ATRIAL FIBRILLATION

























Rate control for A fib

Overview
  • Rate control in A fib involves slowing or preventing the rapid ventricular rate that the arrhythmia may produce
  • Several classes of medications can be used to do this
  • The medications work by blocking the AV node and slowing conduction of depolarization from the atria to the ventricles (see cardiac conduction illustration)

  • Medications used for rate control
    Studies
    AHA recommendations for rate control
    • The AHA recommends that beta blockers or nondihydropyridine calcium channel blockers be used first-line to control heart rate in A fib
    • A heart rate control (resting heart rate < 80 bpm) strategy is reasonable for symptomatic management of A fib
    • A lenient rate control strategy (resting heart rate < 110 bpm) may be reasonable with asymptomatic patients where left ventricular systolic function is preserved (see RACE II study below)
    • Nondihydropyridine calcium channel antagonists should not be used in decompensated heart failure
    • Oral amiodarone may be useful for ventricular rate control when other measures are unsuccessful or contraindicated
    • AV nodal ablation with permanent ventricular pacing is reasonable when pharmacological management is inadequate and rhythm control is not achievable
    • When pre-excitation syndromes are present with A fib (see Wolff-Parkinson-White), digoxin, nondihydropyridine calcium channel antagonists, and amiodarone should not be administered [12]

    Rhythm control for A fib

    Overview
    • Rhythm control in A fib involves converting the A fib arrhythmia back to a sinus rhythm and preventing its recurrence
    • There are three methods for achieving rhythm control: medications (pharmacological cardioversion), electrical cardioversion (heart shock), and catheter ablation

    Factors that may favor rhythm control over rate control
    • Symptomatic A fib
    • Difficulty in achieving adequate rate control
    • Younger patient age
    • Tachycardia-mediated cardiomyopathy
    • First episode of A fib
    • A fib that is precipitated by an acute illness
    • Patient preference [13]

    Pharmacological cardioversion
    • A number of antiarrhythmic medications can be used to convert A fib back into a sinus rhythm
    • These medications are most effective when initiated in the first 7 days after the onset of A fib
    • The medications can have serious side effects and are typically administered by cardiologists in a hospital setting. Some of them can also be used in an outpatient setting to maintain sinus rhythm in appropriate patients.
    • Antiarrhythmic medications are able to maintain sinus rhythm in about 50% of patients who use them [4]
      • Medications used to convert A fib and maintain sinus rhythm include:
        • Amiodarone - convert A fib and maintain sinus rhythm
        • Dofetilide- convert A fib and maintain sinus rhythm
        • Dronedarone- maintain sinus rhythm
        • Flecainide- convert A fib and maintain sinus rhythm
        • Ibutilide- convert A fib
        • Propafenone- convert A fib and maintain sinus rhythm
        • Sotalol- maintain sinus rhythm [12]

    Electrical cardioversion
    • Electrical cardioversion can be performed to convert A fib back into a sinus rhythm
    • During the procedure, patients are sedated and an electrical shock is applied to the heart
    • The procedure may be necessary in patients who are unstable and need immediate conversion. It may also be performed as an elective outpatient procedure.

    Catheter ablation
    • Catheter ablation is a relatively new procedure where a probe is used to ablate tissue in the left atrium
    • The areas surrounding the entrance of the pulmonary veins are typically ablated. These areas are a common source for ectopic atrial foci that have been found to initiate A fib.
    • There are two ways the tissue is ablated. One method ablates tissue with radiofrequency energy and the other by freezing the tissue. A study published in 2016 compared the two methods and found them to be equally effective (see PMID 27042964).
    • Catheter ablation has a success rate around 70% at one year post-ablation. At 2 years, success (defined as no atrial arrhythmia) has dropped to less than 50% in some trials.
    • Repeat ablation is necessary in about 12 - 20% of patients [4,9,11]
    • Catheter ablation is currently only recommended for symptomatic A fib. There are no guidelines that recommend its use solely for the purpose of discontinuing anticoagulation.
    • A number of studies have now compared ablation to medical therapy with varying results (see ablation studies below)
    • Ablation performed the best in a small study (N=363) that enrolled patients with NYHA class II-IV heart failure (see CASTLE-AF study). The results of this study led the AHA to make a recommendation that ablation may be "reasonable" in patients with heart failure and reduced EF.

    Studies
    AHA recommendations for rhythm control
    Electrical cardioversion
    • In pursuing a rhythm-control strategy, cardioversion is recommended for patients with A fib or atrial flutter as a method to restore sinus rhythm. If cardioversion is unsuccessful, repeated direct-current cardioversion attempts may be made after adjusting the location of the electrodes or applying pressure over the electrodes, or following administration of an antiarrhythmic medication.
    • Electrical cardioversion is recommended when a rapid ventricular response to A fib or atrial flutter does not respond promptly to pharmacological therapies and contributes to ongoing myocardial ischemia, hypotension, or heart failure
    • Electrical cardioversion is recommended for patients with A fib or atrial flutter and pre-excitation when tachycardia is associated with hemodynamic instability [12]
    Pharmacological cardioversion
    • Flecainide, dofetilide, propafenone, and intravenous ibutilide are useful for pharmacological cardioversion of A fib or atrial flutter provided contraindications to the selected drug are absent
    • Administration of oral amiodarone is a reasonable option for pharmacological cardioversion of A fib
    • Propafenone or flecainide (“pill-in-the-pocket”) in addition to a beta blocker or nondihydropyridine calcium channel antagonist is reasonable to terminate A fib outside the hospital once this treatment has been observed to be safe in a monitored setting for selected patients
    • Dofetilide therapy should not be initiated out of hospital owing to the risk of excessive QT prolongation that can cause torsades de pointes [12]
    Catheter ablation
    • Catheter ablation is useful for symptomatic paroxysmal or persistent A fib refractory or intolerant to at least one class I or III antiarrhythmic medication when a rhythm control strategy is desired
    • A fib catheter ablation may be reasonable in selected patients with symptomatic A fib and heart failure with reduced left ventricular EF to potentially lower mortality rate and reduce hospitalization for HF
    • Catheter ablation may be a reasonable initial treatment strategy before medication in patients with symptomatic paroxysmal or persistent A fib
    • A fib catheter ablation to restore sinus rhythm should not be performed with the sole intent of obviating the need for anticoagulation [12,16]


    Effect of Weight Loss on A fib Burden and Occurrence, JAMA (2013) [PubMed abstract]
    • Design: Randomized, controlled trial (N=150 | length = 15 months) in overweight patients (average BMI 33) with symptomatic A fib
    • Treatment: Weight loss intervention vs Control
    • Primary outcome: Atrial Fibrillation Severity Scale scores: symptom burden and symptom severity (scale 3.25 [best] - 30 [worst])
    • Results:
      • Weight loss: Intervention - 31 lbs, Control - 8 lbs
      • Primary outcome (point reduction): Intervention - 11.8, Control - 2.6 (p<0.001)
      • Mean A fib episodes on 7-day Holter: Intervention - 0.62, Control - 2.0 (p<0.001)
      • Mean duration of A fib on 7-day Holter (minutes): Intervention - 491, Control - 1546 (p<0.001)
    • Findings: In this study, weight reduction with intensive risk factor management resulted in a reduction in atrial fibrillation symptom burden and severity and in beneficial cardiac remodeling. These findings support therapy directed at weight and risk factors in the management of atrial fibrillation.



    Atrial fibrillation after cardiac surgery

    Overview
    • Atrial fibrillation is one of the most common complications after cardiac surgery occurring in 20 - 50% of patients. Affected patients may be treated with either a rhythm or rate control strategy.
    • In 2016, the CTSN study was published that compared rate vs rhythm control in patients with postoperative A fib after CABG and/or heart valve surgery. The study is detailed below.

    Studies
    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
    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.

    Professional guidelines
    • The AHA recommends rate control with a beta blocker as first-line treatment in patients who develop A fib after postoperative cardiac or thoracic surgery
    • A nondihydropyridine calcium channel blocker is recommended as an alternative if a beta blocker is inadequate [14]

    Straighthealthcare analysis
    • Postoperative A fib is a common complication of cardiac surgery. It is also a very transient condition with 90% of patients returning to a normal rhythm within days.
    • In the CTSN study, there was no significant difference between a rate or rhythm control strategy in patients with postoperative A fib. Rate control with appropriate anticoagulation if necessary is likely the safest and most practical approach to postoperative A fib in hemodynamically stable patients.




    • 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]

    Atrial appendage closure

    Overview
    • The left atrial appendage is an outpocketing in the left atrium (see atrial appendage). In patients with A fib, blood tends to pool in the appendage and clots can form. The left atrial appendage is believed to be the source of > 90% of clots in A fib.
    • A device called the Watchman® device has been developed which closes off the appendage so that blood cannot pool in it
    • The device is inserted during a procedure that is similar to a heart cath
    • The PROTECT AF study compared atrial appendage closure to warfarin therapy in patients with atrial fibrillation. The study now has 5 years of follow-up that are detailed below

    Studies
    PROTECT AF Study - 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 outcome: Composite of stroke, cardiovascular death, or systemic embolism
    Primary safety outcome: Composite of major bleeding, pericardial effusion, or device embolization
    Results

    Duration: average of 18 months
    Outcome Watchman device Warfarin Comparisons
    Primary outcome (events/100 patient-years) 3 4.9 Rate ratio 0.62, 95%CI [0.35 - 1.25]
    Primary safety outcome (events/100 patient-years) 7.4 4.4 Rate ratio 1.69, 95%CI [1.01 - 3.19]
    All-cause mortality (events/100 patient-years) 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 Follow-up at 3.8 Years, JAMA (2014) [PubMed abstract]

    Duration: Average 3.8 years
    Outcome Watchman device Warfarin Comparisons
    Primary outcome (events/100 patient-years) 2.3 3.8 HR 0.61, 95%CI [0.38 - 0.97], p=0.04
    Primary safety outcome (events/100 patient-years) 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 Follow-up at 5 Years, JACC (2017) [PubMed abstract]

    Duration: Average 5 years
    Outcome Watchman device Warfarin Comparisons
    Primary outcome (events/100 patient-years) 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.

    AHA atrial appendage closure recommendations
    • Percutaneous left atrial appendage occlusion may be considered in patients with A fib at increased risk of stroke who have contraindications to long-term anticoagulation
    • Surgical occlusion of the left atrial appendage may be considered in patients with A fib undergoing cardiac surgery, as a component of an overall heart team approach to the management of A fib [16]

    StraightHealthcare analysis:
    • In the PROTECT AF studies, the Watchman® device was superior to warfarin in improving outcomes in A fib. It would be interesting to see how the device performs against newer anticoagulants (e.g. Factor Xa inhibitors, direct thrombin inhibitors).
    • The Watchman® device may be a good option for some patients. Patients who receive the device must take aspirin indefinitely.

    Antiplatelet therapy for stroke prevention in A fib

    Overview
    • Current guidelines from the AHA do not mention aspirin as a therapy for stroke prevention in A fib
    • Past AHA guidelines and the 2012 ACCP guidelines did include aspirin as a potential therapy in patients with a CHA₂DS₂-VASc score of 1 (AHA) or a CHADS₂ score of 0 (ACCP)
    • A handful of studies have looked at aspirin alone or in combination with clopidogrel for stroke prevention in A fib. These studies have found that anticoagulation is clearly superior in most patients.
    • Some patients with A fib refuse anticoagulant therapy because of the cost, blood testing, and other reasons. Although not ideal, aspirin and/or clopidogrel may be an option in these patients. The studies detailed below help to quantify the benefits and risks of antiplatelet therapy in A fib.

    Studies - Aspirin vs Anticoagulant
    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
    • CHADS₂ score: 1 to 2 - 72% | 3 to 6 - 28%
    • Taking warfarin - 40%
    • Taking aspirin - 42%
    • History of stroke or TIA - 13%
    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 Group 1, 26% of the subjects crossed over to aspirin at some point during the study. In Group 2, 17% of patients were taking warfarin at some point during the study.
    • In Group 1, 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
    • 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
    • Deemed unsuitable for warfarin
    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
    • A fib class: paroxysmal - 27% | persistent - 21% | permanent - 52%
    • Prior stroke or TIA - 14%
    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.

    Studies - Aspirin and clopidogrel in A fib
    ACTIVE W trial - Vitamin K antagonist vs Clopidogrel + Aspirin, 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
    • A fib type: permanent - 69% | persistent - 13% | paroxysmal - 18%
    • Duration of A fib > 2 years - 60%
    • History of stroke/TIA - 15%
    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 ASA + Clopidogrel (%/year) Vitamin K antagonist (%/year) 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
    Permanent drug discontinuation 13.8% 7.8% N/A
    • INR was in 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 alone, 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
    • A fib type: permanent - 64% | persistent - 14% | paroxysmal - 22%
    • Duration of A fib > 2 years - 53%
    • History of stroke/TIA - 13%
    • 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 Clopidogrel + ASA (%/year) ASA (%/year) 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









    RACE II Study - Strict vs Lenient Rate Control, 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 Group 1 at the end of the dose adjustment phase was 93 bpm
    • The average resting heart rate in Group 2 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
    StraightHealthcare analysis:
    • The RACE II study showed that a lenient rate control strategy (resting heart rate < 110 bpm) is just as safe, and possibly better than a strict rate control strategy (resting heart rate of < 80 bpm, heart rate of < 110 bpm during moderate exercise)

    AFFIRM Study - Rate Control vs Rhythm Control, 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 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.
    StraightHealthcare analysis:
    • In the AFFIRM study, neither rhythm or rate control was shown to be superior to the other. The rhythm control group had significantly more hospitalizations and adverse events.
    • The rhythm control group also had more than double the number of crossovers as the rate control group which speaks to the limited efficacy of antiarrhythmic medications

    Catheter Ablation vs Antiarrhythmic Drug Therapy for Mortality, Stroke, Bleeding, and Cardiac Arrest 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 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.

    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.
    StraightHealthcare analysis
    • In the CABANA study, catheter ablation was not significantly better than medical therapy for stroke or death in high-risk patients with A fib
    • The study had a high crossover rate with 28% of patients in the drug therapy group receiving ablation. In intention-to-treat analyses, high crossover rates can bias a study towards the null. The authors discuss the fact that their treatment-received analyses and per-protocol analyses showed ablation to be superior to drug therapy. Unfortunately, these types of analyses are also biased because it's likely that sicker patients did not ultimately receive ablation and healthier patients may have been drawn to it.

    CASTLE-AF - Ablation vs Medical Therapy for A Fib with Heart Failure, 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
    • NYHA class: I - 11% | II - 59% | III - 28% | IV - 2%
    • A fib type: Paroxysmal - 33% | Persistent - 67%
    • Median EF - 32%
    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 at provider's discretion
    • 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 Group 1, 15.6% of patients did not receive ablation. In Group 2, 9.8% of patients received ablation.
    • In Group 1, 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.
    StraightHealthcare analysis
    • The results of the CASTLE-AF trial are impressive, particularly for the mortality benefit
    • A larger trial in a more diverse population of A fib patients is needed

    RAAFT-2 Study - First-line Ablation vs Antiarrhythmic Drugs, JAMA (2014) [PubMed abstract]
    • The RAAFT-2 study enrolled 127 patients with treatment-naïve, paroxysmal A fib
    Main inclusion criteria
    • Symptomatic, recurrent, paroxysmal A fib lasting more than 30 seconds (≥ 4 episodes in past 6 months)
    • Experienced at least 1 episode that was documented by surface EKG 6 months before randomization
    • No previous antiarrhythmic drug treatment
    Main exclusion criteria
    • Ejection fraction < 40%
    • Left atrial diameter larger than 5.5 cm
    • Moderate-to-severe left ventricular hypertrophy
    • Valvular heart disease
    • Coronary artery disease
    • Cardiac surgery within the last 6 months
    Baseline characteristics
    • Average age 55 years
    • Average number of A fib episodes in past 6 months ∼ 40
    • Average CHADS₂ score - 0.6
    Randomized treatment groups
    • Group 1 (66 patients) - Radiofrequency ablation
    • Group 2 (61 patients) - Antiarrhythmic drugs (physician's discretion, 69% flecainide, 25% propafenone)
    • After randomization, patients underwent a 90-day blanking period where antiarrhythmic drugs were titrated or ablation was performed. Events in the blanking period did not count towards the outcome measures.
    • All patients were given a transtelephonic monitoring system to record symptomatic events in addition to standard biweekly recordings
    Primary outcome: First documented atrial tachyarrhythmia of more than 30 seconds (symptomatic or asymptomatic A fib, atrial flutter, or atrial tachycardia), detected by either scheduled or unscheduled electrocardiogram, Holter, transtelephonic monitor, or rhythm strip
    Results

    Duration: 21 months
    Outcome Ablation Antiarrhythmics Comparisons
    Primary outcome 54.5% 72.1% HR 0.56, 95%CI [0.35 - 0.90], p=0.02
    First recurrence of symptomatic A fib 41% 57% HR 0.52, 95%CI [0.3 - 0.89], p=0.02
    • In Group 1, 13.6% of patients underwent re-ablation
    • In Group 1, 4 patients experienced cardiac tamponade and 1 patient had severe pulmonary vein stenosis

    Findings: Among patients with paroxysmal AF without previous antiarrhythmic drug treatment, radiofrequency ablation compared with antiarrhythmic drugs resulted in a lower rate of recurrent atrial tachyarrhythmias at 2 years. However, recurrence was frequent in both groups.
    StraightHealthcare analysis
    • The RAAFT-2 study showed that radiofrequency ablation for the initial treatment of paroxysmal A fib is more effective in preventing episodes of recurrent atrial arrhythmia than antiarrhythmic medications. It's important to note that more than half of the patients in the radiofrequency group had a recurrence of an atrial arrhythmia at almost 2 years post-ablation.
    • Radiofrequency ablation was associated with some serious adverse events (cardiac tamponade and severe pulmonary vein stenosis)

    ThermoCool AF Trial - Ablation vs Antiarrhythmic Medications, JAMA (2010) [PubMed abstract]
    • A study in the JAMA enrolled 167 patients with paroxysmal A fib that had not responded to 1 antiarrhythmic drug
    Main inclusion criteria
    • At least 3 symptomatic episodes of paroxysmal A fib within the 6 months prior to randomization
    • A fib that did not respond to at least 1 antiarrhythmic drug
    Main exclusion criteria
    • A fib of more than 30 days in duration
    • EF < 40%
    • Amiodarone within previous 6 months
    • Previous heart valve surgery
    Baseline characteristics
    • Average age 56 years
    • Median A fib duration ∼ 5.8 years
    • Average EF - 62%
    • Previous drug failure: propafenone - 50% | sotalol - 35% | flecainide ∼ 28% | amiodarone ∼ 8%
    Randomized treatment groups
    • Group 1 (106 patients) - Radiofrequency catheter ablation
    • Group 2 (61 patients) - Antiarrhythmic drug that had not been previously used (amiodarone was not allowed)
    • Follow-up was over a 9 month period that started at different times in each group. In the ablation group, follow-up started 3 months after the initial ablation procedure. In the antiarrhythmic drug group, follow-up started 14 days after titration on their new antiarrhythmic drug.
    • Patients were given transtelephonic heart monitoring devices and were required to transmit weekly for 8 weeks and monthly thereafter. In addition, they were required to transmit all symptomatic episodes.
    Primary outcome: Freedom from treatment failure. Treatment failure was defined as symptomatic A fib, repeat ablation > 80 days after the first ablation, absence of entrance block confirmed in all pulmonary veins at the end of the ablation procedure, changes in antiarrhythmic drugs after initial titration, or side effect of antiarrhythmic drug requiring discontinuation.
    Results

    Duration: 9 months
    Outcome Ablation Antiarrhythmics Comparisons
    Primary outcome 66% 16% HR 0.30, 95%CI [0.19 - 0.47], p<0.001
    Freedom from atrial arrhythmia 63% 17% HR 0.29, 95%CI [0.18 - 0.45], p<0.001
    • Additional ablations were performed in 12.6% of the patients in Group 1 within 80 days of the initial procedure
    • Major treatment related adverse events occurred in 4.9% of patients in Group 1 and 8.8% of patients in Group 2

    Findings: Among patients with paroxysmal AF who had not responded to at least 1 antiarrhythmic drug, the use of catheter ablation compared with ADT resulted in a longer time to treatment failure during the 9-month follow-up period
    StraightHealthcare analysis
    • In this small study, ablation was superior to antiarrhythmic medications in preventing A fib recurrence in patients with paroxysmal A fib who had failed a prior antiarrhythmic drug
    • The study is limited by the fact that one of the most effective antiarrhythmics used to treat A fib, amiodarone, was not allowed