recent major hemorrhage within 6 months or high risk of bleeding
  • CrCl < 25 ml/min
Baseline characteristics
  • Average age 70 years
  • Average CHADS2 score - 2.0
  • Prior stroke or TIA - 14%
  • A fib class: paroxysmal - 27% | persistent - 21% | permanent - 52%
Randomized treatment groups
  • Group 1 (2808 patients) - Apixaban 2.5 - 5 mg twice a day
  • Group 2 (2791 patients) - Aspirin 81 - 324 mg once daily
Primary outcome: Occurrence of stroke (ischemic or hemorrhagic) or systemic embolism
Results

Duration: After an average follow-up of 1.1 years, the study was stopped early due to clear superiority of apixaban
Outcome Apixaban Aspirin Comparisons
Primary outcome 1.8% 4.0% HR 0.45, 95%CI [0.32 - 0.62], p<0.001
Stroke 1.0% 3.8% HR 0.46, 95%CI [0.33 - 0.65], p<0.001
Hemorrhagic stroke 0.21% 0.32% HR 0.67, 95%CI [0.24 - 1.88], p=0.45
Overall mortality 3.95% 5.02% HR 0.79, 95%CI [0.62 - 1.02], p=0.07
Major bleeding 1.6% 1.4% HR 1.13, 95%CI [0.74 - 1.75], p=0.57

Findings: In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage.
ACTIVE W trial - Vitamin K antagonist vs Clopidogrel + Aspirin in A fib, Lancet (2006) [PubMed abstract]
  • The ACTIVE W trial enrolled 6706 patients with A fib
Main inclusion criteria
  • A fib + one of the following: age ≥ 75 years, treatment for hypertension, previous TIA/stroke, previous systemic embolism, EF < 45%, PAD, (patients 55 - 74 years with diabetes or CAD were also eligible)
Main exclusion criteria
  • Peptic ulcer disease within previous 6 months
  • Previous intracerebral hemorrhage
  • Thrombocytopenia (< 50,000/mm³)
Baseline characteristics
  • Average age 70 years
  • Average CHA2DS2-VASc score - 2
  • Duration of A fib > 2 years - 60%
  • History of stroke/TIA - 15%
  • A fib type: permanent - 69% | persistent - 13% | paroxysmal - 18%
Randomized treatment groups
  • Group 1 (3335 patients) - Aspirin 75 - 100 mg once daily + Clopidogrel 75 mg once daily
  • Group 2 (3371 patients) - Vitamin K antagonist (target INR of 2-3)
  • Treatment was open-label
Primary outcome: Composite of stroke, non-CNS systemic embolism, myocardial infarction, or vascular death
Results

Duration: After a median follow-up of 1.28 years, the study was stopped early because of clear warfarin superiority
Outcome (%/year) ASA + Clopidogrel Vitamin K antagonist Comparisons
Primary outcome 5.6% 3.93% HR 1.44, [1.18 - 1.76], p=0.0003
Stroke 2.39% 1.4% HR 1.72, [1.24 - 2.37], p=0.001
Non-CNS systemic embolism 0.43% 0.10% HR 4.66, [1.58 - 13.8], p=0.005
Myocardial infarction 0.86% 0.55% HR 1.58, [0.94 - 2.67], p=0.09
Overall mortality 3.8% 3.76% HR 1.01, [0.81 - 1.26], p=0.91
Severe and fatal hemorrhage 2.42% 2.21% HR 1.10, [0.83 - 1.45], p=0.53
Primary outcome + major bleed 7.56% 5.45% HR 1.41, [1.19 - 1.67], p<0.0001
Drug discontinuation 13.8% 7.8% N/A
  • INR was in the therapeutic range 64% of the time

Findings: Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.
ACTIVE A trial - Clopidogrel + Aspirin vs Aspirin in A fib, NEJM (2009) [PubMed abstract]
  • The ACTIVE A trial enrolled 7554 patients with atrial fibrillation who were unsuited for vitamin K antagonists
Main inclusion criteria
  • A fib + one of the following: age ≥ 75 years, hypertension, previous TIA/stroke, previous systemic embolism, EF < 45%, PAD, (patients 55 - 74 years with diabetes or CAD were also eligible)
Main exclusion criteria
  • Peptic ulcer disease within previous 6 months
  • Previous intracerebral hemorrhage
  • Thrombocytopenia (< 50,000/mm³)
Baseline characteristics
  • Average age 71 years
  • Average CHADS2 score - 2
  • Duration of A fib > 2 years - 53%
  • History of stroke/TIA - 13%
  • A fib type: permanent - 64% | persistent - 14% | paroxysmal - 22%
  • Reason for not taking vitamin K antagonist: bleeding risk - 23% | doctor deemed inappropriate - 50% | patient declined - 26%
Randomized treatment groups
  • Group 1 (3772 patients) - Clopidogrel 75 mg once daily + Aspirin 75 - 100 mg once daily
  • Group 2 (3782 patients) - Placebo + Aspirin 75 - 100 mg once daily
Primary outcome: Composite of stroke, systemic embolism, myocardial infarction, or death from vascular causes
Results

Duration: Median of 3.6 years
Outcome (%/year) Clopidogrel Placebo Comparisons
Primary outcome 6.8% 7.6% RR 0.89, 95%CI [0.81 - 0.98], p=0.01
Any stroke 2.4% 3.3% RR 0.72, 95%CI [0.62 - 0.83], p<0.001
Myocardial infarction 0.7% 0.9% RR 0.78, 95%CI [0.59 - 1.03], p=0.08
Overall mortality 6.4% 6.6% RR 0.98, 95%CI [0.89 - 1.08], p=0.69
Major bleeding 2.0% 1.3% RR 1.57, 95%CI [1.29 - 1.92], p<0.001
Any bleeding 9.7% 5.7% RR 1.68, 95%CI [1.52 - 1.85], p<0.001

Findings: In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage








CTSN Study - Rate Control vs Rhythm Control after Cardiac Surgery, NEJM (2016) [PubMed abstract]
  • The CTSN study randomized 523 patients with no prior history of A fib who experienced A fib after cardiac surgery
Main inclusion criteria
  • Postoperative A fib that persisted for more than 60 minutes or recurrent episodes of A fib during the index hospitalization (≤ 7 days after surgery)
  • Hemodynamically stable
  • Underwent elective cardiac surgery to treat coronary artery disease or heart valve disease
Main exclusion criteria
  • Prior history of A fib
Baseline characteristics
  • Average age 69 years
  • Heart valve disease - 55%
  • Index procedure: CABG - 40%, valve repair - 16%, valve replacement - 24%, CABG + valve repair - 3.3% CABG + valve replacement - 16%
  • Taking beta blocker - 59%
  • Taking calcium channel blocker - 21%
Randomized treatment groups
  • Group 1 (262 patients) - Rate control with a target resting heart rate < 100 bpm
  • Group 2 (261 patients) - Rhythm control with amiodarone. If A fib persisted for 24 - 48 hours after randomization, direct current cardioversion was recommended.
  • The average time to the onset of postoperative A fib was 2.4 days
  • If patients remained in A fib or had recurrent A fib 48 hours after randomization, anticoagulation with warfarin (INR 2 - 3) was recommended, and bridging with LMWH was allowed. Anticoagulation was recommended to be continued for 60 days unless complications occurred.
Primary outcome: Total number of days in the hospital (including emergency department visits) within 60 days after randomization
Results

Duration: 60 days
Outcome Rate control Rhythm control Comparisons
Primary outcome (median # of days) 5.1 days 5.0 days p=0.76
Hospital readmission (events/100 patient-months) 18.5 18.5 p=0.99
Stable heart rhythm (no A fib) at discharge 89.9% 93.5% p=0.14
Stroke or TIA 0.8% 0.4% p=0.40
Met criteria for anticoagulation 46.2% 31.8% N/A
Received direct-current cardioversion 9.2% 13.8% N/A
  • In the rate control group, 26.7% of patients received amiodarone or direct-current cardioversion
  • In the rhythm control group, 23.8% of patients did not complete the full course of amiodarone, typically due to side effects. These patients received beta blockers, calcium channel blockers, or both.
  • There was no significant difference in serious or nonserious adverse events between the groups

Findings: Strategies for rate control and rhythm control to treat postoperative atrial fibrillation were associated with equal numbers of days of hospitalization, similar complication rates, and similarly low rates of persistent atrial fibrillation 60 days after onset. Neither treatment strategy showed a net clinical advantage over the other.